Length of secondary schooling and risk of HIV infection in Botswana: evidence from a natural experiment

Background An estimated 2·1 million individuals are newly infected with HIV every year. Cross-sectional and longitudinal studies have reported confl icting evidence for the association between education and HIV risk, and no randomised trial has identifi ed a causal eff ect for education on HIV incidence. We aimed to use a policy reform in secondary schooling in Botswana to identify the causal eff ect of length of schooling on new HIV infection. Methods Data for HIV biomarkers and demographics were obtained from the nationally representative household 2004 and 2008 Botswana AIDS Impact Surveys (N=7018). In 1996, Botswana reformed the grade structure of secondary school, expanding access to grade ten and increasing educational attainment for aff ected cohorts. Using exposure to the policy reform as an instrumental variable, we used two-stage least squares to estimate the causal eff ect of years of schooling on the cumulative probability that an individual contracted HIV up to their age at the time of the survey. We also assessed the cost-eff ectiveness of secondary schooling as an HIV prevention intervention in comparison to other established interventions. Findings Each additional year of secondary schooling caused by the policy change led to an absolute reduction in the cumulative risk of HIV infection of 8·1 percentage points (p=0·008), relative to a baseline prevalence of 25·5% in the pre-reform 1980 birth cohort. Eff ects were particularly large in women (11·6 percentage points, p=0·046). Results were robust to a wide array of sensitivity analyses. Secondary school was cost eff ective as an HIV prevention intervention by standard metrics (cost per HIV infection averted was US$27 753). Interpretation Additional years of secondary schooling had a large protective eff ect against HIV risk in Botswana, particularly for women. Increasing progression through secondary school could be a cost-eff ective HIV prevention measure in HIV-endemic settings, in addition to yielding other societal benefi ts. Funding Takemi Program in International Health at the Harvard T.H.Chan School of Public Health, Belgian American Educational Foundation, Fernand Lazard Foundation, Boston University, National Institutes of Health

Training-of-trainers: A strategy to build country capacity for SLMTA expansion and sustainability

Background: The Strengthening Laboratory Management Toward Accreditation (SLMTA) programme uses a training-of-trainers (TOT) model to build capacity for programme scale-up. The TOT strategy is designed to maximise utilisation of its graduates whilst minimising inconsistencies and ensuring high programme quality during global expansion. Objectives: To describe the SLMTA TOT programme approach. Methods: The two-week training, led by carefully selected and trained master trainers, enables effective and authentic implementation of the curriculum by its graduates. The teachback methodology used allows participants to practise teaching the curriculum whilst learning its content. A trainer’s toolkit provides all the materials necessary for teaching and must be followed faithfully during training. Two surveys were conducted to assess the effectiveness of the TOT strategy: one sent to 316 TOT graduates in 25 countries and the other sent to the programme leaders in 10 countries. Results: By the end of 2013, 433 SLMTA trainers had been trained who, in turn, taught more than 1900 people to implement SLMTA in 617 laboratories in 47 countries. Ninety-seven percent of the 433 TOT graduates and 87% of the 38 master trainers are based in developing countries. Ninety-two per cent of the graduates have been utilised at least once in programme implementation and, as of August 2013, 87% of them were still actively involved in programme activities. Ninety-seven per cent of the graduates stated that the TOT workshop prepared them well for training or other programme tasks. Conclusion: The SLMTA TOT strategy is effective in building local capacity for global programme expansion whilst maintaining programme quality

HIV-1 drug mutations in children from northern Tanzania

Objectives: In resource-limited settings, it is a challenge to get quality clinical specimens due to poor infrastructure for their collection, transportation, processing and storage. Using dried blood spots (DBS) might be an alternative to plasma for HIV-1 drug resistance testing in this setting. The objectives of this study were to determine mutations associated with antiretroviral resistance among children 400 copies/mL. Results: Genotypic resistance mutations were detected in 13 of 46 children (28%). HIV-1 genotypes were A1 (n = 27), C (n = 10), A/D (n = 4), D (n = 3) and CRF10_CD (n = 2). The median age was 12 weeks (IQR 6–28). The mean log10 viral load was 3.87 copies/mL (SD 0.995). All major mutations were detected in the reverse transcriptase gene and none in the protease gene region. The most frequent mutations were Y181C (n = 8) and K103N (n = 4), conferring resistance to non-nucleoside reverse transcriptase inhibitors. Conclusions: One-third of infants newly diagnosed with HIV in northern Tanzania harboured major drug resistance mutations to currently used antiretroviral regimens. These mutations were detected from DBS collected from the field and stored at room temperature. Surveillance of drug resistance among this population in resource-limited settings is warranted

HIV-1 drug mutations in children from northern Tanzania

Objectives: In resource-limited settings, it is a challenge to get quality clinical specimens due to poor infrastructure for their collection, transportation, processing and storage. Using dried blood spots (DBS) might be an alternative to plasma for HIV-1 drug resistance testing in this setting. The objectives of this study were to determine mutations associated with antiretroviral resistance among children 400 copies/mL. Results: Genotypic resistance mutations were detected in 13 of 46 children (28%). HIV-1 genotypes were A1 (n = 27), C (n = 10), A/D (n = 4), D (n = 3) and CRF10_CD (n = 2). The median age was 12 weeks (IQR 6–28). The mean log10 viral load was 3.87 copies/mL (SD 0.995). All major mutations were detected in the reverse transcriptase gene and none in the protease gene region. The most frequent mutations were Y181C (n = 8) and K103N (n = 4), conferring resistance to non-nucleoside reverse transcriptase inhibitors. Conclusions: One-third of infants newly diagnosed with HIV in northern Tanzania harboured major drug resistance mutations to currently used antiretroviral regimens. These mutations were detected from DBS collected from the field and stored at room temperature. Surveillance of drug resistance among this population in resource-limited settings is warranted

Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial

Background Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear. Methods HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14–34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761. Findings From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference –0·2%, 95% CI –1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the cotrimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3–4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3–4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3–4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21). Interpretation Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV

Phylogenetic Relatedness of Circulating HIV-1C Variants in Mochudi, Botswana

Background: Determining patterns of HIV transmission is increasingly important for the most efficient use of modern prevention interventions. HIV phylogeny can provide a better understanding of the mechanisms underlying HIV transmission networks in communities. Methods: To reconstruct the structure and dynamics of a local HIV/AIDS epidemic, the phylogenetic relatedness of HIV-1 subtype C env sequences obtained from 785 HIV-infected community residents in the northeastern sector of Mochudi, Botswana, during 2010–2013 was estimated. The genotyping coverage was estimated at 44%. Clusters were defined based on relatedness of HIV-1C env sequences and bootstrap support of splits. Results: The overall proportion of clustered HIV-1C env sequences was 19.1% (95% CI 17.5% to 20.8%). The proportion of clustered sequences from Mochudi was significantly higher than the proportion of non-Mochudi sequences that clustered, 27.0% vs. 14.7% (p = 5.8E-12; Fisher exact test). The majority of clustered Mochudi sequences (90.1%; 95% CI 85.1% to 93.6%) were found in the Mochudi-unique clusters. None of the sequences from Mochudi clustered with any of the 1,244 non-Botswana HIV-1C sequences. At least 83 distinct HIV-1C variants, or chains of HIV transmission, in Mochudi were enumerated, and their sequence signatures were reconstructed. Seven of 20 genotyped seroconverters were found in 7 distinct clusters. Conclusions: The study provides essential characteristics of the HIV transmission network in a community in Botswana, suggests the importance of high sampling coverage, and highlights the need for broad HIV genotyping to determine the spread of community-unique and community-mixed viral variants circulating in local epidemics. The proposed methodology of cluster analysis enumerates circulating HIV variants and can work well for surveillance of HIV transmission networks. HIV genotyping at the community level can help to optimize and balance HIV prevention strategies in trials and combined intervention packages