A Randomized Clinical Trial of Human Papillomavirus Test-and-Treat as Compared to Cytology-Based Screening for Prevention of Cervical Cancer Among Women With Human Immunodeficiency Virus: AIDS Clinical Trials Group Protocol A5282.

BACKGROUND: Cytology-based cervical cancer screening followed by confirmation and treatment of biopsy-proven high-grade squamous intraepithelial lesions (bHSIL) is difficult to implement in resource-constrained settings. We hypothesized that high-risk human papillomavirus (hrHPV) testing followed by immediate cryotherapy of women with hrHPV (HPV screen-and-treat) may improve outcomes. METHODS: Randomized, open-label, phase 2, multinational clinical trial enrolling women with human immunodeficiency virus (HIV) age 18 or older with cervical hrHPV and having no cervical lesions or lesions appropriate for cryotherapy. Women were randomized to immediate cryotherapy (Arm A) or cytology-based screening (Arm B). For Arm A, cervical biopsies were obtained followed by cervical cryotherapy, and in Arm B, women with abnormal cytology underwent colposcopy followed by loop electroexcision procedure (LEEP) if bHSIL was detected. Women were followed through 30 months. The primary outcome was time to bHSIL detected from Month 6 through study completion. RESULTS: In total, 288 women (145 in Arm A, 143 in Arm B) were randomized: median age 35 years, 84% on antiretroviral therapy, median CD4 501 cells/mm3. In Arm A, 39 (27%) of women had bHSIL at entry, and in Arm B, 88 (62%) had abnormal cytology, 22 (15%) were diagnosed with bHSIL, 12 (8%) underwent LEEP. In follow-up, 30 (21%) and 31 (22%) developed bHSIL; time to bHSIL was similar between arms (P=.94). The prevalence of hrHPV at Month 6 was similar between arms (61% and 70%, P=.13). CONCLUSIONS: HPV test-and-treat was not associated with improved bHSIL outcomes as compared to cytology-based screening. More effective treatment options are required to improve outcomes from screen-and-treat programs. CLINICAL TRIALS REGISTRATION: NCT01315363.

Likely clinical depression and HIV-related decline in antiretroviral therapy untreated women who seroconverted during participation in microbicide trials in sub-Saharan Africa.

Depression worsens HIV outcomes in populations treated with antiretroviral therapy (ART) medications. Data are limited on the relationship between depression and HIV in untreated populations in sub-Saharan Africa. We aimed to identify associations between likely clinical depression, alcohol use, social support by partners, and HIV viral load (VL) among ART untreated women who recently became HIV positive and enrolled in the Microbicide Trials Network (MTN)-015 study. Analyses used cross-sectional data collected at baseline in MTN-015. Participants in this analysis (N = 190) enrolled from other MTN trials were not receiving ART and provided data on their HIV disclosure status to their husband or male partner and alcohol use behavior. The dependent variable, VL, was categorized as: low (≤400 RNA copies/mL; 9.1% of participants), medium (401-20,000 RNA copies/mL; 48.8%), and high (>20,000 RNA copies/mL; 42.0%). Depression was assessed using eight items from Hopkins Symptom Checklist; a cutoff of ≥1.75 indicated likely clinical depression. Independent variables with a significance of p ≤ 0.05 in unadjusted regressions were included in a regression adjusted for age, education, and time since seroconversion. Depressive symptoms were positively associated with high VL, in the adjusted regression (OR = 1.80; 95% CI = 1.07-3.01). Results suggest that likely having clinical depression may have a biological relationship with HIV disease progression.

HIV incidence in a multinational cohort of men and transgender women who have sex with men in sub-Saharan Africa: Findings from HPTN 075.

Few studies have assessed HIV incidence in men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA). We assessed HIV incidence and its correlates among MSM and TGW in SSA enrolled in the prospective, multi-country HIV Prevention Trials Network (HPTN) 075 study, conducted from 2015 to 2017. Participants were enrolled at four sites in SSA (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Eligible participants reported male sex assignment at birth, were 18 to 44 years of age, and had engaged in anal intercourse with a man in the preceding three months. Participation involved five study visits over 12 months. Visits included behavioral assessments and testing for HIV and sexually transmitted infections. Twenty-one of 329 persons acquired HIV during the study [incidence rate: 6.96/100 person-years (PY) (95% CI: 4.3, 10.6)]. Among TGW, HIV incidence was estimated to be 8.4/100 PY (95% CI: 2.3, 21.5). Four participants were found to have acute HIV infection at their first HIV-positive visit. HIV incidence varied among the four study sites, ranging from 1.3/100 PY to 14.4/100 PY. In multivariate longitudinal analysis, factors significantly associated with HIV acquisition were engagement in unprotected receptive anal intercourse [adjusted hazard ratio (AHR) 5.8, 95% confidence interval (CI): 2.4, 14.4] and incident rectal gonorrhea and/or chlamydia (AHR: 2.7, 95% CI: 1.1, 6.8). The higher HIV incidence in Cape Town compared to Blantyre could be explained by the higher prevalence of several risk factors for HIV infection among participants in Cape Town. Annual HIV incidence observed in this study is substantially higher than reported HIV incidence in the general populations in the respective countries and among MSM in the United States. Intensification of HIV prevention efforts for MSM and TGW in SSA is urgently needed.

Healthcare-related stigma among men who have sex with men and transgender women in sub-Saharan Africa participating in HIV Prevention Trials Network (HPTN) 075 study.

ABSTRACT The inability to access health services when needed is a critical barrier to HIV prevention, treatment and care among men who have sex with men (MSM) and transgender women (TGW). Using data collected in HPTN 075, we explored factors associated with any experienced healthcare-related stigma. HPTN 075 was a cohort study to assess the feasibility of recruiting and retaining MSM and TGW in clinical trials in sub-Saharan Africa. Of 401 MSM and TGW enrolled at four sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town, Soweto, South Africa) 397 contributed to the analysis (79.9% cis-gender and 20.1% TGW). Of these, (45.3%; 180/397) reported one or more of healthcare-related stigma experiences. Most frequently reported experiences included fear to seek healthcare services (36.3%) and avoiding seeking such services because of the discovery of MSM status (29.2%). Few men and TGW (2.5%) reported having been denied health services because of having sex with men. In multivariable analysis, more participants in Soweto [adjusted odds ratio (AOR) = 2.60] and fewer participants in Blantyre (AOR = 0.27) reported any healthcare-related stigma experiences, in comparison to participants in Kisumu. MSM and TGW that did not have a supportive gay community to rely on were more likely to report any healthcare-related stigma experiences (AOR = 1.46), whereas MSM and TGW who reported high social support and who never had engaged in transactional sex were less likely to report such experiences (AOR = 0.76 and AOR = 0.43, respectively). Our results suggest that encouraging support groups for MSM and TGW as well as training and sensitizing healthcare staff, and the general community, on MSM and TGW health issues and cultural competence may reduce stigma, improve access to healthcare, which could ultimately reduce HIV transmission.

Pregnancy and Infant Outcomes Among Women Using the Dapivirine Vaginal Ring in Early Pregnancy.

BACKGROUND: Monthly use of the dapivirine vaginal ring has been shown to be safe and effective for HIV-1 prevention in nonpregnant reproductive-aged women. The impact of dapivirine on pregnancy outcomes and infant is not known. We compared pregnancy incidence and outcomes by study arm among HIV-1-uninfected women who became pregnant while participating in MTN-020/ASPIRE. METHODS: ASPIRE was a randomized, double-blind, placebo-controlled phase III safety and effectiveness study of the dapivirine ring for HIV-1 prevention. Sexually active women aged 18-45 years from Malawi, South Africa, Uganda, and Zimbabwe were enrolled. Urine pregnancy tests were performed monthly, and, if positive, study product was withheld during pregnancy and breastfeeding. Pregnancy-related outcomes included the following: pregnancy incidence, pregnancy outcomes (live birth, preterm birth, pregnancy loss, and congenital anomalies), and infant growth. RESULTS: Of 2629 women enrolled in ASPIRE, 169 became pregnant during follow-up, resulting in 179 incident pregnancies and 181 pregnancy outcomes. No difference in pregnancy incidence by study arm was observed (hazard ratio = 0.93; 95% confidence interval: 0.68 to 1.26). The distribution of pregnancy outcomes was similar by study arm, and no difference was noted in the frequency or pattern of congenital anomalies or infant growth parameters by study arm. CONCLUSIONS: Dapivirine use in the periconception period does not seem to be associated with adverse effects on pregnancy or infant outcomes. Our findings provide support for additional safety studies of the dapivirine ring throughout pregnancy.

Chloroquine as weekly chemoprophylaxis or intermittent treatment to prevent malaria in pregnancy in Malawi: a randomised controlled trial.

BACKGROUND: Sulfadoxine-pyrimethamine resistance threatens efficacy of intermittent preventive treatment of malaria during pregnancy, and alternative regimens need to be identified. With the return of chloroquine efficacy in southern Africa, we postulated that chloroquine either as an intermittent therapy or as weekly chemoprophylaxis would be more efficacious than intermittent sulfadoxine-pyrimethamine for prevention of malaria in pregnancy and associated maternal and newborn adverse outcomes. METHODS: We did an open-label, single-centre, randomised controlled trial at Ndirande Health Centre, Blantyre, in southern Malawi. We enrolled pregnant women (first or second pregnancy) at 20-28 weeks' gestation who were HIV negative. Participants were randomly assigned in a 1:1:1 ratio using a computer-generated list to either intermittent sulfadoxine-pyrimethamine (two doses of 1500 mg sulfadoxine and 75 mg pyrimethamine, 4 weeks apart), intermittent chloroquine (two doses of 600 mg on day 1, 600 mg on day 2, and 300 mg on day 3), or chloroquine prophylaxis (600 mg on day 1 then 300 mg every week). The primary endpoint was placental malaria in the modified intent-to-treat population, which consisted of participants who contributed placental histopathology data at birth. Secondary outcomes included clinical malaria, maternal anaemia, low birthweight, and safety. This trial is registered with ClinicalTrials.gov, number NCT01443130. FINDINGS: Between February, 2012, and May, 2014, we enrolled and randomly allocated 900 women, of whom 765 contributed histopathological data and were included in the primary analysis. 108 (14%) women had placental malaria, which was lower than the anticipated prevalence of placental malaria infection. Protection from placental malaria was not improved by chloroquine as either prophylaxis (30 [12%] of 259 had positive histopathology; relative risk [RR] 0·75, 95% CI 0·48-1·17) or intermittent therapy (39 [15%] of 253; RR 1·00, 0·67-1·50) compared with intermittent sulfadoxine-pyrimethamine (39 [15%] of 253). In protocol-specified analyses adjusted for maternal age, gestational age at enrolment, bednet use the night before enrolment, anaemia at enrolment, and malaria infection at enrolment, women taking chloroquine as prophylaxis had 34% lower placental infections than did those allocated intermittent sulfadoxine-pyrimethamine (RR 0·66, 95% CI 0·46-0·95). Clinical malaria was reported in nine women assigned intermittent sulfadoxine-pyrimethamine, four allocated intermittent chloroquine (p=0·26), and two allocated chloroquine prophylaxis (p=0·063). Maternal anaemia was noted in five women assigned intermittent sulfadoxine-pyrimethamine, 15 allocated intermittent chloroquine (p=0·038), and six assigned chloroquine prophylaxis (p>0·99). Low birthweight was recorded for 31 babies born to women allocated intermittent sulfadoxine-pyrimethamine, 29 assigned intermittent chloroquine (p=0·78), and 41 allocated chloroquine prophylaxis (p=0·28). Four women assigned intermittent sulfadoxine-pyrimethamine had adverse events possibly related to study product compared with 94 women allocated intermittent chloroquine (p<0·0001) and 26 allocated chloroquine prophylaxis (p<0·0001). Three women had severe or life-threatening adverse events related to study product, of whom all were assigned intermittent chloroquine (p=0·25). INTERPRETATION: Chloroquine administered as intermittent therapy did not provide better protection from malaria and related adverse effects compared with intermittent sulfadoxine-pyrimethamine in a setting of high resistance to sulfadoxine-pyrimethamine. Chloroquine chemoprophylaxis might provide benefit in protecting against malaria during pregnancy, but studies with larger sample sizes are needed to confirm these results. FUNDING: US National Institutes of Health.