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

A tale of two countries: progress towards UNAIDS 90‐90‐90 targets in Botswana and Australia

UNAIDS 90‐90‐90 targets and Fast‐Track commitments are presented as precursors to ending the AIDS epidemic by 2030, through effecting a 90% reduction in new HIV infections and AIDS‐related deaths from 2010 levels (HIV epidemic control). Botswana, a low to middle‐income country with the third‐highest HIV prevalence, and Australia, a low‐prevalence high‐income country with an epidemic concentrated among men who have sex with men (MSM), have made significant strides towards achieving the UNAIDS 90‐90‐90 targets. These two countries provide lessons for different epidemic settings. This paper discusses the lessons that can be drawn from Botswana and Australia with respect to their success in HIV testing, treatment, viral suppression and other HIV prevention strategies for HIV epidemic control. Botswana and Australia are on target to achieving the 90‐90‐90 targets for HIV epidemic control, made possible by comprehensive HIV testing and treatment programmes in the two countries. As of 2015, 70% of all people assumed to be living with HIV had viral suppression in Botswana and Australia. However, HIV incidence remains above one per cent in the general population in Botswana and in MSM in Australia. The two countries have demonstrated that rapid HIV testing that is accessible and targeted at key and vulnerable populations is required in order to continue identifying new HIV infections. All citizens living with HIV in both countries are eligible for antiretroviral therapy (ART) and viral load monitoring through government‐funded programmes. Notwithstanding their success in reducing HIV transmission to date, programmes in both countries must continue to be supported at current levels to maintain epidemic suppression. Scaled HIV testing, linkage to care, universal ART, monitoring patients on treatment over and above strengthened HIV prevention strategies (e.g. male circumcision and pre‐exposure prophylaxis) will all continue to require funding. The progress that Botswana and Australia have made towards meeting the 90‐90‐90 targets is commendable. However, in order to reduce HIV incidence significantly towards 2030, there is a need for sustained HIV testing, linkage to care and high treatment coverage. Botswana and Australia provide useful lessons for developing countries with generalized epidemics and high‐income countries with concentrated epidemics

Outcomes of the Botswana national HIV/AIDS treatment programme from 2002 to 2010: a longitudinal analysis

Background Short-term mortality rates among patients with HIV receiving antiretroviral therapy (ART) in sub- Saharan Africa are higher than those recorded in high-income countries, but systematic long-term comparisons have not been made because of the scarcity of available data. We analysed the eff ect of the implementation of Botswana’s national ART programme, known as Masa, from 2002 to 2010. Methods The Masa programme started on Jan 21, 2002. Patients who were eligible for ART according to national guidelines had their data collected prospectively through a clinical information system developed by the Botswana Ministry of Health. A dataset of all available electronic records for adults (≥18 years) who had enrolled by April 30, 2010, was extracted and sent to the study team. All data were anonymised before analysis. The primary outcome was mortality. To assess the eff ect of loss to follow-up, we did a series of sensitivity analyses assuming varying proportions of the population lost to follow-up to be dead. Findings We analysed the records of 126 263 patients, of whom 102 713 had documented initiation of ART. Median follow-up time was 35 months (IQR 14–56), with a median of eight follow-up visits (4–14). 15 270 patients were deemed lost to follow-up by the end of the study. 63% (78 866) of the study population were women; median age at baseline was 34 years for women (IQR 29–41) and 38 years for men (33–45). 10 230 (8%) deaths were documented during the 9 years of the study. Mortality was highest during the fi rst 3 months after treatment initiation at 12·8 deaths per 100 person-years (95% CI 12·4–13·2), but decreased to 1·16 deaths per 100 person-years (1·12–1·2) in the second year of treatment, and to 0·15 deaths per 100 person-years (0·09–0·25) over the next 7 years of follow-up. In each calendar year after the start of the Masa programme in 2002, average CD4 cell counts at enrolment increased (from 101 cells/μL [IQR 44–156] in 2002, to 191 cells/μL [115–239] in 2010). In each year, the proportion of the total enrolled population who died in that year decreased, from 63% (88 of 140) in 2002, to 0·8% (13 of 1599) in 2010. A sensitivity analysis assuming that 60% of the population lost to follow-up had died gave 3000 additional deaths, increasing overall mortality from 8% to 11–13%. Interpretation The Botswana national HIV/AIDS treatment programme reduced mortality among adults with HIV to levels much the same as in other low-income or middle-income countries

What do the Universal Test and Treat Trials tell us about the path to HIV epidemic control?

Introduction Achieving HIV epidemic control globally will require new strategies to accelerate reductions in HIV incidence and mortality. Universal test and treat (UTT) was evaluated in four randomized population‐based trials (BCPP/Ya Tsie, HPTN 071/PopART, SEARCH, ANRS 12249/TasP) conducted in sub‐Saharan Africa (SSA) during expanded antiretroviral treatment (ART) eligibility by World Health Organization guidelines and the UNAIDS 90‐90‐90 campaign. Discussion These three‐year studies were conducted in Botswana, Zambia, Uganda, Kenya and South Africa in settings with baseline HIV prevalence from 4% to 30%. Key observations across studies were: (1) Universal testing (implemented via a variety of home and community‐based testing approaches) achieved >90% coverage in all studies. (2) When coupled with robust linkage to HIV care, rapid ART start and patient‐centred care, UTT achieved among the highest reported population levels of viral suppression in SSA. Significant gains in population‐level viral suppression were made in regions with both low and high baseline population viral load; however, viral suppression gains were not uniform across all sub‐populations and were lower among youth. (3) UTT resulted in marked reductions in community HIV incidence when universal testing and robust linkage were present. However, HIV elimination targets were not reached. In BCPP and HPTN 071, annualized HIV incidence was approximately 20% to 30% lower in the intervention (which included universal testing) compared to control arms (no universal testing). In SEARCH (where both arms had universal testing), incidence declined 32% over three years. (4) UTT reduced HIV associated mortality by 23% in the intervention versus control communities in SEARCH, a study in which mortality was comprehensively measured. Conclusions These trials provide strong evidence that UTT inclusive of universal testing increases population‐level viral suppression and decreases HIV incidence and mortality faster than the status quo in SSA and should be adapted at a sub‐country level as a public health strategy. However, more is needed, including integration of new prevention interventions into UTT, in order to reach UNAIDS HIV elimination targets

Rapid antiretroviral therapy initiation in the Botswana Combination Prevention Project: a quasi-experimental before and after study.

BACKGROUND: Ensuring that individuals who are living with HIV rapidly initiate antiretroviral therapy (ART) is an essential step in meeting the 90-90-90 targets. We evaluated the feasibility and outcomes of rapid ART initiation in the Botswana Combination Prevention Project (BCPP). We aimed to establish whether simplified ART initiation with the offer of same-day treatment could increase uptake and reduce time from clinic linkage to treatment initiation, while maintaining rates of retention in care and viral suppression. METHODS: We did a quasi-experimental before and after study with use of data from the BCPP. The BCPP was a community-randomised HIV-prevention trial done in 30 communities across Botswana from Oct 1, 2013, to June 30, 2018. Participants in the 15 intervention clusters, who were HIV-positive and not already taking ART were offered universal HIV-treatment and same-day ART with a dolutegravir-based regimen at first clinic visit. This rapid ART intervention was implemented mid-way through the trial on June 1, 2016, enabling us to determine the effect of rapid ART guidelines on time to ART initiation and rates of retention in care and viral suppression at 1 year in the BCPP intervention group. FINDINGS: We assessed 1717 adults linked to study clinics before rapid ART introduction and 800 after rapid ART introduction. During the rapid ART period, 457 (57·1%, 95% CI 53·7-60·6) individuals initiated ART within 1 day of linkage, 589 (73·7%, 70·6-76·7) of 799 within 1 week, 678 (84·9%, 82·4-87·3) of 799 within 1 month, and 744 (93·5%, 91·6-95·1) of 796 within 1 year. Before the introduction of rapid ART, 163 (9·5%, 95% CI 8·2-11·0) individuals initiated ART within 1 day of linkage, 276 (16·1%, 14·4-17·9) within 1 week, 839 (48·9%, 46·5-51·3) within 1 month, and 1532 (89·2%, 87·7-90·6) within 1 year. 1 year after ART initiation, 1472 (90·5%, 87·4-92·8) of 1627 individuals who linked in the standard ART period were in care and had a viral load of less than 400 copies per mL, compared with 578 (91·6%, 88·1-94·1) of 631 in the rapid ART period (risk ratio 1·01, 95% CI 0·92-1·11). INTERPRETATION: Our findings provide support for the WHO recommendations for rapid ART initiation, and add to the accumulating evidence showing the feasibility, acceptability, and safety of rapid ART initiation in low-income and middle-income country settings. FUNDING: US President's Emergency Plan for AIDS Relief

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

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

Population uptake of HIV testing, treatment, viral suppression, and male circumcision following a community-based intervention in Botswana (Ya Tsie/BCPP): a cluster-randomised trial

BACKGROUND: In settings with high HIV prevalence and treatment coverage, such as Botswana, it is unknown whether uptake of HIV prevention and treatment interventions can be increased further. We sought to determine whether a community-based intervention to identify and rapidly treat people living with HIV, and support male circumcision could increase population levels of HIV diagnosis, treatment, viral suppression, and male circumcision in Botswana. METHODS: The Ya Tsie Botswana Combination Prevention Project study was a pair-matched cluster-randomised trial done in 30 communities across Botswana done from Oct 30, 2013, to June 30, 2018. 15 communities were randomly assigned to receive HIV prevention and treatment interventions, including enhanced HIV testing, earlier antiretroviral therapy (ART), and strengthened male circumcision services, and 15 received standard of care. The first primary endpoint of HIV incidence has already been reported. In this Article, we report findings for the second primary endpoint of population uptake of HIV prevention services, as measured by proportion of people known to be HIV-positive or tested HIV-negative in the preceding 12 months; proportion of people living with HIV diagnosed and on ART; proportion of people living with HIV on ART with viral suppression; and proportion of HIV-negative men circumcised. A longitudinal cohort of residents aged 16-64 years from a random, approximately 20% sample of households across the 15 communities was enrolled to assess baseline uptake of study outcomes; we also administered an end-of-study survey to all residents not previously enrolled in the longitudinal cohort to provide study end coverage estimates. Differences in intervention uptake over time by randomisation group were tested via paired Student's t test. The study has been completed and is registered with ClinicalTrials.gov (NCT01965470). FINDINGS: In the six communities participating in the end-of-study survey, 2625 residents (n=1304 from standard-of-care communities, n=1321 from intervention communities) were enrolled into the 20% longitudinal cohort at baseline from Oct 30, 2013, to Nov 24, 2015. In the same communities, 10 791 (86%) of 12 489 eligible enumerated residents not previously enrolled in the longitudinal cohort participated in the end-of-study survey from March 30, 2017, to Feb 25, 2018 (5896 in intervention and 4895 in standard-of-care communities). At study end, in intervention communities, 1228 people living with HIV (91% of 1353) were on ART; 1166 people living with HIV (88% of 1321 with available viral load) were virally suppressed, and 673 HIV-negative men (40% of 1673) were circumcised in intervention communities. After accounting for baseline differences, at study end the proportion of people living with HIV who were diagnosed was significantly higher in intervention communities (absolute increase of 9% to 93%) compared with standard-of-care communities (absolute increase of 2% to 88%; prevalence ratio [PR] 1·08 [95% CI 1·02-1·14], p=0·032). Population levels of ART, viral suppression, and male circumcision increased from baseline in both groups, with greater increases in intervention communities (ART PR 1·12 [95% CI 1·07-1·17], p=0·018; viral suppression 1·13 [1·09-1·17], p=0·017; male circumcision 1·26 [1·17-1·35], p=0·029). INTERPRETATION: It is possible to achieve very high population levels of HIV testing and treatment in a high-prevalence setting. Maintaining these coverage levels over the next decade could substantially reduce HIV transmission and potentially eliminate the epidemic in these areas. FUNDING: US President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention

Discussing matters of sexual health with children: what issues relating to disclosure of parental HIV status reveal.

Little is published about the disclosure of parents' own HIV status to their children in Africa. Research shows that keeping family secrets from children, including those related to a parent's HIV status, can be detrimental to their psychological well-being and to the structure of the family. Further, children with HIV-positive parents have been shown to be more vulnerable to poorer reproductive health outcomes. This qualitative study in Botswana conducted in-depth interviews among 21 HIV-positive parents on antiretroviral therapy. The data revealed that parents found discussing the issue of HIV with children difficult, including disclosing their own HIV status to them. Reasons for disclosing included: children being HIV positive, the rest of the family knowing, or the parent becoming very sick. Reasons for not disclosing included: believing the child to be too young, not knowing how to address the issue of HIV, that it would be "too painful" for the child/ren. Concern that other people might find out about their status or fear of children experiencing stigmatising behaviour. Interviews elucidated the difficulty that parents have in discussing their own HIV status and more general sexual health issues with their children. Parents and other guardians require support in managing age-appropriate disclosure to their children. This may further enable access to forums that can help children cope with their fears about the future and develop life skills in preparation for dealing with relationships of a sexual nature and sexual health as children move into adulthood. In developing such support mechanisms, changing family roles in Botswana need to be taken into consideration and the role of other family members in the upbringing of children in Tswana society need to be recognised and utilised