Nevirapine Exposure and Response to ART in HIV+ Children
Analyses included 367 previously untreated (except for PMTCT) Ugandan/Zimbabwean children initiating NVP-based ART aged 3 months to less than 36 months in the ARROW trial (ISCRTN24791884). Three children aged below 36 months (32, 35 and 35 months) initiated efavirenz-based ART and were excluded. The trial recruited from March 2007 to November 2008: before this, and during recruitment, sdNVP to the mother and child was the national PMTCT strategy. ART taken by the mother during pregnancy, delivery or breastfeeding, and (separately) ART taken by the child were determined by self-report at enrolment.
The children were randomized 1 : 1 to clinically-driven monitoring vs. laboratory + clinical monitoring for toxicity (haematology/biochemistry) and efficacy (CD4). Children were also randomized 1 : 1 : 1 in a factorial design to open-label lamivudine + abacavir + NNRTI continuously (arm A, no zidovudine) vs. induction-maintenance with four-drug lamivudine + abacavir + NNRTI + zidovudine for 36 weeks, then either lamivudine + abacavir + NNRTI (arm B; short-term zidovudine) or lamivudine + abacavir + zidovudine (arm C; long-term zidovudine). Children were recruited from three centres in Uganda and one in Zimbabwe. All children were examined by a doctor at screening, randomization, weeks 4, 8, and 12, and then every 12 weeks. Every 4–6 weeks, the children were reviewed by a nurse, and adherence was assessed using a questionnaire completed by the carer. The trial was approved by Research Ethics Committees in Uganda, Zimbabwe and the United Kingdom. The caregivers gave written consent.
The viral load was assayed retrospectively on stored plasma samples at 0, 4, 24, 36, 48 and 144 weeks post-ART initiation, and the last study visit before trial closure on 16 March 2012 in all children. The viral load was additionally assayed 24-weekly after week 48 in children enrolled after June 2008 (immunology/virology sub-study); and in an overlapping subset at, and 48 and 96 weeks after, a subsequent randomization to once vs. twice-daily lamivudine + abacavir (which were virologically equivalent). Assays were run using Abbott m2000rt (in Uganda; Abbott, Maidenhead, UK) and Roche Amplicor 1.5 (in Zimbabwe; Roche, Basel, Switzerland). The closest measurement to 4, 24, 36 and 48 weeks on ART, and then 24-weekly (in equally spaced windows), was used in analyses, which used a lower detection limit of 80 copies/ml because many low-volume samples had to be diluted 1 : 2. Samples with more than 1000 copies/ml at week 48 or 144, or any time point in the once/twice-daily study, were genotyped (reverse transcriptase only). The closest genotype to week 144 from week 48 through to trial end was used for analysis. Major nucleoside reverse transcriptase inhibitor (NRTI) mutations were defined according to International AIDS Society (IAS) 2013, and drug susceptibility was predicted using the Stanford algorithm version 7.
Pre-ART characteristics of sdNVP-exposed and non-exposed children were compared using chi-square tests for categorical factors and Wilcoxon rank-sum tests for continuous values. Predictors of suppression below 80 copies/ml, 48 and 144 weeks after ART initiation, were identified using logistic regression (backwards elimination; exit P = 0.1 to develop an explanatory model), forcing into the models sdNVP (the primary exposure), age at ART initiation (a major known confounder) and ART-strategy randomization [because, at week 144, triple NRTI maintenance (arm C) was virologically inferior to 2NRTI + NNRTI (arms A and B) in the trial as a whole]. The 80 copies/ml threshold was chosen to provide the most sensitive investigation of the possible impact of low-level resistant variants following sdNVP exposure. Other factors considered were pre-ART WHO stage, CD4%, weight/height-for-age Z-scores (WHO reference) and viral load; sex, trial centre, CD4 monitoring randomization; current or initial ART taken as all syrups; and whether the caregiver reported missed ART doses (in the last 4 weeks; percentage of scheduled visits in the last 48 weeks). Missing data were very few, so models included complete cases only. Non-linearity in the effects of continuous predictors was explored using natural cubic splines, with three knots at the 10th, 50th and 90th centiles. Interactions between variables included in final models were investigated when heterogeneity P was less than 0.05. In additional main-effect models, the primary caregiver (mother/other) and socioeconomic variables at ART initiation (physical house structure, electricity, household assets) were also included. As children in arm C stopped NNRTI at week 36, secondary analyses considered only arms A and B receiving long-term NNRTI. All analyses were performed using Stata 13.1 (StataCorp, College Station, Texas, USA). All P values were two-sided.
Methods
Analyses included 367 previously untreated (except for PMTCT) Ugandan/Zimbabwean children initiating NVP-based ART aged 3 months to less than 36 months in the ARROW trial (ISCRTN24791884). Three children aged below 36 months (32, 35 and 35 months) initiated efavirenz-based ART and were excluded. The trial recruited from March 2007 to November 2008: before this, and during recruitment, sdNVP to the mother and child was the national PMTCT strategy. ART taken by the mother during pregnancy, delivery or breastfeeding, and (separately) ART taken by the child were determined by self-report at enrolment.
The children were randomized 1 : 1 to clinically-driven monitoring vs. laboratory + clinical monitoring for toxicity (haematology/biochemistry) and efficacy (CD4). Children were also randomized 1 : 1 : 1 in a factorial design to open-label lamivudine + abacavir + NNRTI continuously (arm A, no zidovudine) vs. induction-maintenance with four-drug lamivudine + abacavir + NNRTI + zidovudine for 36 weeks, then either lamivudine + abacavir + NNRTI (arm B; short-term zidovudine) or lamivudine + abacavir + zidovudine (arm C; long-term zidovudine). Children were recruited from three centres in Uganda and one in Zimbabwe. All children were examined by a doctor at screening, randomization, weeks 4, 8, and 12, and then every 12 weeks. Every 4–6 weeks, the children were reviewed by a nurse, and adherence was assessed using a questionnaire completed by the carer. The trial was approved by Research Ethics Committees in Uganda, Zimbabwe and the United Kingdom. The caregivers gave written consent.
The viral load was assayed retrospectively on stored plasma samples at 0, 4, 24, 36, 48 and 144 weeks post-ART initiation, and the last study visit before trial closure on 16 March 2012 in all children. The viral load was additionally assayed 24-weekly after week 48 in children enrolled after June 2008 (immunology/virology sub-study); and in an overlapping subset at, and 48 and 96 weeks after, a subsequent randomization to once vs. twice-daily lamivudine + abacavir (which were virologically equivalent). Assays were run using Abbott m2000rt (in Uganda; Abbott, Maidenhead, UK) and Roche Amplicor 1.5 (in Zimbabwe; Roche, Basel, Switzerland). The closest measurement to 4, 24, 36 and 48 weeks on ART, and then 24-weekly (in equally spaced windows), was used in analyses, which used a lower detection limit of 80 copies/ml because many low-volume samples had to be diluted 1 : 2. Samples with more than 1000 copies/ml at week 48 or 144, or any time point in the once/twice-daily study, were genotyped (reverse transcriptase only). The closest genotype to week 144 from week 48 through to trial end was used for analysis. Major nucleoside reverse transcriptase inhibitor (NRTI) mutations were defined according to International AIDS Society (IAS) 2013, and drug susceptibility was predicted using the Stanford algorithm version 7.
Pre-ART characteristics of sdNVP-exposed and non-exposed children were compared using chi-square tests for categorical factors and Wilcoxon rank-sum tests for continuous values. Predictors of suppression below 80 copies/ml, 48 and 144 weeks after ART initiation, were identified using logistic regression (backwards elimination; exit P = 0.1 to develop an explanatory model), forcing into the models sdNVP (the primary exposure), age at ART initiation (a major known confounder) and ART-strategy randomization [because, at week 144, triple NRTI maintenance (arm C) was virologically inferior to 2NRTI + NNRTI (arms A and B) in the trial as a whole]. The 80 copies/ml threshold was chosen to provide the most sensitive investigation of the possible impact of low-level resistant variants following sdNVP exposure. Other factors considered were pre-ART WHO stage, CD4%, weight/height-for-age Z-scores (WHO reference) and viral load; sex, trial centre, CD4 monitoring randomization; current or initial ART taken as all syrups; and whether the caregiver reported missed ART doses (in the last 4 weeks; percentage of scheduled visits in the last 48 weeks). Missing data were very few, so models included complete cases only. Non-linearity in the effects of continuous predictors was explored using natural cubic splines, with three knots at the 10th, 50th and 90th centiles. Interactions between variables included in final models were investigated when heterogeneity P was less than 0.05. In additional main-effect models, the primary caregiver (mother/other) and socioeconomic variables at ART initiation (physical house structure, electricity, household assets) were also included. As children in arm C stopped NNRTI at week 36, secondary analyses considered only arms A and B receiving long-term NNRTI. All analyses were performed using Stata 13.1 (StataCorp, College Station, Texas, USA). All P values were two-sided.
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