Jared Baeten

Reversibility of Glomerular Renal Function Decline in HIV-Uninfected Men and Women Discontinuing Emtricitabine-Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis.

Background:Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP) use is associated with a small but statistically significant decline in estimated glomerular filtration rate (eGFR). We investigated the reversibility of eGFR decline among HIV-uninfected adults discontinuing PrEP. Methods:Data were from the Partners PrEP Study, a randomized trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African HIV-uninfected men and women with baseline creatinine clearance ≥60 mL/min. Serum creatinine was measured quarterly while on-study medication and at month 1 and 2 after discontinuation. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation. Results:A total of 3924 individuals had a poststudy drug serum creatinine measurement after the scheduled drug discontinuation (1271 for TDF, 1308 for FTC-TDF, and 1345 for placebo); 65% were men, median age was 35 (range 18–64) years. Median time on study drug was 33 (interquartile range 25–36) months overall, and 36 months (interquartile range 30–36) for TDF and FTC-TDF. Mean eGFR at the last on-treatment visit was 129 mL·min−1·1.73 m−2 for TDF and 128 mL·min−1·1.73 m−2 for FTC-TDF versus 131 mL·min−1·1.73 m−2 for placebo (2–3 mL·min−1·1.73 m−2 mean decline for PrEP versus placebo, P ⩽ 0.01), and this difference reversed by 4 weeks after drug discontinuation (mean eGFR at the first postdrug visit: 130 mL·min−1 1.73 m−2 in all groups). More than 96% of participants had a confirmed >75% eGFR rebound to baseline level by 8 weeks after drug discontinuation, with similar proportions across treatment groups. Conclusions:In this large, placebo-controlled study of TDF-based PrEP, the small reduction in mean eGFR associated with PrEP reversed within weeks after discontinuation.

Low Risk of Proximal Tubular Dysfunction Associated with Emtricitabine-Tenofovir Disoproxil Fumarate Preexposure Prophylaxis in Men and Women

OBJECTIVE Tenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction (tubulopathy) when used in the treatment of human immunodeficiency virus (HIV) infection. We evaluated whether TDF causes tubulopathy when used as HIV preexposure prophylaxis (PrEP) and whether tubulopathy predicts clinically relevant decline (≥25%) in the estimated glomerular filtration rate (eGFR). METHODS A subgroup analysis of the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF, alone or with emtricitabine (FTC), in HIV-uninfected African men and women (Clinicaltrials.gov NCT00557245). Tubulopathy was assessed in concurrently obtained urine and serum samples at the 24-month or last on-treatment visit, predefined as ≥2 of the following: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate, and uric acid excretion. RESULTS Of 1549 persons studied (776 receiving FTC-TDF, 773 receiving placebo), 64% were male, and the median age was 37 years. Over a median 24 months of study-drug exposure, the frequency of tubulopathy was 1.7% for FTC-TDF versus 1.3% for placebo (odds ratio, 1.30; 95% confidence interval, .52-3.33; P = .68); Tubulopathy occurred in 2 of 52 persons (3.8%) with versus 3 of 208 (1.4%) without ≥25% eGFR decline (adjusted odds ratio, 1.39; .10-14.0; P > .99). CONCLUSIONS Daily oral FTC-TDF PrEP was not significantly associated with tubulopathy over the course of 24 months, nor did tubulopathy predict clinically relevant eGFR decline.

Brief Report: Hormonal Contraception Is Not Associated With Reduced ART Effectiveness Among Women Initiating ART: Evidence From Longitudinal Data.

Background: To explore the association between concomitant hormonal contraceptive and antiretroviral therapy (ART) use and (1) plasma viral suppression and (2) genital HIV shedding among HIV-positive women initiating ART. Methods: We analyzed plasma viral load and genital viral RNA shedding from 1079 HIV-positive women initiating ART who were followed prospectively in 3 sub-Saharan African HIV prevention studies. Plasma and endocervical swab samples were collected every 6 months. Self-reported contraceptive use was categorized into injectable, implant, oral, or nonhormonal/no contraception. We used multivariate Cox regression to assess time to plasma viral suppression and logistic regression with generalized estimating equations to assess genital viral shedding for each contraceptive method. Results: At the time of ART initiation, there were 211 (20%) injectable, 69 (6%) implant, 50 (5%) oral, and 749 (69%) nonhormonal or no method users. Plasma viral suppression was high (90% by 6 months) and hormonal contraceptives did not diminish time to plasma viral suppression as compared to nonhormonal/no methods [adjusted hazard ratios: injectables 0.89 (95% confidence interval: 0.75 to 1.07), implants 0.91 (0.68 to 1.23), and oral methods 1.33 (1.06 to 1.66)]. Genital viral shedding was uncommon any time after ART initiation (only 9% of samples had detectable viral shedding) and hormonal contraceptives were not associated with an increased detection of genital viral shedding [adjusted odds ratios: injectables 1.07 (0.69 to 1.65), implants 0.67 (0.31 to 1.49), and oral methods 0.56 (0.19 to 1.69)]. Conclusions: The hormonal contraceptives assessed were not associated with reduced ART effectiveness among HIV-positive women initiating ART. HIV-positive women should continue to be offered contraceptive options, including hormonal ones that best meet their needs.

Frequency of monitoring kidney function in HIV-uninfected persons using daily oral tenofovir disoproxil fumarate pre-exposure prophylaxis.

Background: Wide-scale implementation of oral tenofovir-based pre-exposure prophylaxis (PrEP) for HIV prevention is now policy in many settings. However, the optimal frequency for monitoring kidney function remains uncertain. We investigated the impact of 6-monthly compared with 3-monthly creatinine clearance (CrCl) monitoring on the identification of moderate kidney dysfunction, defined as CrCl <60 mL/min. Methods: Data were from 2 prospective daily oral PrEP studies in Kenya and Uganda: the Partners PrEP Study, a randomized safety, and efficacy trial of PrEP that conducted 3-monthly CrCl monitoring (n = 4404) and the Partners Demonstration Project (n = 954), an open-label delivery study of PrEP that used 6-monthly monitoring. CrCl ≥60 mL/min was required for enrollment in both studies. Abnormal results were followed with confirmatory testing within approximately 1 week. Follow-up was for up to 24 months. Results: Of 5358 participants included in the analysis, 87% were younger than 45 years, a third were female, and 21% had a baseline CrCl between 60 and 90 mL/min. Confirmed CrCl <60 mL/min events were rare, occurring in 52 individuals (<1%) in 24 months. The 12-month cumulative proportion of persons with CrCl <60 mL/min was 0.2% with 3-monthly screening and 0.5% with 6-monthly screening. Older age (>45 years), lower weight (<55 kg), elevated blood pressure (>140 mm Hg), and baseline CrCl between 60 and 90 mL/min were independently associated with CrCl decline <60 mL/min during follow-up. Conclusions: In these 2 PrEP studies, with generally young participants, the occurrence and pattern of clinically relevant decline in CrCl were not qualitatively different based on 3- or 6-monthly CrCl monitoring schedule. These data suggest that for most persons receiving PrEP for up to 24 months, less frequent CrCl monitoring would be safe and reduce required expenditures for repeat confirmatory testing.

P3.226 Pre-Exposure Prophylaxis (PrEP) is Estimated to Be a Cost-Effective Addition to Antiretroviral Therapy (ART) For HIV Prevention in a Generalised Epidemic Setting

Background In KwaZulu-Natal, South Africa, young women face an extraordinarily high risk for HIV acquisition, with annual incidence estimates of 6%. ART-based strategies for HIV prevention have the potential to significantly decrease HIV incidence, but the impact of PrEP in addition to ART scale-up is undefined. Modeling studies suggest that PrEP targeted to highest-risk groups could maximise benefits and contain costs. Methods We developed a deterministic transmission model of HIV that stratifies the population by age, sexual activity, and includes HIV infection stage. The model was parameterized using data from community-based HIV counselling and testing studies in KwaZulu-Natal and validated using independent HIV prevalence and incidence estimates. We estimated the effectiveness and cost-effectiveness of a ‘test and treat’ scenario, targeted PrEP by age and sexual activity, and general PrEP provision. Each scenario was in addition to anticipated baseline ART scale-up for CD4≤ 350 from 35% in 2013, as observed in KwaZulu-Natal, to 60% in 2018 (following national guidelines). We assumed PrEP efficacy of 70%. Results ‘Test and treat’ (ART for 80% of all HIV-positive persons) reduced HIV incidence by 58% and averted 25% of cumulative infections by 2025, at an additional

P3.200 Effect of Pregnancy on HIV-1 Disease Progression Among Antiretroviral-Naive HIV-1 Infected Women

39,900 per infection averted compared to baseline ART scale-up. PrEP targeted to 60% of 20–29-year-olds, in addition to baseline ART scale-up, reduced incidence by 42% and averted 22% of infections at an additional

O11.2 Sexual Behaviour of Heterosexual Men and Women Receiving Antiretroviral Pre-Exposure Prophylaxis For HIV Prevention: Post-Unblinding Analysis of the Partners PrEP Study

22,500 per infection averted, whereas PrEP targeted to 80% of high-risk individuals reduced incidence by 33% and averted 13% of infections at an additional

Reversibility of kidney function decline in HIV-1–uninfected men and women using preexposure prophylaxis

7,400 per infection averted. PrEP coverage of 20% of the general population reduced incidence by 37% and incident infections by 18%, at an additional

Cost of integrating non-communicable disease screening into home-based HIV testing and counseling in South Africa

26,900 per infection averted. Conclusion In a generalised HIV epidemic setting PrEP is a cost-effective addition to ART, with targeted PrEP being more cost-effective than generalised PrEP distribution.

Chapter 43 – Syphilis

Background Among HIV-1 infected women who have not initiated full regimen antiretroviral therapy (ART), CD4 counts decline during pregnancy, possibly due to hemodilution. It is unclear if this drop is sustained beyond pregnancy, and if pregnancy results in accelerated HIV-1 disease progression. Methods In a prospective study among 2269 HIV-1 infected ART-naïve women from 7 countries in East and southern Africa, we examined the effect of pregnancy on HIV-1 disease progression. We used random effects models to compare CD4 and plasma viral load changes between pregnant, postpartum and non-pregnant periods (prenatal periods from women who became pregnant and all periods from women who did not become pregnant). Among women who became pregnant, we compared CD4 counts during prenatal, pregnant, and postpartum periods. Results Women contributed 3471 person-years and 475 women became pregnant (7.2% of time was pregnant and 6.8% was postpartum). After accounting for baseline levels, CD4 counts were 67.7 cells/mm3 lower (95% CI 55.5–79.9) during pregnant compared to non-pregnant periods and 81.2 cells/mm3 lower (95% CI 65.3–97.2) during pregnant compared to postpartum periods. After adjustment for baseline viral load, there were small increases in plasma viral load: a 0.05 log10 increase in pregnant vs. non-pregnant periods (95% CI 0.01–0.10) and a 0.08 log10 increase in pregnant vs. postpartum periods (95% CI 0.01–0.14). Postpartum CD4 and plasma viral loads were not different from non-pregnant periods (p = 0.1 and p = 0.5). Among women who experienced pregnancy, CD4 counts were 59.6 cells/mm3 lower (95% CI 35.2–84.0) during pregnant versus prenatal periods and 71.6 cells/mm3 lower (95% CI 48.0–95.1) during pregnant versus postpartum periods. Prenatal and postpartum CD4 counts were similar (p = 0.4). Conclusion CD4 count and plasma viral load changes among HIV-1 infected women during pregnancy are not permanent and are likely to return to prenatal levels. Pregnancy was not associated with subsequent disease progression.