Veronica Mulenga

Excellent adherence to antiretrovirals in HIV+ Zambian children is compromised by disrupted routine, HIV Nondisclosure, and Paradoxical Income Effects

Introduction A better understanding of pediatric antiretroviral therapy (ART) adherence in sub-Saharan Africa is necessary to develop interventions to sustain high levels of adherence. Methodology/Principal Findings Adherence among 96 HIV-infected Zambian children (median age 6, interquartile range [IQR] 2,9) initiating fixed-dose combination ART was measured prospectively (median 23 months; IQR 20,26) with caregiver report, clinic and unannounced home-based pill counts, and medication event monitoring systems (MEMS). HIV-1 RNA was determined at 48 weeks. Child and caregiver characteristics, socio-demographic status, and treatment-related factors were assessed as predictors of adherence. Median adherence was 97.4% (IQR 96.1,98.4%) by visual analog scale, 94.8% (IQR 86,100%) by caregiver-reported last missed dose, 96.9% (IQR 94.5,98.2%) by clinic pill count, 93.4% (IQR 90.2,96.7%) by unannounced home-based pill count, and 94.8% (IQR 87.8,97.7%) by MEMS. At 48 weeks, 72.6% of children had HIV-1 RNA <50 copies/ml. Agreement among adherence measures was poor; only MEMS was significantly associated with viral suppression (p = 0.013). Predictors of poor adherence included changing residence, school attendance, lack of HIV disclosure to children aged nine to 15 years, and increasing household income. Conclusions/Significance Adherence among children taking fixed-dose combination ART in sub-Saharan Africa is high and sustained over two years. However, certain groups are at risk for treatment failure, including children with disrupted routines, no knowledge of their HIV diagnosis among older children, and relatively high household income, possibly reflecting greater social support in the setting of greater poverty.

Determinants of survival without antiretroviral therapy after infancy in HIV-1-infected Zambian children in the CHAP Trial.

Background: There are few data on predictors of HIV progression in untreated children in resource-limited settings. Methods: Children with HIV Antibiotic Prophylaxis (CHAP) was a randomized trial comparing cotrimoxazole prophylaxis with placebo in HIV-infected Zambian children. The prognostic value of baseline characteristics was investigated using Cox models. Results: Five hundred fourteen children aged 1 to 14 (median 5.5) years contributed 607 years follow-up (maximum 2.6 years). Half were boys, and in 67%, the mother was the primary carer; at baseline, median CD4 percentage was 11% and weight was less than third percentile in 67%. One hundred sixty-five children died (27.2 per 100 years at risk; 95% confidence interval 23.3-31.6). Low weight-for-age, CD4 percentage, hemoglobin, mother as primary carer, current malnutrition, and previous hospital admissions for respiratory tract infections or recurrent severe bacterial infections were independent predictors of poorer survival, whereas oral candidiasis predicted poorer survival only when baseline CD4 percentage was not considered. Mortality rates per 100 child years of 44.5 (37.2-53.2), 14.7 (10.9-19.8), and 2.3 (0.3-16.7) were associated with new World Health Organization stages 4, 3, and 1/2, respectively, applied retrospectively; very low weight-for-age was the only staging feature for 42% of stage 4 children. Conclusions: Malnutrition and hospitalizations for respiratory/bacterial infections predict mortality independent of immunosuppression, suggesting that they capture HIV- and non-HIV-related mortality, whereas oral candidiasis is a proxy for immunosuppression.

Effect of cotrimoxazole on causes of death, hospital admissions and antibiotic use in HIV-infected children.

Background:Cotrimoxazole prophylaxis reduces morbidity and mortality in HIV-1-infected children, but mechanisms for these benefits are unclear. Methods:CHAP was a randomized trial comparing cotrimoxazole prophylaxis with placebo in HIV-infected children in Zambia where background bacterial resistance to cotrimoxazole is high. We compared causes of mortality and hospital admissions, and antibiotic use between randomized groups. Results:Of 534 children (median age, 4.4 years; 32% 1–2 years), 186 died and 166 had one or more hospital admissions not ending in death. Cotrimoxazole prophylaxis was associated with lower mortality, both outside hospital (P = 0.01) and following hospital admission (P = 0.005). The largest excess of hospital deaths in the placebo group was from respiratory infections [22/56 (39%) placebo versus 10/35 (29%) cotrimoxazole]. By 2 years, the cumulative probability of dying in hospital from a serious bacterial infection (predominantly pneumonia) was 7% on cotrimoxazole and 12% on placebo (P = 0.08). There was a trend towards lower admission rates for serious bacterial infections in the cotrimoxazole group (19.1 per 100 child-years at risk versus 28.5 in the placebo group, P = 0.09). Despite less total follow-up due to higher mortality, more antibiotics (particularly penicillin) were prescribed in the placebo group in year one [6083 compared to 4972 days in the cotrimoxazole group (P = 0.05)]. Conclusions:Cotrimoxazole prophylaxis appears to mainly reduce death and hospital admissions from respiratory infections, supported further by lower rates of antibiotic prescribing. As such infections occur at high CD4 cell counts and are common in Africa, the role of continuing cotrimoxazole prophylaxis after starting antiretroviral therapy requires investigation.

The Impact of Daily Cotrimoxazole Prophylaxis and Antiretroviral Therapy on Mortality and Hospital Admissions in HIV-Infected Zambian Children

BACKGROUND Data on the population effectiveness of cotrimoxazole prophylaxis and antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected African children are few. METHODS A total of 534 Zambian children with HIV infection were randomized to receive daily cotrimoxazole prophylaxis or placebo in the Children with HIV Antibiotic Prophylaxis trial. Following trial closure, children who received the placebo initiated cotrimoxazole prophylaxis, and all children were observed in a closed cohort. Mortality and hospital admission rates were compared, over calendar time, in 9-month periods: trial recruitment (March 2001 to April 2002, May 2002 to January 2003), trial follow-up to closure (February 2003 to October 2003), initial follow-up posttrial (November 2003 to July 2004), and early and later ART availability (August 2004 to April 2005, and May 2005 to May 2006, respectively). RESULTS A total of 546 child-years of follow-up, 40 deaths, and 80 hospital admissions were observed between the time of trial closure and June 2006. A total of 117 of 283 children who were alive at trial closure received ART in the posttrial period (median child age at first use of ART, 8.8 years). Rates decreased in both groups during the trial period, suggesting a survivorship effect. Mortality and hospital admission rates before trial closure were 14 (95% confidence interval [CI], 9-21) deaths per 100 child-years and 24 (95% CI, 15-39) hospital admissions per 100 child-years, respectively, for children who were receiving cotrimoxazole, and were 23 (95% CI, 16-34) deaths per 100 child-years and 35 (95% CI, 23-53) hospital admissions per 100 child-years, respectively, for children who were receiving the placebo. After trial closure, rates remained stable in the cotrimoxazole group, but decreased to 15 (95% CI, 8-26) deaths per 100 child-years and 19 (95% CI, 10-41) hospital admissions per 100 child-years, respectively, for the group of children who received placebo and then initiated cotrimoxazole prophylaxis. In both groups combined, mortality rates decreased to 6 (95% CI, 3-11) deaths per 100 child-years and then 2 (95% CI, 0.8-6) deaths per 100 child-years during periods of ART availability; hospital admission rates decreased to 17 (95% CI, 11-27) hospital admissions per 100 child-years and 8 (95% CI, 4-15) hospital admissions per 100 child-years, respectively. CONCLUSION The benefits of once-daily cotrimoxazole prophylaxis continued throughout the trial and after trial closure. Mortality and hospital admissions decreased (by approximately 6-fold and approximately 3-fold, respectively) following ART availability, similar to findings observed in resource-rich countries.

The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia.

Objective:To assess the cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia, as implementation at the local health centre level has yet to be undertaken in many resource-limited countries despite recommendations in recent updated World Health Organization (WHO) guidelines. Design:A probabilistic decision analytical model of HIV/AIDS progression in children based on the CD4 cell percentage (CD4%) was populated with data from the placebo-controlled Children with HIV Antibiotic Prophylaxis trial that had reported a 43% reduction in mortality with cotrimoxazole prophylaxis in HIV-infected children aged 1–14 years. Methods:Unit costs (US

Treatment of young children with HIV infection : using evidence to inform policymakers

in 2006) were measured at University Teaching Hospital, Lusaka. Cost-effectiveness expressed as cost per life-year saved, cost per quality adjusted life-year (QALY) saved, cost per disability adjusted life-year (DALY) averted was calculated across a number of different scenarios at tertiary and primary healthcare centres. Results:Cotrimoxazole prophylaxis was associated with incremental cost-effectiveness ratios (ICERs) of US

Strategies for Nevirapine Initiation in HIV-Infected Children Taking Pediatric Fixed-Dose Combination “ Baby Pills” in Zambia: A Randomized Controlled Trial

72 per life-year saved, US

Drug resistance in human immunodeficiency virus type-1 infected Zambian children using adult fixed dose combination stavudine, lamivudine, and nevirapine.

94 per QALY saved and US

Improved Growth and Anemia in HIV-Infected African Children Taking Cotrimoxazole Prophylaxis

53 per DALY averted, i.e. substantially less than a cost-effectiveness threshold of US

Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial

1019 per outcome (gross domestic product per capita, Zambia 2006). ICERs of US