Improved growth and anemia in HIV-infected African children taking cotrimoxazole prophylaxis.

The impact of cotrimoxazole (CTX) on growth and/or anemia was investigated in 541 human immunodeficiency virus-infected, antiretroviral therapy-naive Zambian children enrolled in the Children with HIV Antibiotic Prophylaxis trial. Compared with children randomized to receive placebo, children randomized to receive CTX had slower decreases in weight-for-age (P=.04) and height-for-age (P=.01), and greater increase in hemoglobin level (P=.01). These findings argue for expanded early CTX use.

The evolution of HIV-1 reverse transcriptase in route to acquisition of Q151M multi-drug resistance is complex and involves mutations in multiple domains.

BACKGROUND: The Q151M multi-drug resistance (MDR) pathway in HIV-1 reverse transcriptase (RT) confers reduced susceptibility to all nucleoside reverse transcriptase inhibitors (NRTIs) excluding tenofovir (TDF). This pathway emerges after long term failure of therapy, and is increasingly observed in the resource poor world, where antiretroviral therapy is rarely accompanied by intensive virological monitoring. In this study we examined the genotypic, phenotypic and fitness correlates associated with the development of Q151M MDR in the absence of viral load monitoring. RESULTS: Single-genome sequencing (SGS) of full-length RT was carried out on sequential samples from an HIV-infected individual enrolled in ART rollout. The emergence of Q151M MDR occurred in the order A62V, V75I, and finally Q151M on the same genome at 4, 17 and 37 months after initiation of therapy, respectively. This was accompanied by a parallel cumulative acquisition of mutations at 20 other codon positions; seven of which were located in the connection subdomain. We established that fourteen of these mutations are also observed in Q151M-containing sequences submitted to the Stanford University HIV database. Phenotypic drug susceptibility testing demonstrated that the Q151M-containing RT had reduced susceptibility to all NRTIs except for TDF. RT domain-swapping of patient and wild-type RTs showed that patient-derived connection subdomains were not associated with reduced NRTI susceptibility. However, the virus expressing patient-derived Q151M RT at 37 months demonstrated ~44% replicative capacity of that at 4 months. This was further reduced to ~22% when the Q151M-containing DNA pol domain was expressed with wild-type C-terminal domain, but was then fully compensated by coexpression of the coevolved connection subdomain. CONCLUSIONS: We demonstrate a complex interplay between drug susceptibility and replicative fitness in the acquisition Q151M MDR with serious implications for second-line regimen options. The acquisition of the Q151M pathway occurred sequentially over a long period of failing NRTI therapy, and was associated with mutations in multiple RT domains.

Randomised, placebo-controlled trial to evaluate co-trimoxazole to reduce mortality and morbidity in HIV-infected post-natal women in Zambia (TOPAZ).

OBJECTIVE: To evaluate the role of prophylactic trimethoprim-sulfamethoxazole (co-trimoxazole) antibacterial prophylaxis in reducing morbidity and mortality in HIV-infected post-natal women in southern Africa. METHODS: Double-blind placebo-controlled trial. HIV-infected women with WHO stage 2 or 3 HIV disease who had recently delivered in the Department of Obstetrics and Gynaecology at the University Teaching Hospital, Lusaka, Zambia were randomised to receive daily co-trimoxazole (cotox) or matched placebo daily for the duration of the trial. Participants were followed up for a minimum of 1 year. Primary outcome measures were mortality from any cause or hospital admission and serious adverse events. RESULTS: Of 600 women randomised, follow-up information was available from 355 (180 cotox, 175 placebo) participants. Thirty-six (17 cotox, 19 placebo) women died during the trial, and another 11 (5 cotox, 6 placebo) were admitted to hospital. There was no significant difference in the combined event rates between the two treatment arms: HR = 0.82, 95% CI (0.46, 1.45), P = 0.49; morbidity was reduced over a range of symptoms. Secondary analyses of the outcome in babies indicated some evidence of reduced mortality in those whose mothers were allocated cotox. CONCLUSIONS: Follow-up rates were poor; there was no evidence that co-trimoxazole prophylaxis reduced mortality or hospital admission rates, although fewer symptoms were reported in the cotox arm. Cotox was safe and well tolerated.

Limited sampling models to predict the pharmacokinetics of nevirapine, stavudine, and lamivudine in HIV-infected children treated with pediatric fixed-dose combination tablets.

Full 12-hour pharmacokinetic profiles of nevirapine, stavudine, and lamivudine in HIV-infected children taking fixed-dose combination antiretroviral tablets have been reported previously by us. Further studies with these formulations could benefit from less-intensive pharmacokinetic sampling. Data from 65 African children were used to relate area under the plasma concentration versus time curve over 12 hours (AUC) to plasma concentrations of nevirapine, stavudine, or lamivudine at times t = 0, 1, 2, 4, 6, 8, and 12 hours after intake using linear regression. Limited sampling models were developed using leave-one-out crossvalidation. The predictive performance of each model was evaluated using the mean relative prediction error (mpe%) as an indicator of bias and the root mean squared relative prediction error (rmse%) as a measure of precision. A priori set criteria to accept a limited sampling model were: 95% confidence limit of the mpe% should include 0, rmse% less than 10%, a high correlation coefficient, and as few (convenient) samples as possible. Using only one sample did not lead to acceptable AUC predictions for stavudine or lamivudine, although the 6-hour sample was acceptable for nevirapine (mpe%: -0.8%, 95% confidence interval: -2.2 to +0.6); rmse%: 5.8%; r: 0.98). Using two samples, AUC predictions for stavudine and lamivudine improved considerably but did not meet the predefined acceptance criteria. Using three samples (1, 2, 6 hours), an accurate and precise limited sampling model for stavudine AUC (mpe%: -0.6%, 95% confidence interval: -2.2 to +1.0; rmse%: 6.5%; r: 0.98) and lamivudine AUC (mpe%: -0.3%, 95% confidence interval: -1.7 to +1.1; rmse%: 5.6%; r: 0.99) was found; this model was also highly accurate and precise for nevirapine AUC (mpe%: -0.2%, 95% confidence interval: -1.0 to +0.7; rmse%: 3.4%; r: 0.99). A limited sampling model using three time points (1, 2, 6 hours) can be used to predict nevirapine, stavudine, and lamivudine AUC accurately and precisely in HIV-infected African children.

Adherence to both cotrimoxazole and placebo is associated with improved survival among HIV-infected Zambian children.

In the CHAP randomized placebo-controlled trial of cotrimoxazole prophylaxis in HIV-infected Zambian children conducted between 2001 and 2003, cotrimoxazole was associated with significant mortality reductions. In a secondary analysis we used Cox regression models to estimate the association between adherence measured by bottle weights and caregiver report and subsequent mortality in children surviving >28 days (n = 496, 153 deaths). Adherence was high and similar in both cotrimoxazole and placebo groups; adherence from bottle weights was 100% at 71% of visits, while caregivers reported 100% adherence at 79% of visits. Every 10% lower adherence to cotrimoxazole or placebo measured by bottle weights was associated with a 10-11% increase in mortality risk. Effects remained after adjustment for baseline predictors of survival and for current and recent change in primary caregiver. Caregiver-reported adherence was not associated with survival. The association between bottle-weight adherence to placebo and survival is likely capturing unmeasured caregiver effects, whose identification will be essential for quantifying the impact of antiretroviral therapy (ART) adherence on clinical outcomes in children.

Multidisciplinary and multisectoral coalitions as catalysts for action against antimicrobial resistance: Implementation experiences at national and regional levels.

The multi-faceted complexities of antimicrobial resistance (AMR) require consistent action, a multidisciplinary approach, and long-term political commitment. Building coalitions can amplify stakeholder efforts to carry out effective AMR prevention and control strategies. We have developed and implemented an approach to help local stakeholders kick-start the coalition-building process. The five-step process is to (1) mobilise support, (2) understand the local situation, (3) develop an action plan, (4) implement the plan, and (5) monitor and evaluate. We first piloted the approach in Zambia in 2004, then used the lessons learned to expand it for use in Ethiopia and Namibia and to the regional level through the Ecumenical Pharmaceutical Network [EPN]. Call-to-action declarations and workshops helped promote a shared vision, resulting in the development of national AMR action plans, revision of university curricula to incorporate relevant topics, infection control activities, engagement with journalists from various mass media outlets, and strengthening of drug quality assurance systems. Our experience with the coalition-building approach in Ethiopia, Namibia, Zambia, and with the EPN shows that coalitions can form in a variety of ways with many different stakeholders, including government, academia, and faith-based organisations, to organise actions to preserve the effectiveness of existing antimicrobials and contain AMR.

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.

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

OBJECTIVE: To investigate nevirapine concentrations in African HIV-infected children receiving divided Triomune tablets (stavudine+lamivudine+nevirapine). DESIGN: Cross-sectional study. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Factors influencing breast milk HIV RNA viral load among Zambian women.

In a longitudinal cohort study we investigated factors contributing to breast milk HIV RNA viral load among lactating women in Lusaka, Zambia. Detailed data from 135 HIV-infected women were collected by questionnaires concerning postpartum maternal and infant health and infant feeding practice. Maternal blood was collected during pregnancy and at 6 weeks postpartum. Milk samples collected from each breast at 10 days and 6 weeks postpartum plus a subset collected at other time points were analyzed for HIV RNA viral load. Increased milk viral load was associated in univariate analyses with maternal symptoms of poor health, raised plasma alpha(1)-acid glycoprotein (AGP) at week 6, raised milk sodium/potassium (Na/K) ratio, postpartum need for antibiotics, preterm delivery, and low birth weight infants. In a multiple regression 49% of variability in mean milk viral load was explained by milk Na/K ratio and need for antibiotics, with borderline contributions from plasma AGP and plasma viral load. Maternal blood hemoglobin or receipt of iron supplements and infant feeding variables such as changing the infant's diet by moving from exclusive to nonexclusive breastfeeding or adding solid foods were not associated with milk viral load. Thus maternal health was the main factor contributing to milk viral load. The lack of effect of feeding practices on milk viral load and the previously determined association of poor maternal health with reduced duration of exclusive breastfeeding in this cohort suggest the relation between exclusive breastfeeding and decreased HIV transmission may be secondary to poor maternal health.