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.

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

BACKGROUND: WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. METHODS: In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. FINDINGS: Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75-1·29]; abacavir vs stavudine: HR 0·88 [0·67-1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00). INTERPRETATION: All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines. FUNDING: European Developing Countries Clinical Trials Partnership.

Evaluation of a density-based rapid diagnostic test for sickle cell disease in a clinical setting in Zambia.

Although simple and low-cost interventions for sickle cell disease (SCD) exist in many developing countries, child mortality associated with SCD remains high, in part, because of the lack of access to diagnostic tests for SCD. A density-based test using aqueous multiphase systems (SCD-AMPS) is a candidate for a low-cost, point-of-care diagnostic for SCD. In this paper, the field evaluation of SCD-AMPS in a large (n = 505) case-control study in Zambia is described. Of the two variations of the SCD-AMPS used, the best system (SCD-AMPS-2) demonstrated a sensitivity of 86% (82-90%) and a specificity of 60% (53-67%). Subsequent analysis identified potential sources of false positives that include clotting, variation between batches of SCD-AMPS, and shipping conditions. Importantly, SCD-AMPS-2 was 84% (62-94%) sensitive in detecting SCD in children between 6 months and 1 year old. In addition to an evaluation of performance, an assessment of end-user operability was done with health workers in rural clinics in Zambia. These health workers rated the SCD-AMPS tests to be as simple to use as lateral flow tests for malaria and HIV.

Pediatric malignancies, treatment outcomes and abandonment of pediatric cancer treatment in Zambia.

BACKGROUND: There exist significant challenges to the receipt of comprehensive oncologic treatment for children diagnosed with cancer in sub-Saharan Africa. To better define those challenges, we investigated treatment outcomes and risk factors for treatment abandonment in a cohort of children diagnosed with cancer at the University Teaching Hospital (UTH), the site of the only pediatric oncology ward in Zambia. METHODS: Using an established database, a retrospective cohort study was conducted of children aged 0-15 years admitted to the pediatric oncology ward between July 2008 and June 2010 with suspected cancer. Diagnosis, mode of diagnosis, treatment outcome, and risk factors for abandonment of treatment were abstracted from this database and clinical medical records. RESULTS: Among 162 children treated at the UTH during the study time period that met inclusion criteria, only 8.0% completed a treatment regimen with most of the patients dying during treatment or abandoning care. In multivariable analysis, shorter distance from home to the UTH was associated with a lower risk of treatment abandonment (Adjusted Odds Ratio [aOR]  = 0.48 (95% confidence interval [CI] 0.23-0.97). Conversely maternal education less than secondary school was associated with increased risk for abandonment (aOR = 1.65; 95% CI 1.05-2.58). CONCLUSIONS: Despite availability of dedicated pediatric oncology treatment, treatment completion rates are poor, due in part to the logistical challenges faced by families, low educational status, and significant distance from the hospital. Alternative treatment delivery strategies are required to bring effective pediatric oncology care to the patients in need, as their ability to come to and remain at a central tertiary care facility for treatment is limited. We suggest that the extensive system now in place in most of sub-Saharan Africa that sustains life-long antiretroviral therapy for children with human immunodeficiency virus (HIV) infection be adapted for pediatric cancer treatment to improve outcome.

Clinical patterns of juvenile idiopathic arthritis in Zambia.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders with different disease manifestations among various populations. There are few reports of JIA among indigenous Africans especially sub-Saharan Africa. We present herein the clinical patterns of JIA encountered at a tertiary hospital in Lusaka, Zambia. METHOD: Hospital records of patients with a diagnosis of chronic arthritis with onset at the age of 16 years or less presenting to University Teaching Hospital, Lusaka, Zambia for the periods 1994-98 and 2006-2010 were retrospectively reviewed and reclassified as Juvenile Idiopathic Arthritis (JIA) based on the International League of Associations for Rheumatology (ILA R) JIA diagnostic criteria. RESULTS: In total, 126 patients with chronic arthritis of onset at age 16 years or less were evaluated over these periods at the hospital. Of these, 85 could further be analyzed by ILAR JIA criteria but 7 (8.24%) were HIV seropositive and were assessed separately. The average age at disease onset among the 78 JIA patients was 8.70 years (range: 1-15 years) with average age at first visit to hospital being 11.3 years (range: 2 to 25 years) and with a female to male ratio of 1.2:1. Polyarticular rheumatoid factor negative JIA, at 34.62%, was the most frequent type of chronic arthritis encountered. Oligoarthritis was found in 32.05% while 11.54% and 14.10% were polyarticular rheumatoid factor positive and systemic JIA, respectively. Enthesitis-related arthritis was found in 6.41% and only 1.28% were determined to have psoriatic arthritis among this population. CONCLUSION: JIA is predominantly a polyarticular rheumatoid factor negative disease in Zambia. Late presentation is an issue with major implications for educational input and resource acquisition. There is need to elucidate the genetics and environmental factors of JIA in this region.

Is nevirapine dose-escalation appropriate in young, African, HIV-infected children?

OBJECTIVES: Young children metabolize nevirapine faster than older children/adults. We evaluated nevirapine pharmacokinetics with or without dose-escalation in Zambian, HIV-infected infants/children and its relationship with safety/efficacy. DESIGN: A retrospective pharmacokinetic substudy of the CHAPAS-1 trial. METHODS: HIV-infected, Zambian children were randomized to initiate antiretroviral therapy (ART) with full-dose twice-daily nevirapine versus 2-week nevirapine dose-escalation. Samples taken 3-4 h postmorning-dose 2 weeks after nevirapine initiation were assayed for nevirapine levels. Viral load was measured on available samples at weeks 4 and 48; adverse events were prospectively reported. RESULTS: Of 162 (77%) children with week-2 samples, 79 (49%) were randomized to nevirapine dose-escalation. At ART initiation, median [interquartile range (IQR)] age, weight and CD4% were 5.2 (1.5-8.7) years, 13.0 (8.1-19.0) kg and 13 (8-18)%, respectively; 81 (50%) were male. With full dose, few children aged less than 2 years (3/23, 13%) or more than 2 years (4/60, 7%) had subtherapeutic nevirapine levels (defined as <3.0 mg/l), but with dose-escalation, seven out of 22 (32%) aged less than 2 years versus seven out of 57 (12%) more than 2 years had subtherapeutic nevirapine levels (P=0.05). There was no difference between week-2 nevirapine levels in those with viral load more than 250 versus less than 250 copies/ml at week 4 (P=0.97) or week 48 (P=0.40). Eleven out of 162 children had grade 1/2 rash; all were more than 2 years of age (P=0.04), and 10 were randomized to full dose. CONCLUSION: Subtherapeutic nevirapine levels 3-4 h postdose were more frequent in young children on dose-escalation. Younger children were at lower risk for rash. To simplify ART initiation and reduce the risk of suboptimal dosing, full-dose nevirapine at ART initiation should be considered for African HIV-infected children less than 2 years of age.

Pharmacokinetics of nevirapine in HIV-infected infants weighing 3 kg to less than 6 kg taking paediatric fixed dose combination tablets.

OBJECTIVES: To evaluate pharmacokinetics of nevirapine, lamivudine and stavudine in HIV-infected Zambian infants receiving fixed dose combination (FDC) antiretroviral tablets (Triomune Baby). DESIGN: Phase I/II study. METHODS: Sixteen HIV-infected children at least 1 month, weighing 3 kg to less than 6 kg were enrolled. Blood was sampled at t = 0, 2, 6 and 12 h after observed intake of one FDC tablet (50 mg nevirapine, 6 mg stavudine, 30 mg lamivudine) 4 weeks after starting treatment. Safety and viral load response over 48 weeks were determined. RESULTS: The median [interquartile range (IQR)] age, body weight and daily nevirapine dose in 15 included children (eight girls) were 4.8 (4.2, 8.4) months, 5.3 (4.3, 5.5) kg and 348 (326 385) mg/m, respectively. The median (IQR) nevirapine area under the concentration-time curve (AUC0-12 h), Cmax and C12 h were 70 (56, 104) h mg/l, 7.5 (6.2, 10) mg/l, and 4.3 (2.9, 6.9) mg/l, respectively. Values were on average higher than reported in adults, but approximately 20% lower than previously reported in children weighing at least 6 kg. Four of 15 (27%) children had a subtherapeutic nevirapine C12 h (defined as <3.0 mg/l) compared to only three of 63 (5%) children weighing at least 6 kg (P = 0.02), whereas children aged less than 5 months [three of six (50%)] may have the highest risk for subtherapeutic nevirapine C12 h (P = 0.24). No association was found between viral load values and nevirapine plasma pharmacokinetic parameters (P > 0.3). Stavudine-lamivudine pharmacokinetic parameters were broadly comparable to heavier children. CONCLUSION: Exposure to nevirapine in African, HIV-infected infants with low body weight taking FDC tablets appears on average to be adequate, but due to large intersubject variability a relatively high proportion had subtherapeutic nevirapine C12 h levels, particularly those aged less than 5 months.

Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis treatment.

OBJECTIVE: There is an urgent need to optimize cotreatment for children with tuberculosis and HIV infection. We described nevirapine pharmacokinetics in Zambian children aged less than 3 years, cotreated with nevirapine, lamivudine and stavudine in fixed-dose combination (using WHO weight bands) and rifampicin-based antituberculosis treatment. DESIGN: Twenty-two children received antituberculosis and antiretroviral therapy (ART) concurrently for 4 weeks before pharmacokinetic sampling. Plasma nevirapine concentrations were determined in samples taken immediately before, and 1, 2 and 6 h after an observed dose. Nevirapine pharmacokinetics were compared with those in 16 children aged less than 3 years without tuberculosis. RESULTS: Twenty-two children were treated for HIV/TB coinfection, 10 of whom were girls. One boy was excluded from analysis for nonadherence. The median age was 1.6 years (range: 0.7-3.2). Median weight was 8.0 kg (range: 5.1-10.5). The baseline CD4% was 13.1 (range: 3.9-43.6). Median predose concentration of nevirapine was 2.93 mg/l (range: 1.06-11.4), and peak concentration was 6.33 mg/l (range: 2.61-14.5). The nevirapine AUC up to 12 h was estimated as 52.0 mg.h/l (range: 22.6-159.7) compared with 90.9 mg.h/l (range: 40.4-232.1) in children without tuberculosis (P < 0.001). Predose concentrations of nevirapine were less than 3.0 mg/l in 11 children on tuberculosis treatment versus none of the 16 children without tuberculosis treatment (P = 0.001). AUC was 41% (95% CI: 23-54%) lower in children with tuberculosis than without tuberculosis (P < 0.001) after adjusting for dose per square meter. CONCLUSION: : We found substantial reductions in nevirapine concentrations in young children receiving rifampicin. Further studies are needed to define the pharmacokinetics, safety and efficacy of adjusted doses of nevirapine-based ART in young children with tuberculosis.

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.

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.

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.

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.

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

BACKGROUND: There are few medium-term virologic data in children from resource-limited settings taking adult fixed-dose-combination antiretroviral therapy (cART) without viral load monitoring. METHODS: CHAP2 (Children with HIV Antibiotic Prophylaxis 2) is a prospective cohort of Zambian children using d4T/3TC/NVP adult Triomune30 dosed according to WHO guidelines. RESULTS: A total of 103 children (19 with previous antiretroviral therapy) had follow-up >6 months. Median age at cART initiation was 8 years (IQR, 6-12) and CD4 8% (4-12). At 24 months, CD4% had increased by a median of 15% (7-25). For 74 children viral load was known/inferred: 51 of 74 (69%) had viral load <50 copies/mL (45 of 63 [71%] with no previous cART, 6 of 11 [55%] with previous cART; difference P = 0.30); 22 of 74 (30%) had viral load >1000 copies/mL. Of 26 children with resistance data, 25 (96%) had NNRTI resistance; 22 (84%) had M184V; 2 (8%) had Q151M; and 1 (4%) each had K65R, L74V, or K70E. Eight (31%) had > or =1 TAM. Those failing virologically with a genotypic sensitivity score of 0 for first-line therapy had a somewhat smaller increase in CD4% from baseline compared with those failing therapy with a genotypic sensitivity score >0 (+3 vs. +8, P = 0.13), and had somewhat lower CD4% at initiation of cART (2 vs. 11, P = 0.09). In 6 children with >1 resistance test, the estimated rate of accumulation of TAMs was 0.59/yr (95% confidence interval: 0.22-1.29). CONCLUSIONS: Twenty-four month virologic responses to cART were good. However, the rate of TAM accumulation in those with rebound was higher than reported in Western adult cohorts, and there was some indication of a detrimental effect of high level resistance on CD4% change from baseline.

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.

Role of co-trimoxazole prophylaxis in reducing mortality in HIV infected adults being treated for tuberculosis: randomised clinical trial.

OBJECTIVE: To assess the impact of prophylactic oral co-trimoxazole in reducing mortality in HIV positive Zambian adults being treated for pulmonary tuberculosis. DESIGN: Double blind placebo controlled randomised clinical trial. PARTICIPANTS: Two groups of antiretroviral treatment naive adults with HIV infection: patients newly diagnosed as having tuberculosis and receiving tuberculosis treatment either for the first time or for retreatment after relapse; previously treated patients not receiving treatment. INTERVENTION: Oral co-trimoxazole or matching placebo daily. Primary outcome measures Time to death and occurrence of serious adverse events related to study drug. RESULTS: 1003 patients were randomised: 835 (416 co-trimoxazole, 419 placebo) were receiving treatment for tuberculosis, 762 (376 co-trimoxazole, 386 placebo) of them newly diagnosed previously untreated patients and 73 (40 co-trimoxazole, 33 placebo) receiving a retreatment regimen; 168 (84 co-trimoxazole, 84 placebo) were not on treatment but had received treatment in the past. Of 835 participants receiving tuberculosis treatment, follow-up information was available for 757, with a total of 1012.6 person years of follow-up. A total of 310 (147 co-trimoxazole, 163 placebo) participants died, corresponding to death rates of 27.3 and 34.4 per 100 person years. In the Cox regression analysis, the hazard ratio for death (co-trimoxazole:placebo) was 0.79 (95% confidence interval 0.63 to 0.99). The effect of co-trimoxazole waned with time, possibly owing to falling adherence levels; in a per protocol analysis based on patients who spent at least 90% of their time at risk supplied with study drug, the hazard ratio was 0.65 (0.45 to 0.93). CONCLUSIONS: Prophylaxis with co-trimoxazole reduces mortality in HIV infected adults with pulmonary tuberculosis. Co-trimoxazole was generally safe and well tolerated. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15281875.

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$ 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$72 per life-year saved, US$94 per QALY saved and US$53 per DALY averted, i.e. substantially less than a cost-effectiveness threshold of US$1019 per outcome (gross domestic product per capita, Zambia 2006). ICERs of US$5 or less per outcome demonstrate that cotrimoxazole prophylaxis is even more cost-effective at the local healthcare level. The intervention remained cost-effective in all sensitivity analyses including routine haematological and CD4% monitoring, varying starting age, AIDS status, cotrimoxazole formulation, efficacy duration and discount rates. CONCLUSION: Cotrimoxazole prophylaxis in HIV-infected children is an inexpensive low technology intervention that is highly cost-effective in Zambia, strongly supporting the adoption of WHO guidelines into essential healthcare packages in low-income countries.

Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets.

OBJECTIVE: Triomune Baby and Junior have been developed in response to the urgent need for appropriate paediatric fixed-dose combination antiretroviral tablets, with higher nevirapine to stavudine and lamivudine ratios than adult tablets, in accordance with paediatric recommendations. We determined whether this ratio results in optimal exposure in the target population. METHODS: Seventy-one Zambian children were treated with Triomune Baby or Junior dosed according to weight bands. After 4 weeks or more, a 12-h pharmacokinetic curve was recorded. Antiretroviral plasma concentrations were assayed by high-performance liquid chromatography. RESULTS: Six children were excluded because of poor adherence. Of the remaining 65, 24 (37%) were female, 24 (37%) weighed less than 15 kg and most were malnourished. Mean (range) nevirapine C12h, Cmax and AUC12h of 6.0 (1.4, 16.9) mg/l, 10.0 (3.8, 22.5) mg/l and 94.4 (32.1, 232) mg/l per hour were higher than those reported in adults. Nevirapine C12h was subtherapeutic (< 3.0 mg/l) in four children (6%). Mean stavudine and lamivudine C12h, Cmax, AUC12h (< 0.015 mg/l, 0.45 mg/l, 1.05 mg/l per hour and 0.09 mg/l, 1.33 mg/l, 5.42 mg/l per hour) were comparable to adults. There was no evidence of a difference in nevirapine AUC12h across weight bands (P = 0.2), whereas the difference in stavudine (P = 0.0003) and lamivudine AUC12h (P = 0.01) was driven by the single weight band with unequal dosing. CONCLUSION: Nevirapine concentrations were higher but more variable than in adults; the pharmacokinetic parameters of stavudine and lamivudine were comparable to adults. As nevirapine underdosing is of greater concern than overdosing, the Triomune Baby and Junior ratio appears to be appropriate for children weighing 6 kg and over. Further research is required for children under 6 kg.

Tuberculosis and human immunodeficiency virus co-infection in children: management challenges.

The pattern of childhood human immunodeficiency virus (HIV) and tuberculosis (TB) infection mirror these epidemics in the adult population. The number of children co-infected with HIV and TB is rising, and the incidence of congenital and neonatal TB is similarly increasing. In addition, the emergence of multidrug resistant TB and extensively drug-resistant TB has occurred within the context of a high prevalence of HIV and TB. The diagnosis of TB has always been difficult in children and is compounded by HIV co-infection. The clinical symptoms in both diseases are similar, and the radiological changes may be non-specific. Treatment of both conditions in children is a challenge due to drug interactions and problems with adherence. In most developing countries, there are few medicines specifically tested and manufactured for children, with few stable syrup formulations. Thus antituberculosis and antiretroviral tablets have to be divided, giving rise to unpredictable dosing and the possible emergence of resistance. To reduce the morbidity and mortality of TB and HIV, existing childhood TB programmes must be strengthened, and antiretroviral drug therapy and mother-to-child transmission programmes scaled up. An increased emphasis on childhood TB, with early diagnosis and treatment, must be a priority. The provision of isoniazid prophylaxis to HIV-infected children exposed to an adult case of TB or, in areas with a high prevalence of TB, to HIV-infected children (irrespective of a TB contact) may be effective in reducing the morbidity and mortality from childhood TB.

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.