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.

comment

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

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.

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.

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.

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 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

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

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.

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.

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.

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.

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.

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

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

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

Adrew Wiznia and coworkers from IMPAACT P1066 showed preliminary results from the first paediatric study of raltegravir (RAL).

This is an ongoing prospective, non-randomised, open label, dose-finding trial of RAL plus optimised background regimen (OBR) in treatment-experienced children.

Children aged >12 to <19 years (cohort 1) and >6 to to <12 years (cohort IIA). The children are enrolled sequentially older to younger.

Children in stage I received RAL poloxamer film tablets that were added to a stable, failing ART regimen. Pharmacokinetics (PK) was done on day 7 to 12 and then OBR started.

The study had enrolled 36 patients (22 in cohort I and 14 in cohort IIA. They initially received a 6 or 8mg/kg dose bid with a maximum dose of 600mg bid.

The study demographics included:   47% male, 67% black, and 25% white. Median baseline viral load was 4.4 log (range 3.1 to 5.9) copies/mL and were similar between the cohorts. Median CD4 percentage was 22 (range 0 to 42%).

Six children had grade 3/4 adverse events: 5 had neutropenia, 1 increased lipids, and 1 increased creatinine associated with aminoglycoside use. One grade 4 neutropenia and one elevated GGT was possibly associated with RAL.

There were no deaths. Four children were withdrawn from the study, 3 because of poor adherence (cohort 1) and one at the request of the doctor (cohort IIA).

In an intent-to-treat analysis of those treated at 8 mg/kg 23/30 (77%) and 24 of 14/30 (86%) were <400 copies/mL (50% and 63% <50 copies/mL) at weeks 8 and 12 respectively. Median CD4 percentage was 24% at both timepoints.

The investigators wrote: “Preliminary, short-term and partial data from IMPAACT P1066 suggests that RAL + OBR in children ages 6 to 18 was generally safe, well tolerated and effective. Enrollment into these cohorts, as well as use of a chewable formulation for children <12 years of age, is continuing”.

COMMENT

For cohort IIA, repeat PK and safety evaluations at a uniform dose of 400 mg bid regardless of weight is ongoing.

Merck will continue this paediatric programme with sequential age strata down to 4 weeks of age.

In addition to the chewable formulation, oral granules for suspension are planned for children less than two years old.

Ref: Wiznia A et al. Safety and efficacy of raltegravir in pediatric HIV infection. Preliminary analysis from the International Maternal Pediatric Adolescent AIDS Clinical Trials group, P1066. 16th CROI, February 2009, Montreal, Canada. Poster abstract 874.
http://www.retroconference.org/2009/Abstracts/36282.htm

Levels of the thrombosis marker D-dimer were significantly higher in children and adolescents with an HIV viral load above 1000 copies/mL than in those with lower loads. [1] Protein C and S anticoagulant activity and antithrombin activity were lower in youngsters with high viral loads.

HIV researchers started pondering D-dimer when SMART trial investigators charted significantly rising levels of that marker in people randomised to intermittent antiretrovirals compared with steady therapy. [2] The SMART analysis also disclosed climbing concentrations of IL-6, an inflammation marker, in treatment interrupters. Higher SMART baseline levels of both D-dimer and IL-6 raised the risk of all-cause mortality.

A cross-sectional (“slice-of-time”) study at Rome’s Bambino Gesu Children’s Hospital involved 88 children, adolescents, and young adults seen between December 2007 and June 2008. Their ages averaged 13.6 years and ranged from 3 to 25. Fifty-two cohort members (59%) were female, and 76 (86%) were taking antiretrovirals. The investigators measured the thrombosis marker D-dimer and several inflammation markers–antithrombin, protein C anticoagulant, protein S anticoagulant, and C-reactive protein.

Sixty-three youngsters (72%) had a viral load below 1000 copies, and 25 had a higher load. Sixty-eight people (77%) had a CD4% above 25% and 20 were under 25%. Sixty-one (70%) had CDC class B or C (symptomatic) HIV infection and 27 did not. Defining protein C and S activity deficiency as below 70% activity, the investigators found deficient C activity in 7 people (8%) and deficient S activity in 45 (51%). Antithrombin activity deficiency, defined as below 75% activity, affected only 1 person.

D-dimer levels were significantly higher in cohort members with a viral load above 1000 than in those with lower loads. In contrast, activity of protein C anticoagulant, protein S anticoagulant, and antithrombin was significantly lower in the group with a high viral load. C-reactive protein did not vary significantly by viral load, CD4%, or disease stage. None of the markers correlated with age or duration of HIV infection.

The SMART analysis of D-dimer and IL-6 factored in age, race, use of antiretrovirals, viral load, CD4 count, smoking status, body mass index (BMI), prior cardiovascular disease, diabetes, use of antihypertensives or lipid-lowering drugs, total-to-HDL cholesterol ratio, and coinfection with hepatitis B or C [2]. The Italian study excluded people with hepatitis but did not specify which variables they weighed in their analysis, other than those noted above.

The investigators speculated that the better protein C and anticoagulant activity in children and adolescents with symptomatic HIV infection could reflect antiretroviral treatment of these children compared with those who had less advanced infection. But none of the markers studied varied significantly by antiretroviral treatment status. The 1000-copy cutoff for good viral control may strike some as arbitrary.

Levels of the thrombosis marker D-dimer were significantly higher in children and adolescents with an HIV viral load above 1000 copies/mL than in those with lower loads. [1] Protein C and S anticoagulant activity and antithrombin activity were lower in youngsters with high viral loads.

HIV researchers started pondering D-dimer when SMART trial investigators charted significantly rising levels of that marker in people randomised to intermittent antiretrovirals compared with steady therapy. [2] The SMART analysis also disclosed climbing concentrations of IL-6, an inflammation marker, in treatment interrupters. Higher SMART baseline levels of both D-dimer and IL-6 raised the risk of all-cause mortality.

A cross-sectional (“slice-of-time”) study at Rome’s Bambino Gesu Children’s Hospital involved 88 children, adolescents, and young adults seen between December 2007 and June 2008. Their ages averaged 13.6 years and ranged from 3 to 25. Fifty-two cohort members (59%) were female, and 76 (86%) were taking antiretrovirals. The investigators measured the thrombosis marker D-dimer and several inflammation markers–antithrombin, protein C anticoagulant, protein S anticoagulant, and C-reactive protein.

Sixty-three youngsters (72%) had a viral load below 1000 copies, and 25 had a higher load. Sixty-eight people (77%) had a CD4% above 25% and 20 were under 25%. Sixty-one (70%) had CDC class B or C (symptomatic) HIV infection and 27 did not. Defining protein C and S activity deficiency as below 70% activity, the investigators found deficient C activity in 7 people (8%) and deficient S activity in 45 (51%). Antithrombin activity deficiency, defined as below 75% activity, affected only 1 person.

D-dimer levels were significantly higher in cohort members with a viral load above 1000 than in those with lower loads. In contrast, activity of protein C anticoagulant, protein S anticoagulant, and antithrombin was significantly lower in the group with a high viral load. C-reactive protein did not vary significantly by viral load, CD4%, or disease stage. None of the markers correlated with age or duration of HIV infection.

The SMART analysis of D-dimer and IL-6 factored in age, race, use of antiretrovirals, viral load, CD4 count, smoking status, body mass index (BMI), prior cardiovascular disease, diabetes, use of antihypertensives or lipid-lowering drugs, total-to-HDL cholesterol ratio, and coinfection with hepatitis B or C [2]. The Italian study excluded people with hepatitis but did not specify which variables they weighed in their analysis, other than those noted above.

The investigators speculated that the better protein C and anticoagulant activity in children and adolescents with symptomatic HIV infection could reflect antiretroviral treatment of these children compared with those who had less advanced infection. But none of the markers studied varied significantly by antiretroviral treatment status. The 1000-copy cutoff for good viral control may strike some as arbitrary.

Table 1: Inflammation and coagulation markers by viral load, CD4% and CDC class

The researchers acknowledged that “further studies are necessary to correlate such alterations with clinical events and to investigate the protective role of therapy in this particular population.” This line of research bears watching since treatment interruptions remain high on the research agenda for children, who otherwise face several decades of continuous antiretroviral therapy. But if coagulation and inflammation markers signal a higher risk of non-AIDS diseases in children with higher loads while interrupting therapy (as they do in adults [2]), treatment breaks may not be worth the risk, even in children.

References
1. Pontrelli G et al. D-dimer and anticoagulation activity markers in children and adolescents with HIV infection. 9th International Congress on Drug Therapy in HIV Infection, 9-13 November 2008, Glasgow. Abstract P213.
http://www.jiasociety.org/content/11/S1/P213
2. Kuller LH et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050203#top

Di Gibb presented findings from the PENTA 11 trial on behalf of the Paediatric European network for treatment of AIDS (PENTA).

PENTA 11 was a phase II randomised trial of antiretroviral treatment (ART) strategies, comparing CD4-guided planned treatment interruption (PTI) to continuous therapy (CT) in children with viral load <50 copies/mL, and CD4% ≥30% (2-6 years) or CD4% ≥25% and CD4 ≥500 cells/mm3 (7-15 years). In the PTI arm, ART was stopped and restarted if a child had a confirmed CD4% <20% (7 years) or CD4% <20% or CD4 <350 cells/mm3 (≥7 years).

After a DSMB review following the SMART results, the protocol was amended so that no interuption lasted longer than 48 weeks and further PTIs were only undertaken in children who spent >10 weeks off ART during their first PTI and had been back on ART for at least 24 weeks.

The trial was powered on equivalence; 2-sided with a 15% margin. The primary end-point was CD4% <15% (and/or CD4 <200 cells/mm3 >/=7 years), new CDC C diagnosis or death. Minimum follow up was 72 weeks.

Professor Gibb reported that from 2004 to 2006, 109 children were randomised to CT (n=53) or PTI (n=56): 45% children were boys; their median age was 9.3 (range 2-16) years; 35% white, 31% black; 26% CDC stage C, median time on ART 5.7 (IQR: 3-9) years. Their median baseline CD4% was 37% (IQR: 33-41), CD4 966 (IQR: 793-1258) cells/mm3; prior to ART nadir (at age 3 years) CD4% 18% (IQR: 10-27) and CD4 627 (IQR: 320-1050) cells/mm3.

After a median of 130 (IQR: 80-144) weeks (one child lost to follow up), the investigators found that 4% of the study period was spent off ART by children in the CT arm vs 48% in the PTI arm.

During the first PTI, 9 children restarted treatment in <10 weeks; 21 (38%) children restarted ART <48 weeks (14 failing CD4, 7 non-protocol reasons); 32 (57%) restarted at or after 48 weeks and three remained off ART. 16 children had a 2nd PTI.

Professor Gibb reported no child died or had a CDC C event.CD4 primary end points occured in 1 (2%) CT vs 4 (7%) PTI (difference 5% [95% CI -2%, 13%], p=0.2). 98.4% of total time in CT vs. 95.9% in PTI was spent with CD4 >350 cells/mm3.

The mean change in CD4 count from baseline to 72 weeks was -106 vs. -240 cells/mm3 in CT vs. PTI (difference -134 cells/mm3, 95% CI -237, -31, p = 0.01). Differences between the two groups are difficult to interpret as some children in the PTI arm were off ART at 72 weeks. In an exploratory analysis, the mean CD4 change 0-72 weeks was -124 cells/mm3 in 27 PTI children who had all been back on ART for >/=24 weeks; this is closer to the -106 value observed in CT children.

The CD4 fall of 106 cells in the CT arm is unlikely to be due to the natural fall in CD4 experienced by children throughout childhood, as childrens’ CD4 counts normalise to those of adults by the age of 6 and the median age of the cohort was 9.3 years.

When the investigators looked at CD4 z-score change in the PTI arm from 0-24 weeks (1st PTI) after restarting, they reported that age adjusted CD4 recovery was significantly better in young children (mean, SE): -0.1 (0.3), -0.9, -1.3 for ages 2-6 (n=4), 7-10 (n=20) and 11+ (n=13) years, respectively, p = 0.02. Thus children <6 years almost fully recovered their CD4 values within 24 weeks, but older children did not.

At 72 weeks, 94%/85% vs. 81%/58% children had VL <400/<50 copies/mL in CT vs PTI (p = 0.05/0.003). Of the 28 PTI children back on ART for ≥24 weeks, 89%/68% had VL <400/<50 copies/mL, there was no evidence of more resistance in the PTI arm using standard genotype tests: 10 (5 CT and 5 PTI) of 13 children with 2 consecutive measurements >100 copies/mL on treatment had resistance; of these, 4 CT and 2 PTI had 4 or more mutations.

Although adverse events were more frequent in the PTI arm, these were mostly predictable (more lymphadenopathy, consistent with new onset viraemia).

With respect to both CD4 recovery and viral load suppression after PTI, Professor Gibb noted that because some children were off ART at 72 weeks, results so far are difficult to interpret and longer follow-up is essential, and is ongoing. The investigators concluded, “Longer-term assessment of all children after restarting ART will be required to fully assess risks and benefits of PTI in this population”.

In the meantime, paediatricians have advised all children on PTI to be restarted on ART. These results do provide reassurance that ongoing interruption trials should continue in both chronically infected children (BANA trial in Botswana) and following primary infection (CHER trial in South Africa). Results of adherence/acceptability and immunology/virology studies alongside PENTA 11 are now being analysed.

COMMENT

The PENTA group does not currently support treatment interuptions in children outside of a research study and has recommended that children in this study now restart ART. The same questions raised by the SMART study that now need to be answered in children include:

i) Whether children re-suppress viral load.

ii) Whether higher sensitivity resistance tests show development of resistance.

ii) Whether CD4 recovery similarly lags behind that of baseline levels, even 18 months after reintroduction of treatment, and

iv) What is the long-term implications of ongoing viral replication and importance of ongoing immune activation? (See the study from Pontrelli et al below).

Reference
Gibb DM, Compagnucci A, Green H et al. Treatment interruption in children with chronic HIV-infection: the results of the paediatric European network for treatment of AIDS (PENTA) 11 trial. 9th International Congress on Drug Therapy in HIV Infection, 9-13 November 2008, Glasgow. Abstract O222.
http://www.jiasociety.org/content/11/S1/O21

Sarah Walker from the Medical Research Council presented data from the UK/Irish Collaborative HIV Paediatric Study (CHIPS) cohort looking at paediatric dosing of lopinavir/ritonavir (LPV/r). [1]

Dr Walker explained that the licensed LPV/r paediatric daily dose is 460 mg/m2 without, and 600 mg/m2 with concomitant NNRTI therapy. The 460 mg/m2 dose without NNRTIs was chosen in preference to 600 mg/m2 in a post-hoc drug-interaction analysis [2]. Following the completion of the phase II trial, this post-hoc analysis revealed a significant interaction between NNRTI and LPV/r, leading to the lower dose being licensed for use without NNRTI. The phase II trial showed very good viral load data overall, with 79% of children <400 copies/mL at 48 weeks, but this was based on the higher 600 mg/m2 dose. Because of this uncertainty some paediatricians prefer to prescribe the higher dose of LPV/r irrespective of concomitant NNRTI therapy.

In the CHIPS study the investigators evaluated the LPV/r doses prescribed without NNRTIs in the cohort from 2000–2007.

They looked at predictors of current dose, including sex, VL and CD4, age, CDC stage, height/weight-for-age, calendar year, formulation, frequency and previous PI use, using mixed models allowing child and hospital effects.

They also evaluated the impact of the LPV/r dose on viral load suppression 6 months after starting it using logistic models and over longer follow up using binomial mixed models.

Dr Walker reported, 311/1,336 (25%) children in the cohort had received LPV/r without an NNRTI; for a total of 654 child-years. Of these children, 238 (77%) were still on LPV/r when they were seen last.

The median age of the children at initiation of LPV/r was 9 (IQR 5–12) years. The investigators recorded 684 doses in 299/311 children of which 52% were syrup, 38% capsules and 10% tablets. 662 (97%) doses were taken twice daily.

Overall the dose/m2 could be estimated 2,748 times in 278 children (the remaining children did not have height/weight recorded). They found few (7%) doses were >10% below the 460 mg/m2 target, and few (9%) >10% above the 600 mg/m2 target, with the majority >410–<530 mg/m2 (46%) or >530–<660 mg/m2 (39%).

In a multivariate analysis, the investigators found doses were: 17 mg/m2 [95%CI 0–34], higher in children who had prior CDC C event, p=0.05; 2 mg/m2 [0–3] higher for every log10 higher VL, p=0.02; 48 mg/m2 [38–58] higher with capsules/tablets vs syrups, p<0.001; 22 mg/m2 [4–40] higher with twice- vs once-daily dosing, p=0.02; 19 mg/m2 [15–24], p=0.001, and 10 mg/m2 [6–14], p<0.001 higher for every one unit lower current weight- and height-for-age, respectively; and 9 mg/m2 [5–14] higher for every year younger over 10, p<0.05.

Dr Walker noted that the mean dose for a 10 year old, without prior CDC event, average weight and age for height receiving capsules or tablets was 546mg/m2. She also noted that dosing varied greatly by centre with some using higher and some lower doses.

The investigators found no evidence that the initial LPV/r dose was associated with significantly improved viral load suppression at 6 months and reported: <400 copies/mL, AOR=1.06 per 50 mg/m2 (95%CI 0.87-1.28), p=0.58; <50 copies/mL, AOR=0.81 per 50mg/m2 (95%CI 0.65-1.01), p=0.06.

The investigators concluded: “Doses were higher with capsules/tablets, likely reflecting over- rather than under-dosing when solid formulations cannot achieve exact doses. However, we found no clear evidence that higher doses improved VL suppression.”

Dr Walker added: “Opinion seems to be split as to the most appropriate LPV/r dose in children.”

References
1. Walker AS et al. To overdose or underdose? The question of Kaletra in children in the UK/Irish Collaborative HIV Paediatric Study (CHIPS). 9th International Congress on Drug Therapy in HIV Infection , Glasgow. November 2008. Abstract O123.
http://www.jiasociety.org/content/11/S1/O8
2. Saez-Llorens X, et al.: Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2003, 22:216-224.

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.

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.

Previously, AZT dosing recommendations for the treatment of HIV in children included three times daily dosing with dose calculated using body surface area. The new label has recommendations for twice daily or three times daily dosing by weight or by body surface area. The new recommendations should allow for more convenient dosing (twice daily) of AZT (zidovudine, Retrovir) in children. The main changes include revisions to the Dosage and Administration section to include twice daily dosing in children as follows.

Paediatric patients (6 weeks to <18 years of age): Healthcare professionals should pay special attention to accurate calculation of the dose of AZT, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.

Prescribers should calculate the appropriate dose of AZT for each child based on body weight (kg) and should not exceed the recommended adult dose.

Before prescribing AZT capsules or tablets, children should be assessed for the ability to swallow capsules or tablets. If a child is unable to reliably swallow an AZT capsule or tablet, the AZT Syrup should be prescribed.

The recommended dosage in pediatric patients 6 weeks of age and older and weighing >4 kg is provided in a dosing table (see FDA list serve sit or new prescribing information). AZT Syrup should be used to provide accurate dosage when whole tablets or capsules are not appropriate.

Alternatively, dosing for AZT can be based on body surface area (BSA) for each child. The recommended oral dose of RETROVIR is 480 mg/m2/day in divided doses (240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.

The complete revised label will be available at: FDA/Center for Drug Evaluation and Research
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

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].

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.
http://www.retroconference.org/2008/Abstracts/33235.htm

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 antiretroviral 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.
http://www.retroconference.org/2008/Abstracts/31111.htm

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 adults.
• ETR was generally safe and well tolerated. Two patients developed mild to moderate transient rash (with no apparent association with ETR AUC12h).

As antiretrovirals are frequently under-dosed in children (in part because of increased variability), stage II of this trial with 30% higher dose 95.2mg/kg bid) is underway. A phase II trial to determine safety and efficacy in treatment-experienced children will begin after final dose selection.

References

Unless otherwise stated, all references are from the 15th CROI, February 2008. Boston, MA, USA.

1. Violari A, Cotton M, Gibb D et al. Antiretroviral therapy initiated before 12 weeks of age reduces early mortality in young HIV-infected infants: evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study. Abstract WESS103.
2. Guidelines for the use of antiretroviral agents in pediatric HIV infection. February 28, 2008
3. Capparelli E, Pinto J, Robbins B et al. Lopinavir pharmacokinetic maturational changes and variability in HIV-infected infants beginning Kaletra therapy at <6 weeks of age. Poster abstract 573.
4. Rakhmanina N, Van Den Anker J,Van Guilder M et al. Recommended dose of lopinavir/ritonavir is sub-optimal in protease inhibitor-experienced children. Poster abstract 574.
5. van der Lugt J, Bunupuradah T, Kosalaraska P et al.Therapeutic drug monitoring of lopinavir and saquinavir in Thai HIV-infected children. Poster abstract 575.
6. Capparelli E, D Kabamba D, T Cressey T et al. Nevirapine exposure with WHO paediatric weight band dosing–enhanced therapeutic concentrations predicted based on extensive international pharmacokinetic experience. Poster abstract 576.
7. Chokephaibulkit K, Cressey T, W Prasitsuebsai W et al. Nevirapine pharmacokinetics in Thai children receiving either an adult or paediatric fixed-dose combination of stavudine, lamivudine, and nevirapine. Poster abstract 577.
8. Kakuda K, Konigs C, Feiterna-Sperling C et al. Pharmacokinetics of the next-generation NNRTI TMC125 in HIV-infected children between 6 and 17 years of age. Poster abstract 578.

Ana Blanco and co-workers from the Mozambique Ministry of Health, Health Alliance International, Seattle, University of Washington, Seattle and Seattle Children’s Hospital Research Institute showed findings from an evaluation of infants infected with HIV despite receiving single dose nevirapine (sdNVP) prophylaxis.

The investigators hypothesised that the timing of nevirapine selective pressure relative to when the HIV first infects infants, effects the selection and persistence of NVP resistant virus. They suggest that:

• NVP pressure during “acute” (peri-partum) infection will result in transmission or significant selection of mutations that will populate long-lived viral reservoirs and mutations will persist over time.
• NVP pressure during “established” (in utero) infection will select mutations, however, as HIV-1 reservoirs are already established, fewer will be archived so mutant population will fade over time.

This report was from a prospective observational cohort study of 741 infants of whom 100% received single dose NVP (73% mothers). The investigators estimated the timing of infection using nested PCR for HIV-1 pol in dried blood spots, collected by heel stick, at birth and every 2 weeks for the first 2 months of life, and then every 4-8 weeks until one year of age.

Concentrations of resistant virus were determined using quantitative PCR oligonucleotide ligation assays (OLA) for K103N, V106M, Y181C and G190A.

HIV infection was detected by PCR in 53 infants followed between 0-8 weeks of age. 29 were infected in utero (HIV detected at birth), all had wild type virus and 23 had high and stable viral load at birth ie ”established” infection, and 6 had low viral loads that later increased, suggesting “acute” infection at the time of birth.

The investigators reported that the selection and decay of NVP-resistant HIV-1 varied by timing of infection.

Infants with “established” infection had frequent selection of NVP-resistant HIV-1 (87%, 95%CI 66-97%).

Postpartum infant AZT+sdNVP vs. NVP decreased NVP-resistant HIV-1 (3/6 vs. 0/17, p=0.013). NVP-resistant viruses decayed rapidly compared to infants with peri-partum infection.

Compared to “established”, infants with “acute” in utero infection (ie low viral load at birth) had infrequent (33%) selection of NVP-resistant HIV-1, p=0.01. In this group of infants NVP-resistant HIV-1 appeared to decay more slowly.

Among infants with peripartum infection (n=24) there was infrequent selection of NVP-resistant HIV-1; (38%, 95%CI 19-59% ) compared to “established”, p=0.001. Few infants with NVP-resistance, initially had exclusively wild-type viruses vs. “established” (2/9; 22%, 95%CI 3-60% vs. 21/21 ; 100%, 95%CI 84-100%), p< 0.001.

Also, most infants had 100% NVP-resistant HIV-1 in the first sample with detectable resistance vs. “established”, (6/9; 67%, 95%CI 30-93% vs. 0/22 ;  0%, 95%CI 0-15%), p< 0.001.

The investigators noted a non-significant trend for less NVP-resistance when mothers did not take sdNVP (0/5 vs. 9/19, p= 0.12).

They summarised:

• With “established” in utero infection, viral replication in utero generates mutations that are selected by sdNVP. AZT appears to reduce the selection of NVP mutations, “theoretically by increasing the genetic barrier and decreasing viral replication”. Rapid decay of NVP-resistant virus suggests that after an (undefined) interval, NVP-based HAART may be effective.
• With “acute” in utero infection there is frequently too little viral replication in utero to generate mutations, so there are no NVP-resistant mutations to select. But if selected NVP-resistant HIV-1 decays slowly suggesting that it populates long-lived reservoirs.
• With peri-partum infection, infections with 100% resistant virus suggests transmission of NVP-resistant HIV-1. Persistence of mutations at high concentrations suggests it populates reservoirs. Persistence of mutations suggests that NVP-containing HAART may fail.

The investigators noted a low rate of mother-to-child transmission among infants whose mothers received pre-partum AZT in addition to sdNVP. But this was only a minority of women and access needs to be improved.

Ref:
Miceck MA, Blanco AJ, Beck IA et al. The selection, transmission and persistence of drug-resistant HIV-1 in infants prophylaxed with single dose nevirapine varies by the timing of infection. XVII IHDRW 2008, Sitges. Abstract 71