Expanding Geographical Access to Cancer Care in Botswana: Current Status and Future Prospects.

PURPOSE: The growing cancer burden in Botswana has been linked to aging, lifestyle factors, and high HIV infection prevalence. The government has designated four geographically distributed hospitals as public oncology centers (POCs). A needs assessment was undertaken to ascertain the characteristics of cancer care at these centers. METHODS: A multisite cross-sectional survey study of cancer care was conducted with oncology staff at Princess Marina Hospital (PMH), Nyangabgwe Referral Hospital (NRH), Sekgoma Memorial Hospital (SMH), and Letsholathebe II Memorial Hospital (LMH) from February to April 2021. At each POC, a focal person (experienced nurse working in oncology) identified relevant oncology staff and confirmed service availability. RESULTS: Only PMH and NRH had a broad array of diagnostic, surgical, and treatment services. In addition, PMH was the only center with a a dedicated inpatient oncology service, a multidisciplinary committee to review patients, and a palliative care team. To support the only national cancer screening program, for cervical cancer, all POCs offered Pap tests. Mammography, available at PMH and NRH, was used solely for diagnosis. Patients from POCs requiring radiation therapy were referred to Gaborone Private Hospital at government expense. For perceived service availability, 51 staff, mainly oncologists, physicians, and nurses, were surveyed (66% based at PMH). Perceptions of services revealed a few concerns, for example, numerous staff considered hysterectomies for cervical cancer available when they were only performed at PMH. CONCLUSION: Despite Botswana's efforts to increase the proximity of cancer services to patients, there are marked gaps, particularly at the two district-level POCs, SMH and LMH. In the future, SMH and LMH could provide selected services for specific prevalent cancers on-site, as well as follow-up and palliative care.

Quantitative outcomes of a type 2 single arm hybrid effectiveness implementation pilot study for hypertension-HIV integration in Botswana.

BACKGROUND: Successful HIV treatment programs have turned HIV into a chronic condition, but noncommunicable diseases such as hypertension jeopardize this progress. Hypertension control rates among people with HIV (PWH) are low owing to gaps in patient awareness, diagnosis, effective treatment, and management of both conditions at separate clinic visits. Integrated management, such as in our study, InterCARE, can enhance HIV-hypertension integration and blood pressure (BP) control. METHODS: Our pilot study was conducted in two Botswana HIV clinics between October 2021 and November 2022. Based on our formative work, we adopted three main strategies; Health worker training on HTN/cardiovascular disease (CVD) management, adaptation of HIV Electronic Health Record (EHR) for HTN/CVD care, and use of treatment partners to support PWH with hypertension for implementation. We employed the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to assess implementation effectiveness and outcomes for BP control at baseline, 6 and 12 months. HIV viral load (VL) suppression was also measured to assess impact of integration on HIV care. RESULTS: We enrolled 290 participants; 35 (12.1%) were lost to follow-up, leaving 255 (87.9%) at 12-months. Median age was 54 years (IQR 46-62), and 77.2% were females. Our interventions significantly improved BP control to < 140/90 mmHg (or < 130/80 mmHg if diagnosis of diabetes or chronic kidney disease), from 137/290 participants, 47.2% at baseline to 206/290 participants, 71.0%, at 12 months (p < 0.001). Among targeted providers, 94.7% received training, with an associated significant increase in counseling on exercise, diet, and medication (all p < 0.001) but EHR use for BP medication prescribing and cardiovascular risk factor evaluation showed no adoption. In the intention-to-treat analysis, HIV VL suppression at 12 months decreased (85.5% vs 93.8%, p = 0.002) due to loss to follow-up but the per protocol analysis showed no difference in VL suppression between baseline and 12 months (97.3% vs 93.3%, p = 0.060). CONCLUSION: The InterCARE pilot study demonstrated that low-cost practical support measures involving the integration of HIV and hypertension/CVD management could lead to improvements in BP control. These results support the need for a large implementation and effectiveness trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05414526. Registered 18th May 2022.

Designing an implementation science clinical trial to integrate hypertension and cardiovascular diseases care into existing HIV services package in Botswana (InterCARE).

BACKGROUND: Despite success in HIV treatment, diagnosis and management of hypertension (HTN) and cardiovascular disease (CVD) remains suboptimal among people living with HIV (PLWH) in Botswana, with an overall HTN control of only 19% compared to 98% HIV viral suppressed. These gaps persist despite CVD primary care national guidelines and availability of free healthcare including antihypertensive medications. Our study aims to develop and test strategies to close the HTN care gap in PLWH, through integration into HIV care, leveraging the successful national HIV care and treatment program and strategies. METHODS: The InterCARE trial is a cluster randomized controlled hybrid type 2 effectiveness-implementation trial at 14 sites designed to enroll 4652 adults living with HIV and HTN plus up to 2326 treatment partners. Primary outcomes included effectiveness (HTN control) and implementation outcomes using the Reach Effectiveness Adoption Implementation and Maintenance framework, with explanatory mixed methods used to understand variability in outcomes. InterCARE trial's main strategies include healthcare worker HTN and CVD care training plus long-term practice facilitation, electronic health record (EHR) documentation of key indicators and use of reminders, and use of treatment partners to provide social support to people living with HIV and HTN. InterCARE started with formative research to identify contextual factors influencing care gaps using the Consolidated Framework for Implementation Research. Results were used to adapt initial and develop additional implementation strategies to address barriers and leverage facilitators. The package was pilot tested in two clinics, with findings used to further adapt or add strategies for the clinical trial. DISCUSSION: If successful, the InterCARE model can be scaled up to HIV clinics nationwide to improve diagnosis, management, and support in Botswana. The trial will provide insights for scale-up of HTN integration into HIV care in the region. TRIAL REGISTRATION: ClinicalTrials.gov reference NCT05414526. Registered 18 May 2022, https://clinicaltrials.gov/study/NCT05414526?term=NCT05414526.&rank=1 .

Low Prevalence of Nirmatrelvir-Ritonavir Resistance-Associated Mutations in SARS-CoV-2 Lineages From Botswana.

Background: We evaluated naturally occurring nirmatrelvir-ritonavir (NTV/r) resistance-associated mutations (RAMs) among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains from Botswana, a country with no NTV/r use to date, in order to recommend the usage of the agent for high-risk patients with coronavirus disease 2019 (COVID-19). Methods: We conducted a retrospective analysis using 5254 complete SARS-CoV-2 sequences from Botswana (September 2020-September 2023). We evaluated the mutational landscape of SARS-CoV-2 3-Chymotrypsin-like protease (3CLpro) relative to the highlighted list of RAMs granted Food and Drug Administration Emergency Use Authorization in 2023. Results: The sequenced 5254 samples included Beta variants of concerns (VOCs; n = 323), Delta VOCs (n = 1314), and Omicron VOCs (n = 3354). Overall, 77.8% of the sequences exhibited at least 1 polymorphism within 76/306 amino acid positions in the nsp5 gene. NTV/rRAMs were identified in 34/5254 (0.65%; 95% CI, 0.43%-0.87%) and occurred at 5 distinct positions. Among the NTV/r RAMS detected, A191V was the most prevalent (24/34; 70.6%). Notably, T21I mutation had a prevalence of 20.6% (7/34) and coexisted with either K90R (n = 3) polymorphism in Beta sequences with RAMs or P132H (n = 3) polymorphism for Omicron sequences with RAMs. Other NTV/r RAMs detected included P108S, with a prevalence of 5.88% (2/34), and L50F, with a prevalence of 2.94% (1/34). NTV/r RAMs were significantly higher (P < .001) in Delta (24/35) compared with Beta (4/34) and Omicron (6/34) sequences. Conclusions: The frequency of NTV/r RAMs in Botswana was low. Higher rates were observed in Delta VOCs compared to Omicron and Beta VOCs. As NTV/r use expands globally, continuous surveillance for drug-resistant variants is essential, given the RAMs identified in our study.

Molecular Characterization of Hepatitis B Virus in People Living with HIV in Rural and Peri-Urban Communities in Botswana.

(1) Background: Hepatitis B virus (HBV) sequencing data are important for monitoring HBV evolution. We aimed to molecularly characterize HBV sequences from participants with HBV surface antigen-positive (HBsAg+) serology and occult hepatitis B infection (OBI+). (2) Methods: We utilized archived plasma samples from people living with human immunodeficiency virus (PLWH) in Botswana. HBV DNA was sequenced, genotyped and analyzed for mutations. We compared mutations from study sequences to those from previously generated HBV sequences in Botswana. The impact of OBI-associated mutations on protein function was assessed using the Protein Variation Effect Analyzer. (3) Results: Sequencing success was higher in HBsAg+ than in OBI+ samples [86/128 (67.2%) vs. 21/71 (29.2%)]. Overall, 93.5% (100/107) of sequences were genotype A1, 2.8% (3/107) were D3 and 3.7% (4/107) were E. We identified 13 escape mutations in 18/90 (20%) sequences with HBsAg coverage, with K122R having the highest frequency. The mutational profile of current sequences differed from previous Botswana HBV sequences, suggesting possible mutational changes over time. Mutations deemed to have an impact on protein function were tpQ6H, surfaceV194A and preCW28L. (4) Conclusions: We characterized HBV sequences from PLWH in Botswana. Escape mutations were prevalent and were not associated with OBI. Longitudinal HBV studies are needed to investigate HBV natural evolution.

A mixed methods approach identifying facilitators and barriers to guide adaptations to InterCARE strategies: an integrated HIV and hypertension care model in Botswana.

BACKGROUND: Botswana serves as a model of success for HIV with 95% of people living with HIV (PLWH) virally suppressed. Yet, only 19% of PLWH and hypertension have controlled blood pressure. To address this gap, InterCARE, a care model that integrates HIV and hypertension care through a) provider training; b) adapted electronic health record; and c) treatment partners (peer support), was designed. This study presents results from our baseline assessment of the determinants and factors used to guide adaptations to InterCARE implementation strategies prior to a hybrid type 2 effectiveness-implementation study. METHODS: This study employed a convergent mixed methods design across two clinics (one rural, one urban) to collect quantitative and qualitative data through facility assessments, 100 stakeholder surveys (20 each PLWH and hypertension, existing HIV treatment partners, clinical healthcare providers (HCPs), and 40 community leaders) and ten stakeholder key informative interviews (KIIs). Data were analyzed using descriptive statistics and deductive qualitative analysis organized by the Consolidated Framework for Implementation Research (CFIR) and compared to identify areas of convergence and divergence. RESULTS: Although 90.3% of 290 PLWH and hypertension at the clinics were taking antihypertensive medications, 52.8% had uncontrolled blood pressure. Results from facility assessments, surveys, and KIIs identified key determinants in the CFIR innovation and inner setting domains. Most stakeholders (> 85%) agreed that InterCARE was adaptable, compatible and would be successful at improving blood pressure control in PLWH and hypertension. HCPs agreed that there were insufficient resources (40%), consistent with facility assessments and KIIs which identified limited staffing, inconsistent electricity, and a lack of supplies as key barriers. Adaptations to InterCARE included a task-sharing strategy and expanded treatment partner training and support. CONCLUSIONS: Integrating hypertension services into HIV clinics was perceived as more advantageous for PLWH than the current model of hypertension care delivered outside of HIV clinics. Identified barriers were used to adapt InterCARE implementation strategies for more effective intervention delivery. TRIAL REGISTRATION: ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT05414526 . Registered 18 May 2022 - Retrospectively registered.

Hepatitis B Virus Prevalence among HIV-Uninfected People Living in Rural and Peri-Urban Areas in Botswana.

(1) Background: we determined the prevalence of the hepatitis B virus (HBV) amongst people without human immunodeficiency virus (HIV) in rural and peri-urban areas in Botswana. (2) Methods: We screened for the hepatitis B surface antigen (HBsAg) from archived plasma samples of people without HIV (n = 2135) randomly selected from the Botswana Combination Prevention Program (BCPP) (2013-2018). We sequenced 415 bp of the surface region using BigDye sequencing chemistry. (3) Results: The median age of participants was 31 (IQR: 24-46) and 64% (1360/2135) were female. HBV prevalence was 4.0% (86/2135) [95% CI: 3.3-4.9]) and ranged between 0-9.2%. Older participants (>35 years) had increased odds of HBV positivity (OR: 1.94; 95% CI: [1.32-2.86]; p = 0.001). Thirteen samples were sequenced and seven (53.8%) were genotype A, three (23.1%) were genotype D and genotype E each. Clinically significant mutations were identified in the surface region, but no classic drug resistance mutations were identified. (4) Conclusions: We report an HBV prevalence of 4.0% (95% CI 3.3-4.9) among people without HIV in rural and peri-urban communities in Botswana with varying rates in different communities. A comprehensive national HBV program is required in Botswana to guide HBV prevention, testing and management.

The association between smoking and cervical human papillomavirus infection among women from indigenous communities in western Botswana.

INTRODUCTION: Cervical cancer, a malignancy caused by infection with oncogenic human papillomavirus, disproportionally affects women from low resource settings. Persistence of human papillomavirus infection may mediate an association between tobacco use and cervical cancer. In limited resource settings, women from indigenous communities are often marginalized and do not benefit from evidence-based interventions to prevent tobacco use or cervical cancer due to the limited reach of mainstream healthcare services to these communities. This study determined the association between smoking and high-risk human papillomavirus infection among women from indigenous communities in western Botswana. METHODS: A cross-sectional study of women in indigenous communities was conducted between June and October 2022. Demographic, clinical and self-reported smoking data were collected. Cervical cytology and HPV DNA testing for high-risk human papillomavirus genotypes were performed. Multilevel multivariable logistic regression models were fit to evaluate the association between smoking and high-risk human papillomavirus infection while adjusting for potential confounders. RESULTS: A total of 171 participants with a median (interquartile range) age of 40 (31-50) years from three settlements and two villages were recruited for the study. Of these, 17% were current smokers, 32.8% were living with HIV and high-risk human papillomavirus DNA was detected in 32.8% of the cervical specimens. Women who were current smokers, were nearly twice as likely to have cervical high-risk human papillomavirus infection compared to non-smokers (Adjusted Odds Ratio (95% CI); 1.74(1.09, 2.79)) after controlling for confounders. CONCLUSION: These data underscore the need for effective tobacco control to help mitigate cervical cancer risk in this setting. These findings can help inform decisions about targeted cervical cancer prevention and tobacco cessation interventions for women from indigenous communities.

Cytomegalovirus Immunoglobulin G Levels and Subclinical Arterial Disease among People Living with HIV in Botswana: A Cross-Sectional Study.

Cytomegalovirus (CMV) has been linked with increased cardiovascular risk and monocyte activation in people living with HIV (PLWH). This cross-sectional study aimed to compare CMV immunoglobulin G (IgG) levels between combined antiretroviral therapy (cART)-treated PLWH versus ART-naïve PLWH and those without HIV, and to investigate their associations with biomarkers of endothelial injury and carotid atherosclerosis, in Gaborone, Botswana. All participants were between 30 and 50 years old. Carotid intimal media thickness (cIMT) and biomarkers of endothelial injury and monocyte activation were also assessed. The association between quantitative CMV IgG and cardiovascular disease risk was assessed in multivariate logistic regression analysis. The results showed that the mean CMV IgG level among ART-naïve participants was significantly higher than both the cART group and controls. However, CMV IgG levels did not differ significantly between the controls and cART groups. Among PLWH, CMV IgG levels were associated with ICAM-1 levels and cIMT. Increases in CMV IgG among ART-naïve participants were significantly associated with increases in log VCAM-1. In conclusion, CMV IgG levels are elevated among PLWH in sub-Saharan Africa, and higher levels are associated with biomarkers of endothelial injury and cIMT. Future research should investigate the long-term impact of elevated CMV IgG among PLWH.

Self-reported cardiovascular disease risk factor screening among people living with HIV vs. members of the general population in Botswana: a community-based study.

BACKGROUND: Morbidity and mortality due to cardiovascular diseases (CVDs) are high and increasing in low- and middle-income countries. People living with HIV (PLWH) are more likely to experience CVD than members of the general population. Therefore, we aimed to assess whether PLWH were more likely to have previously been screened for cardiovascular disease risk factors (CVDRFs) than people without HIV. METHODS: A population-based, cross-sectional study was conducted among individuals aged 16 to 68 years across 22 communities in Botswana from February to August 2017 as part of a larger community-based cluster randomized HIV treatment-as-prevention trial. Participants were asked if they had been screened for and counselled on cardiovascular disease risk factors (history of hypertension or blood pressure check, blood glucose and cholesterol measurements, weight check and weight control, tobacco smoking and cessation, alcohol use and physical activity) in the preceding 3 years. HIV testing was offered to those with an unknown HIV status. Multiple logistic regression analysis controlling for age and sex was used to assess the relationship between CVDRF screening and HIV status. RESULTS: Of the 3981 participants enrolled, 2547 (64%) were female, and 1196 (30%) were PLWH (93% already on antiretroviral therapy [ART]). PLWH were more likely to report previous screening for diabetes (25% vs. 19%, p < 0.001), elevated cholesterol (17% vs. 12%, p < 0.001) and to have had their weight checked (76% vs. 55%, p < 0.001) than HIV-uninfected participants. PLWH were also more likely to have received counselling on salt intake (42% vs. 33%, p < 0.001), smoking cessation (66% vs. 46%, p < 0.001), weight control (38% vs. 29%, p < 0.001), physical activity (46% vs. 34%, p < 0.001) and alcohol consumption (35% vs. 23%, p < 0.001) than their HIV-uninfected counterparts. Overall, PLWH were more likely to have received screening for and/or counselling on CVDRFs (adjusted odds ratio 1.84, 95% CI: 1.46-2.32, p < 0.001). CONCLUSION: PLWH were almost two times more likely to have been previously screened for CVDRFs than those without HIV, indicating a need for universal scale-up of integrated management and prevention of CVDs in the HIV-uninfected population.

Hepatitis B surface antigen loss in individuals with chronic hepatitis B virus and HIV-1 infections in Botswana.

OBJECTIVES: We sought to determine hepatitis B surface antigen (HBsAg) loss and its predictors among people with chronic hepatitis B (CHB) infections and HIV (PWH) in Botswana. METHODS: Archived plasma samples from a cohort of PWH in Botswana (2013-2018) with 3 yearly time-points were used. Samples were screened for HBsAg, immunoglobulin M HBV core antibodies (anti-HBc IgM) and HBV e-antigen (HBeAg) at all time points. HBV deoxyribonucleic acid (DNA) quantification was done at baseline. The Wilcoxon rank-sum was used to compare continuous variables while the chi-squared test and Fishers exact test were used for categorical data wherever appropriate. Logistic regression was used to assess predictors of seroclearance. RESULTS: Of 141 participants with HBsAg-positive serology (HBsAg+) at baseline, 92.2% (131/141) [95% confidence interval (CI) 87.4-96.1] were persistently HBsAg+ at year 1. We report a HBsAg loss of 7.1% (10/141) (95% CI 3.9-12.6) among participants with negative HBeAg and negative IgM serologies. HBsAg loss was 6.3% (7/111) among antiretroviral therapy (ART)-experienced participants and 10.7% (3/28) (95% CI 0.4-5.0) in ART-naive participants. Most participants who had positive anti-HBc IgM serology and did not lose HBsAg were on either lamivudine (3TC)-based therapy or non-tenofovir disoproxil fumarate (TDF)-based therapy, except for one participant. The participants also had varying HBeAg status. HBsAg loss was independent of HIV viral load, CD4 + cell count, age, and sex. CONCLUSION: We report a HBsAg loss of 6.3% over a 3-year period among ART-experienced CHB participants. Future studies that focus on HBsAg loss in mono-infected patients and the possible correlation between HBeAg status and HBsAg loss are warranted.

Safety of AZD1222 COVID-19 vaccine and low Incidence of SARS-CoV-2 infection in Botswana following ChAdOx1(AZD1222) vaccination: A single-arm open-label interventional study - final study results.

Objectives: We report the final analysis of the single-arm open-label study evaluating the safety and COVID-19 incidence after AZD1222 vaccination in Botswana conducted between September 2021 and August 2022. Methods: The study included three groups of adults (>18 years), homologous AZD1222 primary series and booster (AZ2), heterologous primary series with one dose AZD1222, and AZD1222 booster (HPS), and primary series other than AZD1222 and AZD1222 booster (OPS). We compared the incidence of AEs in participants with and without prior COVID-19 infection using an exact test for rate ratios. Results: Among 10,894 participants, 9192 (84.4%) were enrolled at first vaccine dose, 521 (4.8%) at second vaccine, and 1181 (10.8%) at the booster vaccine. Of 10,855 included in the full analysis set, 1700 received one dose of AZD1222; 5377 received two doses; 98 received a heterologous series including one AZD1222 and a booster; 30 in the HPS group; 1058 in the OPS group; and 2592 in the AZ2 group. No laboratory-confirmed COVID-19 hospitalizations or deaths were reported. The incidence of laboratory-confirmed symptomatic COVID infection for the AZ2 group was 6.22 (95% confidence interval: 2.51-12.78) per 1000 participant-years (1000-PY) and 3.5 (95% confidence interval: 0.42-12.57) per 1000-PY for AZ2+booster group. Most adverse events were mild, with higher incidence in participants with prior COVID-19 infection. Individuals with prior COVID-19 exposure exhibited higher binding antibody responses. No differences in outcomes were observed by HIV status. Conclusion: AZD1222 is safe, effective, and immunogenic for people living with and without HIV.

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.

Breast cancer patient experiences in the Botswana health system: Is it time for patient navigators?

BACKGROUND: New models of care are required to support women with breast cancer due to rising incidence and mortality in sub-Saharan Africa (SSA). This study gives voice to the experiences of advanced-stage breast cancer patients in the Botswana healthcare system, to guide improved service provision and the potential utility of patient navigator (PN) programs. METHODS: focus group discussions (FGD) were conducted with advanced-stage breast cancer patients recruited from the oncology ward of the public Princess Marina Hospital located in Gaborone, Botswana. RESULTS: FGDs included 7 female breast cancer patients and their 7 caregivers (2 male and 5 females). Findings fell into the following themes: experiences with cancer diagnosis, experiences with treatment, roles of caregivers, information needs, views on cancer resources, and attitudes towards cancer research. The study identified several barriers across the cascade of care for breast cancer patients in the Botswana health system. These correspond to challenges with timely diagnosis and comprehensive management and highlight community level barriers to achieving the targets of the WHO Global Breast Cancer initiative (GBCI). CONCLUSION: The study findings suggest PN programs have the potential to bridge barriers identified in the Botswana healthcare system by improving communication, meeting information needs, providing emotional or practical support, and by addressing logistical barriers to cancer diagnosis and treatment in Botswana.

The impact of free antiretroviral therapy for pregnant non-citizens and their infants in Botswana.

INTRODUCTION: In December 2019, the Botswana government expanded free antiretroviral therapy (ART) to include non-citizens. We evaluated the impact of this policy change on antenatal care (ANC), antiretroviral therapy coverage and adverse birth outcomes. METHODS: The Tsepamo Surveillance study collects data at up to 18 delivery sites in Botswana. We compared outcomes in citizens and non-citizens living with HIV before and after antiretroviral therapy expansion to non-citizens. Adverse birth outcomes included preterm delivery (PTD) <37 weeks, very preterm delivery (VPTD) <32 weeks, small for gestational age (SGA) <10th percentile, very small for gestational age (VSGA) <3rd percentile, stillbirth and neonatal death. Log-binomial regression models were constructed to generate risk ratios. RESULTS: From August 2014 to September 2021, 45,576 (96.5%) citizens and 1513 (3.2%) non-citizens living with HIV delivered; 954 (62.9%) non-citizen deliveries were before the antiretroviral therapy expansion, and 562 (37.1%) were after. Non-citizen ANC attendance among pregnant people living with HIV increased from 79.2% pre-expansion to 87.2% post-expansion (p<0.001), and became more similar to citizens (96.0% post-expansion). Non-citizens receiving any antenatal antiretroviral therapy increased from 65.5% pre-expansion to 89.9% post-expansion (p < 0.001), also more similar to citizens (97.2% post-expansion). Infants born to non-citizens with singleton gestations in the pre-expansion period had significantly greater risk of PTD (aRR = 1.28, 95% CI, 1.11, 1.46), VPTD (aRR = 1.89, 95% CI, 1.43, 2.44) and neonatal death (aRR = 1.69, 95% CI, 1.03, 2.60), but reduced SGA risk (aRR = 0.75; 95% CI, 0.62, 0.89) compared with citizens. Post-expansion, greater declines in most adverse outcomes were observed in non-citizens, with largely similar outcomes between non-citizens and citizens. Non-significant differences were observed for non-citizenship in PTD (aRR = 0.84, 95% CI, 0.66, 1.06), VPTD (aRR = 0.57, 95% CI, 0.28, 1.01), SGA (aRR = 0.91, 95% CI, 0.72, 1.13), VSGA (aRR = 0.87, 95% CI, 0.58, 1.25), stillbirth (aRR = 0.71, 95% CI, 0.35, 1.27) and neonatal death (aRR = 1.35, 95% CI, 0.60, 2.62). CONCLUSIONS: Following the expansion of free antiretroviral therapy to non-citizens, gaps narrowed in ANC and antiretroviral therapy use in pregnancy between citizens and non-citizens living with HIV. Disparities in adverse birth outcomes were no longer observed.

Archived rilpivirine-associated resistance mutations among ART-naive and virologically suppressed people living with HIV-1 subtype C in Botswana: implications for cabotegravir/rilpivirine use.

OBJECTIVES: Pre-existing rilpivirine resistance-associated mutations (RVP-RAMs) have been found to predict HIV-1 virological failure in those switching to long-acting injectable cabotegravir/rilpivirine. We here evaluated the prevalence of archived RPV-RAMs in a cohort of people living with HIV (PWH). METHODS: We analysed near full-length HIV-1 pol sequences from proviral DNA for the presence of RPV-RAMs, which were defined according to the 2022 IAS-USA drug resistance mutation list and Stanford HIV drug resistance database. RESULTS: RPV-RAMs were identified in 757/5805 sequences, giving a prevalence of 13.0% (95% CI 12%-13.9%). Amongst the ART-naive group, 137/1281 (10.7%, 95% CI 9.1%-12.5%) had at least one RPV-RAM. Of the 4524 PWH with viral suppression on ART (VL <400 copies/mL), 620 (13.7%, 95% CI 12.7%-14.7%) had at least one RPV-RAM. E138A was the most prevalent RPV-RAM in the ART-naive group (7.9%) and the ART-suppressed group (9.3%). The rest of the mutations observed (L100I, K101E, E138G, E138K, E138Q, Y181C, H221Y, M230L, A98G, V179D, G190A, G190E and M230I) were below a prevalence of 1%. CONCLUSIONS: RPV-RAMs were present in 10.7% of ART-naive and 13.7% of ART-suppressed PWH in Botswana. The most common RPV-RAM in both groups was E138A. Since individuals with the E138A mutation may be more likely to fail cabotegravir/rilpivirine, monitoring RPV-RAMs will be crucial for effective cabotegravir/rilpivirine implementation in this setting.

High Prevalence of Hepatitis B Virus Infection Among People With HIV in Rural and Periurban Communities in Botswana.

Background: We aimed to determine the prevalence of hepatitis B virus (HBV) infection among people with human immunodeficiency virus (PWH) in rural and periurban communities in Botswana. Methods: PWH from a previous population-based study, the Botswana Prevention Combination Project, which enrolled adults in 30 communities across Botswana (2013-2018), were screened for HBV surface antigen (HBsAg) and HBV core antibody (anti-HBc). HBsAg-positive (HBsAg+) samples were further screened for HBV core immunoglobulin M antibodies (anti-HBc immunoglobulin M [IgM]) and HBV e antigen (HBeAg). We quantified HBV viral load on participants who tested positive (n = 148) and negative for HBsAg (n = 381). Results: Of 3304 participants tested, 271 (8% [95% confidence interval {CI}, 7%-9%]) were HBsAg+ while 1788 (56% [95% CI, 54%-57%]) of 3218 PWH whom we tested had positive anti-HBc. Approximately 88% of HBsAg+ participants were on antiretroviral therapy (ART), 40% and 56% of whom were receiving lamivudine- and tenofovir-containing ART, respectively. Male sex (relative risk ratio [RRR], 1.8 [95% CI, 1.2-2.7]) and the northern geographic region (RRR, 2.5 [95% CI, 1.4-4.7]) were independent predictors of HBV infection (HBsAg+). Of 381 persons with negative HBsAg who were tested for occult HBV, 126 (33% [95% CI, 29%-38%]) had positive HBV DNA. Eleven participants were highly viremic with high HBV viral load while on a lamivudine- or tenofovir-containing regimen. Ten (91%) of these participants also had positive HBeAg serology, while 4 (36%) had positive anti-HBc IgM serology. Conclusions: The prevalence of HBV was high among PWH in Botswana while on ART regimens with activity against HBV.

Epidemiological and viral characteristics of undiagnosed HIV infections in Botswana.

BACKGROUND: HIV-1 is endemic in Botswana. The country's primary challenge is identifying people living with HIV who are unaware of their status. We evaluated factors associated with undiagnosed HIV infection using HIV-1 phylogenetic, behavioural, and demographic data. METHODS: As part of the Botswana Combination Prevention Project, 20% of households in 30 villages were tested for HIV and followed from 2013 to 2018. A total of 12,610 participants were enrolled, 3596 tested HIV-positive at enrolment, and 147 participants acquired HIV during the trial. Extensive socio-demographic and behavioural data were collected from participants and next-generation sequences were generated for HIV-positive cases. We compared three groups of participants: (1) those previously known to be HIV-positive at enrolment (n = 2995); (2) those newly diagnosed at enrolment (n = 601) and (3) those who tested HIV-negative at enrolment but tested HIV-positive during follow-up (n = 147). We searched for differences in demographic and behavioural factors between known and newly diagnosed group using logistic regression. We also compared the topology of each group in HIV-1 phylogenies and used a genetic diversity-based algorithm to classify infections as recent (< 1 year) or chronic (≥ 1 year). RESULTS: Being male (aOR = 2.23) and younger than 35 years old (aOR = 8.08) was associated with undiagnosed HIV infection (p < 0.001), as was inconsistent condom use (aOR = 1.76). Women were more likely to have undiagnosed infections if they were married, educated, and tested frequently. For men, being divorced increased their risk. The genetic diversity-based algorithm classified most incident infections as recent (75.0%), but almost none of known infections (2.0%). The estimated proportion of recent infections among new diagnoses was 37.0% (p < 0.001). CONCLUSION: Our results indicate that those with undiagnosed infections are likely to be young men and women who do not use condoms consistently. Among women, several factors were predictive: being married, educated, and testing frequently increased risk. Men at risk were more difficult to delineate. A sizeable proportion of undiagnosed infections were recent based on a genetic diversity-based classifier. In the era of "test and treat all", pre-exposure prophylaxis may be prioritized towards individuals who self-identify or who can be identified using these predictors in order to halt onward transmission in time.

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.