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      Cross-sectional estimates revealed high HIV incidence in Botswana rural communities in the era of successful ART scale-up in 2013-2015

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          Abstract

          Background

          Botswana is close to reaching the UNAIDS “90-90-90” HIV testing, antiretroviral treatment (ART), and viral suppression goals. We sought to determine HIV incidence in this setting with both high HIV prevalence and high ART coverage.

          Methods

          We used a cross-sectional approach to assessing HIV incidence. A random, population-based sample of adults age 16–64 years was enrolled in 30 rural and peri-urban communities as part of the Botswana Combination Prevention Project (BCPP), from October 2013 –November 2015. Data and samples from the baseline household survey were used to estimate cross-sectional HIV incidence, following an algorithm that combined Limiting-Antigen Avidity Assay (LAg-Avidity EIA), ART status (documented or by testing ARV drugs in plasma) and HIV-1 RNA load. The LAg-Avidity EIA cut-off normalized optical density (ODn) was set at 1.5. The HIV-1 RNA cut-off was set at 400 copies/mL. For estimation purposes, the Mean Duration of Recent Infection was 130 days and the False Recent Rate (FRR) was evaluated at values of either 0 or 0.39%.

          Results

          Among 12,610 individuals participating in the baseline household survey, HIV status was available for 12,570 participants and 3,596 of them were HIV positive. LAg-Avidity EIA data was generated for 3,581 (99.6%) of HIV-positive participants. Of 326 participants with ODn ≤1.5, 278 individuals were receiving ART verified through documentation and were considered to represent longstanding HIV infections. Among the remaining 48 participants who reported no use of ART, 14 had an HIV-1 RNA load ≤400 copies/mL (including 3 participants with ARVs in plasma) and were excluded, as potential elite/viremic controllers or undisclosed ART. Thus, 34 LAg-Avidity-EIA-recent, ARV-naïve individuals with detectable HIV-1 RNA (>400 copies/mL) were classified as individuals with recent HIV infections. The annualized HIV incidence among 16–64 year old adults was estimated at 1.06% (95% CI 0.68–1.45%) with zero FRR, and at 0.64% (95% CI 0.24–1.04%) using a previously defined FRR of 0.39%. Within a subset of younger individuals 16–49 years old, the annualized HIV incidence was estimated at 1.29% (95% CI 0.82–1.77%) with zero FRR, and at 0.90% (95% CI 0.42–1.38%) with FRR set to 0.39%.

          Conclusions

          Using a cross-sectional estimate of HIV incidence from 2013–2015, we found that at the time of near achievement of the UNAIDS 90-90-90 targets, ~1% of adults (age 16–64 years) in Botswana’s rural and peri-urban communities became HIV infected annually.

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          Most cited references38

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          HIV Infection and AIDS in Sub-Saharan Africa: Current Status, Challenges and Opportunities

          Global trends in HIV infection demonstrate an overall increase in HIV prevalence and substantial declines in AIDS related deaths largely attributable to the survival benefits of antiretroviral treatment. Sub-Saharan Africa carries a disproportionate burden of HIV, accounting for more than 70% of the global burden of infection. Success in HIV prevention in sub-Saharan Africa has the potential to impact on the global burden of HIV. Notwithstanding substantial progress in scaling up antiretroviral therapy (ART), sub-Saharan Africa accounted for 74% of the 1.5 million AIDS related deaths in 2013. Of the estimated 6000 new infections that occur globally each day, two out of three are in sub-Saharan Africa with young women continuing to bear a disproportionate burden. Adolescent girls and young women aged 15-24 years have up to eight fold higher rates of HIV infection compared to their male peers. There remains a gap in women initiated HIV prevention technologies especially for women who are unable to negotiate the current HIV prevention options of abstinence, behavior change, condoms and medical male circumcision or early treatment initiation in their relationships. The possibility of an AIDS free generation cannot be realized unless we are able to prevent HIV infection in young women. This review will focus on the epidemiology of HIV infection in sub-Saharan Africa, key drivers of the continued high incidence, mortality rates and priorities for altering current epidemic trajectory in the region. Strategies for optimizing the use of existing and increasingly limited resources are included.
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            Estimation of HIV incidence in the United States.

            Incidence of human immunodeficiency virus (HIV) in the United States has not been directly measured. New assays that differentiate recent vs long-standing HIV infections allow improved estimation of HIV incidence. To estimate HIV incidence in the United States. Remnant diagnostic serum specimens from patients 13 years or older and newly diagnosed with HIV during 2006 in 22 states were tested with the BED HIV-1 capture enzyme immunoassay to classify infections as recent or long-standing. Information on HIV cases was reported to the Centers for Disease Control and Prevention through June 2007. Incidence of HIV in the 22 states during 2006 was estimated using a statistical approach with adjustment for testing frequency and extrapolated to the United States. Results were corroborated with back-calculation of HIV incidence for 1977-2006 based on HIV diagnoses from 40 states and AIDS incidence from 50 states and the District of Columbia. Estimated HIV incidence. An estimated 39,400 persons were diagnosed with HIV in 2006 in the 22 states. Of 6864 diagnostic specimens tested using the BED assay, 2133 (31%) were classified as recent infections. Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56,300 (95% confidence interval [CI], 48,200-64,500); the estimated incidence rate was 22.8 per 100,000 population (95% CI, 19.5-26.1). Forty-five percent of infections were among black individuals and 53% among men who have sex with men. The back-calculation (n = 1.230 million HIV/AIDS cases reported by the end of 2006) yielded an estimate of 55,400 (95% CI, 50,000-60,800) new infections per year for 2003-2006 and indicated that HIV incidence increased in the mid-1990s, then slightly declined after 1999 and has been stable thereafter. This study provides the first direct estimates of HIV incidence in the United States using laboratory technologies previously implemented only in clinic-based settings. New HIV infections in the United States remain concentrated among men who have sex with men and among black individuals.
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              Quantitative detection of increasing HIV type 1 antibodies after seroconversion: a simple assay for detecting recent HIV infection and estimating incidence.

              We have devised a simple enzyme immunoassay (EIA) that detects increasing levels of anti-HIV IgG after seroconversion and can be used for detecting recent HIV-1 infection. Use of a branched peptide that included gp41 immunodominant sequences from HIV-1 subtypes B, E, and D allowed similar detection of HIV-specific antibodies among various subtypes. Because of the competitive nature of the capture EIA, a gradual increase in the proportion of HIV-1-specific IgG in total IgG was observed for 2 years after seroconversion. This was in contrast to results obtained with the conventional EIA using the same antigen in solid phase, which plateaus soon after seroconversion. The assay was used to test 622 longitudinal specimens from 139 incident infections in the United States (subtype B) and in Thailand (subtypes B and E). The assay was also performed with an additional 8 M urea incubation step to assess the contribution of high-avidity antibodies. Normalized optical density (OD-n) was calculated (ODspecimen/ODcalibrator), using a calibrator specimen. An incremental analysis indicated that a cutoff of 1.0 OD-n and a seroconversion period of 160 days offered the best combination of sensitivity and specificity for classifying incident or long-term infections. The urea step increased the seroconversion period to 180 days with similar sensitivity and specificity. Separate analysis of B and E subtype specimens yielded the same optimal OD-n threshold and similar seroconversion periods. The assay was further validated in African specimens (subtypes A, C, and D) where the observed incidence was within 10% of the expected incidence. This assay should be useful for detecting recent HIV-1 infection and for estimating incidence among diverse HIV-1 subtypes worldwide.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Methodology
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 October 2018
                2018
                : 13
                : 10
                : e0204840
                Affiliations
                [1 ] Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana
                [2 ] Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
                [3 ] Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, Massachusetts, United States of America
                [4 ] Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston Massachusetts, United States of America
                [5 ] Harvard Medical School, Boston, Massachusetts, United States of America
                [6 ] Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [7 ] Botswana Ministry of Health and Wellness, Gaborone, Botswana
                [8 ] Bennett Statistical Consulting, Inc., Ballston Lake, New York, United States of America
                [9 ] Goodtables Data Consulting, Norman, OK, United States of America
                [10 ] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
                [11 ] Departments of Internal Medicine and Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [12 ] U.S. Centers for Disease Control, Atlanta, Georgia, United States of America
                [13 ] Johns Hopkins Hospital, Baltimore, MD, United States of America
                Boston University, UNITED STATES
                Author notes

                Competing Interests: Kara Bennett is employed by Bennett Statistical Consulting, Inc and Jean Leidner was employed by Goodtables Data Consulting. The entities above provided support in the form of salaries for authors Kara Bennett and Jean Leidner, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-3821-4592
                http://orcid.org/0000-0002-9465-8983
                Article
                PONE-D-18-00719
                10.1371/journal.pone.0204840
                6200198
                30356287
                dc25e4bb-1325-4797-9101-86dc65ba6db8

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 8 January 2018
                : 12 September 2018
                Page count
                Figures: 1, Tables: 2, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009054, U.S. President’s Emergency Plan for AIDS Relief;
                Award ID: U01 GH000447
                Award Recipient :
                Funded by: Fogarty International Center (US) and National Institute of Mental Health
                Award ID: D43 TW010543
                Award Recipient :
                Funded by: Wellcome Trust DELTAS Initiatives/Sub-Saharan Africa Network for TB/HIV Research Excellence (SANTHE)
                Award ID: 107752/Z/15/Z
                Award Recipient :
                Funded by: Wellcome Trust DELTAS Initiatives/Sub-Saharan Africa Network for TB/HIV Research Excellence (SANTHE)
                Award ID: 107752/Z/15/Z
                Award Recipient :
                Funded by: Wellcome Trust DELTAS Initiatives/Sub-Saharan Africa Network for TB/HIV Research Excellence (SANTHE)
                Award ID: 107752/Z/15/Z
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: K23AI091434
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R37 AI51164
                Award Recipient :
                This study was supported by the US President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of cooperative agreement U01 GH000447 to SM, SG, TM, MPH, EKY, UC, EVW, TG, MOM, RL, KEW, ETT, JM, SL, JMM, ME, and VN. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies. SM was supported by the Fogarty International Center and National Institute of Mental Health, of the National Institutes of Health under Award Number D43 TW010543. SM, SG and LM were partially funded by Wellcome Trust DELTAS Initiatives/Sub-Saharan Africa Network for TB/HIV Research Excellence (SANTHE) (107752/Z/15/Z). SDP was funded by the National Institutes of Health under the award K23AI091434. RW was supported by R37 AI51164 from the National Institutes of Health. The funders had no role in the study design, data collection and decision to publish, or in the preparation of the manuscript. Additionally, Bennett Statistical Consulting Inc. and Goodtables Data Consulting provided support in the form of salaries for authors KB and JL respectively, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
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                The aggregated data supporting the study results are provided in the manuscript. The de-identified survey data are available from the Botswana Combination Prevention Project Executive Committee for researchers who meet the criteria for access to confidential data. Data requests may be sent to the following emails: mpretori@ 123456hsph.harvard.edu or jmakhema@ 123456bhp.org.bw . Data access can also be made by applying to the Botswana Ministry of Health and Wellness Human Research Development Committee (HRDC). IRB contact: Seeletso Mosweunyane (Head of Health Research Unit, Ministry of Health and Wellness, Botswana; phone: +267-3914467; email: smosweunyane@ 123456gov.bw ).

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