Cost-effectiveness analysis of alternative screening strategies for the detection of cervical cancer among women in rural areas of Western Kenya.

While the incidence of cervical cancer has dropped in high-income countries due to organized cytology-based screening programs, it remains the leading cause of cancer death among women in Eastern Africa. Therefore, the World Health Organization (WHO) now urges providers to transition from widely prevalent but low-performance visual inspection with acetic acid (VIA) screening to primary human papillomavirus (HPV) DNA testing. Due to high HPV prevalence, effective triage tests are needed to identify those lesions likely to progress and so avoid over-treatment. To identify the optimal cost-effective strategy, we compared the VIA screen-and-treat approach to primary HPV DNA testing with p16/Ki67 dual-stain cytology or VIA as triage. We used a Markov model to calculate the budget impact of each strategy with incremental quality-adjusted life years and incremental cost-effectiveness ratios (ICER) as the main outcome. Deterministic cost-effectiveness analyses show that the screen-and-treat approach is highly cost-effective (ICER 2469 Int$), while screen, triage, and treat with dual staining is the most effective with favorable ICER than triage with VIA (ICER 9943 Int$ compared with 13,177 Int$). One-way sensitivity analyses show that the results are most sensitive to discounting, VIA performance, and test prices. In the probabilistic sensitivity analyses, the triage option using dual stain is the optimal choice above a willingness to pay threshold of 7115 Int$ being cost-effective as per WHO standards. The result of our analysis favors the use of dual staining over VIA as triage in HPV-positive women and portends future opportunities and necessary research to improve the coverage and acceptability of cervical cancer screening programs.

Exploring computer-aided health decision-making on cervical cancer interventions through deliberative interviews in Ethiopia.

Cervical cancer is a significant disease burden in Ethiopia. Mathematical models and computer simulations on disease dynamics can support effective resource allocation. The objectives of this work are (i) to explore the perspectives of health decision-makers on computer-aided predictions supporting cervical cancer interventions, (ii) to identify their information needs from these predictions, and (iii) their willingness to apply the results in their work. We conducted deliberative interviews with 15 health decision-makers and advisors in Ethiopia in autumn 2019. We analyze the data using a five steps framework approach drawing on thematic analysis and find that Ethiopian health decision-makers are willing to use computer-aided predictions in their decisions. Data on HPV prevalence and the cervical cancer burden are scarce but valued highly and decision-makers are particularly interested in the identification of local HPV hotspots. Data-driven mathematical models and computer simulations may increasingly influence health decision-making in Ethiopia.

International cooperation to fight cancer's late-stage presentation in low- and middle-income countries.

Cancer is becoming a massive public health burden in low- and middle-income countries (LMIC). 70% of all cancer deaths globally are attributed to LMIC while the incidence proportion is below 60%. The main reason for the higher mortality rate is "late-stage presentation" of patients with stage III or IV diseases when being diagnosed. Main reasons for this are limited (financial) resources, poor knowledge of health service provider about cancer, misbelieves and fear among patients as well as low health literacy rate. During the 1st International Conference on Hospital Partnerships, conducted by the German Agency for International Cooperation (GIZ), cancer specialists from seven LMIC and Germany discussed opportunities, challenges and solutions of the development of cancer services. Two days of in-depths discussion identified five topics to be playing a key role in the effort to reduce the cancer burden in LMIC: Health Policy & Financing, Barriers to Access, Capacity Building, Cancer Registries and Adapted Treatment Guidelines. By using mind-mapping technique, stakeholders, core topics, main and important topics were visualized and interconnections displayed. Many topics can be addressed through international cooperations but political willingness and commitment in the respective countries plays the crucial role. An essential contribution will be to assist policy makers in formulating and endorsing affordable and effective health policies. Another lesson learned from this workshop is the similarity of challenges among the participating representatives from different LMIC. The authors of this letter emphasize on the importance of building international long-term cooperations to advance oncology care on a global scale.

Accuracy of HPV testing on self-collected and clinician-collected samples for different screening strategies in African settings: A systematic review and meta-analysis.

OBJECTIVES: Cervical cancer still poses a considerable threat to women in low- and middle-income countries, particularly on the African continent. Self-collection of a vaginal sample promises advantages over the established sampling by clinicians. We aimed to assess the accuracy of self-sampling compared to clinician sampling in order to inform its application in primary care in the African context. METHODS: We searched Pubmed, Livivo, Web of Science, Cochrane Library and African Index Medicus on the 07th of February 2022. The eligibility criteria were: reporting (i) self-sampling against clinician-sampling, (ii) study location in Africa, (iii) relevant outcome-measures: (a) Cohen's kappa (b) sensitivity and specificity of self-sampling tests. We combined Cohen's kappa effects, additionally sensitivity and specificity estimates using random-effects models. The study is registered with PROSPERO (CRD42020218081). RESULTS: We included 28 studies in the systematic review and 21 studies in the meta-analysis. Self-sampling was used to test for high-risk HPV infections. Two studies additionally tested for low-risk HPV infections. The pooled Cohen's kappa was 0.66 (95%CI: 0.61-0.71). Populations at risk yielded 0.63 (95%CI: 0.56-0.71). Target amplification tests based on PCR performed best with a kappa of 0.68 (95%CI: 0.63-0.73) compared to isothermal mRNA tests, 0.61 (95%CI: 0.51-0.71). Point of care tests performed exceptionally well, 0.73 (95%CI: 0.67-0.80). Sensitivities are close to 80% and specificities close to 90% of self-sampling to detect high-risk HPV. CONCLUSIONS: Self-sampling agrees moderately to substantially with clinician sampling in the African context. Point of care tests might be particularly suited for application in cervical cancer primary screening in low- and middle-income countries. Populations at risk should get special attention while using self-sampling. Screening protocols should be established.

Community cervical cancer screening: Barriers to successful home-based HPV self-sampling in Dabat district, North Gondar, Ethiopia. A qualitative study.

OBJECTIVE: To explore the barriers to successful home-based human papillomavirus (HPV) self-sampling in North Gondar, Ethiopia. METHODS: The study participants were women who had previously participated in a community-wide home-based HPV self-sampling pilot study, community health workers, women's development army leaders, and the sample collectors of the home-based HPV self-sampling pilot study. A community based qualitative descriptive study was conducted. We applied purposive and convenience sampling. In total, 47 women participated in the study (in-depth interviews n = 22, four focus group discussions n = 25, 6-7 participants each). The study employed thematic analysis for clustering the emerged themes. RESULTS: Husband disapproval was identified as the main barrier to the acceptance of home-based HPV self-sampling. Social influence, lack of knowledge about cervical cancer and screening, lack of health education on cervical cancer and HPV-based screening, feeling healthy, and religious influence were identified as additional barriers. Fear of using Evalyn brush® for self-sampling was found to be the main barrier to the provision of a quality sample. The inability of the sample collectors to check the proper utilization of Evalyn brush® and the difficulty in understanding the instructions did also contribute to the low-quality. Providing health education concerning cervical cancer and HPV self-sapling to women, male involvement in the screening program, and linking the screening service to existing local health facilities were suggested to guarantee the success of home-based HPV self-sampling. CONCLUSIONS: Educating women regarding cervical cancer and HPV testing, providing clear instructions on how to collect self-sample, and male involvement in the screening program are prerequisites for a successful implementation of home-based HPV testing. Women empowerment should also be focused to overcome the identified sociocultural barriers. Furthermore, the screening program should guarantee the timely provision of the test results and offering women follow-up examinations and treatment for abnormal findings.

Novel concepts in cervical cancer screening: a comparison of VIA, HPV DNA test and p16INK4a/Ki-67 dual stain cytology in Western Kenya.

BACKGROUND: Screening of unvaccinated women remains essential to mitigate the high morbidity/mortality of cervical cancer. Here, we compared visual inspection with acetic acid (VIA), recommended by WHO as the most cost-effective screening approach in LMICs, with HPV-based screening, and usage of p16INK4a/Ki-67 dual stain cytology. METHODS: We prospectively enrolled women participating in a VIA-based cervical cancer screening program in two peri-urban health centers of Kenya. Consenting women had a VIA examination preceded by collection of a liquid-based cytology sample from the cervix stored in PreservCyt medium (Hologic®). Analysis of all samples included a hrHPV DNA test and evaluation of a p16INK4a /Ki-67 (CINtecPLUS®) dual stained slide that was prepared using the ThinPrep® 2000 Processor and evaluated by a pathologist trained in the methodology. RESULTS: In 701 of a total of 800 women aged 18-64 years, all three investigations were performed and data could be analyzed. The HPV, VIA and dual stain cytology positivity were 33%, 7%, and 2% respectively. The HPV positivity rate of VIA positive cases was 32%. The five most common HPV types were HPV16, 52, 68, 58 and 35. The OR among HIV infected women of an HPV infection, VIA positivity and positive dual stain cytology were 2.6 (95%CI 1.5-4.3), 1.9 (95%CI 0.89-4.4) and 3.4 (95%CI 1.07-10.9) respectively. The sensitivity of VIA to detect a p16INK4a/Ki-67 positive transforming infection was 13% (95%CI 2-38). CONCLUSIONS: Primary HPV testing appears feasible and should be considered as a primary screening test also in LMICs. The poor sensitivity of VIA renders it unsuitable as a triage test for HPV positive women. The utility of p16INK4a/Ki-67 dual stain cytology as a triage test for HPV positive women in LMICs should be further studied.

Lifetime Prevalence of Cervical Cancer Screening in 55 Low- and Middle-Income Countries.

Importance: The World Health Organization is developing a global strategy to eliminate cervical cancer, with goals for screening prevalence among women aged 30 through 49 years. However, evidence on prevalence levels of cervical cancer screening in low- and middle-income countries (LMICs) is sparse. Objective: To determine lifetime cervical cancer screening prevalence in LMICs and its variation across and within world regions and countries. Design, Setting, and Participants: Analysis of cross-sectional nationally representative household surveys carried out in 55 LMICs from 2005 through 2018. The median response rate across surveys was 93.8% (range, 64.0%-99.3%). The population-based sample consisted of 1 136 289 women aged 15 years or older, of whom 6885 (0.6%) had missing information for the survey question on cervical cancer screening. Exposures: World region, country; countries' economic, social, and health system characteristics; and individuals' sociodemographic characteristics. Main Outcomes and Measures: Self-report of having ever had a screening test for cervical cancer. Results: Of the 1 129 404 women included in the analysis, 542 475 were aged 30 through 49 years. A country-level median of 43.6% (interquartile range [IQR], 13.9%-77.3%; range, 0.3%-97.4%) of women aged 30 through 49 years self-reported to have ever been screened, with countries in Latin America and the Caribbean having the highest prevalence (country-level median, 84.6%; IQR, 65.7%-91.1%; range, 11.7%-97.4%) and those in sub-Saharan Africa the lowest prevalence (country-level median, 16.9%; IQR, 3.7%-31.0%; range, 0.9%-50.8%). There was large variation in the self-reported lifetime prevalence of cervical cancer screening among countries within regions and among countries with similar levels of per capita gross domestic product and total health expenditure. Within countries, women who lived in rural areas, had low educational attainment, or had low household wealth were generally least likely to self-report ever having been screened. Conclusions and Relevance: In this cross-sectional study of data collected in 55 low- and middle-income countries from 2005 through 2018, there was wide variation between countries in the self-reported lifetime prevalence of cervical cancer screening. However, the median prevalence was only 44%, supporting the need to increase the rate of screening.

Home-based HPV self-sampling assisted by a cloud-based electronic data system: Lessons learnt from a pilot community cervical cancer screening campaign in rural Ethiopia.

Primary HPV testing and triage of HPV-positive women is an effective cervical cancer screening strategy. Such a multi-visit screening algorithm is also promising for community-based screening in resource-poor communities, provided a robust tracking system is in place. A cervical cancer screening campaign was conducted in a rural community in Ethiopia. All women aged 25-65 years were offered genital self-sampling using the Evalyn Brush®. Samples were HPV-DNA-tested at a central laboratory. Key indicators were captured on tablet computers and linked by a cloud-based information system. HPV-positive women were examined at the local clinic using portable colposcopy, p16/Ki-67 dual stain cytology and biopsy examination. CIN2+ women were referred for LEEP to the referral hospital. Of 749 enumerated age-eligible women 634 (85%, (95% CI 82-88)) consented to screening, 429 samples were adequate for HPV testing, giving a total testing coverage of 57% (95% CI 53-62). The hrHPV prevalence was 14% (95% CI 5-22), 72% (95% CI 60-84) attended the clinic for a triage examination. Home-based HPV-DNA self-sampling and clinic-based triage assisted by cloud-based information technology is feasible in rural Ethiopia. Key components of such strategy are broad community awareness, high competency of community workers, and establishment of an adequate self-sampling and HPV-DNA testing platform.

Loop Electrosurgical Excision Procedure Treats Cervical Intraepithelial Neoplasia 2/3 Among HIV- and HIV+ Women in Kenya.

OBJECTIVE: The aim of the study was to compare loop electrosurgical excision procedure (LEEP) as treatment for cervical intraepithelial neoplasia (CIN) 2/3 in HIV- versus HIV+ women. MATERIALS AND METHODS: Seventy-five HIV- and 75 HIV+ women at 6 months or more after LEEP for CIN 2/3 were enrolled between September 2013 and November 2014 in this prospective cohort study at the cervical cancer screening clinic in Eldoret, Kenya. Visual inspection with acetic acid (VIA), followed by cervical cytology with conventional cytology, was performed on all women. Women with positive VIA or abnormal cervical cytology underwent colposcopy/biopsy. Lesion progression, persistence, and regression were assessed to quantify the efficacy of LEEP. RESULTS: Post-loop electrosurgical excision procedure screening test showed both a negative VIA and normal cervical cytology in 64 (85%) of HIV- and 57 (77%) HIV+ women (risk difference = 8.3%, CI = -4.2% to 21%, p = .20). Eleven (15%) HIV- and 17 (23%) HIV+ (p = .20) women had positive VIA, abnormal cervical cytology, or both and were referred for colposcopy/biopsy. Twenty-one (8 HIV-, 13 HIV+) women were biopsied. Of the 8 HIV- women, 4 (50%) had CIN lesions that regressed, 3 (38.0%) persisted, and 1 (12%) progressed to invasive cancer after LEEP. Of the 13 HIV+ women, 6 (46%) had CIN lesions that regressed, 7 (54%) had CIN lesions that persisted, and no HIV+ women had CIN lesions that progressed after LEEP. There was no difference in estimated efficacies of LEEP for HIV- and HIV+ women (92.7% versus 89.4%, risk difference = 3.3%, CI = -4.8% to 15.3%, p = .85). CONCLUSIONS: Loop electrosurgical excision procedure for CIN 2/3 is effective treatment for HIV- and HIV+ women in low-resource settings. Future efforts should improve follow-up after treatment.

Genital self-sampling for HPV-based cervical cancer screening: a qualitative study of preferences and barriers in rural Ethiopia.

BACKGROUND: In the context of WHO's "task shifting" project and growing global consensus on primary HPV-based cervical cancer screening, self-sampling is a promising new tool to expand screening access, uptake and coverage for women worldwide. We aimed to explore perceptions and acceptability of HPV self-sampling-based cervical cancer screening among community members and health professionals in rural northwest Ethiopia and to identify preferences and socio-cultural barriers regarding self-sampling in order to design a suitable high-coverage screening intervention for a rural African setting. METHODS: Four community-based focus group discussions (FGD) were conducted in the rural district of Dabat, Northwest Ethiopia, each comprising 8 to 14 female participants, counting a total of 41 participants. The groups were homogenously composed in terms of their socio-economic status in the community. They included health centre attendees, community members, nurses and health development army leaders (HDAL). Two qualitative data collection experts conducted the interviews in the local language, using a FGD guide with several thematic areas. All participants granted written informed consent prior to the conduct of the interviews. As a concrete example of an existing self-sampling approach for cervical cancer screening we used the Evalyn® Brush. RESULTS: Emerging themes included (i) misconceptions and low awareness about cervical cancer among community residents and primary health care providers in rural northwest Ethiopia, (ii) stigmatization and social exclusion of affected women, (iii) delay in seeking of health care due to poor access and availability of services, and lacking of a concept of early cancer prevention, (iv) need of spousal permission, (v) fear of financial burden and (vi) fear of social marginalization. The self-sampling device was regarded to be acceptable and was judged to be easy to use for most women. The existing Ethiopian health care structure could facilitate a community approach. CONCLUSION: Home-based self-sampling for cervical cancer screening is a socially acceptable and feasible "task shifting" method that will increase cervical cancer screening access and coverage in the Ethiopian study community. Education, awareness creation, community mobilization and family inclusion are identified as key activities to promote, implement and facilitate "task shifting" approaches like self-sampling.

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

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

The effect of micronutrient supplementation on active TB incidence early in HIV infection in Botswana.

BACKGROUND: Coinfection with active tuberculosis (TB) is one of the leading causes of death in people living with HIV (PLWH) in Africa. This investigation explores the role of micronutrient supplementation in preventing active TB in PLWH. METHODS: A randomized trial of nutritional supplementation was conducted among antiretroviral- naïve (without previous antiretroviral treatment [ART]) HIV-infected people in Botswana between 2004 and 2009. The study had a factorial design with four arms: the selenium (Se) alone arm, the multivitamins (MVT) alone arm that contained vitamin B complex and vitamins C and E, the combined Se+MVT group and the placebo group. Those participants with prior or current active TB were excluded, as were participants with advanced HIV disease (CD4 <250 cells/µL) or who had already qualified for ART. HIV-positive adults (N=878) were followed monthly for study pill dispensation, every 3 months for CD4 cell count and every 6 months for viral load during 24 months or until they were started on ART. RESULTS: The participants' characteristics were not significantly different among the four groups at baseline. Supplementation with Se alone (hazard ratio =0.20, 95% confidence interval: 0.04, 0.95, P=0.043) and the two combined SE groups (Se and Se+MVT) had significantly lower risk of developing incident TB disease compared with placebo in multivariate adjusted models (hazard ratio=0.32, 95% confidence interval: 0.11, 0.93, P=0.036). Multivitamins alone did not affect the incidence of TB. Isoniazid preventive therapy was received by 12.2% of participants, a rate that was not significantly different among the four study arms (P=0.122) and the newly diagnosed cases. CONCLUSION: Se supplementation, alone and with MVT, decreased the incidence of TB disease in PLWH who were ART-naïve. Supplementation with these micronutrients should be considered in HIV infection, prior to ART, in areas where TB and malnutrition are endemic.

Genome-Wide Analyses Reveal Gene Influence on HIV Disease Progression and HIV-1C Acquisition in Southern Africa.

Sub-Saharan Africans infected with HIV-1C make up the largest AIDS patient population in the world and exhibit large heterogeneity in disease progression before initiating antiretroviral therapy. To identify host variants associated with HIV disease progression, we performed genome-wide association studies on a total of 556 treatment-naive HIV-infected individuals in Botswana. We characterized the pattern of HIV disease progression using a novel functional principal component analysis, which can better capture longitudinal CD4 and viral load (VL) trajectories. Two single-nucleotide polymorphisms (SNPs) near HCG22 (chr6, peak variant rs2535307, combined p = 3.72 × 10-7, minor allele as risky allele) and CCNG1 (chr5, peak variant kgp22385164, combined p = 1.88 × 10-6, minor allele as risky allele) were significantly associated with CD4 and VL dynamics. Inspection of SNPs in these gene regions in a third Botswana cohort (using GWATCH) also revealed a strong association of HCG22 with HIV-1C acquisition, suggesting that this region is associated with infection as well as disease progression. Our study uncovered two genetic regions that are significant and have specific effects on HIV-1C acquisition or progression in sub-Saharan Africans, and the result suggested new potential targets for AIDS prevention and treatment. In addition, our results also indicate the possibility of using genetic markers as HIV disease progression indicators in sub-Saharan Africans to prioritize fast progressors for antiretroviral treatment.

Short Communication: Low False Recent Rate of Limiting Antigen-Avidity Assay Combined with HIV-1 RNA Data in Botswana.

Cross-sectional estimation of HIV incidence could misclassify some established or chronic HIV infections as recent. Usually long-term nonprogressors, elite and viremic controllers, and individuals on ART contribute to misclassification. Local data on the false recent rate (FRR) could minimize misclassification during estimation of HIV incidence. To improve monitoring of HIV incidence, we estimated local FRR in Botswana. A total of 1,036 specimens from individuals infected for at least 1.5-2 years were sampled between 2004 and 2009 and tested using the limiting antigen (LAg)-avidity assay using a cutoff of 1.5 normalized optical density units. The FRR was 0.97% (10/1,036; 95% confidence interval [CI] 0.46-1.77). Four samples had HIV-1 RNA >1,000 cps/ml, giving an adjusted FRR of 0.39% (4/1,036; 95% CI 0.11-0.99). A combination of LAg and HIV-1 RNA load data resulted in FRR below 1% in the Botswana population.

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

BACKGROUND: HIV programmes face challenges achieving high rates of HIV testing and treatment needed to optimise health and to reduce transmission. We used data from the Botswana Combination Prevention Project study survey to assess Botswana's progress toward achieving UNAIDS targets for 2020: 90% of all people living with HIV knowing their status, 90% of these receiving sustained antiretroviral therapy (ART), and 90% of those having virological suppression (90-90-90). METHODS: A population-based sample of individuals was recruited and interviewed in 30 rural and periurban communities from Oct 30, 2013, to Nov 24, 2015, as part of a large, ongoing community-randomised trial designed to assess the effect of a combination prevention package on HIV incidence. A random sample of about 20% of households in each community was selected. Consenting household residents aged 16-64 years who were Botswana citizens or spouses of citizens responded to a questionnaire and had blood drawn for HIV testing in the absence of documentation of positive HIV status. Viral load testing was done in all HIV-infected participants, irrespective of treatment status. We used modified Poisson generalised estimating equations to obtain prevalence ratios, corresponding Huber robust SEs, and 95% Wald CIs to examine associations between individual sociodemographic factors and a binary outcome indicating achievement of the three individual and combined overall 90-90-90 targets. The study is registered at ClinicalTrials.gov, number NCT01965470. FINDINGS: 81% of enumerated eligible household members took part in the survey (10% refused and 9% were absent). Among 12 610 participants surveyed, 3596 (29%) were infected with HIV, and 2995 (83·3%, 95% CI 81·4-85·2) of these individuals already knew their HIV status. Among those who knew their HIV status, 2617 (87·4%, 95% CI 85·8-89·0) were receiving ART (95% of those eligible by national guidelines, and 73% of all infected people). Of the 2609 individuals receiving ART with a viral load measurement, 2517 (96·5%, 95% CI 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 had virological suppression, close to the UNAIDS target of 73%. INTERPRETATION: UNAIDS 90-90-90 targets are achievable even in resource-constrained settings with high HIV burden. FUNDING: US President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention.

Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis.

Although HIV-1 RNA levels are measured at the time of initial diagnosis, the results are not used for the clinical follow-up of the patients. This study evaluates the prognostic value of the baseline HIV-1 RNA levels (above or below 10,000 copies/ml) on rate of disease progression, among antiretroviral therapy (ART)-naive patients in Botswana. A prospective cohort of 436 HIV-infected ART-naive adults with baseline CD4 > 400 cells/mm(3) were followed quarterly for 5 years in an urban clinic in Botswana. Baseline HIV-1 RNA levels and longitudinal CD4(+) T-cell count data were analyzed, using mixed-effects regression jointly modeled with the times to a composite endpoint defined by AIDS-defining clinical conditions or death. During 1,547 person-years (PYs) follow-up time, 106 individuals became eligible for ART initiation (incidence rate: 0.07 PYs) and 6 participants died of AIDS-related illness. There were 203 (47%) individuals with baseline HIV-1 RNA <10,000 copies/ml and 233 (53%) individuals with baseline RNA >10,000 copies/ml. The slope of the predicted CD4 trajectory for individuals with baseline HIV-1 RNA >10,000 copies/ml is 30% steeper than that for those with baseline RNA <10,000. The hazard of reaching the composite endpoint for the individuals with baseline HIV-1 RNA >10,000 copies/ml was 2.3 (95% confidence interval: 1.5-3.0) times higher than that for those with baseline HIV-1 RNA <10,000 copies/ml. CD4 decline in individuals with HIV-1 RNA >10,000 copies/ml is much faster than that in those with RNA <10,000. The elevated HIV-1 RNA can be used as a marker to identify individuals at risk of faster disease progression.

Estimated age and gender profile of individuals missed by a home-based HIV testing and counselling campaign in a Botswana community.

INTRODUCTION: It would be useful to understand which populations are not reached by home-based HIV-1 testing and counselling (HTC) to improve strategies aimed at linking these individuals to care and reducing rates of onward HIV transmission. METHODS: We present the results of a baseline home-based HTC (HBHTC) campaign aimed at counselling and testing residents aged 16 to 64 for HIV in the north-eastern sector of Mochudi, a community in Botswana with about 44,000 inhabitants. Collected data were compared with population references for Botswana, the United Nations (UN) estimates based on the National Census data and the Botswana AIDS Impact Survey IV (BAIS-IV). Analyzed data and references were stratified by age and gender. RESULTS: A total of 6238 age-eligible residents were tested for HIV-1; 1247 (20.0%; 95% CI 19.0 to 21.0%) were found to be HIV positive (23.7% of women vs. 13.4% of men). HIV-1 prevalence peaked at 44% in 35- to 39-year-old women and 32% in 40- to 44-year-old men. A lower HIV prevalence rate, 10.9% (95% CI 9.5 to 12.5%), was found among individuals tested for the first time. A significant gender gap was evident in all analyzed subsets. The existing HIV transmission network was analyzed by combining phylogenetic mapping and household structure. Between 62.4 and 71.8% of all HIV-positive individuals had detectable virus. When compared with the UN and BAIS-IV estimates, the proportion of men missed by the testing campaign (48.5%; 95% CI 47.0 to 50.0%) was significantly higher than the proportion of missed women (14.2%; 95% CI 13.2 to 15.3%; p<0.0001). The estimated proportion of missed men peaked at about 60% in the age group 30 to 39 years old. The proportions of missed women were substantially smaller, at approximately 28% within the age groups 30 to 34 and 45 to 49 years old. CONCLUSIONS: The HBHTC campaign seems to be an efficient tool for reaching individuals who have never been tested previously in southern African communities. However, about half of men from 16 to 64 years old were not reached by the HBHTC, including about 60% of men between 30 and 40 years old. Alternative HTC strategies should be developed to bring these men to care, which will contribute to reduction of HIV incidence in communities.

Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions­a proxy for recent infection­yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs­K101E, K103N, Y181C, and G190A­accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Evaluation of the false recent classification rates of multiassay algorithms in estimating HIV type 1 subtype C incidence.

Laboratory cross-sectional assays are useful for the estimation of HIV incidence, but are known to misclassify individuals with long-standing infection as recently infected. The false recent rate (FRR) varies widely across geographic areas; therefore, accurate estimates of HIV incidence require a locally defined FRR. We determined FRR for Botswana, where HIV-1 subtype C infection is predominant, using the BED capture enzyme immunoassay (BED), a Bio-Rad Avidity Index (BAI) assay (a modification of the Bio-Rad HIV1/2+O EIA), and two multiassay algorithms (MAA) that included clinical data. To estimate FRR, stored blood samples from 512 antiretroviral (ARV)-naive HIV-1 subtype C-infected individuals from a prospective cohort in Botswana were tested at 18-24 months postenrollment. The following FRR mean (95% CI) values were obtained: BED 6.05% (4.15-8.48), BAI 5.57% (3.70-8.0), BED-BAI 2.25% (1.13-4.0), and a combination of BED-BAI with CD4 (>200) and viral load (>400) threshold 1.43% (0.58-2.93). The interassay agreement between BED and BAI was 92.8% (95% CI, 90.1-94.5) for recent/long-term classification. Misclassification was associated with viral suppression for BED [adjusted OR (aOR) 10.31; p=0.008], BAI [aOR 9.72; p=0.019], and MAA1 [aOR 16.6; p=0.006]. Employing MAA can reduce FRR to <2%. A local FRR can improve cross-sectional HIV incidence estimates.