Paediatric studies at EACS: trends in antiretroviral use in the Madrid Cohort; life expectancy significantly increased HIV/HCV co-infected children since HAART; use of tenofovir in treatment experienced children; switching to lopinavir/r from double protease inhibitor regimen; once daily lopinavir/r, 3TC and abacavir; planned treatment interruptions in children

11 February 2006. Related: Conference reports, Paediatric care, EACS 10 Dublin 2005.

Polly Clayden, HIV i-Base

Several posters at this meeting looked at paediatric antiretroviral treatment strategies, includiong structured treatment interruptons in European cohorts.

Trends in antiretroviral use in the Madrid Cohort

Maria Martinez and colleagues described trends in treatment across a cohort of 247 HIV positive children from the Madrid cohort [1].

The cohort was set up in January 2003 and data are collected prospectively every six months. This study compared two cross sectional dates, January 2003 and July 2005.

As of July 2005, the median age of the children was 13 years (range: 1-23 years). Their median CD4 nadir was 15% (IQR: 6-23%). Of the group 83% of children were receiving HAART, 5% were still receiving dual therapy and 12% were untreated. Of children receiving HAART, 29% were on their first antiretroviral regimen, 36% their second and 34% on their third or more regimen. Overall, the median CD4 percentage was 31% (IQR: 25-37%) and 57% of the group had a viral load of <400 copies/mL.

The authors report the most common nucleosides used are d4T and 3TC, protease inhibitors nelfinavir and lopinavir/r, and efavirenz was the most commonly used NNRTI. They noted a trend for an increase in use of lopinavir/r (21% to 27%) and abacavir (16% to 23%) and a decrease in the use of nelfinavir (34% to 25%) and d4T (66% to 52%) since the cohort was initiated. There was also an increase in untreated children (5.7% to 12%).

They described reasons for changes in antiretroviral therapy as ‘concern about adherence, toxicity and resistance’.

Life expectancy significantly increased HIV/HCV co-infected children since HAART

HIV/HCV coinfection and its treatment has been poorly characterised in children. Antoni Noguera and co-workers presented data from a prospective observational study of two paediatric cohorts in Barcelona: vertically HIV infected or HIV/HCV co-infected children followed between 1984 and 2004 [2]. Data was collected at least very three months. HAART was introduced early in 1997.

The authors identified a group of 31 (11 girls, 20 boys) HIV positive and 15 (7 girls, 8 boys) HIV/HCV co-infected children. During the pre-HAART period 44% (19/43) children died. The remaining 24 received HAART in 1997 and three children were born after 1997.

There was a highly significant difference in progression to death between children before and after the introduction of HAART (19/43 deaths vs 2/24, p<0.0001).

The authors reported a higher but not statistically significant rate of AIDS diagnoses and progression to death amongst the HIV/HCV co-infected children after the introduction of HAART but this was not related to hepatoxicity. They reported only one 11-year old co-infected girl with clinically significant HCV associated hepatopathy, which led to discontinuation of HAART.

The authors concluded: ‘In our series, HCV infection in HIV-HCV co-infected children does not worsen HIV infection progress – which is basically determined by HIV disease characteristics and access to HAART, which has dramatically increased life expectancy in both groups of patients’.

Use of tenofovir in treatment experienced children

Carlos Moreno and colleagues from Barcelona reported findings from a small cohort of drug-experienced children receiving tenofovir (TDF) – once daily 300 mg tablet – as part of a HAART regimen through a compassionate use programme [3].

The children (n=11) had a median age of 14 years (range: 10-17 years), 6 were girls. Two were excluded from the analysis (a girl of 14 years and a boy of 17 years) due to poor adherence.

The authors describe the reasons for initiating a TDF containing regimen as virological failure, HAART simplification and severe facial lipoatrophy.

At a median of 19 months (range: 10-28 months) 7/9 children had undetectable viral loads <50 copies/mL (the remaining children had viral loads of <200 copies/mL and 5440 copies/mL) and all children improved or sustained their CD4 counts. Most of the children (6/9) received 3-drug regimens, including a protease inhibitor or NNRTI. One child received TDF with ddI and 3TC. Three children received 4 drugs: TDF+3TC+T-20+TPV/r; TDF+3TC+EFV+TPV/r and TDF+d4T+ddI+3TC.

Additionally the authors reported a favourable lipid profile with only one patient developing de novo hypercholesterolemia. The children’s amylase, creatinine and lactate levels remained within normal values.

Switching to lopinavir/r from double protease inhibitor regimen

Drug-experienced children may receive salvage regimens including two protease inhibitors. Although often successful this can mean a large pill count and challenges with adherence.

Jose Ramos and colleagues from Madrid presented findings from a multicentre prospective study across seven Spanish hospitals to assess the safety and efficacy of switching to two protease inhibitors from a non-failing regimen to lopinavir/r [4]. Additionally this study looked at the effect of the switch on lipid levels and the impact of reduced pill count on quality of life.

As of July 2005 12 children (5 girls and 7 boys) were included with a median age at time of switching of 12 years (range: 6-15 years). The children had been receiving antiretrovirals since a median age of 45 months (range: 9-115 months). All children had failed their first protease inhibitor-containing regimen and were receiving four antiretrovirals including two protease inhibitors prior to switching. The median time with undetectable viral load <50 copies/mL was 42 months (25-58 months). The median CD4 percentage at switching was 32% (range: 17-46%) and absolute CD4 was 813 cells/mm³ (range 360-2193 cells/mm³).

The authors reported 10/12 children remained undetectable after a median of 16 months (range: 6-28 months) from the switch to lopinavir/r. Of the remaining two children, one child had irregular adherence and the other was lost to follow up at 3 months. They wrote: ‘Switching to lopinavir/ritonavir from a non-failing double PI regimen appears to be safe and efficacious in maintaining the CD4 cell count and viral suppression’. Additionally, they noted a moderate decrease in cholesterol at 6 and 12 months, and a significant decrease in pill burden that ‘could improve adherence and quality of life in this selected population of heavily pretreated children’.

Once daily lopinavir/r, 3TC and abacavir

In paediatric HIV care particularly, once daily dosing (QD) may offer an advantages in terms of convenience and adherence for both children and their carers.

Wendy Zijdel and co-workers from two centres in the Netherlands presented findings from the RONDO study; this is an observational study to evaluate a QD LPV/r+ABC+3TC regimen in children [5].

Nineteen children with a median age of 5.2 years (range 1.4-12.8 years) had received protease-containing HAART twice daily (BID) for a median of 24 months and had a viral load <50 copies/mL for a minimum of 6 months prior to switching. Children then received LPV/r 460/115 mg/m2 QD, while maintaining existing nucleosides BID for 6 months, after which they switched to 3TC+ABC QD.

Adherence support was given by clinical nurse specialists at every visit, this included information on food intake with LPV/r and an educational CD-rom. At month 12 an adherence questionnaire was completed.

Twelve months follow up data were available for 14/19 children. The authors reported at 12 months 13/14 children had undetectable viral load <50 copies/mL, one child had a detectable viral load of 80 copies/mL.

At day 14 LPV C-min was too low in 10/14 children. 4/10 children achieved adequate plasma levels after their food intake was altered and 6/10 required dose increase (to 600 or 800 mg/m2), as well as food intake adjustment. 13/14 children took their medications with the evening meal. The authors noted that children <3 years old experienced the greatest difficulties with intake of medication and food to maintain adequate plasma levels (5/6 children requiring dose increase were <3 years old).

13/14 adherence questionnaires were completed, all 13 patients preferred once daily dosing to twice daily.

The authors wrote that LPV/r+3TC+ABC sustained good virological response in this group. Additionally, they emphasised the usefulness of TDM to determine the correct dose for each child, the role of correct intake of food and the importance of adherence support by a clinical nurse specialist.

Planned treatment interruptions in children

Three Spanish studies looked at treatment interruptions in children.

Current guidelines recommend initiation of HAART early in HIV positive asymptomatic infants.

Monica Marco and colleagues from Barcelona described their experiences with of treatment interruption in five vertically infected infants that had initiated early HAART. [6]

The group was three girls and two boys. Two children were believed to be infected in utero, and the remainder during labour. Four children were asymptomatic at diagnosis, one child presented with thrombocytopenia that resolved following two weeks of HAART. The median CD4 percentage was 42% (range: 41 – 47%) and viral load was 5.5 log copies/mL (range: 5.0 – 6.5 log copies/mL).

Treatment was initiated at a median age of 6 weeks (range: 1-8 weeks). Three children achieved undetectable viral load between 8 and 12 weeks. One child required a year of treatment despite receiving four drugs from three classes (ddI+d4T+NVP+NFV). One child had several blips in viral load and received three HAART regimens before achieving and undetectable viral load (ddI+d4T+NVP; ddI+d4T+3TC+NFV and AZT+ABC+NVP+NFV) and interrupting treatment at 36 months. This was probably due to poor adherence and the authors report no detectable resistance in this child.

All children interrupted treatment at a median of 40 months (range 35 – 71 months). The authors gave the reasons as: parents‚ wishes or mild drug toxicity. To date they all remain off-treatment. with a median time of 17 months (range 2 – 42 months). The last median CD4 percentage was 35% (range: 25 – 51%) and median viral load was 4.7 log 10 copies/mL (range: 3.7 – 5.4 log 10 copies/mL).

The authors write: ‘Early implementation of HAART was safe and effective and allowed for an interruption several years later. This therapeutic strategy could be considered for vertically transmitted acute HIV infection’. They also noted a progressive improvement in toxicities and patient quality of life after interruption of therapy.

Claudia Fortuny and colleagues from the same group reported findings from a prospective observational study of 14 vertically infected children (11 girls and 3 boys) undergoing planned treatment interruption [7]. The inclusion criteria for this study was: receiving first line HAART (or simplified first line HAART) with wild type virus by genotype test; viral load of <200 copies/mL for a minimum of 6 months; CD4 count of >25% for children <12 years and 350 cells/mm³ for adolescents, for a minimum of 6 months.

Patients were closely monitored and HAART resumed if CD4 dropped to <17% or <350 cells/mm³, or in the case of a clinical event. Children were divided into Group A, who initiated treatment after acute infection before 8 weeks of age (n=3, see previous study); and Group B who initiated HAART during chronic infection (n=11). The main reasons for interrupting treatment in both groups were parents/patients wishes and drug toxicities.

Median age at initiation of treatment was 5 years (range: 3-6 years) and 12.3 years (range: 5.5-17.2 years) in groups A and B respectively. At the time of interrupting treatment patients had been a median of 4.8 and 5.2 years on treatment and 4.3 and 4.8 years with an undetectable viral load in groups A and B respectively.

At a median of 18 months (range: 4-18 months) children in Group A remain off treatment, symptom free and with CD4 cells >25%. The authors report a decrease in CD4 counts during treatment interruption of a median of 0.9% and 87 cells/mm³ per month.

In Group B 4/11 children (36%) resumed HAART during the study. They were: a 17 year old girl with CD4 decrease from 47% to 9% within 2 months of interrupting treatment; a 9 year old girl with HIV related thrombopenia after 2 months; an 8 year old girl with HCV progression after 39 months off treatment and a CD4 count of 49% and a 12 year old girl with a decrease in CD4 cells from 858 to 250 cells/mm³ after 43 months off treatment. The authors reported good virological and immunological response after resuming treatment for a median time of 3 months (range: 1-6 months).

In Group B the authors report a median slope in CD4 cells of 0.7% and 15 cells/mm³ per month. No other HIV related clinical or laboratory events were reported. They again note an improvement in antiretroviral related toxicity and quality of life.

They conclude: ‘Planned treatment interruptions in selected cases may represent a useful therapeutic strategy for the management of vertically transmitted HIV infection, especially in children diagnosed and treated during acute infection’.

Similar conclusions were drawn by Jose Ramos and colleagues from Madrid who conducted a retrospective analysis of children having undergone treatment interruptions at their clinic [8]. Amoung 76 children currently being followed 25 (33%; 16 girls and 9 boys) had had a treatment interruption.

The authors defined two groups according to reasons for interrupting treatment: children in Group A (n=16) were receiving suboptimal treatment and Group B (n=9) interrupted treatment due to toxicities. In children with either CD4 percentage of 15% or absolute CD4 <350 cells/mm³ treatment was reintroduced. Group A children received genotype guided optimised treatment and Group B children were scheduled to have the same treatment reintroduced.

The median age of the children (16 girls, 9 boys) at time of treatment interruption was 9.5 years (range: 4-19.5 years) and the median length of time previously on HAART was 37 months (range: 7-92 months). Median nadir CD4 counts were 19% (range: 2-34%) and 578 cells/mm³ (range: 23-2817 cells/mm³). At time of interruption these were 31.5% (20-47%) and 777cells/mm³ (range: 440-1572 cells/mm³). Median viral load was 3.8 log10 (range: 1.7-4.71 log10 copies/mL).

In Group A the authors reported prior dual therapy (n=3), non-suppressive triple therapy (n=3), poor adherence (n=6) and lipoatrophy (n=4) as reasons for treatment interruption. Lipoatrophy (n=2) and ‘to spare accumulated toxicity’ (n=7) were the reasons given for children in Group B. Four children restarted treatment due to rapid decline in CD4 percentage (to </=15%) at a median of 6 months (range: 2-15 months) and one child because of thrombocitpenia and hepatitis C.

In a sub-study of children in Group B, median length of treatment interruption was 7 months (range: 3-20 months). They reported an average decline in CD4 percentage of 3.31% (range: 1-9% in the first 3 months and 1.8% range: 0.17-9%) in the first 6 months. The average absolute CD4 decline per month was 99 cells/mm³ (range: 21-164 cells/mm³) in the first 3 months and 77 cells/mm³ (range: 40-155 cells/mm³) in the first 6 months. Viral load increased a median of 2.18 log10 copies/mL (range: 0.49-3.17) in the first month, 2.4 log10 copies/mL (range: 1.1-3.29 log10) in the first 3 months, and 2.61 log10 copies/mL (1.69-3.22 log10) in the first 6 months of treatment interruption.

Overall, the authors reported a median of 18 months treatment interruption (range: 16-36 months). They also reported improvement of lipoatrophy in 3 children. They concluded: ‘Treatment interruption is a safe option in selected HIV-1 infected children, provided they are closely monitored, since rapid CD4 decline is observed in the first months. Improvement in some metabolic side-effects may be observed’.

References:

1. Martinez M, Guillen S, Ramos JT et al. Trends in antiretroviral therapy use and virological outcome for a large cohort of HIV infected children. 10th European AIDS Conference. November 2005, Dublin, Ireland. Abstract PE15.2/3.
2. Noguera A, Claret G, Marco M et al. The influence of HCV co-infection in perinatally HIV infected patients: the role of HAART. 10th European AIDS Conference. November 2005, Dublin, Ireland. Abstract PE15.1/1.
3. Moreno C, Fortuny C, Noguera A et al. Tenofovir in the treatment of paediatric HIV infection. 10th European AIDS Conference. November 2005, Dublin, Ireland Abstract PE 15/28.
4. Ramos JT, Snachez-Granados JM, Cina L et al. Safety and efficacy of switching to lopinavir from a 4 drugs non-failing double PI antiretroviral regimen in HIV infected children. 10th European AIDS Conference. November 2005, Dublin, Ireland. Abstract PE 15. 2/4.
5. Zijdel W, Verweel G, van der Knaap L et al. Once daily lopinavir/ritonavir, lamivudine and abacavir in HIV infected children: importance of adherence support during the RONDO study evaluated at month 12. 10th European AIDS Conference. November 2005, Dublin, Ireland. Abstract PE 15.2/7.
6. Marco M, Fortuny C, Noguera A et al. Response to HAART after vertically transmitted acute HIV infection. 10th European AIDS Conference. November 2005, Dublin, Ireland. Abstract PE15.2/9.
7. Fortuny C, Noguera A, Marco M. Treatment interruption in HIV infected children on first line HAART regimens and undetectable viral load. 10th European AIDS Conference. November 2005, Dublin, Ireland. Abstract PE15. 2/10.
8. Ramos JT, Drummond T, Garrido-Lestache E et al. Outcome of antiretroviral treatment interruptions in HIV infected children. 10th European AIDS Conference. November 2005, Dublin, Ireland. Abstract PE15.2/5.