Shahin Lockman

Background: People with human immunodeficiency virus (HIV) (PWH) experience substantially increased risk of anogenital cancer. Whether long-term antiretroviral therapy (ART) reduces anogenital cancer risk is unknown. Methods: A target trial emulation using a case-cohort design among Botswana adults aged 30–65, sampled via a probability-based household survey across 30 communities. Cases of cervical, vulvar, anal, and penile cancer were prospectively ascertained at the country's principal treatment centers. We estimated the marginal relative risk (RR) of incident anogenital cancer by ART duration, compared with adults without HIV, using g-computation from weighted models that accounted for shared determinants of human papillomavirus, and HIV infection, access to cancer care, and ART duration. Results: 14 312 participants were enrolled (42% PWH), including 1045 (79% PWH) with incident anogenital cancer—792 cervical, 106 vulvar, 80 anal, and 67 penile cancers. Compared with people without HIV, the marginal RR (95% CI) of anogenital cancer increased with longer durations of ART (P = .001) (no ART: 4.6; 4.3–5.0; <5 years: 4.0; 3.7–4.3; 5–9 years: 4.6; 4.2–5.0; ≥10 years: 7.4; 6.8–8.1). Individuals receiving ART for ≥10 years had the highest RR for each cancer evaluated: cervix, 4.4 (4.0 to 4.8); vulva, 36 (22–57); anus, 15 (11–20); and penis, 102 (42–250). Prior advanced HIV disease was associated with increased risk but this effect diminished on ART and contributed relatively little to overall risk. Conclusions: Long-term utilization of ART was not associated with a reduction in anogenital cancer risk. Improved prevention strategies are needed for PWH.

Background: Concomitant HIV/HBV infection results in worse health outcomes, with HBV reactivations being observed in immunocompromised individuals. However, data on HBV infection in people with advanced HIV disease (AHD) remains sparse in Botswana. We aimed to determine the prevalence and molecular characteristics of HBV in people living with HIV (PLHIV) with CD4+ T-cell counts ≤100 cells/µL in Botswana. Methods: Plasma samples (n = 1097) of PLHIV with CD4+ T-cell count ≤100 cells/uL collected between 2014 and 2016 were screened for hepatitis B surface antigen (HBsAg) and HBV core antibodies (anti-HBc). A 415bp region of the HBV surface gene was amplified and sequenced using Sanger sequencing. Genotypic and mutational analysis was performed using Geno2pheno. Adjusted prevalence ratios (aPRs) were estimated from a modified Poisson regression model to explore factors associated with HBV infection. p-values < 0.05 indicated statistical significance. Results: The median age was 37 years (IQR: 32–43), and 565/1097 (51.5%) were male. HBsAg prevalence was 10.6% (95%CI: 8.8–12.5%) and anti-HBc prevalence was 50.0% (95%CI:46.9–52.9%). Factors associated with HBV infection were male sex [aPR: 1.6 (p < 0.01)] and those that were ART-experienced [aPR: 1.43 (p = 0.04). Eighteen samples were successfully genotyped. The prevalence of genotype A was (12/18, 66.7%) and D (6/18, 33.3%). Sixty-three mutations were identified as associated with drug resistance and immune and diagnostic escape. Highly prevalent immune escape mutations in the surface region were S207N (12/63, 19%) and A194V (9/63, 14.3%). V163I (12/63, 19%) and M129L (12/63, 19%) were highly prevalent in the reverse transcriptase region. Two classical lamivudine-associated drug resistance mutations were observed, each occurring in one participant (L180M and V173L). Conclusions: The prevalence of HBV in people with AHD is high, highlighting the importance of HBV screening and HIV/HBV co-management in this population.

Introduction: We performed an analysis of incident hypertension in a randomized trial comparing dolutegravir (DTG) + emtricitabine (F)/tenofovir alafenamide (TAF) versus DTG + F/tenofovir disoproxil fumarate (TDF) versus efavirenz (EFV)/F/TDF in pregnant and postpartum women with HIV. Methods: Women were randomized at 14–28 weeks gestational age (GA) to start DTG + F/TAF, DTG + F/TDF, or EFV/F/TDF and followed through 50 weeks postpartum. The composite incident hypertension outcome was defined as initiation of antihypertensive medication or ≥2 elevated blood pressures categorized as elevated (130–139 and/or 80–89 mmHg), mild (140–159 and/or 90–99 mmHg), moderate (≥160–179 and/or ≥100–109 mmHg), and severe (≥180 and/or ≥110 mmHg). Incident gestational hypertension was defined by initiation of antihypertensive medication or ≥2 blood pressures ≥ 140 and/or ≥90 mmHg at ≥20 weeks GA with resolution by 12 weeks postpartum. Cox proportional hazard models were used for by-arm comparisons of the composite outcome and to look for the effect of weight change within arm. Results: Of 626 women without baseline hypertension (median age 26.6 years), the composite incident outcome occurred in 49% (n = 308), predominantly due to the incident elevated category of elevated blood pressure, with no significant differences by arm, although hypertension was numerically more likely in the DTG arms. Each additional 5 kg of weight was associated with an 8%–17% higher hazard of the composite hypertension outcome. Twenty-seven participants (4.3%) had gestational hypertension with no apparent differences between arms. Conclusions: Our data contribute information regarding the safety of DTG-based ART and TAF in pregnant and postpartum women and highlight the importance of monitoring weight and performing hypertension screening as part of maternal health care for young women with HIV.

Broadly neutralizing antibodies (bnAbs) are evaluated as possible alternatives to standard antiretroviral treatment (ART) for maintaining control of HIV-1 replication and may enhance immune responses to reduce or control the viral reservoir. However, the immunological and virological effects of bnAbs in infants and children are unknown. We conducted a detailed analysis of proviral reservoir dynamics and antiviral immune responses in a unique group of young children from Botswana who started ART at birth and then stopped standard ART while receiving the bnAbs 10-1074 and VRC01-LS in a subsequent clinical trial. No quantitative changes in frequencies of proviral sequences were observed during bnAb treatment, but selection of genome-intact proviruses in transcriptionally repressive heterochromatin regions occurred in some study participants. Faster viral rebound following standard ART cessation was linked to elevated proportions of KIR2DL1-positive NK cells. In contrast, delayed viral rebound and more limited viral reservoir size were associated with elevated proportions of NKG2A-positive NK cells and with the HLA-B-21M signal peptide polymorphism. HIV-specific T cell responses were low in all study participants and unrelated to viral reservoir sizes or clinical outcomes following ART interruption. These results suggest that, in young children, specific NK cell subsets and KIR-HLA interactions might be linked to HIV-1 rebound kinetics after substitution of standard ART with bnAbs.

Background: Multiple concurrent sexual partnerships (MCP) may drive new HIV infections. We investigated the association between MCP and recent or incident HIV infection in a cluster-randomized HIV prevention trial that followed a population-based HIV incidence cohort across 30 communities in Botswana. Methods: We used structured questionnaires to evaluate MCP for prior 12 months, defined as either (1) MCP per UNAIDS definition or (2) concurrent sexual relationship per survey questions. Recent HIV infection was determined using an avidity assay-based algorithm or seroconversion within 2 years, and incident infection was determined through annual HIV testing for up to 3 years. We estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) for MCP predictors using univariate and multivariable Poisson regression with log-link and fixed effects for matched pairs. Results: We included 11,965 (94.9%) of the 12,610 participants in the Botswana Combination Prevention Project with sexual history data. Among 9363 sexually active persons in prior 12 months, 2770 (29.6%) were engaged in MCP. Factors independently associated with MCP included male sex (aPR = 1.57; 95% CI: 1.45 to 1.71), age < 25 years (aPR = 1.25, 95% CI: 1.01 to 1.56), alcohol consumption ≥ 2 times/week (aPR = 1.38, 95% CI: 1.26 to 1.51), transactional sex (aPR = 1.69, 95% CI: 1.49 to 1.92), having a partner with MCP (aPR = 1.82, 95% CI: 1.65 to 2.02), and intergenerational sex (partners 10 years younger: aPR = 1.16, 95% CI: 1.06 to 1.28 or 10 years older: aPR = 1.32, 95% CI: 1.15 to 1.51). Reporting prior MCP was associated with HIV seroconversion during follow-up (aPR= 1.28, 95% CI: 1.05 to 1.57) but not with prevalent or recent HIV infection at baseline. Conclusions: MCP was common and associated with incident HIV infection. People reporting MCP may benefit from pre-exposure prophylaxis.

Background: Long-acting antiretroviral therapy (LA-ART) may reduce adherence barriers for postpartum women with HIV (PPWH), reducing vertical transmission (VT) and improving pediatric life expectancy (pLE), but efficacy and drug costs are uncertain. Methods: Using a microsimulation model, we simulated mother-infant dyads for two cohorts of PPWH engaged in care, receiving oral tenofovir/lamivudine/dolutegravir (TLD) in pregnancy, and facing adherence challenges in Zimbabwe: mothers without (NVS) and with (VS) viral suppression at delivery. We modeled two post-delivery strategies: standard of care (SOC: TLD continuation) or LA-ART (switching to LA-cabotegravir/rilpivirine [CAB/RPV]). Key inputs included: 6-month-postpartum viral suppression (LA-ART: NVS = 85%/VS = 90%; SOC: NVS = 63%/VS = 78%), ART costs/year (CAB/RPV=$144/TLD=$43.20), and VT risk (0.06%–0.89%/month, range by maternal RNA). Outcomes include VT, pLE, costs (maternal ART in breastfeeding plus pediatric HIV-related lifetime care), and incremental cost-effectiveness ratios (ICERs, $/year-of-life-saved [YLS]; cost-effective: ICER≤$800/YLS [0.5× Zimbabwe GDP]. Results: LA-ART would reduce VT compared with SOC (NVS: from 7.49% to 6.58%/VS: from 4.17% to 3.80%), averting ∼160 infections/year in Zimbabwe. For NVS, LA-ART would improve pLE (SOC = 66.08y, LA-ART = 66.40y) at nearly equal cost (SOC = $764/child, LA-ART = $763/child); LA-ART would not be cost-effective if CAB/RPV cost >$228/year or 6-month suppression were <74%. For VS, LA-ART would lead to higher pLE and costs (67.52y, $555/child) than SOC (67.40y, $445/child), with ICER=$2449/YLS; LA-ART would become cost-effective if CAB/RPV cost ≤$84/year. Conclusions: LA-ART for breastfeeding women experiencing adherence challenges could reduce infant infections. If efficacies and costs are confirmed, LA-ART for NVS women would improve outcomes and be minimally cost-saving; for VS women, LA-ART would be cost-effective in Zimbabwe at costs ≤$84/year.

Background: Broadly neutralizing antibodies (bNAbs) are a promising treatment option for children with HIV-1, but their long-term impact on virologic, immunologic, and clinical outcomes is unknown. Methods: The Tatelo Study investigated dual bNAbs as an alternative to standard antiretroviral treatment (ART) in children. Children received bNAb-only treatment for 24 weeks (or until detectable viremia ≥400 copies/mL occurred) and were followed initially through 24 weeks after restarting ART. We continued follow-up from 24 to 96 weeks post-bNAb intervention to identify the long-term clinical, immunologic, and viral reservoir outcomes. Results: Median age at the start of long-term follow-up was 4.9 years (range 3.4, 6.8 years). From 23.0 to 43.6 weeks post-bNAb intervention, all 25 children transitioned to dolutegravir-based ART; 3 (12%) had a single episode of HIV-1 RNA ≥ 40 copies/mL after starting the DTG-based regimen and re-suppressed with adherence counseling on the same regimen. There were no grade 3 or 4 events, and no child died. Absolute CD4 cell counts remained stable at 96 weeks post-bNAb intervention (median: 1130 cells/mm3, IQR: 840, 1249 cells/mm3), and clinical biomarkers (serology, qualitative HIV DNA) were stable. At last available sampling, only 8 (32%) participants had detectable intact provirus (5 had rebounded during the bNAb-only intervention phase), with a low median HIV-1 DNA in PBMCs of 0.39 log10 (range 0.1 to 3.8 log10) copies/106 cells. Conclusions: There was no long-term impact on safety, clinical, immunologic, or virologic outcomes after bNAb-only treatment, including for children who rebounded during the intervention. These findings support further bNAb treatment trials in children. Clinical Trials Registration: Clinicaltrials.gov, NCT03707977, https://clinicaltrials.gov/.

Objectives: We assessed HIV-1 drug resistance profiles among people living with HIV (PLWH) with detectable viral load (VL) and on dolutegravir-based antiretroviral therapy (ART) in Botswana. Methods: The study utilised available 100 residual HIV-1 VL samples from unique PLWH in Francistown who had viraemia at-least 6 months after initiating ART in Botswana’s national ART program from November 2023 to January 2024. Viraemia was categorized as low-level viraemia (LLV) (VL: 200–999 copies/mL) or virologic failure (VF) (VL ≥1000 copies/mL). HIV-1 protease, reverse transcriptase and integrase genes were sequenced using an in-house next-generation sequencing Oxford nanopore technology. HIV-1 drug resistance mutations (DRMs) were identified using the HIVdb Program in the Stanford HIV drug resistance database and compared between VL groups. Results: Among 100 participants, 83.0% were on dolutegravir-based, 10.0% were on non-dolutegravir-based ART and 7.0% had unknown/undocumented ART regimens. Thirty (30%) participants had LLV and 70 (70%) had VF. Among 58 successfully sequenced, 32.8% [95% Confidence Interval (CI): 21.8–46.0] had DRMs to any drug class, 33.3% (4/12) in the LLV group and 32.6% (15/46) in the VF group. Among individuals on dolutegravir-based ART, the overall HIV DRMs were 34.8% (95% CI: 22.7–49.2). By VL groups, 40.0% (95% CI: 16.8–68.7) and 33.3% (95% CI: 20.2–50.0) had DRMs at LLV and VF, respectively. Conclusions: A high but similar prevalence of any DRMs was observed among individuals with LLV and those with VF on dolutegravir-based therapy. Monitoring DRMs in individuals with detectable VL is crucial for preserving dolutegravir-based ART.

PURPOSE: Breast cancer (BC) is the most common female cancer worldwide, and the burden is increasing across sub-Saharan Africa. For women with hormone receptor–positive (HR+) cancers, endocrine therapy (ET) taken for 5-10 years can reduce the risk of recurrence by half. We explored experiences with ET and barriers to utilization among survivors in Botswana. METHODS: We recruited women with nonmetastatic disease from a survivorship cohort who had undergone mastectomy within 1-5 years for semi-structured interviews to explore experiences with treatment. This thematic content analysis focused on ET, so the sample included women with HR+ cancer who should have received ET and HR− women who reported taking ET. RESULTS: We analyzed interviews with 19 women (mean age 54 years, 42% stage I/II, 58% stage III). Three key themes were identified: (1) limited provider counseling, (2) challenges refilling prescriptions at public pharmacies, and (3) high medication and transportation costs associated with private pharmacies. Subthemes included immunohistochemistry result communication, lack of knowledge, frequent public pharmacy stockouts, inconvenient prescription refill policies, and medication switching and discontinuation, especially among participants with low socioeconomic positions (SEPs). Women's persistence, SEP, and financial support facilitated refills. Although some experienced side effects, they were not a common reason for discontinuation. CONCLUSION: BC survivors in Botswana face multilevel barriers to accessing and adhering to ET. Provider and health system improvements are needed to effectively communicate ET importance and increase access to consistently available and affordable medication.

Botswana, like the rest of the world, has been significantly impacted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In December 2022, we detected a monophyletic cluster of genomes comprising a sublineage of the Omicron variant of concern (VOC) designated as B.1.1.529.5.3.1.1.1.1.1.1.74.1 (alias FN.1, clade 22E). These genomes were sourced from both epidemiologically linked and unlinked samples collected in three close locations within the district of Greater Gaborone. In this study, we assessed the worldwide prevalence of the FN.1 lineage, evaluated its mutational profile, and conducted a phylogeographic analysis to reveal its global dispersal dynamics. Among approximately 16 million publicly available SARS-CoV-2 sequences generated by 30 September 2023, only 87 were of the FN.1 lineage, including 22 from Botswana, 6 from South Africa, and 59 from the UK. The estimated time to the most recent common ancestor of the 87 FN.1 sequences was 22 October 2022 [95% highest posterior density: 2 September 2022—24 November 2022], with the earliest of the 22 Botswana sequences having been sampled on 7 December 2022. Discrete trait reconstruction of FN.1 identified Botswana as the most probable place of origin. The FN.1 lineage is derived from the BQ.1.1 lineage and carries two missense variants in the spike protein, S:K182E in NTD and S:T478R in RDB. Among the over 90 SARS-CoV-2 lineages circulating in Botswana between September 2020 and July 2023, FN.1 was most closely related to BQ.1.1.74 based on maximum likelihood phylogenetic inference, differing only by the S:K182E mutation found in FN.1. Given the early detection of numerous novel variants from Botswana and its neighbouring countries, our study underscores the necessity of continuous surveillance to monitor the emergence of potential VOCs, integrating molecular and spatial data to identify dissemination patterns enhancing preparedness efforts.