Universal Testing, Expanded Treatment, and Incidence of HIV Infection in Botswana.

BACKGROUND: The feasibility of reducing the population-level incidence of human immunodeficiency virus (HIV) infection by increasing community coverage of antiretroviral therapy (ART) and male circumcision is unknown. METHODS: We conducted a pair-matched, community-randomized trial in 30 rural or periurban communities in Botswana from 2013 to 2018. Participants in 15 villages in the intervention group received HIV testing and counseling, linkage to care, ART (started at a higher CD4 count than in standard care), and increased access to male circumcision services. The standard-care group also consisted of 15 villages. Universal ART became available in both groups in mid-2016. We enrolled a random sample of participants from approximately 20% of households in each community and measured the incidence of HIV infection through testing performed approximately once per year. The prespecified primary analysis was a permutation test of HIV incidence ratios. Pair-stratified Cox models were used to calculate 95% confidence intervals. RESULTS: Of 12,610 enrollees (81% of eligible household members), 29% were HIV-positive. Of the 8974 HIV-negative persons (4487 per group), 95% were retested for HIV infection over a median of 29 months. A total of 57 participants in the intervention group and 90 participants in the standard-care group acquired HIV infection (annualized HIV incidence, 0.59% and 0.92%, respectively). The unadjusted HIV incidence ratio in the intervention group as compared with the standard-care group was 0.69 (P = 0.09) by permutation test (95% confidence interval [CI], 0.46 to 0.90 by pair-stratified Cox model). An end-of-trial survey in six communities (three per group) showed a significantly greater increase in the percentage of HIV-positive participants with an HIV-1 RNA level of 400 copies per milliliter or less in the intervention group (18 percentage points, from 70% to 88%) than in the standard-care group (8 percentage points, from 75% to 83%) (relative risk, 1.12; 95% CI, 1.09 to 1.16). The percentage of men who underwent circumcision increased by 10 percentage points in the intervention group and 2 percentage points in the standard-care group (relative risk, 1.26; 95% CI, 1.17 to 1.35). CONCLUSIONS: Expanded HIV testing, linkage to care, and ART coverage were associated with increased population viral suppression. (Funded by the President's Emergency Plan for AIDS Relief and others; Ya Tsie ClinicalTrials.gov number, NCT01965470.).

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.

Integrating Sexually Transmitted Infection Testing and Treatment With Routine HIV Care in Gaborone, Botswana.

BACKGROUND: Sexually transmitted infection (STI) testing is not routinely offered in many countries, and management is symptoms based. Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are associated with an increased risk of HIV transmission. We assess the feasibility and acceptability of integrating CT/NG testing into routine HIV care in Botswana, as well as the prevalence and correlates of CT/NG infections. METHOD: A prospective study was conducted at an HIV clinic in Gaborone between February and October 2019. Eligibility criteria included the following: ≥18 years, HIV infected, and not treated for CT/NG in the past month. Participants self-collected samples and responded to a questionnaire on sociodemographic and health characteristics. Samples were processed using the GeneXpert. Patients were offered same-day results in person or by telephone. Those who tested positive were treated. RESULTS: Of 806 patients informed of the study, 526 (65%) expressed interest and 451 (60%) were enrolled. The median age was 48 years, and 66% were women. All participants provided self-collected samples, were successfully tested, and received results. Almost all reported sample self-collection was easy. The prevalence of CT/NG was 5%. Most participants (73%) with a positive result were asymptomatic. Among infected, 20 (91%) received same-day results and all were treated. Younger age, female sex, and pain during sex were associated with having CT/NG. CONCLUSIONS: Integrating STI testing into routine HIV care was feasible, self-collecting specimens was highly acceptable, but uptake of testing was low. Where blanket screening to the entire clinic population may not be feasible because of resource limitation, one strategy could be to prioritize sexually active patients, younger patients, and women.

Implementation of Universal HIV Testing and Treatment to Reduce HIV Incidence in Botswana: the Ya Tsie Study.

PURPOSE OF REVIEW: Antiretroviral treatment (ART) can dramatically reduce the risk of HIV transmission, but the feasibility of scaling up HIV testing, linkage and treatment to very high population levels, and its impact on population HIV incidence, were unknown. We review key findings from a community-randomized trial in which we evaluated the impact of "universal test and treat" (UTT) on population HIV incidence in Botswana, a resource-constrained country with both high HIV prevalence and high ART coverage before study inception. RECENT FINDINGS: We conducted a community-randomized trial (the "Ya Tsie" trial or Botswana Combination Prevention Project (BCPP)) in 30 villages in Botswana from 2013 to 2018, with the goal of determining whether a combination of prevention interventions-with a focus on universal HIV testing and treatment-would reduce population-level HIV incidence. The intervention included universal HIV testing (home-based and mobile), active linkage to HIV care and treatment with patient tracing for persons not linking, universal ART coverage, rapid ART start (at the first clinic visit), and enhanced male circumcision services. Botswana had very high HIV diagnosis, treatment, and viral suppression levels (approaching the UNAIDS "90-90-90" targets) prior to intervention roll-out. By study end, we were able to exceed the overall 95-95-95 coverage target of 86%: an estimated 88% of all persons living with HIV were on ART and had viral suppression in the Ya Tsie intervention arm. In addition, annual HIV incidence was 30% lower in the intervention arm as compared with the control arm over a 29-month follow-up period. With universal HIV testing and relatively simple linkage activities, it was possible to achieve one of the highest reported population levels of HIV diagnosis, linkage to care, and viral suppression globally and to reduce population HIV incidence by about one-third over a short period of time (< 3 years). We were able to significantly increase population viral suppression and to decrease HIV incidence even in a resource-constrained setting with pre-existing very high testing and treatment coverage. Universal community-based HIV testing and tracing of individuals through the HIV care cascade were key intervention components.

Barriers and facilitators to linkage to care and ART initiation in the setting of high ART coverage in Botswana.

We conducted a qualitative study using focus groups and in-depth interviews to explore barriers to and facilitators of linkage-to-care and antiretroviral treatment (ART) initiation in Botswana. Participants were selected from communities receiving interventions through the Ya Tsie Study. Fifteen healthcare providers and 49 HIV-positive individuals participated. HIV-positive participants identified barriers including stigma, discrimination and overcrowded clinics, and negative staff attitudes; personal factors, such as a lack of acceptance of one's HIV status, non-disclosure, and gender differences; along with lack of social/family support, and certain religious beliefs. Healthcare providers cited delayed test results, poverty, and transport difficulties as additional barriers. Major facilitators were support from healthcare providers, including home visits, social support, and knowing the benefits of ART. Participants were highly supportive of universal ART as a personal health measure. Our results highlighted a persistent structural health facility barrier: HIV-positive patients expressed strong discontent with HIV care/treatment being delivered differently than routine healthcare, feeling inconvenienced and stigmatized by separately designated locations and days of service. This barrier was particularly problematic for highly mobile persons. Addressing this structural barrier, which persists even in the context of high ART uptake, could bring gains in willingness to initiate ART and improved adherence in Botswana and elsewhere.

Variation in attrition at subnational level: review of the Botswana National HIV/AIDS Treatment (Masa) programme data (2002-2013).

OBJECTIVE: To evaluate the variation in all-cause attrition [mortality and loss to follow-up (LTFU)] among HIV-infected individuals in Botswana by health district during the rapid and massive scale-up of the National Treatment Program. METHODS: Analysis of routinely collected longitudinal data from 226 030 patients who received ART through the Botswana National HIV/AIDS Treatment Program across all 24 health districts from 2002 to 2013. A time-to-event analysis was used to measure crude mortality and loss to follow-up rates (LTFU). A marginal structural model was used to evaluate mortality and LTFU rates by district over time, adjusted for individual-level risk factors (e.g. age, gender, baseline CD4, year of treatment initiation and antiretroviral regimen). RESULTS: Mortality rates in the districts ranged from the lowest 1.0 (95% CI 0.9-1.1) in Selibe-Phikwe, to the highest 5.0 (95% CI 4.0-6.1), in Mabutsane. There was a wide range of overall LTFU across districts, including rates as low as 4.6 (95% CI 4.4-4.9) losses per 100 person-years in Ngamiland, and 5.9 (95% CI 5.6-6.2) losses per 100 person-years in South East district, to rates as high as 25.4 (95% CI 23.08-27.89) losses per 100 person-years in Mabutsane and 46.3 (95% CI 43.48-49.23) losses per 100 person-years in Okavango. Even when known risk factors for mortality and LTFU were adjusted for, district was a significant predictor of both mortality and LTFU rates. CONCLUSION: We found statistically significant variation in attrition (mortality and LTFU) and data quality among districts. These findings suggest that district-level contextual factors affect retention in treatment. Further research needs to investigate factors that can potentially cause this variation.

Lower Levels of Antiretroviral Therapy Enrollment Among Men with HIV Compared with Women - 12 Countries, 2002-2013.

Equitable access to antiretroviral therapy (ART) for men and women with human immunodeficiency virus (HIV) infection is a principle endorsed by most countries and funding bodies, including the U.S. President's Emergency Plan for AIDS (acquired immunodeficiency syndrome) Relief (PEPFAR) (1). To evaluate gender equity in ART access among adults (defined for this report as persons aged ≥15 years), 765,087 adult ART patient medical records from 12 countries in five geographic regions* were analyzed to estimate the ratio of women to men among new ART enrollees for each calendar year during 2002-2013. This annual ratio was compared with estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS)(†) of the ratio of HIV-infected adult women to men in the general population. In all 10 African countries and Haiti, the most recent estimates of the ratio of adult women to men among new ART enrollees significantly exceeded the UNAIDS estimates for the female-to-male ratio among HIV-infected adults by 23%-83%. In six African countries and Haiti, the ratio of women to men among new adult ART enrollees increased more sharply over time than the estimated UNAIDS female-to-male ratio among adults with HIV in the general population. Increased ART coverage among men is needed to decrease their morbidity and mortality and to reduce HIV incidence among their sexual partners. Reaching more men with HIV testing and linkage-to-care services and adoption of test-and-treat ART eligibility guidelines (i.e., regular testing of adults, and offering treatment to all infected persons with ART, regardless of CD4 cell test results) could reduce gender inequity in ART coverage.

HIV Prevalence and Risk Behaviors Among Female Sex Workers in Botswana: Results from the 2012 HIV/STI Bio-Behavioral Study.

To evaluate HIV/STI prevalence among female sex workers (FSWs) in Botswana, and assess HIV-related risk behaviors. Cross-sectional study using time-location sampling in three districts of Botswana. Adjusted HIV prevalence at district level ranged from 53.5 to 68.5 %. Syphilis prevalence ranged from 3.7 to 14.5 %; chlamydia prevalence ranged from 4.8 to 16.3 %; and gonorrhoea prevalence ranged from 8.3 to 11.7 %. FSWs had been practicing sex work for a mean of 4.7 years, and had a mean of 7.6 sex partners in the week before the survey. While 67.1 % of FSWs surveyed reported always using condoms with clients in the past month. 59.5 % reported one or more of the following: being paid more not to use a condom, having a condom break, or being forced not to use a condom by clients. Predictors of HIV infection in the multivariate analysis included: age (over 30 years), perceiving oneself to be at high risk of HIV, selling sex for 2 or more years, and having a mean of 11 or more partners in the last week. High HIV prevalence, high rates of partner exchange, a sizable population, and Inconsistent condom use combine together help fuel the country's hyper epidemic. HIV prevention interventions need to take into account the important influence of clients and boyfriends on condom use behavior.

Follow-up of infants diagnosed with HIV - Early Infant Diagnosis Program, Francistown, Botswana, 2005-2012.

The 2011 prevalence of human immunodeficiency virus (HIV) among pregnant women in Botswana was 30.4%. High coverage rates of HIV testing and antiretroviral prophylaxis have reduced the rate of mother-to-child transmission of HIV in Botswana from as high as 40% with no prophylaxis to <4% in 2011. In June 2005, the national Early Infant Diagnosis (EID) Program began testing HIV-exposed infants (i.e., those born to HIV-infected mothers) for HIV using polymerase chain reaction (PCR) at 6 weeks postpartum. During 2005-2012, follow-up of all HIV-infected infants diagnosed in all 13 postnatal care facilities in Francistown, Botswana, was conducted to ascertain patient outcomes. A total of 202 infants were diagnosed with HIV. As of September 2013, 82 (41%) children were alive and on antiretroviral therapy (ART), 79 (39%) had died, and 41 (20%) were either lost to follow-up, had transferred, or their mothers declined ART. Despite success in preventing mother-to-child transmission in Botswana, results of the EID program highlight the need for early diagnosis of HIV-infected infants, prompt initiation of ART, and retention in care.

Strengthening monitoring and evaluation (M&E) and building sustainable health information systems in resource limited countries: lessons learned from an M&E task-shifting initiative in Botswana.

BACKGROUND: The demand for quality data and the interest in health information systems has increased due to the need for country-level progress reporting towards attainment of the United Nations Millennium Development Goals and global health initiatives. To improve monitoring and evaluation (M&E) of health programs in Botswana, 51 recent university graduates with no experience in M&E were recruited and provided with on-the-job training and mentoring to develop a new cadre of health worker: the district M&E officer. Three years after establishment of the cadre, an assessment was conducted to document achievements and lessons learnt. METHODS: This qualitative assessment included in-depth interviews at the national level (n = 12) with officers from government institutions, donor agencies, and technical organizations; and six focus group discussions separately with district M&E officers, district managers, and program officers coordinating different district health programs. RESULTS: Reported achievements of the cadre included improved health worker capacity to monitor and evaluate programs within the districts; improved data quality, management, and reporting; increased use of health data for disease surveillance, operational research, and planning purposes; and increased availability of time for nurses and other health workers to concentrate on core clinical duties. Lessons learnt from the assessment included: the importance of clarifying roles for newly established cadres, aligning resources and equipment to expectations, importance of stakeholder collaboration in implementation of sustainable programs, and ensuring retention of new cadres. CONCLUSION: The development of a dedicated M&E cadre at the district level contributed positively to health information systems in Botswana by helping build M&E capacity and improving data quality, management, and data use. This assessment has shown that such cadres can be developed sustainably if the initiative is country-led, focusing on recruitment and capacity-development of local counterparts, with a clear government retention plan.

Improving the quality of health information: a qualitative assessment of data management and reporting systems in Botswana.

BACKGROUND: Ensuring that data collected through national health information systems are of sufficient quality for meaningful interpretation is a challenge in many resource-limited countries. An assessment was conducted to identify strengths and weaknesses of the health data management and reporting systems that capture and transfer routine monitoring and evaluation (M&E) data in Botswana. METHODS: This was a descriptive, qualitative assessment. In-depth interviews were conducted at the national (n = 27), district (n = 31), and facility/community (n = 71) levels to assess i) M&E structures, functions, and capabilities; ii) indicator definitions and reporting guidelines; iii) data collection forms and tools; iv) data management processes; and v) links with the national reporting system. A framework analysis was conducted using ATLAS.ti v6.1. RESULTS: Health programs generally had standardized data collection and reporting tools and defined personnel for M&E responsibilities at the national and district levels. Best practices unique to individual health programs were identified and included a variety of relatively low-resource initiatives such as attention to staffing patterns, making health data more accessible for evidence-based decision-making, developing a single source of information related to indicator definitions, data collection tools, and management processes, and utilization of supportive supervision visits to districts and facilities. Weakness included limited ownership of M&E-related duties within facilities, a lack of tertiary training programs to build M&E skills, few standard practices related to confidentiality and document storage, limited dissemination of indicator definitions, and limited functionality of electronic data management systems. CONCLUSIONS: Addressing fundamental M&E system issues, further standardization of M&E practices, and increasing health services management responsiveness to time-sensitive information are critical to sustain progress related to health service delivery in Botswana. In addition to high-resource initiatives, such as investments in electronic medical record systems and tertiary training programs, there are a variety of low-resource initiatives, such as regular data quality checks, that can strengthen national health information systems. Applying best practices that are effective within one health program to data management and reporting systems of other programs is a practical approach for strengthening health informatics and improving data quality.

Establishing a health information workforce: innovation for low- and middle-income countries.

BACKGROUND: To address the shortage of health information personnel within Botswana, an innovative human resources approach was taken. University graduates without training or experience in health information or health sciences were hired and provided with on-the-job training and mentoring to create a new cadre of health worker: the district Monitoring and Evaluation (M&E) Officer. This article describes the early outcomes, achievements, and challenges from this initiative. METHODS: Data were collected from the district M&E Officers over a 2-year period and included a skills assessment at baseline and 12 months, pre- and post-training tests, interviews during stakeholder site visits, a survey of achievements, focus group discussions, and an attrition assessment. RESULTS: An average of 2.7 mentoring visits were conducted for M&E Officers in each district. There were five training sessions over 18 months. Knowledge scores significantly increased (p < 0.05) during the three trainings in which pre/post tests were administered. Over 1 year, there were significant improvements (p < 0.05) in self-rated skills related to computer literacy, checking data validity, implementing data quality procedures, using data to support program planning, proposing indicators, and writing M&E reports. Out of the 34 district M&E Officers interviewed during site visits, most were conducting facility visits to review data (27/34; 79%), comparing data sets over time (31/34; 91%), backing up data (32/34; 94%), and analyzing data (32/34; 94%). Common challenges included late facility reports (28/34; 82%), lack of transportation (22/34; 65%), inaccurate facility reports (10/34; 29%), and colleagues' misunderstanding of M&E (10/34; 29%). Six posts were vacated in the first year (6/51; 12%). A total of 49 Officers completed the achievements survey; of these, common accomplishments related to improvements in data management (35/49; 71%), data quality (31/49; 63%), data use (29/49; 59%), and capacity development (26/49; 53%). CONCLUSIONS: The development of a cadre of district M&E Officers has contributed positively to the health information system in Botswana. In the absence of tertiary training related to health information, on-the-job training and mentoring of university graduates can be an effective approach for developing a new professional cadre of M&E expertise and for strengthening capacity within a national health system.

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.

HIV Incidence in Botswana Rural Communities With High Antiretroviral Treatment Coverage: Results From the Botswana Combination Prevention Project, 2013-2017.

BACKGROUND AND SETTING: The Botswana Combination Prevention Project demonstrated a 30% reduction in community HIV incidence through expanded HIV testing, enhanced linkage to care, and universal antiretroviral treatment and exceeded the Joint United Nations Programme on HIV/AIDS 90-90-90 targets. We report rates and characteristics of incident HIV infections. METHODS: The Botswana Combination Prevention Project was a community-randomized controlled trial conducted in 30 rural/periurban Botswana communities from 2013 to 2017. Home-based and mobile HIV-testing campaigns were conducted in 15 intervention communities, with 39% of participants testing at least twice. We assessed the HIV incidence rate [IR; number of new HIV infections per 100 person-years (py) at risk] among repeat testers and risk factors with a Cox proportional hazards regression model. RESULTS: During 27,517 py, 195 (women: 79%) of 18,597 became HIV-infected (0.71/100 py). Women had a higher IR (1.01/100 py; 95% confidence interval: 0.99 to 1.02) than men (0.34/100 py; 95% confidence interval: 0.33 to 0.35). The highest IRs were among women aged 16-24 years (1.87/100 py) and men aged 25-34 years (0.56/100 py). The lowest IRs were among those aged 35-64 years (women: 0.41/100 py; men: 0.20/100 py). The hazard of incident infection was the highest among women aged 16-24 years (hazard ratio = 7.05). Sex and age were significantly associated with incidence (both P < 0.0001). CONCLUSIONS: Despite an overall reduction in HIV incidence and approaching the United Nations Programme on HIV/AIDS 95-95-95 targets, high HIV incidence was observed in adolescent girls and young women. These findings highlight the need for additional prevention services (pre-exposure prophylaxis and DREAMS) to achieve epidemic control in this subpopulation and increased efforts with men with undiagnosed HIV.

Male circumcision uptake during the Botswana Combination Prevention Project.

INTRODUCTION: Voluntary medical male circumcision (VMMC) uptake has been slow in some countries, including Botswana. To inform demand creation efforts, we examined sociodemographic characteristics and referral procedures associated with VMMC uptake in the Botswana Combination Prevention Project (BCPP) and examined the effectiveness of referral of men to MC services from HIV testing venues. DESIGN: BCPP was a community-randomized trial evaluating the impact of a combination HIV prevention package which included VMMC on community HIV incidence. We conducted a sub-analysis of VMMC uptake in intervention communities. METHODS: During the initial VMMC campaign in 15 intervention communities, baseline male circumcision (MC) status was assessed among men eligible for HIV testing. Uncircumcised male community residents aged 16-49 years with negative/unknown HIV status were mobilized and linked to study VMMC services. Outcomes included MC baseline status and uptake through study services. Univariate and multivariate logistic regressions were performed to identify factors associated with MC uptake. RESULTS: Of 12,864 men eligible for testing, 50% (n = 6,448) were already circumcised. Among the uncircumcised men (n = 6,416), 10% (n = 635) underwent MC. Of the 5,071 men identified as eligible for MC through HIV testing services, 78% declined referral and less than 1% of those were circumcised. Of those accepting referral (n = 1,107), 16% were circumcised. Younger (16-24 years) (aOR: 1.51; 95%CI:1.22,1.85), unemployed men (aOR:1.34; 95%CI: 1.06,1.69), and those undergoing HIV testing at mobile venues (aOR: 1.88; 95%CI: 1.53,2.31) were more likely to get circumcised. Fear of pain was the most prevalent (27%) reason given for not being circumcised. CONCLUSION: Younger, unemployed men seeking HIV testing at mobile sites in Botswana were more likely to get VMMC. Addressing unique barriers for employed and older men may be necessary. Given the simplicity of VMMC as an intervention, the HIV testing programs offer a platform for identifying uncircumcised men and offering information and encouragement to access services.

Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial - BCPP/Ya Tsie trial.

Background: Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. Methods: To elucidate patterns of HIV spread in universal test-and-treat trials, we quantified the contribution of geographic-location, gender, age, and randomized-HIV-intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana. We sequenced HIV viral whole genomes from 5114 trial participants among the 30 trial communities. Results: Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 - 56.7] vs. 3% [0.1 - 27.3]) than at baseline (7% [1.5 - 25.3] vs. 5% [0.9 - 22.9]) compatible with a benefit from treatment-as-prevention. Conclusions: Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies. Funding: This study was supported by the National Institute of General Medical Sciences (U54GM088558), the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610), and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911).

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.

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.

To achieve 95-95-95 targets we must reach men and youth: High level of knowledge of HIV status, ART coverage, and viral suppression in the Botswana Combination Prevention Project through universal test and treat approach.

BACKGROUND: Increasing HIV treatment coverage is crucial to reducing population-level HIV incidence. METHODS: The Botswana Combination Prevention Project (BCPP) was a community randomized trial examining the impact of multiple prevention interventions on population-level HIV incidence and was conducted from October 2013 through June 2017. Home and mobile campaigns offered HIV testing to all individuals ≥ age 16. All identified HIV-positive persons who were not on antiretroviral therapy (ART) were referred to treatment and tracked to determine linkage to care, ART status, retention in treatment, and viral suppression. RESULTS: Of an estimated total of 14,270 people living with HIV (PLHIV) residing in the 15 intervention communities, BCPP identified 13,328 HIV-positive persons (93%). At study start, 10,703 (80%) of estimated PLHIV knew their status; 2,625 (20%) learned their status during BCPP, a 25% increase with the greatest increases occurring among men (37%) and youth (77%). At study start, 9,258 (65%) of estimated PLHIV were on ART. An additional 3,001 persons started ART through the study. By study end, 12,259 had initiated and were retained on ART, increasing coverage to 93%. A greater increase in ART coverage was achieved among men (40%) compared to women (29%). Of the 11,954 persons who had viral load (VL) test results, 11,687 (98%) were virally suppressed (HIV-1 RNA ≤400 copies/mL). Overall, 82% had documented VL suppression by study end. CONCLUSIONS: Knowledge of HIV-positive status and ART coverage increased towards 95-95 targets with universal testing, linkage interventions, and ART. The increases in HIV testing and ART use among men and youth were essential to reaching these targets. CLINICAL TRIAL NUMBER: NCT01965470.

Finding, treating and retaining persons with HIV in a high HIV prevalence and high treatment coverage country: Results from the Botswana Combination Prevention Project.

INTRODUCTION: The scale-up of Universal Test and Treat has resulted in reductions in HIV morbidity, mortality and incidence. However, healthcare system and personal challenges have impacted the levels of treatment coverage achieved. We implemented interventions to improve linkage to care, retention, viral load (VL) coverage and service delivery, and describe the HIV care cascade over the course of the Botswana Combination Prevention Project (BCPP) study. METHODS: BCPP was designed to evaluate the impact of prevention interventions on HIV incidence in 30 communities in Botswana. We followed a longitudinal cohort of newly identified and known HIV-positive persons not on antiretroviral therapy (ART) identified through community-based testing activities through BCPP and referred with appointments to local HIV clinics in 15 intervention communities. Those who did not keep the first or follow-up appointments were tracked and traced through phone and home contacts. Improvements to service delivery models in the intervention clinics were also implemented. RESULTS: A total of 3,657 newly identified or HIV-positive persons not on ART were identified and referred to their local HIV clinic; 90% (3,282/3,657) linked to care and of those, 93% (3,066/3,282) initiated treatment. Near the end of the study, 221 persons remained >90 days late for appointments or missing. Tracing efforts identified 54/3,066 (2%) persons who initiated treatment but died, and 106/3,066 (3%) persons were located and returned to treatment. At study end, 61/3,066 (2%) persons remained missing and were never reached. Overall, 2,951 (98%) persons living with HIV (PLHIV) who initiated treatment were still alive, retained in care and still receiving ART out of the 3,001 persons alive at the end of the study. Of those on ART, 2,854 (97%) had current VL results and 2,784 (98%) of those were virally suppressed at study end. CONCLUSIONS: This study achieved high rates of linkage, treatment initiation, retention and VL coverage and suppression in a cohort of newly identified and known PLHIV not on ART. Tracking and tracing interventions effectively identified those persons who needed more resource intensive follow-up. The interventions implemented to improve service delivery and data quality may have also contributed to high linkage and retention rates. Clinical trial number: NCT01965470.