Global, regional and country-level 90–90–90 estimates for 2018: assessing progress towards the 2020 target Background: In 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and partners set the 90–90–90 target for the year 2020: diagnose 90% of all people living with HIV (PLHIV); treat 90% of people who know their status; and suppress the virus in 90% of people on treatment. In 2015, countries began reporting to UNAIDS on progress against 90–90–90 using standard definitions and methods. Methods: We used data submitted to UNAIDS from 170 countries to assess country-specific progress towards 90–90–90 through 2018. To assess global and regional progress, overall and by sex for adults 15 years and older, we combined country-reported data with estimates generated with a Bayesian hierarchical model. Results: A total of 60 countries reported on all three 90s in 2018, up from 23 in 2015. Among all PLHIV worldwide, 79% (67–92%) knew their HIV status. Of these, 78% (69–82%) were accessing treatment and 86% (72–92%) of people accessing treatment had suppressed viral loads. Of the 37.9 million (32.7–44.0 million) PLHIV worldwide, 53% (43–63%) had suppressed viral loads. The gap to fully achieving 73% of PLHIV with suppressed viral load was 7.7 million; 15 countries had already achieved this target by 2018. Conclusion: Increased data availability has led to improved measures of country and global progress towards the 90–90–90 target. Although gains in access to testing and treatment continue, many countries and regions are unlikely to reach 90–90–90 by 2020. Correspondence to Kimberly Marsh, Please check the current corresponding author information for correctness.Department of Strategic Information, The Joint United Nations Programme on HIV/AIDS (UNAIDS), 20 Avenue Appia, Geneva 27, Switzerland. E-mail: Marshk@unaids.org Received 5 April, 2019 Accepted 20 August, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2019 Wolters Kluwer Health, Inc.

Decreased HIV-associated mortality rates during scale-up of antiretroviral therapy, 2011–2016: a population-based cohort study Objective: HIV-associated mortality rates in Africa decreased by 10%–20% annually in 2003–2011, after the introduction of antiretroviral therapy (ART). We sought to document HIV-associated mortality rates in the general population in Kenya after 2011 in an era of expanded access to ART. Design: We obtained data on mortality rates and migration from a health and demographic surveillance system (HDSS) in Gem, western Kenya, and data for HDSS residents aged 15–64 years from home-based HIV-counseling and testing (HBCT) rounds in 2011, 2012, 2013, and 2016. Methods: Mortality trends were determined among a closed cohort of residents who participated in at least the 2011 round of HBCT. Results: Of 32,467 eligible HDSS residents, 22,688 (70%) participated in the 2011 round and comprised the study cohort. All-cause mortality rates declined from 10.0 (95% confidence interval [CI] 8.4–11.7) per 1000 in 2011 to 7.4 (95% CI 5·7–9·0) in 2016, while the mortality rate was stable among HIV-uninfected residents, at 5.7 per 1000 person-years. Among HIV-infected residents, mortality rates declined from 30.5 per 1000 in 2011 to 15.9 per 1000 in 2016 (average decline, 6% per year). The HIV-infected group receiving ART had higher mortality rates than the HIV-uninfected group (adjusted rate ratio (aRR), 2.8; 95% CI 2.2–3.4), as did the HIV-infected group who did not receive ART (aRR, 5.3; 95% CI 4.5–6.2). Conclusions: Mortality rates among HIV-infected individuals declined substantially during ART expansion between 2011 and 2016, though less than during early ART introduction. Mortality trends among HIV-infected populations are critical to understanding epidemic dynamics. Correspondence to Emily Zielinski-Gutierrez, CDC-Kenya, c/o KEMRI Headquarters, Mbagathi Road off Mbagathi Way, Nairobi, Kenya. E-mail: ebz0@cdc.gov Received 12 May, 2019 Revised 7 August, 2019 Accepted 13 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

MicroRNA biomarkers associated with type 1 myocardial infarction in HIV positive individuals Objective: Individuals with HIV suffer a higher burden of cardiovascular diseases. Traditional cardiovascular risk scores consistently underestimate cardiovascular risk in this population. Subsets of microRNAs (miRNAs) are differentially expressed among individuals with cardiovascular disease and individuals infected with HIV. However, no study has clarified whether specific miRNAs may be biomarkers for cardiovascular disease in individuals with HIV. Design/Methods: We compared the miRNA expression profiles of 34 HIV positive individuals who had experienced clinically adjudicated Type I myocardial infarctions (MI) with the profiles of 76 HIV positive controls matched by traditional cardiovascular risk factors and HIV-specific measures. Using the elastic net algorithm, we selected miRNAs most strongly associated with incident MI and then used conditional Cox proportional hazards regression and cross-validation to evaluate miRNAs and their association with incident MI. We evaluated whether miRNA markers would improve risk classification relative to the Framingham Risk Score. Results: Higher miR-125a-5p and miR-139-5p expression levels were each associated with increased risk of developing MI after adjustment for Framingham Risk Score and HIV-related factors (HR 2.43, p = 0.018; HR 2.13, p = 0.048, respectively). Compared to the Framingham Risk Score alone, adding expression levels of miR-125a-5p or miR-139-5p resulted in an integrated discrimination improvement of 10.1% or 5.8% respectively. Conclusions: MiR-125a-5p and miR-139-5p, transcripts known to be differentially expressed in HIV positive individuals, may serve as unique biomarkers predictive of cardiovascular disease in these patients and may help clarify processes due to HIV infection that contribute to cardiovascular pathology in this population. Correspondence to Neal Yuan, 505 Parnassus Avenue Suite M987, San Francisco, CA 94143-0119. E-mail: Neal.Yuan@cshs.org Received 27 May, 2019 Revised 13 August, 2019 Accepted 18 August, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.

High Incidence of tuberculosis in the first year of antiretroviral therapy in the Botswana National ART programme between 2011 and 2015 Objective: Tuberculosis (TB) remains one of the leading causes of mortality and morbidity among people living with HIV. We sought to estimate the incidence of TB in a national database of HIV-infected patients receiving antiretroviral therapy (ART) in Botswana. Design: A retrospective analysis of HIV-infected adult patients (≥18years) who initiated ART between 2011 and 2015 in the Botswana ART program. Methods: Multivariable analysis using Cox regression included sex, age, viral load and CD4 counts. Results: Of 45,729 patients, with a median follow-up of 1·7 years Q1, Q3: 0·5,3·1), 1,791 patients developed TB over a median of 1·5 years (Q1, Q3: 0·3,3·1) of follow-up (IR 1·9 per 100 py; 95% CI 1·8–2·0). At baseline, the median CD4+ T-cell count was 272 cells/μl (Q1:Q3 146, 403). The risk of TB was greatest within the first year of ART (IR 2·9 per 100 py; 95% CI 2·7–3·1) and in patients with CD4 counts below 50 cells/μl (IR 8·3/100 py; 95% CI 7·1–9·7). Patients with viral loads above 10,000 copies/ml at 3 months post ART initiation had two-times higher risk of TB, HR 2.5 (95% CI 1·8–2·3). Conclusions: We report a high incidence of TB within the first year of ART and in patients with advanced immunodeficiency. Improved screening strategies and virologic monitoring during this early period on ART, coupled with TB preventative treatment, will reduce the burden of TB. Correspondence to Simani Gaseitsiwe, Botswana-Harvard AIDS Institute Partnership Gaborone & Department of Immunology & Infectious Diseases, Harvard TH Chan School of Public Health, Boston MA. Tel: +2673902671; e-mail: sgaseitsiwe@gmail.com Received 5 June, 2019 Revised 15 August, 2019 Accepted 19 August, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.

Association between HIV antiretroviral therapy and preterm birth based on antenatal ultrasound gestational age determination: a comparative analysis Objective: To evaluate the association between HIV antiretroviral therapy (ART) and preterm birth (PTB), when defined by gold standard antenatal ultrasound versus newborn exam. Design: A secondary analysis of the PROMISE 1077BF/1077FF randomized controlled trial, which compared antiretroviral strategies to reduce perinatal HIV transmission and improve maternal health. The trial used newborn exam (i.e., New Ballard Score, NBS) to assess gestational age. This analysis included liveborn singleton pregnancies with both newborn exam and ultrasound data. The primary exposure was the trial's antiretroviral strategies: 1) zidovudine plus intrapartum nevirapine (“ZDV alone”); 2) zidovudine/lamivudine/lopinavir–ritonavir (“ZDV-based ART”); or 3) tenofovir/emtricitabine/lopinavir–ritonavir (“TDF-based ART”). The primary outcome was PTB < 37 and <34 weeks based on the gold standard of ultrasound dating. We evaluated the association between antiretroviral strategy and PTB. We fit multivariable logistic regression models, adjusting for maternal characteristics, obstetric history, and HIV disease severity. Results: Among 720 assessed pregnant women, PTB<37 weeks was 15.4% by NBS and 18.3% by ultrasound. The NBS was specific but not sensitive for PTB<37 weeks (92.0% and 48.5%). Women receiving ZDV- and TDF-based ART had significantly higher odds of PTB<37 by ultrasound compared to ZDV alone (AORs: 1.68; 95% CI: 1.10 to 2.57, and 2.71; 95% CI: 1.39 to 5.29), as well as for PTB<34 weeks. These results held for ultrasounds performed<24 weeks, and were generally consistent with prior analyses from the PROMISE trial using the NBS. Conclusions: Women starting HIV ART in pregnancy remained at higher risk of PTB when determined by ultrasound, consistent with prior data using newborn exam. However, newborn exam misclassified cases of PTB compared to gold standard ultrasound. Correspondence to Kartik Kailas Venkatesh, MD, PhD, University of North Carolina, Chapel Hill, NC, United States. E-mail: kartik.k.venkatesh@gmail.com Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.

Pharmacokinetic profiles of boosted darunavir, dolutegravir and lamivudine in aging patients enrolled in the Swiss HIV Cohort Study Objectives: The pharmacokinetics (PK) of antiretroviral drugs may differ in elderly people living with HIV (PLWH) due to age related physiological changes. We aimed to assess the PK of several antiretroviral drugs in aging PLWH enrolled in the Swiss HIV Cohort (SHCS). Design: Full PK profiling nested in a multicenter, observational, prospective cohort study. Additional collection of single point PK data during SHCS follow-up visits (unselected PLWH). Methods: PLWH were eligible for the full PK investigation if they were over the age of 55 years, on a stable boosted darunavir- or dolutegravir-containing regimen. Single point measurements were prospectively collected during SHCS follow-up visits to compare antiretroviral drug exposure in aging (≥ 65 years) and younger (< 65 years) PLWH. Results: Nineteen PLWH with a median age of 64 participated to the full PK investigations. Single point PK data were collected for 804 PLWH with a median age of 52. Boosted darunavir clearance was 40% lower in aging (≥ 65 years) compared to younger (< 65 years) PLWH, consistent with other drugs predominantly metabolized by CYP3A. Dolutegravir exposure was similar between age groups whereas lamivudine exposure increased by 11% in aging PLWH. Median boosted darunavir, dolutegravir and lamivudine t1/2 were 148%, 45% and 32% higher in aging compared to younger PLWH. Conclusion: Advanced age did not affect boosted darunavir exposure to a clinically significant extent despite the observed high variability in exposure. Age minimally affected dolutegravir and lamivudine exposure. Thus, dose adjustment based on age is a priori not warranted. Correspondence to Laurent Arthur Decosterd, Service of Clinical Pharmacology, University Hospital of Lausanne and University of Lausanne, Rue du Bugnon 19, CH-1011 Lausanne. Tel: +41 21 314 42 88; fax:+41 21 314 42 72; e-mail: laurentarthur@decosterd@chuv.ch Received 19 July, 2019 Revised 23 August, 2019 Accepted 27 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc.

Delayed GALT reconstitution in duodenum compared to rectum in hiv-infected patients initiating antiretroviral therapy Background: We aimed to characterize the impact of ART initiation on GALT at various sites along the gastrointestinal site. Methodology: Peripheral blood and duodenal and rectal biopsies were obtained from 12 HIV- and 33 treatment-naïve HIV+ subjects at baseline and after 9-months ART. Tissue was digested for immunophenotyping. Inflammatory, bacterial translocation and intestinal damage markers were measured in plasma. Results: Twenty-six HIV+ subjects completed follow-up. The lowest reconstitution of CD4+ T-cells and the lowest CD4/CD8 ratio during ART compared to blood were observed in the duodenum with the rectum being either intermediate or approaching blood levels. Regulatory T-cells (Treg) were in higher proportions in the duodenum than the rectum and neither declined significantly during ART. Several correlations with biomarkers of microbial translocation were observed including increases in LTA levels, which reflects gram-positive bacterial translocation, correlated with increases in %CD4+ T-cells in duodenum (Rho 0.773, P = 0.033), and with decreases duodenal Treg populations (Rho -0.40, P = 0.045). Conclusions: HIV-mediated immunological disruption is greater in the duodenum than rectum and blood before and during ART. Small intestine damage may represent a unique environment for T-cell depletion, which might be attenuated by interaction with gram positive bacteria. Correspondence to David M. Asmuth, University of California Davis Medical Center, Sacramento, CA United States. Tel: +916 734 8695; fax: +916 734 7766; e-mail: dasmuth@ucdavis.edu, Sergio Serrano-Villar, University Hospital Ramón y Cajal, Madrid, Spain. Tel: +34 91 336 8975; e-mail: Sergio.serrano@salud.madrid.org Received 10 February, 2019 Revised 29 May, 2019 Accepted 15 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.

Early diagnosis and risk factors of acute hepatitis c in high-risk men who have sex with men on pre-exposure prophylaxis Background: A high incidence of acute HCV (AHCV) infection has been reported among at-risk HIV-negative Men who have Sex with Men (MSM). The optimal strategy for early diagnosis of AHCV in this population is not clearly defined. Methods: In the ANRS IPERGAY PrEP trial among high risk HIV-negative MSM, HCV serology and serum ALT were used for screening at enrollment and during follow-up. Behavioral risk factors were compared at baseline between participants who were diagnosed with AHCV during the study compared to those who did not. In subjects with a positive HCV serology, we used stored sera to perform the following tests at diagnosis and on previous visits: HCV-antibodies rapid tests, plasma HCV viral load and HCV antigen immunoassay. We evaluated the sensitivity of each test for AHCV diagnosis. Results: Among 429 enrolled participants, 14 were diagnosed with AHCV infection, with a median follow-up of 2.1 (IQR: 1.5–2.8) years. AHCV incidence was 1.40 per 100 person-years (95%CI, 0.74–2.39). Patients with AHCV reported a significantly higher number of sexual acts and/or partners, and more frequent recreational drug use at baseline. At the prior visit before AHCV diagnosis (median of 2 months earlier), sensitivities of HCV RNA and HCV antigen tests were respectively 100% and 89%, whereas none of the patients had a positive serology, and only 25% had elevated ALT. Conclusion: HCV antigen and RNA tests were positive within a median of 2 months before the detection of antibodies and ALT elevation. These tests could be considered for HCV screening in high-risk MSM. Correspondence to Julien Gras, Infectious Diseases Department, APHP-Saint Louis Hospital, 1 avenue Claude Vellefaux, Paris, France. Tel: +33 1 42 49 49 91; fax: +33 1 42 49 90 67; e-mail: julien.gras@aphp.fr, Constance Delaugerre, Virology Department, APHP-Saint Louis Hospital, 1 avenue Claude Vellefaux, Paris, France. Tel: +33 1 42 49 94 93; fax: +33 1 42 49 92 00; e-mail: constance.delaugerre@aphp.fr Received 20 February, 2019 Revised 20 June, 2019 Accepted 29 June, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.

Recently formed age-disparate partnerships are associated with elevated HIV incidence among young women in South Africa Objective: Cross-sectional and cohort studies draw different conclusions on whether age-disparate partnerships increase HIV-acquisition risk for young women. We investigated whether age-disparities were associated with HIV-infection risk early in relationships. This could result in the exclusion of women who seroconverted during high-risk age-disparate partnerships from cohort studies of HIV-incidence – which exclude HIV-positive women – and explain null findings in these studies. Design: Prospective cohort study Methods: We used data on 15–24 year-old, HIV-negative women in heterosexual partnerships (N=830) in KwaZulu-Natal, South Africa. The association between age-disparate partnering (i.e., male partner ≥5 years older) and subsequent HIV-seroconversion was assessed using Cox hazard models. We examined heterogeneity in HIV-acquisition risk by duration of partnership (defined by quartiles) at cohort enrolment. Results: During 1139 person-years (mean: 1.4 years) of follow-up, 54 (6.5%) women seroconverted, a weighted HIV-incidence estimate of 4.41/100 person-years (95% CI 3.30–6.06). HIV-acquisition risk did not differ significantly between women in age-disparate vs. age-similar partnerships (aHR 1.10, 95% CI 0.55–2.21). However, for women in the shortest partnership quartile (<1.09 years) at baseline, risk of HIV-seroconversion was higher for women in age-disparate partnerships (aHR 3.13, 95% CI 1.02–9.65, p = 0.047). HIV-acquisition was not statistically different by partnership type among women in longer partnerships. Conclusions: The association between age-disparate partnerships and HIV-acquisition risk is evident early in young women's relationships. Results provide a potential explanation for null findings in cohort studies, whose research designs may exclude women in such partnerships, and affirms the elevated risk of HIV acquisition for young women in age-disparate relationships. Correspondence to Brendan Maughan-Brown, PhD, Southern Africa Labour and Development Research Unit, University of Cape Town, Private Bag, Rondebosch, 7701, Cape Town, South Africa. Tel: +27-21-650-5695; fax: ++27-21-650-5697; e-mail: brendan.maughanbrown@gmail.com Received 27 March, 2019 Revised 18 July, 2019 Accepted 19 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.

Female genital tract shedding of HIV-1 is rare in women with suppressed HIV-1 in plasma Objective: Determine the frequency of genital HIV-1 shedding in a large cohort of women on long-term suppressive antiretroviral therapy (ART) and its association with mucosal inflammation. Design: We measured levels of HIV-1 RNA and inflammation biomarkers in cervicovaginal lavage (CVL) from HIV-seropositive women enrolled in the Women's Interagency HIV Study (WIHS). Methods: HIV-1 was quantified (Abbott RealTime HIV-1 assay) from CVL samples of 332 WIHS participants with and without clinical evidence of genital inflammation at the time of CVL collection; participants had suppressed plasma viral load (PVL) (limit of quantitation <20-4000 copies/ml depending on year of collection) for a median of 7.1 years (interquartile range=3.4–9.8, Group 1) or for a median of 1.0 years (IQR = 0.5–1.0, Group 2). Twenty-two biomarkers of inflammation were measured in CVL to compare with clinical markers. Results: HIV-1 was detected in 47% of 38 pre-ART CVL samples (median 668 copies/ml) and detection in CVL was associated with higher pre-ART PVL. HIV-1 was detected in only 1 of 38 CVL samples from these women on suppressive antiretroviral therapy for one year. No HIV-1 RNA was detected in 294 CVL samples from a cross-sectional set of women with suppressed PVL for a median of 7 years. Clinical inflammation markers were correlated with inflammatory biomarkers in CVL specimens, although genital inflammation was not associated with measurable genital HIV-1 shedding in these WIHS participants on ART. Conclusions: ART that suppresses HIV-1 in the plasma of women also prevents genital tract HIV-1 shedding, even in the presence of genital tract inflammation. Correspondence to Julie A.E. Nelson, CB 7295, UNC-CH, Chapel Hill, NC 27599. e-mail: jnelson@med.unc.edu Received 27 March, 2019 Revised 24 June, 2019 Accepted 27 June, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.