Harry Moultrie

Nevirapine versus Ritonavir-Boosted Lopinavir for HIV-Infected Children

BACKGROUND Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Outcomes of the South African national antiretroviral treatment programme for children : the IeDEA southern Africa collaboration

OBJECTIVES To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20% of the South African national treatment programme. DESIGN AND SETTING Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and KwaZulu-Natal provinces. SUBJECTS ART-naive children (< or = 16 years) who commenced treatment with > or = 3 antiretroviral drugs before March 2008. OUTCOME MEASURES Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox proportional hazards models stratified by site. Immune status, virological suppression and growth were described in relation to duration of ART. RESULTS The median (interquartile range) age of 6 078 children with 9 368 child-years of follow-up was 43 (15 - 83) months, with 29% being < 18 months. Most were severely ill at ART initiation. More than 75% of children were appropriately monitored at 6-monthly intervals with viral load suppression (< 400 copies/ml) being 80% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7% (95% confidence interval 7.0 - 8.6%) and 81.4% (80.1 - 82.6%), respectively. Together with young age, all markers of disease severity (low weight-for-age z-score, high viral load, severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality. CONCLUSIONS Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.

Challenges to Pediatric HIV Care and Treatment in South Africa

It is estimated that almost 300,000 children in South Africa have human immunodeficiency virus (HIV) infection. The disease is responsible for reversing decreases in child mortality. Few data exist evaluating the outcomes of the prevention of mother-to-child transmission of HIV (PMTCT) program, although PMTCT coverage appears to be low. Hospitals are still witnessing large numbers of admissions of HIV-infected children. Postnatal transmission of HIV is high, reflecting poor education of and support for women in their infant feeding choices. Too few infants and children are entering care through early diagnosis, which should be widely available. Cotrimoxazole prophylaxis coverage is inadequate, contributing to high morbidity and mortality in infants. The number of children receiving antiretroviral therapy (ART) is increasing steadily. However, significant inequalities in access to ART exist between and within provinces. Challenges for pediatric ART include a lack of sufficiently trained health care personnel and inadequate facilities, as well as the complexity of drug regimens and formulations. The compartmentalization of the ART rollout program hinders PMTCT and makes it difficult for children to be identified and referred into appropriate services. This article delineates the challenges to pediatric HIV care in South Africa and provides some practical recommendations to improve it.

Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa

Background:Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account. Patients and Methods:Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year. Results:Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6%) were included; 391 (4.8%) died and 523 (7.0%) were LTFU in the first year. Mortality at 1 year was 4.5% [95% confidence interval (CI): 2.8% to 7.4%] in children remaining in care, but 8.7% (5.4% to 12.1%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95% CI: 0.25 to 0.54 comparing ≥120 months with <18 months], CD4 cell percent (HR: 0.56; 95% CI: 0.39 to 0.78 comparing ≥20% with <10%), and clinical stage (HR: 0.12; 95% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV). Conclusions:In children starting ART and remaining in care in Southern Africa mortality at 1 year is <5% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.

Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration.

Background: With expanding pediatric antiretroviral therapy (ART) access, children will begin to experience treatment failure and require second-line therapy. We evaluated the probability and determinants of virologic failure and switching in children in South Africa. Methods: Pooled analysis of routine individual data from children who initiated ART in 7 South African treatment programs with 6-monthly viral load and CD4 monitoring produced Kaplan-Meier estimates of probability of virologic failure (2 consecutive unsuppressed viral loads with the second being >1000 copies/mL, after ≥24 weeks of therapy) and switch to second-line. Cox-proportional hazards models stratified by program were used to determine predictors of these outcomes. Results: The 3-year probability of virologic failure among 5485 children was 19.3% (95% confidence interval: 17.6 to 21.1). Use of nevirapine or ritonavir alone in the initial regimen (compared with efavirenz) and exposure to prevention of mother to child transmission regimens were independently associated with failure [adjusted hazard ratios (95% confidence interval): 1.77 (1.11 to 2.83), 2.39 (1.57 to 3.64) and 1.40 (1.02 to 1.92), respectively]. Among 252 children with ≥1 year follow-up after failure, 38% were switched to second-line. Median (interquartile range) months between failure and switch was 5.7 (2.9-11.0). Conclusions: Triple ART based on nevirapine or ritonavir as a single protease inhibitor seems to be associated with a higher risk of virologic failure. A low proportion of virologically failing children were switched.

The contribution of maternal HIV seroconversion during late pregnancy and breastfeeding to mother-to-child transmission of HIV

Background:The prevention of mother-to-child transmission (PMTCT) of HIV has been focused mainly on women who are HIV positive at their first antenatal visit, but there is uncertainty regarding the contribution to overall transmission from mothers who seroconvert after their first antenatal visit and before weaning. Method:A mathematical model was developed to simulate changes in mother-to-child transmission of HIV over time, in South Africa. The model allows for changes in infant feeding practices as infants age, temporal changes in the provision of antiretroviral prophylaxis and counseling on infant feeding, as well as temporal changes in maternal HIV prevalence and incidence. Results:The proportion of mother-to-child transmission (MTCT) from mothers who seroconverted after their first antenatal visit was 26% [95% confidence interval (CI): 22% to 30%] in 2008, or 15,000 of 57,000 infections. It is estimated that by 2014, total MTCT will reduce to 39,000 per annum, and transmission from mothers seroconverting after their first antenatal visit will reduce to 13,000 per annum, accounting for 34% (95% CI: 29% to 39%) of MTCT. If maternal HIV incidence during late pregnancy and breastfeeding were reduced by 50% after 2010, and HIV screening were repeated in late pregnancy and at 6-week immunization visits after 2010, the average annual number of MTCT cases over the 2010–2015 period would reduce by 28% (95% CI: 25% to 31%), from 39,000 to 28,000 per annum. Conclusion:Maternal seroconversion during late pregnancy and breastfeeding contributes significantly to the pediatric HIV burden and needs greater attention in the planning of prevention of MTCT programs.

Monitoring the South African National Antiretroviral Treatment Programme, 2003 – 2007: The IeDEA Southern Africa Collaboration

OBJECTIVES To introduce the combined South African cohorts of the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterise patients accessing these services; and to describe changes in services and patients from 2003 to 2007. DESIGN AND SETTING Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal. SUBJECTS Adults and children (<16 years old) who initiated ART with > or =3 antiretroviral drugs before 2008. RESULTS Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17,835 patients per site. Among 45,383 adults and 6,198 children combined, median age (interquartile range) was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5), respectively. Of adults, 68% were female. The median CD4 cell count was 102 cells/microl (44-164) and was lower among males than females (86, 34-150 v. 110, 50-169, p<0.001). Median CD4% among children was 12% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/microl, p<0.001) and for those in stage IV (39-89 cells/microl, p<0.001). Among children <5 years, baseline CD4% increased over time (11.5-16.0%, p<0.001). CONCLUSIONS IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increased enrolment over time. Late diagnosis and ART initiation, especially of men and children, need attention. Investment in sentinel sites will ensure good individual-level data while freeing most sites to continue with simplified reporting.

Antiretroviral Therapy Responses among Children Attending a Large Public Clinic in Soweto, South Africa

Background: Antiretroviral therapy (ART) access with successful outcomes for children is expanding in resource-limited countries. The aim of this study was to determine treatment responses of children in a routine setting where first-line therapy with lopinavir/ritonavir is routinely included for young children. Methods: Outpatient records of children who initiated ART between April 2004 and March 2008 at a government clinic in Soweto were reviewed. Children <3 years initiated ART with lopinavir/ritonavir and those ≥3 years initiated with efavirenz-containing regimens. Results: ART was initiated at a median age of 4.3 years, 28.6% also received tuberculosis treatment. During 3155 child-years of follow-up (median follow-up 17 months), 132 children (6%) died giving a mortality rate of 4.2 (95% confidence interval: 3.5, 5.0) deaths per 100 child-years. By 12 and 24 months, 84% and 96% of children achieved virologic suppression. The proportion of children with viral rebound increased from 5.4% to 16.3% at 24 and 36 months from start of ART. Younger children (receiving lopinavir/ritonavir-based first-line therapy) with higher viral loads suppressed more slowly and were more likely to die. Children who were started on treatment for tuberculosis at the time of viral suppression were more likely to have virologic rebound. Conclusion: Despite good treatment outcomes overall, children with advanced disease at ART initiation had poorer outcomes, particularly those <3 years of age, most of whom were treated with lopinavir/ritonavir-containing therapy. The increasing risk of viral rebound over time for the whole cohort is concerning, given currently limited available treatment options for children.

The effect of early initiation of antiretroviral treatment in infants on pediatric AIDS mortality in South Africa: a model-based analysis.

Background: Guidelines for treatment of pediatric HIV have recently changed to recommend that all infants who are identified as HIV-infected should start antiretroviral treatment (ART) immediately, regardless of their immunologic or clinical status. This study aims to assess the likely impact of this change in guideline in South Africa. Methods: A mathematical model was developed to simulate mother-to-child transmission of HIV, disease progression, and death of HIV-infected children <15 years of age. The model is calibrated to South African data sources, including prevention of mother-to-child transmission program coverage data, pre-ART survival data, ART program statistics, and pediatric HIV prevalence studies. Results: Relative to what would be expected in the absence of early ART initiation, the number of infant AIDS deaths over the 2010–2025 period is expected to drop by 23.6% (95% confidence interval [CI]: 22.5–24.5%) at current levels of polymerase chain reaction (PCR) diagnosis, and by 34.2% (95% CI: 32.7–35.6%) if PCR diagnosis increases to 80% of perinatally infected infants at 2 months. However, the pediatric HIV disease burden has shifted toward older children in recent years. The effect of early ART on total pediatric AIDS mortality during the 2010–2025 period is therefore modest: a 9.8% reduction (95% CI: 7.9–12.6%) at current levels of PCR diagnosis, and a 14.2% reduction (95% CI: 11.4–18.2%) if PCR coverage increases to 80% of perinatally infected infants. Conclusion: The changes in ART guidelines for infants will have a significant impact on pediatric AIDS mortality at young ages, but further efforts are required to reduce the substantial growing AIDS mortality in older children.

Effect on mortality and virological response of delaying antiretroviral therapy initiation in children receiving tuberculosis treatment.

Objective:To estimate the effect of delaying antiretroviral treatment (ART) for 15, 30, or 60 days after tuberculosis (TB) treatment initiation on mortality and virological suppression. Design:Cohort of 573 ART-naive HIV-infected children initiated on TB treatment at an outpatient clinic in South Africa between April 2004 and March 2008. Methods:Hazard ratios for mortality and viral suppression were estimated using marginal structural models and multivariate Cox models, respectively. Results:During follow-up (median 9.64 months), 37 HIV-infected children died after a median of 62 days of TB treatment. ART was initiated in 461 children at a median of 17 days after TB treatment initiation, 415 (90%) achieved viral suppression. The hazard ratios of death for initiating ART more than 15, more than 30, or more than 60 days of TB treatment compared with initiating within 15, 30 and 60 days, respectively, were 0.82 (95% CI: 0.48, 1.41), 0.86 (95% CI: 0.46, 1.60), and 1.32 (95% CI: 0.55, 3.16). Hazard ratios for analysis restricted to severely immunosuppressed children were: 0.92 (95% CI: 0.51, 1.63), 1.08 (95% CI: 0.56, 2.08), and 2.23 (95% CI: 0.85, 5.80), respectively. Hazard ratios for viral suppression were 0.98 (95% CI: 0.76, 1.26), 0.95, (95% CI: 0.73, 1.23), 0.84 (95% CI: 0.61, 1.15), respectively and did not change with restriction to children severely immunosuppressed. Conclusion:In this observational study, we found that delaying ART for 2 months or more in children diagnosed with TB may be associated with poorer virological response and increased mortality, particularly in children with severe immunosuppression. These findings should be confirmed in a randomized controlled trial.