The decision to start ART in children is made with guidance based on age and CD4 percentage or count. Guideline recommendations are based on observed short-term risk of morbidity and mortality. ART can be delayed in children with CD4 values above the recommended thresholds for initiation to avoid toxicities, resistance and some of the practical considerations associated with giving ART to children.

Investigators from ICH and the PENTA group suggest that current guidance assumes such a delay in treatment initiation is without detrimental long-term consequences. In a paper published ahead of print in JID, 28 December they write that evidence suggests differences between children and adults in the level of T-cell repopulation due to children’s greater thymic activity. A number of paediatric studies show poorer recovery of CD4 count on ART is associated with older age and lower CD4 count at initiation. Using longitudinal data from the PENTA 5 study and non-linear mixed-effects models, the group investigated the relationships between age, CD4 count at start of treatment, and CD4 repopulation. As well as confirming the associations previously described, their findings illustrate the importance of the naïve subpopulation for this recovery and they explore the consequences for ART naïve children of different age groups and with different CD4 counts.

The PENTA 5 trial assessed different ARV regimens in perinatally infected, treatment-naïve children. Among the 127 children starting treatment, the median age at initiation was 5.3 (IQR 2.4 to 8.6) years; CD4 count was 620 (IQR 343 to 912) cells/mm3; z-score (indicating the rank of a recorded CD4 count within the expected distribution for HIV-negative children of the same age, born to HIV-positive mothers expressed in terms of the standard, normal distribution) was -2.3 (IQR -4.1 to -1.3) and follow-up was 5.7 (IQR 5.1 to 6.5) years.

In a multivariate model the investigators estimated the children’s pre-treatment z-score to be -0.41+ 0.07 (point estimate ±SE) lower for each year older at initiation and their long term z-score -0.5+ 0.03 lower for each year older at initiation, both p<0.001. In addition to these effects, there was a strong positive association (p<0.001) between pre-treatment and long-term z-score – that is, children with z-scores below (or above) average for their age before treatment still had below (or above)-average scores in the long term.

Naïve and memory CD4 counts were recorded in a substudy of 26 children. This analysis revealed T-cell reconstitution in these children appeared to arise mainly from the naïve compartment with a comparatively small increase memory cell count, although on a faster timescale. However this potential for recovery via the naïve pool is apparently progressively reduced with age and/or duration of infection. The model illustrated suggests that the threshold currently recommended for initiating treatment in younger children results in a higher count in the long term than that for older children. Therefore guidelines for older children may not be optimal for maintaining CD4 counts in adulthood.

Reference:

Lewis J et al. Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. JID. Published ahead of print 28 December 2011.

An article in the December 1 2011 edition of JAIDS describes efavirenz (EFV) exposure in African children in the ARROW trial, dosed according to the 2006 WHO weight bands, which are similar to the manufacturer’s recommendations (the current approved paediatric doses).

ARROW is an open label randomised trial comparing routine laboratory to clinical monitoring (a paediatric version of DART) in children in Uganda and Zimbabwe. It also compares different ART strategies. Quirine Fillekes and colleagues from the trial team conducted a pharmacokinetic (PK) sub study in Ugandan children aged 3-12 years. The children evaluated had received twice daily lamivudine plus abacavir (3TC+ABC) with once daily EFV and participated in a crossover study comparing twice to once daily 3TC+ABC.

EFV was dosed according to WHO 2006 weight bands. Doses were 200, 250, 300 and 350 mg for children weighing 10 to <15, 15 to <20, 20 to <25 and 25 to >30 kg respectively. The children received 200/50mg capsules or halved 600mg tablets.

At week 36 from initiating treatment (once daily EFV plus NRTIs), 12 hour PK sampling was performed, pre-dose and at 1, 2, 4, 6, 8 and 12 hours post dose. The children were switched to once daily NRTIs at 36 weeks. Intensive PK sampling was repeated at 40 weeks, including an extra PK sample at 24 hours post dose.

A total of 41 (24 girls and 17 boys) were enrolled in this sub study. Of these, 4 children increased weight bands between the first and second PK sampling but were included in the analyses and 2 were excluded due to implausible time concentration curves (believed to be labeling errors).

Eighteen of the children were age 3 to 6 years and 23 children were 7 to 12 years. The majority were moderately stunted and wasted. Five, 16, 17 and 3 children were in the 10 to <15, 15 to <20, 20 to <25 and 25 to >30 kg weight bands respectively, at the first PK sampling.

Doses in mg/kg were highest in the 15 to <20 kg (median 14.7 mg/kg) and lowest in the 20 to <25 kg (median 13.0 mg/kg) weight bands. The median dose received overall was 13.6mg/kg.

The geometric mean EFV plasma concentrations time curves obtained at the first and second samplings were similar. Six children at the first sampling and 7 children at the second had subtherapeutic (<1.0 mg/L) plasma concentrations at 8 hours and/or at 12 hours; 7/41 (17%) at either sampling. At the second sampling 15/39 (38%) of children had subtherapeutic levels at 24 hours. Ten (24%) children at the first sampling and 11 (28%) at the second had potentially toxic levels >4 mg/L at 8 hours and/or at 12 hours; 12/41 at either sampling.

Overall the EFV Cmax, Cmin and AUC0-24 were respectively 15%, 36% and 10% lower than those observed in adults receiving the 600mg tablet.

The authors observed wide intersubject but modest intrasubject variability across EFV PK parameters. There was no evidence of significant differences across the four weight bands for all PK parameters evaluated (suggesting no major effect of using divided tablets) however, with only 41 children in total the sub study was rather underpowered to show this.

They wrote that these data (and that of two previous studies) strongly suggest that children should receive EFV doses higher than the WHO 2006 recommendations or the manufacturers daily dose in the leaflet (50mg higher only for children weighing 14 to <15 kg and 30 to 32.5 kg).

More recent 2010 dosing guidelines have higher EFV doses than evaluated in this study for children weighing 14 to <20, 25 to <30 and 35 to <40 kg. The authors noted that these higher doses were not only selected in response to concerns about under doing but to remove the 50 mg tablets from dosing tables as these were being discontinued.

They expressed concern that although these data suggest that higher doses should lead to greater exposure and in turn better virological efficacy, the trade off is that more than one-third of children will be exposed to potentially toxic EFV levels.

Reference:

Fillekes Q et al. pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda. J Acquir Immune Defic Syndr. Volume 58. Number 4. December 1, 2011.

Investigators from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord evaluated response to antiretroviral therapy (ART) and predictors of switching or interrupting treatment in children starting in infancy up to 5 years from treatment initiation. Findings from this study were reported in the 28 November 2011 edition of AIDS.

The study evaluated data from nine observational cohorts in 13 European countries. A total of 437 HIV-infected, ART naïve infants, less than 12 months of age, born between 1996 and 2008 were included.

The infants started ART at a median of 3.7 (IQR 2.1-5.8) months. About 40% were from UK/Ireland and 20% each from France and Italy. About half were black and half female. Just over a third had been exposed to maternal antiretrovirals in pregnancy and just under a third neonatal prophylaxis. One third were breast-fed.

The median duration of follow up after starting ART was 5.9 (IQR 2.3 – 7.6) years. During this time 20 children died and 32 were lost to follow up. The median CD4 percentage and viral load at treatment initiation of were 29% (IQR 17 – 39%) and 5.7(IQR 4.9 – 5.9) log10 copies/mL respectively.

The majority (76%) started ART before 6 months of age. Twenty four percent started on an NNRTI plus 2 NRTIs, the most common backbone being ddI/d4T from 1996 – 1999 and AZT/3TC from 2000 onwards. Four drug regimens, most frequently NNRTI plus 3NRTIs, were used more often in the later time period (18% compared to 3%) and in UK/Ireland. Boosted PIs were used only from 2001 onwards (34% 2004-2008). Nelfinavir use declined over calendar time.

Just over half (53%) the infants initiating ART in 1996 – 1999 had viral load <400 copies/mL by 12 months, this increased to 57% in 2000 – 2003 and 77% in 2004 – 2008, but the difference was not statistically significant, p=0.09. Infants aged 6 -12 months at ART initiation were more likely to be suppressed than those aged <3 months AOR 1.98 (95% CI 0.92 – 4.25), but again, this difference did not reach statistical significance, p=0.06.

Four-drug NNRTI regimens were associated with significantly better viral load suppression; AOR 3.00 (95% CI 1.24 – 7.23) compared to three drug NNRTI (reference) regimens, p<0.001. But boosted PI plus 2 NRTI regimens performed similarly to the reference regimen, AOR 1.39 (0.62 – 3.13). Higher baseline viral load was associated with less likelihood of virological suppression, AOR 0.67 per log10 copies/mL (95%CI 0.50 – 0.89), p=0.01.

For infants with data available, median baseline and 12 month CD4 count, CD4 percentage and CD4 z-score were 520 (IQR 271 – 1340) cells/mm3, 6% (-6 to 16%) and 0.92 (-0.14 to 2.34), respectively. Median CD4 z-score increase was 2.29 in infants receiving four-drug NNRTI regimens compared to 0.65 in those receiving three-drug NNRTI regimens and 0.91 for boosted PI regimens, p=0.04.

Eighteen percent of infants switched to second line treatment. The cumulative incidence of switching was 10.2% (95% CI 7.5 – 13.4) and 16.7% (13.0 – 20.7%) by 2 and 5 years respectively. Children starting treatment with a four drug NNRTI or boosted PI-based regimen were slower to switch; AHR 0.41 (95% CI 0.15 – 1.14) and AHR 0.26 (95% CI 0.06 – 1.19) respectively, p=0.03. Although the investigators noted data were sparse.

Twenty eight percent of children experienced at least one treatment interruption of more than 14 days, no factors predicted interruption.

Sixty five percent of children remained on treatment without interruption at last follow-up. Of these 36% had been treated for at least 5 years. The estimated probability of remaining on first-line ART without interruption was 79.3% (95% CI 75.1 – 83.1%) and 63.8% (95% CI 58.7 – 68.9%) by 2 and 5 years from starting ART respectively.

comment

That boosted PI-based regimens performed similarly to NNRTI-based is contradictory to findings from IMPAACT 1060 that showed 20% higher rates of failure at 24 weeks in children aged 2 months to 3 years receiving NNRTI-based regimens compared to PI-based (whether or not they had been NNRTI exposed through PMTCT). Although IMPAACT 1060 was an RCT and these are cohort data – the difference in length of follow up is considerable.

That four drug NNRTI-based regimens did well is notable and induction/maintenance strategies in young children remain under explored.

Reference:

European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Early antiretroviral in HIV-1 infected infants, 1996-2008; treatment response and duration of first-line regimens. AIDS: 25(18):2279-2287, 28 November 2011.

In an article in the September 2011 edition of Antimicrobial Agents and Chemotherapy, Jennifer R King and colleagues from the P1058 protocol team reported pharmacokinetic (PK) data from children and adolescents treated with tenofovir (TDF) in combination with antiretrovirals with potential interactions.

PK results were shown for 47 participants aged 8 to 18 years, receiving a 300mg once daily TDF-based regimen. Participants received regimens that also contained an NTRI plus efavirenz (EFV) or darunavir/ritonavir (DRV/r) or atazanavir/ritonavir (ATV/r). The antiretrovirals and doses combined with TDF in are shown in Table 1.

Plasma samples were obtained pre-dose and over 24 hours. Statistical comparisons determined whether the 90% confidence intervals of the geometric mean (GM) AUC and Cmin for each antiretroviral were within 25% of those observed in previous studies demonstrating safety and efficacy. The AUC and Cmin target ranges and GMs (90% CI) are shown in Table 2.

BD: twice-daily; QD: once-daily.

Values mg*h/liter (AUC) and mg/liter (Cmin)

In the presence of EFV only the GM for TDF Cmin was very slightly above the target upper limit of the 90% CI. In contrast the GM (90% CI) for EFV Cmin was above the target upper limit. The investigators noted that EFV exposure was high overall in this analysis although the participants were dosed according to FDA recommendations; six participants with high exposure were receiving the EFV-based triple fixed dose combination (Atripla) which they suggest may alter drug absorption in this population. They recommend a crossover study comparing Atripla to the individual formulations in children and adolescents to answer this question.

The GMs (90% CI) for TDF AUC and Cmin were within the target ranges when it was given with DRV/r, however they were below the target ranges for DRV. The investigators wrote that these data suggest that higher than recommended doses of DRV may be necessary in paediatric patients in the presence of TDF, but the small sample size warrants a larger study to confirm these findings.

The GMs (90%CI) for TDF AUC and Cmin were only slightly higher in the presence of ATV/r, in contrast with that observed in healthy adults where these elevations are significant.

The investigators also observed that TDF PK did not differ between groups 1,2 and 3. This finding was unexpected as several PIs modestly alter TDF concentrations.

They concluded that none of the 90% CI AUC and Cmin values for the drugs tested were entirely outside the target range. So the recommended doses should provide exposure levels similar to that seen in adults. However they recommended that if individual patients experience adverse events or reduced clinical outcomes, while taking these agents in combination, monitoring exposure could be considered.

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Gilead has now filed with the FDA and EMA for an indication for tenofovir for the 2-12 year age group. In Europe tenofovir is not approved for adolescents aged 12-18 (although there is considerable off label use), so we may be faced with the curious situation of approval for the younger but not older age group of children and adolescents.

The WHO expert paediatric group, consider a fixed dose combination dispersible tablet of EFV/TDF/3TC, scored once on one side and twice on the other to make dividing easy, to be an essential missing formulation for treating children. Modelling suggests that dosing delivered with divided tablets could work with weight band tables.

WHO is producing a white paper on tenofovir use in children.

Reference:

King JR et al. Steady state pharmacokinetics of tenofovir-based regimens in HIV-infected paediatric patients. Antimicrob Agents Chemother 55: 4290-4.

An article in the July 31 2011 edition of AIDS describes atazanavir (ATV) pharmacokinetics (PKP in infants, children and adolescents given alone and boosted with ritonavir (ATV/r). Jennifer J Kiser and colleagues from the IMPAACT 1020A phase I/II study evaluated two formulations of ATV, capsules and a dispersible orange-vanilla flavoured powder across a range of age groups in treatment naïve and experienced participants from the United States and South Africa.

Participants were aged 91 days to 21 years and received unboosted or boosted (using ritonavir capsule or liquid formulations) ATV as part of a combination antiretroviral regimen. All participants underwent intensive 24-hour PK sampling on day 7; 195 enrolled and 172 had evaluable data.

All groups were started at a target dose of 310mg/m2. To establish an acceptable ATV or ATV/r dose for an age group, 10 participants had to meet PK and safety criteria as defined by the protocol.

For PK these were: ATV AUC AUC0-24hr of at least 30,000ng x h/mL and C24 of at least 60ng/mL in at least 80% of participants; no AUC0-24hr less than 15,000ng x h/mL and median AUC0-24hr of 60,000ng x h/m/L or less. And for safety: no life threatening toxicities; one or fewer participants with grade 3 or 4 toxicities (excluding bilirubin) linked to study treatment, and two or fewer participants with total bilirubin values greater than 5.1 times the upper limit of normal.

If these criteria were not met, the ATV starting dose was modified for the age group, either increased to 415, 520 then 620mg/m2 or decreased to 205mg/m2.

Nearly half (45%) of the participants were antiretroviral naïve at enrollment; 62% received ATV capsules and the remaining 38% ATV powder.

The investigators found unboosted ATV capsules met PK criteria at a dose of 520mg/m2 for participants >2 to 13 years of age and 620mg/m2 for those >13 to 21 years of age. Boosted ATV capsules met PK criteria at a dose of 205mg/m2 for those >2 to 21 years of age. Boosted ATV powder met PK criteria at a dose of 310mg/m2 for those >2 to 13 years of age.

Infants and young children aged 3 months to 2 years dosed with boosted ATV powder failed to meet PK criteria. There was a lot of intersubject variability in exposures this age group so that a dose escalation to 415mg/mL may have given ATV exposures in some young children greater than 90,000ng x h/mL.

The investigators wrote that additional studies are needed in this age group to determine if an appropriate ritonavir boosted dose can be identified.

Reference:

Kiser JJ et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV infected infants, children and adolescents. AIDS 2011, 25:1489-96.

Crushing lopinavir/ritonavir (LPV/r; Kaletra) tablets is not recommended by the manufacturer as pre-clinical studies showed poor absorption with this method of administration compared to whole tablets with a single dose.

The liquid formulation of LPV/r is unpalatable and inconvenient so administrating crushed tablets could potentially overcome this barrier to the paediatric use of this PI.

As single dose pharmacokinetics (PK) do not predict steady state LPV concentrations (due to the complex interaction with ritonavair [RTV]), investigators from the Children’s National Medical Center (CMC) in Washington, DC, looked at LPV/r exposure in whole and crushed 200/50mg tablets in children. Results were published ahead of print in JAIDS.

Brookie M Best and colleagues conducted a prospective, open label, cross over PK study in 13 (6 boys, 7 girls) children and adolescents with a median age of 13 years (range 10-16) taking LPV/r tablets BID as part of their antiretroviral regimen with two NRTIs. The median LPV/r dose was 275/69mg/m2 (range 193/48-372/93mg/m2. Two participants were excluded from the analysis, one refused to take the crushed tablets, and the other had very low or undetectable levels of LPV with both methods of administration. Data are from 11 participants.

The median LPV AUC, after receiving crushed and whole tablets respectively were, 92 (IQR 79-103) mg*hr/L and 144 (IQR 101-202) mg*hr/L; crushed/whole GM 0.55 (90% CI0.45-0.69), p=0.003. The corresponding values for RTV were AUC 7(IQR 4.5 -11.1) mg*hr/L and 13.3 (IQR 9.6-17.9) mg*hr/L; GM 0.53 (90% CI 0.4-0.71), p=0.006.

Oral CL/F (L/hr/m2) was significantly increased with crushed tablets for both drugs, respectively 1.4 and 1.6 times for LPV and RTV. The maximum post dose concentrations (Cmax) were also reduced, (significantly for LPV, p=0.021) with crushed tablets.

The investigators wrote: “The reduced exposure with crushed Kaletra tablet dosing reinforces the need to discourage this practice.”

comment

This study was conducted prior to the introduction of the smaller tablet formulation (100/25 mg, LPV/RTV).

These data reinforce both the importance of following manufacturers instructions about dividing protease inhibitors and the need for an alternative formulation to the oral suspension. The sprinkle formulation, being developed by Cipla and studied in CHAPAS 2, is still eagerly awaited, particularly for the very young age group.

Reference:

Best BM et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. JAIDS. Publish ahead of print. DOI: 10.1097/QAI.0b013e318232b057.
http://217.160.60.64/2/medicine/art/jaids.htm

Polly Clayden, HIV i-Base

Information to guide initiation of treatment in children older than one year of age is scarce.

Results from the PREDICT trial – presented as late breakers at both IAS 2011 and the preceding pediatric workshop – found that deferring ART until CD4 count fell below 15% or the occurrence of CDC category C events did not affect AIDS-free survival in children compared to starting ART at a CD4 count between 15% and 24%. [1]

PREDICT was conducted in 299 children from nine sites in Thailand and Cambodia between April 2006 and September 2008. Children were randomised to receive immediate ART or defer until their CD4 reached less than 15%. The children’s baseline characteristics are shown in table 1.

The primary endpoints were AIDS free survival at week 144 and neurodevelopmental outcome by Beery visual motor interrogation test.

Age, CD4%, HIV RNA, weight-for-age z-score and height-for-age z-score are mean values.

Retention was high in this study (96%). At week 144, 69 (46%) children had started ART with a mean CD4 at initiation of 13.8% (SD+2.8%). Of these, 17 children were <5 years and had a mean CD4 count of 591 cells/mm3 (SD+508) and 52 children were >5 years and had a mean CD4 count of 309 cells/mm3 (SD+141).

AIDS-free survival was 97.9% (95% CI, 93.7 -99.3) in the immediate arm and 98.7% (95%CI 94.7-99.7) in the deferred arm. The incidence of CDC C events or death per 1000 person-years was 7.6 (95%CI 2.5-23.6) in the immediate arm and 4.9 (95%CI 1.2-19.7) in the deferred arm.

The incidence of CDC category B events per 1000 person-years was broadly similar in both arms, 88 (95%CI 61-123) in the immediate arm compared to 110 (95%CI 80-147) in the deferred arm. But there were more episodes of herpes zoster (2 vs 13) and thrombocytopenia (1 vs 10) in the immediate and deferred arms respectively. There were only two episodes of TB, one in each arm.

Weight for age z-score was similar, deferred vs immediate -0.12 (95%CI -0.25 to 0.01), p=0.074. But children grew at a slower rate in the deferred arm, height for age z-score, deferred vs immediate -0.23 (95%CI -0.38 to 0.08), p=0.003.

And at 144 weeks of follow up there was no significant difference by Beery visual motor test between the two arms; Beery score deferred vs immediate, 84.7 vs 86.8, p=0.5.

The investigators noted that at approximately three years of follow up, the rate of progression to AIDS is extremely low in both the immediate and deferred arms. The finding reflects a slow disease progression among HIV-infected children who survive the first year of life without treatment.

comment

This study is important and a bit of a surprise to many as it appears to contradict both adult data and that for young infants. But the median age in the study reflects a population that have survived without treatment for the first few years and therefore selects a group of healthier children without rapid disease progression.

References

Puthanakit T et al. Randomised clinical trial of immediate versus deferred antiretroviral therapy initiation in children older than one year with moderate immunodeficiency: the PREDICT Study (NCT00234091). 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract LB 01.

Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE023.

Polly Clayden, HIV i-Base

Data were presented at the paediatric workshop and IAS 2011describing recent developments in the paediatric pipeline.

Etravirine

Thomas Kakuda from Tibotec showed pharmacokinetic (PK) data of the NNRTI etravirine (ETV) in treatment experienced children and adolescents aged 6 to <18 years. [1, 2]

These 24-week results are from PIANO (Pediatric trial with Intelence as an Active NNRTI Option). PIANO is an ongoing Phase II, open label trial looking at the safety, efficacy and PK of ETV 5.2mg/kg bid (maximum dose 200mg bid).

In this study, 101 children (6 to <12 years, n=41) and adolescents (12 to <18 years, n=60) received ETV plus background regimen of a boosted protease inhibitor plus nucleoside/nucleotide inhibitors with optional enfuvirtide and/or raltegravir for 48 weeks. The trial participants received 25mg and 100mg tablets of ETV.

Sparse samples for population PK were taken at weeks 4, 8, 12, 24 and 48. At week 24 two samples were collected, a trough and one at least an hour after ETV dose. ETV plasma concentrations were measured using a validated high performance liquid chromatography-mass spectrometry/mass spectrometry assay.

The investigators developed a paediatric population PK model based on previous adult modelling and supplemented with rich and sparsely sampled PK data from TMC125-C126 [HTB ref] and PIANO respectively. They used the model to determine ETV AUC12h and C0h for all participants enrolled in PIANO up to 24 weeks.

There were 476 plasma concentration time samples available from 101 participants completing 24 weeks. There was an overall mean (SD) AUC12h and C0h of 5236 (+4314) ng*h/mL and 347 (+342) ng/mL respectively. In children in the younger age group these values were 5764 (+4044) ng*h/mL and 381 (+321) ng/mL. In adolescents they were 4834 (+4483) ng*h/mL and 323 (+357) ng/mL respectively. Adult reference values from the DUET trial were 5506 (+4710) ng*h/mL and 393 (+391) ng/mL for AUC12 and C0h respectively.

The investigators observed slightly lower exposures in the adolescents compared to the adults despite the majority (93%) of adolescents receiving the adult ETV dose of 200mg bid.

A dose of 5.2 mg/kg ETV is expected to be recommended for this population.

A related poster authored by Gareth Tudor Williams and colleagues described safety and efficacy from the same study. [3] The incidence of serious adverse events (AEs, grade 3 or 4) was low. A total of eight participants discontinued the trail due to AEs, this occurred more frequently in the older (n=6) than younger (n=2) age group. The most common AEs were upper respiratory tract infection (n=27) and rash (n=23).

Approximately half (n=51) of participants achieved a viral load <50 copies/mL. Response rates were higher in children than adolescents, with 24/41 (59%) achieving an undetectable viral load compared to 28/60 (47%). Response was similar in participants in both age groups considered adherent (measured by pill count and questionnaire) compared to non-adherent, respectively 48% (<95% adherent) compared to 53% (>95% adherent).

Of 28 participants with available genotype results at the time of virological failure, 54% developed NNRTI resistance mutations, mainly Y181C, E138A and V901.

Maraviroc

Carlo Giaquinto and colleagues presented preliminary PK data for the CCR5 antagonist maraviroc (MVC) in children and adolescents aged 2 to <18 years. [4, 5]

Data are from Study A4001031 – an ongoing open-label, non-comparative, multi-centre study in two stages (1: dose finding; 2: safety/efficacy) in treatment-experienced children, infected with CCR5-tropic HIV-1, receiving MVC 40-450 mg BID with optimised background therapy (OBT).

MVC PK were determined at Week 2. Participants (n=31) were stratified into four age cohorts. They were dosed twice daily. The initial dosing was calculated according to body surface area (BSA) with adjustments to take into account interactions between MVC and OBT (adult-recommended doses with/without CYP3A4 inhibitors/inducers).

Doses were adjusted and PK reevaluated if average concentrations (Cavg) at week 2 were <100 ng/mL. Cavg was estimated from AUC (AUC12h) calculated from seven samples taken over 12 hours.

The investigators reported, out of 22 participants receiving MVC with a potent CYP3A4 inhibitor (protease inhibitor based regimens). Only one failed to meet the PK target with the initial dose (this was due to poor adherence). But all five participants who did not receive a protease inhibitor (two nevirapine based regimens; two raltegravir based regimens; one NRTI based regimen) needed at least twice the initial MVC dose.

At the time of enrolment into stage 2, one participant did not meet the target after two dose adjustments but responded well clinically so was therefore included in the PK analysis. See Table 1: Preliminary PK results for maraviroc in children and adolescents aged 2 to <18 years.

The authors concluded that these preliminary data show that BSA-based dosing of MVC with CYP3A4 inhibitors provides MVC exposures associated with near- maximal efficacy (Cavg>100 ng/mL) in all age groups studied. But they noted that additional PK analyses are required to evaluate appropriate dosing when MVC is administered without CYP3A4 inhibitors in children.

A second poster from the same group showed safety and efficacy from the same study. [6]

At the time of analysis 35 children had been randomised (n=2, n=12, n=6 and n=15 in cohorts 1 to 4 respectively) and had received at least one dose of MVC. The median duration of treatment was 396, 493, 435 and 211 days in cohorts 1 to 4 respectively. The investigators observed 101 non-serious AEs in 21 patients; they considered 17 of these in 8 patients to be treatment related. Of those with elevated liver function test results, none were of grade 3 or higher. There were 8 serious adverse events of which none were judged to be treatment related and all resolved. There were no deaths.

Viral load <50 copies was achieved by 17/24 (71%) and 11/17 (65%) of participants at weeks 24 and 48 respectively. Five participants had virological failure; in four, this was due to poor adherence. The fifth had emergence of dual-mixed virus and developed 3TC resistance.

Enrollment in this study is continuing and long-term data will be collected and analysed.

References

1. Kakuda TN et al. Population pharmacokinetics of etravirine in HIV-1 infected treatment experienced children and adolescents (6 to <18 years). 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract PP_1.(PDF)
2. Kakuda TN et al. Population pharmacokinetics of etravirine in HIV-1 infected treatment experienced children and adolescents (6 to <18 years). 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE026.
3. Tudor-Willaims G et al. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents (6-17 years): week 24 primary analysis of the phase II PIANO study. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE027.
4. Vourvahis M et al. Maraviroc (MVC) pharmacokinetics (PK) in CCR5-tropic HIV-1-infected children aged 2 to < 18 years: preliminary results from study A4001031. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract PP_4. (PDF)
5. Vourvahis M et al. Maraviroc (MVC) pharmacokinetics (PK) in CCR5-tropic HIV-1-infected children aged 2-< 18 years: preliminary results from study A4001031. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract MOPE232.
6. Giaquinto et al. Safety and efficacy of Maraviroc (MVC) in CCR5-tropic HIV-1 infected children aged 2 to <18 years. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Poster abstract P_51. Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract MOPE237.

Polly Clayden, HIV i-Base

Prematurity is a known risk for infant mortality. Other risks include maternal immunosuppression, delayed initiation of ART and low baseline CD4 percentage.

Investigators from the Perinatal HIV Research Unit (PHRU) in Soweto, South Africa showed findings at the 2011 paediatric workshop from a cohort study designed to investigate prematurity among children born in 2009 and initiated on ART before one year of age. The study was a database and record review.

The background characteristics of the infants at time ART initiation are shown in Table 1.

The investigators reported no difference in mortality between preterm and term infants, respectively, 3% vs 4% (OR 1.9; 95%CI 0.5-6.7). Lost to follow up was 8% overall.

Univariate analysis revealed non-significant p-values for all variables ie preterm vs term, baseline CD4%, baseline viral load, breast vs formula feeding and maternal PMTCT. The investigators noted the small sample size and that the mortality rate was low in this study.

They concluded that although HIV-infected preterm infants have significantly lower CD4% than term infants, with early ART initiation they are not at increased risk of mortality.

Reference

Lazarus E et al. Prematurity is not a risk factor for early mortality in HIV-infected infants on antiretroviral therapy. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Poster abstract P_18.

Polly Clayden, HIV i-Base

NEVEREST was a study in which young children who were exposed to nevirapine as PMTCT and initiated on PI-based HAART were randomised to continue on this regimen or switch to a nevirapine based regimen (we report the final results from NEVEREST later in this issue of HTB).

NEVEREST investigators evaluated body composition and metabolic abnormalities in 156 children exiting the trial. The objectives were to compare lipid profiles, markers of inflammation and regional fat distribution in children receiving a PI-based regimen of LPV/r plus 3TC plus d4T to those switched to an NVP-based regimen. [1]

The children’s weight (kg) and height (cm) was measured and weight-for-age, height-for-age and BMI-for-age z-scores (WAZ, HAZ, BAZ) calculated. Fasting total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), C-reactive protein (CRP), viral load, absolute CD4 and CD4 percentage were obtained. Circumferences and skinfolds were also measured; waist to hip ratio (MWC:MHC) and skinfold sum (SFS) were calculated. Upper arm and thigh fat estimates (UFE, UTFE) were calculated by Rolland Cachera. Analyses were intent to treat.

At the time of analyses, children were a mean age of 5.1 (range 3.6 – 6.9) years and approximately half were boys; 85 (42 boys) were randomised to the PI arm and 71 (40 boys) to the NNRTI arm. There were no differences between the two groups in sex, age, total time on ART, time since randomisation, WAZ, HAZ or BAZ or proportion with viral load <50 copies/mL. But children in the NNRTI group had a higher CD4 count, 1480 cells/mm3 compared to 1356 cells/mm3, p=0.049.

The investigators found differences in metabolic measurements. Mean TC was greater in the PI group, 171 (SD+39) mg/dL vs 161 (SD+31) mg/dL, p=0.05 as was the proportion of children with hypercholesterolemia (TC >200 mg/dL), 18.8% vs 8.5%, p=0.03. They also observed lower mean HDL levels, 51 (SD+14) mg/dL vs 59 (SD+16) mg/dL, p=0.006 and higher mean LDL levels, 100 (SD 34) mg/dL vs 88 (SD+27) mg/dL, p=0.018, in the PI group. The mean TG level was also greater in the PI group, 94 (SD+39) mg/dL vs 72 (SD+29) mg/dL, p<0.001 as was the proportion with hypertriglceridemia (TG >150 mg/dL), 12.9% vs 2.8%, p=0.038.

The children in the PI group had significantly greater amount of total body fat compared to those receiving an NNRTI, with a mean SFS of 43 (SD+11.1) mm vs 39 (SD+10.1) mm, p=0.029 and % body fat by BIA (Horlick Equation) of 0.17 (SD+0.7) vs 0.14 (SD+0.08), p=0.042.

The percentage of fat in the upper arm did not differ between groups but the percentage of fat in the upper thigh was greater in the PI group, p=0.021. Also the PI group had a smaller ratio of trunk fat relative to thigh fat, p=0.03.

The investigators wrote: “These unfavourable alterations in lipids and lipoproteins are of great concern with respect to potential increase in long term CVD risk and should be considered in treatment strategies, such as the reuse of NNRTIs for NNRTI-exposed infants”.

References

Shiau S et al. Body composition and metabolic abnormalities of perinatally HIV-infected children in South Africa on long-term ARV treatment. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract O_2. Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract 252.

Two oral presentations at CROI 2011 showed further findings from studies looking at treatment in children previously exposed or unexposed to maternal/infant single dose nevirapine (NVP) in prevention of mother to child transmission (PMTCT) programmes.

IMPAACT 1060

IMPAACT P1060 was a randomised trial to determine whether NVP- or lopinavir/ritonavir (LPV/r)-based treatment performed better in young children exposed and unexposed to single dose NVP. All children received AZT plus 3TC. The trial comprised of Cohort 1 (exposed children) and Cohort 2 (unexposed children). Data from Cohort 1 have previously been reported and this part of the study was stopped early after a scheduled Data Safety Monitoring Board (DSMB) review, as there was an unsurprising trend towards more failure in the children receiving NVP- compared to LPV/r-based treatment.

Peter Palumbo presented results from Cohort 2. This cohort enrolled children aged 2 to 36 months, who met WHO criteria for treatment and were unexposed to single dose NVP. Children were stratified by age < or ≥ 12 months. Children with TB were excluded from the trial.

The study had a composite primary endpoint of treatment failure, which comprised viral failure (<1 log10 decline from baseline to after 12 to 24 weeks or >400 copies/mL at week 24), or permanent discontinuation of NVP or LPV/r, including death by 24 weeks. Rates were calculated from Kaplan-Meier curves for each treatment group and age group.

Secondary endpoints included time to virological failure by 24 weeks, time to treatment failure throughout follow up and time to virological failure or death throughout follow up.

P1060 Cohort 2 was fully enrolled with 288 children by March 2010 and had 48-week planned follow-up to March 2011.  In October 2010, the DSMB recommended that the study was unblinded. All children had completed 24 weeks of follow up.

Dr Palumbo reported that the children’s median age at enrollment was 1.7 years (73% >12 months) and their median baseline viral load and CD4 percentage were 535,632 copies/mL and 15% respectively. The majority (79%) of children were subtype C.  The median follow-up was 72 weeks.

At week 24, 87 children had reached an endpoint; 60 in the NVP and 27 in the LPV/r arms. The overall difference in failure rate was 21.5% (95% CI, 11.2-31.8) in favour of LPV/r, p<0.001. This was similar in both age groups: 22.0% (<12 months) and 21.3% (>12 months).

There was also a significant difference in time to off study drug, over the full length of the trial, p<0.001. There were 10 vs 3 deaths in the NVP vs LPV/r arms during the entire follow-up

period (none judged related to study drugs), but this did not reach statistical significance, p=0.63.

There was a notable amendment during the course of the trial. In 2007 the recommended NVP dose in WHO guidelines increased from the FDA recommended dose of 7mg/kg to 160-200mg/m2 (max 200mg). Only 32 children were enrolled under the lower dose compared to 115 at the higher one but the investigators saw no effect associated with this change.

Dr Palumbo noted that the main reasons for off study were more virological failure, toxicity and death in the NVP arm.

As both the NEVEREST and P1060 Cohort 1 data had suggested poorer weight and CD4 improvement in children receiving LPV/r compared to NVP, the investigators also looked at this in Cohort 2. They did not find a statistically significant difference in CD4 improvement between the two arms but there was a difference in weight z-score favouring NVP at 24 and 48 weeks, respectively p=0.007 and p=0.009.

When the investigators looked at NVP resistance in samples from subsets of children at baseline and time of virological failure, they found 2.4% (5/206) with resistance at baseline compared to 56% (10/18) at time of virological failure.

These results were different to those in the sister study, OCTANE P1060, in which maternal data demonstrated non-inferiority of NVP- to LPV/r-based treatment, by the study definition, for NVP- unexposed women.

This highlighted the “unique and challenging situation of early paediatric HIV infection”, Dr Palumbo said, including very high baseline viral load and the unforgiving nature of NVP resistance. LPV/r is already recommended for NVP-exposed children and discussions are ongoing as to whether this recommendation should expand to all young children, possibly up to three years of age.

These data once again point to the importance of developing new first and second line options for use in this age group.

NEVEREST

Louise Kuhn presented data from NEVEREST, a study designed to evaluate a treatment switch strategy from LPV/r to NVP in NVP-exposed children.

In this study, 323 children aged 6 weeks to 2 years and eligible for treatment were initiated on LPV/r plus 3TC plus d4T. After achieving a viral load <400 copies/mL and maintaining it for > 3 months, children were randomised (n=195) to either remain on LPV/r (n=99) or switch to NVP (n=96). Time to any viral load >50 copies/mL or confirmed >1000 copies/mL was compared using Kaplan-Meier methods and log-rank tests.

Fifty-two week data post switch from this study has been reported previously. These data revealed a higher proportion of children suppressed to <50 copies/mL (the primary endpoint) in the NVP arm but also a higher proportion in that group with confirmed >1000 copies/mL.

Dr Kuhn showed longer term results from this study with follow up of 18-53 months.

There were three deaths in each group. At 36 months post randomisation, as with the earlier analysis, more children in the NVP group (40.5%) maintained viral load <50 copies/mL than those in the LPV/r group, p=0.01. Again, more in the NVP (23.9%) than in the LPV/r (11.1%) had confirmed >1000 copies/mL, p=0.01.

This difference persisted at 48 months, for <50 copies/mL and >1000 copies/mL, respectively p=0.02 and p=0.08.

At 6 months 59.1% of the failures in the NVP group had occurred vs 10% in the LPV/r group. By 12 months these proportions were 100% in the NVP group and 50% in the LPV/r group. Dr Kuhn noted that among children in the LPV/r group, 6% of failures occurred between 12 and 48 months.

Treatment failure >1000 copies/mL was associated with the presence of pre-treatment NVP mutations, p=0.02. There was no difference in response between children in the NVP and LPV/r groups in children who had no pre-treatment NVP resistance. Half the children with detectable NVP mutations failed when re-challenged with NVP.

Dr Kuhn concluded that viral load testing can identify all switch failures and that switching can be accomplished safely if viral load testing is available. Also that pre-treatment screening for resistance can be used to identify the children who could benefit from this strategy.

References

1. Palumbo P et al. NVP- vs LPV/r-based ART among HIV⁺ infants in resource-limited settings: the IMPAACT P1060 Trial. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 129LB.
2. Kuhn L et al. Long-term outcomes of switching children to NVP-based therapy after initial suppression with a PI based regimen. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 128.

Lopinavir/ritonavir (LPV/r, Kaletra) oral solution is approved by the FDA for infants 14 days of age and older. US guidelines do not recommend its use in preterm infants.

LPV/r oral solution has particular pharmacokinetic properties that make its use complicated in neonates. It contains high volumes of both ethanol (356.3 mg/mL, 42% volume solute/volume solution (v/v) and propylene glycol (152.7 mg/mL, 15.3% v/v).

Neonates have reduced alcohol dehydrogenase and CYP3A4 activity and immature renal function. Ethanol is 95% and propylene glycol is 55-75% metabolised in the liver by alcohol dehydrogenase. Ethanol inhibits the metabolism of propylene glycol by alcohol dehydrogenase leading to elevated concentrations. LPV is metabolised by CYP3A.

Reduced hepatic metabolism and renal clearance in neonates, particularly in preterm infants, can lead to accumulation of all three ingredients to toxic levels.

Acute ethanol toxicity is linked to central nervous system (CNS) and respiratory depression, and gastritis. Propylene glycol is also associated with CNS and respiratory depression, as well as renal failure and metabolic acidosis. LPV has been shown to cause PR and QT interval prolongation and AV block in adults with very high levels of the drug.

Cases of toxicity in neonates – particularly preterm – have been reported to the FDA Adverse Event Reporting System (AERS).

A poster authored by Debra Boxwell and colleagues from the FDA showed data from case studies from a search of the AERS database for all reports of toxicity in children 2 years of age or under following dosing with LPV/r oral solution.

The search revealed 10 unduplicated cases in neonates of whom 8 were preterm. Of the preterm infants, 3 were born at 28 weeks gestation, 1 at 30 weeks, 2 at 32 weeks and 2 at 34 weeks.

The documented adverse events included cardiac toxicity (bradycardia, complete AV block, bundle branch block, or cardiac failure; (n=7), acute renal failure (n=5), increased serum creatinine (n=1), elevated serum lactate level (n=2), hyperkalemia (n=4), respiratory failure (n=2), hypotonia (n=1), abnormal EEG (n=1), and CNS depression (n=1).

Outcomes included 1 death, 2 life threatening and 4 hospitalisations. Therapy was initiated on the day of birth in 7 neonates, day after birth in 1, day 34 in 1, and unknown in 1.

Onset the first adverse event occurred within 1 to 6 days (n = 8). Discontinuation of Kaletra (n=9) resulted in recovery within 1 day in 1, 2 days in 2, 3 days in 2, 6 days in 3, 20 days in 1 and was unknown in 1.

WHO set 25mg/kg as a maximum acceptable daily intake of propylene gel when it is used as a food additive. The European Medicines Agency (EMA) recommends that a 12.5mg/dL blood concentration of ethanol after a dose of any medication should not be exceeded. In IMPAACT P1030 – a PK sub-study in full-term infants 6 weeks of age – the mean steady state of LPV was 5.2+1.8ug/m2 twice daily. When the FDA investigators looked at neonatal exposure to the three ingredients in the cases for which data were available, the results were far in excess of these recommendations. See Table 1: Neonatal exposure to lopinavir, ethanol and propylene glycol.

The investigators concluded that the ten cases to the AERS suggest that neonates, especially those born preterm, who received LPV/r oral solution, were at increased risk of toxicities from drug accumulation. They added that the improvement of symptoms when the drug was stopped support this association.

There are limitations to the AERS however. Because reporting is voluntary, the quality of reporting is very variable. The database is subject to under reporting as well as reporting bias and both the numerator and the denominator are unknown for any event reviewed. Therefore the incidence or estimated risk cannot be calculated.

comment

This analysis provoked a FDA label change and the lopinavir/r oral solution is not recommended for neonates particularly preterm.

Reference

Boxwell D et al. Neonatal toxicity of Kaletra oral solution—LPV, ethanol or propylene glycol? 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 708.

Two posters at CROI 2011 presented pharmacokinetic (PK), efficacy and safety data of paediatric formulations of antiretroviral drugs. [1, 2]

Darunavir

ARIEL (TMC114-C228) is a 48-week, open-label, single-arm, phase II trial evaluating PK, safety and efficacy of darunavir/ritonavir (DRV/r) plus an optimised background regimen (OBR) in HIV-positive treatment-experienced children. Avy Violari and colleagues reported interim (24 week) data from ARIEL.

Children aged 3 to <6 years, weighing 10 to <20kg, with viral load >1000 copies/mL and <3 DRV resistance-associated mutations (RAM) at screening, received DRV. The formulation used in this study is a high concentrate oral suspension (100 mg/mL) – initially dosed at 20 mg/kg BID plus ritonavir (RTV) 2.6 to 3.2mg/kg BID with an OBR (>2 active NRTI) – over 48 weeks.

After a PK analysis at week 2, the DRV dose was amended to 25mg/kg BID children weighing 10 to 15kg and 375mg BID fixed for those weighing 15 to <20 kg (following Data Safety Monitoring Board recommendations).

A total of 27 patients – 55.6% male and mean age 4.6 years at screening – with DRV/r + an OBR. At baseline, the children’s median viral load was 4.51 log copies/mL, median CD4 count was 927 cells/mm3, and median CD4 percentage was 27.7% cells/mm3. The children had a median of 0 primary PI mutations at baseline and 4 PI RAM, 1 NRTI RAM, and 1 NNRTI RAM.

The majority of children, 23 (85.2%) experienced at least one adverse event (AE). One child discontinued treatment (due to grade 2 vomiting, believed to be associated with ritonavir). Most side effectss were grade 1-2. Grade 3-4 and serious side effects were reported in 18.5% and 11.1% of patients, respectively but none was considered treatment-related. Most commonly reported adverse events (occurring in over 10% of patients) were diarrhea, vomiting, pyrexia, nasopharyngitis, rhinitis, upper respiratory tract infection, hypokalemia, cough, acidosis, and alkalosis.

One child had a grade 3 laboratory abnormality – neutropenia – but this was present since baseline and not considered to be related to treatment.

There was a steady increase in response from week 2 to 24. By week 24, 55.6% of the children met the primary efficacy endpoint of viral load <50 copies/mL (ITT-TLOVR). The mean increase in CD4 at week 24 was 109 cells/mm3.

Two children had DRV RAMs at baseline but both were <50 cells/mL at week 24. Eleven children (40.7%) were considered virological failures. None of the six children with paired baseline/endpoint genotype samples developed PI or NRTI RAMS.

Raltegravir

P1066 is an open-label study of raltegravir (RAL) in treatment experienced HIV-positive children and adolescents. Sharon Nachman and colleagues reported PK, and week 12 and 24 efficacy and safety data for treatment-experienced children aged 2 to 5 years receiving the RAL chewable tablet formulation.

In this dose finding study, intensive PK was initially performed on 4 children and once PK targets were met, 8 more were enrolled. Inclusion criteria included viral load >1000 copies/mL, prior ART experience but naïve to integrase inhibitors. A RAL chewable tablet 6 mg/kg twice daily was added to the existing  regimen, intensive PK samples were taken between days 5 and 12. Once the dose was selected, an additional 9 children were enrolled to assess longer-term safety and efficacy.

PK parameters were evaluated and a dose was selected using an AUC12h target (range 14 to 25uM*h) based on available PK data with a C12h target to exceed the protein-adjusted IC95 of RAL against wild type virus. The investigators compared PK parameters to existing data from 6 to 18 year old children and adolescents receiving the adult formulation and 6 to 11 year old children receiving RAL chewable tablet. Of the 12 children, 67% were female, they were a mean, age of 3 years old, viral load 4.14 log10 copies/mL, CD4%, 33% cells/mm3, CD4 count, 1505 cells/mm3, and weight, 14.3 kg. They received a mean RAL dose of 6.24 mg/kg (0.67).

The geometric mean AUC12 was 8.8hr*mg/L, 18uM*h; C12h 32ng/mL, 71nM; Cmax 4329ng/mL, 9.7uM; CL/F 10.5L/hr and %CV 77%.A 6mg/kg BID dose (maximum 300mg) was selected.

At week 24, by ITT analysis, 62% (95% CI, 53-92) of children (n=21) were <400 copies/mL and 52% (95% CI, 30-74) <50 copies/mL. CD4 gain from baseline was a median of 4.1% (95% CI 2.0-9.9) and 218 (95% CI 39-290) cells/mm3.

No child discontinued RAL due to AEs in this study. One child had grade 3 ALT (2 events), grade >3 AST and ungraded elevated GGT (5 events), considered possible treatment related. Three children had grade >3 neutropenia (7 events) but this was not judged to be treatment related. Other non-treatment related events were: grade 3 bronchopneumonia, grade 3 hydrogen ion concentration, ungraded lactic acidosis, decreased blood glucose, acute gastro enteritis and impetigo.

References

1. Violari A et al. ARIEL: 24-week safety and efficacy of DRV/r in treatment-experienced 3- to <6-year-old patients. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 713.

2. Nachman S et al. Interim results from IMPAACT P1066: RAL oral chewable tablet formulation for 2- to 5-year-olds. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 715.

Fewer antiretroviral options exist for children than for adults. Last year’s Pipeline Report introduced a new chapter looking at paediatric formulations of antiretrovirals.¹ The chapter detailed some of the hurdles to be overcome to ensure access to antiretrovirals in appropriate forms for children with HIV. It also showed some recent advances.

Since last year’s report, new paediatric development has been scant. Despite incentives and penalties from regulatory authorities to innovator manufacturers designed to ensure that children benefit from these drugs, the disincentives to develop and produce them are considerable. Paediatric drug markets are generally smaller and less interesting to industry than those of adults. In rich countries paediatric HIV has been almost eliminated, meaning there is decreasing demand in these markets.

The best way to deal with paediatric HIV is to prevent it from happening in the first place. At present the elimination of mother-to-child transmission continues to elude most poor countries. Paradoxically, if maternal health and prevention of mother-to-child transmission (PMTCT) programmes become more effective, the advantages in child health this brings will reduce demand further in the paediatric antiretroviral market.

Children are also unaffected by the growing case to provide treatment as prevention.

All this not withstanding, there has been significant progress in recent years in terms of both research and treatment scale-up. United Nations agencies, nongovernmental organizations (NGOs) such as Médecins Sans Frontières (MSF) and the Clinton Health Access Initiative (CHAI); and UNITAID and other major donors have made a concerted effort to highlight children with HIV and ensure that they have access to the medicines they need.

However, an analysis of the global paediatric antiretroviral market performed in 2010 revealed only a few generic fixed-dose combinations (FDCs) in solid and dispersible forms quality certified by the World Health Organization (WHO) Prequalification Programme or the US Food and Drug Administration (FDA) since 2005.² One quality-certified manufacturer produced most (67%) of these FDCs, and they combine only older antiretrovirals. UNITAID accounted for 97-100% of 2008-2009 FDC market volume.

Price reductions for paediatric FDCs do not have the same potential as those for adults due to small volume. The analysis reported low uptake of FDCs, but this is likely to be largely due to the time required to register products and phase out syrups rather than countries not wanting to use them.

Meanwhile, in 2009 an estimated 2.3 million children were living with HIV. Although an impressive 355,000 children started antiretrovirals that year, 370,000 were newly infected. HIV kills 700 children every day.³

Data produced by CHAI, as part of an internal review, illustrate the paediatric antiretroviral development inertia.⁴ They show that paediatric determination (PD) – which occurs when manufacturers have completed all FDA requested studies and paediatric exclusivity is awarded – took an average of 6.5 years to achieve after approval for use in adults. This ranged from a laudable less than a year for abacavir to a spectacularly sluggish 14.9 years for saquinavir, which was never approved for children (see Table 1).

Table 1. Time frames between adult approval and PD for antiretrovirals with paediatric exclusivity

Source: CHAI
* Still not approved

When drugs are approved for children, multiple label changes may take place because paediatric populations are studied in sequence. As paediatric investigation plans work in de-escalated age bands, the youngest age groups will have the most prolonged delay in labeling.

Sometimes there is no indication or appropriate formulation for the very youngest children, complicating the implementation of universal treatment as early as possible in infancy.⁵

Perhaps the most notable change since the 2010 Pipeline Report is that Drugs for Neglected Diseases Initiative (DNDi) has recently entered the field.That this organization considers paediatric HIV to be a neglected disease speaks volumes.⁶

This chapter gives an update on recent results from clinical trials that will help inform guidance, new approvals and contraindications, the generic and innovator pipelines, “ones to watch,” and how the new drugs might be used.

What to start with?

WHO guidelines recommend that young children less than two years who have been exposed to maternal or infant nevirapine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs) for maternal treatment or PMTCT, start antiretroviral therapy with a lopinavir/ritonavir–based regimen. Nevirapine- or NNRTI-unexposed children, or children older than two years, should start with an NNRTI-based regimen of nevirapine, or efavirenz if the child is older than three years.

Nucleoside reverse transcriptase inhibitor (NRTI) backbones should be one of the following pairs: lamivudine plus zidovudine, lamivudine plus abacavir, or lamivudine plus stavudine. Stavudine is no longer preferred due to its toxicity.

Results from two recent studies may have an impact on future guidance with regard to the use of NNRTIs versus protease inhibitors (PIs) for younger children.

Findings from the IMPAACT P1060 study showed about 20% higher rates of failure at 24 weeks in children aged two months to three years receiving NNRTI-based regimens compared with those receiving PI-based regimens with or without NNRTI exposure.^7,8 These results are unsurprising for the NNRTI-exposed children. What is surprising and controversial is the superiority of the PI regimen for NNRTI-unexposed children in this trial – particularly for providers with experience in using NNRTIs in this population in resource-limited settings.

In reality, many caregivers in resource-limited settings prefer nevirapine first-line, even for children exposed to it in utero, due to cost constraints, ease of use, and to preserve lopinavir/ritonavir for second-line.

The NEVEREST trial, also recently presented, showed that children started on lopinavir/ritonavir-based regimens who remained on them had about 10% higher rates of virological failure than children switched to nevirapine.^9,10

Currently, WHO guidelines remain unchanged from last year, and opinion differs as to whether it is better to start with a PI or an NNRTI for all young infants. It is argued that many children will still not have been NNRTI-exposed through PMTCT, but this is usually poorly documented. NNRTI-based regimens remain attractive because of cost constraints, formulation, and palatability. PI-based regimens are more potent and can be used in exposed or unexposed children. NEVEREST data suggest it may be possible to switch to an NNRTI after initial suppression with a PI, but this would depend on access to virological monitoring.

There is agreement, however, that current drugs are far from perfect and a suitable first-line agent, to fit with current guidance, could be a cheaper, more user-friendly PI or a more robust NNRTI suitable for exposed or unexposed children (see Table 2).

As far as older children are concerned, data from the PENPACT-1/PACTG 390 study showed no significant difference at four years with viral suppression with regimens containing either an NNRTI or a PI.¹¹ The PLATO II/Cohere study showed no difference in triple-class failure by initial regimen at four years of age in European children starting treatment with three or more antiretroviral drugs.¹²

Table 2. Use of NNRTIs compared to PIs in young children in resource limited settings

*At temperatures higher than 25°C, the oral solution of lopinavir/ritonavir requires refrigeration. There are no stability data at temperatures higher than 25°C for lopinavir/ritonavir. Some providers cannot safely prescribe this to infants in households without a fridge.

† Sometimes called “baby grappa”! The lopinavir/ritonavir syrup contains 42% ethanol and 15% polyethylene glycol.

Induction/maintenance strategies (where people are started on very potent combinations of drugs which are then reduced in number once full viral suppression is achieved) are underexplored in children, – as are questions as to whether a child starting treatment in infancy can ever stop.

Data from several ongoing studies, which will give more information about these issues are still awaited:

• ARROW is investigating a strategy of induction/maintenance – starting with a potent combination of four drugs and maintaining treatment with three versus continual treatment with four drugs.¹³
• CHER, which demonstrated a big AIDS-free survival advantage from universally starting children on treatment at birth, will continue to follow these children’s progress and look at whether after starting early they can stop treatment after one or two years.¹⁴
• BANA and PENTA 11 will determine whether taking CD4-guided planned interruptions disadvantages children on stable therapy.^15,16

Recent changes

New FDA tentative approvals and WHO prequalifications

Since last year’s Pipeline Report there have been a number of new tentative approvals and prequalifications (see Table 3).^17,18

The good news is that there are several formulations that include abacavir, both stand-alone products and as part of FDCs. Not such good news is that the only PI included is nelfinavir powder, which is barely used in rich countries and is not recommended in guidelines.

Table 3. FDA tentative approvals (TA) and WHO prequalifications (PQ) of paediatric antiretrovirals, 2010–2011

*Formulations already prequalified by the WHO at the time of last year’s review.

FDA warning for lopinavir/ritonavir oral solution use in neonates

In February 2011, the FDA made changes to the Kaletra (lopinavir/ritonavir) oral solution product label to include a warning of potential toxicity in neonates. This was due to life-threatening side effects related to either lopinavir and/or the inactive ingredients propylene glycol and ethanol that had been seen in ten infants, eight of whom were preterm.^19,20

This formulation should not be given to neonates before they are of a postmenstrual age (calculated from the first day of the mother’s period until the baby’s birth plus the time from the birth) of 42 weeks and a postnatal age of at least 14 days.

Reduced metabolism by the liver and reduced kidney function in newborns can lead to an accumulation of lopinavir as well as of alcohol and propylene glycol. Preterm babies may be at increased risk because they cannot metabolise propylene glycol.

This warning is important, as both maternal HIV and highly active antiretroviral therapy (HAART) are associated with preterm delivery (although infants exposed to maternal HAART are a small niche as very few infants will be infected if their mothers receive treatment).

Missing drugs and formulations

An important formulation in the generic pipeline at present is an alternative to the oral solution of lopinavir/ritonavir.

Cipla is developing a heat-stable sprinkle formulation of lopinavir/ritonavir that may fill this gap. This has been in development for a while now and has undergone a few changes. The sprinkles are tasteless and have a texture similar to granular sugar.

Bioequivalence studies are being undertaken in healthy adults. Pharmacokinetcs and tolerability studies comparing the sprinkles with liquid in 12-month- to three-year old children and with junior tablets in older children, up to four years old will be performed in CHAPAS 2.²¹

Acceptability of the formulation in young children is very important. The company is still deciding on how to package the 40/10mg dose. Cipla expects to apply for approval with the FDA at the end of 2011.

Darunavir is needed for third-line regimens or for second-line where lopinavir/ritonavir was used first-line. Preclinical studies – showing dangerously high darunavir exposure and in turn adverse events in juvenile rats – meant that paediatric studies were not conducted in children under three years old. Ritonavir boosting of darunavir does not lend itself to easily adjusted doses using WHO weight bands.

A 25mg tablet of ritonavir is included in WHO’s Essential Medicines List but is not yet on the market.²² A 25mg sprinkle formulation is needed for very young children. A 50mg tablet would be useful for super-boosting (giving extra booster to achieve sufficient drug concentration in circumstances where this is reduced by drug-drug interaction) PIs. Super-boosting PIs, when they are given with rifampicin, is not straightforward and urgently needs better guidance and better formulations.

Other generics in development for treating children or considered to be a high priority by the Paediatric Antiretroviral Group of the WHO are shown in Table 4. FDCs that are not stavudine based are also a priority.

Table 4. Paediatric drugs and formulations needed

Source: WHO Essential Medicines List

*It may not be possible to coformulate some combinations, as the individual drugs may have different dosing schedules. Dual blister packaging is preferred in these cases. Emtricitabine is considered interchangeable with lamivudine.

The working group also considered atazanavir, darunavir, etravirine, raltegravir, and tenofovir to be high priority. These drugs are currently approved for adolescents and adults but not for children. The development status and formulations of these drugs are described in Table 5.

As new antiretrovirals become approved, there will be more options for coformulations and copackaging.

Ones to watch: the innovator pipeline

Since last year’s report there have been a few changes:

• The paediatric investigational plan has begun with dolutegravir. (Shionogi/ GSK/ViiV integrase inhibitor S/GSK-572).
• The cobicistat and Quad development plans were given a positive opinion by US and European Union (EU) regulatory agencies.
• The rilpivirine development plan is going ahead with the granule formulation.
• The dossier for the oral suspension of darunavir (boosted) for treatment-experienced children aged three to six years has been submitted to US and EU regulatory agencies.
• Raltegravir will be studied in neonates, first in a passive pharmacokinetic study and then dosed directly.

Nonnucleoside reverse transcriptase inhibitors

Etravirine: The recommended dose per weight band for children and adolescents aged six to 17 will be based on 5.2mg/kg bid. The company will present 24-week data from the PIANO study in experienced adolescents this year; 48 weeks of the trial will be completed in the last patient later this year.²³

An IMPAACT 1090 protocol is in development and the first patient is expected to enroll this year.

There is an upcoming submission for an indication for treatment experienced children and adolescents aged six to17 years and for the 25mg tablet.

Rilpivirine: The PAINT trial is of treatment-naive adolescents, aged 12 to18 years, weighing more than 32kg and receiving 25mg qd plus a background regimen.

TMC278-C220 is an open-label single-arm trial using the granule formulation, planned in children aged two to 12 years. This trial is taking a staggered approach and will study the drug in de-escalated age groups, down to two years of age.²⁴

Nucleotide reverse transcriptase inhibitor

Tenofovir DF: Although tenofovir was approved for adults in 2001 and is a preferred NRTI/nucleotide (Nt)RTI in international guidelines, paediatric development and approval has been slow. Bone toxicity and maturation concerns have been raised about using this drug in children.

The 300mg tablet is approved for adolescents 12 to18 years old weighing more than 35kg in the United States. However, recently the European Medicines Agency (EMA) did not approve an indication for this age group.The decision was based on the GS-US-104-0321 trial of treatment-experienced adolescents, in which tenofovir performed no better than placebo, but this study was underpowered, and on concerns about bone toxicity.

An additional study is ongoing to determine safety and efficacy in children below 12 years of age and under 35kg in weight, in which the 40mg/g oral powder is being evaluated.

A randomised open-label trial, 104-0352, is comparing switching stavudine or zidovudine to tenofovir versus continuing stavudine or zidovudine in virologically suppressed children. Children under 37kg receive the oral powder and those above this weight the 300mg tablet. This trial is ongoing.²⁵

Protease inhibitors

Atazanavir: The capsule formulation is approved for children in the United States aged six years and older who are treatment-naive and weigh 15kg or more and for treatment-experienced children weighing 25kg or more. In the EU it is approved for both treatment-naive and treatment-experienced children aged six years and older and weighing 15kg or more.

Younger children receiving atazanavir boosted with ritonavir are being studied in PACTG 1020A and PRINCE 1 and 2.^{26, 27}

Darunavir: The 75mg tablet is approved when boosted with ritonavir for children over six years of age. The dossier for the oral suspension for treatment-experienced children has been submitted for approval at the following doses: darunavir/ritonavir 25/3mg/kg bid for children weighing 10 to <15kg and darunavir/ritonavir 375/50mg bid for those weighing 15 to <20kg. There is a waiver for children under three years of age.

Integrase inhibitors

Dolutegravir (S/GSK-572): The IMPAACT P1093 study will work with de-escalated age bands of children down to six-week-old infants. The older children will receive tablets and the younger ones the paediatric formulation. A granule formulation is in development.²⁸

Elvitegravir: The 183-0152 study was a phase IB open label nonrandomised trial in treatment-experienced adolescents receiving 150mg qd plus a PI-optimised background regimen. Of the 21 subjects enrolled in the 10-day PK study, 9 of 11 eligible subjects continued elvitegravir plus ritonavir-boosted PI-containing optimised background regimen and completed 48 weeks of treatment.

The paediatric committee of the EMA granted positive opinion toward the cobicistat and Quad paediatric investigational plan in April 2011.

The Quad study will start after a review of data for elvitegravir and cobicistat. Age-appropriate formulations are planned.

Raltegravir: IMPAACT 1060 is investigating this drug in de-escalated age bands. Data for children six to11 years of age and interim data for those two to five years of age, receiving the chewable formulation, have been presented. A dose of 6mg/kg (maximum 300mg) has been chosen. The chewable formulation has lower oral clearance than that of the adult tablet.²⁹

Children under two years of age are now being enrolled in a study to determine the dose of the oral granule formulation.

IMPAACT P1097 is a washout (passive) pharmacokinetc and safety study. This is the first clinical trial of an investigational antiretroviral to look at neonatal pharmacokinetics. Raltegravir crosses the placenta well. It is metabolised primarily by an enzyme in the liver (UGT-1A1), that is immature in neonates. UGT pathways increase in activity hugely in the first weeks of life. This study is recruiting mothers already receiving raltegravir in pregnancy (the infants are not dosed directly). The infants will be sampled at intervals up to 30 to 36 hours after dosing.

After a review of pharmacokinetc and safety data from both trials the company is planning a study of infants born to HIV-positive mothers from immediately after the time of birth until their HIV status has been confirmed.

CCR5 receptor antagonists

Maraviroc: The A4001031 study is ongoing in children two to 12 years old who are infected with the CCR5-tropic virus (virus variants that use the CCR5 receptor for entry).³⁰

Use of this drug requires a tropism assay, as it will not work for people with the CXCR4-tropic virus or in mixed-virus (CCR5/CXCR4) populations.

Further along the pipeline, and one that got stuck

Other promising pipeline drugs, such as the prodrug of tenofovir, GS 7340, and the stavudine derivative festinavir, need to be studied in children as soon as sufficient adult data are obtained.

Over 12 years after efavirenz was approved in adults, there is finally a smattering of data for its use in children under three years of age – including TB-coinfected infants – from IMPAACT P1070 and a couple of other investigator-led trials. Dosing difficulties with large variability remain. The bioavailability of the oral solution is less than 70% of that of the solid forms. High doses (i.e., large volumes of liquid) are needed to achieve adequate exposure in plasma.

This drug is important, as dosing with TB medications – specifically rifampin (rifampicin) – is complicated by boosted PIs and nevirapine. Whether there will be a suitable formulation of efavirenz with an indication for very young children remains to be seen.

Table 5. The innovator pipeline

What to expect in the future

Various ongoing discussions have anticipated how paediatric treatment guidelines might look in 2013 and 2016. This will depend on the approval status of some of the pipeline drugs and the results of ongoing trials.

When to start?

2013: Universal treatment of all young children is anticipated to extend from up to 24 months to up to 36 months (or possibly five years) old.

2016: Universal treatment of all children less than five years old.

Children aged five or older share the criteria for treatment initiation with adults. This is currently at a CD4 count of 350 cells/mm³ or lower, or at any CD4 count in the presence of active TB or hepatitis B.

The change will depend on the results of the INSIGHT START study 001. It is expected to mean starting at a CD4 count of 500 cells/mm³ or lower, or a higher threshold.³¹

What to start with?

2013: FDCs as much as possible and progressive phase-out of stavudine. Lopinavir/ ritonavir–based treatment for all infants and children under three years of age regardless of NNRTI exposure.

2016: For all children under five years of age; either induction/maintenance of two NRTIs plus a boosted PI to achieve suppression and switch to rilpivirine to maintain suppression (this will depend on NEVEREST results) or two NNRTIs plus dolutegravir with or without switch.

What to use second-line?

2013: If lopinavir/ritonavir is used first, either NNRTI or darunavir (depending on approval – possibly etravirine or raltegravir).

If NNRTI is used first-line, boosted PI as second-line.

NRTIs will depend on the status of tenofovir and what was used first-line. Didanosine will continue to be an option although its phase-out is anticipated.

2016: Induction/maintenance first-line would allow for reuse of boosted PI or douletegravir for second-line, even if these were part of the initial (induction) regimen.

If integrase inhibitors are available, then second-line will probably be a boosted PI plus one of these; if not, then a boosted PI. Hopefully atazanavir and darunavir will be available in appropriate formulations.

If cobicistat is available it may offer an alternative to ritonavir as booster.

What to use third-line?

2013: Two or three regimens of integrase inhibitors (raltegravir), newer boosted PIs (darunavir) and newer NNRTIs (etravirine).

2016: Unclear, but etravirine may be less useful if ripivirine is given as maintenance.

The drugs for neglected diseases initiative

As a postscript to the paediatric pipeline, it deserves a mention that the Drugs for Neglected Diseases Initiative (DNDi) recently decided to add paediatric HIV to its portfolio. DNDi is a needs-driven, nonprofit, research and development organization founded in 2003 by partners including MSF and five public-sector research institutions. As the name suggests, the DNDi develops new treatments for the most neglected patients. DNDi’s focus to date has been on visceral leishmaniases, Chagas disease, sleeping sickness (human African trypansomiasis, or HAT), and malaria. With its partners DNDi has introduced the first new treatment for HAT in 25 years and two inexpensive, field-adapted treatments for malaria.

DNDi was called on by various organizations, including MSF and UNITAID, to apply its expertise to the needs of children with HIV who are under three years old, NNRTI-exposed or -unexposed, and in need of first-line therapy, regardless of prior antiretroviral exposure.

They have come up with a target product profile that includes appropriate dosage forms usable across WHO weight bands, high genetic barriers to resistance, no cold chain needed, well tolerated, no lab monitoring required, and affordable. Any treatment would ideally be compatible with TB medicines.

We welcome DNDi’s involvement and hope that it will usher in a promising new antiretroviral regimen – and at faster pace than we have become used to.

References

1. Treatment Action Group, Pipeline Report 2010. New York: Treatment Action Group, 2010.
2. Waning B et al. The global pediatric antiretroviral market: Analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children. BMC Pediatrics, 17 October 2010;
   http://www.biomedcentral.com/1471-2431/10/74.
3. UNAIDS, Report on the global AIDS epidemic. Geneva, Switzerland: UNAIDS, 2010.
   http://www.unaids.org/globalreport/global_report.htm.
4. Clinton Health Access Initiative. Personal communication, May 2011.
5. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Recommendations for a public health approach. Geneva, Switzerland: World Health Organization, 2010.
   http://www.who.int/hiv/pub/paediatric/ infants2010/en/index.html.
6. Drugs for Neglected Diseases initiative. Needs assessment for paediatric R&D. Geneva, Switzerland:Drugs for Neglected Diseases Initiative, 2011.
   http://www.dndi.org/diseases/new-disease-areas/781-paediatric-hiv.html.
7. Palumbo P et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med 2010;363:1510–20. Palumbo P et al. NVP- vs LPV/r-based ART among HIV+ infants in resource-limited settings: The IMPAACT P1060 trial. 18th CROI, Boston, February 2011. Oral abstract 129LB.
8. Coovadia A et al. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: A randomised controlled trial JAMA 2010;304:1082–90.
9. Kuhn L et al. Long-term outcomes of switching children to NVP-based therapy after initial suppression with a PI-based regimen. 18th CROI, Boston, February 2011. Oral abstract 128.
10. PENPACT-1 (PENTA 9/PACTG 390) Study Team. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: An open-label, randomised phase II/ III trial. Lancet Infect Dis. 2011;11(4):273–83.
11. Pursuing Later Treatment Options II (PLATO II) Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Risk of triple-class virological failure in children with HIV: A retrospective cohort study. Lancet 2011;377(9777): 1580 – 1587
12. Medical Research Council, Clinical Trials Unit. ARROW Antiretoviral Research for Watoto.
    http://arrowtrial.org/research_areas/ study_details.aspx?s=6.
13. Violari A et al. Early antiretroviral therapy among HIV-infected infants. N Engl J Med 2008;359.(21)2233–44.
14. Baylor International Pediatric AIDS Initiative. BANA II Clinical trial.
    http://www.bipai.org/Botswana/clinical-research.aspx.
15. Paediatric European Network for Treatment of AIDS. PENTA 11 Trial.
    http://www.pentatrials.org/p11v5.pdf.
16. US Food and Drug Administration. President’s Emergency Plan for AIDS Relief: Approved and tentatively approved antiretrovirals in association with the President’s Emergency Plan.
    http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm.
17. World Health Organization. Prequalification Programme.
    http://apps.who.int/prequal/.
18. US Food and Drug Administration. Kaletra (lopinavir/ritonavir) oral solution label changes related to toxicity in preterm neonates. February 2011.
    http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm244639.htm.
19. Boxwell D et al. Neonatal toxicity of Kaletra oral solution – LPV, ethanol, or propylene glycol? 18th CROI, Boston, February 2011. Poster abstract 708.
20. Current Controlled Trials Ltd. Children with HIV in Africa – Pharmacokinetics and adherence of simple antiretroviral regimens (CHAPAS-2).
    http://www.controlled-trials.com/isrctn/pf/01946535.
21. World Health Organization. WHO model list of essential medicines for children. 3rd list. Geneva, Switzerland: World Health Organization, 2011.
22. International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). INSIGHT Home.
    http://insight.ccbr.umn.edu/.
    TMC125-TiDP35-C213: Safety and Antiviral Activity of Etravirine (TMC125) in Treatment-Experienced, HIV Infected Children and Adolescents.
    http://clinicaltrials.gov/ct2/show/NCT00980538
23. TMC278-TiDP38-C213 (PAINT): An Open Label Trial to Evaluate the Pharmacokinetics, Safety, Tolerability and Antiviral Efficacy of TMC278 in Antiretroviral Naive HIV-1 Infected Adolescents.
    http://clinicaltrials.gov/ct2/show/NCT00799864
24. Safety and Efficacy of Switching From Stavudine or Zidovudine to Tenofovir DF in HIV-1 Infected Children (Ages 2- <12).
    http://clinicaltrials.gov/ct2/show/NCT00528957
25. PRINCE: Study of Atazanavir (ATV)/Ritonavir (RTV) (PRINCE1).
    http://clinicaltrials.gov/ct2/show/NCT01099579
26. Phase IIIB Pediatric ATV Powder for Oral Use (POU) (PRINCE2).
    http://clinicaltrials.gov/ct2/show/NCT01335698
27. Safety of and Immune Response to GSK1349572 in HIV-1 Infected Infants, Children, and Adolescents.
    http://clinicaltrials.gov/ ct2/show/NCT01302847
28. Safety and Effectiveness of Raltegravir (MK-0518) in Treatment-Experienced, HIV-Infected Children and Adolescents
    http://clinicaltrials.gov/ct2/show/NCT00485264
29. An Open Label Pharmacokinetic, Safety And Efficacy Study Of Maraviroc In Combination With Background Therapy For The Treatment Of HIV-1 Infected, CCR5 -Tropic Children.
    http://clinicaltrials.gov/ct2/show/NCT00791700

Additional sources

Untangling the Web of Antiretroviral Price Reductions:
http://utw.msfaccess.org/

Globally there are an estimated 2.1 million children under 15 infected with HIV. In the UK, the Collaborative HIV Paediatric Study (CHIPS) estimates the number of HIV-positive children to be 1,645 as of March 2010. Of these, 65% are over 10 years. A total of 262 have now been transferred to adult care.

As HAART has only been available since 1996, this is the first generation born with HIV to have survived to adulthood. As a result the long-term outcomes of HIV infection from birth and HIV treatment in childhood is still relatively uncertain.

This study aimed to examine the health outcomes of a cohort of 58 young people with perinatally acquired HIV infection that were originally part of the 900 clinic at St Mary’s Hospital and are now in adult care. The 900 clinic provides services for young people who were diagnosed with HIV when they were children and have been treated at St Mary’s Hospital since their diagnosis.

This was a case note review of all HIV-positive young people seen at the 900 clinic between January 2006-2011.

The median age of transfer from paediatric care in this cohort was 17.2 years (range 16.3 – 18.6) and the current median age was 20.6 (range 16.9 – 26.1) years. Overall outcomes of the 58 young people includes 5 (9%) who were transferred to local adult services, 51 who were still patients at the 900 clinic and 2 (4%) died (one 20 year old female due to MDR end-stage HIV disease and a 21 year old female due to nephropathy and sepsis who had declined ART). There was no loss to follow up and 7 of the patients included in the study had babies.

Of the 51 patients currently at the 900 clinic, their median current CD4 count was 425 cells/mm3 (IQR: 30-1140). More specifically, 22% had a CD4 count of <200 cells/mm3, 8% had a CD4 count of 200-350 cells/mm3 and 69% had a CD4 count of >350 cells/mm3. Of the 51 patients, 5 (10%) were ART naïve, 14 (27%) were on NNRTI-based regimens, 18 (35%) were on PI-based regimens, 2(4%) were on triple NRTI-based regimens and 12 (24%) had stopped ART.

Focusing on the 34 patients currently on ART, the median CD4 count was 480 with 6 patients had a CD4 count of <200 cells/mm3 (of which 3 had detectable viral loads), 2 had a CD4 count of 200-350 (of which 1 had a detectable viral load) and 26 had a CD4 count of >350 (of which 1 had a detectable viral load).

As far as complications of disease and treatment were concerned, 2 patients required gastrostromy tubes to help adherence, 6 (12%) had severe lipodystrophy (5 requiring surgery and 1 injectable fillers), 11 patients had a history of mental health problems (this included 4 patients who had intentional overdoses requiring admission to hospital) and 7 (14%) who had been prescribed antidepressants at some point.

Of the 51 patients currently at the 900 clinic, 13 (25%) had been admitted to adult inpatient services for a median duration of 9 days (range 3-133), 2 for OIs (PCP and MAI), 4 following overdoses and 1 for CVA and osteonecrosis.

The investigators concluded that after 2 decades of living with HIV, 20% of the patients at the 900 clinic have severe immunosuppression (CD4 <200), 25% have required hospital admission an 3% died. There were high rates of co-morbidity, lipodystrophy and depression. There are also a small group of young people who remain off ART with low CD4 counts. Overall 85% of those on ART currently have undetectable viral loads.

comment

The high rate of suppression on HAART (>85%) is a significant achievement given complicated treatment histories. Complicated balance for people still of treatment given the focus of long-term uncontrolled viraemia in adult patients, but also balanced with concern for long-term complications including cardiovascular and bone health.

Rate of psychiatric-related morbidity is especially concerning.

Reference:

Wan T et al. Health outcomes for young adults with perinatally acquired HIV-1 infection following transfer to adult services. 17th Annual BHIVA Conference, 6–8 April 2011, Bournemouth. Oral abstract O31.

Children who switched from twice- to once-daily lopinavir/ritonavir plus efavirenz had a low lopinavir trough concentration in a small Thai study [1]. Troughs were not as low during twice-daily lopinavir/ritonavir dosing with or without efavirenz or with once-daily lopinavir/ritonavir without efavirenz. All children maintained an undetectable viral load, and those with low troughs had a dose increase.

In the United States once-daily lopinavir/ritonavir is licensed for antiretroviral-naive adults and for adults with fewer than three lopinavir-related resistance mutations. But data are sparse on the once-daily lopinavir/ritonavir tablet for children. To fill that pharmacokinetic gap, researchers in Thailand mounted a pilot study involving children already taking twice-daily lopinavir/ritonavir with or without the nonnucleoside efavirenz.

The 12 study participants had maintained a viral load below 40 copies for at least 3 months with twice-daily lopinavir/ritonavir. When children enrolled in the pilot trial, researchers collected blood samples over 12 hours to measure lopinavir levels. Then all children switched to an equivalent dose of once-daily lopinavir/ritonavir. Two weeks after the switch, the investigators collected blood samples over 24 hours.

Study group ages ranged from 9.3 to 17.7 years (median 13.1), weight from 26.8 to 50.3 kg (median 40.8), CD4 count from 456 to 1239 (median 699), and CD4 percent from 16% to 31% (median 23%). Five of six children taking lopinavir/ritonavir with efavirenz and six taking the protease inhibitors without efavirenz completed both pharmacokinetic evaluations. Among children not taking efavirenz with the PIs, five were taking tenofovir/lamivudine and one zidovudine/didanosine.

Children combining lopinavir/ritonavir with two nucleosides and without efavirenz took lopinavir doses ranging from 255 to 283 mg/m(2) (median 271) with twice-daily dosing and from 514 to 570 mg/m(2) (median 544) with once-daily dosing. These children had the following areas under the concentration-time curve (AUC), maximum concentrations (Cmax), and trough concentrations (C12h or C24h) before and after switching to once-daily lopinavir/ritonavir. See Table 1.

Children combining lopinavir/ritonavir with efavirenz took lopinavir doses ranging from 273 to 338 mg/m(2) (median 303) with twice-daily dosing and from 538 to 645 mg/m(2) (median 612) with once-daily dosing. They had the following lopinavir concentrations before and after switching to once-daily lopinavir/ritonavir. See Table 1.

* P <0.05 for once vs twice daily concetrations within group (not between group)

For all 11 children who completed the study, the geometric mean ratio of lopinavir AUC once daily/twice daily was 1.01 (90% confidence interval 0.85 to 1.21). For Cmin, the geometric mean ratio of lopinavir once daily/twice daily was 0.21 (90% confidence interval 0.09 to 0.48). When taking lopinavir/ritonavir twice daily, all children had a lopinavir 12-hour (trough) concentration above 1 mcg/mL. After the switch to once-daily dosing, 5 of 6 children taking lopinavir without efavirenz and 0 of 6 taking lopinavir with efavirenz had a trough above 1.0 mcg/mL. The 7 children with a 24-hour lopinavir concentration below that cutoff after the switch to once-daily dosing had their dose increased by 20% to 30% after 12 weeks. Troughs remained low in 4 of these 7 children after the dose increase.

With once-daily lopinavir/ritonavir, median efavirenz concentrations were 62.6 (range 36.2 to 197.2) mcg x hr/mL for AUC, 4.1 (range 3.1 to 10.8) mcg/mL for Cmax, and 1.7 (range 0.9 to 6.0) mcg/mL) for Cmin.

All children maintained a viral load below 40 copies/mL through 24 weeks of once-daily lopinavir/ritonavir. No lopinavir/ritonavir side effects emerged, as might be expected in a group already tolerating twice-daily lopinavir/ritonavir well.

Several published studies have addressed lopinavir/ritonavir pharmacokinetics with once-daily dosing [2-4] or with twice-daily dosing with efavirenz [5-7]. In Canada a study of 7 children with a median age of 9.8 years found similar pharmacokinetics with once- and twice-daily dosing and no observable difference in tolerability [2]. A Netherlands study of 19 children with a median age of 4.5 found evidence that a lopinavir/ritonavir dose of 460/115 mg/m(2) “leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children” [3]. Another Dutch study of 15 children with a median age 11.8 years found that a lopinavir/ritonavir dose of 300/75 mg/m(2) twice daily compensates for the enzyme-inducing effect of efavirenz given at 14 mg/kg once daily.

References:

1. Chokephaibulkit K et al. Pharmacokinetics of lopinavir/r tablets administered once versus twice daily with/without efavirenz in antiretroviral treatment experienced children. 12th International Workshop on Clinical Pharmacology of HIV Therapy, 13–15 April 2011, Miami. Abstract P_19.
2. la Porte C et al. Pharmacokinetics and tolerability of once- versus twice-daily lopinavir/ritonavir treatment in HIV-1-infected children. Antivir Ther. 2009;14:603-606.
3. van der Lee M et al. Pharmacokinetics of a once-daily regimen of lopinavir/ritonavir in HIV-1-infected children. Antivir Ther. 2006;11:439-445
4. Rosso R et al. Lopinavir/ritonavir exposure in treatment-naive HIV-infected children following twice or once daily administration. J Antimicrob Chemother. 2006;57:1168-1171.
5. King JR et al. Steady-state pharmacokinetics of lopinavir/ritonavir in combination with efavirenz in human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. 2009;28:159-161.
6. Bergshoeff AS et al. Increased dose of lopinavir/ritonavir compensates for efavirenz-induced drug-drug interaction in HIV-1-infected children. J Acquir Immune Defic Syndr. 2005;39:63-68.
7. Fraaij PL et al. Safety and efficacy of a NRTI-sparing HAART regimen of efavirenz and lopinavir/ritonavir in HIV-1-infected children. Antivir Ther. 2004;9:297-299.

World Health Organisation (WHO) and national guidelines recommend universal treatment with antiretrovirals for all HIV-infected infants.

Guidelines also recommend using protease inhibitor-based treatment for children exposed to single dose nevirapine through PMTCT.

Initiation of therapy is recommended as soon as possible but there are limited data to guide treatment of very young infants.

Ellen Chadwick and colleagues from IMPAACT P1030 showed data in AIDS, published ahead of print in February 2011, from a study designed to look at the pharmacokinetics (PK) and safety of the liquid formulation of lopinavir/ritonavir (LPV/r) in HIV-infected infants starting treatment between 2 weeks and 6 months of age.

This was a prospective, open label, phase I/II study of 31 children from 17 centres in the US and Brazil treated with a high dose (300mg LPV/75mg RTV/m2 twice daily). Children were enrolled into two age groups: 14 days to 6 weeks and 6 weeks to <6 months. Children were followed until 48 weeks after the last child was enrolled.

The median duration of follow up was 123 (range 4-252) weeks. Ten (32%) children permanently discontinued the study including four before 12 months of age. Two discontinued after viral rebound to >50,000 copies/mL (weeks 43 and 176); three after parents refusal to attend study visits and/or give medication (weeks 2,42 and 145), three had non-treatment related conditions (CMV resulting in death at week 8; failure to thrive due to severe food allergy at week 70 and severe iron-deficiency anaemia at week 120) and two because their research sites closed (weeks 73 and 120).

Intensive PK sampling was performed at in 26 children at 12 months of age, pre-dose and 2, 4, 8 and 12 hours after an observed dose. Of these, 20 children had evaluable results.

The investigators found, the median AUC of the two groups was comparable at 12 months of age (99.1 ug h/mL [IQR 82.4-124.5] vs 112 ug h/mL [IQR 95.0-148.8], p=0.93). They also found a significant positive correlation of LPV trough concentration and age, p<0.0001.

By ITT analysis, at week 48, 22/31 (71%) children had a viral load <400 copies/mL; 6/10 in group 1 and 16/21 in group 2. Of these 11/15 (73%) on study treatment at 48 weeks had a viral load <50 copies/mL. Overall 29/31 (94%) children achieved a viral load <400 copies/mL while on study treatment and 19/29 (66%) children remained undetectable until the end of the study at a median of 123 (range 42-252) weeks. The children who sustained viral suppression had a higher percentage of predose time points at which concentrations exceeded the LPV target of 1 ug/ML (92 vs 71%), p=0.002.

The median baseline CD4 percentage was 35% (range 11-59%). There was a median increase of 4% (95% CI – 4 to 13%), p=0.12, among the 24 children with data available at 48 weeks and 23 (96%) had CD4 percentage >25%. Among the 19 children with follow up through 96 weeks there was a median increase of 8% (95% CI -2 to 13%), p=0.15.

The investigators noted that low LPV levels occurred at two weeks of therapy, with the lowest in infants <6 weeks of age. In this very young age group the median AUC was approximately half that seen in the older children >6 months of age. But these values were comparable between the two groups by 12 months of age and comparable to adults. They also noted that the LPV dose of 300mg/m2 is higher than the currently recommended dose for children >6 months of age.

Reference:

Chadwick EG et al. Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. AIDS, 25(6):767-776 (13 March 2011).
http://journals.lww.com/aidsonline/toc/2011/03130

The effects of in antiretroviral (ARV) exposure through PMTCT on HIV-uninfected infants are poorly understood, particularly in resource-limited settings.

Two papers published in JAIDS report findings from sub-studies of the Mashi and Mma Bana randomised controlled PMTCT trials, both conducted in Botswana. [1, 2]

We have covered both these trials extensively in HTB, including early findings from these analyses reported at CROI 2010. [3]

Increased severe anaemia risk with HAART

Scott Dryden-Peterson and colleagues conducted a post hoc analysis of pooled data from the trials. Infants were grouped by three ARV exposure categories: infants exposed to maternal HAART in utero and during breastfeeding and one month post natal AZT (HAART-BF); infants exposed to maternal AZT in utero and 6 months postnatal AZT during breastfeeding (AZT-BF); and infants exposed to AZT in utero and formula feeding (AZT-FF).

Overall, the investigators analysed data from 1719 infants (691 HAART-BF, 503 AZT-BF and 525 AZT-FF).

They observed severe incident anaemia (grade 3 or 4) in 118 (7.4%) infants from birth through 6 months of age. This occurred in 82 (12.5%) infants in the HAART-BF group, 25 (5.3%) in the AZT-BF and 11 (2.5%) in the AZT-FF groups. Severe anaemia was more frequent in the HAART-BF, group compared to infants in either of the other two groups: OR 2.53 (95% CI 1.59-4.04) and OR 5.96 (95% CI 3.14-11.3) vs AZT-BF and AZT-FF respectively, both p<0.001.

They noted that different frequency of assessment between the groups (AZT-BF group had haemoglobin measured monthly) could create potential bias. There was little evidence of this though, as they did not detect significant differences in the rate of treatment-modifying anaemia between birth, 1, 3-4 or 6-7 month visits among the study groups, p=0.15.

In multivariate analysis, besides HAART-BF exposure, which remained the strongest risk factor: gestational age, per week OR 0.89 (95% CI, 0.82-0.96) p=0.005; male sex OR 1.53 (95% CI 1.03-2.27) and low maternal income <$100 a month OR 2.04 (1.12-3.71) p=0.02, were all associated with severe incident anaemia. The investigators did not find an association with maternal BMI, CD4, viral load or haemoglobin. Nor was there and association with maternal HAART regimen or duration of antenatal HAART. Infants who were small for their gestational age were not at greater risk of severe anaemia.

The majority of episodes of severe anaemia were resolved with multivitamin and iron supplements or stopping AZT but 11 infants from the HAART-BF group needed transfusion. Six infants died (1 HAART-BF, 2 AZT-BF and 3 AZT-FF), three of the infants had severe anaemia reported as cause of death. Two infants were lost to follow up before their severe anaemia was resolved.

Microcytosis and hypochromia occurred in 21.2% and 29.3% of incident anaemias with measurements available. Estimated haemoglobin iron at birth was lower for HAART-BF infants than the other two groups (p<0.001).

The investigators suggested these findings deserve further investigation and emphasised the established benefits of maternal HAART. They wrote: “Mitigating strategies such as iron supplementation to HIV-exposed breastfed infants or alternative antiretrovirals should be evaluated to maximise the benefits of maternal HAART while minimising potential risks.”

Lower weight HAART-exposed infants catch up by 6 months

Kathleen Powis and colleagues from the same group looked at the effects of in utero ARV exposure on longitudinal growth through 6 months of age in 619 HAART-exposed and 440 AZT-exposed uninfected infants from the two trials.

This was a retrospective analysis of infants carried to 37 weeks gestation or greater.

The investigators used WHO’s Child Growth Standards to calculate z-scores for an infant’s weight for age (WAZ), length for age (LAZ) and weight for length (WLZ).

They reported mean birth weights of 3.01kg and 3.15kg for HAART- and AZT-exposed infants respectively, p<0.001. HAART-exposed infants had lower values for all three z-scores at birth, all p<0.001.

HAART-exposed infants had greater improvement compared to AZT-exposed infants in WAZ from birth through 2 months, p=0.03, but the investigators observed no difference in WAZ between the two exposure groups from 3 through 6 months, p= 0.26.

Similarly, LAZ increased more in the HAART-exposed infants through 2 months, p=0.002, but this difference did not remain significant at 3 to 6 months, p=0.08.

HAART-exposed infants also had a more rapid increase in WLZ through 2 months than AZT-exposed infants, p<0.001. Between 3 and 6 months, the WLZ z-score in HAART-exposed infants declined while the AZT group had small increase. The difference in growth patterns between the two groups was significant, p=0.04.

There was no difference in wasting or stunting between groups, which occurred in about 6% and 5% of infants overall respectively.

The investigators wrote: “This analysis is the first to provide reassurance that lower birth weight associated with in utero HAART exposure does not persist during early infancy. It also highlights the importance of early and routinely scheduled health care for HAART- exposed HIV-uninfected infants.”

References:

1. Dryden-Peterson S et al. Increased risk of severe infant anaemia following exposure to maternal HAART, Botswana. J Acquir Immune Defic Syndr. Volume 56. Number 5. 15 April 2011.
2. Powis KM et al. Effects of in utero antiretroviral exposure on longitudinal growth of HIV-exposed uninfected infants in Botswana. J Acquir Immune Defic Syndr. Volume 56. Number 2. February 1, 2011.
3. Clayden P. Pregnancy outcomes in infants exposed to maternal antiretrovirals in utero. HTB. Vol 11. No 3/4 March/April 2010.
   http://i-base.info/htb/10238

Lopinavir/ritonavir (LPV/RTV) is first line treatment for young children in South Africa. Concomitant treatment for TB is common in children with HIV. There is a complicated interaction between this boosted protease inhibitor and the first line TB drug, rifampicin (RIF), which reduces the bioavailabilty and Cmin of LPV by approximately 75% and 99% respectively.

Two strategies are possible to increase the LPV levels when it is dosed with RIF – either increasing the dose of RTV to a LPV:RTV 4:4 ratio or doubling the dose to a LPV:RTV ratio 8:2.

Chao Zhang and colleagues from the University of Cape Town showed a population pharmacokinetic (PK) model developed to describe the interactions between LPV, RTV and RIF in children. They used this to look at the effect of various factors (age, BSA, weight, gender, haemaglobin, albumin, ALT) on LPV and RTV PK, and make dosing recommendations for HIV/TB coinfected children receiving these drugs concurrently. [1]

In this study, 39 children with HIV only received the standard dose of LPV/RTV, 4:1, (control group); 15 coinfected children received the super-boosted dose, 4:4; and 20 the double dose, 8:2. Then 11 coinfected children received the standard dose following RIF-based treatment. Repeated sampling was performed (4-6 from each child) up to 12 hours post dose.

The children were a median age of 21 months (range 6 months to 4.5 years) and a medium weight of 10.2kg (range 5-17kg).

Using a one-compartment model with first order absorption for LPV and a one-compartment model with transit absorption for RTV, the investigators modelled the effect of RTV concentration on LPV clearance as direct inhibition with an Emax model.

The investigators found that, during concomitant treatment with RIF, the relative oral bioavailability of LPV was reduced by 79% in children receiving the twice the standard dose of LPV/RTV. RTV clearance was 18 L/h with RIF and 13L/h without.

The estimated baseline clearance of LPV, when there was no detectable RTV was 4.34 L/h. As the concentrations of RTV increased, the clearance of LPV decreased in a sigmoid relationship (EC 50, 0.051 mg/L). They found volume of distribution for LPV and RTV were 11.7 and 102 L respectively.

When the investigators performed simulations for dose optimisation during RIF-based TB treatment with a target of LPV concentrations with Cmin >1mg/L in 95% of children, they predicted doses of LPV/RTV as described in Table 1. They noted that smaller children required higher mg/kg doses of LPV/RTV, in both 4:1 and 1:1 ratios, than larger children.

Table 1: Simulation for dose optimistion of LPV/RTV during RIF-based TB treatment

comment

The same group previously presented data to show that the double dose LPV/r is not sufficient for children when coadministration with rifamipicin. [2]

The current median LPV dose using double dose strategy in this study is 23 mg/kg,

The investigators suggestion for dose adjustment in this study is much higher than double dose. Or they suggest switching to an 8 hourly dose strategy considering the adverse effect slinked to higher doses. [3]

References:

1. Zhang C et al. Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Oral abstract O24. Published in Journal of the International AIDS Society 2010 13(Suppl 4). O223.
   http://www.jiasociety.org/content/13/S4/O24
2. McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.
   http://www.retroconference.org/2009/Abstracts/34615.htm
3. Personal communication with the author.

The shortage of appropriate paediatric antiretroviral formulations has been a major barrier to scale up of treatment of children in resource-limited settings. The initiation of nevirapine is complicated by the recommendation to escalate the dose, requiring a regimen change two weeks after starting treatment.

The Children with HIV in Africa – Pharmacokinetics and Adherence of Simplified Antiretroviral Regimens (CHAPAS) Trials, are investigating new antiretroviral formulations and strategies for children. This is a joint project of the University of Zambia and University Teaching Hospital Zambia, the Medical Research Council (UK), Radboud University Nijmegen, Netherlands and the University of Padova, Italy, began in 2005. [1] We have followed this project in HTB for some time.

CHAPAS-1 looked at treatment with Triomune Baby/Junior – fixed dose combination (FDC) scored, dispersible “mini pills” of stavudine (d4T), lamivudine (3TC) and nevirapine in the correct ratios for children, manufactured for the trial by Cipla. The doses of the tablets are: 6 and 12 mg d4T, 30 and 60 mg 3TC and 50 and 100 mg nevirapine in Triomune Baby and Junior respectively. Data from this trial contributed to the tentative approval by the FDA for these formulations, and to the WHO dosing recommendations by weight band for fixed dose combinations of these drugs, down to 3kg.

Nevirapine toxicity has been reported to be uncommon in children receiving full dose nevirapine at initiation, but there have been no randomised trials to evaluated the safety of this strategy. CHAPAS-1 compared the initiation of antiretroviral therapy (ART) with full dose nevirapine versus half dose nevirapine for the first two weeks of treatment.

An article, authored by Veronica Mulenga and colleagues and published in the November 1, 2010 issue of Clinical Infectious Diseases, showed findings from this trial.

Children aged 3 months to 14 years, indicated for treatment in accordance with WHO 2006 guidelines, were randomised 1:1 to receive either Triomune Baby or Junior twice daily for the first two weeks (full dose group, or Triomune Baby/Junior once daily plus once daily Lamivir-S, Baby or Junior – dual 3TC and d4T combination tablets (dose escalation group).

The primary end point was grade 3 or 4 adverse events (AEs) related to nevirapine.

A total of 211 children were randomised and included in the intent to treat analysis. Children in the two groups were similar. The median age at ART initiation was 5 years (IQR 2-9 years) and 35% were less than 3 years. The median CD4 percentage was 13% and 99% of children had WHO stage 3 or 4 disease. Severe wasting and/or stunting were common.

All children were seen by a nurse at 2 and 4 weeks from initiation and subsequently every 4 weeks. Children were weighed and measured, any adverse events or new WHO events were recorded and additional ART prescribed. They were also routinely seen by a doctor at weeks 2, 4, 8 and 12 and then every 12 weeks where they had a clinical examination and blood samples were obtained.

There were 60 (31 the full dose and 29 in the escalated groups), grade 3 or 4 AEs reported in 49 children (25 in the full dose and 24 in the dose escalated) that were considered definitely or probably related to nevirapine (n=8), or there was uncertainty as to their relation to nevirapine (n=52). This gave 18 vs 16.5 events per 100 child years in the full dose and dose escalated groups respectively; incidence rate ratio [IRR] 1.09 (95% CI 0.63-1.87), p=0.74.

All AEs were asymptomatic and the children continued treatment with nevirapine. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) were the most common; 11 events in the full dose and 3 in the dose elevated groups), and elevated bilirubin levels (n=34).

There was no grade 3 or 4 rash, but 13 and 2 children had grade 1 (2 in the full dose group) or grade 2 (11 in the full dose and 2 in the dose elevated groups) rashes, p=0.003. One child in the full dose group developed a second grade 2 rash after reintroducing nevirapine at half dose. Rashes started at a median of 17 days (range 8-25 days) after initiation and lasted for a median of 9 days 9range 2-24 days).

Of the 15 children who developed rashes, 3 continued full dose nevirapine; 9 (8 full and 1 elevated dose) stopped nevirapine temporarily and then successfully dose escalated; 1 in whom the rash returned after changing from full dose to half dose, substituted efavirenz and 2 (1 full and 1 dose escalated) substituted efavirenz without retrying half dose nevirapine. All but 2 children in the full dose group were managed as outpatients.

In multivariate analysis, older age (per year increase), OR 1.35(95% CI, 1.10-1.64) p=0.003, and higher CD4 count for age (per unit increase), OR 1.51 (1.03-2.20) p=0.03 were associated with nevirapine rash. More rash occurred in the full dose group versus dose escalated, OR 9.79 (1.97-48.6), p=0.005.

Twenty-two children (10%) died (12 in the full dose and 10 in the dose escalated groups). More than half the deaths occurred within the first 3 months of ART, and were most frequently due to diarrheoa and pneumonia. Most children who died had advanced HIV disease and very low weight-for-age z-scores. No deaths were judged to be drug-related.

Children in both groups had similar increases in weight for age and height for age z-scores and CD4 counts or percentages (+17.3%) at 96 weeks.

The investigators concluded that rash occurred more frequently among children starting nevirapine at full dose but 88% had no clinical toxicity. Where possible they recommend using dual d4T/3TC paediatric tablets for dose escalation

If children are initiated on full dose Triomune, caregivers need to be aware of the timing of rash. For those in whom this occurs the options are to treat through under careful observation or to manage temporarily with half dose Triomune or efavirenz.

They noted that the elevated AST or ALT values were unconfirmed, transient and resolved spontaneously. They suggested that their results concur with that of the DART trial, which showed no difference in AEs requiring regimen modifications among adults receiving routine versus clinical biochemistry monitoring, including those receiving nevirapine. The results from both DART and CHAPAS-1 suggest that routine liver function tests are not necessary after nevirapine initiation in resource-limited settings.

References:

1. European and developing countries clinical trails partnership (EDCTP). Project at a glance: Custom made treatments for HIV-infected children.
   http://www.edctp.org/Project-at-a-glance-Custom-made.671.0.html
2. Mulenga V et al. Strategies for nevirapine initiation in HIV-infected children taking paediatric fixed-dose combination “baby pills” in Zambia: A randomised controlled trial. Clin Infect Dis 2010: 51. 1 November 2010.
   http://www.journals.uchicago.edu/doi/abs/10.1086/656628?journalCode=cid

The new WHO paediatric guidelines now recommend immediate antiretroviral therapy for children with confirmed HIV infection aged <24 months. However identifying HIV-infected infants and linking them to treatment programmes, particularly fast, is easier said than done.

DNA-PCR testing is generally used for early infant diagnosis (EID), but it is expensive and requires sophisticated, centralised laboratories and trained technicians. Although DNA-PCR has been used in resource-limited settings, its long turnaround time contributes to infant loss-to-follow-up and loss of benefit of immediate initiation of treatment. Currently, no point-of-care (POC) HIV tests are available for infants.

In a special session at IAS 2010, Susan Fiscus presented an excellent overview of the current tools available and the prospects of POC technology for early EID. [1,2]

She began with a list of desirable qualities for a POC diagnostic test:

• Rapid (< one hour)
• Sensitive (> 95%)
• Specific (> 98%)
• Inexpensive (<$5 per test)
• Simple (equipment: battery operated, few moving parts, small footprint/technique: minimum training required)
• Robust – no cold chain required
• Commercially available
• CE marked/FDA cleared

But she quoted Bill Rodriguez’s remark on the subject: “Cheap, fast or accurate. Pick two.”

The current tests used for EID are HIV DNA and total nucleic acid assays. The gold standard is the Roche AMPLICOR HIV DNA assay, version 1.5. This test is used in many countries and can use whole blood pellets or dried blood spots (DBS).

The Roche Qualitative Total Nucleic Acid Assay has also been introduced. This test works on whole blood and DBS. In one study it was shown to be 100% sensitive and 99.7% specific.

Abbott is also developing a DNA assay.

These tests need large, expensive equipment and are probably only suitable for sophisticated, centralised laboratories.

For resource limited settings, HIV DNA assays need to be POC. Dr Fiscus described three tests in development.

Researchers at the Centre for Innovation in Global Health Technologies (CIGHT) at Northwestern University are working on a POC DNA-PCR. At CROI in February, they reported a lower limit of detection of 5 copies/reaction and good sensitivity and specificity. [3] This assay uses a small, portable, battery-operated analyser, which can assemble the reaction and perform fluorescence detection and thermal cycling. The analyser card integrates DNA extraction, PCR reagent storage without refrigeration and PCR amplification.

Data from Micronics Real Time PCR was also presented at CROI 2010. [4] This assay uses a credit card sized device and microfluidic principles for both nucleic acids extraction and amplification. The investigators reported good sensitivity and specificity in this study.

The Biohelix Isolamp is another simple HIV DNA test under development. This assay couples helicase-dependent isothermal amplification (HDA) with amplicon detection using a disposable cassette. Early data were presented at the 2010 HIV Diagnostics Conference. [5]

She explained that the CIGHT test is not yet ready for field-testing and is on hold while the group focuses on a POC p24 test. Both the Micronics and BioHelix tests appear to be in the proof of concept stage and are not ready for field testing yet either.

It is possible to use qualitative HIV RNA assays as an alternative to HIV DNA. The qualitative Gen-Probe Aptima is the only HIV RNA test approved by the FDA for diagnosis. Although the FDA approval is for plasma or serum, this system works well with DBS. It is very sensitive and specific and is being used by the State of New York for EID.

She mentioned that it is unclear whether HIV RNA assays will be as sensitive when infants are being prophylaxed or if mothers are receiving antiretrovirals and breastfeeding the child.

Several other HIV viral load assays are currently commercially available, but are not POC, require large expensive equipment, and are suitable for centralised laboratories.

Dr Fiscus described three POC RNA assays that are in development. The SAMBA (simple amplification based assay) is currently being developed by the University of Cambridge and Diagnostics for the Real World. Data were recently published in JID. [6] This test uses isothermal amplification and visual detection by dipstick. It has a limit of detection of 75 copies/mL using 250 mL of plasma, and 400 copies/mL using 100 mL whole blood. No cold chain is required and it can be battery operated. It is simple to operate and little training is needed. There will be a clinical trail for regulatory approval in 2011.

Dr Fiscus showed recent unpublished data from her own research group. The IQuum LIAT quantative POC HIV assay is a real time PCR, which can be battery operated, is easy to use and requires little training. It gave 92% correlation with Abbott m2000 with 75 plasma samples. It has not yet been tested with whole blood. The assay takes 60 minutes to perform but does need a cold chain.

Inverness Medical Innovation’s CLONDIAG, uses a microarray, real time detection method. It can use fingerstick, whole blood or plasma. The sample is applied directly onto the test cartridge, which is processed by a compact, battery driven instrument. Preliminary data provided by the manufacturer are promising.

Finally p24 antigen tests, which have limited use in adult diagnostics, can be used for EID. The ultrasensitive, heat dissociated p24 antigen assay has been shown to work well with both plasma and DBS.

As far as POC is concerned, Dr Fiscus showed results from the CIGHT p24 antigen rapid test that were recently published ahead of print in JAIDS. [7] This assay is performed, by adding 25mL of plasma to 75mL buffer. This mixture is heated in a water bath at 90 degrees for four minutes. A test strip is then inserted and gives a read out after 20 minutes. Trials in Cape Town showed 95% sensitivity and 99% specificity.

She also described an improved CIGHT POC p24 antigen rapid test under development. This assay uses whole blood and heat shock to increase sensitivity. It consists of a plasma separator, reaction tube, reaction buffer and rapid test strip. It is battery operated and each test should cost $1-2.

In keeping with Bill Rodriguez’s remark she presented the most likely future tests in a table. See Table 1.

Table 1: ‘Cheap, fast or accurate. Pick two” Susan Fiscus

She concluded that promising POC assays for EID today include: IQuum’s LIAT, SAMBA, CIGHT p24 and possibly CLONDIG’s viral load assay.

comment

This was an incredibly useful overview and it looks like we can be optimistic about having a POC test for EID in the next couple of years.

Other presentations at the conference dealt with the challenges of access to EID. In the same session, Shaffiq Essajee noted that EID access has improved and in some countries more than 50% of exposed infants are tested. [1] But infant testing is usually linked to PMTCT and if coverage is low, so is infant testing coverage. Globally only 15% of exposed infants get a test. Even when there is access to EID, infected infants do not necessarily get ART.

Laura Guay showed that there are similar coverage cascades with EID to that of PMTCT. [8] Losses occur at each step of the cascade. She showed data from a programme of the Elizabeth Glaser Pediatric AIDS Foundation in which there were 4226 infants with known exposure. Of these 4099 (97%) had EID drawn, 895 (70%) had results returned from the lab with 449 (15%) positive results. Then only, 230, (51%) received results, 200 (87%) enrolled in care and 178 (89%) infants initiated treatment. Overall, she explained, there were 633 infected children, of which 71% were identified and 28% treated. “And this” she said “is a good programme”.

A related poster showed Ministry of Health data from 84 sites in Cambodia, Namibia, Senegal and Uganda with >21,000 infants tested. [9] Although the study was called “Increasing uptake of HIV early infant diagnosis services in four countries” and showed steady increases in sample volume, in 2008, it was still low in three of the countries reviewed: Cambodia 14%, Senegal 9% and Uganda 21%. Namibia however achieved 86-100% EID coverage. Less than half these infants ever tested via EID were tested in their first two months of life. Coverage of optimal service (early testing) is consequently even lower. And of those infants tested HIV positive via EID, attrition is significant 72%, 67% and 67% were not alive and on ART in Uganda, Cambodia and Senegal respectively.

The investigators concluded: “Significant strides to establish and increase access to and uptake of EID testing have been made across all countries reviewed. When decentralising, it is important for programming to focus on early identification and access to the full package of exposed infant services including EID.”

So as well as a POC test for EID, which will take care of some of the obstacles to successful diagnosis and treatment, programmes need to ensure good systems for patient management and links between services to ensure that they can take full advantages of the promise of these new technologies.

References

1. Scaling Up Early Infant Diagnosis of HIV as the Bridge between Prevention, Care and Treatment: Successes, Challenges and Potential Solutions. 18th IAS. July, 2010. Vienna. Special session SUSS03.
   http://pag.aids2010.org/session.aspx?s=150
2. Fiscus S. EID – current tools and prospects of point of care technology. 18th IAS. July, 2010. Vienna. Special session SUSS0302.
3. Jangam S et al. A point-of-care DNA PCR test for infants. 17th CROI. February 2010. San Francisco. Poster abstract 891.
4. Granade T et al. rapid extraction and amplification of HIV-1 DNA from whole blood using a disposable microfluidics device. 17th CROI. February 2010. San Francisco. Poster abstract 945.
5. Jordan JA et al. Evaluation of the IsoAmp HIV detection kit using whole blood samples. HIV Diagnostics Conference, March 24-26, Orlando, Florida. Poster abstract 34.
6. Lee H et al. Simple Amplification-Based Assay: A nucleic assay based point-of-care platform for HIV-1 testing. Jour Infect Dis 2010:201 (Supp 1) S65-72.
7. Parpia ZA et al. p24 antigen rapid test for diagnosis of acute pediatric HIV infection. J Acquir Immune Defic Syndr. Published ahead of print August 2010.
8. Guay L. Early infant diagnosis of HIV: successes, challenges and potential solutions. 18th IAS. July, 2010. Vienna. Special session SUSS0301.
9. Tripathi S et al. Increasing uptake of HIV early infant diagnosis (EID) services in four countries (Cambodia, Namibia, Senegal and Uganda. 18th IAS. July, 2010. Vienna. Poster abstract TUPDB205.
   http://pag.aids2010.org/Abstracts.aspx?SID=185&AID=14996

The US Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in Pediatric Infection were updated on August 16 2010. Key revisions to the 23 February 2009 version are:

Diagnosis

Viral diagnostic testing at birth is recommended for high risk infants, for instance, those born to HIV-positive mothers who received no prenatal care and or prenatal antiretroviral therapy or who had viral loads >1000 copies/mL close to the time of delivery. The recommendation for testing HIV-exposed infants 14–21 days, 1–2 months, and 4–6 months remains.

They also recommend that an HIV qualitative RNA assay (APTIMA HIV-1 RNA Qualitative Assay) can be used as an alternative test.

When to start

The guidelines still recommend universal treatment for all infants age one year or less.

Guidance for asymptomatic or mildly symptomatic children with CD4 >25% (or >350 cells/mm3 if older than five years) and viral loads >100,000 copies/mL is strengthened. The current guidelines now “recommend” therapy in this situation compared to “consider” in the previous edition.

They also recommended that therapy can be “considered or deferred” for asymptomatic or mildly symptomatic children with CD4 >25% (or >350 cells/mm3 if older than five years) and viral loads <100,000 copies/mL; previously deferral was recommended in this situation.

They make specific recommendations in the following situations:

• Starting antiretroviral treatment is “recommended” for children age one year or less with AIDS or significant symptoms (Clinical Category C or most Clinical Category B conditions), regardless of CD4 percentage/count or viral load.
• Starting treatment is also “recommended” for children one year or above who have reached the age-related CD4 threshold for initiating treatment (CD4 <25% for children age one to five years of age and <350 cells/mm3 for children above five) regardless of symptoms or viral load.
• It is also “recommended” for children one year or above who are asymptomatic or with mild symptoms (Clinical Categories N and A or with Clinical Category B conditions: single episode of serious bacterial infection or lymphoid interstitial pneumonitis) and have CD4 >25% for children age one to five or ≥350 cells/mm3 for children age five or above and have viral load >100,000 copies/mL.
• Starting may be “considered or deferred” for children one year or above who are asymptomatic or have mild symptoms and who have CD4 >25% for children age one to five and >350 cell/mm3 for children five years old or above and have viral loads <100,000 copies/mL.

What to start with

The guidelines discuss recent data from clinical trials of nevirapine versus lopinavir/ritonavir-based regimens in children with single-dose nevirapine exposure for prevention of mother-to-child transmission. NNRTI-based therapy is not recommended for infants or children age <3 years with single-dose nevirapine exposure.

Darunavir/ritonavir is now recommended as an alternative protease inhibitor for initial therapy in children age >6 years.

Nelfinavir has changed from an alternative protease inhibitor for initial therapy to a protease inhibitor for use in special circumstances in children age >2 years.

Key updates usefully highlighted in yellow throughout the guidelines.

The new guidelines also include a ratings system for strength and quality of evidence and have amended some of the appendices.

Ref: Guidelines for the use of antiretroviral agents in pediatric HIV infection, August 16, 2010.
http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf

WHO recommends daily cotrimoxazole preventative therapy (CPT) for infants and children. US guidelines recommend either daily or three days a week. Adult studies suggest that thrice-weekly CPT is as effective as daily but with a decrease in side effects and an increase in tolerability. The optimum frequency for CPT in children has not been determined.

A paper, published in AIDS, by Heather Zar and colleagues, reported results from a South African study of children randomised to receive either daily or thrice-weekly CPT.

The study looked at mortality, bacterial infections, hospitalisation and adverse events.

A total of 339 children, attending, either Red Cross War Memorial Children’s Hospital, University of Cape Town or Tygerberg Hospital at Stellenbosch University, aged eight months and above were enrolled. Of these, 10 tested negative and five were lost to follow up within a month from randomisation.

The study, which commenced in December 2002, originally had a factorial design and compared both three times weekly CPT vs daily CPT, and isoniazid (INH) vs. placebo. The placebo arm was stopped in May 2004, on the advice of the DSMB, and all children were switched to INH. INH was then discontinued in December 2007 as most children were receiving HAART. The investigators continued to study three times weekly CPT vs daily CPT. Results are from this investigation from January 2003 through December 2007.

Of the 324 children, 165 (50.9%) were randomised to receive intermittent therapy and 159 to daily therapy. They were a median age of 23 months (IQR 9.5-48.6 months). Almost one third (30.3%) were less than 12 months of age. The majority (88.6%) were symptomatic and the median CD4 percentage was 20%. At enrolment 8.6% of children were receiving HAART, and 63.9% received it during the study. Malnutrition was common. Baseline characteristics were similar in both groups.

Overall 9% of children were lost to of which 57% were in the group receiving daily CPT. An additional 24% withdrew from the study, 13% from the daily group, mostly due to logistics. Median follow up was 1.97 years (IQR 1.3-3.3 years) vs 1.92 years (IQR 0.5-3.29 years), p=0.37, in the intermittent and daily groups respectively. The investigators reported excellent adherence in both groups.

They found similar mortality rates in both groups: 24/165 (14.5%) vs 29/159 (18.2%) deaths in the intermittent and daily groups respectively, HR 0.75 (95% CI, 0.44-1.29), p=0.3. The difference in the cumulative survival proportions estimated at one year was 0.04 (90% CI -0.03- 0.10). Therefore thrice weekly was defined as non inferior to daily CPT as the CI for difference included zero and exceeded the predefined delta of -0.1 at one year of follow up. The choice of inferiority margin was based on expert opinion.

Infants had a six-fold higher incidence of death compared to children greater than one year of age (20 vs 3.6 per 100 child years), IRR 5.91 (95% CI 3.3-11.2) p<0.0001.

Causes of death were similar in both groups. Overall this was, 32% sepsis, 25% pneumonia and 15% diarrhoea.

However intermittent CPT was associated with a two increased incidence of bacteraemia, IR 9.6 vs 4.07 per 100 child years, IRR 2.36 (95% CI 1.21-4.87), p=0.006.

Additionally children receiving intermittent IPT spent significantly more days in hospital than those receiving daily, 228.5 vs 198.5 days per 100 child years, IRR 1.15 (95% CI 1.04-1.28), p=0.004. The admission rate was similar between the two groups.

Toxicity was similar in both groups, with an overall incidence of 6.8 grade 3 or 4 events per 100 child years (46 events; 25 intermittent, 21 daily).

The investigators concluded that their results support the current WHO recommendations of daily CPT for infants and children. They acknowledge that their results may not apply to settings with different burdens of bacterial disease. They wrote: “Widespread implementation of CPT is needed in areas of sub-Saharan Africa where this intervention is not available.”

Ref: Zar HJ et al. A randomised controlled trial of intermittent compared to daily cotrimoxazole therapy in HIV-infected children. AIDS 2010, volume 24: 2225-2232.

The new WHO 2010 paediatric guidelines – Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access – also summarised on their website in a preliminary version for programme planning in June, were released at IAS 2010.

Lynne Mofenson provided an excellent summary of the new guidelines at the paediatric meeting and Shaffiq Essajee in the Early Infant Diagnostics (EID) session at IAS. [1,2] We will review developments in diagnostics including EID in the next issue of HTB.

When to start

Universal treatment is recommended for all infants and young children under two years irrespective of CD4 or clinical indication. The recommendation is strong for less than 12 months and conditional for 12-24 months.

Data to guide when to start for children one to five years old are scant and this is reflected in differences in recommendations between guidelines (see statement from PENTA in the comment below). After five years of age, guidance is similar to that for adults (see Table 1). Table 2 shows a comparison between the 2006 and 2010 WHO guidelines.

*CD4 percentage/absolute CD4 count mm3

Adapted from WHO 2010 revision. Essajee S.

comment

PENTA have published a letter in support of the new guidance for resource limited settings and are continuing to recommend PENTA guidance ie universal treatment for infants less than 12 months and immunological and clinical criteria for those above for treating children in Europe. In the letter they write:

“Both PENTA 2009 and WHO 2010 guidelines considered the same body of evidence, and several experts took part in the drafting of both sets of recommendations. The universal treatment of infants is based on evidence from the CHER study, children over five are treated at adult thresholds in both guidelines, based on comparisons between the HPPMCS child cohort and CASCADE adult seroconverter cohort. The recommendations for children aged between 2 and 5 are based on cohort data, largely from the HPPMCS study.

The new recommendations in the WHO guidance for children between age one and five are based on programmatic considerations, in particular the ability to closely monitor a child clinically and by repeat CD4 count measurement if they are not started on ART. Such monitoring is available in Europe, and in many settings outside Europe. It is also noted that the evidence basis for these recommendations is weak or very weak, and that studies expected to publish results soon may shed more light on the subject. We endorse WHO’s recommendation to treat early where the ability to provide monitoring is limited, as well as the call for more research to provide RCT evidence for treatment initiation thresholds after infancy. We continue to recommend PENTA 2009 guidance as appropriate for European and other settings with the facility to monitor closely children in whom treatment is deferred.”

http://www.pentatrials.org/PENTA%20letter%20re%20WHO%20jul%202010.pdf

What to start with

Recommended regimens are:

• For children less than two not exposed to maternal or infant nevirapine or whose exposure status is unknown: nevirapine plus two NRTIs.
• For children exposed to maternal or infant nevirapine or other NNRTIs used for maternal treatment or PMTCT: lopinavir/ritonavir plus two NNRTIs (with the caveat that nevirapine is better than nothing).
• For children over two but under three: nevirapine plus two NRTIs.
• All others (irrespective of nevirapine exposure): nevirapine or efavirenz (efavirenz preferred for TB treatment)
• Under three and needs TB treatment: nevirapine plus two NRTIs or abacavir plus lamivudine plus zidovudine/stavudine.
• • Adolescents over 12 with hepatitis B: tenofovir plus lamivudine/emitricitabine plus efavirenz/nevirapine (can take FDC of lamivudine/emitricitabine plus efavirenz if this is available).
• Adolescents with hepatitis C: preferred regimen is efavirenz plus two NRTIs.

The guidelines also recommend a preferential order of NRTIs (zidovudine/lamivudine > abacavir/lamivudine > stavudine/lamivudine).

They recommend that any child with active TB begin TB treatment immediately and start ART in the first eight weeks of TB treatment.

For children already on ART who develop TB, they recommend that ART regimens may need to be adjusted to decrease the potential for toxicities and interactions: if on nevirapine substitute for efavirenz if over three years; if under three ensure nevirapine is at high dose (2 mg/m2) and if on lopinavir/ritonavir consider adding ritonavir to a 1:1 ratio lopinavir/ritonavir to achieve the full therapeutic dose of ritonavir.

The guidelines recommend solid in preference to liquid formulations, use of heat stable FDCs or co-packaged formulations wherever possible and dosing in accordance with WHO weight band tables.

When to switch

Switching to second line treatment is recommended when clinical, immunological or virological failures occur.

• Clinical failure is defined as the appearance (or reappearance) of WHO clinical stage 3 or 4 events at least 24 weeks on ART and child is adherent.
• Immunological failure is defined as returning to age related thresholds in a treatment adherent child: CD4 count of <200 cells/mm3 or CD4 percentage <10% for a child over two and less than five years of age; CD4 count of <100 cells/mm3 for a child of five years or more.
• Virological failure is defined as a persistent viral load above 5000 copies/mL after at least 24 weeks on ART for a treatment adherent child.

What to switch to

Choice of second line ART is dependent on the first line regimen received:

• After failure on an NNRTI: boosted PI plus 2NRTIs. Lopinavir/r is preferred.
• After failure on zidovudine or stavudine plus lamivudine: abacavir plus lamivudine is the preferred NRTI backbone, abacavir plus didanosine is an alternative.
• After failure on abacavir plus lamivudine, zidovudine plus lamivudine is the preferred NRTI backbone; zidovudine plus didanosine is an alternative.

comment

These guidelines represent a liberalisation of criteria and if they are followed should ensure that many more children are identified and treated.

They are available on the WHO website. [3]

Annexe E has updated weightband dosing tables and formulations that are needed. We also look at paediatric formulations in the TAG/i-Base Pipeline Report. [4]

References:

1. Mofenson L. What’s new in WHO Pediatric Treatment Guidelines? 2nd International Workshop on HIV Pediatrics. July 2010, Vienna, Austria.
   http://regist2.virology-education.com/2ndHIVPed/docs/I_04Mofenson.pdf
2. Essajee S. Scaling up early infant diagnosis of HIV as the bridge between prevention, care and treatment: successes, challenges and potential solutions. Special session SUSS03.
   http://pag.aids2010.org/session.aspx?s=150
3. World Health Organisation. Antiretroviral therapy for HIV infection in infants and children : Recommendations for a public health approach (2010 revision)
   http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html
4. Clayden P. Paediatric antiretroviral pipeline. TAG 2010 Pipeline Report. July 2010.
   http://i-base.info/htb/13436

In 2008, the CHER trial demonstrated the effectiveness of universal early antiretroviral treatment for all infants regardless of CD4 or clinical stage.

This in turn influenced paediatric guidance worldwide.

For resource limited countries one of the main obstacles to the implementation of this strategy is cost.

In an oral late breaker, Gesine Meyer-Rath, showed findings from a cost comparison of early (from 6-12 weeks of age) vs deferred (based on CD4 percentage threshold or clinical criteria in accordance with previous WHO guidelines) initiation of antiretrovirals in young infants. The study also included a third arm that used a cost analysis of children in routine care in a standard HIV clinic.

The investigators used data describing outpatient/inpatient resource use during the first 12 months of life from 411 children in the CHER trial randomised to early (n=252) or deferred (n=125) treatment, and 130 infants initiating treatment at the Empilweni Clinic in Johannesburg between 2005 and 2007.

Patient level resource data was accessed from patient files and included information on: antiretroviral drugs, laboratory tests, clinic consultations and inpatient days.

Other costs were obtained from multiple sources: the government drug depot provided drug costs; the National Health Laboratory Service the cost of tests; staff salaries, equipment and overheads were accessed from clinic/hospital accounts and inpatient days calculated on a hospital cost per- patient day equivalent. Cost data was from 2009.

The evaluation revealed that early treatment for children was cost saving.

The cost of early treatment per child for a mean time in care of 10 months was $1349 compared to $2432 for deferred treatment (mean time in care 9 months) and $2908 for routine care (mean time in care 3 months). Dr Meyer-Rath explained that the difference in time in care across the three scenarios was due to higher loss to follow up in the deferred arm and higher loss to follow up and later presentation in the routine care arm.

The differences in cost were largely due to differences in frequency of hospitalistion, which was an average of 2, 7 and 13 days and a maximum of 68, 84 and 121 days per child in the early, deferred and routine care arms respectively.

The proportion of the total cost spent on inpatient care rose from 26% in the early therapy arm to 84% in the routine care arm.

Details of the cost per child are shown in Table one.

Table one: Cost per child (2009 US dollars)

The investigators estimated that in South Africa the cost of 90% coverage early treatment for 103,000 infants in 2010/11 would be $67 million, and for 202,000 infants in 2012/13 would be $133 million. This represents 6-7% of the total cost of the national antiretroviral treatment programme and 1% of the public health service budget.

Dr Math-Reyer remarked that the cost of the paediatric programme, “will always be dwarfed by the cost of the adult programme, regardless of eligibility criteria.”

Among the limitations of the analysis she noted that the cost of screening HIV-exposed children was not included and would add about $300 per child.

Reference: Meyer-Rath G et al. The cost of early vs. deferred paediatric antiretroviral treatment in South Africa – a comparative economic analysis of the first year of the CHER trial. 18th IAS Conference, 18–23 July 2010, Vienna. Oral abstract THLBB103.
http://pag.aids2010.org/Abstracts.aspx?SID=644&AID=17823

In an oral late breaker, Ann Melvin presented data on behalf of the PENPACT 1 study (a collaboration between PENTA and PACTG/IMPAACT). This was a long-term comparison of antiretroviral naïve children initiating treatment on PI or NNRTI based regimens as well as two different viral load criteria for switching from first to second line treatment (>1000 vs 30,000 copies/mL).

This was a randomised study with a 2×2 factorial design. Children in PENPACT 1 received an initial regimen of two NRTIs plus either an NNRTI or a PI and the second randomisation compared switch to second-line at the two different viral load measurements. The primary outcome was viral load change between baseline and 4 years. The minimum follow up was 4 years.

Children were randomised between September 2002 and September 2005 and 263/266 included in the analysis. At the end of the study in August 2009, 218 (83%) children were still in follow up. The median length was 5 years (IQR 4.2-6.0 years).

At baseline, the children were a median age of 6.5 years (IQR 2.8-12.9), CD4 17% (IQR 10-25%), viral load 5.1(4.5-5.7) log10copies/mL. Only 15% had received antiretrovirals for prevention of mother to child transmission and 4% (10/239) had one or more major mutation.

Choice of antiretrovirals within the randomised arm was open label. Lopinavir/r (49%) and nelfinavir (48%) were the most common PIs and efavirenz (61%) the most common NNRTI.

At the end of follow up the majority of children (188/263, 71%) were on their first line regimen. There was no difference between PI (73%) and NNRTI (70%). The median viral load at switch was 6720 copies/mL (IQR 1,380-26,100) compared to 35,712 copies/mL (IQR 8,060-72,800), p<0.01 in the 1000 copies/mL and 30,000 copies/mL switch groups respectively. Children with the higher viral load criterion switched approximately one year later (p=0.04).

The investigators observed no significant differences in change in viral load between baseline and 4 years between children initiating treatment on a PI or NNRTI: -3.16 vs -3.31 log10 copies/mL, giving a difference of -0.15 (95% CI, 0.41-0.11), p=0.26; or children switching earlier or later: -3.26 vs -3.20, difference 0.06 (95% CI, 0.2-0.32), p=0.56.

Similar proportions of children (>70% all groups) had viral load <50 copies/mL and CD4 percentage increase of approximately 16%.

Overall, one child died at week 277 from a malignancy and there were 14 new CDC stage C events in 9 children (3 PI/1000; 3 PI/30,000; 1 NNRTI/1000; 2 NNRTI/30,000). Grade 3 or 4 adverse events occurred in 60 children (28 PI; 32 NNRTI. 30 1000; 30 30,000) of which 17 had their regimen modified.

There were a low number of children for which resistance testing could be performed but preliminary results showed more children with 3 NRTI mutations or more in the NNRTI/30,000 copies/mL group. The most frequent being the M184V.

Dr Melvin suggested that these results are reassuring for paediatric treatment scale up worldwide and, in the absence of nevirapine exposure through PMTCT, either PI or NNRTI are equally good options for first line regimens. She added that although routine viral load testing may help identify children at risk of developing NRTI resistance it is unlikely to have an impact on the acquisition of NNRTI resistance as this occurs soon after viral rebound.

comment

As Dr Melvin remarked, these data are extremely useful for paediatric treatment programmes worldwide.

Ref: Melvin A et al. PENPACT-1 (PENTA 9/PACTG 390): a randomised trial of protease inhibitor (PI) vs non-nucleoside reverse transcriptase inhibitor (NNRTI) combination antiretroviral (ART) regimens and viral load (VL) treatment switching strategies in HIV-1-infected ART-naive children age >30 days and < 18 years. 18th IAS Conference, 18–23 July 2010, Vienna. Oral abstract. THLBB104
http://pag.aids2010.org/Abstracts.aspx?SID=644&AID=17536

Provided accurate dosing is possible, tablets are usually more feasible than syrups for treating children in resource limited settings.

A substudy of the ARROW trial – an ongoing randomised paediatric trial of antiretroviral monitoring and treatment strategies conducted in Uganda and Zimbabwe – looked at the acceptability of syrup and scored tablets among children substituting syrups with tablets. The children were dosed in accordance with WHO weight band tables, which recommend substitution of liquids with tablets at around three years of age.

A poster authored by P Nahirya Ntege and colleagues showed findings from questionnaires given to the children’s carers to discover their experiences with syrups and with tablets.

A total of 1207 children, aged 3 months to 17 years, were enrolled during 2007/2008. At enrollment, 34% (406/1207) of children received the antiretrovirals in their regimen (NNRTI + two or three of zidovudine, abacavir and lamivudine) as syrups.

Just over half (236/406, 58%) of this group substituted scored tablets for syrups between May 2008 and December 2009. The first questionnaires were given at baseline (time of substitution) and follow up questionnaires eight weeks later.

The investigators found, among the 186/236 (79%) of questionnaires included in the analysis, the median age of the children at time of substitution was 2.9 years (IQR 2.4-3.4).

Over three quarters (77%) of carers reported problems with the number and weight of the bottles as they were difficult to transport. About half (53%) expected difficulties with the tablets at baseline but only 27% of carers reported problems at 8 weeks.

Most tablets were dissolved/crushed in liquid. The most frequent problems were with taste, swallowing and vomiting.

Overall 69% of carers at baseline and 93% at eight weeks reported a preference for tablets. They also reported that 24% of children at baseline and 56% at eight weeks preferred tablets to syrups.

At eight weeks none had switched back to syrups. The investigators are evaluating longer-term information after the children have received tablets for 24 weeks. They will also evaluate the affect of tablet acceptability on adherence.

comment

These data reinforce the WHO recommendation of solid formulations as the preferred regimens for children. They should also act as an incentive to manufacturers (particularly generic) to produce more innovative solid formulations including fixed dose combinations.

Liquid formulations have been a barrier to more rapid scale up and are less convenient and more costly for all involved in treating children with HIV.

Ref: Nahirya Ntege P et al. Tablets are more acceptable and give fewer problems than syrups among young HIV-infected children in resource-limited settings in the ARROW trial. 18th IAS Conference, 18–23 July 2010, Vienna. Poster abstract TUPDB206.
http://pag.aids2010.org/Abstracts.aspx?AID=13055

TMC 278 or rilpivirine is currently being evaluated for adults in a tablet formulation at a once daily dose of 25mg.

A poster at IAS2010 authored by Herta M Crauwels and colleagues showed bioavailability data from a Phase 1 trial looking at a new granule formulation intended for use in paediatric patients compared to the adult tablet formulation.

This was an open label, randomised, three way crossover trial in 12 HIV-negative adults, under both fed and fasted conditions.

Volunteers were randomised to receive:

• Treatment A: granule formulation within 10 minutes of a standardised breakfast.
• Treatment B: granule formulation after 10-hour overnight fast.
• Treatment C: Tablet formulation within 10 minutes of a standardised breakfast.

The granules were dispersed in water.

Volunteers were in six groups of two and received Treatments A, B and C in six different sequences with a washout period of at least 14 days in between.

Plasma samples from a full pharmacokinetic (PK) profile were analysed for TMC278 using a validated liquid chromatography-mass spectrometry/mass spectrometry method with a lower limit of 1.0 ng/mL.

Evaluable PK parameters were available for 11 volunteers. Comparisons were made between Treatments A and B with C (reference 1), and between A (reference 2) and B for food effects on the granule formulation.

The investigators noted that plasma concentrations were quantifiable from 30 minutes post dose for the granule formulations compared to one to two hours for the tablet formulation. However the time to achieve the maximum plasma concentrations were similar between the three treatments.

They reported increases in the PK parameters with the granule formulation under both fed and fasted conditions of 18%, 28% and 26% in Cmax, AUClast and AUCinf respectively. The granule formulation under fasted conditions achieved similar exposure to tablets taken with food.

There was a decrease of 30%, 29% and 28% in exposure for the granules taken under fasted conditions compared to with food in the Cmax, AUClast and AUCinf respectively. See Table 1.

Table1: Comparing TMC 278 granules and tablet formulations LSM (95% CI)

In a taste questionnaire 10/12 volunteers rated the granules “acceptable” or “good”. The investigators noted that all treatments were generally well tolerated and no new safety signals were observed.

They concluded that the TMC 278 granule formulation has good oral biovailability and palatability and will be developed further for use in paediatric trials.

Reference:

Crauwels HM et al. Relative bioavailability of a concept paediatric formulation of TMC278, an investigational NNRTI. 18th IAS Conference, 18–23 July 2010, Vienna. Abstract THPE0158.
http://pag.aids2010.org/Abstracts.aspx?AID=12590

This was based on results from the open label multicentre PACTG 1020A study. [2]

The study included 182 naïve and experienced paediatric patients aged 6 to 18 years old, using once daily atazanavir, with (n=141) or without (n=41) ritonavir, in combination with two NRTIs. The data from the 41 patients using ritonavir-boosting (n=16 naïve and 25) supported this new paediatric indication.

The recommended atazanavir/ritonavir doses by body weight are 150 mg/100 mg (15kg–less than 20 kg) and 200 mg/100 mg (20 kg–less than 40 kg); with children weighing over 40 kg recommended to use the standard adult dose of 300 mg/100 mg.

Source: BMS press release (07 July 2010).
http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=24756

The ARCHITECT HIV Ag/Ab Combo Assay is the first HIV diagnostic assay to be approved in the US that detects both antigen and antibodies for HIV.

The new test is also the first diagnostic test approved by FDA for use in children as young as 2 years of age, and pregnant women.

It is specific for the detection of the HIV-1 p24 antigen (the substance found on the virus that triggers the production of antibodies), as well as antibodies to HIV-1 groups M and O, and as antibodies to HIV-2.

Levels of p24 antigen increase early after initial infection, before HIV antibody is produced and extends diagnosis to earlier, acute phase (recent) infection with HIV, reducing the window period (that period after initial infection and before the detection of infection based on formation of detectable antibodies).

The median detection time was demonstrated to be 7 days earlier (range 0 to 20 days) compared to 3rd generation enzyme immunoassay antibody tests.

comment

Fourth generation tests have been widely used in Europe for many years, although a handful of clinics, still use third generation despite current guidelines.

Although these tests reduce the window period between potential exposure and the opportunity to test down to 2–3 weeks, from a public health perspective, 28 days/4weeks is now possible.

Testing guidelines still refer to a six-week window by which time p-24 which peaks before 3 weeks and disappears after 2–3 months, is already fading.

Despite the widespread use of fourth generation testing, it is difficult to understand why many clinics in the UK still routinely refer to a three-month window period. This not only prolongs the anxiety for anyone who is concerned about recent exposure, but also undoubtedly misses the opportunity to diagnose some people during early infection. Many people who are concerned enough to test early, may be less likely to test three months later once their initial anxiety has abated, especially give the sometimes difficult access to walk-in, same day and out-of-hours testing services.

The British Association for Sexual Health and HIV (BASHH) guidelines on HIV testing state: [2]

“Fourth generation tests will detect the great majority of individuals who have been infected with HIV at one month (4 weeks) after specific exposure.”

“Patients attending for HIV testing who identify a specific risk occurring more that 4 weeks previously, should not be made to wait three months (12 weeks) before HIV testing. They should be offered a 4th generation laboratory HIV test and advised that a negative result at 4 weeks post exposure is very reassuring/highly likely to exclude HIV infection. An additional HIV test should be offered to all persons at three months (12 weeks) to definitively exclude HIV infection. Patients at lower risk may opt to wait until three months to avoid the need for HIV testing twice.”

References:

1. FDA list serve announcement. (18 June 2010).
2. The British Association for Sexual Health and HIV (BASHH) statement on HIV window period (15 March 2010).
   http://www.bashh.org/guidelines

This new chapter of the Treatment Action Group’s Pipeline Report looks at antiretroviral formulations suitable for use in children. In resource-rich countries, most HIV-positive children are treated early with highly active antiretroviral therapy (HAART) employing three or more antiretroviral drugs (ARVs).

As with adults, HAART has changed the course of HIV in children dramatically, and the majority can expect to survive into adulthood.1,2 Furthermore, identifying women of unknown status in pregnancy, and appropriate care and treatment for HIV-positive mothers, has led to a sharp decline in perinatal infections. [3]

However, UNAIDS estimated in 2008 that there were 2.1 million children living with HIV; among them, 430,000 were newly infected (about 1,200 new infections per day), and 390,000 were in sub-Saharan Africa. The overwhelming majority were infected through mother-to-child transmission (MTCT). [4]

One study of nearly 3,500 children enrolled in perinatal trials in Africa estimated that, without treatment, 35% would die before their first birthday and 53% by the time they reached two years of age. By five years of age, it was deemed likely that 62–89% of these children would die. [5]

A more recent analysis, using pooled data from 12 African studies describing almost 11,000 children born to HIV-positive women, has suggested that by one year of age, an estimated 16% infected through breast-feeding and 44 % perinatally infected children would die. [6]

Unfortunately, the rollout of antiretroviral therapy (ART) to treat children with HIV has been gradual and has lagged behind that of adults. More recently, though, there has been significant progress and in 2008 almost 276,000 children received HAART worldwide, compared to 127,300 in 2006. Despite this increase, every year, new infections are nearly double the number of children who gained access to HAART in 2008.

This chapter looks at all new ARVs in the pipeline for children, with the main focus being products (often new formulations of existing medicines) suitable for use in parts of the world with the greatest and most urgent need. The emphasis is also on infants and younger children, as older children are treated with adult antiretroviral formulations.

Why not avoid paediatric HIV in the first place?

That MTCT is almost entirely preventable deserves emphasis. In more richly resourced countries, where use of ARVs in pregnancy and avoidance of breastfeeding are routine, MTCT has been reduced to 1–2%, and new paediatric HIV infections are rare.

In sharp contrast, several areas of unmet prevention, care, and treatment collide to swell the paediatric epidemic in poorly resourced settings. First, in prevention of HIV in women: in 2008, one million women were estimated to have been infected. Second, in prevention of unwanted pregnancies: an alarming proportion of pregnancies have been reported to be unwanted—51%, 74%, 84%, and 93% in studies of HIV-positive women in Cote d’Ivoire, Rwanda, South Africa, and Uganda, respectively. [7, 8, 9, 10] Third, the implementation of prevention of mother to child transmission (PMTCT)
interventions has been limited and relied on regimens with poor efficacy. And fourth, few eligible pregnant women receive HAART to treat their own HIV.

This global failure of prevention means that children continue to be infected, and that those children will need treatment with ARVs for life.

When to start children on antiretroviral therapy

Following the announcement of early results from the Children with HIV Early Antiretroviral Therapy (CHER) trial—which found that starting antiretroviral therapy (ART) before 12 weeks of age reduced early mortality by a highly significant 75% when compared to starting at CD4 cell percentages less than 25%, or starting it based on clinical symptoms—international guidelines recommended universal ART for children age one year or less. [11, 12, 13, 14]

Furthermore, new World Health Organization (WHO) guidelines recommend universal ART for children up to two years of age in recognition of the high mortality risk and less-frequent monitoring in this age group in resource-limited settings.

Data to guide when to start ART between one and five years of age are scant, and this is reflected in differences in recommendations among guidelines. After five years of age, guidance is similar to that for adults (see tables 1 and 2).

Table 1. WHO 2010 guidelines: when to start children on ART

Note:*CD4 percentage/absolute CD4 count, cells/mm3

Table 2. Guideline comparison, United States and Europe: when to start children on ART

Note:*CD4 percentage/absolute CD4 count, cells/mm3; DHHS = U.S. Department of Health and Human Services; PENTA= Paedeatric European Network for Treatment of AIDS.

Additionally, the WHO recommends that uninfected, breastfed infants born to HIV-positive women who are not receiving HAART receive antiretroviral prophylaxis to reduce the risk of MTCT during breastfeeding. [15]

Identifying children with HIV and starting them on treatment

Although the benefits of early treatment are clear, in reality, when children do start treatment it tends to be late. A literature review of 30 paediatric studies or treatment programmes has revealed that children receiving HAART ranged from infants aged two months to adolescents aged 15 years. Five of 26 studies that reported age at HAART initiation, 19 (73%) showed a mean or median age at start of treatment of greater than five years. Only two studies reported a median age at start of treatment of less than two years. [16]

In order to initiate treatment immediately, infants need to be diagnosed at the earliest opportunity. Infants with known HIV exposure—that is, born to mothers in PMTCT programmes—should be tested at four to six weeks of age using HIV virologic assays.

Any infant at a health facility presenting signs or symptoms that may be an indication for HIV should also be tested. All infants should have their HIV status established upon their first contact with the health system, preferably before six weeks of age. There needs to be an evaluation to determine where and with what symptoms, when infants present at a health facility, it is best to test them in order to identify most infections—for example, those presenting with malnutrition are very frequently HIV-infected.

If virological testing is not available, the WHO recommends presumptive diagnosis in accordance with nationally defined algorithms, and serological tests are used. (It is important to note that infants and children younger than 18 months of age will often test positive on an HIV antibody test even if they are uninfected. This is because of the passive transplacental transfer of maternal HIV antibodies to the infant. Therefore, accurate diagnoses require more expensive and complex virological tests.)

If children are identified as HIV-infected in PMTCT programmes this means they will have been infected despite maternal prophylaxis, so they are likely to have resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and a greater proportion are likely to have been infected in utero and have faster disease progression.

Preliminary results from the IMPAACT 1060 study (in which children previously exposed and unexposed to nevirapine were randomised to start treatment with either nevirapine or lopinavir/ritonavir–based regimens) were sufficiently concerning for the study’s data safety monitoring board to stop the nevirapine-exposed, nevirapine-initiating arm early. [17]

Infants with NNRTI exposure through PMTCT are usually recommended to begin treatment with a protease inhibitor–based regimen. Unexposed children or those with unknown or less recent exposure will start with an NNRTI-based regimen.

Data are needed to guide ongoing strategies for children starting treatment. Whether children initiated early on treatment can discontinue it later is unclear (and this is also an important question for adolescents who are at risk for treatment non-adherence). There are also questions about the reuse of NNRTIs in nevirapine-exposed children and whether an initial, more potent, regimen could be a useful strategy.

The NEVEREST (nevirapine resistance) studies are looking at switching children who are initiated on lopinavir/ritonavir–based regimens to nevirapine versus remaining on lopinavir/ritonavir. Early findings suggest reuse of nevirapine may be possible in some circumstances. [18]

The ARROW (Antiretroviral Research for Watoto) study is looking at an induction/maintenance strategy: whether there is an advantage to starting with a more potent combination of four drugs for 36 weeks and then maintaining treatment with three drugs, versus continual treatment with three drugs. [19]

The CHER study is continuing to follow children to look at whether after starting early they can stop treatment after one or two years.

The BANA (Botswana/Baylor Antiretroviral Assessment) II and PENTA 11 studies will determine whether children on stable therapy are disadvantaged by taking CD4-guided planned treatment interruptions. [20, 21]

What to start with?

The WHO’s and some national guidelines recommend starting with lopinavir/ritonavir for nevirapine-exposed infants and young children less than two years of age.

Unexposed children under three years should receive nevirapine, and those over three years efavirenz. All others (including nevirapine-exposed children) should receive an NNRTI (efavirenz is preferred for children receiving TB treatment unless they are less than three years of age).

Recommended nucleosides are zidovudine plus lamivudine, abacavir plus lamivudine, or stavudine plus lamivudine.

Appropriate formulations are available to facilitate all these combinations, including many generics and fixed-dose combinations (FDCs) pre-qualified by the WHO and/or with tentative approval (for use outside the U.S., particularly for PEPFAR programmes) from the U.S. Food and Drug Administration [22, 23] see Table 3).

Table 3: Antiretroviral formulations suitable for paediatric use with tentative approval from the FDA and/or pre-qualified by the WHO

Dosing

Paediatric dosing can be complicated. There are often insufficient pharmacokinetic (PK) data to determine target concentrations, and there is wide interpatient variability, particularly in very young children. In industrialized countries providers usually use a body surface area calculation to determine dosing, which is not feasible in many healthcare settings with less-experienced health workers. In order to simplify dosing, the WHO has developed weight-band tables offering a single, harmonized dosing schedule. [24]

Notably, manufacturers (particularly generic manufacturers) have produced dosing forms to use with these dosing schedules—including FDCs, such as 200mg tablets of efavirenz scored in two directions (approved) or 600mg scored once on one side and twice on the other (awaiting approval)—to enable accurate division of tablets and, in turn, dosing. Triomune Baby, an FDC from Cipla (stavudine 6 mg/lamivudine 30 mg/nevirapine 50 mg) is suitable for dosing infants down to 3kg and is dispersible in breast milk.

Formulations

Some, but not all, approved adult ARVs have paediatric formulations for children who are too young to swallow tablets; traditionally these have been liquids or syrups. These formulations are expensive (about six times more costly than solid forms), often require a cold chain, have a short shelf life, and are not easy to store or transport. Cost and logistical barriers have prohibited their widespread use. Besides transport to and storage at the dispensary, the following example illustrates the lack of practicality for the caregiver:

A 10 kg child being treated with standard doses of stavudine, lamivudine, and nevirapine, for whom a 3-month supply of drugs is dispensed at a clinic visit, would require 18 bottles of liquid weighing almost half as much as the child (4.3kg). For a rural family who may have walked a long distance to reach the clinical centre, this is a significant issue. [25]

For manufacturers, development of liquid formulations is not always as simple as it sounds. Development of a liquid formulation of efavirenz has been besieged by set-backs for years. Efavirenz has potential for oral mucosa irritation; it also has poor aqueous solubility. Early development focused on palatable alternatives to the aqueous suspensions using oily vehicles that were known to mask irritation. The original oral solution, a suspended sugar solution, was found to have a low level of bacterial contamination; the culprit was confectioner’s sugar. A heating step was then incorporated into the process to destroy the bacteria, but this then led to clumping. The current formulation is a sugar-free strawberry mint flavor 30mg/mL solution. It does not provide sufficient drug exposure for children less than three years of age.

It was not possible to formulate tenofovir as a liquid; this formulation would have required huge volume and tasted very nasty. The paediatric formulation will now be a powder of coated granules, which will mask the taste (although anecdotally it may still be fairly unpalatable) but the powder does not dissolve. Nor was it possible for etravirine, which will be a dispersible mini-pill, or atazanavir, which will be a powder.

The extremely unpleasant taste is not uncommon, and taste has been documented as a factor in treatment failure. Conversely, masking taste and developing palatable flavors for children can also be a barrier to creating a successful oral solution.

More recently, manufacturers (notably generic manufacturers) have developed more useful ARV formulations such as crushable mini-pills, scored tablets, dispersible formulations, “sprinkles” and FDCs that can be used by very young children. This has been a very important aspect of paediatric drug development in recent years, and along with the simplified dosing tables has overcome two significant barriers to widespread paediatric treatment (see Table 4).

Table 4: Desirable qualities

An ARROW substudy looked at the acceptability of tablets and syrups (NNRTI plus two of zidovudine, abacavir, and lamivudine). The children in this substudy received syrups on enrollment and switched to crushable tablets. Eight weeks after switching, 93% of caregivers and 56% of their children (median age at switch, 2.9 years) preferred tablets. [26]

Protease inhibitors, however, have poor bioequivalence with crushed tablets. In a recent study, investigators observed significantly lower exposure with crushed lopinavir/ritonavir compared to the reference product. [27] For young nevirapine-exposed children, lopinavir/ritonavir “sprinkles” are currently being studied in the Children with HIV in Africa—Pharmacokinetics and Acceptability of Simple Antiretroviral Regimens trials. [28]

These trials have looked at or are looking at simplifying antiretroviral regimens—for example, toxicity and adherence/acceptability profiles of new paediatric FDCs that contain abacavir or zidovudine rather than stavudine, and simplification strategies such as once-daily regimens and whether it is necessary to dose-escalate nevirapine. The trials use WHO weight-band tables.

Approval of paediatric formulations

There are now considerable incentives and/or penalties from regulatory agencies to ensure that any new drug that may be of benefit to children must be studied in children.

This is mandatory on the part of both the FDA, which also extends six-month patent protection to companies that perform requested paediatric studies (voluntary), and the European Medicines Agency (EMA), which enforces penalties for companies that do not provide a paediatric investigational plan as part of their application (or request a waiver). [29]

Companies must include PK data for all age groups of children, efficacy, tolerability, and differences in side effects. They must have stability and palatability data for formulations and demonstrate that they are able to achieve PK targets associated with efficacy in adults.

Most paediatric development programmes take a staggered approach, starting with the older cohorts of children and working down in age. The studies are conducted in children as soon as there are sufficient data from studies in adults.

Applications for generic formulations must demonstrate bioequivalence. A single product needs to be compared to the reference product (innovator). Generic FDCs need to be compared to the individual reference drugs taken together. Preferred bioequivalence studies are randomised, single-dose, two-way crossover studies. Bioequivalence studies need not be done in children.

Dissolution testing is required when evaluating solid or suspension formulations to assure reproducible drug release.

The innovator pipeline

Nucleotide reverse transcriptase inhibitors

Gilead’s tenofovir disoproxil fumarate is one of the most widely used antiretroviral drugs in adults. Development of a paediatric formulation has been slow, and there have been concerns about loss of bone mineral density in children. There has been considerable off-label use with adult tablets in drug-experienced children; the FDA recently gave a new indication for children and adolescents from 12 to 18 years of age. Gilead plans to file the oral powder formulation with regulatory agencies in the second half of 2010.

Protease inhibitors

Atazanavir is approved for children over six years of age in capsule formulation. Trials of atazanavir powder are ongoing for younger age groups, with and without ritonavir boosting, within the Bristol-Myers Squibb–supported PACTG 1020 programme.

The darunavir oral suspension, boosted with a ritonavir solution, is currently in phase II studies in treatment-experienced children ages three to six, twice daily; there is a waiver for children under three years of age. Tibotec’s darunavir is approved for children over six years, and there is a 75mg tablet.

Nonnucleoside reverse transcriptase inhibitors

Tibotec’s etravirine is in the phase II safety and efficacy stage of its paediatric development programme using 25mg mini-pills.

Rilpivirine (TMC 278), also manufactured by Tibotec, is beginning pediatric trials with an oral granule formulation following bioavailability and palatability trials in healthy adult volunteers of three concept formulations.

Integrase inhibitors

Merck’s raltegravir has two paediatric formulations, a chewable tablet for children under 12 years old, and granules for children less than two years old. They are being studied in the IMPAACT P1066 study.

Plans for elvitegravir from Gilead include both liquid and solid age-appropriate dosage forms for children. Gilead will also attempt, if the doses of all four drugs are similarly scalable with age/body weight, to make a coformulated quad pill (an FDC with elvitegravir, cobicistat, tenofovir, and emtricitabine) for children able to swallow tablets.

Pharmacokinetic enhancers

Gilead’s cobicistat (GS-9350) is a heat stable boosting agent that will also be produced as a stand-alone to boost other antiretrovirals as an alternative to ritonavir. Gilead plans to make it available in both age-appropriate liquid and solid forms for children. It is hoped that cobicistat will offer an alternative to ritonavir, which is only
available as 100mg or as an unpleasant-tasting liquid.

CCR5 receptor antagonists

Pfizer’s maraviroc is currently being evaluated in children 2–18 years of age infected with CCR5-tropic HIV-1. As with adults, this drug is expected to have less clinical utility than other ARVs in children, as it requires an expensive CCR5 tropism assay.

Table 5: The innovator paediatric pipeline

Generic pipeline/wish list

Many of the new paediatric formulations will not be available for some time; moreover, some of them may be too expensive or complicated to use in resource-limited settings. WHO and national guidance in resource-limited settings (for both adults and children) is weak beyond second-line therapy. Table 6 lists formulations, either known to be in development by generic companies or will be needed, that will work with dosing according to WHO weight band tables.

Table 6: Paediatric formulations needed

Adapted from World Health Organization 2010 Paediatric guidelines Annex E.

References

All web references were retrieved on 24 June 2010.

1. McConnell MS et al. Trends in antiretroviral therapy use and survival rates for a large cohort of HIV-infected children and adolescents in the United States, 1989–2001. J Acquir Immune Defic Syndr. 2005;38:488–94.
2. Gibb DM et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. BMJ 2003;327:1019 (1 November), doi:10.1136/bmj.327.7422.1019 Published correction appears in BMJ 2004;328(7441):686].
3. Townsend C et al. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000–2006. AIDS 2008;22(8):973–81.
4. UNAIDS. Report on the global AIDS epidemic. Geneva, Switzerland: UNAIDS, 2008.
5. Newell ML et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: A pooled analysis. Lancet 2004;364:1236–43.
6. Becquet R and UNAIDS Child Survival Working Group. Survival of children HIV-infected perinatally or through breastfeeding: A pooled analysis of individual data from Sub-Saharan Africa. CROI, Abstract 840.
7. Degrees-du-Lou A et al. Contraceptive use, protected sexual intercourse and incidence of pregnancies among African HIV-infected women: DITRAME ANRS 049 Project, Abidjan 1995–2000. Int J STD AIDS 2002;13:462–68.
8. Bangendanye L. Pregnancy, pregnancy desires, and contraceptive use among HIV-infected women. Paper presented at the Third Rwandan Paediatric Conference on Children Affected by HIV and AIDS, Kigali, Rwanda, 2–4 December 2007.
9. Rochat TJ et al. Depression Among Pregnant Rural South African Women Undergoing HIV Testing. JAMA March 22/29 2006. Vol 295, no 12.
10. Hornsy J et al. Reproductive intentions and outcomes among women on antiretroviral therapy in rural Uganda: A prospective cohort study. PloS One 2009.; 10.1371/journal.pone.0004149
11. Violari A et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008;359: 2233–44.
12. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Executive summary of recommendations. Preliminary version for programme planning. Geneva, Switzerland: World Health Organization, 2010.
13. U.S. Department of Health and Human Services. DHSS guidelines for the use of antiretroviral agents in pediatric HIV infection. Washington, D.C: U.S. Department of Health and Human Services, 2009.
14. Pediatric European Network for Treatment of AIDS. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med. 2009;10(10):591–613.
15. World Health Organization. Rapid advice: Infant feeding in the context of HIV. Geneva, Switzerland: World Health Organization, 2009.
16. Sutcliffe CG et al. Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa. Lancet Infect Dis. 2008;8:477–89.
17. Violari A et al. Nevirapine vs. lopinavir-ritonavir-based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)- exposed HIV infected infants: Preliminary results from the IMPAACT P1060 trial. (Abstract O_08.) Paper presented at the conference HIV Pediatrics, 17–18 July 2009, Cape Town, South Africa.
18. Coovadia A et al. Randomized clinical trial of switching to NVP-based therapy for infected children exposed to nevirapine prophylaxis. (Abstract O_09.) Paper presented at the conference HIV Pediatrics, 17–18 July 2009, Cape Town, South Africa.
19. Antiretroviral Research for Watoto website.
    http://www.arrowtrial.org/.
20. Baylor International Pediatric AIDS Initiative. BANA II Clinical Trial.
    http://bayloraids.org/africa/banaii.shtml.
21. Plasma drug concentrations and virologic evaluations after stopping treatment with non-nucleoside reverse-transcriptase inhibitors in HIV-1 infected children. Clin Infect Dis. 2008;46(10):1601–8.
22. World Health Organization. Prequalification Programme.
    http://mednet3.who.int/prequal/.
23. U.S. Food and Drug Administration. President’s Emergency Plan for AIDS Relief: Approved and tentatively approved antiretrovirals in association with the President’s Emergency Plan.
    http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm.
24. World Health Organization. WHO generic tool for assessing paediatric ARV dosing (2010).
    http://www.who.int/hiv/paediatric/generictool/en/index.html.
25. Committee on Pediatric AIDS, Section on International Child Health. Increasing antiretroviral drug access for children with HIV infection. Pediatrics 2007;119(40).
    http://aappolicy.aappublications.org/cgi/content/full/pediatrics;119/4/838 .
26. Nahirya Ntege P et al. Tablets are more acceptable and give fewer problems than syrups among young HIV-infected children in resource-limited settings in the ARROW trial. XVIII International AIDS Conference. July 18-23 2010. Vienna, Austria. Abstract TUPDB206.
27. Diep H et al. Pharmacokinetics of lopinavir/ritonavir crushed vs whole tablets in children. 17th CROI, 16-19 February 2010, San Francisco.  Poster abstract 877.
28. FDA, Department of Health and Human Services, Pediatric Drug Developent.
    http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm
29. European Medicines Association, Medicine for Children.
    http://www.ema.europa.eu/htms/human/paediatrics/regulation.htm
30. U.S. Food and Drug Administration. Pediatric drug development.
    http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm.

There is little research and information reported on young women growing up with HIV. But a study at the meeting showed some interesting data on the pregnancy outcomes of young women who were born with HIV 10–20 years ago. The study looked at a cohort of 172 women, born with HIV and accessing services in 19 centres across the UK and Ireland.

Overall, there were 36 pregnancies reported in 27 women, with a median age of 18 years at first pregnancy. Of these, 27 (75%) were unplanned, 7 (19%) were planned and 2 were unknown. The women all conceived before September 2009. Seventeen women were on HAART, with a median CD4 count of 244 cells/mm3, but 8 out of the10 women who were not on treatment had CD4 counts below 200 cells/mm3.

Of the reported pregnancies, 86% (31/36) were with regular partners, of whom 22 (61%) reported being unaware of their partners HIV status. The pregnancies resulted in 5 (14%) 1st trimester miscarriages, 9 (25%) elective terminations, 18 (50%) live births and 4 (11%) pregnancies were ongoing.

At the time of delivery, 89% of the mothers were on HAART, with a median CD4 count of 254 cells/mm3 and a median viral load of 79 copies/mL (range <50–580,000). Seven women delivered with viral load <50 copies/mL, four had VL >1,000 copies/mL. Two women were admitted for Directly Observed Therapy and two were non-adherent to HAART at delivery. Mode of delivery was 9 elective and 5 emergency C-sections with 4 vaginal deliveries. 6 (33%) infants delivered at <37/40, five of whom required Neonatal Intensive Care. None of the babies were infected and there were no congenital anomalies were reported. Five of the babies were fostered and 3 have ongoing concerns.

The study showed without a doubt, that prevention of mother to child transmission worked, even though some mothers had advanced HIV and were not well adherent. Additionally, the study also highlighted a worrying high number of unplanned pregnancies, a population with social needs despite access to contraceptive services.

Ref: Williams B et al.  Pregnancy outcomes in women growing up with HIV acquired perinatally or in early childhood. 2nd Joint Conference of BHIVA with BASHH, 20–23 April 2010, Manchester. Poster abstract P144.

http://www.aegis.org/conferences/BHIVA/2010/16BHIVA-2010.pdf

Although the interpretation of the role HIV and vitamin D deficiency remains a focus in HIV-positive populations in relation to reductions in bone mineral density in adults, the impact on children is potentially more worrying.  If HIV-related complications prevent optimum bone development earlier in life (generally until the age of 30), this could result in higher rates of bone complication in later in life.

Atkinson and colleagues presented results of such low vitamin D levels in HIV-positive children that suggest further research should be an urgent priority.

An audit of plasma bone biochemistry, 25(OH) vitamin D and PTH levels in a cohort of 131 HIV-positive children receiving routine clinical care at a single UK centre between January and December 2009.  Median age was 12 years (IQR 9, 15); 51% were female and 85% were African/Caribbean. Median CD4 count (%) was 760 (32%) and 104 children (79%) were on HAART.

64 children (49%) were deficient (defined as 25nmol/L) and a further 37 (28%) had insufficient levels (25-50nmol/L). Abnormal PTH (>6.8 pmol/L) was seen in 15/52 children who had these levels (28.9%).

In multivariate analysis 25(OH) vitamin D deficiency was associated with older age (p=0.001), African/Caribbean ethnicity (p=0.04), winter season (0.008) and NNRTI use (P=0.01).

The authors concluded that Vitamin D deficiency and insufficiency is very common in children with HIV. Maximising bone health is increasingly important as this population enter adult life and the role of vitamin D supplementation requires further elucidation.

Ref: Atkinson S et al. Vitamin D deficiency in children with perinatally acquired HIV-1 infection living in the UK. 2nd Joint Conference of BHIVA with BASHH, 20–23 April 2010, Manchester. Poster abstract P159.

http://www.aegis.org/conferences/BHIVA/2010/16BHIVA-2010.pdf

There are limited paediatric antiretroviral options. Despite manufacture labelling, crushing and/or  dissolving tablets, against recommendations, has been reported. Two studies, presented as posters at CROI 2010, looked at bioequivalence of crushed and dissolved Atripla and crushed lopinavir/ritonavir (LPV/r) tablets, compared to whole tablets, in healthy volunteers and HIV-positive children respectively.

Neither strategy met FDA bioequivalence criteria (predefined as, 90%CI 0.8 to 1.25).

Atripla is a fixed dose combination (FDC) tablet combining efavirenz (EFV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF).

Use of this FDC is limited to patients who can swallow tablets, since there is no liquid formulation currently on the market.

Jennifer King and colleagues from the University of Alabama looked at the bioequivalence of the FDC tablet and a compounded liquid formulation made from the crushed tablet, dissolved in 5 mL of water and diluted with 20 mL of Ora-Sweet oral vehicle.

This was a randomised, single dose, open label, crossover study in 14 healthy volunteers.

Subjects received single doses of both formulations on an empty stomach separated by a 14-day washout period. Samples were taken pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.

The area under the concentration-time curve (AUC-inf) and maximum concentration (Cmax) of TDF, FTC and EFV were determined using noncompartmental methods. Geometric mean ratio (GMR) of liquid to tablet Cmax, AUC-inf, and 90% confidence intervals (CI) were calculated to determine bioequivalence

The mean ± standard deviation age and weight for the subjects were 33.3 ± 10.9 years and 85.7 ± 18.4 kg, respectively.

The bioequivalence geometric means (percent coefficient of variation) and 90% CI for each drug are shown in Table 1.

Table 1: Bioequivalence, geometric mean ratios for EFV, FTC and TDF liquid and tablet formulations (n=14)

The investigators found only the 90%CI for FTC Cmax and AUC fell within the range to meet bioequivalence in this study.

The 90% CI for EFV Cmax was below the range for bioequivalence and AUC above. TDF Cmax and AUC were approximately 40% and 20% higher with the liquid formulation.

The authors suggested careful consideration before crushing Atripla tablets to construct a compounded oral solution.

A related poster authored by Huy Diep and colleagues from the University of California and Children’s National Medical Center, Washington DC,showed data from a PK study to determine the impact of crushing LPV/r on drug exposure in paediatric patients.

LPV/r is recommended for treating HIV-positive children. Although there is an oral formulation, it tastes unpleasant, contains 42% alcohol, needs to be refrigerated and must be taken with food.

The newer film coated tablet formulation of LPV/r does not require refrigeration and has no food restrictions. Although the manufacturer’s instructions state that tablets should not be crushed or chewed, routine use of crushed tablets has been reported.

This was a randomised, open-label, cross over study of 12 patients (13 were enrolled but one child refused to take the crushed dose), age 10-16, already taking LPV/r for at least two weeks.

Two separate 12 hour PK sampling following observed doses of LPV/r 400/100mg either whole or crushed tablets were performed. Samples were taken at 0, 1, 2, 4, 6, 8 and 12 hours. Plasma concentrations of LPV and RTV were measured by HPLC and used to calculate non-compartmental area under the curve (AUC) and clearance (CL/F). Median PK values were compared, using the Wilcox signed rank test. Table 1 shows ratios of crushed to whole tablets.

Table 2: Ratios (90% CI) of crushed to whole tablets

The investigators reported significantly lower exposure after crushed than whole tablets; approximately 40% decreased oral absorption for LPV and RTV. They noted high interpatient variability, eg crushed/whole LPV AUC ratio range: 5-75%.

The extent and variability of reduced exposure after multiple crushed doses at steady state in HIV-positive children remains unpredictable. The investigators concluded that these data reinforce the need to discourage this dosing practice.

comment

Besides emphasising the importance of following the manufacturer’s instructions, these data once again highlight the need for appropriate paediatric formulations.

The development of a liquid formulation of efavirenz has been problematic, but the originator company are continuing with the programme and it is hoped that we will have one soon.

For lopinavir/r, as recommended, dividing tablets clearly is not a good option. Cipla are developing sprinkles using melt extrusion technology to make tiny beads. Bioequivalence studies are underway and this formulation will offer a very useful option to the lopinavir/r liquid.

References

1. King J et al. Assessment of Bioequivalence of Tenofovir, Emtricitabine, and Efavirenz Fixed-dose Combination Tablet Compared with a Compounded Oral Liquid Formulation Derived from the Tablet. 17th CROI, 16-19 February 2010, San Francisco.  Poster abstract 605.

http://www.retroconference.org/2010/Abstracts/37400.htm

2.   Diep H et al. Pharmacokinetics of lopinavir/ritonavir crushed vs whole tablets in children. 17th CROI, 16-19 February 2010, San Francisco.  Poster abstract 877.

http://www.retroconference.org/2010/Abstracts/37445.htm

The raltegravir paediatric programme is ongoing in collaboration with IMPAACT (P1006). Children and adolescents age 2-18 who have failed at least one previous regimen, with viral load >1000 copies/mL are eligible. Age strata are accrued sequentially with the oldest group first.

Acceptable pharmacokinetics (PK), safety and short term efficacy has been reported for 6-11 and 12-18 year olds receiving the adult formulation. (poster 873)

In an oral presentation, Sharon Nachman presented initial PK, 12-week efficacy and safety data (as of January 4 2010) for children age 6-11 receiving a new chewable raltegravir tablet.

In this study, raltegravir was added to the children’s existing antiretroviral regimen. Intensive PK sampling was performed between days 5-12 and then background therapy was optimised.

This was an AUC targeted design for the chewable formulation based on adult data. PK parameters and variability were compared to the adult formulation in children of the same age range.

There were 10 children in this cohort, of which 50% were male, 60% white and 30% black. They were a median of 8.5 years old and 33 kg in weight. Their median absolute CD4, CD4% and viral load were 456 cells/mm3, 22.5% and 4.2 log respectively. The median follow up was 19 weeks.

Initially the dose studied was 8 mg/kg (n = 4). This was reduced to 6 mg/kg because of the high AUC12 with maximum dose of 300 mg.  All dosing was twice daily.

The actual geometric mean (GM) chewable formulation dose was 223 mg (vs 400 mg adult formulation).

At 6 mg/kg, GM AUC12 was 22.6 (range 12.8- 40.6) Mxh (n = 10). GM raltegravir trough (C12h) and peak (Cmax) concentrations were 128 (range 62-397) nM and 10.5 (4-23) uM, respectively.

Raltegravir oral clearance (CL/F) was 21 L/hr for chewable vs 49.6 L/hr for adult formulations. Overall PK variability (%CV) was less for chewable vs adult formulations (AUC12 34 vs 120%; Cmax, 53 vs 130%; C12h 84 vs 221%).

There was one grade 3 adverse event: possibly related (elevated fasting LDL). There were no grade 4 events and no treatment discontinuations. At Week 12, 7/10 children (70%, 95%CI 35% to 93%) had viral load <400 copies/mL (3/7 initially received 8 mg/kg).

The investigators concluded that the raltegravir chewable tablet had less PK variability and lower oral clearance compared to the adult tablet. The differences in clearance are likely to be due to greater relative bioavailability of the chewable tablet.

Study of raltegravir in children age 6-11 will continue with a dose of 6mg/kg (maximum 300mg) of the chewable tablet.

Ref: Nachman S et al. Interim results from IMPAACT P1066: raltegravir oral chewable tablet formulation in children 6 to 11 Years. 17th CROI, 16-19 February 2010, San Francisco. Oral abstract 161LB.

http://www.retroconference.org/2010/Abstracts/39677.htm

Efavirenz (EFV) is used widely in children over 3 years old throughout the world.  To date there is limited information about the steady state pharmacokinetics (PK) of EFV in African children.

A poster from Sabrina Bakeera-Kitaka and colleagues from the ARROW trial showed results from an investigation conducted to determine whether WHO recommended weight band dosing results in optimal EFV exposure in Ugandan children aged 3-12 years.

In this substudy, 41 HIV-positive children receiving generic EFV plus lamivudine (3TC) and abacavir (ABC) were enrolled in a crossover, PK study of twice vs once daily 3TC+ABC. This was conducted 36 weeks after the children started HAART in ARROW.

Children were dosed in accordance with WHO weight bands: 200/250/300*/350*mg for those weighing 10–15, 15–20, 20–25, and 25–30 kg respectively, using EFV capsules or *halved 600 mg tablets. Intensive sampling was performed at t=0, 1, 2, 4, 6, 8, and 12 hours post observed dose on twice-daily HAART at steady state and repeated 4 weeks later including a further 24 hour sample.

The investigators estimated EFV AUC0-24 and clearance (CL/kg) using WinNonlin, and predictors of log10AUC and CL were accessed using multivariate mixed models.

Of the children enrolled, 39 and 37 children had evaluable EFV profiles at the first and second PK sampling respectively.

The children were 41% (16/39) boys, 18 (46%) were aged 3–6 years and 21 (54%) 7–12 years. There were 5, 16, 15, and 3 children in the 10–15, 15–20, 20–25 and 25–30 kg weight-bands, respectively.

The investigators reported geometric mean (%CV) AUC0-24 of 50.4 (91.7%) and 54.0 (80.8%) h.mg/L at the first and second sampling respectively. They found no significant variation across weight-bands (p=0.51).

They noted a large inter- and intra-patient variability in EFV PK parameters (eg 81% and 28% for AUC0-24). They found 15% (6/39) children at the first sampling, and 7/37 at the second (7 children in total) had subtherapeutic C8hr and C12hr levels (<1.0mg/L); 38% (14/37) had therapeutic C24hr levels at the second sampling. They also found 23% (9/39) and 27% (10/37) children in the first and second sampling respectably (11 children in total) with a toxic C8hr and/or C12hr level (>4.0mg/L).

The investigators identified three groups of children using normal mixture modeling:  40% with geometric mean AUC0-24 27.2 h.mg/L, 32% with 49.9 h.mg/L and 28% with 137 h.mg/L. They suggested that genetic polymorphisms might play a role.

Mean clearance overall was 6.8 (SD 3.9) and 6.2 (3.7) L/h at the first and second sampling respectively (p =0.04). C/F increased by 0.50L/h for every year older (p=0.05), but was independent of weight (p=0.85), weight-for-age (p=0.52) or height-for-age (p=0.80).

Overall they found lower exposure than that previously reported in the tablets.

The ARROW group, are conducting ongoing investigations into the relationship between efavirenz concentrations and toxicity. The children’s viral loads will also be tested retrospectively. They wrote: “Increasing the EFV dose for children should be investigated, and has been proposed by WHO. However higher proportions of children with toxic levels might be expected.”

Ref: Natukunda E et al. Pharmacokinetics of efavirenz dosed according to the WHO weight-bands in children in Uganda. 17th CROI, 16-19 February 2010, San Francisco. Poster abstract 878.

http://www.retroconference.org/2010/Abstracts/37642.htm

Avy Violari and colleagues from the CHER trial showed data describing response in young infants after early HAART initiation in South Africa.

Largely because of this trial, current guidelines recommend early treatment in HIV-infected infants and, where possible, infants exposed to nevirapine in prevention of mother to child transmission (PMTCT) should receive lopinavir/ritonavir (LPV/r) first line. There are few data describing virological outcomes in African infants.

In CHER, infants aged 6-12 weeks with CD4% >25% (n = 411) and CD4 <25% (n=40) started LPV/r, zidovudine (AZT), lamivudine (3TC) either immediately or when clinically or immunologically indicated.

In this analysis, the investigators defined virological response as viral load <400 copies/mL and immunological response as CD4% increase >10% from pre-treatment level, at 24 and 40 (or 48 if missing at 40) weeks after starting HAART. Using logistic regression, the investigators examined the association between age at baseline, CD4%, absolute CD4, viral load, weight for age z-score, TB and gender with virological and immunological response. By the end April 2009, 387/451 children had started HAART and had data for >1 outcome.

At baseline, the children were a median: age of 8.4 (IQR 7.1–11.4) weeks; weight-for-age z-score -0.8 (-1.6–0.0); CD4% 32% (24-38%). Over half (59%) had a viral load >750,000 copies/mL. The majority (79%) started HAART by 12 weeks.

At 24 weeks, 71% (95% CI, 65–75%, 246/349) of children had a viral load <400 copies/mL; 77% (245/320) at 40/48 weeks. Assuming loss to follow up as failure, these proportions were 65% and 68% at 24 and 40/48 weeks, respectively.

The investigators found no association between virological response and age at initiation (OR at 24 weeks 1.04 per 4 weeks increase, 95%CI 0.95–1.14, p=0.39), CD4%, weight-for-age z-score, viral load or gender.

Only 5/15 (33%) children with active TB (diagnosed before or within 1 month after initiation) receiving concurrent TB treatment were <400 copies/mL at 24 weeks vs 241/334 (72%) of the remaining children (RR 0.47, 95%CI 0.23–0.96, p=0.04).

Median change in CD4% from baseline was similar at 24 weeks (7%, IQR 1–13%) and 40/48 weeks (7%, 1% -13%). CD4% increase >10% occurred in 33% and 32% at 24 and 40/48 weeks respectively.

CD4% increase >10% was more likely with lower CD4% at initiation. The investigators noted this was the only predictor of immunological response at both time-points.

The investigators concluded: “Virological response was satisfactory in this large cohort of infants initiating lopinavir-based ART in South Africa, and similar to rates reported in infants from well-resourced settings”

They plan to look at suppression in relation to adherence in this trial and resistance in children with detectable viral load.

Ref: Violari A et al. Virological and Immunological Responses in Infants Receiving a LPV/r-based Regimen. 17th CROI, 16-19 February 2010, San Francisco. Poster abstract 843.

http://www.retroconference.org/2010/Abstracts/39129.htm

Katherine Boyd and colleagues from the Collaborative HIV Paediatric Study (CHIPS) and the UK HIV Drug Resistance Database looked at the prevalence of duranavir associated mutations in children.

As duranavir boosted by ritonavir (DRV/r) has the potential for first or second line PI use in the UK, Identifying the prevalence of resistance associated mutations (RAM) in children is important for determining the clinical utility of this drug.

In this study, data from CHIPS (a cohort of approximately 95% of reported HIV-positive children in UK/Ireland since 1996) and the UK drug resistance database from 2000–2007 were combined.

The investigators identified DRV RAM from the 2008 IAS mutations list (V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V) and the Stanford database (I47A, G73S/T/C, I84A/C, V82F).

The prevalence of RAM was estimated in both PI and PI-naïve children. Using multivariate linear regression, the investigators examined the time on a PI, the area under the viraemia curve, and the type of PI. They used the Stanford database algorithm to assess the children’s resistance to DRV/r.

Of 344 children tested when they were PI-naïve, 14 (3%) had a single RAM (2 V11I, 2 V32I, 1 I47A, 7 I50V, 1 G73S, 1 L89V). No child had more than one RAM. Of 156 PI-experienced children tested while receiving a PI, 21(13%) had one RAM, 5 (3%) had 2, and 3 (2%) had 3: 55 (35%) children received prior LPV/r only, median (IQR) 2.6 (1.2 to 5.0) years on PI.

In multivariate analysis, there were significant associations between greater number of DRV/r RAM and longer time on a PI (RR 1.14, p=0.04 +1 year), larger area under the viraemia curve since the start of PI (RR 1.78, p=0.01), and previous use of a PI other than LPV/r (RR 6.15, p=0.02 vs LPV/r only).

The investigators noted, only 3 (2%) PI-experienced children had intermediate level resistance to DRV/r using Stanford. They concluded that these results suggest that DRV/r is useful both a first PI and an alternative second PI as prevalence resistance is low.

Ref: Boyd K et al. Prevalence of Darunavir-associated Mutations in PI-naive and PI-experienced HIV-1-infected Children in the UK. 17th CROI, 16-19 February 2010, San Francisco. Poster abstract 851.

http://www.retroconference.org/2010/Abstracts/38696.htm

Several posters at CROI 2010 showed findings from studies looking at outcomes in infants exposed to maternal antiretrovirals in utero.

Tenofovir exposure in DART

Enniie Chidziva and colleagues from the DART trial evaluated infants born to women mainly receiving tenofovir (TDF) based HAART in Uganda and Zimbabwe from 2004 to 2009. [1]

We have reported earlier results from the DART trial and pregnancy outcomes in previous issues of HTB. [2, 3]

During DART there were 223 live births with 6 infant deaths; 217 infants were alive two weeks after birth. Of these 129 (59%) were exposed to TDF in utero. Infants were evaluated in DART and in a separate follow up study.

The investigators reported that congenital abnormalities occurred in 7/217 (3%) of infants overall and 4/129 (3%) with TDF exposure. The abnormalities were: talipes 3 (2 with TDF exposure), cardiac 1, hydrocephalus 1(with TDF exposure), skin tag 1 (with TDF exposure) and undescended testes 1.

The majority 182/217 (84%) of infants were enrolled in the infant follow up study.  At their last visit they were a median age of 26 months (IQR 13–39); 69% were <12 months of age. The investigators noted that infants who were not enrolled in the follow up study were likely to have been born during the earlier part of the trial.

Prophylaxis was given to 152/182 (84%) of infants  (single-dose nevirapine 44%, AZT 18%, sd NVP+AZT 23%, other 15%)

Of the 182 infants, 73 were ever breastfed for median 92 days (range 5-1186 days). Unadjusted HR for currently BF vs never BF 0.45 (95% CI 0.05–3.62) and for stopped vs never BF 0.7 (95% CI 0.19–2.57, p=0.59).

Of the 171 children tested, all were HIV-negative, 3 were lost to follow up and 8 died before testing. Fourteen children died at a median age of 9.4 months, giving 6% 12-month mortality. Of these, 8 had in utero TDF exposure, 6 were HIV-negative and 8 untested.

Only 4/386 creatinine and 7/310 phosphate measurements were abnormal, all were grade 1 and confined to 7 children of which 4 were exposed to TDF in utero (3 throughout pregnancy and one 61% of time in utero). There was no evidence of an effect of TDF in utero on growth after 48 weeks (p=0.31) and there were no bone fractures.

Additionally, an Italian cohort study reported by Alessandra Vigano and colleagues showed that exposure to TDF during the second and third trimesters of gestation, when bone formation occurs, does not impair bone mass and bone metabolism in HIV-negative children born to HIV-positive women. [2]

Mashi and Mma Bana

Two studies with data combined from the Mashi and Mma Bana PMTCT trials in Botswana looked at infant anaemia and birthweight respectively. [5, 6]

We have reported on both trials in previous issues of HTB. [7, 8, 9, 10, 11]

Scott Dryden-Peterson and colleagues compared the incidence of severe and life-threatening (grade 3 or 4, DAIDS 2004 toxicity tables) anaemia in breastfed (BF) infants exposed to HAART in utero with BF and formula fed (FF) infants exposed to AZT in utero in these trials.

Endpoints were incidence of first severe anaemia from birth to 7 months and the analyses used scheduled measurements of first born uninfected infants.

A total of 1788 infants met the inclusion criteria (1096 Mashi, 692 Mma Bana). Of this group, 743 were exposed to maternal HAART (AZT+3TC+LPV/r or AZT+3TC+NVP), one month of post natal AZT and BF (categorised as HAART+BF; 517 to in utero AZT, 6 months of post-natal AZT, and breastfeeding (AZT+BF); and 528 infants to in utero AZT, 1 month of post-natal AZT, and formula feeding (AZT+FF).

The investigators reported there were 126 infants with severe anaemia by 7 months with a cumulative incidence of 12.6 % (n=89) in HAART+BF, 5.4 % (n=26) in AZT+BF, and 2.3 % (n=110 in AZT+FF.

Severe anaemia occurred more frequently among HAART+BF infants than either AZT+BF infants (OR 2.51, 95% CI 1.59-3.95), or AZT+FF infants (OR 6.11, 95% CI 3.2-11.6), both p<0.0001.

In multivariate analysis, predictors of severe anaemia (AOR; 95%CI) were:  HAART+BF (2.4; 95%CI 1.5–3.8 and 5.7; 95%CI 3.0–10.7) compared to AZT+BF and AZT+FF, respectively; low birth weight <2.5 kg (2.4; 95%CI 1.5–3.9); and male sex (1.5; 95%CI 1.0–2.2). Maternal CD4, VL, haemaglobin, education, income, study site and gestation at delivery were not significantly associated with severe anaemia.

Birthweight <2.5kg occurred in 103 (13.97%), 43 (8.4%) and 31 (5.9%) of infants in the HAART+BF, AZT+BF and AZT+FF groups respectively.

The investigators reported no differences in infant anaemia according to maternal HAART regimen. Microcytosis or hypochromia occurred in 39/89 (43.8%) infants in the HAART+BF group, with severe anaemia.

Patients with severe anaemia were treated with iron/multivitamin supplementation, and 10 infants (7.9%) received transfusions. Of those who improved to grade <3 with iron/multivitamin supplementation alone this occured in <30 days in 43 (34%), 31–90 days in 50 (39.7%) and >90 days in 18 (14.3%) infants. Three (2.4) infants died while grade 3–4 and 2 (1.6) were lost to follow up.

The investigators concluded: “The clinical implication of this finding requires further investigation to ensure that the established benefits of using HAART for MTCT prevention are maximised for all infants.”

The same research group looked at the impact of HAART and short course AZT on longitudinal growth in a subset of Mashi and Mma Bana infants. They noted that HAART for PMTCT may lead to lower birth weight but longitudinal effects of in utero exposure on infant growth have not been previously reported.

In this analysis, Kathleen Powis and colleagues evaluated breastfed, HIV-uninfected infants born >37 weeks and exposed in utero to at least 2 weeks of either HAART or AZT. Infants in the HAART-exposed group received postnatal AZT for 1 month. Infants in the AZT-exposed group received 6 months of AZT-prophylaxis during breastfeeding.

The investigators calculated gender-based weight-for-age, length-for-age, and weight-for-length z-scores were using WHO Child Growth Standards. They compared mean z-scores using the Student’s t- test and analysis of response profiles.

This analysis included 437 AZT-exposed infants from Mashi, and 592 HAART-exposed infants from Mma Bana.

Median maternal baseline CD4 counts were 393 and 337 cells/mm3 (p=<0.001) and median viral load 4.34 and 4.19 log copies/mL (p=0.04) for Mashi and Mma Bana women, respectively  Demographics were similar between cohorts.

The median time of in utero AZT exposure was 5.7 weeks (range 2.0–10.9 weeks), and median in utero HAART exposure was 12.1 weeks (range 2.6–22.3 weeks).

Median birth weights were 3.1kg in AZT-exposed and 3.0kg in HAART-exposed (p<0.001). HAART exposed infants had significantly lower mean weight-for-age, length-for-age, and weight-for-length z-scores (p<0.001, p = 0.02, and p= 0.007, respectively).

However, the investigators reported that by 3 months of age the infants’ median weight was no longer different by exposure group, and their weight remained similar to 6 months. Mean weight-for-age differed over time by exposure group (p <0.001). Length-for-age remained lower in the HAART-exposed group to 6 months of age, but weight-for-length improved significantly over time compared with AZT-exposed infants (p<0.001).

They noted that the proportions of infants with z-scores >2 standard deviations below the mean were not different between exposure groups.

These early developmental comparisons are useful and longer-term comparisons are planned. The investigators wrote: “The early correction of birth weight differences among HAART exposed infants is reassuring for programmes utilising maternal HAART for treatment and PMTCT.”

comment

Both DART and the Botswana group continue to provide urgently needed and excellent data on maternal /infant health and outcomes.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco.

1. Chidziva E et al. Outcomes in infants born to HIV-infected mothers receiving long-term ART in the DART trial, 2004 to 2009. Poster abstract 924.

http://www.retroconference.org/2010/Abstracts/38485.htm

2. Pregnancy outcomes in the DART trial. HTB, April 2007.

http://i-base.info/htb/2667

3.    Pregnancy rates and outcomes among women in the DART trial. HTB, October 2009.

http://i-base.info/htb/5945

4. Vigano A et al. Exposure during gestation to HAART, including tenofovir, does not impair bone status and metabolism in HIV-positive children born to HIV-positive mothers. Poster abstract 926.

http://www.retroconference.org/2010/Abstracts/38485.htm

5. Dryden-Peterson S et al. Increased risk of severe but reversible anemia following perinatal exposure to maternal HAART in infants in Botswana. Poster abstract 927.

http://www.retroconference.org/2010/Abstracts/37152.htm

6. Powis K et al. Impact of HAART and short-course zidovudine on longitudinal growth of HIV-exposed uninfected breastfed infants, Botswana. Poster abstract 928.

http://www.retroconference.org/2010/Abstracts/38185.htm

7. Mashi study – late breakers on breastfeeding. HTB, April 2005.

http://i-base.info/htb/7450

8. Risk factors for breastfeeding transmission, HTB, April 2008.

http://i-base.info/htb/1831

9. Breast milk, HIV suppression and decreased mother to child transmission. HTB, October 2005.

http://i-base.info/htb/7036

10. Response to nevirapine containing HAART following single dose nevirapine for PMTCT. HTB, February 2007.

http://i-base.info/htb/2745

11.  Reducing HIV transmission during breastfeeding. HTB, August 09.

http://i-base.info/htb/4466

Comments can be made online and the draft document downloaded from the BHIVA website:

http://www.bhiva.org/InfantFeedingConsultation.aspx.

Deadline for comments is Friday 21 May 2010.

Affordable protease inhibitors in suitable formulations for children are urgently needed.

De Kanter and colleagues from the University Nijmegan, the Netherlands, showed pharmacokinetic (PK) data from a phase I, open-label crossover study to evaluate two generic paediatric formulations of lopinavir/ritonavir developed by Cipla Pharmaceuticals (Lopimune tablets and granules 100/25mg). This was a pilot study designed to exclude large (>40%) differences in the exposure to lopinavir achieved using the generic formulations compared to the originator product (Kaletra).

Twelve HIV-negative adult volunteers were randomised to receive the following sequences of regimen ABC, ACB, BCA, BAC, CAB, CBA: A=Kaletra tablets, B=Lopimune granules and C=Lopimune paediatric tablets. They were given single doses of medication (400mg lopinavir) on an empty stomach at one-week intervals and a 32-hour PK curve was recorded. A 32- hour PK curve was also recorded for 5/12 volunteers after receiving lopinavir granules and Kaletra oral formulation both with food.

The volunteers were a median age 24 (range 21-55) years, height 1.79 (range 1.63-1.95) meters and weight 72 (range 51-87) kg. One third of the group were women.

The investigators found the median lopinavir AUC0-t was 71.8 h.mg/L (IQR 48.7-93.5) with Kaletra tablets (A), and 38.7 h.mg/L (IQR 28.7-52.2) and 58.7 h.mg/L (IQR 42.5-79.4) with Lopimune granules (B) and Lopimune tablets (C) respectively. With Kaletra tablets as a reference these differences were statically significant, B vs A, p=0.003 and C vs A, 0.015. Cmax median values were 7.2 mg/L (IQR 5.8-8.3), 4.6 mg/L (IQR 4.1-5.2) and 6.5mg/L (IQR 5.0-7.1); B vs A, p=0.003 and C vs A, p= 0.012.

The investigators also noted lower ritonavir concentrations with the Lopimune formulations compared to Kaletra.

A sub-group of volunteers received Lopimune granules (n=5) and Kaletra oral solution (n=4) with food. In this comparison, the median lopinavir AUC0-t was 62.1 h.mg/L (IQR 43.8-126.3) with Kaletra tablets, and 58.5 (IQR 55.4-77.6) and 49.6 h.mg/L (IQR 39.1-58.1).
Cmax median values were 7.2 mg/L (IQR 4.6-9.1), 6.4 mg/L (IQR 5.5-7.6) and 5.2mg/L (IQR 4.3-5.7).

The investigators concluded that it is possible to exclude large differences in PK parameters for the Lopimune paediatric tablets, compared to Kaletra, when received on an empty stomach. Large differences can also be excluded for the Lopimune granules when these are received with food.

They added that, based on these results, it was acceptable to start PK and dose finding trials of the Lopimune paediatric tablets and granules even though the Cipla bioequivalence study was not yet complete.

COMMENT

This study did not test the effect of different compositions of meals on the absorption of LPV/r. They used a standardised “normal” European/Dutch breakfast, to see if the absorption would be better with food than without, as this is the case with the absorption of lopinavir from Kaltera oral solution. The absorption from the granules might be dependent on the amount of fat in the meal as is stated in the Summary of Product Characteristics.

Since this small study, the Cipla formulation has changed and has been slightly refined, so there is an ongoing bioequivlance study. CHAPAS 2, which will look at these products in children, is waiting on these results before it begins (probably around March). CHAPAS 2 will be able to investigate absorption among breastfeeding  children and also those who are malnourished.

Ref: de Kanter et al. The pharmacokinetics of two generic co-formulations of lopinavir/ritonavir for HIV-infected children: a pilot study of pediatric lopimune formulations vs the branded product in healthy volunteers. 12th EACS, Cologne, November 11-14, 2009. Abstract PE15.2/1.

Researchers from 14 sites in Belgium, Poland and Italy reported the prevalence of lipodystrophy in a cohort of 468 children and adolescents (92% infected at birth). Data collected included demographic and clinical history and used standardised assessment to determine fat loss or accumulation in the face, limbs, buttocks, breasts, neck and trunk.

The cohort was evenly split by gender, with median age 13.5 years (IQR 9.9-17.0). Tanner puberty stage included 28% stage I and 34% stage V. In this group, 73% were white and 22% Black African. HIV treatment was used by 95% of the cohort for a median 8.8 years, with 62% having viral load suppressed <50 copies/mL. The median CD4% was 31% (IQR 24-38) and just over 300 children were currently asymptomatic.

Assessment of symptoms was by clinician-completed questionnaire. Over 40% of children had at least one lipodystrophy symptom: 15% had just fat loss, 13% just fat accumulation (mostly trunk) and 13% had both symptoms. This group included 14 cases of severe fat accumulation and 11 cases of both severe fat loss and fat accumulation.

In multivariate analysis, after controlling for duration of treatment, maternal lipodystrophy, maximal CDC status, and having ever used d4T, indinavir, d-drugs and efavirenz, significant associations were found for d4T use (AOR 4.23; 2.02, 8.85), efavirenz use (AOR=2.72; 1.36, 5.46), indinavir use (AOR 3.23) and clinical stage (AOR 3.30; 1.28, 8.02) and either fat loss or fat accumulation.

Even stronger associations were found for children who had both symptoms.

Maternal lipodystrophy was also associated with an adjusted OR of 3.01 (1.78, 5.57) for any symptom and 4.75 (1.60, 14.20) for both symptoms.

Ref: Alam NM et al. Risk factors for body fat redistribution in a European cohort of HIV-infected children and adolescents. 11th Intl Workshop on Adverse Drug Reactions. 26-28 October 2009, Philadelphia. Poster abstract P-06. Antiviral therapy 2009; 14 Suppl 2: A27.

Several guidelines now recommend universal treatment for HIV-infected infants. However, in resource-limited settings early infant diagnosis (EID) is frequently an obstacle to early initiation of antiretrovirals.

A survey by World Health Organization (WHO) asked, “What is available for early infant diagnosis?” and found the number of laboratories in several countries mismatched to the estimated number of HIV-exposed infants and necessary tests. This assessment of national capacity was conducted to inform revisions to their guidelines for infant diagnosis and treatment. [1]

For this survey, a questionnaire on clinical and laboratory capacity was sent to HIV experts in 34 high-burden countries and data were collected between February and April 2008. Replies were received from 18 of the 34 selected countries: 12 African, two South American, two Asian and one Middle Eastern.

This revealed huge variation in the number of children assessed per laboratory (range 7 – 190 000 during the study period). When virological tests were offered, the entry points were usually inpatient/outpatient services, prevention of mother-to-child transmission (PMTCT) or antiretroviral therapy (ART) sites, and laboratories were centralised and usually located in capital cities. Six countries surveyed implement HIV DNA polymerase chain reaction (PCR), 5 RNA PCR and 7 both. Ten countries used filter paper with dried blood spots (DBS) to transport samples. All the countries that responded had capacity to measure CD4% and absolute CD4 cell counts.

Although the survey confirmed that several high-burden countries are building capacity for EID, it showed that at present in many countries capacity does not reflect estimated need.

In many resource-limited countries it is only possible to use a single diagnostic test. The optimal time to perform this is unclear, however, particularly when children are breastfed. The WHO researchers used a model to calculate the number of children becoming infected and being diagnosed at different time points from birth in order to estimate the optimal time to diagnose the maximum number of children but at the same time minimise mortality. [2]

This modelling showed a decreasing trend of infant survival at 6 months, depending on the time the test was performed. The investigators suggested that 4 – 6 weeks of age is the optimal time for infant testing in a breastfeeding population.

With greater laboratory capacity and newer technology, testing earlier than 6 weeks could mean earlier initiation of treatment. But the sensitivity of viral detection tests before 6 weeks of age is unknown, particularly when performed on infants with antiretroviral exposure for PMTCT.

A South African study looked at the sensitivity of assays at earlier time points in infants born to HIV-positive women at Rahima Moosa Hospital, Johannesburg.3 Blood was sampled at birth and at 2, 4, 6 and 10 weeks, and stored. HIV-exposed infants were routinely tested at 6 weeks with HIV DNA PCR using a liquid blood sample.

Stored DBS samples from each time point were tested with HIV DNA PCR (Amplicor v1.5), TaqMan HIV-1 (CAP/CTM) and APTIMA HIV-1 (GEN-PROBE) assays. The investigators used samples from two age-matched, PCR-negative infants as controls.

Mothers received a range of PMTCT interventions: no antiretrovirals, single-dose nevirapine (NVP), single-dose NVP plus zidovudine (AZT) or HAART.

At 9 months of the study, 253/373 (68%) infants had 6-week PCR results; the remaining 120 (32%) did not return for testing. Eighteen (7.1%) were HIV infected at 6 weeks despite the majority receiving formula milk exclusively and all receiving NVP and AZT PMTCT prophylaxis.

Of the 17 infected infants with complete results, both CAP/CTM and APTIMA assays were positive in 11/17, 13/13 and 14/14 birth, 4- and 6-week samples, respectively.

The quantitative CAP/CTM assay showed lower viral load results at 2 weeks of age (the only time point when false negatives occurred). The investigators noted that this was probably due to PMTCT prophylaxis increasing the proportional number of infants infected in utero who can therefore be diagnosed at birth.

Both assays were more sensitive for earlier HIV detection than HIV DNA PCR, which detected 9/17 birth samples. CAP/CTM had the highest specificity (100%) and HIV DNA PCR the lowest (95%).

Although this is a small sample, newer technologies appear to be more sensitive than standard PCR. These initial results suggest that the majority of in utero and perinatal infections can be detected by using either CAP/CTM or APTIMA assays if they are available.

There were also reports from programmes using DBS.

A sub-study of the PMTCT Keso Bora trial conducted in Burkina Faso used a quantitative HIV RNA assay (Biocentric) and assessed DBS samples compared with paired plasma samples obtained from HIV-exposed infants aged up to 6 weeks, 3 – 6 months and 9 – 18 months.[4] All measurements were performed locally.

The study investigators reported 100% sensitivity (102/102) and specificity (105/105) (95% confidence interval (CI) 97.2 – 100%, correlation 0.906) using DBS. Of note, Biocentric is the homebrew ANRS assay, so they would have to develop their own probes, reagents, etc.

A Cambodian study assessed the feasibility of very early diagnosis (0 – 3 days of age) using heel-prick samples on DBS and a real time DNA assay (Bicentric). [5] A second DBS was performed at week 6. Infants with positive results at 0 – 3 days or 6 weeks were followed up with HIV RNA quantification as soon as possible.

At 0-3 days, 3/370 (0.8%) infants had positive results (1 infant died before week 6). 327/333 were confirmed negative at 6 weeks and 6 were DNA positive (1.8%) and subsequently confirmed RNA positive.

The investigators suggested that these preliminary results demonstrate the feasibility of a minimally invasive very early diagnosis using DBS.

This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.

http://www.sahivsoc.org

References

Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.

1. Penazzato M, Crowley S. What is available for early infant diagnosis?: results from WHO survey 2008. Abstract WEPEB269.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2644
2. Penazzato M, Crowley S. Early infant diagnosis in resource limited settings: determining the optimum timing in a breastfeeding population. Abstract WEPEB270.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2656
3. Sherman G et al. Earlier diagnosis of HIV infection in infants in low resource settings. Abstract WEPEB267.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2093
4. Gampini SE et al. Early diagnosis of paediatric HIV-1 infection among West-African breast-fed children using dried blood spots and a quantitative HIV-1 RNA assay. Abstract WEPEB264.
http://www.ias2009.org/pag/Abstracts.aspx?AID=938
5. Ngin S et al. Very early diagnosis of HIV infection in newborn at day 0-3 on DBS in Cambodia. Abstract MOPEB009.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2212

A study from Swaziland, conducted by the national ART programme and the Clinton Foundation, highlighted the difficulties of treatment initiation in infants following early diagnosis. [6]

Since March 2007 the EID programme using DNA PCR was expanded in response to high infant mortality in HIV-infected children. By November 2008, however, this had led to neither an increase in infants receiving treatment nor a decrease in mortality.

The study was a retrospective record review of all infants testing positive at 15 health facilities in the Manzini Region from January to August 2008. The investigators reported that 78% of results were available at the facility, and 44% of results were documented as having been received by the caregiver. Only 58/176 (33%) of children were enrolled at an ART centre and 34 initiated on treatment. Of those with data available 81% were eligible for ART, and among eligible children, 82% initiated treatment. Overall 19% of infants testing positive were initiated on treatment at the time of the evaluation.

This study found that the greatest points of loss are return of the result to caregivers and infant enrollment at the ART centre for treatment.

This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.

http://www.sahivsoc.org

References

Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.

6. Sundaram M et al. Identification patient loss points from testing to treatment initiation among infants tested in Swaziland. Abstract MOPDD103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1981

There are limited data describing outcomes for infants initiating treatment at less than 1 year.

The MTCT Plus Initiative showed data from sites in eight African countries and Thailand comparing infants with older children initiated between February 2003 and September 2008. [7]

The investigators looked at change in CD4 percentage from baseline using linear modelling adjusted for duration of highly active antiretroviral therapy (HAART), country, baseline CD4 percentage, NVP exposure for PMTCT, and age at initiation.

Of 542 children initiating treatment and followed up for a median of 30 months (intraquartile range (IQR) 12 – 39), 190 (35%) were aged <12 months at initiation and the remainder >12 months (median 36 months, IQR 19.5 – 67), 51% were male, and18% had Centers for Disease Control (CDC) stage C disease.

The infants had a higher mortality rate than the older children, 7.5 v. 3.2/100 person-years. Of 31 (54%) infant deaths, 81% occurred within 3 months of treatment initiation.

Among the children for whom data were available there was no difference between infants and older children in change of CD4 percentage from baseline. Baseline CD4 percentage (p<0 .01) and time on HAART (p<0.001) were significantly associated with an increase in CD4 percentage in multivariate analysis.

In this analysis, although infants initiating HAART had a higher mortality at the start of treatment, the infants who survived had good immunological response over >3 years of follow-up, similar to that of older children.

A South African review of infants initiated on HAART at the Family Clinic for HIV at Tygerberg Hospital and Ikwezi community clinic from June 2007 to August 2008 showed high levels of virological suppression to 24 weeks. [8]

Infants received lopinavir/ritonavir (LPV/r) with stavudine (d4T) and lamivudine (3TC) in accordance with South African guidelines. Of 98 initiated, 47 had 24 weeks of follow-up. Of the remainder, 6 (6%) were lost to follow-up, 6 (6%) died and 33 (33.7%) were transferred.

The median age at initiation was 4.5 months and 33 (70%) infants were ≤6 months old (median age 3.68 months). All had immunological or clinical criteria for treatment. The majority, 42/47 (89.4%) of all infants and 30/33 (91%) ≤6 months of age, had WHO stage 3 or 4 disease.

Tuberculosis (TB) is a common co-morbidity in this population, and 11/47 infants required co-therapy with rifampicin (given with additional ritonavir).

At 24 weeks 37/47 children (79%) in the > 6 months age group and 26/33 (82%) aged <6 months had viral loads <50 copies/mL.

The investigators noted that the low age of initiation of treatment in this cohort reflected young infants with severe HIV disease rather than early initiation of treatment to prevent mortality and morbidity.

This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.

http://www.sahivsoc.org

References

Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.

7. Carter RJ et al. Immunologic response and survival of infants initiating antiretroviral treatment (ART) at less than one year of age compared to older children enrolled at MTCT-Plus Initiative sites in 8 African countries and Thailand. Abstract MOPEB048.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2021
8. Rabie H et al. 24 week outcome of infants started on lopinavir/ ritonavir based HAART in a resource limited setting. Abstract MOPEB076.
http://www.ias2009.org/pag/Abstracts.aspx?AID=492

The developing brain is a major target for HIV. It is not yet known whether timing of initiation of antiretroviral therapy will affect neurodevelopmental outcomes in infants.

A substudy of CHER compared neurodevelopmental outcomes of 115 infants in this study from Tygerberg Children’s Hospital with 84 control infants enrolled in a linked vaccine study, CIPRASA Project4. [9]

In this prospective study, the investigators looked at the neurodevelopmental profile, according to the Griffiths Mental Developmental Scales (GMDS), at 10 – 15 months of age in four groups of infants:

• HIV-unexposed, uninfected
• HIV-exposed, uninfected
• HIV-infected, HAART initiated before 12 weeks of age
• HIV infected, HAART deferred until eligibility criteria met.

The investigators were blinded to the infants’ groups and a translator was used for Xhosa-speaking participants.

Of 115 infants from CHER enrolled, 13 withdrew from the study and/or were not co-enrolled (10 early, 3 deferred), 8 died (all deferred) and 4 were excluded (3 early, 1 deferred).

The investigators found that infants initiated on early ART have significantly better locomotor and general scores on the Griffiths Mental Development Scales at a median age of 11 months compared with infants on deferred HAART. Although mean quotients were lower on the other subscales in the deferred group, the differences were not significant. The mean scores on all subscales in the unexposed, uninfected group and the early HAART group were similar. They noted these results were “despite careful monitoring and ready access to ART in the latter” (Table I).

Table I. Mean quotients of infants for deferred vs early HAART and HIV- exposed uninfected and unexposed infants

This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.

http://www.sahivsoc.org

References

Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.

9. Laughton B et al. Early antiretroviral therapy is associated with improved neurodevelopmental outcome in HIV infected infants: evidence from the CHER (Children with HIV Early Antiretroviral Therapy) trial. Abstract MOPEB080.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1629

Two studies looked at treatment of HIV-infected children with prior exposure to NVP to prevent MTCT.

Preliminary findings from IMPAACT 1060 confirmed concerns that NVP-exposed children could do less well receiving NVP containing HAART than protease inhibitor (PI)-containing HAART. [10, 11]

This was a randomised trial of treatment-eligible children aged 6 months – 3 years conducted in seven African countries. NVPexposed (cohort 1, n=288) and unexposed (cohort 2, n=288) children received either LPV/r or NVP, plus 3TC and AZT. Children were stratified by age <12months v. ≥12 months with an equal number to be enrolled in each age group.

A similar study of exposed and unexposed mothers had also been conducted (A5208). In this trial, the arm in which exposed mothers received NVP-containing HAART, was stopped early by the Data Safety Monitoring Board (DSMB). This was due to superior performance of the LPV/r-containing HAART arm. [12, 13]

Following a scheduled DSMB review of IMPAACT 1060 on 20 April 2009, enrolment to cohort 1 also closed prematurely owing to a trend towards consistency with the A5208 results. At 24 weeks, virological failure (<400 copies/mL) was observed in 40% of the 60 infants <12 months v. 23% ≥12 months receiving NVP and LPV/r, respectively. Among the older children, 29% out of 22 and 17% of 19 receiving NVP and LPV/r experienced failure.

Several guidelines already recommend using LPV/r-based treatment for single-dose NVP-exposed infants.

The NEVEREST study investigated whether NVP-exposed children, initially suppressed on LPV/r-based HAART, can safely switch to a NVP-based regimen. [14, 15]

In this study children aged 6 weeks – 2 years and eligible for treatment (n=323) were initiated on LPV/r plus 3TC and d4T. Children achieving a viral load <400 copies/mL and stable for ≥3 months were randomised (N=195) to either remain on LPV/r (control, n=99) or switch to NVP (switch, n=96), and then followed up to 52 weeks.

When the investigators looked at viral load <50 copies/ml to 52 weeks they found that 42.4% of children in the control group and 56.2% in the switch group sustained viral suppression (p=0.01). However, allowing for one elevated result (blip) the two groups were similar, 72.8% vs 73.4% in the control and switch groups, respectively.

They suggested that poorer adherence in the control group, due to the unpleasantness in taste of LPV/r syrup, may have led to more blipping and, in turn, unsustained viral suppression to 50 copies/mL during follow-up.

In contrast, when they looked at sustained suppression to <1 000 copies/mL, 98% v. 80% of children in the control and switch groups achieved this (p=0.001).

The investigators suggest that this study provides proof of concept that re-use of NVP is possible under some circumstances for HIV-infected children exposed to NVP prophylaxis and should be further investigated. They note that the clinical significance of low-level viraemia in the control group needs further study. This group also showed data from an evaluation of lipid profiles in children in the control and switch groups. [16]

They found no difference between the two groups at randomisation. But at 9 months after the change in regimen non-fasting total cholesterol (TC) and high-density lipoprotein (HDL) were significantly higher among the switch group (mean TC 4.13, HDL 1.36 mmol/l) compared with the control group (mean TC 3.73, HDL 1.07 mmol/l). Significantly lower triglyceride (TG) levels were found in the switch group (mean TG 1.36 mmol/l) compared with the control group (mean TG 1.53 mmol/l).

They noted that the clinical significance of these non-fasting lipid changes requires further investigation.

Switching may provide a promising option for children originally initiated on PI-based HAART to preserve second-line options. At this stage, switching requires close virological monitoring after the switch in order to be done safely.

Another NEVEREST trial of efavirenz (EFV) vs LPV/r is planned in nevirapine-exposed children >3 years old.

These studies all underscore the limited treatment options available for children, particularly in resource-limited settings.

This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.

http://www.sahivsoc.org

References

Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.

10. Violari A et al. Nevirapine vs. lopinavir-ritonavir-based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV infected infants: preliminary results from the IMPAACT P1060 trial. HIV Pediatrics, 17 – 18 July 2009, Cape Town. Abstract O_08.
http://www.hivpresentation.com/index.cfm?vID=5B52BC82-423AF6F7- C31E763DE1C6FAB7
11. Palumbo P et al. Nevirapine (NVP) vs. lopinavir-ritonavir (LPV/r)- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV-infected infants: preliminary results from the IMPAACT P1060 trial. Abstract LBPEB12.
12. http:/i-base.info/htb/261
13. http://i-base.info/htb/1449
14. Coovadia A et al . Randomized clinical trial of switching to NVP-based therapy for infected children exposed to nevirapine prophylaxis. HIV Pediatrics, 17 – 18 July 2009, Cape Town. Abstract O_09.
http://www.hivpresentation.com/index.cfm?vID=5B526AE8-423AF6F7- C3840703869307AA
15. Coovadia A et al. Randomized clinical trial of switching to nevirapine-based therapy for infected children exposed to nevirapine prophylaxis. Abstract MOAB103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3746
16. Strehlau R et al. Changes in lipid profiles after switching young children from a suppressive lopinavir/ritonavir-based regimen to a nevirapine-based regimen. Abstract TUPEB166.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1125

Paediatric fixed dose combination (FDC) tablets provide simpler alternatives to liquids for children.

Cipla have produced scored, dispersible tablets of d4T/3TC/ NVP (baby and junior Triomune) with the correct dose ratios for children.

A sub-study of the CHAPAS trial (Children with HIV in Africa Pharmocokinetics and Adherence of Simple Antiretroviral Regimens), in Zambia, evaluated the need for dose escalation of NVP.[17] This strategy is currently recommended but requires dosing with separate tablets, making initial treatment more complex.

Children were randomised to start antiretroviral therapy with full-dose NVP (Triomune am/pm) vs dose escalation, using an initial 14 days of half-dose NVP (Triomune am; Lamivir-S (combined d4T/3TC) pm) followed by full dose. Children were dosed in accordance with WHO weight band tables. The primary endpoint was clinical/laboratory grade 3/4 adverse events (AEs) related to NVP.

In this comparison, 211 children aged 2 – 9 years with a median CD4 percentage of 13% were followed for a median of 92 weeks. Severe stunting, wasting and immunosuppression were common in the children. Seventeen children were lost to follow-up.

The investigators reported 31(18 per 100 person-years) vs 29 (16.5 per 100 person-years) grade 3/4 AEs definitely/probably or uncertainly NVP-related in children receiving full-dose vs dose-escalation (incidence rate ratio (IRR) 1.09 (95% CI 0.63 – 1.87), p=0.74).

Twelve (11%) full-dose vs 2 (2%) dose escalation children had grade 2 disseminated skin rash and 1 receiving full dose had grade 1 rash. Two children (one from each arm) substituted with EFV; 3 continued full-dose NVP; 9 (8 full dose and 1 dose escalation) stopped NVP and restarted with successful dose escalation; and 1 full dose stopped, started a lower NVP dose, had another rash and substituted EFV.

Overall 90% of children who started with full-dose NVP continued uninterrupted in this study. As dose escalation requires provision of separate drug formulations, the evaluation of policy implications for dose escalation of NVP in fixed-dose combination HAART is ongoing.

The CHAPAS trial also investigated the pharmacokinetics of NVP in children treated with Triomune Baby/Junior and rifampicinbased tuberculosis treatment. [18]

EFV-based regimens are currently recommended for concomitant use with rifampicin, but EFV is not currently indicated for children below 3 years of age. Earlier CHAPAS data suggest that the higher dose ratio of NVP to NRTI in Triomune Baby/Junior may compensate for the dose reduction induced by rifampicin.

Pharmacokinetic sampling was performed in 22 children after 4 weeks of concurrent NVP and rifampicin-containing regimens. Rifampicin was dosed at 10 – 20 mg/kg per day. Samples were pre-dose (C0) and 1, 2 and 6 hours post-dose, and nevirapine plasma concentrations were determined using LC-MS/MS. NVP pharmacokinetics in children without TB treatment (n=16) were compared in multivariate linear regression analysis. The median age of the 21 children analysed was 1.55 (range 0.66 – 3.18) years, and 10 were girls.

The investigators found that only 11 (52%) of the children receiving TB treatment reached sufficient NVP trough levels (C0 <3.0 mg/L). Multvariate analysis revealed a 41% (95% CI 24 – 55%) reduction in nevirapine AUC with concomitant rifampicin. They noted a 3.4% increase in AUC for each 10 mg/m2 increase in NVP dose/m2.

They recommend caution with this approach in young children until more efficacy and safety data are available. They suggest that an increased NVP dose is likely to be necessary and requires further evaluation.

This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.

http://www.sahivsoc.org

References

Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.

17. Kabamba D et al. Strategies for nevirapine initiation in HIV-infected children taking paediatric fixed-dose combination ‘baby pills’ in Zambia: a randomised controlled trial. Abstract MOPEB090.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3011
18. Oudijk JM et al. Pharmacokinetics of nevirapine in young children during combined ART and rifampicin-containing antituberculosis treatment. Abstract LBPEB10.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3715

Simplification of HAART regimens provides benefit for children, caregivers and health workers. To date there are no data on oncedaily use of 3TC and abacavir (ABC) in resource limited settings.

A substudy from the ARROW trial (a randomised trial of monitoring and first-line induction-maintenance strategies) compared the PK of once- v. twice-daily 3TC and abacavir (ABC) (Kivexa).[19] This was a cross-over study performed in 41 Ugandan children aged 3 – 12 years receiving HAART, dosed according to weight bands. The ARROW trial uses scored tablets of ABC/3TC to ensure better accuracy of division and more flexible dosing. Total daily doses were 150+300 mg, 225+450 mg and 300+600 mg for children weighing 12 – 20 kg, 20 – 25 kg and >25 kg, respectively.

PK sampling was performed for twice-daily dosing at steady state (36 weeks) pre-dose, and 1, 2, 4, 6, 8 and 12 hours post dose. Children were then switched to the once-daily dose and further sampling was performed at 4 weeks with an additional sampling at 24 hours.

Daily area under the curve (AUC0-24) and peak level (Cmax) were compared by geometric mean ratios (GMR). GMR with 90% CI within 0.80 – 1.25 was considered to be bioequivalent.

PK parameters were available for 35 and 36 children for 3TC and ABC, respectively. Approximately half were in the younger age group.

The investigators reported that in children 3 – 12 years, AUC0-24 of both 3TC and ABC were bioequivalent with once and twice daily regimens but Cmax was 76% and 64% higher for 3TC and ABC respectively. No grade 3/4 adverse events were reported and no child discontinued after the switch to once-daily dosing.

In this analysis, in contrast to data from European children in PENTA 13, 3TC AUC levels in 3 – 6- and 7 – 12-year-old children were similar for both once- and twice-daily dosing and similar to levels in older children. The investigators noted that many younger children in PENTA 13, whose 3TC levels were lower, received syrups, but ARROW children received tablets. They concluded that these results suggest that once-daily dosing of 3TC and ABC is feasible in resource-limited settings.

The ARROW investigators also showed data describing successful management of hypersensitivity reactions among children in this trial in Uganda and Zimbabwe.[20]

The WHO recommends ABC for paediatric first-line treatment. Hypersensitivity reactions (HSR) occur in 2 – 5% of people receiving ABC in clinical trials and are strongly associated with the presence of the HLA-B*5701 allele. Prospective screening for HLA-B*5701 is sometimes recommended, but this pharmacogenetic test is rarely available in resource limited settings.

Clinical diagnosis and management may be complicated in this setting due to widespread use of NVP and cotrimoxazole and febrile infections.

Health workers and caregivers were trained in recognition and management of ABC-HSR and all suspected HSR underwent independent clinical review. ABC was only discontinued in 7 cases.

The investigators reported that suspected ABC-HSR was rare (3/1 207, 0.2% (95% CI, 0.05 – 0.7%)) in this trial, consistent with reports of a lower prevalence of HLA-B*5701 in black populations. Clinical symptoms (fever, rash) occurred 9 – 13 days after initiation of HAART; 2/3 cases had additional gastrointestinal and respiratory symptoms and required hospitalisation.

ABC-HSR was successfully managed despite co-administration of cotrimoxazole and NVP, and the investigators recommend that ABC can be used safely in resource-limited settings.

This article first appeared in issue 36 of the Journal of HIV Medicine, the journal of the Southern African Clinicians Society.

http://www.sahivsoc.org

References

Unless otherwise stated, all references are to the programme and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19 – 22 July 2009, Cape Town.

19. Musiime V et al. Pharmacokinetics of once versus twice daily lamivudine and abacavir in HIV-1 infected Ugandan children in the ARROW trial. Abstract WEPEB271.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1594
20. Nahirya-Ntege P et al. Successful management of suspected abacavir hypersensitivity reactions among African children in the ARROW (AntiRetroviral Research for Watoto) trial. Abstract TUPEB183.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1737

The developing brain is known to be a target for HIV, and there is concern about the long-term effect on the cognitive and behavioural development of HIV-positive children. Additionally before the introduction of HAART, the prevalence of HIV encephalopathy in HIV-positive children was up to 50%.

Two studies published in the 10 September 2009 edition of AIDS, examine long-term neurocognitive and psychiatric outcomes of vertically infected adolescents and the impact of HAART on HHIV encephalopathy among children and adolescents in two American cohorts.

Impact of AIDS diagnoses on neurocognitive and psychiatric outcomes of vertically infected adolescents

Sarah Woods and colleagues conducted a retrospective cohort study at the Children’s Hospital of Philadelphia, USA, to examine the association between previous AIDS and neurocognitive and psychiatric outcomes in vertically infected adolescent long-term survivors. [1]

Adolescents attending the HIV clinic, born before 1 September 1995 and above 11 years of age were enrolled this study in which those with previous CDC Class C diagnosis (AIDS defining) were compared to those with non-Class C diagnosis.

Of the 172 meeting these criteria 39 (23%) patients had died, 45 (26%) transferred and 7 (4%) were lost to follow up. The remaining 81 adolescents were eligible for evaluation of whom 38 (46.9%) were girls and 58 (71.6%) were African-American. Their median age was 15.2 years (range 11.1-23.8, IQR 13.2-17.2 years). Almost half (47%) the participants were Class C and there were no significant differences in sex, race or current age between the class C and non-Class C groups. HIV diagnosis was at a median of 9 months and Class C diagnosis was at a median of 3.1 years of age. Of the Class C group, 51% had at least one additional Class C diagnosis.

Most recent viral load, CD4 percentage and CDC immunological category were similar in both groups. By the end of the study period 93% of the cohort were receiving HAART. There was no difference between the groups in those achieving and not achieving an undetectable viral load when on HAART. The cohort was heavily treatment experienced and patients with Class C diagnosis had received a greater number of regimens p=0.002. Of this group 68.4% had initiated HAART before their AIDS diagnosis.

The median full scale intelligence quotient (FSIQ) of the cohort, measured on the Weschler Intelligence Scale for Children-IV (WISC-IV) or the Weschler Abbreviated Scale of Intelligence, was 87 (IQR 78-99), which falls within the “average” category.

However, Class C patients had significantly lower median FSIQ than non-class C, 82 (IQR 73-90) vs 93.5 (IQR 84-100) respectively, p=0.0003. Learning disabilities had been diagnosed in 42% of the cohort and 17% had a lifetime history of HIV-related progressive encephalopathy (HPE).

Almost half the cohort (47%) had a diagnosed psychiatric illness and18.5% had multiple psychiatric illnesses. Treatment with psychotropic medications had been prescribed to 32% of the cohort, and 16% had a history of mental health hospitalisation.

The investigators performed a multivariate logistic regression analysis, adjusted for age at ART initiation, to look at the association between Class C diagnosis and neurocognitive and psychiatric status.

They found a significant association between previous Class C diagnosis and neurocognitive impairment: learning disabilities, adjusted OR 4.1 (95% CI 1.5-11.1), p=0.014 and lower FSIQ (median), -12.1 (-18.7 to 5.5), p=0.002. There was also significant association with psychiatric diagnosis AOR 3 (95% CI, 1.1-8.1), p=0.027, in particular multiple psychiatric diagnosis AOR 19.3 (95% CI, 2.3-162.6), p=0.001; mood disorder AOR 3.3 (95% CI, 1.1-10), p=0.023 and receiving mental health treatment AOR 4 (95% CI, 1.3-13), p=0.042.

The investigators found no difference in FSIQ or rates of learning or psychiatric disorders between Class C patients starting HAART before and after their AIDS diagnosis. But they noted that the number of patients with Class C disease was small and they were underpowered to detect even modest associations in this sub-analysis.

Impact of HAART on encephalopathy

Kunjal Patel and colleagues from The PACTG 219 study team looked at the effects of HAART and CNS penetrating regimens on the incidence of HIV encephalopathy in perinatally infected children and adolescents. [2] This study was conducted between 1994 and 2006 in a large American multicentre paediatric cohort.

The study followed 2398 perinatally infected children with at least one neurological examination.

The investigators used Cox regression models to estimate the effects of time varying HAART vs non HAART and time varying medium and high CNS penetrating regimens vs low CNS penetrating regimens on the incidence of HIV encephalopathy. They also looked at overall survival and survival following encephalopathy diagnosis. Covariates included baseline age and CD4 percentage, sex, ethnicity and birth weight. Secondary analyses used Cox models to estimate the effects of HAART and CNS penetrating regimens on HIV encephalopathy also adjusted for viral load and to evaluate the effect of HIV encephalopathy on mortality.

There were 2398 children, with a median of 6.4 years of follow up, included in this analysis. At baseline the 2272 children followed for incident HIV encephalopathy and survival analyses were equally divided between the sexes, the majority (85%) were less than or equal to 10 years of age, 24% had low birth weight, 56% had a CD4 percentage above 25% and there were no viral load data for 54%.

At the time of their first neurological examination 35% of children were on a HAART regimen and 27% were on a high CNS penetrating regimen. During the study period there were 77 incident cases of HIV encephalopathy, giving an incident rate of 5.1 per 1000 person years (95% CI 4-6.3).

The investigators reported a 10-fold decline in incidence of HIV encephalopathy. This began in 1996 and stablised after 2002. This decrease paralleled a significant increase in the use of HAART in the cohort.

They found the risk of developing HIV encephalopathy in children initiated on HAART was halved compared to those who were not on HAART (hazard ratio 0.5, 95% CI 0.29-0.86), p=0.01. Baseline CD4 less than 15% was associated with over 8-fold increase in risk of developing HIV encephalopathy (hazard ratio 8.41, 95% CI 4.79-14.76). Infants were also at greater risk, age less than or equal to 1 year at first neurological examination was associated with a over 3-fold increase in HIV encephalopathy (hazard ratio 3.38, 95% CI 1.36-8.44).

In the subanalysis looking at ranked CNS penetrating regimens, the investigators found a 41% reduction in incidence of HIV encephalopathy in high CNS penetrating regimens compared to low (hazard ratio 0.59, 95% CI 0.31-1.10). Due to the small sample size in this analysis, this association was not significant, p=0.64.

Across the cohort (n=2272) both HAART and high CNS penetrating regimens were associated with increased survival, hazard ratio 0.41(95% CI 0.29-0.58), and hazard ratio 0.31(0.22-0.45), both p<0.0001, compared to no HAART and low CNS penetrating regimens respectively.

Children with an HIV encephalopathy diagnosis had a 12-fold increase in risk of death compared to those without (hazard ratio 12.42, 95% CI 8.46-18.24).

There was a 50% increased survival benefit associated with HAART use among the 77 children with an incident diagnosis of HIV encephalopathy (hazard ratio, 0.51, 95% CI 0.25-1.05) but this was not statistically significant, p=0.07. High CNS penetrating regimens were associated with greater survival benefit, giving a 74% reduction in risk of death (hazard ratio 0.26, 95%CI 0.11-0.61, p=0.002) compared to low penetrating regimens.

COMMENT

Wood and colleagues write that their findings suggest that early HAART, initiated before the onset of symptomatic HIV, may be warranted to protect the developing CNS in children with HIV. For infants, they suggest that alongside CHER findings, and in keeping with some recent guideline changes, that HAART should be given to all infants immediately after birth. However, in an accompanying commentary, Marc Tadieu suggests that it is not possible to conclude directly from this study that very early treatment would have prevented class C events and possibly ensure normal cognitive and behavioural development, “although, it is tempting to do so.”

Patel and colleagues found HAART use to be highly effective in reducing the risk of HIV encephalopathy. They suggest that among children with HIV encephalopathy diagnosis, treatment decisions should take into account the effectiveness of ARVs in penetrating the CNS, as high CNS penetrating regimens offered increased survival benefit (74% reduction in risk of death compared to low penetrating). Editorial commentary from Bruce Brew describes HIV, the brain, children and “neuro-HAART” as “a complex mix” and suggests it is time for randomised clinical trials to establish whether “neuro-HAART” treats brain disease better than standard HAART.

References
1. Wood SM et al. The impact of AIDS diagnoses on long-term neurocognitive and psychiatric outcomes of surviving adolescents with perinatally
acquired HIV. AIDS 2009, 23:1859-1865.
2. Patel K et al. Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and
adolescents. AIDS 2009, 23:1893-1901.

There are conflicting reports concerning the association between preterm birth or low birth weight and HAART.

Karin van der Merwe and coresearchers investigated the impact of HAART exposure on birth weight and gestational age among infants of South African women with advanced HIV disease attending antenatal antiretroviral clinics in Johannesburg. [1]

This review included 1630 women attending clinics between April 2004 and July 2008. All women had CD4 <250 cells/mm³.

Gestation and birth weight of infants were compared: maternal HAART exposed vs unexposed; early (<28 weeks gestation) vs late (>=28 weeks) and PI-based vs NVP-based vs EFV-based. Multivariate logistic regression was used and included maternal CD4 and infant HIV status (PCR).

The investigators found the median CD4 counts for mothers of infants exposed and unexposed to HAART were 154 (IQR 101-229 and 191(IQR 136-220) cells/mm³ respectively, p<0.001. The two groups were similar for other risks of adverse infant outcomes: smoking, alcohol, hypertension, diabetes, anaemia, syphillis serology and history of previous miscarriage.

Prematurity rates were 6% (8/143) in HAART-unexposed infants vs 14%(129/949) in HAART-exposed infants (p=0.01). The HAART-exposed infants had mothers with a higher rate of previous preterm infants than the unexposed group, 11% vs 6%, p=0.055.

See Tables 1 and 2 for infant outcomes by duration of exposure and HAART regimen.

Table 1: Infant outcomes in women exposed and unexposed to HAART and by duration of exposure

The investigators concluded that, in this analysis, any HAART exposure was associated with preterm birth between 34-37 weeks gestation. This was strongest when HAART was initiated before 28 weeks gestation. However, they did not find an increased risk of extremely preterm birth (<34 weeks gestation).

Table 2. Infant outcomes in women exposed to HAART by regimen

Overall, they found neither low birth weight nor very low birth weight to be associated with HAART exposure. In this cohort, infants unexposed to HAARTwere more likely to have low birth weight.

PI exposure was not a risk factor for preterm or low birth weight. But, of the three regimens, early EFV exposure was associated with low birth weight. The investigators suggested that higher levels of TB among this group of women could be confounding, as EFV is frequently used in South Africa in pregnancy in the presence of HIV/TB coinfection. TB is a risk factor for preterm birth and low birth weight.

They added that these findings could help guide PMTCT policies in South Africa.

COMMENT

As the investigators suggest, the observation that there was an association between early efavirenz exposure and low birth weight may be subject to confounding due to TB.

They included two useful tables (see Tables 3 and 4) showing published studies that looked at HAART exposure and preterm delivery or low birth weight. Data from Africa is slowly emerging.

Table 3: Major studies showing a link between preterm birth or low birth weight and HAART exposure

Table 4: Major studies showing no link between preterm birth or low birth weight and HAART exposure

References
1. van der Merwe K et al. The impact of in-utero antiretroviral therapy (HAART) exposure on infant outcomes in Johannesburg, South Africa. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract WEPEB262.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2256
2. Lorenzi P et al. Antiretroviral therapies in pregnancy: maternal, foetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS 1998, 12:241-247.
3. Thorne C et al. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS 2004, 18:2337-2339.
4. Cotter A et al.Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis 2006. 193:1195-1201.
5. Townsend CL et al. Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland. AIDS 2007, 21: 1019-1026.
6. Tuomala RE et al. Antiretroviral therapy in pregnancy and the risk of adverse outcome. N Eng J Med 2002, 346: 1863-1870.
7. Tuomala RE et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir immune Defic Syndr 2005, 38: 449-473.
8. Szyid EG et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS 2006, 20: 2345-2353.
9. Schulte J et al. Declines in low birth weight and preterm birth among infants who were born to HIV-infected women during an era of increased use of maternal antiretroviral drugs. Pediatric spectrum of HIV disease, 1989-2004. Pediatrics 2007, 119: 900-906.

Two studies presented at the 1st International Workshop on HIV Pediatrics, 17-18 July 2009, Cape Town, South Africa and 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009 looked at strategies for treatment of HIV-infected children with prior exposure to nevirapine (NVP) to prevent mother to child transmission.

IMPAACT  P1060

In an oral presentation at the paediatric workshop, Avy Violari from the University of Witwatersrand, Johannesburg, South Africa, presented preliminary findings from the IMPAACT P1060 trial. [1] These data were also shown at the 5th IAS Conference as a late breaker poster. [2]

IMPAACT 1060 was a randomised trial conducted at 10 sites in 7 African countries. In this trial, two groups of HIV-infected children age 6 months to 3 years and eligible for treatment according to WHO criteria: Cohort 1, exposed (n=288) and Cohort 2, unexposed (n=288) to single dose NVP, were randomised to receive either lopinavir/r or NVP plus zidovudine (AZT) and lamivudine (3TC), with 144 children in each treatment group.

Children were stratified by age <12months vs. >=12 months with equal number to be enrolled in each age group.

The primary endpoint was virologic failure (defined as <1 log decrease in viral load between weeks 12 -24 or >400 copies/mL at week 24), treatment discontinuation or death by week 24.

The investigators used Kaplan-Meier curves to estimate failure rates at week 24. Differences between treatment arms were weighted by the inverse of the variance in each age group.

A similar study of mothers exposed and unexposed to single dose NVP had also been conducted (A5208). In this trial – which we reported in previous issues of HTB – the arm in which exposed mothers received NVP-containing HAART was stopped early by the Data Safety Monitoring Board (DSMB) due to superior performance of the LPV/r- containing HAART arm. [3, 4]

Dr Violari reported that following a scheduled DSMB review of IMPAACT 1060 on 20 April 2009, enrolment to Cohort 1 had also closed prematurely due to a trend towards consistency with the A5208 results. Children in Cohort 1 were evaluated and discussions with their parents or guardians were held to decide whether to switch children receiving NVP to LPV/r. Cohort 2 is to continue enrolment and study as planned.

At the time of the DSMB review, Cohort I had enrolled 153/288 children with a median follow up of 48 weeks. The median baseline age of the children was 0.7 years (75% <12 months), median CD4 percentage 19%, and median viral load >750,000 copies/mL. Results at week 24 by primary endpoints are detailed in Table 1.

Table 1: Cohort 1, week 24 primary endpoints (from Kaplan- Meier curve)

Difference in week 24 failure rate (NVP-LPV/r): all 18% (95% CI 2%-33%), p=0.015.

Of 115 children tested, 16 (14%) had baseline NVP resistance, mostly Y181C (n=14). The investigators found the difference in viral failure between arms was greater among the 16 children with baseline resistance (57%) compared to the 99 without resistance (17%).

The investigators suggested these data emphasise the need for better prevention of mother to child transmission strategies including post partum “tail” coverage and maternal HAART. And that prioritisation of resources for mother-infant pairs should be encouraged.

NEVEREST

Several guidelines already recommend using LPV/r-based treatment for single dose NVP-exposed infants.

Louise Kuhn from Colombia University, New York, USA and Ashraf Coovadia from the University of the Witswatersrand, Johannesburg, South Africa, presented findings from the NEVEREST study. NEVEREST is an investigation to see if NVP-exposed children, initially suppressed on LPV/r-based HAART can safely switch to a NVP based regimen.

In this study children 6 weeks to 2 years of age and eligible for treatment (n=323), were initiated on LPV/r plus 3TC and d4T. After achieving a viral load <400 copies/mL and maintaining it for >= 3months, children were randomised (n=195) to either remain on LPV/r (control, n=99) or switch to NVP (switch, n=96), and then followed to 52 weeks post randomisation.

Baseline (pre-treatment) characteristics of the randomised children were mostly similar: median age, 11 months vs. 9 months; median CD4 percentage 19.0% vs. 18.4%; and 57% vs. 54% had a viral load >750,000 copies/mL in the control and switch groups respectively. There was a larger group of younger children age 1-12 months in the switch group, 57.6% vs. 68.8%, but this difference was not significant.

At randomisation the median age of the children were 20 months vs. 19 months; median CD4 percentage 28.9% vs. 28.5% and 61% vs. 66% had a viral load <50 copies/mL in the control and switch groups respectively. The median time on LPV/r based therapy was 9 months in both groups.

Two children in each group died; 3 children in the control and 5 in the switch group were lost to follow up and 3 children in the control and 5 in the switch group started TB treatment.

The investigators reported 80% vs. 86% of children were adherent to the study medication at 36 weeks post randomisation in the control and switch groups respectively.

When the investigators looked at viral load <50 copies/mL to 52 weeks they found 42.4% children in the control group and 56.2% in the switch group sustained viral suppression, p=0.01. But allowing for one elevated result (blip) the two groups were similar, 72.8% vs. 73.4% in the control and switch groups respectively.

They suggested that poorer adherence in the control group, due to the unpleasantness in taste of LPV/r syrup, may have led to more blipping and, in turn, unsustained viral suppression to 50 copies/mL during follow up.
In contrast, when they looked at sustained suppression to <1000 copies/mL, 98% vs. 80% of children in the control and switch groups achieved this, p=0.001.

An analysis of patterns of viral suppression after the children were randomised revealed that of the children >50 copies/mL, 56% in the control group had viral load between 50-1000 copies/mL and the remaining 2% more than 1000 copies/mL. In the switch group more children had viral load more than 1000 copies/mL 20%; but fewer, 24%, were between 50-1000 copies/mL.

In the switch group, viral suppression <50 copies/mL at randomisation was predictive of sustained viral suppression <1000 copies/mL through 52 weeks: 86.1% of children with viral load <50 copies/mL at randomisation sustained viral suppression <1000 copies/mL through 52 weeks vs. 63.5% with viral load 50-400 copies/mL at randomisation, p<0.001. Likewise, the presence of NNRTI mutations prior to treatment predicted sustained viral suppression after switch: 88% children with no mutations sustained viral load <1000 copies/mL through 52 weeks vs. 55.3% with mutations, p=0.007.

The median CD4 percentage at 24 weeks in the control group was 30.0% vs. 33.2% in the switch group, p<0.0001. In the control group 16.3% of children had a CD4 percentage decline of 10% vs. 3.2% in the switch group, p=0.004. Weight for age declined >1 z-score in 13.1% of children in the control group vs. 4.2% in the switch group, p=0.03.

The investigators wrote that this study provides proof of concept that re-use of NVP is possible under some circumstances for HIV-infected children exposed to NVP prophylaxis and should be further investigated. They note that the clinical significance of low-level viraemia in the control group needs further study. Switching may provide a promising option for children originally initiated on PI-based HAART to preserve second-line options. At this stage, switching requires close virological monitoring after the switch in order to be done safely.

COMMENT

The 1060 results are unsurprising and entirely consistent with the earlier maternal data. Baseline nevirapine resistance and younger age appear to be associated with the performance of the nevirapine arm.

NEVEREST was interesting and this strategy deserves further investigation. Another NEVEREST trial of efavirenz vs. lopinavir/r is planned in nevirapine-exposed children >3 years old.

Both studies underscore the limited treatment options that are available for children, particularly in resource limited settings.

References

1. Violari A et al. Nevirapine vs. lopinavir-ritonavir- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV infected infants: preliminary results from the IMPAACT P1060 trial. HIV Pediatrics, 17-18 July 2009, Cape Town. Abstract O_08.
2. Palumbo et al. Nevirapine (NVP) vs. lopinavir-ritonavir (LPV/r)- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV-infected infants: preliminary results from the IMPAACT P1060 trial. 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009, Cape Town. Abstract LBPEB12.
3. http://i-base.info/htb/261
4. http://i-base.info/htb/1449
5. Coovadia A et al. Randomized clinical trial of switching to NVP-based therapy for infected children exposed to nevirapine prophylaxis. HIV Pediatrics, 17-18 July 2009, Cape Town. Abstract O_09.
6. Coovadia A et al. Randomized clinical trial of switching to nevirapine-based therapy for infected children exposed to nevirapine prophylaxis. 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009, Cape Town. Abstract MOAB103.

Edmund Capparelli from the University of California, San Diego, USA, presented a population pharamcokinetic (PK) model of nevirapine (NVP) concentrations in maternal plasma, breast milk and infant dried blood spots (DBS) to better characterise infant NVP exposure via breast milk.

This analysis used data collected in a previously published substudy of the Kisumu breastfeeding study in Kenya (in which pregnant women received NVP-containing HAART to prevent mother to child transmission via breastmilk), the substudy measured antiretroviral concentrations in maternal plasma, breastmilk and infant DBS in 67 mother and infant pairs. There were 153 paired plasma and breast milk samples and 191 DBS samples.

The investigators performed PK modelling using the NONMEM programme. They developed a semi-physiologic population model to describe maternal plasma and breast milk concentrations simultaneously. These were linked with infant feeding times in order to estimate breast milk NVP concentrations at the time of feeding. In turn these breast milk concentrations were used to estimate NVP doses for the infant PK model of DBS concentrations.

Liquid chromatography mass spectrometry was used to measure NVP concentrations in the samples. The limits of quantification of the assay were 17ng/mL for plasma and breast milk, 40ng/mL for DBS and 43ng/mL for NVP.
The analysis found maternal plasma NVP PK parameters were stable during the study period. Breast milk and plasma NVP concentrations reached equilibrium rapidly, relative to elimination, providing relatively stable breast milk: plasma ratio with breast milk concentrations above the IC50 throughout the dosing interval.

The investigators reported an overall population NVP breast milk: plasma of 0.74. The typical estimated PK parameters for infants were: CL/F 0.0265 (±0.003)L/h/kg and V/F 0.97 (±0.125) L/h/kg. CL/F among infants increased with age giving lower median DBS concentrations at 14 weeks (717ng/mL) compared to 2-6 weeks of age (1005ng/mL).

They concluded that infant NVP exposure via breastfeeding achieves prophylactic concentrations as seen in the first weeks of age with PMTCT dose (2mg/kg). They noted that, “NVP breast milk concentrations rapidly equilibrate with maternal system concentrations and while slightly lower than plasma were well in excess of therapeutic NVP concentrations”. Also that the variability in both maternal and infant NVP elimination contributes more to infant exposure than NVP the breast milk:plasma ratio variability.

Ref: Capparelli et al. Population pharmacokinetic model of nevirapine (NVP) maternal to infant transfer through breastfeeding. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract 0_18.

Natella Rakhmanina from the children’s National Medical Center, Infectious Diseases, Special Immunology and Pharmacology, Washington, showed findings from a study to investigate whether the lopinavir (LPV) phenotypic inhibitory quotient (PIQ) and genotypic inhibitory quotient (GIQ) in treatment experienced children correlate with treatment response, when receiving LPV containing HAART, as observed in treatment experienced adults.

In this study the investigators collected 52 weeks prospective data from children and adolescents aged 4-15 years receiving LPV/r as single PI within antiretroviral regimens. 12-hour pharmacokinetic (PK) samples were collected and LPV susceptibility measured within 3 months of enrollment. Treatment histories, including resistance information, were obtained from medical records. Viral load and self reported adherence were measured 3 monthly.

IQ was calculated as the rate of plasma 12-hour trough concentration (Cmin) after observed dose divided by the protein-adjusted IC50 for PIQ and the number of LPV-associated mutations for GIQ.

In this analysis, 45 PI experienced children and adolescents were followed for 52 weeks. Their median age was 11 (5.3-17.8) years; 24 were girls and the majority (n=41) were African American. Of the group 40 (89%) received background regimens of 2 NRTIs, 2 received 3 NRTIs and 3 received NRTI plus NNRTI.

The median length of PI experience was 5.2 (0.7-9.2) years and of previous LPV exposure was 2.2 (0.5-5.0) years. Self reported adherence was a mean of 88% (41-100%). About half, 24/45(53%), of the patients achieved viral load, 400 copies/mL, at least once during the study. The median LPV Cmin was 6.2 (0.1- 16.7) mg/L.

Median PIQ (n=36) was 12.6 (0.03-231.1). The investigators noted that a baseline PIQ cutoff of 15 (as in adults) did not distinguish those achieving a viral load of <400 copies/mL from those that did not, p=0.09.

In multivariate analysis, only baseline PIQ >25 was significantly associated with viral load <400 copies/mL: 11/16 (69%) patients with PIQ >25 achieved viral load <400 copies/mL vs. 5/20 (20%) with PIQ <25, p=0.01.

The geometric mean PIQ in those patients achieving viral load <400 copies/mL was 16.7 vs 2.4 in those who did not, p=0.09.
The investigators found for every increase in baseline PIQ of 10, the probability of achieving viral load <400 copies/ml, when adjusted for prior duration of LPV treatment, increased 9.6-fold (95% CI 9.2-9.9), p=0.02.

They reported a median GIQ (n=22) of 1.0 (0.03-6.5) and a median of 6 (1-13) LPV mutations per patient. The geometric mean GIQ in those achieving viral load <400 copies/mL was 1.0 vs. 0.7 in those who did not, p=0.56.

The investigators concluded that LPV PIQ was associated with viral load <400 copies in PI experienced HIV-positive children and adolescents but GIQ was not. They suggest that a cutoff of LPV PIQ >25 may be a target for maximising efficacy.

Ref: Rakhmanina N et al. The phenotypic and genotypic susceptibility lopinavir scores and virologic response in treatment experienced children with HIV. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract 0_17.

J King and coworkers reported pharmacokinetc (PK) parameters of tenofovir (TDF) tablets received in combination with efavirenz (EFV) or duranavir/ritonavir (DRV/r) or atazanavir/ritonavir (ATV/r) in a group of children and adolescents age 8-18 years.

This study enrolled patients receiving >=2 weeks TDF 300mg in combination with:

Arm 1: EFV 300mg or 600mg once-daily

Arm 2: DRV/ritonavir dosed at 300/100 or 600/100 twice-daily

Arm 3: ATV/ritonavir dosed at 200-400mg/100mg twice-daily

Plasma samples were taken at 0, 1, 2, 4, 6, 8, 12 and 24 hours post dose and plasma concentrations of TDF were measured.
The investigators performed statistical tests to evaluate whether the 90% confidence intervals of the geometric mean (GM) for the PK parameters of TDF were within the target range ie 0.5-2.0 fold of adult values: 2.8 (2.3-3.6) mgxh/L and 0.06 (0.05-0.08) mg/L AUC and Cmin respectively.

They found that among patients receiving EFV (n=15) the TDF GM (90% CI) AUC and Cmin were 2.9 (2.4-3.4) mg.h/L and 0.07 (0.05-0.09) mg/L respectively. AUC and Cmin were 3.1(2.4-4.0) mg.h/L and 0.07 (0.05-0.09) mg/L in patients receiving DRV/r (n=10) and 3.6 (3.0-4.5) mg.h/L and 0.07 (0.06-0.10) mg/L respectively in patients receiving ATZ/r (n=17).

They noted that the TDF Cmin 90% CI included values above the target upper limit of 0.08 mg/L in all three arms and the AUC 90% CI included values above the upper target limit of 3.6 mg.h/L in patients receiving DRV/r or ATV/r.

The investigators concluded: “These data suggest that DRV/r and ATV/r may increase TDF exposure in HIV-infected children and adolescents.”

Ref: King J et al. A comparison of tenofovir pharmacokinetics across three tenofovir-based antiretroviral regimens in HIV-infected children and adolescents. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract P_53

The World Health Organization (WHO) recommends ARV treatment for all HIV-infected infants <12 months old, and that this should be started as early as possible. [1]

Nevirapine (NVP)-based ART is recommended for infants with no perinatal NVP exposure from mother-to-child transmission prophylaxis or NNRTI-based maternal ART. Protease inhibitor-based ART, usually lopinavir/ritonavir (LPV/r), is recommended for NNRTI-exposed infants.

There is however a scarcity of pharmacokinetic (PK) data on which to base dosing to support these recommendations. Two posters at CROI provided useful data for NVP and LPV/r in this age group.

Nevirapine exposure infants weighing 3-6kg receiving paediatric fixed dose combinations

A study conducted by Veronica Mulenga and coworkers from the CHAPAS trial in Zambia, looked at PK in infants weighing 3-6kg receiving fixed dose combination tablets. [2]

This group had previously reported data from a 12-hour PK study of nevirapine (NVP), stavudine (d4T) and lamivudine (3TC) receiving Triomune Baby (50mg NVP, 6mg d4T and 30mg 3TC) and Triomune Junior (double Baby dose). These tablets were developed with higher ratios of NVP to NRTI doses, according to paediatric dosing recommendations, to prevent under dosing of NVP. [3]

This earlier evaluation only included two children weighing 3-6kg, therefore the investigators performed a further PK sub-study of 14 children weighing 3-6kg.

The sub-study enrolled 16 children >1month of age and eligible for treatment in accordance with WHO guidelines. Children were initiated on full-dose NVP with a target dose of 300mg/m2. Target doses for d4T and 3TC were 2 mg/kg and 8 mg/kg respectively. With these targets, children in the WHO 3-6kg weightband receive one tablet twice daily. [4]

Samples were taken at t=0, 2, 6 and 12 hours after an observed dose, within four weeks of starting Triomune Baby.

One child was excluded because of non-adherence. Among the remaining 15 children there were 8 girls and 7 boys with a median (IQR) age of 5.3 months (4.1-8.4) and weight of 5.3kg (4.2-5.5). The children’s daily doses were 348 mg/m2 (324-386), 2.3 mg/kg (2.2-2.9) and 11.3 mg/kg (10.9-14.2) for NVP, d4T and 3TC respectively. See table 1 for PK parameters.

Table 1. PK parameters children 3-6kg

Mean (IQR), [standard deviation]

The investigators found large interpatient variability in Cmin concentrations of NVP.

When these data were compared with PK parameters from the previous study of children >6kg there was a difference of 15-20% lower NVP exposure in the 3-6kg weight band. d4T and 3TC parameters were comparable to the higher weight bands.

The investigators noted that 4/15 (27%) children had sub-therapeutic levels of NVP Cmin(<3.0mg/L compared to 3/63 >6kg (p=0.02). This occurred most frequently in children <5 months (3/6, 50%) vs >5 months (1/9, 11%) but the number of children was too small for this to reach statistical significance. The dose range in the younger children was 324-406 mg/m2 daily.

They suggest that the clinical consequences of NVP exposure may be minor as infants will be <5 months for a short time after treatment initiation, but that this requires further evaluation.

Model predicts rapid increase in lopinavir exposure in infants <6 months

Mina Nikanjam and coworkers performed a population PK analysis to characterise changes in lopinavir/ritonavir (LPV/r) PK in maturing young infants, and to assess dosing in this population. [5]

This group had previously shown that LPV/r exposure in infants <6 weeks of age receiving 300mg/75mg/m2 12 hourly, is lower than in older children receiving recommended doses. [6] However, the exact age at which LPV PK becomes similar to that in older populations is poorly understood.

This analysis used PK data from 31 infants <6 weeks of age from a prospective study, IMPAACT/PACTG P1030 to evaluate a 300mg/75mg/m2 12 hourly dose. 12 hour PK profiles (pre, 2, 4, 8 and 12 hr) were performed at week 2 of treatment and at 1 year of age.

Infants who did not achieve target LPV exposure at week 2 (Cpre >1mcg/mL) received a modified dose and a repeat analysis after 2 weeks. Trough LPV concentrations were taken regularly for up to 4 years and determined using LC/MS/MS method.

The investigators developed a population PK model using 549 LPV concentrations using
NONMEM non-linear regression software and allometric weight scaling. Empiric post-hoc LPV PK parameter estimates were generated from visits with multiple samples. The final model used Monte Carlo simulations to estimate appropriate LPV dosing in this infant population.

The investigators reported that age to was a powerful predictor of apparent clearance (CL/F), and was best described as a non-linear co-variate for bioavailability (F). They found half-life to be less affected by age. Ritonavir (RTV) levels correlated with LPV levels.

The interpatient variability for CL and volume of distribution (V) were 31.6% and 42.9% respectively. The median CL/F decreased with increasing age: 0.34 (<3 months, n=17), 0.22 (3-6months, n=19), 0.13 (approx 1 year, n=26) L/h/kg. As did the median V/F: 3.2 (<3 months), 2.4 (3-6 months) and 1.4 (approx 1 year) L/h/kg. The median AUC increased with increasing age: 49.8 (<3 months), 67.1 (3-6 months) and 11.10 (approx 1 year) mcg*hr/mL. Based on this model LPV AUC in a typical infant would reach the adult value of 80mcg*hr/mL by 9 months of age.

Monte Carlo simulations predicted very low troughs of LPV (<1 ug/mL) occurring with the study dose with 20% frequency in infants <3months but <1% in older infants. Using new WHO weightband dosing recommendations, the model predicted a lower frequency (13%) of troughs <1 ug/mL in the very young infants.

The investigators suggested that LPV concentration increases during the infants’ first year are likely to be due to increased bioavailability. Also the rapid increase in LPV exposure was likely to account for overall good virological suppression observed (most infants achieved viral load <400 copies/mL at 48 weeks) despite low concentrations at the start of therapy.

COMMENT

Both studies suggest large interpatient variability in exposure in young infants, but that this may be of little clinical consequence (and clearly things get easier as the children get older).

The introduction of food with LPV/r may play a significant role in increasing the absorption as the infants mature. However, there are probably some developmental issues relating to pancreatic exocrine function that also contribute to this.

The WHO dosing guidelines were constructed with the doses “rounded-up” and represent on average larger doses that the FDA labelled dose, which will counter the reduced absorption to some degree.

Although the investigators recommend frequent monitoring in young infants, the clinical response in the earlier LPV/r study provides the rationale for LPV/r use in resource-limited settings where this is not available.

Healthcare workers should be cautious of mal-absorption in infants with diarrhoea as well as in those that do not experience a clinical improvement.

Suitable solid paediatric formulations also make treating children more feasible. The fixed dose combination tablets used in CHAPAS are dispersible and can therefore be used in even the youngest infants in place of oral formulations. The investigators have not reported problems, according to Zambian health workers, and they are popular with families, as they are easy to carry. Of note, this study initiated the children with full dose NVP, which meant there was no change of dosing at two weeks after starting treatment.

Urgently required now is an easier to use, store and transport paediatric formulation of LPV/r. Cipla (who also produce Baby and Junior Triomune) have developed a “sprinkle” formulation using melt extrusion technology (similar to the newer LPV/r tablets). The formulation is in the same 4:1 drug ratio in 100/25 mg sachets. This is appropriate for even the youngest children, as it allows the drug to be easily mixed in with food. PK studies are currently planned or underway.

References
1. WHO Antiretroviral Therapy for Infants and Children 2008. Report of the WHO Technical Reference Group, Paediatric HIV/ART Care Guideline Group Meeting WHO Headquarters, Geneva, Switzerland, 10-11 April 2008.
http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_2008.pdf
2. Mulenga et al. Pharmacokinetics of nevirapine in 3- to 6-kg, HIV-infected infants taking pediatric fixed-dose combination tablets. 16th CROI, 2009. Poster abstract 881.
http://www.retroconference.org/2009/Abstracts/34683.htm
3. L’homme et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on fixed dose combination tablets. AIDS 2008: 22(5), 557-559.
4. WHO Summary of Paediatric Dosing.
http://www.who.int/hiv/paediatric/Sum_WHO_ARV_Ped_ARV_dosing.pdf
5. Nikanjam et al. Lopinavir population pharmacokinetic model and dose simulation predicts rapid increase in exposure for HIV-infected infants initiating therapy at <6 months of age. 16th CROI, February 2009, Montreal, Canada. Abstract 880.
http://www.retroconference.org/2009/Abstracts/34368.htm
6. Carrarelli et al. Lopinavir pharmacokinetic maturational changes and variability in HIV-infected infants beginning Kaletra therapy at <6 weeks of age. 15th CROI, February 2008, Boston, MA, USA. Abstract 573.
http://www.retroconference.org/2008/Abstracts/31505.htm

Rifampicin-based TB treatment is recommended for children (there is no formulation of rifabutin for young children nor is it widely available). In South Africa children with HIV who are <3 years old receive lopinavir/ritonavir-based antiretroviral 1st line regimens. Rifampicin reduces
trough concentrations of lopinavir by more than 90%. Additional boosting with ritonavir to a 1:1 ratio during TB treatment provides adequate concentrations in adults and children but this strategy is complex with oral solutions and not always feasible.

Helen McIlleron from the University of Cape Town presented findings from a pharmacokinetic (PK) study using double dose lopinavir/r (LPV/r) (ratio 4:1) with rifampicin in young children who were >6 months of age. This strategy has achieved adequate concentrations in healthy adult volunteers.

In this study, children with TB/HIV (n=17), received 460/115mg/m2 LPV/r +2NRTIs, once established on rifampicin-based TB treatment. Children without TB (n=24) were used as a control group and received the standard dose LPV/r 230/57.5mg/m2 +2 NRTIs.

Table 1. Baseline characteristics and PK of children receiving LPV/r

Baseline characteristics and PK parameters are median (IQR).

Pre-dose sampling was performed at 2, 4, and 8 hours after dose and determined using LC-MSMS method.

Following an interim analysis and DSMB review of plasma levels in 15 children with TB/HIV the study was stopped.

The investigators reported a median (IQR) LPV dose of 486 mg/m2 (478-497) in cases and 234 mg/m2 (228-241) in controls.

Characteristics and PK of the children are shown in Table 1. There were more girls than boys with TB/HIV and children with TB weighed less than controls.

They noted that among a subgroup of 5 cases sampled 12 hours after the observed dose 12-hour LPV concentrations were 0.65 mg/L lower than Cpre showing that adherence to the previous dose is unlikely to be the reason for the low concentrations.

The investigators found high interpatient variability within both groups of children. The median LPV Cpre, Cmax and AUC0-8h were reduced by 82%, 44% and 51% respectively among children receiving double dose LPV/r with rifampicin-based TB treatment; 10(59%) had subtherapeutic LPV/r Cpre (<1mg/L) vs 2 (8%) controls.

They do not recommend this approach in young children and Dr McIlleron concluded: “There is an urgent need to establish safe, effective and feasible co-treatment for young children with HIV associated tuberculosis”.

COMMENT

These data are important to offer guidance for “what not to do” in this population. They also argue for easier to use solid paediatric formulations of LPV/r and RTV.

Ref: McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.
http://www.retroconference.org/2009/Abstracts/34615.htm

South African HIV guidelines recommend PI-based regimens for children <3 years old. Young children mostly receive lopinavir/ritonavir (LPV/r) but in some cases full-dose ritonavir (RTV) is used if a child is also being treated for TB.

Cordula Reitz and co-workers evaluated factors associated with virologic suppression among children receiving protease inhibitors in Johannesburg in the NEVEREST study.

NEVERST enrolled HIV-infected children who had been perinatally exposed to nevirapine (NVP). Children age >6 months to 24 months received LPV/r based ART and children less than 6 months old or receiving TB treatment (rifampicin/isoniziazid for 6 months + pyrazinamide for 2 months) received RTV-based ART. All children received d4T+3TC.

Viral suppression was defined as reducing viral load to <400 copies/mL. Kaplan Meier methods were used to calculate the probability of achieving viral suppression at 9 months or death.

This analysis included 254 children with a median age of 8.75 months (IQR 5.18-13.8), median CD4 percentage 18.95% (IQR 12.8-24.5) and 80.2% were WHO stage III or IV.

Of these, 138 (54.3%) children started ART with a LPV/r-based regimen and 116 (45.7%) a RTV-based regimen. 54 (46.6%) were <6 months old and 62 (54.3%) were receiving TB treatment (by 9 months an additional 37 [14.6%] children began TB treatment).

The investigators reported an overall mortality rate of 14%. Higher mortality was significantly associated with younger age <12 months vs >12 months [AHR 2.9, 95%CI 1.1-7.8], pre-treatment weight for age z-score (WAZ) <-4 vs >-2 [AHR 3.3; 95%CI 1.4-8.2] and higher pre treatment viral load >750,000 copies/mL vs <100,000 copies/mL [AHR 3.1; 95%CI 0.4-23.5.

The probability of viral suppression (<400 copies/mL) was 83.7% at 9 months after starting ART. Children receiving TB treatment were less likely to achieve viral suppression than children never treated for TB, 78.3% vs 94.1% respectively.

The overall probability of viral rebound at 4 months was 17.6%. Only TB treatment was associated with viral rebound; 8/15 (53.3%) children who started TB treatment after ART and achieved viral suppression had viral rebound compared to 12% without TB and 2.8% probability among those who started TB treatment before ART, p<0.0001 [AHR 5.2; 95% CI 2.1-12.9].

Although the researchers reported high rates of viral suppression among children <2 years they wrote; “How best to treat HIV-infected children who require TB treatment remains an unsolved problem. There is an urgent need to further evaluate the pharmacokinetics and clinical outcomes in children co-treated for these two diseases so that evidence-based recommendations can be made.”

COMMENT

Once again, we need more PK data in younger children and better PI formulations.

Ref:

Reitz et al. Virologic Response to protease inhibitor-based ART among children younger than 2 Years of age co-treated for TB in South Africa. 16th CROI, February 2009, Montreal, Canada. Abstract 910.
http://www.retroconference.org/2009/Abstracts/34444.htm

Chistoph Konigs and coworkers from paediatric centres in Europe performed a dose finding study of etravirine (ETR) in treatment experienced children >6 years and weighing >20kg.

This was a phase 1, open label trial in two sequential stages. 21 HIV-positive children on stable lopinavir/r-based ART with viral load <50 copies/mL were enrolled in each stage. Children in stage I received 4mg/kg ETR bid following a meal (included in HTB reports from CROI last year). Children in Stage II received 5.2mg/kg ETR bid following a meal. ETR was added to background regimen for 7 days. After the morning dose on day 8 the investigators performed a 12 hour PK evaluation. 100mg and proportional 25mg tablets were used in this study. PK for 19 and 20 children were available in stages I and II, respectively.

The investigators reported the mean (SD) Cmax in stage I and II, respectively, was 495 (453) and 757 (680) ng/mL; Cmin was 184 (151) and 294 (278) ng/mL; and AUC12h was 4050 (3602) and 6141 (5586) ng•h/mL.

When they compared PK parameters to those reported in adult trials (n = 575), population derived Cmin was 393 [391] ng/mL and AUC12h was 5506 [4710] ng•h/mL, they found the levels achieved in children participating in stage II with the higher dose to be more appropriate.

All children had a viral load <50 copies/mL on day 8. The majority of side effects were grade 1 or 2, most commonly rhinitis or headache. Two children in stage 1 had a mild to moderate rash on day 8. No child discontinued treatment due to toxicity.

The target dose of ETR in children 6-17 years was selected as 5.2mg/kg bid, which provides comparable exposure to the adult dose of 200mg bid.

Further studies in children are ongoing or planned.

COMMENT

Tibotec intend to market the 25-mg tablet for children (and adults who have difficulty swallowing the 100-mg tablets) once they have the initial paediatric indication.

Ref: Konigs et al. Pharmacokinetics and dose selection of etravirine in HIV-infected children between 6 and 17 years inclusive. 16th CROI, February 2009, Montreal, Canada. Poster abstract 879.
http://www.retroconference.org/2009/Abstracts/35446.htm

Dr Tammy Meyers presented data from a large cohort of children on HAART at Harriet Shezi Children’s Clinic in Chris Hani Baragwanath Hospital, Soweto, South Africa. [1]

Of the 2,102 children who started treatment between April 2004 and March 2008), 1,734 (82%) are still alive and in the programme. Most of these children started with severely compromised immune systems. Based on earlier studies of untreated children at this stage of HIV disease [2, 3], nearly all would have died had they not been placed on HAART. By the end of the study, half the children had been on HAART for at least 17 months.

Kaplan Meier analysis showed that more than 90% of the cohort suppressed viral load to <400 copies/mL after 18 months on the programme. On average, CD4 percentage rose from 11% to over 25%. The children showed remarkable improvements in both weight and height improvement.

Most of the 132 deaths (6% of the cohort) occurred within the first 90 days of treatment, relating to late treatment. Meyers stressed that infants should now be treated on diagnosis, based on the findings of the CHER study, published last year, which showed that treating infants treated immediately upon diagnosis (as opposed to deferring treatment until their CD4 percentage met the current SA guidelines for initiating treatment) had much lower mortality. [4]

The factors at baseline that predicted death included being severely underweight, having a high viral load, being on TB treatment and younger age. But even among some of these categories, children did well. For example, 28% of children were on TB treatment, a much greater percentage than the number of deaths.

Both clinical trials and cohorts of children have previously been published showing excellent results on HAART. For example, a widely publicised successful cohort on 94 Haitian children was reported in 2005. [5]

The contribution of the Harriet Shezi study is that this is a large African cohort in a resource-limited setting.

From over 3,550 children in the clinic database, 369 were excluded because they were in the clinic before the start of the cohort period. Another 389 were excluded because they had no follow-up. This left 2,795, of whom 2,216 were initiated on HAART. 91 were excluded from the study because they had no further visits after initiation. 23 were excluded because they were over 15. Of the remaining 2,102 included in the analysis, 1,734 were alive and active at study end. 132 died. 104 transferred and 132 were lost to follow up.

Interestingly, of the 579 children who did not start HAART (presumably because they were ineligible according to SA guidelines), 264 are alive and active in the programme. 78 died (double the proportion in the treatment cohort). 189 were lost to follow up (more absolutely than the treatment cohort) and 67 transferred.

The cohort was roughly half boys and half girls. Median viral load was over 100,000 [IQR log viral load: 4.6-5.8 copies/mL]. Median CD4% was 11.5% [IQR: 6.9-16.2%]. Weight and height for age z-score median was 2.12 [IQR: -3.3 to 1.14] and -2.6 [IQR: -3.6 to -1.7]. Median age was 4.3 years.

The median follow-up time on HAART was 17 months [IQR 6-29]. The mortality rate was nearly 15 per 100 child years follow-up (CY) within the first 90 days and then about 2/100 CY. The mortality rate was markedly higher in children under 18 months old: over 30/100C within the first 90 days and 5/100CY after that. Based on a graph reading, the median CD4 rose to between 25 and 30%.

An important conclusion by the authors is that a high percentage of children starting HAART are co-treated for TB, warranting investigation of drug interactions.

References
1. Moultrie H et al. Mortality and virological outcomes of 2105 HIV-infected children receiving ART in Soweto, South Africa. 16th CROI, Montreal, 2009.
2. Little K et al. Disease progression in children with vertically-acquired HIV infection in sub-Saharan Africa: reviewing the need for HIV treatment. Curr HIV Res 2007, Mar;5(2):139-53.
http://www.ncbi.nlm.nih.gov/pubmed/17346131
3. Cross Continents Collaboration for Kids Analysis and Writing Committee. Markers for predicting mortality in untreated HIV-infected children in resource-limited settings: a meta-analysis. AIDS. 2008 Jan 2;22(1):97-105.
http://www.ncbi.nlm.nih.gov/pubmed/18090397
4. Violari A et al. Early antiretroviral therapy and mortality among HIV-infected infants [Internet]. N Engl J Med. 2008 Nov 20;359(21):2233-44.
http://www.ncbi.nlm.nih.gov/pubmed/19020325
5. Severe P et al. Antiretroviral therapy in 1000 patients with AIDS in Haiti. N Engl J Med. 2005 Dec 1;353(22):2325-2334.
http://content.nejm.org/cgi/content/abstract/353/22/2325

A South African study looked at isoniazid (INH) prophylaxis in young infants and found no increase in TB free survival. [1]

PACTG 1041 was a phase II/III double blind, randomised, placebo-controlled study of primary INH prophylaxis for prevention TB disease and latent infection infants with perinatal HIV-exposure.

In this study, HIV-positive, BCG vaccinated infants of 3-4 months of age were randomised to daily INH (10-20mg/kg/day) or placebo for 96 weeks. The infants also received cotrimoxazole, and ART where indicated, in accordance with WHO guidelines.

The primary objective of the study was to investigate whether INH increases TB disease-free survival in young infants.

Endpoints were TB disease and mortality at 96 weeks.

HIV-positive children (n=452, 226 per arm) with median age 96 days were enrolled between December 2004 and March 2008.

The children’s baseline median CD4% was 27% (range: 6-58%); 91% were CDC clinical category N/A, their median viral load was 666,500 copies/mL and 28% were receiving ART. At time of this scheduled interim analysis 66% of children were receiving ART.

The investigators found, at a median of 36 weeks follow up, 39 (17.3%) and 32 (14.2%) children in the INH and placebo groups, respectively, had TB or died, p=0.34. There were 24 (10.6%) and 22 (8.4%) (p=0.69) cases of TB and 15 (6.6%) and 10 (4.4%) non-TB related deaths in the INH and placebo groups, respectively. They reported no significant difference in rates of adverse event rates between the two groups.

In this study the overall cumulative incidence of TB by 96 weeks was high (22.2%; 95%CI: 15.7, 31.0).

The investigators wrote: “INH prophylaxis did not improve TB-disease free survival in HIV-positive African children with access to ART, indicating the need for alternative strategies to reduce the high public-health burden of childhood TB.”

As the appropriate INH infant dose is unknown, PACTG 1041 also investigated INH PK, and determined N-acetyltransferase-2 (NAT2) genotype to evaluate if PG explains INH PK [2].

The PK study target enrollment is 336 infants. Half of the infants were sampled at weeks 0 and 84 at 2 and 4 hours post dose, and the remaining children at weeks 12 and 84 at 1 and 3 hours post dose. INH was quantified in plasma (HPLC). NAT2 genotype was determined using RFLP and phenotypes assigned as slow (S), intermediate (I), and fast (F) acetylators.

This study used a 1-compartment model with first-order absorption and elimination (NONMEM v.VI). Covariates, including NAT2 phenotype, age, weight, sex, and HIV status, were evaluated using stepwise forward inclusion (p=0.05) and backward elimination (p=0.01).

The investigators modeled 306 INH concentrations from 131 infants. The infants had a median age of 171 days (range 91-717 days) at sampling; 53 were HIV-positive; 65 were girls; NAT2 phenotype, 32 S, 46 I, 30 F. Mean (SD) INH dose, 14 (3) mg/kg/d. Mean (SD) INH concentrations at 1, 2, 3, and 4 hours post dose were 12.0 (4.7), 8.3 (3.8), 6.3 (3.0), and 4.4 (3.0) mg/L, respectively.

They found the infants’ weight and NAT2 phenotype but not HIV status explained most of the interpatient variability in INH oral clearance (CL/F). Typical CL/F at weeks 0 and 12 for F phenotype were 3.3 and 3.9 L/hr and were 1.4 and 1.7 L/hr for S.

They wrote: “INH PK at a dose of 10-20 mg/kg/d in these infants are similar to published data in older (median 3.8 years) children receiving 10 mg/kg/d. The comparability of PK supports continued evaluation of this dose, which is at least twice that recommended by WHO.”

COMMENT

The full results of this trial are not yet out (but are unlikely to change). The investigators are studying the data to explain why no benefit was found for pre-exposure prophylaxis despite a high rate of incident TB.

References
1. Madhi SA, Nachman S, Violari A et al. Lack of efficacy of primary isoniazid (INH) prophylaxis in increasing tuberculosis (TB) free survival in HIV-infected (HIV+) South African children. 48th ICAAC, 25-28 October 2008. Washington. Abstract G2-1346a.
2. Kiser J, Zhu R, Nachman S et al. Pharmacokinetics (PK) and Genetics (PG) of Isoniazid (INH) in South African HIV-Exposed Infants-PACTG 1041. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-1826.

48-week data was presented from the DELPHI (TMC114-C212) study. DELPHI is a multi site open-label, two-part Phase II study assessing the safety and efficacy of DRV/r plus OBR in treatment-experienced children and adolescents.

Children were dosed according to body weight for >/=48 weeks: 20-<30kg, 375/50mg bid (20 patients); 30-<40kg, 450/60mg bid (24 patients); >/=40kg, 600/100mg bid (36 patients). PK, safety and efficacy (viral load, CD4 % and CD4 counts) were evaluated throughout the study.

80 children with a median age of 14 years (range: 6-17 years) of which 71% were male received DRV/r. At baseline their mean viral load was 4.64 log, median CD4 was 330 cells/mm3 and CD4 % was 17%. They had a median of 3 primary PI mutations, 11 PI RAMs (65% had >/=10 PI RAMs), 2 NNRTI and 4 NRTI RAMs.

The investigators reported that target DRV PK concentrations for treatment-experienced adults were achieved across all ages and weight bands, which confirmed the dose selection.

The majority of patients (74, 93%) experienced one AE. The most frequently reported were: fever, cough, upper respiratory tract infection and diarrhea. Most were grade 1/2. 21 (26%) patients had grade 3/4 AEs but most were considered to be unrelated to DRV/r. 11 (14%) of patients (14%) experienced serious AEs but there were no deaths. One patient discontinued the study because of grade 3 anxiety but this was not considered to be DRV/r related. 6 pts (8%) had grade 2-4 AEs possibly related to DRV/r.

At week 48, 65% of patients had ≥1.0 log10 viral load reduction (TLOVR); 59% and 48% were undetectable to <400 and <50 copies/mL (TLOVR), respectively. Their mean CD4 increase was 147 cells/mm3.

The investigators noted that predictive analyses will be performed to evaluate the contribution of the OBR to response rates in this population.

Ref: Blanche S, Bologna R, Cahn P et al. 48-wk safety and efficacy of Darunavir/ritonavir (DRV/r) in treatment-experienced children and adolescents in DELPHI. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-894.

Older age, perinatal HIV infection, antiretroviral therapy, and an on-treatment viral load below 400 copies independently raised the risk of lipodystrophy in a LEGACY cohort study involving 1490 US children, adolescents, and young adults. [1]

Girls were twice more likely than boys to be diagnosed with lipodystrophy.

Use of nucleosides, usually blamed for lipodystrophy, did not independently boost the risk of body fat abnormalities in this cohort, although treatment with a protease inhibitor (PI) or a nonnucleoside (NNRTI) did. The overall lipodystrophy prevalence stood at only 9% in the LEGACY cohort, much lower than rates in some other studies of antiretroviral-treated children [2-4], but similar to prevalence in another large US study. [5]

The LEGACY cohort includes 1490 people between 2 and 24 years old, 140 (9%) of whom had a diagnosis or symptoms of lipodystrophy in the cross-sectional part of this study. The investigators looked more closely at 575 youths for whom they had a complete treatment history from 2001 through 2006. Eighty-five youngsters and young adults in this longitudinally studied group (15%) had lipodystrophy, a rate still well below those found in three non-US studies. [2-4]

Multivariate analysis in the 1490-person group isolated seven factors that independently hoisted the risk of lipodystrophy at the following odds ratios (OR) and 95% confidence intervals (CI):

• Age 11 years or older: OR 1.1, 95% CI 1.0 to 1.1, P = 0.0068
• Perinatal HIV infection: OR 6.5, 95% CI 2.4 to 17.4, P = 0.0002
• Female gender: OR 2.2, 95% CI 1.5 to 3.2, P = 0.0002
• Viral load below 400 copies: OR 2.3, 95% CI 1.5 to 3.4, P < 0.0001
• Any NNRTI use: OR 2.1, 95% CI 1.3 to 3.3, P = 0.0012
• Any PI use: OR 1.9, 95% CI 1.2 to 2.9, P = 0.0047
• Serum triglycerides at or above 500 mg/dL: OR 3.2, 95% CI 2.1 to 4.7, P < 0.0001

Four of these factors (age, perinatal infection, low viral load, high triglycerides) suggest that longer HIV infection and longer antiretroviral treatment boosted the risk of lipodystrophy in this cohort. It is curious that nucleoside use did not make lipodystrophy more likely since the vast majority of cohort members taking a PI or an NNRTI would also be taking a nucleoside. Other factors that did not significantly affect lipodystrophy risk in the multivariate analysis were race/ethnicity, total cholesterol at or above 200 mg/dL, and CD4% above 25.

In the 575-person subgroup analysis, youngsters with lipodystrophy started potent combination therapy at a significantly earlier average age than those without lipodystrophy (8.2 versus 10.9 years, P = 0.007). Cohort members with lipodystrophy were significantly younger than those without lipodystrophy when they started any PI, ritonavir, any nucleoside, stavudine (d4T), or any NNRTI.

Three recently published pediatric cohort studies found higher rates of lipodystrophy in Europe (26% in 477 children) [2], Thailand (9% after 48 weeks of NNRTI therapy for 90 children, but 65% after 144 weeks) [3], and Romania (33% in 88 children) [4]. But a longitudinal 1999-2004 study of 178 US children in the PACTS-HOPE Group charted a lipodystrophy rate of only 5.6%. [5]

References
1. Paul ME, Frederick T, Siberry GK, et al. Risk factors associated with lipodystrophy in HIV-infected children and adolescents in the LEGACY cohort study, USA, 2006. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-462.
2. European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004;18:1443-1451.
3. Aurpibul L, Puthanakit T, Lee B, et al. Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Antivir Ther. 2007;12:1247-1254.
4. Ene L, Goetghebuer T, Hainaut M, et al. Prevalence of lipodystrophy in hIV-infected children: a cross-sectional study. Eur J Pediatr. 2007;166:13-21.
5. Carter RJ, Wiener J, Abrams EJ, et al; Perinatal AIDS Collaborative Transmission Study-HIV Follow-up after Perinatal Exposure (PACTS-HOPE) Group. Dyslipidemia among perinatally HIV-infected children enrolled in the PACTS-HOPE cohort, 1999-2004: a longitudinal analysis. J Acquir Immune Defic Syndr. 2006;41:453-460.

An article in the August edition of the Lancet Infectious Diseases reported findings from a literature review, conducted by Catherine Sutcliffe and co-workers, looking at 30 paediatric HIV studies or treatment programmes in sub-Saharan Africa. In this assessment, the authors found that children receiving antiretroviral therapy (ART) ranged from infants aged two months to adolescents aged 15 years. Out of 26 studies that reported age at ART initiation, 19 (73%) showed a mean or median age at starting treatment of >5 years. Only two studies reported a median age of starting treatment of <2 years.

The majority of children had severe immunosuppression at initiation of ART. The proportion of children with a CD4 percentage <15% ranged from 56% to 96%.

Only two studies reported how children were referred for treatment. In a Kenyan programme 69% of children were referred following admission to hospital and the remaining children were from other outpatient clinics. In Cote D’Ivoire, the paediatric department or other healthcare settings referred 64% of children, 24% were referred through the people living with HIV/AIDS network and 12% through prevention of mother to child transmission (PMTCT) programmes.

24/30 studies reported the antiretroviral regimens used, the majority (92%) of which included two NRTI inhibitors plus one NNRTI. Typically a regimen of: AZT or d4T plus 3TC with either EFV or NVP.

In the 17 studies that provided information on clinical outcomes, children gained 1.8-3.6 kg in the first year of treatment. There were improvements in weight for age Z scores with a median or mean -2 below baseline with a 1 SD improvement by 3 months. These improvements were sustained 2-3 years after start of treatment in those studies with longer follow up.

There was also significant immunological improvement reported in 28 studies, with a median gain in CD4 percentage of 7.0-13.8% at 6-8 months and 10-16% at 12-15 months of starting ART. And virological data from the 17 studies with the capacity to measure viral load showed a median 2.0 log10 reduction within 1 year. Undetectable viral load was defined differently across studies but for those reporting <250 copies/mL, 400 copies/mL or unknown, 54-55% of children were suppressed at 3 months, 46-81% at 6 months and 49-81% at 12 months after starting treatment.

In the studies reporting <50 copies/mL, undetectable viral load was achieved in 64% and 84% of children at 6 months and 67-100% at 12 months. The authors noted that the explanation for the higher level of suppression in studies using the more sensitive assays was unclear but this trend continued among the small number of children with longer follow up.

Overall mortality during follow up was mostly low with a probability of survival at one year after initiation of ART of 84-97%. A study from Cote D’Ivoire reported over 3 years of follow up, with 92-3% survival at six months, 91% at 12 months, 88% at 18-36 months and 86% at 42 months from initiation of ART.

The majority of deaths were within 6 months of starting treatment. The most commonly reported risk factor for death was low CD4 percentage at initiation of treatment. Age >12-18 months was among the other risk factors. One study from Mozambique compared mortality among children receiving ART and those ineligible for treatment. This comparison found that mortality was higher (HR 3.8, 95% CI 1.9-7.5) for the untreated group despite having better immunological and virological conditions at baseline.

Loss to follow up was generally low: 0-11% and 0.1-7.3% transfers among studies of <1year; 1-9% and 6.0-11.2% transfers, studies of 1-2years and 5.0-7.6% and 15% transfers among studies of up to 3 years.

The authors wrote: “Older children with slower disease progression are more likely to gain access to antiretroviral therapy in sub-Saharan Africa. By contrast, nearly two thirds of HIV-infected children who would have benefited from life prolonging treatment before reaching age 5 years are not being diagnosed or treated.”

COMMENT

This assessment gives a very useful picture of children receiving antiretroviral therapy in sub-Saharan Africa.

As the new WHO recommendations of universal treatment for all infants <12 months begin to be implemented, hopefully the picture should change considerably.

Links:

WHO recommendations:
http://www.who.int/hiv/pub/meetingreports/art_meeting_april2008/en/index.html

Ref: Sutcliffe CG, van Dijk JH, Bolton C et al. Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa. Lancet
Infect Dis August 2008; 8: 477–89].

The complexities of using liquid formulations of paediatric antiretrovirals (such as transportation, storage, cost, taste and dosing) are a barrier to scale up of HIV treatment in children. The WHO and UNICEF have requested the development and registration of solid paediatric formulations. Four posters showed novel combination dose and single drug tablets suitable
for paediatric use.

AZT and 3TC fixed dose combination tablet

GlaxoSmithKlein (GSK) have developed scored tablets of AZT 300mg/3TC 150mg (Combivir) for children >14kg and able to swallow tablets. [1]

Ivy Song and co-workers showed pharmacokinetic modelling, performed to support manufacturers’ dosing recommendations.

Doses were selected by weight bands using half and whole tablet regimens to provide daily AZT/3TC doses from -10% to +40% of those from the approved mg/m² (AZT) or mg/kg (3TC) dose of the liquid formulations (see table 1).

Table 1: Manufacturer recommended dose regimens of AZT/3TC scored tablets

Systemic drug exposures from these regimens were predicted using Monte Carlo simulations and reanalysis of historical data, and compared with historical exposure at approved doses in adults and children.

The investigators found the simulated AZT daily AUC for the scored tablet to be similar to historical controls while Cmax is 30-80% higher. Simulated 3TC daily AUC is 10-50% higher than historical controls while Cmax is higher than historical controls from BID dosing but similar to historical adult controls at approved 300 mg QD regimen.

Based on this model these dosing regimens of scored tablet are expected to provide similar safety and antiviral efficacy to 3TC and AZT at previously approved doses. The investigators note that there is a possibly of higher frequency of AZTassociated gastrointestinal effects (because of association with the higher Cmax) in some patients. They suggest that taking the whole tablet before bedtime may improve tolerability.

The manufacturer recommended doses overlap with but are “slightly more conservative” than the WHO recommendations for AZT/3TC (see table 2).

Table 2: WHO recommended dose regimens of AZT/3TC scored tablets

This formulation has been approved for use in the EU and review by the FDA is underway.

Dispersible fixed dose combination of 3TC/AZT/NVP

Ranbaxy laboratories have developed dispersible, scored 3TC/AZT/NVP fixed dose combination (FDC) Tablets for Oral Suspension (TFOS) for children. [2]

Raghuvanshi and co-workers summarised their findings from the prototype development. They describe the characteristics of this product as:

1. Dispersible into an oral suspension in 5 ml of water within 2 minutes.
2. Showing stability under accelerated conditions.
3. Similar in-vitro dissolution profile as that of three reference liquid products.
4. Complying to divisibility test.
5. Palatable and acceptable lemon flavor.
6. Having comparable pharmacokinetic parameters to individual reference liquid formulation under fasting conditions (n=18), (see table 3).

Table 3. Pharmacokinetic parameters of 3TC/AZT/NVP FDC compared to reference products

These investigations supported product feasibility for paediatric 3TC/AZT/NVP FDC. The investigators have completed the comparative bioavalability study for this product and it was filed for prequalification with WHO in November 2007.

Dispersible fixed dose combination of 3TC and d4T

Ranbaxy has also developed TFOS combining 3TC and d4T. [3]

They summarised the product characteristics:

1. Quickly dispersing into a suspension in 5 ml of water within 1 minute.
2. Having similar in-vitro dissolution profile as that of two reference liquid products.
3. Showing stability under accelerated conditions.
4. Having palatable and acceptable orange flavor.
5. Complying to divisibility test
6. Having comparable pharmacokinetic parameters to individual reference liquid formulation under fasting conditions (N=23) (see table 4)

The investigators concluded: “All the studied parameters of TFOS were satisfactory which support the product feasibility for paediatric therapy using lamivudine and stavudine FDC.”

Bioavailability of the 100mg etravirine tablet dispersed in water and of the 25mg tablet formulation

Tibotec have developed a 25mg paediatric tablet of etravirine (TMC125). Additionally the 100mg tablet can be dispersed in water.

Schöller-Gyüre and co-workers evaluated the oral bioavalability of the 100mg tablet dispersed in water and of the compositionally proportional 25mg pediatric relative to the 100mg tablet swallowed whole. In addition to treatment in children, the investigators suggest this evaluation will support adult patients with swallowing difficulties. [4]

This study was an open-label, randomised, 3-period crossover trial in HIV-negative volunteers. Three single doses of etravirine were administered as:

• Treatment A (reference) – one 100mg tablet swallowed whole
• Treatment B – four 25mg tablets
• Treatment C – one 100mg tablet dispersed in 100mL water

37 volunteers participated (7 women). All treatments were received within 10 minutes of a standardised meal and were separated by 14-days wash-out periods.

Pharmacokinetics of etravirine were assessed over 96 hours after each administration and least square means ratios compared to reference (see table 5).

Table 5: Pharmacokinetic parameters and LSM ratios of etravirine

The investigators noted that the decrease of Cmax by 15% when etravirine is received as four 25mg tablets is not considered clinically relevant.

They reported that etravirine was generally safe and well tolerated. The most frequently reported adverse event was headache (n=8). One volunteer discontinued prematurely because of Grade 3 lipase increase during Treatment B. No other Grade 3 or 4 adverse events were reported.

They concluded that the 25mg tablet of etravirine is suitable for paediatric use. Additionally paediatric or adult patients requiring an alternative to swallowing tablets can disperse etravirine tablets in water. They added that the stability of etravirine in liquids other than water has not yet been determined.

References
All references are to the Programme and Abstracts of the 17th International AIDS Conference, Mexico City, 2008.
1. Song H, Yuen G, Weller S et al. Development of Combivir (CBV) scored tablet: simplified dosing initiative for treatment of HIV infection in younger paediatric patient. 17th IAS, Mexico City, 2008. Abstract MOPE0186
2. Raghuvanshi RS, Jaiswal A, Chhabra A et al. Formulation development of novel dispersible fixed dose combination (FDC) of lamivudine,
nevirapine and zidovudine for pediatric use. 17th IAS, Mexico City, 2008. Abstract MOPE0183.
3. Raghuvanshi RS, Jaiswal A, Veera R et al. Dispersible novel fixed dose combination (FDC) of lamivudine and stavudine for pediatric use. 17th IAS, Mexico City, 2008. Abstract MOPE0185.
4. Schöller-Gyüre M, Kakuda TN, Van Solingen-Ristea RM et al. Bioavailability of the 100mg etravirine tablet dispersed in water and of the 25mg pediatric tablet formulation. 17th IAS, Mexico City, 2008. Abstract MOPE0184.

In an oral presentation, M Prime and coworkers presented findings from an investigation of clinical characteristics and circumstances in a group of vertically infected adolescents diagnosed in the UK or Ireland at 13 years of age or above. This study was conducted by investigators from: St George’s Hospital, London, London School of Hygiene and Tropical Medicine, St Mary’s Hospital, London, MRC Clinical Trials Unit, UCL Institute of Child Health and Mortimer Market Centre, London.

In the UK and Ireland, HIV positive children diagnosed at <16 years of age are reported to the National Study of HIV in Pregnancy and Childhood and followed up through the Collaborative HIV Paediatric Study. New HIV diagnoses made at adult services are reported to the Health Protection Agency and the Survey of Prevalent HIV Infections Diagnosed collects annual data on patients receiving care.

This study was an analysis of data to the end of 2005.

The investigators identified 38 cases; of these 19 (50%) were male and 36 (95%) were black African. 34 (89%) were born in sub-Saharan Africa, and three of these were diagnosed before arrival in the UK/Ireland.

The median age of the adolescents at diagnosis was 14.3 years (IQR: 13.6-15 years) with a median of 1.8 years (IQR: 0.2-5.6 years) between arrival in the UK and HIV diagnosis. 24 (63%) of those diagnosed presented with symptoms; the others were tested for HIV as part of screening for STIs or following diagnosis of a family member. Their median CD4 count at diagnosis was 208 cells/mm³ (IQR: 23-251 cells/mm³) and 11 developed AIDS before or within 2 years of diagnosis.

Thirty two patients began antiretroviral therapy (ART), the majority (88%) within a year of their HIV diagnosis.

The investigators wrote: “Young people with vertically acquired HIV infection are surviving childhood without ART and being diagnosed in adolescence. In this cohort a third were asymptomatic, highlighting the importance of testing all children born to HIV infected women, regardless of age or symptoms.” They added: “Increased awareness amongst clinicians is urgently required to prevent presentation with advanced disease and to reduce ongoing transmission as this population become sexually active.”

Ref:
Prime K, Ferrand R, Foster C et al. First presentation of vertically acquired HIV infection in adolescence. 14th Annual BHIVA Conference, Dublin, 2008. HIV Medicine, 9 Suppl. 1. Abstract O2.

Following a meeting In April 2008 of the WHO Technical Reference Group for Paediatric HIV/Antiretroviral Therapy and Care to consider the implications of recent research findings, the WHO have revised their guidelines for treatment and care of infants infected with HIV.

Of particular importance is the new recommendation: “All infants under 12 months of age with confirmed HIV infection should be started on antiretroviral therapy, irrespective of clinical or immunological stage.” This was made in light of findings from the CHER study, in which dramatic reduction in mortality (75%) was observed in infants treated immediately irrespective of immunological or clinical criteria compared to infants whose treatment was deferred until criteria as outlined in the previous treatment guidelines were met.

Other research and observational data also suggest that early antiretroviral therapy in infancy dramatically reduces the risk of death and disease progression.

The full report from the meeting and new recommendations can be accessed at:
http://www.who.int/hiv/events/paediatricmeetingreport.pdf

A paper authored by Tim Cressey and co-workers from the PENTA-11 study group, published in the 15 May 2008 edition of Clinical Infectious Diseases, showed findings from an evaluation plasma concentrations, viral load, and development of drug resistance after a planned treatment interruption of a NNRTI–containing regimen in HIV-positive children.

PENTA-11 is an ongoing, randomised, phase II trial evaluating the role of planned treatment interruptions (PTI) in the treatment of HIV-positive children with a good response to antiretroviral therapy.

In this study children on stable HAART for at least 6 months with viral loads <50 copies/mL and CD4 percentages of 30% (for children aged 2–6years) or CD4 percentages of 25% and CD4 counts of 500 cells/mm3 (for children aged 7–15 years) were randomised to either a PTI or to continuous therapy.

The PTI arm used one of two strategies for stopping NNRTIs:

1. Treatment with nevirapine or efavirenz was stopped, and treatment with the remaining drugs was continued for 7–14 days.

2. Nevirapine or efavirenz were replaced by a protease inhibitor, and all drugs were stopped after 7–14 days.

Choice between the strategies was at the discretion of the paediatrician.

Sampling for plasma concentrations, viral load, and drug resistance testing were performed on days 0, 7 (drug concentrations only), 14 and 28 after interruption of treatment with an NNRTI.

Of 110 children enrolled in PENTA-11 between November 2004 and December 2006, 56 were randomised to the PTI arm. Of these children, treatment with an NNRTI was stopped for 35 children of which 20 were receiving nevirapine, and 15 were receiving efavirenz). The median age of the children was 8.9 years (range, 3.6-15.9).

Median time from stopping treatment with an NNRTI to stopping all drugs was 9 days (range, 6–15 days) for nevirapine and 14 days (range, 6–18 days) for efavirenz.

The investigators reported that at 7 days, 1/19 (5%) and 4/8 (50%) children had detectable nevirapine and efavirenz concentrations respectively. Efavirenz remained detectable in 3/12 (25%) children at 14 days. At 14 days, viral load was 50 copies/mL in 6/16 (38%) children interrupting treatment with nevirapine (range, 52–7000 copies/mL) and in 2/12 (17%) children interrupting treatment with efavirenz (range, 120–1600 copies/mL).

They found that no new NNRTI or mutations were detected. Additionally, they reported no detection of 3TC-associated mutations.

The investigators concluded that in virologically suppressed children who interrupt an NNRTI-based regimen during their first PTI cycle, staggered or replacement stopping strategies for a median of 9 days for nevirapine and 14 days for efavirenz were not associated with the selection of NNRTI resistance mutations.

They noted that in this study it could not be determined whether a replacement or staggered stopping strategy is preferable. They suggest however that there are theoretical reasons to prefer a replacement stop strategy, particularly for efavirenz.

Ref: Cressey TR, Green H, Khoo S et al. Plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reversetranscriptase inhibitors in HIV type 1–infected children. Clinical Infectious Diseases 2008; 46.1601-8.

There has been limited data describing immune reconstitution inflammatory syndrome (IRIS) in infants and children.

In an oral presentation Kelly Smith showed findings from a case note review of children enrolled in NEVEREST 2 (between April 2005 and November 2006), a South African trial in which HIV-positive children <2 years, exposed to nevirapine through PMTCT receive d4T/3TC/LPV/r (or RTV if <6months). Children in this cohort receive BCG vaccination as a matter of routine. Often this occurs prior to HIV diagnosis.

In this study children were monitored for IRIS during the first four months of HAART.

The investigators found 34/162 children initiated on HAART were confirmed to have IRIS. The median time from initiation to first symptom was 16 days (range 7-115 days), with 73.5% of symptoms occurring within 30 days from HAART initiation.

BCG-osis, most commonly BCG injection site inflammation or ipsilateral axillary lymphadenitis with abscess formation, were the most common, 24/34 (70.6%) of all the IRIS events and14.8% of all children initiating HAART.

Other IRIS events included: TB in 11/34 (32%) children, CMV pneumonia, PCP, seborrheic dermatitis, herpes simplex, S peumoniae sepsis and pneumonia.

The investigators reported that children with IRIS were younger, 47% <6months vs 25%; had lower CD4%, 56% CD4% <15% vs 34% and had higher baseline viral load, >750,000 copies/mL
45% vs 21% than children with no IRIS.

These children also had lower average weight for age z-score, mean -3.26 vs -2.09 and 82% vs 49% had < -2 SD below the mean (p=0.0004).

See Table 1 for baseline predictors for development of IRIS.

Table 1: Baseline predictors for development of IRIS

After 24 weeks, response to HAART was lower the children with IRIS, with 28% vs 62% <400 copies/mL and 14% vs 44% <50 copies/mL.

Increase in CD4 percentage was similar between groups, but children with IRIS had lower mean CD4% at 24 weeks, 21.5% vs 29.0%, (p=0.001).

Dr Smith concluded that IRIS, particularly BCG-related disease, was common in this cohort of young children initiating HAART. Children with very advanced disease and low weight for age appear to be at particularly high risk.

Additionally, children with IRIS are less likely to achieve complete viral suppression by 24 weeks.

She added, “Further research is required to understand the pathogenesis and diagnosis of IRIS and determine best practices for prevention and treatment.”

COMMENT

Diagnosing IRIS in children remains difficult and is an inexact science. BCG reactions are the most clear-cut clinical presentations of IRIS (see also study below). CMV pneumonia, PCP, seborrheic dermatitis, herpes simplex, S. pneumoniae sepsis and pneumonia carry an element of subjective assessment.

Was the decision to call a condition IRIS made by clinicians blinded to the CD4 percentage? There is great potential for bias, if the diagnostic criteria for calling a condition IRIS is based in part on the knowledge that the initial CD4 is low. Also, a child developing a new opportunistic infection within a few days or weeks of starting ART, may have been so profoundly immunosuppressed that they remained at much the same risk of OIs as they had prior to initiating ART. Including such children in the data set further perpetuates the notion that IRIS occurs in children with a low CD4 %.

The conclusion that further research is needed to understand the pathogenesis is entirely correct.

Ref: Smith K, Kuhn L, Coovadia A et al. Immune reconstitution inflammatory syndrome in HIV-infected infants and young children initiating ART. 15th CROI, February 2008, Boston, MA, USA. Oral abstract 75.

A poster from the CHER study group looked at Bacille-Calmette-Guerin (BCG)-related complications in this cohort and in a comparator group of HIV-negative infants born to mothers participating in a vaccine trial.

In this study 292 HIV-positive infants 6 to12 weeks of age were randomised to immediate ART and 125 to deferred ART. The HIV-negative infants in the study were born to HIV-positive (n=125) and HIV-negative mothers (n=125).

All children received BCG vaccination at birth as is standard in South Africa. Signs of local reaction to BCG and other clinical events were compared among the infants.

This was data after a median follow up of 40 weeks.

The investigators reported that the prevalence of regional BCG-adenitis among the HIV-positive infants was 33/417, 7.9% (5.5 to 10.9), of which13 (10.4%), were in the deferred arm and 20 (6.9%) in the early ART arm (OR 1.6, 0.8 to 3.3; p =0.22). By comparison none of the HIV-negative infants had local BCG-adenitis.

The majority, 31/33 (93.9%) of cases of BCG-related regional adenitis occurred following initiation of HAART, which suggested IRIS. 2 infants in the deferred arm had pre-existing adenitis.

There was no difference in the development of IRIS-related BCG-adenitis between the early-HAART 20/292 (6.8%), p= 0.48 and the deferred HAART 11/125 (8.8%) groups.

Out of the 33 infants with BCG-adenitis, 3 died (2 in the deferred arm and 1 in the early ART group). One of the deaths (in the deferred arm) was considered to be associated with BCG disease.

The investigators noted that the infants in the deferred arm received more concomitant therapy than in the early ART group (7/13 infants vs 4 /20 for TB treatment). Of 8 infants that received prednisone, 7 were in the deferred arm (53.9%) and 1 in the early ART group (0.5%).

The percentage of local BCG reactogenicity to BCG was similar (>50%) regardless of HIV status.

In the discussion section of this poster the investigators explained that in May 2007, the WHO revised its guidelines for BCG vaccination for children born to HIV-positive mothers. WHO recommended that it should not be given to children known to be HIV-positive. By that time, the CHER trial was fully recruited.

The investigators concluded:

• HIV-positive infants receiving BCG at birth have a high risk of BCG-associated IRIS.
• Associated factors are lower CD4 count/percentage and low WAZ.
• In infants with baseline CD4 >/=25%, early ART is associated with significantly less IRIS than deferred ART
• Children in the deferred arm developed IRIS sooner after ART initiation with longer time to resolution
• TB drugs +/- steroids did not improve the time to resolution.

They wrote: “Early ART is associated with a significant reduction in BCG-associated IRIS, probably by limiting the degree of CD4 depletion.”

Ref:
Rabie H Violari A, Madhi S et al. Complications of BCG vaccination in HIV-infected and -uninfected children: CHER Study. 15th CROI. February 2008. Boston, USA. Poster abstract 600.

There are very few descriptions of characteristics of very young HIV-positive and HIV-exposed infants (<60 days). In settings with no access to PCR or CD4% quantification where clinical presumptive diagnosis is often used, these data could guide diagnostic algorithms for infants.

In an oral presentation, Heather Jaspen from the Faculty of Health Science, University of Stellenbosch, Cape Town, South Africa reported findings from an evaluation of the clinical and immunological parameters of HIV-positive infants and clinical characteristics of exposed, uninfected (EU), and unexposed, uninfected (UU) infants aged 4 to 10 weeks.

HIV-positive infants in this study were enrolled from the CHER study (n=540), and EU (n=125) and UU (n=125) infants were from a vaccine study in Cape Town and Soweto.

The median age of all infants was 44 days (range 28 to 78 days).

The investigators found weight below the 10th centile, oral thrush, lymphadenopathy and hepatomegaly to be significantly associated with HIV-positive status in infants in this study (all p<0.001). Nappy rash, was also more likely in infants with HIV (p<0.05).

Anaemia, neutropenia, gastroenteritis and gastric reflux (GERD) were also associated (p<0.005).

When the investigators looked at clinical characteristics and severe immunosupression (</=25%) in the HIV-positive infants only weight (OR 1.6, 95% CI 1.1-2.4) and lower respiratory tract infection (OR 0.3, 95% CI 0.1-0.7) were associated in an age adjusted analysis.

So the study largely focused on the association between clinical characteristics and HIV infection.

After age adjustment, the investigators found weight in the lowest 10th percentile (OR
3.3, 95% CI 1.6-6.6), oral thrush (OR 5.6, 95%CI 3.0 to 10.2), any lymphadenopathy (OR 8.9, 95%CI 3.8 to 29.8), generalized LAD (OR 9.2, 95% CI 2.9-29.8) and nappy rash (OR 2.4, 95% CI 1.5-4.0) were associated with HIV infection.

When the investigators performed a sensitivity analysis including the following symptoms: oral thrush, any LAD, hepatomegaly, splenomegaly, GERD and weight below the 10th percentile, presence of one symptom gave a sensitivity of 49.6% and specificity of 78.4%. Increasing the cut off to two or more symptoms decreased sensitivity but rapidly increased specificity. Two symptoms gave a specificity of 97.6% with 25% sensitivity. Three or four symptoms gave 100% specificity with 10.2% and 5.6% sensitivity for three and four symptoms respectively.

Dr Jaspen remarked that this is at least as good as the IMCI and WHO algorithms for diagnosis in older children. But, she explained, “Many HIV-infected children will still be missed, therefore PCR in resource limited settings is essential.” She added that these findings need to be validated in different populations before an algorithm can be developed.

COMMENT

A previous small study from the Cote d’Ivoire [Rouet et al. AIDS 2002, 16:2303 – 2309] described a mononucleosis-like syndrome, dermatitis, and generalised lymphadenitis as independent factors associated with acute retroviral infection in breast fed infants. Generalised lymphadenopathy had a specificity of 96% and a sensitivity of 32%.

The negative and positive predictive values depended on the MTCT rate: the higher the rate of transmission, the higher the PPV but the lower the NPV. Clinical algorithms are no substitute for affordable sensitive and specific tests, when it comes to decision making about starting ARVs.

Ref:
Jaspan H, Myer L, Violari A et al. Clinical and immunological characteristics of very young infants with HIV infection: Children with HIV Early Antiretroviral Study. 15th CROI, February 2008, Boston, MA, USA. Oral abstract 76, 2008.

In an oral late breaker Sabrina Spinosa-Guzman from Tibotec presented data for duranavir boosted with ritonavir (DRV/r) in a group of treatment experienced children and adolescents.

TMC114-C212 or DELPHI, (Darunavir EvaLuation in Pediatric HIV-1-Infected treatment-experienced patients) trial is an ongoing 48-week, open-label, two-part phase II dose finding, pharmacokinetics, safety, tolerability and efficacy study in a group of paediatric patients aged 6 to 17 years.

In part I, patients were randomised to 2 DRV/r dose groups. In part II all patients received the recommended dose per body weight. Dr Spinosa-Guzman presented safety and efficacy results of part II from a primary analysis at 24 weeks.

In this study patients received doses according to weight bands: 20 to <30 kg, 375/50 mg twice a day (20 patients); 30 to <40 kg, 450/60 mg twice a day (24 patients); ≥40 kg, 600/100 mg twice a day (36 patients). With optmised background therapy.

80 children and adolescents (71% male; median age of 14) received DRV/r in this study. Mean baseline viral load was 4.64 log10 (SD=/-0.80) copies/mL, median baseline CD4 count was 330 (range 6-1505; 31% had CD4 <200) cells/mm3, and CD4 percentage was 17% (range 0.7-47).

Median number of previously used antiretrovirals was 9 (range 3-13). Median baseline of 3 (range 0-6) International AIDS Society (IAS) -USA primary protease inhibitor (PI) mutations, 11(0-19) PI resistance-associated mutations (RAM; 65% had ≥10 PI RAM) and 1 NNRTI and 4 NRTI RAM.

The investigators reported that the target DRV pharmacokinetic exposures for treatment-experienced adults were achieved across all age groups and weight bands.

71 patients (89%) reported 1 adverse event. The most common (>10% of patients) were upper respiratory tract infection, cough, pyrexia, vomiting, diarrhea, and lymphadenopathy. Most adverse events were grade 1 or 2. Grade 3 or 4 adverse events were reported in 18 patients (23%); most were single events in individuals and were considered unrelated to DRV/r. Serious adverse events were reported in 9 patients (11%). No deaths were reported during treatment period. One patient permanently discontinued treatment due to grade 3 anxiety, considered to be unrelated to DRV/r by the investigator.

At week 24, 74% of patients had a viral load reduction of ≥1.0 log10 from baseline. Viral load <400 copies/mL and <50 copies/mL were achieved by 64% and 50% of patients, respectively. The mean increase in CD4 cell count from baseline was 117 cells/mm3.

The investigators concluded: “DRV/r was an effective treatment in treatment-experienced HIV-1-infected pediatric patients (6 to 17 years) due to the favorable tolerability and pharmacokinetics profiles, and virologic response rates at week 24.”

COMMENT

The optimised background therapy in this study did not permit the use of TMC125 (etravirine) or integrase inhibitors. T20 was allowed and it would be helpful to know how much this contributed to achieving virological suppression.

Frankly, we need to do better than 50% of patients achieving <50 copies/mL, although the ITT outcomes at Week 48 are still pending.

Ref:
Bologna R, Rugina S, Cahn P et al. Safety and efficacy of darunavir co-administered with low-dose ritonavir in treatment-experienced children and adolescents at week 24. 15th CROI. February 2008. Boston, MA, USA. Oral abstract 78LB.

A poster authored by Megan Palmer and coworkers from the United States and South Africa presented findings from PACTG 1020A. This is a phase I/II study of atazanavir (ATV) with or without ritonavir (r) with 2 NRTI (excluding tenofovir [TDF]) in HIV-positive treatment-naïve children aged 91 days to 21 years.

This poster showed data from treatment-naïve South African children participating in the dose-finding study, for age (<2 years, 2 to 13 years, >13 years) and formulation (powder vs capsule) groups.

Each group started with a dose of 310 mg/m2 of ATV, which was adjusted based on day 7 24-hour, intensive PK and week 4 safety data. Acceptable PK and safety dose criteria were:  AUC >/=30 ug*hour/mL and C24 >/=60 ng/mL in 4 of 5 children; no AUC <15 ug*hour/mL; and median AUC for 5 children </=60 ug*hour/mL and </=1 of 5 children with >/= grade 3 adverse events, none life-threatening.

Guided by these criteria, the investigators either enrolled an additional 5 children at the starting dose or the starting dose was adjusted. An optimal dose was based on >=10 evaluable children with acceptable PK and safety results.

The study has enrolled 183 children to date of this evaluation; 62 from South Africa.

This report showed 48-week treatment outcomes for 57 South African children receiving unboosted (n=22) and boosted (n=35) ATV. Approximately half (29/57) of the children were girls.

At baseline, the children were a median of 6 years of age
(91 days to 21 years); CD4 count, 411 cells/mm3 (24 to 2192); CD4%, 13% (1 to 35); log10 viral load, 5.0 (3.6 to 5); and mean height z-score, –2.09 (–4.56 to 0.73) and weight z-score, –1.98 (–5.80 to 0.91).

The investigators reported that 35/48 of the children (73%, 95%CI 58% to 85%) had viral load <400 copies/mL at 48 weeks, in an intent-to-treat analysis. Weight and height z-score improved significantly at the same time point; mean change in height z-score +0.27 (p=0.04) and mean change in weight z-score +0.79 (p<0.0001).

11 children discontinued ATV, of these, 5 were due to toxicity (hyperbilirubinemia, LFT increase, or QT interval changes), 1 due to death (unrelated, pneumonia), and 5 for other reasons (eg lost to follow-up, need for protocol disallowed medications).

The investigators noted that RTV boosting of the capsule significantly improved PK parameters of ATV. The dose of 310 mg/m2 for powder and 205 mg/m2 for capsule plus RTV passed protocol defined safety parameters.

They also found in this South African cohort children were severely malnourished at baseline and weight and height z-scores improved significantly.

Ref:
Meyers T, Rutstein R, Samson P et al. Treatment responses to atazanavir-containing HAART in a drug-naïve paediatric population in South Africa. 15th CROI. February 2008. Boston, Mass, USA. Poster abstract 582.

Children’s responses to ART in Africa may be different from children in well-resourced settings due to non-HIV-related factors including nutritional status, exposure to infections, food scarcity and malnutrition.

Addy Kekitiinwa and coworkers compared 6 and 12-month immunological, virological and growth responses to ART in HIV-postitive children from 54 hospitals in the United Kingdom and Ireland (Collaborative HIV Paediatric Study, CHIPS) and from the Mulago Hospital, Uganda.

This study looked at predictors of viral load suppression <400 copies/mL, CD4 percentage increases >10%, and height- and weight-for-age z-score increases >+0.5, 6 months post-ART (starting >3 drugs, >2 classes).

Children in the CHIPS cohort (n=582) initiating ART naive 1997-2006 and Mulago cohort (n=876) initiating ART naïve 2003-2007 were evaluated.

The investigators found at baseline, CHIPS children (76% black African) were younger than Mulago children median age 5.0 (IQR 1.6-8.9) vs 7.6 (IQR 4.4-11.6) years, with higher pre-ART CD4 percentage (14% vs 8%), lower viral load (172,491 vs 346,810 copies/mL), less stunting (–0.8 vs –2.8) and wasting (–0.6 vs –2.8).

After initiation of ART, the two groups showed similar changes in CD4 percentage (median +12%, +14%) and weight (+0.5, +0.4) at 12-months.

There was less change in height in the Mulago children (+0.06 vs +0.20, heterogeneity p<0.001). 16% in CHIPS vs 70% in Mulago had height <2.5th centile at ART initiation; this reduced to 11% at 12 months in CHIPS but remained at 70% in Mulago. The investigators noted that if these z-scores continued throughout childhood the average 17 year old would be 1.72 and 1.60 metres tall in CHIPS for boys and girls respectively (average UK population 1.76 and 1.64 metres) but only 1.53 and 1.47 metres tall in Mulago.

In multivariate analysis, in both cohorts, younger children had better immunological, weight and growth responses (all p<0.001) but slightly poorer viral load responses (p= 0.08) and girls had a better immunological response than boys (OR 1.55, p= 0.001).

In contrast, lower pre-ART CD4 predicted better immunological response in CHIPS but poorer response in Mulago (heterogeneity p=0.005). The investigators suggest that this may reflect poorer nutrition status and/or other environmental factors such as lower background incidence of infectious diseases in UK and Ireland.

Although 70% of the children in both cohorts had viral load <400 copies/mL at 6 months, adolescents starting ART in CHIPS had a poorer viral load responses than those in Mulago, which may reflect poorer adherence.

The investigators concluded that these findings highlight the importance of monitoring growth as well as weight gain over longer periods on ART in resource-limited settings. They suggest that investigations to evaluate the effect of nutritional support on growth in children initiating ART in resource- limited settings are urgently needed.

They wrote: “Finally, this study has relevance for questions currently being raised about the timing of initiation of ART in resource—limited settings in both adults and children. Earlier HIV diagnosis and nutritional support are clearly required for children in Africa, and initiating ART earlier in the course of the disease may well be beneficial.”

Ref: Kekitiinwa A, Lee K, Walker A et al. Initial growth, CD4, and viral load responses to HAART in Ugandan compared to UK/Irish HIV-infected children. 15th CROI. February 2008. Boston, USA. Poster abstract 584.

Correct dosing of antiretrovirals in HIV-positive children is complicated due to age-dependent changes in pharmacokinetics (PK) and the scarcity of data.

There were a number of posters at CROI showing PK data of old and new antiretrovirals in children from different age groups, and settings and with varying treatment experience.

Lopinavir/ritonavir in young infants

Data from the CHER study demonstrated a 76% reduction in early mortality in very young infants starting antiretroviral therapy (ART), regardless of clinical status, CD4 percentage or viral load. [1]

Since this finding, US guidelines (and others are expected to follow) recommend initiation of ART as soon as possible after birth for all infants age <12 months. [2]

Infants started on LPV/r 300 mg/m2 before 6 weeks of age have low LPV exposure after two weeks of treatment. The clinical relevance of these low concentrations depends on how rapidly infants acquire therapeutic LPV exposure.

Edmund Capparelli and co-workers from the USA and Brazil evaluated longitudinal PK and response to treatment in young infants initiated on LPV/r-containing regimens.

This was a prospective, phase I/II, open-label, dose-finding study using a dose of 300/75 mg/m2 twice daily + 2 NRTI in young infants >/=2 and <6 weeks of age.

Infants had a 12-hour PK evaluation after 2 weeks of treatment and a second PK evaluation at approximately 1 year of age. Trough LPV concentrations and viral load were assessed regularly during the first year of treatment.

Doses were modified to maintain LPV pre-dose (C-pre) >1 µg/mL and AUC <170 ug.hr/mL based on week-2 pharmacokinetic results.

10 infants were enrolled in the study before 6 weeks of age (median 5.6 weeks) with median viral load of 5.9 log copies/mL. Of these, 9 infants had evaluable PK at 2 weeks and 7 had repeat evaluations at 1 year of age.

The investigators reported that during the first year of treatment the overall median LPV C-pre was 2.3 µg/mL; 20% of levels were sub-therapeutic (<1 µg/mL). In individual infants, C-pre <1 was observed in 0% to 50% of levels. 9/10 and 7/10 infants had viral loads <1000 copies/mL at 16 weeks and 48 weeks, respectively.

Table1: LPV exposure increase during the first year of life

They found that infants with viral blips >1000 copies/mL between 8 wand 48 weeks were more likely to have sub-therapeutic C-pre, (r= 0.73, p= 0.016).

The investigators concluded that LPV/r exposure is initially low in infants <6 weeks of age but increases dramatically during the first year of life. But despite the low initial LPV exposure, most infants achieved viral load <400 copies/mL at 48 weeks.

They noted that viral loads >1000 copies/mL at 8 weeks and later, seen more frequently in infants with intermittently low LPV concentrations, suggested a link with difficulties in drug administration or adherence.

Recommended dose of lopinavir/ritonavir too low in protease inhibitor-experienced children

Lopinavir/r is approved for paediatric use in children aged 6 months and older at a dose of 230 mg/m2 twice daily, with a maximum of 400 mg/dose.

In adult PI-experienced patients, a target trough LPV concentration of <5.7 mg/L is associated with less likelihood of an undetectable viral load.

Natella Rahmanina and coworkers from the US reported findings from a study using modelling to determine whether this target is relevant in children, and can be achieved at the current recommended paediatric dose. [3]

Over 52 weeks, the investigators evaluated 50 PI-experienced children (4 to 17 years) receiving LPV/r-based therapy (single PI). Baseline resistance tests and 12-hour PK evaluations were performed (at second visit); viral load and adherence were assessed throughout the study.

Using multiple logistic regression, trough LPV concentration, adherence, and resistance were modelled as predictors of virologic outcome. PK data were fitted to candidate PK models. The model with the highest log-likelihood was used to simulate 5000 children to find the percentage with trough LPV concentration <5.7 mg/L after standard dosing.

The investigators found LPV resistance at baseline (p=0.003) and trough concentrations <5.7 (p=0.03) were significant predictors of never achieving viral load <400 copies/mL during the study period. In this model adherence did not predict virological outcome. LPV trough was <5.7 in 40% of the 5000 children simulations from this model.

The investigators wrote: “In this validated paediatric population pharmacokinetic model of LPV/r, the currently recommended dose of LPV will fail to consistently achieve this target in a large percentage of children. Further studies on therapeutic drug monitoring of LPV/r in children are warranted.”

Therapeutic drug monitoring of lopinavir and saquinavir in Thai children

Torsak Bunupuradah and coworkers from Thailand and the Netherlands looked at drug levels of PIs in a group of 50 Thai children. [4]

This was a prospective, open-label single-arm study of children receiving LPV/r and saquinavir (SQV) at standard doses.

Pre-dose plasma concentrations (Cmin) were taken at weeks 12, 24, 36, 48, 60, 72, 84, and 96. Children with Cmin <0.1 mg/L for LPV or 0.02 mg/L for SQV were excluded from the analysis because of suspected nonadherence.

Doses were adjusted according to clinical, growth, and Cmin. Cmin above the 50% inhibitory concentration (IC50) of >1.0 mg/L for LPV and >0.28 mg/L for SQV
were targetted.

The children in this study had a median age at baseline of 9.3 years (IQR 7.1 to 11.2). For each time-point, 42 to 48 samples were available for analysis (348 for LPV and 353 for SQV).

The investigators found the overall mean (SD) of the Cmin were 5.52 (3.85) and 1.37 (1.24) mg/L for LPV and SQV, respectively. They reported no significant change over time for the Cmin levels.

At week 96, 5.5% and 3.7% had Cmin >IC50 for LPV and SQV respectively. The average dose for SQV decreased from 43 mg/kg at baseline to 34 mg/kg at week 96. The LPV dose remained almost the same: 228 mg/m2 and 229 mg/m2, at the same time-points.

The median intravariability over 96 weeks was 55% (IQR 41 to 76) and 67% (IQR 54 to 85) for LPV and SQV, respectively. The median intervariability was 69% (IQR 60 to 74) for LPV and 81% (IQR 76 to 94) for SQV.

The investigators noted that despite the dose reduction of 32% from standard dosing for SQV at week 96, the plasma levels indicate that further dose reduction is possible and that the high LPV Cmin suggests that dose reduction is reasonable. “Further research is warranted to establish a more appropriate dose for this Asian population”, they wrote.

Nevirapine exposure with WHO paediatric weight band dosing

Nevirapine (NVP) is dosed according to body surface area (150 to 200 mg/m2) or weight and age (7 mg/kg <8 years and 4 mg/kg >/=8 years). These dosing guidelines are far too complex for implementation in resource- limited settings and are themselves inconsistant. World Health Organisation (WHO) has developed a simple weight-band tables based on body surface area calculations of appropriate dose of key antiretroviral drugs for use in these settings. To date dosing of NVP(or other drugs) in this way has not been validated.

Edmund Capparelli and coworkers presented combined data from several paediatric trials of nevirapine PK and NVP exposure. PK values were modeled and comparisons made between values expected from dosing according to WHO guidelines to Food and Drug Administration (FDA) approved method (per kg). [5]

NVP PK data from 5 Pediatric AIDS Clinical Trials Group (PACTG) studies conducted in the United States were combined with data from Zambia (CHAPAS) and Thailand (IMPAACT P1056). Data from 565 children were included.

The AUC and Cmin with WHO dosing using 50-mg or 60-mg NVP (as part of FDC baby tablets with 3TC and d4T ie NVP/3TC/d4T of 50/30/6mg or 60/30/6mg) were assessed from the ratio of doses (parameter x WHO Dose/Study Dose). The frequency of sub-therapeutic concentrations (Cmin <3 µg/mL or AUC <48 ug.h/mL) and supra-therapeutic concentrations, 120 ug.h/mL (2x average) were determined.

The investigators performed a Monte Carlo simulation using a population PK model that included age, weight, ritonavir (RTV) use, and CYP 2B6 genotype. Using weight-band dosing, 7720 paediatric NVP concentration profiles were simulated.

The investigators found NVP AUC and Cmin were similar across the 3 countries (ie no difference in PK in the much more malnourished Zambian children). 94 children receiving RTV and 88 who were outside the WHO dosing weight groups (<5 or >30 kg) were excluded from the analysis.

The median, Cmin and AUC were 174 mg/m2 (IQR 162 to 187), 5.7 µg/mL (IQR 3.8 to 8.0), and 77.7 ug.h/mL (IQR 55.8 to 107.2) for WHO weightband dosing using 50/30/6mg ratios (based on the principal that NVP doses never go below 300mg/m2 and 153 mg/m2 (IQR 112 to 172), 4.6 µg/mL (IQR 3.0 to 6.9), and 62.2 ug.h/mL (IQR 45.1 to 90.8) for FDA dosing (4 or 7mg/kg). WHO dosing exceeded Cmin and AUC targets in 85% and 84% of children. The FDA dose met these targets in only 75% and 72% of children. The frequency of AUC >120 was higher with WHO than FDA dosing (18% vs 10%).

Increasing the ratio of NVP in FDCs (from 50mg to 60 mg NVP to be combined with 30mg 3TC and 6mg d4T) reduced the frequency of sub-therapeutic levels by 5%, but increased supra-therapeutic levels (>120%) by 12%. Monte Carlo simulation exceeded target AUC and Cmin in 77% of simulated patients.

The investigators concluded:

• The recommended WHO weight band dosing of NVP will result in therapeutic concentrations in approximately 80% of children without incurring a high frequency of excessive NVP exposures.
• The WHO weight band dosing of NVP achieves target exposure in a greater portion of children than the FDA dose of 4-7 mg/kg.
• Monte Carlo simulations produced similar NVP exposure to observed results from multiple clinical trials and can be used to help to optimise dose recommendations.
• The 50mg NVP tablet strength (50/30/6mg of NVP/3TC/d4T in FDC tablets used according to WHO weightbands) maximises the therapeutic index compared to other potential tablet strengths (such as 60/30/6 mg).
• WHO weight band dosing should be adopted in resource limited settings.

Nevirapine PK in Thai children receiving either an adult or paediatric fixed-dose combination of d4T, 3TC, and NVP

HIV-positive Thai children freqently receive a divided adult fixed-dose combination of stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) (30/150/200 mg/tablet.

A new chewable fixed-dose combination tablet of d4T/3TC/NVP (7/30/50 mg/tablet) for children has recently been introduced by the Thailand Government Pharmaceutical Organisation (GPO). (These are is the same ratios as in the Zambian Chapas trial 6/30/50 mg).

Kulkanya Chokephaibulkit from Thailand and the United States looked at NVP PK in Thai children receiving either adult (GPOvir S30) or paediatric (GPOvir S7) fixed-dose combinations [6].

In this study, NVP concentration data from 44 children (age 8.6+/- 2.9 years and weight 24.3+/- 8.3 kg) was combined from two clinical trials. Results from 9 children enrolled in IMPAACT P1056, an ongoing PK study comparing GPOvir S7 with the standard liquid formulations, who had intensive PK sampling pre-dose, and 0.5, 1, 2, 4, 8, and 12 hours post-dose were combined with data from a separate study of 35 children who received GPOvir S30 and had PK sampling pre-dose, and 2, 6 hours post-dose.

The investigators used a 1-compartment model and population approach to analyse the data. They found median NVP clearance was 0.081 L/h/kg and volume of distribution 1.79 L/kg across both formulations.

Children receiving NVP GPOvirS30 showed a slower absorption rate (p<0.001), but had comparable bioavailability (p>0.20) to those receiving GPOvirS7. The average NVP AUC was 75.5+- 40.5 and 81.1+/- 34.7 ug.hr/mL for GPOvir S30 and GPOvir S7, respectively. Median pre-dose NVP concentrations were higher with GPOvirS30 compared to GPOvirS7, 6.0 µg/mL (3.4 to 24.0) vs 4.3 µg/mL (3.0 to 10.0), p=0.06. All children achieved a pre-dose NVP concentration above the recommend target of 3.0 µg/mL.

The investigators concluded: “NVP pharmacokinetic parameters in Thai children using fixed-dose combination tablets containing either NVP 200mg or 50mg were within the range observed in prior paediatric studies.” They observed no clinically significant differences in NVP concentrations between the two formulations.

PK of etravirine (ETR, TMC125) in HIV-positive children between 6 and 17 years of age

Thomas Kakuda and coworkers from Tibotec showed findings from a study to determine the weight-based dose of ETR that will achieve exposures in children comparable to those in adults. [8]

This study enrolled HIV-1-positive children between 6 and </=17 years of age on a stable (at least 2 consecutive viral loads <50 copies/mL) on a LPV/r –containing regimen. TMC125 4 mg/kg twice daily was added for 7 days followed by a morning dose, and 12-hour PK assessment on day 8. Both 25 and 100-mg tablets were used. The 25mg tablet is currently only available for research purposes.

TMC125 PK was assessed using non-compartmental analysis; Cmin and AUC12h were compared to PK parameters in adults receiving 200 mg twice daily on a LPV/r-containing regimen.

PK assays were available for 16/17 children.10 children were aged between 6 and <12 years, and 6 between >/=12 and </=17 years. The mean (SD) Cmax and Cmin in 16 children were 555.2 (514.6) ng/mL and 233.2 (237.9) ng/mL, respectively.

Mean (SD) AUC12h was evaluable in 15 children and was 4788 (4459) ng.h/mL.

The investigators reported, relative to adults, the least square means ratio for Cmin and AUC12h was 1.08 (90% CI: 0.69 to 1.69) and 1.11 (90% CI: 0.76- 0.62), respectively.

They found interpatient PK variability was greater in children than adults, primarily as a result of 1 outlier. When the outlier was removed range of exposures in children was similar to that in adults. Exposure was not associated with age or body surface area (BSA).

There were no serious adverse events. 12 children reported at least 1 adverse event, mostly grade 1 or 2; 2 children (12%) developed a rash on treatment (grade 1 and 2, respectively), both on day 8 and resolving after 5 to 6 days; the AUC12h in these children were 7408 and 1826 ng.h/mL, respectively.

The investigators concluded:

• ETR at 4mg/kg bid following a meal provides comparative exposure in children age 6-17 to 200mg bid in a