Lower academic performance among children with perinatal HIV exposure in Botswana.

INTRODUCTION: Studies have reported a higher risk of suboptimal neurodevelopment among children who are HIV-exposed uninfected (HEU) compared to children HIV-unexposed uninfected (HUU). Actual academic performance among school-aged children by HIV exposure status has not been studied. METHODS: Academic performance in Mathematics, Science, English, Setswana and overall among children enrolled in the Botswana-based FLOURISH study who were attending public primary school and ranging in age from 7.1 to 14.6 years were compared by HIV exposure status using a Cochran-Mantel-Haenszel test. Lower academic performance was defined as a grade of "C" or lower (≤60%). Unadjusted and adjusted logistic regression models were fit to assess for an association between HIV exposure and lower academic performance. RESULTS: Between April 2021 and December 2022, 398 children attending public primary school enrolled in the FLOURSH study, 307 (77%) were HEU. Median age was 9.4 years (IQR 8.9-10.2). Only 17.9% of children HEU were breastfeed versus 100% of children HUU. Among children HEU, 80.3% had foetal exposure to three-drug antiretroviral treatment, 18.7% to zidovudine only and 1.0% had no antiretroviral exposure. Caregivers of children HEU were older compared to caregivers of children HUU (median 42 vs. 36 years) and more likely to have no or primary education only (15.0% vs. 1.1%). In unadjusted analyses, children HEU were more likely to have lower overall academic performance compared to their children HUU (odds ratio [OR]: 1.96 [95% confidence interval (CI): 1.16, 3.30]), and lower performance in Mathematics, Science and English. The association was attenuated after adjustment for maternal education, caregiver income, breastfeeding, low birth weight and child sex (aOR: 1.86 [95% CI: 0.78, 4.43]). CONCLUSIONS: In this Botswana-based cohort, primary school academic performance was lower among children HEU compared to children HUU. Biological and socio-demographic factors, including child sex, appear to contribute to this difference. Further research is needed to identify modifiable contributors, develop screening tools to identify the risk of poor academic performance and design interventions to mitigate risk.

Predicted resistance to broadly neutralizing antibodies (bnAbs) and associated HIV-1 envelope characteristics among seroconverting adults in Botswana.

We used HIV-1C sequences to predict (in silico) resistance to 33 known broadly neutralizing antibodies (bnAbs) and evaluate the different HIV-1 Env characteristics that may affect virus neutralization. We analyzed proviral sequences from adults with documented HIV-1 seroconversion (N = 140) in Botswana (2013-2018). HIV-1 env sequences were used to predict bnAb resistance using bNAb-ReP, to determine the number of potential N-linked glycosylation sites (PNGS) and evaluate Env variable region characteristics (VC). We also assessed the presence of signature mutations that may affect bnAb sensitivity in vitro. We observe varied results for predicted bnAb resistance among our cohort. 3BNC117 showed high predicted resistance (72%) compared to intermediate levels of resistance to VRC01 (57%). We predict low resistance to PGDM100 and 10-1074 and no resistance to 4E10. No difference was observed in the frequency of PNGS by bNAb susceptibility patterns except for higher number of PNGs in V3 bnAb resistant strains. Associations of VC were observed for V1, V4 and V5 loop length and net charge. We also observed few mutations that have been reported to confer bnAb resistance in vitro. Our results support use of sequence data and machine learning tools to predict the best bnAbs to use within populations.

Prevalence and control of hypertension in a high HIV-prevalence setting, insights from a population based study in Botswana.

In a population-based representative sample of adults residing in 22 communities in Botswana, a southern African country with high HIV prevalence, 1 in 4 individuals had high blood pressure. High blood pressure was less prevalent in adults with HIV than without HIV. Sixty percent of persons with high blood pressure had not previously been diagnosed. Among individuals with a prior diagnosis of high blood pressure who reported being prescribed anti-hypertension medications, almost half had elevated blood pressure, irrespective of HIV-status. One-third of adults in this setting (mainly men) declined free non-invasive blood pressure assessments in their households. In conclusion, our study highlights alarmingly high hypertension rates in the community, with low levels of awareness and control, emphasizing the urgent need for community level BP screening and active management to reach recommended targets.

Predicted broadly neutralizing antibody (bnAb) resistance and associated envelope characteristics of adults with HIV-1 seroconversion in Botswana.

We used HIV-1C sequences to predict (in silico) resistance to 33 known broadly neutralizing antibodies (bNAbs) and evaluate the different HIV-1 env characteristics that may affect virus neutralization. We analyzed proviral sequences from adults with documented HIV-1 seroconversion (N=140) in Botswana (2013-2018). HIV-1 env sequences were used to predict bnAb resistance using bNAb-ReP, to determine the number of potential N-linked glycosylation sites (PNGS) and evaluate env variable region characteristics (VC). We also assessed the presence of signature mutations that may affect bnAb sensitivity in vitro. We observe varied results for predicted bnAb resistance among our cohort. 3BNC117 showed high predicted resistance (72%) compared to intermediate levels of resistance to VRC01 (57%). We predict low resistance to PGDM100 and 10-1074 and no resistance to 4E10. No difference was observed in the frequency of PNGS by bNAb susceptibility patterns except for higher number of PNGs in V3 bnAb resistant strains. Associations of VC were observed for V1, V4 and V5 loop length and net charge. We also observed few mutations that have been reported to confer bnAb resistance in vitro. Our results support use of sequence data and machine learning tools to predict the best bnAbs to use within populations.

HIV-1C in-House RNA-Based Genotyping Assay for Detection of Drug Resistance Mutations in Samples with Low-Level Viral Loads.

Purpose: Monitoring HIV-1 drug resistance mutations (DRM) in treated patients on combination antiretroviral therapy (cART) with a detectable HIV-1 viral load (VL) is important for the selection of appropriate cART. Currently, there is limited data on HIV DRM at low-level viremia (LLV) (VL 401-999 copies/mL) due to the use of a threshold of VL ≥1000 copies/mL for HIV DRM testing. We here assess the performance of an in-house HIV drug resistance genotyping assay using plasma for the detection of DRM at LLV. Methods: We used a total of 96 HIV plasma samples from the population-based Botswana Combination Prevention Project (BCPP). The samples were stratified by VL groups: 50 samples had LLV, defined as 401-999 copies/mL, and 46 had ≥1000 copies/mL. HIV pol (PR and RT) region was amplified and sequenced using an in-house genotyping assay with BigDye sequencing chemistry. Known HIV DRMs were identified using the Stanford HIV Drug Resistance Database. Genotyping success rate between the two groups was estimated and compared using the comparison of proportions test. Results: The overall genotyping success rate was 79% (76/96). For VL groups, the genotyping success was 72% (36/50) at LLV and 87% (40/46) at VL ≥1000 copies/mL. Among generated sequences, the overall prevalence of individuals with at least 1 major or intermediate-associated DRM was 24% (18/76). The proportions of NNRTI-, NRTI- and PI-associated resistance mutations were 28%, 24%, and 0%, respectively. The most predominant mutations detected were K103N (18%) and M184V (12%) in NNRTI- and NRTI-associated mutations, respectively. The prevalence of DRM was 17% (6/36) at LLV and 30% (12/40) at VL ≥1000 copies/mL. Conclusion: The in-house HIV genotyping assay successfully genotyped 72% of LLV samples and was able to detect 17% of DRM amongst them. Our results highlight the possibility and clinical significance of genotyping HIV among individuals with LLV.

Doravirine-associated resistance mutations in antiretroviral therapy naïve and experienced adults with HIV-1 subtype C infection in Botswana.

OBJECTIVES: There are limited data on the prevalence of doravirine (DOR)-associated drug resistance mutations in people with HIV (PWH) in Botswana. This cross-sectional, retrospective study aimed to explore the prevalence of DOR-associated resistance mutations among ART-naïve and -experienced PWH in Botswana enrolled in the population-based Botswana Combination Prevention Project (BCPP). METHODS: A total of 6078 HIV-1C pol sequences were analysed for DOR-associated resistance mutations using the Stanford HIV drug resistance database, and their levels were predicted according to the Stanford DRM penalty scores and resistance interpretation. Virologic failure was defined as HIV-1 RNA load (VL) >400 copies/mL. RESULTS: Among 6078 PWH, 5999 (99%) had known ART status, and 4529/5999 (79%) were on ART at time of sampling. The suppression rate among ART-experienced was 4517/4729 (96%). The overall prevalence of any DOR-associated resistance mutations was 181/1473 (12.3% [95% confidence interval {CI}: 10.7-14.1]); by ART status: 42/212 (19.8% [95% CI: 14.7-25.4]) among ART-failing individuals (VL ≥400 copies/mL) and 139/1261 (11.0% [95% CI: 9.3-12.9]) among ART-naïve individuals (P < 0.01). Intermediate DOR-associated resistance mutations were observed in 106/1261 (7.8% [95% CI: 6.9-10.1]) in ART-naïve individuals and 29/212 (13.7% [95% CI: 9.4-8.5]) among ART-experienced participants (P < 0.01). High-level DOR-associated resistance mutations were observed in 33/1261 (2.6% [95% CI: 1.8-3.7]) among ART-naïve and 13/212 (6.1% [95% CI: 3.6-10.8]) among ART-failing PWH (P < 0.01). PWH failing ART with at least one EFV/NVP-associated resistance mutation had high prevalence 13/67 (19.4%) of high-level DOR-associated resistance mutations. CONCLUSION: DOR-associated mutations were rare (11.0%) among ART-naive PWH but present in 62.7% of Botswana individuals who failed NNRTI-based ART with at least one EFV/NVP-associated resistance mutation. Testing for HIV drug resistance should underpin the use of DOR in PWH who have taken first-generation NNRTIs.

Health Impact and Cost-Effectiveness of HIV Testing, Linkage, and Early Antiretroviral Treatment in the Botswana Combination Prevention Project.

BACKGROUND: The Botswana Combination Prevention Project tested the impact of combination prevention (CP) on HIV incidence in a community-randomized trial. Each trial arm had ∼55,000 people, 26% HIV prevalence, and 72% baseline ART coverage. Results showed intensive testing and linkage campaigns, expanded antiretroviral treatment (ART), and voluntary male medical circumcision referrals increased coverage and decreased incidence over ∼29 months of follow-up. We projected lifetime clinical impact and cost-effectiveness of CP in this population. SETTING: Rural and periurban communities in Botswana. METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications model to estimate lifetime health impact and cost of (1) earlier ART initiation and (2) averting an HIV infection, which we applied to incremental ART initiations and averted infections calculated from trial data. We determined the incremental cost-effectiveness ratio [US$/quality-adjusted life-years (QALY)] for CP vs. standard of care. RESULTS: In CP, 1418 additional people with HIV initiated ART and an additional 304 infections were averted. For each additional person started on ART, life expectancy increased 0.90 QALYs and care costs increased by $869. For each infection averted, life expectancy increased 2.43 QALYs with $9200 in care costs saved. With CP, an additional $1.7 million were spent on prevention and $1.2 million on earlier treatment. These costs were mostly offset by decreased care costs from averted infections, resulting in an incremental cost-effectiveness ratio of $79 per QALY. CONCLUSIONS: Enhanced HIV testing, linkage, and early ART initiation improve life expectancy, reduce transmission, and can be cost-effective or cost-saving in settings like Botswana.

HIV-1 drug resistance mutations among individuals with low-level viraemia while taking combination ART in Botswana.

OBJECTIVES: To assess whether a single instance of low-level viraemia (LLV) is associated with the presence of drug resistance mutations (DRMs) and predicts subsequent virological failure (VF) in adults receiving ART in 30 communities participating in the Botswana Combination Prevention Project. METHODS: A total of 6078 HIV-1 C pol sequences were generated and analysed using the Stanford HIV drug resistance database. LLV was defined as plasma VL = 51-999 copies/mL and VF was defined as plasma VL ≥ 1000 copies/mL. RESULTS: Among 6078 people with HIV (PWH), 4443 (73%) were on ART for at least 6 months. Of the 332 persons on ART with VL > 50 copies/mL, 175 (4%) had VL ≥ 1000 copies/mL and 157 (4%) had LLV at baseline. The prevalence of any DRM was 57 (36%) and 78 (45%) in persons with LLV and VL ≥ 1000 copies/mL, respectively. Major DRMs were found in 31 (20%) with LLV and 53 (30%) with VL ≥ 1000 copies/mL (P = 0.04). Among the 135 PWH with at least one DRM, 17% had NRTI-, 35% NNRTI-, 6% PI- and 3% INSTI-associated mutations. Among the 3596 participants who were followed up, 1709 (48%) were on ART for ≥6 months at entry and had at least one subsequent VL measurement (median 29 months), 43 (3%) of whom had LLV. The OR of experiencing VF in persons with LLV at entry was 36-fold higher than in the virally suppressed group. CONCLUSIONS: A single LLV measurement while on ART strongly predicted the risk of future VF, suggesting the use of VL > 50 copies/mL as an indication for more intensive adherence support with more frequent VL monitoring.

HIV diagnostic algorithm requires confirmatory testing for initial indeterminate or positive screens in the first week of life.

BACKGROUND: Risk for nondiagnostic and false-positive HIV testing has not been quantified for neonates. METHODS: From April 2015 to July 2018, we screened HIV-exposed infants in Botswana less than 96 h from birth by qualitative DNA PCR. Repeat blood draws for DNA and RNA PCR testing occurred for initial positive and indeterminate results to establish final diagnosis. We compared screening DNA PCR cycle threshold values with final HIV status of the child. RESULTS: Of 10 622 HIV-exposed infants, 10 549 (99.3%) had no HIV DNA detected (negative), 42 (0.4%) had HIV DNA detected (positive), and 31 (0.3%) tested indeterminate at first HIV screen. Repeat testing identified 2 (5.0%) of 40 positive screens (2 declined additional testing) as false positives and confirmed 2 (6.5%) of 31 indeterminate screens as infected. Median cycle threshold value at screening was 28.1 (IQR 19.8--34.8) for children with final positive status, and 35.5 (IQR 32.8--41.4) for indeterminates who were ultimately negative. Six (15%) of 40 infants with final positive status had cycle threshold value greater than 33 at first screen, whereas 3 (9.7%) of 31 indeterminates with final negative status had cycle threshold value 33 or less at first screen. This threshold resulted in a negative predictive value of 82% and a positive predictive value of 92% for a single screen. CONCLUSION: Although a DNA PCR cycle threshold value of 33 was predictive of the final HIV status in newborns, overlap occurred for true positives, false positives, and initial indeterminates. Testing additional samples should be standard practice for positive and indeterminate HIV DNA PCR tests in the first week of life.

Modelling the impact of migrants on the success of the HIV care and treatment program in Botswana.

INTRODUCTION: Botswana offers publicly financed HIV treatment to citizens, but not migrants, who comprised about 7% of the population in 2016. However, HIV incidence is not declining in proportion to Botswana's HIV response. In 2018, Botswana had 86% of citizens living with HIV diagnosed, 95% of people diagnosed on treatment, and 95% viral suppression among those on treatment. We hypothesised that continued exclusion of migrants is hampering reduction of HIV incidence in Botswana. Hence, we modelled the impact of including migrants in Botswana's HIV response on achieving 90-90-90 and 95-95-95 Fast-Track targets by 2020 and 2030, respectively. METHODS: The Optima HIV model, with demographic, epidemiological, and behavioural inputs, was applied to citizens of and migrants to Botswana. Projections of new HIV infections and HIV-related deaths were compared for three scenarios to the end of 2030: (1) continued status quo for HIV testing and treatment coverage, and maintenance of levels of linkage to care, loss to follow-up, and viral suppression among citizens and migrants (baseline); (2) with scaled-up budget, optimised to achieve 90-90-90 and 95-95-95 Fast-Track targets by 2020 and 2030, respectively, for citizens only; and (3) scaled-up optimised budget to achieve these targets for both citizens and migrants. RESULTS: A baseline of 172,000 new HIV infections and 8,400 HIV-related deaths was projected over 2020-2030. Scaling up to achieve targets among citizens only averted an estimated 48,000 infections and 1,700 deaths. Achieving targets for both citizens and migrants averted 16,000 (34%) more infections and 442 (26%) more deaths. Scaling up for both populations reduced numbers of new HIV infections and deaths by 44% and 39% respectively compared with 2010 levels. Treating migrants when scaling up in both populations was estimated to cost USD 74 million over 2020-2030. CONCLUSIONS: Providing HIV services to migrants in Botswana could lead to further reductions in HIV incidence and deaths. However, even with an increased, optimised budget that achieves 95-95-95 targets for both citizens and migrants by 2030, the 90% incidence reduction target for 2020 will be missed. Further efficiencies and innovations will be needed to meet HIV targets in Botswana.

Low rates of nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drug resistance in Botswana.

BACKGROUND: Scale-up of antiretroviral therapy (ART) and introduction of treat-all strategy necessitates population-level monitoring of acquired HIV drug resistance (ADR) and pretreatment drug resistance (PDR) mutations. METHODS: Blood samples were collected from 4973 HIV-positive individuals residing in 30 communities across Botswana who participated in the Botswana Combination Prevention Project (BCPP) in 2013-2018. HIV sequences were obtained by long-range HIV genotyping. Major drug-resistance mutations (DRMs) and surveillance drug resistance mutations (SDRMs) associated with nucleoside reverse transcriptase inhibitors (NRTI) and nonnucleoside reverse transcriptase inhibitors (NNRTI) were analyzed according to the Stanford University HIV Drug Resistance Database. Viral sequences were screened for G-to-A hypermutations. A threshold of 2% was used for hypermutation adjustment. Viral suppression was considered at HIV-1 RNA load ≤400 copies/ml. RESULTS: Among 4973 participants with HIV-1C sequences, ART data were available for 4927 (99%) including 3858 (78%) on ART. Among those on ART, 3435 had viral load data and 3297 (96%) were virologically suppressed. Among 1069 (22%) HIV-infected individuals not on ART, we found NRTI-associated and NNRTI-associated SDRMs were found in 1.5% (95% confidence interval [CI] 1.0-2.5%) and 2.9% (95% CI 2.0-4.2%), respectively. Of the 138 (4%) of individuals who had detectable HIV-1 RNA, we found NRTI-associated and NNRTI-associated drug resistance mutations in 16% (95% CI 10-25%) and 33% (95% CI 25-42%), respectively. CONCLUSION: We found a low prevalence of NRTI-associated and NNRTI-associated PDR-resistance mutations among residents of rural and peri-urban communities across Botswana. However, individuals on ART with detectable virus had ADR NRTI and NNRTI mutations above 15%.

Cross-sectional estimates revealed high HIV incidence in Botswana rural communities in the era of successful ART scale-up in 2013-2015.

BACKGROUND: Botswana is close to reaching the UNAIDS "90-90-90" HIV testing, antiretroviral treatment (ART), and viral suppression goals. We sought to determine HIV incidence in this setting with both high HIV prevalence and high ART coverage. METHODS: We used a cross-sectional approach to assessing HIV incidence. A random, population-based sample of adults age 16-64 years was enrolled in 30 rural and peri-urban communities as part of the Botswana Combination Prevention Project (BCPP), from October 2013 -November 2015. Data and samples from the baseline household survey were used to estimate cross-sectional HIV incidence, following an algorithm that combined Limiting-Antigen Avidity Assay (LAg-Avidity EIA), ART status (documented or by testing ARV drugs in plasma) and HIV-1 RNA load. The LAg-Avidity EIA cut-off normalized optical density (ODn) was set at 1.5. The HIV-1 RNA cut-off was set at 400 copies/mL. For estimation purposes, the Mean Duration of Recent Infection was 130 days and the False Recent Rate (FRR) was evaluated at values of either 0 or 0.39%. RESULTS: Among 12,610 individuals participating in the baseline household survey, HIV status was available for 12,570 participants and 3,596 of them were HIV positive. LAg-Avidity EIA data was generated for 3,581 (99.6%) of HIV-positive participants. Of 326 participants with ODn ≤1.5, 278 individuals were receiving ART verified through documentation and were considered to represent longstanding HIV infections. Among the remaining 48 participants who reported no use of ART, 14 had an HIV-1 RNA load ≤400 copies/mL (including 3 participants with ARVs in plasma) and were excluded, as potential elite/viremic controllers or undisclosed ART. Thus, 34 LAg-Avidity-EIA-recent, ARV-naïve individuals with detectable HIV-1 RNA (>400 copies/mL) were classified as individuals with recent HIV infections. The annualized HIV incidence among 16-64 year old adults was estimated at 1.06% (95% CI 0.68-1.45%) with zero FRR, and at 0.64% (95% CI 0.24-1.04%) using a previously defined FRR of 0.39%. Within a subset of younger individuals 16-49 years old, the annualized HIV incidence was estimated at 1.29% (95% CI 0.82-1.77%) with zero FRR, and at 0.90% (95% CI 0.42-1.38%) with FRR set to 0.39%. CONCLUSIONS: Using a cross-sectional estimate of HIV incidence from 2013-2015, we found that at the time of near achievement of the UNAIDS 90-90-90 targets, ~1% of adults (age 16-64 years) in Botswana's rural and peri-urban communities became HIV infected annually.

Point-of-Care Cepheid Xpert HIV-1 Viral Load Test in Rural African Communities Is Feasible and Reliable.

Routine monitoring of HIV-1 RNA or viral load (VL) in patients on antiretroviral therapy (ART) is important, but there are multiple impediments to VL testing in resource-constrained settings. An accurate point-of-care (POC) HIV-1 VL test could alleviate many of these challenges. We compared the performance of the Cepheid Xpert HIV-1 VL assay against the laboratory-based Abbott m2000sp/m2000rt assay (Abbott assay). ART-naive individuals participating in the Botswana Combination Prevention Project in 20 communities provided EDTA-blood specimens during household surveys. Both the POC Xpert HIV-1 VL and Abbott assays were performed on specimens sampled from 277 individuals. We found a high correlation between the Xpert HIV-1 VL and Abbott assay results (r2 = 0.92; P < 0.001). The overall mean difference in the HIV-1 RNA values obtained by Xpert HIV-1 VL assay and Abbott assay was 0.34 log10 copies/ml (95% confidence interval [CI], 0.26 to 0.40 log10 copies/ml) (P < 0.001). Using a clinically relevant level of 1,000 copies/ml as a threshold, agreement was 90.6% (95% CI, 87.9 to 93.1%), with a sensitivity of 98.6% (95% CI, 97.2 to 100%). The two methods agreed on their detectability of HIV-1 RNA (>40 copies/ml) at 97.1% (95% CI, 95.5 to 98.7%), with a sensitivity of 99.6% (95% CI, 97.2 to 100%). The POC Cepheid Xpert HIV-1 VL assay showed high agreement and accuracy with a laboratory-based method of HIV-1 RNA testing. The POC Xpert HIV-1 VL assay tended to overestimate HIV-1 VL, although the difference was below a clinically relevant threshold of 0.5 log10 copies/ml. The POC Cepheid Xpert HIV-1 VL assay is a promising tool for monitoring patients on ART in southern Africa.

Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis.

Although HIV-1 RNA levels are measured at the time of initial diagnosis, the results are not used for the clinical follow-up of the patients. This study evaluates the prognostic value of the baseline HIV-1 RNA levels (above or below 10,000 copies/ml) on rate of disease progression, among antiretroviral therapy (ART)-naive patients in Botswana. A prospective cohort of 436 HIV-infected ART-naive adults with baseline CD4 > 400 cells/mm(3) were followed quarterly for 5 years in an urban clinic in Botswana. Baseline HIV-1 RNA levels and longitudinal CD4(+) T-cell count data were analyzed, using mixed-effects regression jointly modeled with the times to a composite endpoint defined by AIDS-defining clinical conditions or death. During 1,547 person-years (PYs) follow-up time, 106 individuals became eligible for ART initiation (incidence rate: 0.07 PYs) and 6 participants died of AIDS-related illness. There were 203 (47%) individuals with baseline HIV-1 RNA <10,000 copies/ml and 233 (53%) individuals with baseline RNA >10,000 copies/ml. The slope of the predicted CD4 trajectory for individuals with baseline HIV-1 RNA >10,000 copies/ml is 30% steeper than that for those with baseline RNA <10,000. The hazard of reaching the composite endpoint for the individuals with baseline HIV-1 RNA >10,000 copies/ml was 2.3 (95% confidence interval: 1.5-3.0) times higher than that for those with baseline HIV-1 RNA <10,000 copies/ml. CD4 decline in individuals with HIV-1 RNA >10,000 copies/ml is much faster than that in those with RNA <10,000. The elevated HIV-1 RNA can be used as a marker to identify individuals at risk of faster disease progression.

Non-nucleoside reverse transcriptase inhibitor outcomes among combination antiretroviral therapy-treated adults in Botswana.

BACKGROUND: National initiatives offering non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination antiretroviral therapy (cART) have expanded in sub-Saharan Africa. The Tshepo study is the first clinical trial evaluating the long-term efficacy and tolerability of efavirenz versus nevirapine-based cART among adults in Botswana. METHODS: A 3-year randomized study (n = 650) using a 3 x 2 x 2 factorial design comparing efficacy and tolerability among: (i) zidovudine/lamivudine versus zidovudine/didanosine versus stavudine/lamivudine; (ii) efavirenz versus nevirapine; and (iii) community-based supervision versus standard adherence strategies. This paper focuses on comparison (ii). RESULTS: There was no significant difference by assigned NNRTI in time to virological failure with resistance (log-rank P = 0.14), nevirapine versus efavirenz [risk ratio (RR) 1.54, 95% CI 0.86-2.70]. Rates of virological failure with resistance were 9.6% nevirapine-treated (95% CI 6.8-13.5) versus 6.6% efavirenz-treated (95% CI 4.2-10.0) at 3 years. Women receiving nevirapine-based cART trended towards higher virological failure rates when compared with efavirenz-treated women, Holm-corrected (log-rank P = 0.072), nevirapine versus efavirenz (RR 2.22, 95% CI 0.94-5.00). A total of 139 patients had 176 treatment-modifying toxicities, with a shorter time to event in nevirapine-treated versus efavirenz-treated patients (RR 1.85, 1.20-2.86; log-rank P = 0.0002). CONCLUSION: Tshepo-treated patients had excellent overall immunological and virological outcomes, and no significant differences were observed by randomized NNRTI comparison. Nevirapine-treated women trended towards higher virological failure with resistance compared with efavirenz-treated women. Nevirapine-treated adults had higher treatment modifying toxicity rates when compared with those receiving efavirenz. Nevirapine-based cART can continue to be offered to women in sub-Saharan Africa if patient education concerning toxicity is emphasized, routine safety monitoring chemistries are performed and the potential risk of efavirenz-related teratogenicity is considered.