Nevirapine concentrations in HIV-infected children treated with divided fixed-dose combination antiretroviral tablets in Malawi and Zambia

Department of Paediatrics, College of Medicine, Blantyre, Malawi.
Antiviral therapy (Impact Factor: 3.02). 01/2007; 12(2):253-60.
Source: PubMed


To investigate nevirapine concentrations in African HIV-infected children receiving divided Triomune tablets (stavudine+lamivudine+nevirapine).
Cross-sectional study.
Steady-state plasma nevirapine concentrations were determined in Malawian and Zambian children aged 8 months to 18 years receiving Triomune in routine outpatient settings. Predictors from height-for-age, body mass index (BMI)-for-age, age, sex, post-dose sampling time and dose/m2/day were investigated using centre-stratified regression with backwards elimination (P<0.1).
Of the 71 Malawian and 56 Zambian children (median age 8.4 vs 8.5 years, height-for-age -3.15 vs -1.84, respectively), only 1 (3%) of those prescribed > or =300 mg/m2/day nevirapine had subtherapeutic concentrations (<3 mg/l) compared with 22 (23%) of those prescribed <300 mg/m2/day; most children with subtherapeutic nevirapine concentrations were taking half or quarter Triomune tablets. Lower nevirapine concentrations were independently associated with lower height-for-age (indicating stunting) (0.37 mg/l per unit higher [95% confidence interval (CI): -0.003, +0.74]; P=0.05), lower prescribed dose/m2 (+0.89 mg/l per 50 mg/m2 higher [95% CI: 0.32, 1.46]; P=0.002) and higher BMI-for-age (indicating lack of wasting) (-0.42 mg/l per unit higher [95% CI: -0.80, -0.04]; P=0.03).
Currently available adult fixed-dose combination tablets are not well suited to children, particularly at younger ages: Triomune 30 is preferable to Triomune 40 because of the higher dose of nevirapine relative to stavudine. Further research is required to confirm that concentrations are reduced in stunted children but increased in wasted children. Development of appropriate paediatric fixed-dose combination tablets is essential if antiretroviral therapy is to be made widely available to children in resource-limited settings.

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    • "As with most other paediatric HIV treatment programmes in resource-limited settings [38,39], we resorted to using adult, generic fixed-dose combination tablets cut in half or quartered. In the absence of pill-cutters this usually resulted in unequal-sized fractions and could have inadvertently contributed to inappropriate, particularly sub-therapeutic, drug doses particularly with the LPV/r gel capsules [40]. "
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    ABSTRACT: There is little data on responses to combination antiretroviral therapy (cART) among HIV-infected children in the West African region. We describe treatment outcomes among HIV-1 and HIV-2 infected children initiating cART in a research clinic in The Gambia, West Africa. All treatment naive HIV-infected children who initiated cART according to the WHO ART guidelines for children between October 2004 and December 2009 were included in the analysis. Kaplan-Meir estimates and sign-rank test were used to investigate the responses to treatment. 65 HIV-1 and five HIV-2 infected children aged < 15 years were initiated on cART over this time period. HIV-1 infected children were treated with a combination of Zidovudine or Stavudine + Lamivudine + Nevirapine or Efavirenz while children with HIV-2 were treated with Zidovudine + Lamivudine + ritonavir-boosted Lopinavir. HIV-1 infected children were followed-up for a median (IQR) duration of 20.1 months (6.9 - 34.3), with their median (IQR) age at treatment initiation, CD4% and plasma viral load at baseline found to be 4.9 years (2.1 - 9.1), 13.0% (7.0 - 16.0) and 5.4 log10 copies/ml (4.4 - 6.0) respectively. The median age at treatment initiation of the five HIV-2 infected children was 12 years (range: 4.6 - 14.0) while their median baseline CD4+ T cell count and HIV-2 viral load were 140 cells/mm3 (Range: 40 - 570 cells/mm3) and 4.5 log10copies/mL (Range: 3.1 - 4.9 log10copies/mL) respectively.Among HIV-1 infected children <5 years of age at ART initiation, the median (IQR) increases in CD4% from baseline to 12, 24 and 36 months were 14% (8 - 19; P = 0.0004), 21% (15 - 22; P = 0.005) and 15% (15 - 25; P = 0.0422) respectively, while the median (IQR) increase in absolute CD4 T cell count from baseline to 12, 24 and 36 months for those ≥5 years at ART initiation were 470 cells/mm3 (270 - 650; P = 0.0005), 230 cells/mm3 (30 - 610; P = 0.0196) and 615 cells/mm3 (250 - 1060; P = 0.0180) respectively. The proportions of children achieving undetectable HIV-1 viral load at 6-, 12-, 24- and 36 months of treatment were 24/38 (63.2%), 20/36 (55.6%), 8/22 (36.4%) and 7/12 (58.3%) respectively. The probability of survival among HIV-1 infected children after 12 months on ART was 89.9% (95% CI 78.8 - 95.3). CD4 T cell recovery was sub-optimal in all the HIV-2 infected children and none achieved virologic suppression. Two of the HIV-2 infected children died within 6 months of starting treatment while the remaining three were lost to follow-up. The beneficial effects of cART among HIV-1 infected children in our setting are sustained in the first 24 months of treatment with a significant improvement in survival experience up to 36 months; however the outcome was poor in the few HIV-2 infected children initiated on cART.
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    • "With regard to the use of adult fixed-dose combination tablets, accurate cutting can be difficult to achieve. Moreover, the ratio between the three drugs is not suitable for paediatric use, since children have a faster nevirapine metabolism than adults.13 Given the low genetic barrier of the NNRTIs, selection of resistance can occur rapidly in patients with suboptimal adherence or reduced serum concentrations. "
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    • "This approach has been shown to result in satisfactory virologic and immunologic benefit to children [1]. However, there are concerns about NVP drug levels in children on fractionated adult tablets [2]. There is also evidence that single-dose NVP (sdNVP)-containing mother to child transmission (MTCT) antiretroviral (ARV) prophylaxis regimens increase the risk of resistance and failure of NVP-based ART regimens in children [3]. "
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    ABSTRACT: The standard first-line antiretroviral (ART) regimen in Malawi for both adults and children is a fixed-dose combination tablet containing stavudine (d4T), lamivudine (3TC) and nevirapine (NVP). This regimen has been shown to yield satisfactory virologic and immunologic outcomes in children. Published studies have described insights into discontinuation of first-line regimen and toxicities of ART in adults, but similar studies in paediatric populations are lacking. A retrospective cohort study was undertaken to assess reasons for discontinuation of the standard first-line ART regimen (d4T/3TC/NVP) in a paediatric population. In total, 1434 patients met eligibility criteria and were included. The cohort had mean and median age at ART initiation of 4.7 years and 2.9 years, respectively (range: 0.1 months-18.7 years). The gender distribution was 47% female and 53% male. Median follow-up time on ART was 1.8 years (range: 2 weeks-3.9 years). A majority (96.2%) of patients were on the standard first-line ART regimen, while 3.8% (54) were on a different regimen. Twenty-eight patients (2.0%) were on an alternative first-line regimen due to toxicities, 22 patients (1.5%) were on a second-line regimen due to ART failure, and four patients (0.3%) were on a non-standard regimen for other clinical reasons. Of the 28 patients who experienced toxicities requiring ART regimen change, 60.7% (17) were caused by NVP, 39.3% (11) by d4T, and none by 3TC. The median time from first-line ART initiation to alternative first-line ART was two months (range: 10 days-28.1 months); 60.7% of patients on alternative first-line ART were male. Average time on ART until switch to second-line ART regimen was 16.3 months (SD: 9.3 months). The probability of failure after one year on first-line regimen was 1.6% (95% CI: 0.9-2.6). There was no compelling evidence in this cohort, representing approximately 10% of all children on ART in Malawi, to support changing the standard paediatric first-line regimen based on early toxicities or failure. However, experience from the national adult cohort, longer term follow up of the paediatric cohort in this study, emerging data on resistance after single-dose NVP containing mother to child transmission antiretroviral prophylaxis, and new 2009 World Health Organization ART recommendations may influence national policy change to a different first-line regimen.
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