Design and rationale of the Botswana Smoking Abstinence Reinforcement Trial: a protocol for a stepped-wedge cluster randomized trial.

BACKGROUND: With expanded and sustained availability of HIV treatment resulting in substantial improvements in life expectancy, the need to address modifiable risk factors associated with leading causes of death among people living with HIV/AIDS (PLWH), such as tobacco smoking, has increased. Tobacco use is highly prevalent among PLWH, especially in southern Africa, where HIV is heavily concentrated, and many people who smoke would like to quit but are unable to do so without assistance. SBIRT (Screening, Brief Intervention and Referral to Treatment) is a well-established evidence-based approach successful at supporting smoking cessation in a variety of settings. Varenicline is efficacious in supporting smoking cessation. We intend to assess the effectiveness of SBIRT and varenicline on smoking cessation among PLWH in Botswana and the effectiveness of our implementation. METHODS: BSMART (Botswana Smoking Abstinence Reinforcement Trial) is a stepped-wedge, cluster randomized, hybrid Type 2 effectiveness-implementation study guided by the RE-AIM framework, to evaluate the effectiveness and implementation of an SBIRT intervention consisting of the 5As compared to an enhanced standard of care. SBIRT will be delivered by trained lay health workers (LHWs), followed by referral to treatment with varenicline prescribed and monitored by trained nurse prescribers in a network of outpatient HIV care facilities. Seven hundred and fifty people living with HIV who smoke daily and have been receiving HIV care and treatment at one of 15 health facilities will be recruited if they are up to 18 years of age and willing to provide informed consent to participate in the study. DISCUSSION: BSMART tests a scalable approach to achieve and sustain smoking abstinence implemented in a sustainable way. Integrating an evidence-based approach such as SBIRT, into an HIV care system presents an important opportunity to establish and evaluate a modifiable cancer prevention strategy in a middle-income country (MIC) setting where both LHW and non-physician clinicians are widely used. The findings, including the preliminary cost-effectiveness, will provide evidence to guide the Botswanan government and similar countries as they strive to provide affordable smoking cessation support at scale. CLINICAL TRIAL REGISTRATION: NCT05694637 Registered on 7 December 2022 on clinicaltrials.gov, https://clinicaltrials.gov/search?locStr=Botswana&country=Botswana&cond=Smoking%20Cessation&intr=SBIRT.

Feasibility and acceptability of peer-delivered interventions using mHealth for PrEP services among adolescent girls and young women in DREAMS program in Botswana.

BACKGROUND: Adolescent girls and young women accounted for 25% of all new HIV infections despite representing only 10% of the population in Sub Saharan Africa. PEPFAR has launched the Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) initiative, a comprehensive HIV prevention program including PrEP services. Among adolescent girls and young women, PrEP adherence is currently sub-optimal. Tailored strategies for adolescent girls and young women to improve access and use of PrEP delivery are urgently needed to maximise its potential. Recommended interventions include peer-delivered interventions using mobile technology. However, data on the feasibility and acceptability of this approach is limited for SSA. OBJECTIVES: We assessed the feasibility and perceived acceptability of providing mHealth peer-delivered interventions to support PrEP services among adolescent girls and young women in Botswana. METHODS: This cross-sectional study included HIV-negative women aged 18-24 years old seeking health services at DREAMS-supported facilities. Participants completed a survey assessing the feasibility and perceived acceptability of the mHealth peer-delivered interventions, which included the Acceptability of Intervention Measure (AIM). Descriptive analyses were performed. RESULTS: A total of 131 participated in the study. Overall, 89% owned a mobile phone (feasibility). There was no difference in cell phone ownership between participants from rural and urban settings. Among participants, 85% reported interest in participating in a mHealth peer-delivered intervention if it was available to them. Regarding perceived acceptability for mHealthpeer support groups for PrEP, the average score on the AIM was 3.8 out of 5 (SD = 0.8). CONCLUSION: mHealthpeer-delivered interventions appear to be feasible and perceived acceptable among adolescent girls and young women in Botswana. This modality should be incorporated into PEPFAR's programmatic toolkit of implementation strategies to improve PrEP services.

Testing modality associated with fast-track ART initiation in Botswana.

OBJECTIVES: The aim of this study was to identify community testing modalities associated with fast-track ART initiation in Botswana. METHODS: We conducted a retrospective cohort study that included all Botswana citizens 15 years or older who were newly identified as HIV-positive from 1 May 2017 to 31 January 2019, in Mahalapye and Southern districts. We used Poisson regression with robust error variance and generalised linear mixed models to control for cluster effects to model risk of ART initiation within 7 and 30 days of HIV diagnosis, testing modality factors. RESULTS: A total of 1436 individuals were newly identified HIV-positive, with men accounting for 60% across all testing modalities. 22% of all HIV-positive individuals were initiated on ART within 7 days. Clients diagnosed through index testing were more likely to be started on ART within 7 days (adjusted risk ratio [aRR] = 1.38, 95% CI 1.37-1.38) and 30 days (aRR = 1.17, 95% CI 1.09-1.26) than those diagnosed through mobile/outreach testing. CONCLUSIONS: Community HIV testing can complement facility-based testing by reaching individuals who may be less likely to seek HIV services at a facility, such as men. Monitoring ART initiation by testing modalities is critical to identify the optimal ones and to guide continuous programme improvement.

Improving same-day antiretroviral therapy in Botswana: effects of a multifaceted national intervention.

BACKGROUND: In 2019, the Botswana Ministry of Health and Wellness (MOHW) implemented an HIV national Reboot program, which was needed for refocusing and intensifying efforts for achieving epidemic control. The strategies deployed as part of Reboot were reviewed and evaluated for their effect on same-day and within-seven-days (fast-track initiation) antiretroviral therapy (ART) initiation among adults newly identified with HIV. METHODS: We conducted a retrospective cohort analysis of patients aged 18 years or older who were newly diagnosed with HIV from October 2018 to September 2019 across 41 health facilities. We used generalized linear mixed models, adjusting for clustering by facility, to assess the association of the Reboot with same-day or within-seven-days ART initiation (fast-track initiation). RESULTS: From October 2018 to January 2019, 28% (636/2269) of newly diagnosed HIV patients were initiated the same day of diagnosis, and 56% (1260/2269) were initiated within seven days. Following the launch of Reboot (February to September 2019), 59% (2092/3553) were initiated the same day of diagnosis, and 77% (2752/3553) were initiated within seven days. Clients were 2.08 (adjusted risk ratio 95% confidence interval 1.79-2.43) times more likely to be initiated the same day of diagnosis and 1.39 (adjusted risk ratio 95% confidence interval 1.28-1.52) times more likely to be initiated within seven days than before Reboot after adjusting for sex and age. CONCLUSION: In Botswana, a multifaceted national intervention improved timely ART initiation. Identifying and implementing different client-centered strategies to facilitate ART initiation is critical to preventing AIDS-related complications and prevent ongoing transmission.

Botswana's HIV response: Policies, context, and future directions.

This brief report describes key periods in the history of the national public health response to the human immunodeficiency virus (HIV) epidemic in Botswana. It reveals the context leading to the development of HIV policies presently in place and current challenges that remain. The report concludes with opportunities for future directions, initiatives, and policy changes to reduce the high rates of HIV.

Peripheral clinic versus centralized laboratory-based Xpert MTB/RIF performance: Experience gained from a pragmatic, stepped-wedge trial in Botswana.

BACKGROUND: In 2011, the Botswana National Tuberculosis Program adopted World Health Organization guidelines and introduced Xpert MTB/RIF (Xpert) assay to support intensified case finding among people living with HIV enrolling in care. An evaluation was designed to assess performance under operational conditions to inform the national Xpert scale-up. METHODS: Xpert was implemented from August 2012 through November 2014 with 13 GeneXpert instruments (GeneXpert) deployed in a phased approach over nine months: nine centralized laboratory and four point-of-care (POC) peripheral clinics. Clinicians and laboratorians were trained on the four-symptom tuberculosis screening algorithm and Xpert testing. We documented our experience with staff training and GeneXpert performance. Test results were extracted from GeneXpert software; unsuccessful tests were analysed in relation to testing sites and trends over time. RESULTS: During 276 instrument-months of operation a total of 3,630 tests were performed, of which 3,102 (85%) were successful with interpretable results. Mycobacterium tuberculosis complex was detected for 447 (14%); of these, 36 (8%) were rifampicin resistant. Of all 3,630 Xpert tests, 528 (15%) were unsuccessful; of these 361 (68%) were classified as "error", 119 (23%) as "invalid" and 48 (9%) as "no result". The total number of recorded error codes was 385 and the most common reasons were related to sample processing (211; 55%) followed by power supply (77; 20%) and cartridge/module related (54; 14%). Cumulative incidence of unsuccessful test was similar between POC (17%, 95% CI: 11-25%) and centralized laboratory-based GeneXpert instruments (14%, 95% CI: 11-17%; p = 0.140). CONCLUSIONS: Xpert introduction was successful in the Botswana setting. The incidence of unsuccessful test was similar by GeneXpert location (POC vs. centralized laboratory). However, unsuccessful test incidence (15%) in our settings was higher than previously reported and was mostly related to improper sample processing. Ensuring adequate training among Xpert testing staff is essential to minimize errors.

Implementation of a pragmatic, stepped-wedge cluster randomized trial to evaluate impact of Botswana's Xpert MTB/RIF diagnostic algorithm on TB diagnostic sensitivity and early antiretroviral therapy mortality.

BACKGROUND: In 2012, as a pilot for Botswana's national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the "Xpert package". METHODS: The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the "Xpert package" on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster-randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is ≤52.5 % and post-Xpert sensitivity ≥82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is ≥13/100 person-years. DISCUSSION: Only one small previous trial (N = 424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov: NCT02538952 .

Immunohaematological reference values for HIV-negative healthy adults in Botswana.

BACKGROUND: Clinical laboratories in Botswana have relied entirely on the reference intervals for normal immunohaematological values provided by manufacturers' kits and textbooks. OBJECTIVES: The aim of this study was to determine the means, medians, 2.5th and 97.5th percentile reference intervals, for normal immunohaematological values in healthy adults in Botswana. METHOD: A total of 261 healthy participants comprising 126 men (48%) and 135 (52%) women were enrolled in the southern part of Botswana, and immunological and haematological laboratory parameters were measured. RESULTS: The mean age was 28.8 (95% Confidence Interval [CI] 27.7-29.8) years, with a median of 27 years and a range 18-66 years. The mean haemoglobin level was significantly lower for women (12.4 g/dL; 95% CI 12.1% - 12.7%) than men (15.1 g/dL; 95% CI 14.9% - 15.3%). The women's haemoglobin reference values (9.0 g/dL - 15.0 g/dL) levels were lower than observed in predominantly White populations (12.0 g/dL - 16.0 g/dL), but comparable with regional consensus reference intervals (9.5 g/dL - 15.8 g/dL) recently defined for East and Southern Africa. CONCLUSION: The established values provide an important tool for patient management and could influence decisions on inclusion of participants and adverse events in clinical trials conducted locally.

Immunohaematological reference values for HIV-negative healthy adults in Botswana.

BACKGROUND: Clinical laboratories in Botswana have relied entirely on the reference intervals for normal immunohaematological values provided by manufacturers' kits and textbooks. OBJECTIVES: The aim of this study was to determine the means, medians, 2.5th and 97.5th percentile reference intervals, for normal immunohaematological values in healthy adults in Botswana. METHOD: A total of 261 healthy participants comprising 126 men (48%) and 135 (52%) women were enrolled in the southern part of Botswana, and immunological and haematological laboratory parameters were measured. RESULTS: The mean age was 28.8 (95% Confidence Interval [CI] 27.7-29.8) years, with a median of 27 years and a range 18-66 years. The mean haemoglobin level was significantly lower for women (12.4 g/dL; 95% CI 12.1% - 12.7%) than men (15.1 g/dL; 95% CI 14.9% - 15.3%). The women's haemoglobin reference values (9.0 g/dL - 15.0 g/dL) levels were lower than observed in predominantly White populations (12.0 g/dL - 16.0 g/dL), but comparable with regional consensus reference intervals (9.5 g/dL - 15.8 g/dL) recently defined for East and Southern Africa. CONCLUSION: The established values provide an important tool for patient management and could influence decisions on inclusion of participants and adverse events in clinical trials conducted locally.

Five-year follow up of genotypic resistance patterns in HIV-1 subtype C infected patients in Botswana after failure of thymidine analogue-based regimens.

OBJECTIVE: Our objective was to establish genotypic resistance profiles among the 4% of Batswana patients who experienced virologic failure while being followed within Botswana's National Antiretroviral Treatment Program between 2002 and 2007. METHODS: At the beginning of the national program in 2002, almost all patients received stavudine (d4T), together with didanosine (ddI), as part of their first nucleoside reverse transcriptase inhibitor (NRTI)-based regimen (Group 1). In contrast, the standard of care for all patients subsequently enrolled (2002-2007) included zidovudine/lamivudine (ZDV/3TC) (Group 2). Genotypes were analyzed in 26 patients from Group 1 and 37 patients from Group 2. Associations between mutations were determined using Pearson's correlation coefficient and Jaccard's coefficient of similarity. RESULTS: Seventy-eight percent of genotyped patients possessed mutations associated with protease inhibitor (PI) resistance while 87% and 90%, respectively, exhibited mutations associated with NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The most frequent PI mutations involving resistance to NFV were L90M (25.2%) and D30N (16.2%), but mutations at positions K45Q and D30N were often observed in tandem (P = 60.5, J = 50; p = 0.002; Group 2) alongside Q61E in 42.8% of patients who received ZDV/3TC. Both major patterns of thymidine analogue mutations, TAM 1 (48%) and TAM 2 (59%), were represented in patients from Group 1 and 2, although M184V was higher among individuals who had initially received ddI (61% versus 40.5%). In contrast, L74V was more frequent among individuals from Group 2 (16.2% versus 7.7%). Differences in regard to NNRTI mutations were also observed between Group 1 and Group 2 patients. CONCLUSION: Despite a low rate of therapeutic failure (4%) among these patients, those who failed possessed high numbers of resistance mutations as well as novel resistance mutations and/or polymorphisms at sites within reverse transcriptase and protease.

Quantitation of human immunodeficiency virus type 1 viral load in plasma using reverse transcriptase activity assay at a district hospital laboratory in Botswana: a decentralization pilot study.

Roche COBAS Amplicor monitor version 1.5 assay is considered gold standard for viral load monitoring in Botswana. Due to its demand for elaborate infrastructure, viral load testing has been confined to the national HIV reference laboratories. Cavidi ExaVir Load version 2 assay was considered as a potential alternative to decentralize viral load testing to the rural/remote hospital laboratories and thus increase access to therapy. This study compared the performance of ExaVir Load v2 assay at a district hospital laboratory in Serowe and COBAS Amplicor monitor v1.5 assay at the Botswana Harvard HIV Reference Laboratory using quality assessment samples and plasma from HIV-positive individuals. ExaVir Load v2 and COBAS Amplicor monitor v1.5 assays had very good agreement; Kappa statistic 0.951. The COBAS Amplicor monitor v1.5 and ExaVir Load v2 assays detected HIV-1 RNA in 84 and 86 samples but did not detect HIV-1 RNA in 221 and 219 samples, respectively. The two assays detected HIV-1 RNA concordantly in 82 samples and were strongly correlated (r=0.8554, P<0.0001). ExaVir Load v2 assay provided a simple and reliable alternative viral load system that is adaptable to district hospital laboratories. The cost per test is less than RT-PCR. The ExaVir Load v2 systems have since been placed in four more district and primary hospital laboratories.

Response to zidovudine/didanosine-containing combination antiretroviral therapy among HIV-1 subtype C-infected adults in Botswana: two-year outcomes from a randomized clinical trial.

BACKGROUND: Numerous national antiretroviral (ARV) treatment initiatives offering protease inhibitor-sparing combination antiretroviral therapy (cART) have recently commenced in southern Africa, the first of which began in Botswana in January 2002. Evaluation of the efficacy and tolerability of various protease inhibitor-sparing cART regimens requires intensive study in the region, as does investigation of the development of drug resistance and the optimal means of sustaining adherence. The "Tshepo" Study is the first large-scale, randomized, clinical trial that addresses these important issues among HIV-1 subtype C-infected ARV treatment-naive adults in southern Africa. METHODS: The Tshepo Study is a completed, open-labeled, randomized study that enrolled 650 ARV-naive adults between December 2002 and 2004. The study is a 3 x 2 x 2 factorial design comparing the efficacy and tolerability among factors: (1) 3 combinations of nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (ZDV) + lamivudine (3TC), ZDV + didanosine (ddI), and stavudine (d4T) + 3TC; (2) 2 different nonnucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine and efavirenz; and (3) 2 different adherence strategies: the current national "standard of care" versus an "intensified adherence strategy" incorporating a "community-based directly observed therapy." Study patients were stratified into 2 balanced CD4 T-cell count groups: less than 201 versus 201-350 cells per cubic millimeter with viral load greater than 55,000 copies per milliliter. Following Data Safety Monitoring Board recommendations in April 2006, ZDV/ddI-containing arms were discontinued due to inferiority in primary end point, namely, virologic failure with resistance. We report both overall data and pooled data from patients receiving ZDV/ddI- versus ZDV/3TC- and d4T/3TC-containing cART through April 1, 2006. RESULTS: Four hundred fifty-one females (69.4%) and 199 males with a median age of 33.3 years were enrolled into the study. The median follow-up as of April 1, 2006, was 104 weeks, and loss to follow-up rate at 2 years was 4.1%. The median baseline CD4 T-cell count was 199 cells per cubic millimeter [interquartile ratio (IQR) 136-252], and the median plasma HIV-1 RNA level was 193,500 copies per milliliter (IQR 69-250, 472-500). The proportion of participants with virologic failure and genotypic resistance mutations was 11% in those receiving ZDV/ddI-based cART versus 2% in those receiving either ZDV/3TC- or d4T/3TC-based cART (P = 0.002). The median CD4 T-cell count increase at 1 year was 137 cells per cubic millimeter (IQR 74-223) and 199 cells per cubic millimeter (IQR 112-322) at 2 years with significantly lower gain in the ZDV/ddI arm. At 1 and 2 years, respectively, 92.0% and 88.8% of patients had an undetectable plasma HIV-1 RNA level (< or = 400 copies/mL). Kaplan-Meier survival estimates at 1 and 2 years were 96.6% and 95.4%. One hundred twenty patients (18.2%) had treatment-modifying toxicities, of which the most common were lipodystrophy, anemia, neutropenia, and Stevens-Johnson syndrome. There was a trend toward difference in time to treatment-modifying toxicity by pooled dual-NRTI combination and no difference in death rates. CONCLUSIONS: The preliminary study results show overall excellent efficacy and tolerability of NNRTI-based cART among HIV-1 subtype C-infected adults. ZDV/ddI-containing cART, however, is inferior to the dual NRTIs d4T/3TC or ZDV/3TC when used with an NNRTI for first-line cART.

Five-year outcomes of initial patients treated in Botswana's National Antiretroviral Treatment Program.

BACKGROUND: Antiretroviral treatment (ART) initiatives have now been established in many sub-Saharan African countries showing early benefits. To date, few results are available concerning long-term clinical outcomes in these treatment programs. METHODS: Response to ART is described in the first HIV-1C-infected adults enrolled in the Botswana Antiretroviral Treatment Program in 2002. Data analysis was conducted on available longitudinal data up to 1st April 2007. RESULTS: Six hundred thirty-three severely immunodeficient patients with a median CD4+ cell count of 67 cells/microl were initiated on non-nucleoside reverse transcriptase inhibitor-based combination ART and followed for a median of 41.9 months. The median CD4+ cell count increases were 169, 302, and 337 cells/microl at 1, 3, and 5 years, respectively. The percentages of patients with a viral load of less than 400 copies/ml at 1, 3, and 5 years were 91.3, 90.1, and 98.3%, respectively. Seventy-five percent of patients did not miss a single, or missed only one, monthly ART pickup per year with a mean pickup rate of 92.5%. The Kaplan-Meier survival estimates [95% confidence interval (CI)] at 1, 3, and 5 years were 82.7% (81.2 and 84.3%), 79.3% (77.6 and 81.0%), and 79.0% (77.3 and 80.7%), respectively. At 6 months, the risk of treatment modification for anemia was 6.94% (5.9 and 8.0%) for cutaneous hypersensitivity reactions, 1.3% (0.8 and 1.7%), and 1.1% (0.7 and 1.6%) for hepatotoxicity. CONCLUSION: This initial group of adults on ART in Botswana had excellent sustained immunologic, virologic, and clinical outcomes for up to 5 years of follow-up with low mortality among those surviving into the second year of ART.

Strengthening healthcare capacity through a responsive, country-specific, training standard: the KITSO AIDS training program's support of Botswana's national antiretroviral therapy rollout.

In parallel with the rollout of Botswana's national antiretroviral therapy (ART) program, the Botswana Ministry of Health established the KITSO AIDS Training Program by entering into long-term partnerships with the Botswana-Harvard AIDS Institute Partnership for HIV Research and Education and others to provide standardized, country-specific training in HIV/AIDS care. The KITSO training model has strengthened human capacity within Botswana's health sector and been indispensable to successful ART rollout. Through core and advanced training courses and clinical mentoring, different cadres of health care workers have been trained to provide high-quality HIV/AIDS care at all ART sites in the country. Continuous and standardized clinical education will be crucial to sustain the present level of care and successfully address future treatment challenges.

Overestimates of survival after HAART: implications for global scale-up efforts.

BACKGROUND: Monitoring the effectiveness of global antiretroviral therapy scale-up efforts in resource-limited settings is a global health priority, but is complicated by high rates of losses to follow-up after treatment initiation. Determining definitive outcomes of these lost patients, and the effects of losses to follow-up on estimates of survival and risk factors for death after HAART, are key to monitoring the effectiveness of global HAART scale-up efforts. METHODOLOGY/PRINCIPAL FINDINGS: A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswana's National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [1-year Kaplan Meier survival estimate 0.92 (95% confidence interval, 0.88-0.94 before tracing and 0.83 (95% confidence interval, 0.79-0.86) after tracing, log rank P<0.001]. In addition, a significantly increased risk of death after HAART among men [adjusted hazard ratio 1.74 (95% confidence interval, 1.05-2.87)] would have been missed had patients not been traced [adjusted hazard ratio 1.41 (95% confidence interval, 0.65-3.05)]. CONCLUSIONS/SIGNIFICANCE: Due to high rates of death among patients lost to follow-up after HAART, survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced. Patient tracing and uniform reporting of outcomes after HAART are needed to enable accurate monitoring of global HAART scale-up efforts.

Higher-than-expected rates of lactic acidosis among highly active antiretroviral therapy-treated women in Botswana: preliminary results from a large randomized clinical trial.

BACKGROUND: The ability of nucleoside reverse transcriptase inhibitors (NRTIs) to inhibit human mitochondrial polymerase-gamma results in impaired synthesis of mitochondrial enzymes that generate adenosine triphosphate (ATP) by oxidative phosphorylation. This has been associated with several long-term mitochondrial toxicities, which include lactic acidosis and pancreatitis, peripheral neuropathy, and lipoatrophy. METHODS: Enrolled highly active antiretroviral therapy (HAART)-treated adults have completed nearly 2 years of follow-up as part of the ongoing randomized clinical trial Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study. All patients were intensively screened for the presence of ARV-related toxicities. RESULTS: Six hundred fifty adults (69% female) were initiated on NRTI-based HAART. Overall, 2.0% of patients developed moderate to severe symptomatic hyperlactatemia, with 7 (1.0%), all female, diagnosed with lactic acidosis. Female gender (P = 0.008) and being overweight, namely having a body mass index (BMI) of greater than 25 (P = 0.001), were predictive for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis. Older age (age >40 years) showed a statistical trend (P = 0.053) as a predictor for the development of toxicity, whereas exposure to d4T and/or ddI for 6 or more months was not predictive (P = 0.102). Those diagnosed with lactic acidosis had a mean BMI of 32.38 (interquartile range [IQR] = 29.4 to 35) at the time of toxicity and had been receiving HAART for a mean of 12.1 months (IQR = 7 to 20.8). Four of the 7 (57%) died of lactic acidosis and/or hemorrhagic pancreatitis; these 4 patients also had a comorbid diagnosis of severe clinical pancreatitis with grade 3/4 lipase elevations and abdominal symptoms at the time of their demise. CONCLUSIONS: Rates of lactic acidosis appear to be higher in southern Africa when compared with rates previously described elsewhere. Risk factors for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis appear to be multifactorial but include female gender and having a BMI of greater than 25. Additional studies are ongoing to evaluate for other possible risk factors, such as host genetic differences.

Serological evidence of HIV-associated infection among HIV-1-infected adults in Botswana.

In industrialized countries, it is recommended that adults with human immunodeficiency virus type 1 (HIV-1) infection undergo baseline screening for pathogens that might cause latent or active infections, such as syphilis, hepatitis B, hepatitis C, infection due to Toxoplasma gondii, and cytomegalovirus infection. A paucity of data exist from sub-Saharan Africa describing the prevalence of these pathogens. We report data for HIV-1-infected adults referred for initiation of highly active antiretroviral therapy in Botswana.

High prevalence of the K65R mutation in human immunodeficiency virus type 1 subtype C isolates from infected patients in Botswana treated with didanosine-based regimens.

We analyzed the reverse transcriptase genotypes of human immunodeficiency virus type 1 subtype C viruses isolated from 23 patients in Botswana treated with didanosine-based regimens. The K65R mutation was selected either alone or together with the Q151M, S68G, or F116Y substitution in viruses from seven such individuals. The results of in vitro passage experiments were consistent with an apparent increased propensity of subtype C viruses to develop the K65R substitution.

Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy.

OBJECTIVE: To derive and internally validate a clinical prediction rule for virologic response based on CD4 cell count increase after initiation of HAART in a resource-limited setting. DESIGN AND METHODS: A retrospective cohort study at two HIV care clinics in Gaborone, Botswana. The participants were previously treatment-naive HIV-1-infected individuals initiating HAART. The main outcome measure was a plasma HIV-1 RNA level (viral load) < or = 400 copies/ml (i.e. undetectable) 6 months after initiating HAART. RESULTS: The ability of CD4 cell count increase to predict an undetectable viral load was significantly better in those with baseline CD4 cell counts < or = 100 cells/microl [area under the ROC curve (AUC), 0.78; 95% confidence interval (CI), 0.67-0.89; versus AUC, 0.60; 95% CI, 0.48-0.71; P = 0.018]. The sensitivity, specificity, and positive and negative predictive values of a CD4 cell count increase of > or = 50 cells/microl for an undetectable viral load in those with baseline CD4 cell counts < or = 100 cells/microl were 93.1, 61.3, 92.5 and 63.3%, respectively. Alternatively, these values were 47.8, 87.1, 95.0 and 24.5%, respectively, if a increase in CD4 cell count of > or = 150 cells/microl was used. CONCLUSIONS: CD4 cell count increase after initiating HAART has only moderate discriminative ability in identifying patients with an undetectable viral load, and the predictive ability is higher [corrected] in patients with lower baseline CD4 cell counts. Although HIV treatment programs in resource-constrained settings could consider the use of CD4 cell count increases to triage viral load testing, more accurate approaches to monitoring virologic failure are urgently needed.

Out-of-pocket costs of HAART limit HIV treatment responses in Botswana's private sector.

A large number of HIV-infected patients in sub-Saharan Africa pay out-of-pocket for HAART. This analysis from Botswana indicates that higher median out-of-pocket regimen costs to patients for the initial 30 days of HAART are associated with failure to achieve a viral load< 400 copies/ml [US$32; interquartile range (IQR), 20-84 compared with US$22; (IQR, 17-36), P = 0.001]. HAART costs should be minimized as scale-up efforts in sub-Saharan Africa progress.