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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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=.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Risk factors for subclinical mastitis among HIV-infected and uninfected women in Lusaka, Zambia.

Subclinical mastitis, defined as raised milk sodium/potassium (Na/K) ratio, is associated with poor infant growth and, among HIV-infected women, with increased milk HIV viral load. We conducted a longitudinal cohort study in Lusaka, Zambia, in order to investigate the relative importance of several potential causes of subclinical mastitis: maternal infection, micronutrient deficiencies and poor lactation practice. Women (198 HIV-infected, 189 HIV-uninfected) were recruited at 34 weeks' gestation and followed up to 16 weeks postpartum for collection of information on their health, their infant's health, infant growth and infant feeding practices.

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.

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.