Botswana's Progress Toward Achieving the 2020 UNAIDS 90-90-90 Antiretroviral Therapy and Virological Suppression Goals: a Po

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Botswana’s progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a population-based survey

Tendani Gaolathe, Kathleen E Wirth, Molly Pretorius Holme, Joseph Makhema, Sikhulile Moyo, Unoda Chakalisa, Etienne Kadima Yankinda, Quanhong Lei, Mompati Mmalane, Vlad Novitsky, Lillian Okui, Erik van Widenfelt, Kathleen M Powis, Nealia Khan, Kara Bennett, Hermann Bussmann, Scott Dryden-Peterson, Refeletswe Lebelonyane, Shenaaz el-Halabi, Lisa A Mills, Taﬁ reyi Marukutira, Rui Wang, Eric J Tchetgen Tchetgen, Victor DeGruttola, M Essex, Shahin Lockman, and the Botswana Combination Prevention Project study team

Summary Background HIV programmes face challenges achieving high rates of HIV testing and treatment needed to Lancet HIV 2016; 3: e221–30 optimise health and to reduce transmission. We used data from the Botswana Combination Prevention Project Published Online study survey to assess Botswana’s progress toward achieving UNAIDS targets for 2020: 90% of all people living March 23, 2016 with HIV knowing their status, 90% of these receiving sustained antiretroviral therapy (ART), and 90% of those http://dx.doi.org/10.1016/ S2352-3018(16)00037-0 having virological suppression (90-90-90). See Comment page e195 Methods Botswana Harvard AIDS A population-based sample of individuals was recruited and interviewed in 30 rural and periurban Institute Partnership, communities from Oct 30, 2013, to Nov 24, 2015, as part of a large, ongoing community-randomised trial designed Gaborone, Botswana to assess the eff ect of a combination prevention package on HIV incidence. A random sample of about 20% of (T Gaolathe MD, households in each community was selected. Consenting household residents aged 16–64 years who were J Makhema FRCP, S Moyo MSc, U Chakalisa MD, Botswana citizens or spouses of citizens responded to a questionnaire and had blood drawn for HIV testing in the E Kadima Yankinda MPH, absence of documentation of positive HIV status. Viral load testing was done in all HIV-infected participants, M Mmalane MSc, irrespective of treatment status. We used modifi ed Poisson generalised estimating equations to obtain prevalence V Novitsky PhD, L Okui MPH, ratios, corresponding Huber robust SEs, and 95% Wald CIs to examine associations between individual E van Widenfelt BA, K M Powis MD, H Bussmann MD, sociodemographic factors and a binary outcome indicating achievement of the three individual and combined S Dryden-Peterson MD, overall 90-90-90 targets. The study is registered at ClinicalTrials.gov, number NCT01965470. Prof M Essex PhD, S Lockman MD); Department of Findings 81% of enumerated eligible household members took part in the survey (10% refused and 9% were Epidemiology (K E Wirth ScD, Prof E J Tchetgen Tchetgen PhD), absent). Among 12 610 participants surveyed, 3596 (29%) were infected with HIV, and 2995 (83·3%, 95% CI Harvard T H Chan School of 81·4–85·2) of these individuals already knew their HIV status. Among those who knew their HIV status, Public Health AIDS Initiative, 2617 (87·4%, 95% CI 85·8–89·0) were receiving ART (95% of those eligible by national guidelines, and 73% of all Department of Immunology infected people). Of the 2609 individuals receiving ART with a viral load measurement, 2517 (96·5%, 95% CI and Infectious Diseases (K E Wirth, 96·0–97·0) had viral load of 400 copies per mL or less. Overall, 70·2% (95% CI 67·5–73·0) of HIV-infected people M Pretorius Holme MS, had virological suppression, close to the UNAIDS target of 73%. J Makhema, V Novitsky, K M Powis, Interpretation UNAIDS 90-90-90 targets are achievable even in resource-constrained settings with high HIV N Khan MPH, H Bussmann, S Dryden-Peterson, burden. Prof M Essex, S Lockman), and Department of Biostatistics Funding US President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention. (Q Lei PhD, R Wang PhD, Prof E J Tchetgen Tchetgen, Prof V DeGruttola DSc), Harvard Introduction such as sub-Saharan Africa. According to UNAIDS, in T H Chan School of Public In 2014, UNAIDS proposed new targets directed at sub-Saharan Africa in 2013, only 45% of HIV-infected Health, Boston, MA, USA; ending the AIDS epidemic, namely that 90% of all HIV- adults knew their HIV status; however, 86% of Departments of Medicine and infected people will know their HIV status, 90% of diagnosed people were on ART and an estimated 76% Pediatrics, Massachusetts General Hospital, Boston, MA, 9 those diagnosed with HIV infection will receive of those on ART achieved virological suppression. This USA (K M Powis); Department sustained combination antiretroviral therapy (ART), fi nding translates to 29% of all HIV-positive people in of Medicine, Harvard Medical and 90% of all people receiving ART will have viral sub-Saharan Africa having virological suppression School, Boston, MA, USA suppression by 2020 (90-90-90 targets).1 The rationale compared with the overall UNAIDS target of 73%. (K M Powis, S Dryden-Peterson, R Wang, S Lockman); Bennett underpinning these targets is related both to the health Recent estimates of progress toward reaching this Statistical Consulting, Inc, benefi t of ART to infected individuals2,3 and to the target range from 68% in Switzerland10 and 62% in Ballston Lake, NY, USA potent eff ect of ART on reducing sexual4–6 and Australia11 to 30% in the USA,12 and as little as 9% in (K Bennett MS); Department of 7,8 13 Medicine, Division of Infectious perinatal HIV transmission. Russia. Diseases (S Dryden-Peterson, However, uncertainty remains as to whether these Botswana is a middle-income country with a stable S Lockman) and Departments ambitious UNAIDS targets are achievable, particularly democracy, high HIV prevalence (25·2% of people aged of Medicine and Neurology in high-HIV-burden, resource-constrained settings 15–49 years),14 and a mature public ART programme (R Wang), Brigham and www.thelancet.com/hiv Vol 3 May 2016 e221 Articles

Women’s Hospital, Boston, MA, USA; Ministry of Health, Research in context Republic of Botswana, Gaborone, Botswana Evidence before this study component of the HIV treatment cascade are available from (R Lebelonyane MPH, Accumulating evidence that providing antiretroviral therapy high-HIV-burden, resource-constrained settings. S el-Halabi MPH); and Division (ART) to all people living with HIV (irrespective of disease of Global HIV/AIDS, Center for Added value of this study stage) optimises their health and will help end the global HIV Global Health, Centers for Botswana is a middle-income country in sub-Saharan Africa epidemic, has led UNAIDS to propose new HIV testing and Disease Control and Prevention with a very high prevalence of HIV (25·2% among people Botswana, Gaborone, treatment targets: that by 2020, 90% of all people living with aged 15–49 years) and a national treatment programme that Botswana (L A Mills MD, HIV will know their HIV status, 90% of all people with T Marukutira MD) oﬀ ers antiretrovirals to HIV-infected adults with CD4 counts diagnosed HIV infection will be on ART, and 90% of all people of 350 cells per μL or less. We directly measured Correspondence to: receiving treatment will have virological suppression. Prof M Essex, Botswana Harvard population-level coverage of HIV testing, ART, and virological However, uncertainty remains as to whether these targets are AIDS Institute Partnership, suppression (the three UNAIDS 90-90-90 targets) in the Harvard T H Chan School of achievable, especially in resource-constrained settings where context of a cluster-randomised HIV combination prevention Public Health AIDS Initiative, the burden of HIV is the largest. We searched PubMed, study that is underway in 30 communities across Botswana. FXB 402, 651 Huntington UNAIDS, WHO, and US Centers for Disease Control and Avenue, Boston, MA, USA A survey was administered before the trial intervention to Prevention websites, and the Google search engine for [email protected] more than 12 000 adult residents recruited from a 20% simple conference proceedings using the search terms “HIV testing random sample of all households in the communities. We coverage”, “antiretroviral treatment coverage”, and “national found one of the highest overall coverage levels of the antiretroviral treatment”, for all English language UNAIDS 90-90-90 targets that has been described to date publications until Feb 22, 2016. Most available numbers that worldwide—a level that nearly achieves the UNAIDS target. describe global progress toward achieving these targets are model-based estimates of the relevant numerators and Implications of all the available evidence denominators rather than directly measured data. Moreover, Our ﬁ ndings provide evidence that the UNAIDS targets, estimates of virological suppression among HIV-positive although ambitious, are achievable even in people receiving treatment are largely restricted to resource-constrained settings with high HIV burden. high-resource nations; only limited data on this key

that started in 2002. In Botswana, HIV-infected citizens total population of about 180 000 people (ﬁ gure 1), receive free three-drug ART from decentralised health representing nearly 10% of Botswana’s estimated clinics if they have a CD4 count of 350 cells per μL or population. 15 com munities were randomised to a less, WHO stage III or IV illness (including recent combination prevention group, and 15 to a non- tuberculosis diagnosis), or a history of cancer or if they intervention group. Interventions in the combination are pregnant or breastfeeding (irrespective of CD4 prevention group include home-based and mobile HIV count). We have a unique opportunity to assess testing and counselling; point-of-care CD4 testing; population-level coverage of HIV testing, ART, and linkage to care support; expanded ART (for CD4 counts virological suppression in the context of a large, of 351–500 cells per μL or >500 cells per μL with HIV-1 ongoing, cluster-randomised combination prevention RNA ≥10 000 copies per mL, in addition to local study in 30 communities across Botswana. criteria); and enhanced male circumcision services. The protocol has been amended to oﬀ er universal Methods treatment (irrespective of disease stage) in the Study design intervention com munities, and the Botswana Ministry The Botswana Combination Prevention Project (BCPP; of Health plans to provide universal ART in 2016 (a also known as the Ya Tsie study), is a pair-matched, change that will also apply to non-intervention cluster-randomised trial funded by the US President’s communities). ART and other services are provided at Emergency Plan for AIDS Relief that is designed to test or above the evolving local standard of care, throughout whether a package of combination prevention inter- the study. ventions reduces population-level cumulative 3 year The study protocol, informed consent, and other HIV incidence. Another primary objective of the study materials were approved by the Botswana Health includes assessment of population-level uptake of HIV Research Development Committee (institutional review testing and ART at baseline and over time; the baseline board of the Botswana Ministry of Health) and the US cross-sectional results are presented in this report. The Centers for Disease Control and Prevention institutional trial is being done in 30 communities in Botswana review board. All participants provided written (15 pairs matched according to size, pre-existing health informed consent. Participants aged 16–18 years services, population age structure, and geographical provided written assent (with parents or guardians location, including proximity to urban areas), with a providing written permission). e222 www.thelancet.com/hiv Vol 3 May 2016 Articles

1 Ranaka and Digawana

2 Molapowabojang and Otse 13 Chobe 3 Letlhakeng and Lentswelatau

4 Bokaa and Oodi 13 Ngamiland 5 Mmathethe and Mmankgodi Nokaneng Okavango Swamps Maun 6 Sefophe and Lerala Tsau Nata 12 15 10 7 Ramokgonami and Maunatlala Sehithwa 10 15 8 Mmadinare and Shoshong Rakops Central 11 North 12 Francistown East 9 Metsimotlhaba and Tati Siding Drapa 9 11 Letlhakane 10 Sebina and Nkange Ghanzi Seruli 8 Ghanzi Selebi-Phikwe Sefophe Serowe 6 Mamuno 14 Palapya 7 11 Mandunyane and Mathangwane 7 6 8 Maharapye 14 12 Rakops and Gweta

13 Shakawe and Gumare Kang Kweneng 14 Tsetsebjwe and Sefhare Tshane 3 3 Kgatleng 15 Molepolole 4 Mochudi Nata and Masunga Kgalagadi Jwaneng 9 4 Khakhea 1 5 Gaborone Kanye 2 Southern 2 1 5

Tshabong

Bokspits

Figure 1: Map of the 15 matched community pairs participating in the Botswana Combination Prevention Project study

Study population and procedures sampled than in any other household in the same Survey participants were recruited with a household- community over the preceding 12 months, docu- based probabilistic sampling strategy at the community mentation of Botswana citizenship or marriage to a level. Within each of the 30 communities, the sampling Botswana citizen, and ability to provide informed strategy began with identifying and geocoding every consent. Participants received a BWP20 (about US$2) plot with a household-like structure by the use of cellular telephone prepaid voucher as compensation for satellite imagery captured between 2012 and 2015 their time. Plots were visited up to three times to (Google Earth, Mountain View, CA, USA) overlaid with enumerate household members; up to three additional enumeration boundaries used in the 2011 Botswana attempts were made to enrol each potentially eligible census.15 A simple random 20% sample was then enumerated household member. selected from the list of geocoded plots. For each The baseline household survey included questions household on the selected plots, a household about sociodemographics, health, and HIV risk behaviour. representative (aged 18 years or older) was asked to list People who self-reported a positive HIV status and who each household member with their age, gender, time were able to provide corresponding documentation (eg, spent in the household, and relationship to the written test result, ART prescription) were not retested household head. Based on this information, research for HIV. All other participants were off ered counselling staff identifi ed potentially eligible household members and rapid HIV testing according to the algorithm and invited them to provide written consent to approved by the Botswana Government, which includes participate, complete a questionnaire, and undergo KHB (KHB, Shanghai Kehua Bio-Engineering Co Ltd, HIV testing. Eligibility criteria were being age Shanghai, China) and Unigold (Trinity Biotech Plc, Bray, 16–64 years, spending on average at least three nights Ireland) parallel HIV rapid tests. Documentation of ART per month in the community over the preceding 12 receipt was sought for all people who reported that they months, spending more nights in the household being were on ART (eg, prescriptions, clinical notes showing www.thelancet.com/hiv Vol 3 May 2016 e223 Articles

ART receipt, or pills). HIV-1 RNA was tested in all HIV- We used modifi ed Poisson generalised estimating infected people, irrespective of ART status. HIV-1 RNA equations to obtain prevalence ratios, corresponding was assayed with the Abbott RealTime HIV-1 assay on Huber robust SEs, and 95% Wald CIs to examine the automated m2000 system (Abbott Laboratories, associations between individual sociodemographic Wiesbaden, Germany; range 40–10 000 000 copies per factors and a binary outcome indicating achievement of mL) in the Botswana–Harvard HIV Reference Laboratory, the three individual and combined overall 90-90-90 which participates in virology quality assurance and is targets.16 SAS software version 9.4 (SAS Institute, Cary, accredited to ISO 17025. Point-of-care CD4 count (Pima, NC, USA) was used for all analyses. Alere Inc, Waltham, MA, USA) was obtained on We did three additional analyses to assess the extent HIV-positive people who were not taking ART. CD4 count to which our results might be sensitive to selection bias and HIV-1 RNA results were shared with participants. due to non-participation. First, complete-case inverse- Research assistants participated in the point-of-care CD4 probability weighting was used to re-estimate each and HIV testing external quality assurance programme 90-90-90 target, adjusting for non-participation by and were assessed for competence with masked testing. accounting for fully observed potential predictors HIV-infected participants not yet on ART were common to non-participation and the targets.17,18 referred to their local clinic for prompt ART initiation if Inverse-probability weighting adjusts for non- their CD4 count was 350 cells per μL or less, or if participation by empirically breaking the association pregnant. HIV-infected participants with a CD4 count between observed predictors and non-participation, greater than 350 cells per μL were referred to their local allowing for unbiased estimation in the weighted clinic for assessment for possible ART initiation, and sample provided a regression for non-participation is for other services as needed, including assessment for correctly specifi ed, and no unobserved correlates of tuberculosis. non-participation and outcomes defi ning the 90-90-90 After completion of the baseline survey, community- targets exist. Inverse-probability weights for parti- wide HIV testing and counselling, linkage to care, cipation were constructed by the use of predicted expanded ART, and expanded male circumcision probabilities from a multivariable logistic regression interventions were started in the combination model containing the following fully observed prevention communities. All participants in the covariates and their two-way interactions: age, gender, baseline survey will be contacted annually for 3 years, relationship to household head, community, and for HIV testing (if previously negative), and for repeat presence of household member during enumeration. interview, with ongoing interventions in the We then did a weighted, complete-case crude analysis combination prevention group during this period. using modifi ed Poisson generalised estimating equations to estimate the marginal probability of each Statistical analysis 90-90-90 target. We restricted the present analysis to data collected from Although inverse-probability weighting adjusts for the baseline household survey of all 30 study observed diff erences between enrolled and unenrolled communities, before the roll-out of any intervention enumerated people found to be eligible, the enumerated activities. The 90-90-90 targets were calculated as follows: population itself might systematically diff er from the general population. Therefore, in a second sensitivity % diagnosed = (HIV-positive people with documented analysis, we standardised our observed 90-90-90 previous knowledge of HIV status) / (HIV-positive estimates to the age and gender distribution of HIV- people) positive people in Botswana by use of the 2011 Botswana census15 and the 2013 Botswana AIDS Indicator Survey.19 % on treatment = (HIV-positive people with documented Finally, we did a third sensitivity analysis which previous knowledge of HIV status receiving ART) / entailed re-estimating the 90-90-90 targets by com- (HIV-positive people with documented previous bining complete-case outcomes observed among knowledge of HIV status) enrolled participants with potential outcomes of unenrolled, eligible household members, assuming a % virally suppressed = (HIV-positive people with hypothetical scenario in which non-partici pating documented previous knowledge of HIV status residents had substantially lower rates of HIV receiving ART with HIV-1 RNA <400 copies per mL) / testing, ART coverage, and virological suppression. (HIV-positive people with documented previous The study is registered at ClinicalTrials.gov, number knowledge of HIV status receiving ART) NCT01965470.

% overall cascade = (HIV-positive people with Role of the funding source documented previous knowledge of HIV status The funders played no role in study design, in the receiving ART with HIV-1 RNA <400 copies per mL) / collection, analysis, or interpretation of data, in the (HIV-positive people) writing of this report, or in the decision to submit it e224 www.thelancet.com/hiv Vol 3 May 2016 Articles

for publication. The corresponding author (ME) had regularly occupied, and of those, 7696 (75%) were full access to all the data in the study and had enumerated (fi gure 2). Reasons for non-enumeration fi nal responsibility for the decision to submit for included absence of an eligible household informant publication. (10%), absence of any people (7%), and refusal (6%). 28 174 residents were enumerated; 55% were eligible Results for participation and, of these, 81% completed the The baseline household survey was done in 30 com- baseline survey. Among the 15 475 enumerated eligible munities from Oct 30, 2013, to Nov 24, 2015. Research household members, 9286 (60%) were women and staff visited 13 147 randomly selected plots identifi ed 6189 (40%) were men. Reasons for non-participation on satellite imagery and categorised 9982 (76%) as residential and habitable. On these plots, 11 582 households were identifi ed, 10 306 (89%) were Number (%) Gender (n=3596) Male 962 (27%)

11 582 households identiﬁed on Female 2634 (73%) residential and inhabitable plots Age (n=3596) 16–19 years 47 (1%) 20–29 years 460 (13%) 492 households seasonally, rarely, or never occupied 30–39 years 1222 (34%) 784 households had no one at home and 40–49 years 1069 (30%) unable to determine occupancy status 50–59 years 631 (18%) 60 years and older 167 (5%) 10 306 regularly occupied households Median age (IQR) 40 (33–48) identiﬁed Relationship status (n=3593) Single or never married 2799 (78%) Household level 580 households refused enumeration Married 539 (15%) 1004 households had no eligible Widowed, divorced, or separated 255 (7%) household representative 764 households had no one at home Education (n=3572) 262 households not visited Non-formal 531 (15%) Primary 1072 (30%)

7696 households enumerated Junior secondary 1412 (40%) Senior secondary 311 (9%) Higher than senior secondary 246 (7%) Employment status (n=3594) 28 174 people identiﬁed from household enumerations Employed 1173 (33%) Unemployed and looking for work 1766 (49%) Unemployed but not looking for work* 655 (18%) 11 762 people aged <16 or >64 years 456 not a Botswana citizen Monthly income (n=3572)† 481 other None 1999 (56%) <$96 647 (18%)

15 475 eligible to participate $96 to $477 795 (22%) >$477 131 (4%) Time spent away from community in the past 12 months (n=3594) 1519 refused participation None 1838 (51%) 1346 absent

Participant level Participant <1 week 736 (20%) 1–2 weeks 303 (8%) 12 610 enrolled in study 3–4 weeks 325 (9%) 5–12 weeks 296 (8%) >12 weeks 96 (3%) 8974 HIV negative 40 refused HIV testing *Unemployed and not looking for work includes participants who report being housewives, students, or retired as primary reasons for unemployment. †Botswana pula (BWP) were converted to US$ based on a rate of 3596 HIV-positive BWP10·49 per $1.

Table 1: Baseline characteristics of HIV-positive individuals enrolled in Figure 2: Recruitment, eligibility, and enrolment of participants for the the Botswana Combination Prevention Project from 30 communities Botswana Combination Prevention Project at the household and in Botswana participant level

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among eligible people included refusal (10%) and Among the 3596 HIV-infected people identiﬁ ed, absence (9%). 2995 (83·3%, 95% CI 81·4–85·2) already knew their Of the 12 610 participants, 2995 (24%) had docu- positive status and provided supporting documentation. mentation of a previous positive HIV test, 9575 (76%) 466 participants newly tested HIV-positive and 135 self- underwent HIV testing, and 40 (<1%) refused testing. reported being HIV-positive but could not provide Overall, 3596 participants (including individuals known documentation. Although these individuals were to be infected with HIV and those newly testing positive positive, to be conservative, they were not included in for HIV) were infected with HIV, with an overall HIV the numerator of the ﬁ rst 90-90-90 target. prevalence of 29%. HIV-1 RNA testing was completed Among the 2995 HIV-infected people who knew their in 3585 (99·7%) HIV-infected participants. positive status, 2617 (87·4%, 95% CI 85·8–89·0) were 73% of HIV-infected participants were women, and receiving ART; an additional 26 participants reported median age was 40 years (table 1). 8050 (87%) of taking ART previously, but were not on ART. The 9268 women residing in participating households were 2617 parti cipants receiving ART represented 95% of the enrolled, compared with 4560 (74%) of 6189 men. 2754 people eligible for ART according to Botswana 78% of participants reported being single and 45% had guidelines. a primary school education or less (table 1). 33% were Finally, 2517 (96·5%, 95% CI 96·0–97·0) of the employed and 56% reported no monthly income. 72% 2609 participants on ART with a viral load measurement of participants spent less than 1 week outside the had HIV-1 RNA of 400 copies per mL or less; community during the previous 12 months (table 1). 2428 (93·1%, 92·1–94·0) had HIV-1 RNA of 40 copies per mL or less. Among the 2635 people who reported ever starting ART for their health (including defaulters) 100 100·0% with a viral load measurement, 2520 (95·6%, 95% CI Goal: 90% 95·0–96·3) had HIV-1 RNA of 400 copies per mL Goal: 81% 80 83·3% Goal: 73% or less. 72·8% 70·2% Overall, among all HIV-infected people, 2995 (83·3%, 60 95% CI 81·4–85·2) knew their status, 2617 (72·8%, 70·1–75·5) were receiving ART and 2517 (70·2%,

40 67·5–73·0) were on ART and had virological suppression (HIV-1 RNA ≤400 copies per mL; ﬁ gure 3). 136 parti cipants reported that they were not receiving 20 ART but had an HIV-1 RNA of 400 copies per mL or

Proportion of HIV-positive participants (%) of HIV-positive Proportion less. To conﬁ rm the ART status, we queried the 0 Botswana Ministry of Health electronic medical records HIV-positive Diagnosed Currently Suppressed people on ART viral load systems for evidence of recent receipt of ART services. BCPP baseline household survey UNAIDS goal We were able to retrieve records for 96 (71%) of these individuals and 40 (42%) had initiated ART before the Figure 3: Proportions of HIV-infected individuals enrolled in the Botswana Combination Prevention Project meeting the UNAIDS 90-90-90 targets survey. If we include these 40 additional participants at baseline with HIV-1 RNA of 400 copies per mL or less, the

Observed Adjustment for Direct standardisation of Hypothetical assumptions for non-participation by observed estimates to unenrolled eligible household unenrolled, eligible Botswana census age and members compared with household members* gender distribution enrolled participants† First 90: knowledge of HIV status 83·3% (81·4–85·2) 82·8% (80·9–84·7) 77·8% (76·2–79·4) 77·8% (73·7–81·9) (among HIV-positive people) Second 90: receiving ART 87·4% (85·8–89·0) 87·4% (85·8–89·1) 85·0% (83·3–86·8) 83·0% (79·1–86·9) Third 90: virologically suppressed‡ 96·5% (96·0–97·0) 96·5% (96·0–97·0) 93·9% (92·4–95·3) 92·3% (88·5–96·2) Overall: knows HIV status, on ART, and 70·2% (67·5–73·0) 69·8% (67·1–72·6) 63·4% (61·6–65·1) 63·6% (60·1–67·0) virologically suppressed

Data are proportion (95% CI). ART=antiretroviral therapy. *Inverse-probability weighting estimated with modiﬁ ed Poisson generalised estimating equations model with weights constructed to adjust for non-participation with the following fully observed covariates and their two-way interacions: age, sex, relationship to head of household, community, and whether the household member was present at the time of enumeration. †HIV prevalence among unenrolled, eligible people set to 42·8%; proportion of assumed HIV-positive unenrolled, eligible people who know their status set to 62·3%; ART coverage among assumed HIV-positive unenrolled, eligible people who know their status set to 65·6%; viral suppression among assumed HIV-positive unenrolled, eligible people who know their status and on ART set to 72·4% (HIV prevalence, 50% higher; knowledge of status, 25% lower; ART coverage, 25% lower; viral suppression, 25% lower). ‡Virologically suppressed deﬁ ned as HIV viral load of 400 copies per mL or less; HIV viral load not available for eight participants on ART and two participants naive to ART due to missing specimens.

Table 2: Sensitivity analyses done to assess the potential eﬀ ect of non-participation on the observed estimates of achievement of 90-90-90 targets

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First 90: knowledge of HIV Second 90: receiving ART Third 90: virologically suppressed*† Overall: knows HIV status, on ART, status (among HIV-positive (among HIV-positive people (among HIV-positive people who and virologically suppressed† people) who know their status) know their status and receiving ART) (among HIV-positive people) Gender Male 0·90 (0·87–0·94) 1·04 (1·01–1·07) 0·99 (0·97–1·01) 0·92 (0·87–0·98) Female 1 1 1 1 Age 16–19 years 0·74 (0·60–0·92) 0·80 (0·66–0·97) 0·70 (0·56–0·87) 0·41 (0·29–0·59) 20–29 years 0·74 (0·68–0·81) 0·79 (0·73–0·86) 0·91 (0·88–0·94) 0·53 (0·47–0·60) 30–39 years 0·92 (0·87–0·98) 0·93 (0·88–0·99) 0·96 (0·95–0·97) 0·82 (0·75–0·91) 40–49 years 1·00 (0·95–1·06) 0·97 (0·92–1·02) 0·97 (0·96–0·99) 0·94 (0·86–1·03) 50–59 years 1·01 (0·96–1·06) 1·00 (0·94–1·07) 0·99 (0·98–1·00) 1·00 (0·92–1·09) 60 years and older 1 1 1 1 Relationship status Married 1 1 1 1 Single or never married 0·92 (0·89–0·95) 0·93 (0·89–0·96) 0·97 (0·95–0·98) 0·83 (0·78–0·87) Widowed, divorced, or separated 1·01 (0·97–1·06) 1·00 (0·95–1·05) 1·00 (0·98–1·02) 1·01 (0·93–1·10) Time spent away from community in the past 12 months None 1 1 1 1 <1 week 0·96 (0·93–0·99) 0·97 (0·94–1·00) 0·99 (0·97–1·01) 0·92 (0·87–0·97) 1–2 weeks 0·98 (0·92–1·03) 0·94 (0·89–1·00) 0·99 (0·96–1·02) 0·91 (0·84–0·97) 3–4 weeks 0·94 (0·90–0·99) 0·99 (0·95–1·03) 0·99 (0·97–1·02) 0·93 (0·86–1·00) 5–12 weeks 0·95 (0·88–1·02) 0·98 (0·92–1·04) 0·97 (0·93–1·00) 0·90 (0·81–0·99) >12 weeks 0·83 (0·71–0·97) 0·98 (0·88–1·09) 0·96 (0·90–1·03) 0·78(0·64–0·95) Education Non-formal 1 1 1 1 Primary 0·99 (0·95–1·03) 0·96 (0·93–1·00) 1·00 (0·99–1·01) 0·95 (0·90–1·01) Junior secondary 0·95 (0·92–0·98) 0·93 (0·90–0·96) 0·97 (0·96–0·99) 0·86 (0·81–0·91) Senior secondary 0·83 (0·76–0·90) 0·91 (0·85–0·97) 0·94 (0·90–0·99) 0·71 (0·63–0·79) Higher than senior secondary 0·88 (0·83–0·94) 0·95 (0·90–1·00) 0·97 (0·94–1·00) 0·81 (0·73–0·89) Employment status Employed 1 1 1 1 Unemployed, looking for work 1·05 (1·01–1·09) 0·99 (0·96–1·01) 1·00 (0·98–1·01) 1·03 (0·96–1·09) Unemployed, not looking for work‡ 1·04 (1·00–1·08) 1·03 (0·99–1·06) 0·99 (0·97–1·01) 1·06 (1·00–1·12) Monthly income§ None 1 1 1 1 <$96 0·99 (0·96–1·02) 1·00 (0·96–1·03) 1·00 (0·98–1·02) 0·99 (0·93–1·05) $96 to $477 0·96 (0·93–0·99) 1·02 (0·99–1·06) 1·01 (1·00–1·03) 1·00 (0·94–1·05) >$477 0·90 (0·83–0·97) 1·06 (0·99–1·13) 0·94 (0·88–1·01) 0·88 (0·75–1·03)

Data are prevalence ratio (95% CI). ART=antiretroviral therapy. *Virologically suppressed deﬁ ned as HIV viral load of 400 copies per mL or less. †HIV viral load not available for eight participants on ART and two participants naive to ART due to missing specimens. ‡Unemployed and not looking for work includes participants reporting housewife, student, and retired as the primary reason for unemployment. §Botswana pula (BWP) were converted to US$ based on a rate of BWP10·49 per US$1.

Table 3: Univariable prevalence ratios and 95% CIs for the association between baseline sociodemographic characteristics and achievement of the UNAIDS 90-90-90 goals individually and overall coverage estimates increase for treatment (88·7%) and an overall target estimate of 69·8% (95% CI 67·1–72·6) virological suppression (96·5%); and 71·3% of HIV- and 63·4% (61·6–65·1), respectively (table 2). Finally, infected people would have achieved the overall 90-90- when we assumed that HIV prevalence was 50% higher 90 target. and knowledge of HIV status, ART coverage, and We did three sensitivity analyses to examine the virological suppression were each 25% lower in non- potential impact of selection bias resulting from either participants than what was recorded among enrolled non-participation among enumerated eligible residents participants, the overall target estimate was 63·6% or diﬀ erences between our enumerated sample and (95% CI 60·1–67·0). Botswana’s general population. Adjustment by inverse- Male gender, younger age, being single or never probability weighting and standardisation resulted in married, increased time spent outside the community, www.thelancet.com/hiv Vol 3 May 2016 e227 Articles

and higher levels of education were signifi cantly programme has included virological monitoring for associated with lower levels of coverage for the overall patients on ART since inception, enabling adherence target (table 3). For example, HIV-infected participants assessment and inter ventions. Many of these younger than 30 years were nearly one-half as likely to approaches could be adopted by other countries and know their status, be on ART, and achieve viral programmes. suppression compared with those 60 years or older. High rates of treatment coverage and virological Similarly, spending longer than 12 weeks outside the suppression should help reduce HIV incidence. community and having higher than senior secondary However, the most recent estimate of annual adjusted education were each associated with about a 20% lower HIV incidence in Botswana (1·35% in 2013) indicates likelihood of meeting the overall target (table 3). substantial ongoing transmission.19 This incidence is presumably a result of ongoing transmission from the Discussion 30% of HIV-infected people who remain untreated in We found very high levels of diagnosis, treatment, and this setting of high HIV prevalence; furthermore, these viral suppression among HIV-infected individuals in data (and the 90-90-90 targets) do not capture the our study population: 83·3% of HIV-infected people complexities of sexual networks, risk behaviour knew their positive status, 87·4% of these individuals patterns, and biological factors that also contribute to were receiving ART, and 96·5% of people receiving ongoing HIV transmission. Nevertheless, in totality, ART had virological suppression. Overall, 70·2% of all evidence from this and other studies suggests that HIV-infected people had virological suppression, universal ART (irrespective of CD4 count), as recently compared with the UNAIDS goal of 73%. Younger age recommended by WHO,23 will be important in lowering was the strongest predictor of being undiagnosed, not new infections. on ART, and not virologically suppressed in our The main strength of this analysis is that it draws population, followed by more time spent outside the upon a large population-based random sample of community (>12 weeks per year). Women were more household residents from 30 geographically and likely to know their positive HIV status than men, ethnically diverse communities across Botswana. potentially as a result of near universal testing of Routinely collected programmatic data cannot provide pregnant women in Botswana.20 the actual number of people living with HIV. Rather, Very few countries, including those in North America the number is usually estimated indirectly from and Europe, have achieved similarly high coverage. In population distributions and HIV prevalence. Similarly, recent national-level analysis of HIV treatment cascades programmatic data generally cannot directly estimate by Levi and colleagues,21 no country met the overall the numbers of HIV-infected individuals who have UNAIDS goal of 73% virological suppression among been diagnosed with HIV. We were able to collect data people living with HIV. It might be informative for on both of these indicators, and to test for virological countries and programmes to assess their success in suppression in more than 99% of HIV-infected reaching the 90-90-90 targets, even if they have not yet participants; viral load information is infrequently moved to universal testing and treatment. available in resource-constrained settings. Several factors probably contribute to Botswana’s Our study has several limitations. First, about 25% of successful HIV treatment programme. Botswana was potentially inhabited households were not enumerated, among the fi rst high-HIV-burden countries to make and nearly 20% of age-eligible and residency-eligible prevention of mother-to-child transmission services members of enumerated households were not enrolled. (starting in 2000) and ART (starting in 2002 with Botswana has a highly mobile population, and the most expansion nationwide by 2006) available to citizens for common reasons for non-participation were free. There has been a strong political will to speak absenteeism and refusal. People not found in the openly about HIV in public forums and destigmatise household might diff er from enrolled participants with HIV testing. In 2004, former Botswana President respect to diagnosis, treatment, and virological Festus Mogae introduced routine opt-out HIV testing suppression as defi ned by the 90-90-90 targets. For and counselling in health-care settings. According to example, nearly 75% of our participants were female UNAIDS, the lack of widely available testing might compared with 60% of household residents. A weighted constitute the major impediment to achieving high sensitivity analysis accounting for diff erences between ART coverage, particularly in sub-Saharan Africa.1 With enumerated, unenrolled eligible household members a widely dispersed population, Botswana prioritised and enrolled participants did not substantially change early decentralisation of HIV treatment: ART is our fi ndings. Additionally, our estimates were derived available from more than 600 clinics nationwide from smaller rural and periurban communities. alongside other health services. Distance to services is Whether individuals residing in other areas (including correlated with retention in care22 and an estimated urban settings) would have similar HIV testing, 95% of the Botswana population resides within 10 km treatment, and adherence rates is unknown. However, of an ART-dispensing facility. Furthermore, the given earlier and more widespread availability of HIV e228 www.thelancet.com/hiv Vol 3 May 2016 Articles

testing and treatment facilities, we anticipate coverage manuscript and provided comments. KEW, MPH, ME, and SL fi nalised to be higher in urban areas. Furthermore, according to the report based on feedback from other authors. TG, SM, UC, EKY, Botswana national treatment and UNAIDS14 statistics, QL, MM, LO, EvW, KMP, NK, KB, HB, RW, and EJTT collected or prepared the data. KEW, QL, RW, EJTT, and VDG analysed and about 270 000 (about 70%) people believed to be living interpreted the data. TG, MPH, JM, MM, LO, KMP, SD-P, RL, Se-H, with HIV in Botswana are on ART, which is similar to EJTT, VDG, ME, and SL helped provide overall guidance to the conduct the 72·8% estimate in our study population. According of the study. JM, MM, VN, EJTT, VDG, ME, and SL were involved in to the 2013 Botswana AIDS Indicator Survey, the overall the origination and development of the concept of the study. estimated HIV prevalence (ages 6 weeks to 64 years) Declaration of interests VDG reports personal fees from Gilead Sciences for service on data was slightly lower in rural and periurban villages, such monitoring committees, outside the submitted work. SD-P reports as those taking part in the BCPP (17·4–18·7%), than in royalties from UpToDate, Inc, for an article on antiretroviral therapy in cities or towns (19·5–21·6%); overall HIV prevalence lower-to-middle-income countries. The other authors declare no varies by region (11·1–27·5%).19 A sensitivity analysis competing interests. that standardised estimates of 90-90-90 targets to Acknowledgments Botswana’s national HIV-infected population did not This study was supported by the US President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and substantially alter our fi ndings. The overall target Prevention (CDC) under the terms of cooperative agreement estimate after standardisation was 63·4% (95% CI U01 GH000447. Its contents are solely the responsibility of the authors 61·6–65·1), compared with our observed estimate of and do not necessarily represent the offi cial views of CDC. VDG was 70·2% (67·5–73·0). Lastly, our eligibility criteria supported by an NIAID grant number R37 51164. excluded several key populations, including adolescents References 1 UNAIDS. 90-90-90: an ambitious treatment target to help end the and children younger than 16 years, adults aged 65 years AIDS epidemic. Geneva, Switzerland: UNAIDS, 2014. and older, and non-citizens. Given our home-based 2 Danel C, Moh R, Gabillard D, et al. A trial of early antiretrovirals recruit ment approach (which might reach populations and isoniazid preventive therapy in Africa. N Engl J Med 2015; diff erent to those reached by other HIV testing 373: 808–22. 24 3 Lundgren JD, Babiker AG, Gordin F, et al. Initiation of strategies), our study also did not attempt to enrol antiretroviral therapy in early asymptomatic HIV infection. other key populations, such as commercial sex workers. N Engl J Med 2015; 373: 795–807. We estimate that about 2% of enumerated residents 4 Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; were not Botswana citizens. This fi nding might be 365: 493–505. important because non-citizens are ineligible to receive 5 Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 ART free of charge in the country. transmission after initiation of antiretroviral therapy: Despite these limitations, our data are among the a prospective cohort analysis. Lancet 2010; 375: 2092–98. 6 Tanser F, Barnighausen T, Grapsa E, Zaidi J, Newell ML. most complete, population-level estimates available High coverage of ART associated with decline in risk of HIV from the region, and show very high rates of coverage acquisition in rural KwaZulu-Natal, South Africa. Science 2013; related to HIV testing, ART initiation, and virological 339: 966–71. 7 Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens suppression. That Botswana has achieved such high in pregnancy and breast-feeding in Botswana. N Engl J Med 2010; rates of ART coverage and virological suppression is 362: 2282–94. remarkable given that the national CD4 threshold for 8 Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission ART eligibility has been 350 cells per μL or less; this rates, 2000–2011. AIDS 2014; 28: 1049–57. could show a more mature epidemic, and might diff er 9 UNAIDS. The gap report. Geneva, Switzerland: UNAIDS, 2014. in other settings. We found that 95% of HIV-infected 10 Kohler P, Schmidt AJ, Cavassini M, et al. The HIV care cascade in people eligible for ART by current guidelines are Switzerland: reaching the UNAIDS/WHO targets for patients diagnosed with HIV. AIDS 2015; 29: 2509–15. already on ART. These fi ndings suggest that Botswana 11 The Kirby Institute. HIV, viral hepatitis and sexually transmissible should reach and exceed the UNAIDS 90-90-90 targets infections in Australia: annual surveillance report, 2014. sooner than 2020, if treatment eligibility changes to Sydney, Australia: The Kirby Institute for Infection and Immunity in Society, 2014. include ART to all people living with HIV irrespective 12 Bradley H, Hall HI, Wolitski RJ, et al. Vital signs: HIV diagnosis, of their CD4 count, assuming the health system is able care, and treatment among persons living with HIV—United to test and treat those not yet on ART, and that people States, 2011. MMWR Morb Mortal Wkly Rep 2014; 63: 1113–17. 13 Pokrovskaya A, Popova A, Ladnaya N, Yurin O. The cascade of starting ART with higher CD4 counts will have high HIV care in Russia, 2011–2013. J Int AIDS Soc 2014; 17: 19506. levels of adherence. 14 UNAIDS. Botswana: HIV and AIDS estimates (2014). Geneva, Although Botswana is a middle-income country with Switzerland: UNAIDS. http://www.unaids.org/en/regions a total population of about 2 million, it has suff ered countries/countries/botswana (accessed Dec 18, 2015). 15 Botswana Central Statistics Offi ce. Botswana 2011 population and from a very substantial burden of HIV disease. The housing census. Gaborone, Botswana: Botswana Central Statistics high rates of HIV testing, ART, and virological Offi ce, 2011. suppression in Botswana provide good evidence that 16 Yelland LN, Salter AB, Ryan P. Performance of the modifi ed Poisson regression approach for estimating relative risks from the UNAIDS targets are achievable elsewhere. clustered prospective data. Am J Epidemiol 2011; 174: 984–92. Contributors 17 Horvitz DG, Thompson DJ. A generalization of sampling without TG, KEW, MPH, ME, and SL prepared the fi rst draft. KEW, MPH, SM, replacement from a fi nite universe. J Am Stat Assoc 1952; EKY, VN, EvW, KMP, HB, SD-P, LAM, TM, and EJTT reviewed the 41: 663–85.

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18 Robins JM, Rotnitzky A, Zhao LP. Estimation of regression 22 Siedner MJ, Lankowski A, Tsai AC, et al. GPS-measured distance coeﬃ cients when some regressors are not always observed. to clinic, but not self-reported transportation factors, are J Am Stat Assoc 1994; 89: 846–66. associated with missed HIV clinic visits in rural Uganda. AIDS 19 Statistics Botswana. Botswana AIDS impact survey (BAIS) IV. 2013; 27: 1503–08. Gaborone, Botswana: Statistics Botswana, 2013. 23 WHO. Consolidated guidelines on the use of antiretroviral drugs 20 Dryden-Peterson S, Lockman S, Zash R, et al. for treating and preventing HIV infection: what’s new. Initial programmatic implementation of WHO option B in November 2015. Geneva, Switzerland: World Health Organization, Botswana associated with increased projected MTCT. 2015. J Acquir Immune Deﬁ c Syndr 2015; 68: 245–49. 24 Sharma M, Ying R, Tarr G, Barnabas R. Systematic review and 21 Levi JRA, Pozniak A, Vernazza P, Kohler P, Hill A. Can the meta-analysis of community and facility-based HIV testing to UNAIDS 90-90-90 target be achieved? Analysis of 12 national level address linkage to care gaps in sub-Saharan Africa. Nature 2015; HIV treatment cascades. 8th IAS Conference on HIV 528: S77–85. Pathogenesis, Treatment and Prevention; Vancouver, Canada; July 19–22, 2015. Abstract MOAD0102.

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