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Two randomized controlled trials demonstrated no clinical benefit of hydroxychloroquine (HCQ) for either postexposure prophylaxis or early treatment of SARS-CoV-2 infection. Using data from these studies, we calculated the time-weighted average change from baseline SARS-CoV-2 viral load and demonstrated that HCQ did not affect viral clearance.

BackgroundHighly efficacious oral pre-exposure prophylaxis (PrEP) is the global standard for human immunodeficiency virus (HIV)-1 prevention, including in clinical trials of novel PrEP agents using active-comparator designs. The analysis assessed whether incident sexually transmitted infections (STIs) can serve as a surrogate indicator of HIV-1 incidence that might occur in the absence of PrEP.MethodsWe analyzed data from 3256 women randomized to placebo groups of oral and vaginal PrEP trials (MTN-003/VOICE and MTN-020/ASPIRE). Regression modeling assessed the correlation between incident individual STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, each considered separately) and incident HIV-1.ResultsAcross 18 sites in 4 countries (Malawi, South Africa, Uganda, Zimbabwe), STI and HIV-1 incidences were high: HIV-1 4.9, N gonorrhoeae 5.3, C trachomatis 14.5, and T vaginalis 7.1 per 100 person-years. There was limited correlation between HIV-1 incidence and incidence of individual STIs: N gonorrhoeae (r = 0.02, P = .871), C trachomatis (r = 0.49, P =

Coronavirus disease 2019 symptom definitions rarely include symptom severity. We collected daily nasal swab samples and symptom diaries from contacts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case patients. Requiring ≥1 moderate or severe symptom reduced sensitivity to predict SARS-CoV-2 shedding from 60.0% (95% confidence interval [CI], 52.9%-66.7%) to 31.5% (95% CI, 25.7%- 38.0%) but increased specificity from 77.5% (95% CI, 75.3%-79.5%) to 93.8% (95% CI, 92.7%-94.8%).

ObjectiveVaccine-preventable human papillomavirus (HPV) infection is common, especially in sub-Saharan Africa where HIV risk is also high. However, unlike other sexually transmitted infections (STIs), HPV's role in HIV acquisition is unclear. We evaluated this relationship using data from MTN-003, a clinical trial of HIV chemoprophylaxis among cisgender women in sub-Saharan Africa.DesignA case-control study.MethodsWe matched 138 women who acquired HIV (cases) to 412 HIV-negative controls. Cervicovaginal swabs collected within 6 months before HIV seroconversion were tested for HPV DNA. We estimated the associations between carcinogenic (high-risk) and low-risk HPV types and types targeted by HPV vaccines and HIV acquisition, using conditional logistic regression models adjusted for time-varying sexual behaviors and other STIs.ResultsMean age was 23 (±4) years. Any, high-risk and low-risk HPV was detected in 84, 74 and 66% of cases, and 65, 55 and 48% of controls. Infection with at least two HPV types was common in cases (67%) and controls (49%), as was infection with nonavalent vaccine-targeted types (60 and 42%). HIV acquisition increased with any [adjusted odds ratio (aOR) 2.5, 95% confidence interval (95% CI) 1.3-4.7], high-risk (aOR 2.6, 95% CI 1.5-4.6) and low-risk (aOR 1.8, 95% CI 1.1-2.9) HPV. Each additional type detected increased HIV risk by 20% (aOR 1.2, 95% CI 1.1-1.4). HIV acquisition was associated with HPV types targeted by the nonavalent (aOR 2.1, 95% CI 1.3-3.6) and quadrivalent vaccines (aOR 1.9, 95% CI 1.1-3.2).ConclusionHPV infection is associated with HIV acquisition in sub-Saharan African women. In addition to preventing HPV-associated cancers, increasing HPV vaccination coverage could potentially reduce HIV incidence.

BackgroundEffective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.ObjectiveTo test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.DesignHousehold-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).SettingNational U.S. multicenter study.ParticipantsClose contacts recently exposed ( 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026).LimitationThe delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.ConclusionThis rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.Primary funding sourceBill & Melinda Gates Foundation.

BackgroundTwo phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation.MethodsWe did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037.FindingsBetween July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p

BackgroundA limitation of the Agatston coronary artery calcium (CAC) score is that it does not use all of the calcium density information in the computed tomography scan such that many individuals have a score of zero. We examined the predictive validity for incident coronary heart disease (CHD) events of the spatially weighted coronary calcium score (SWCS), an alternative scoring method for CAC that assigns scores to individuals with Agatston CAC=0.MethodsThe MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study that conducted a baseline exam from 2000 to 2002 in 6814 participants including computed tomography scanning for CAC. Subsequent exams and systematic follow-up of the cohort for outcomes were performed. Statistical models were adjusted using the MESA risk score based on age, sex, race/ethnicity, systolic blood pressure, use of hypertension medications, diabetes, total and HDL (high-density lipoprotein) cholesterol, use of lipid-lowering medications, smoking status, and family history of heart attack.ResultsIn the 3286 participants with Agatston CAC=0 at baseline and for whom SWCS was computed, 98 incident CHD events defined as definite or probably myocardial infarction or definite CHD death occurred during a median follow-up of 15.1 years. In this group, SWCS predicted incident CHD events after multivariable adjustment (hazard ratio=1.30 per SD of natural logarithm [SWCS] [95% CI, 1.04-1.60]; P=0.005); and progression from Agatston CAC=0 at baseline to CAC>0 at subsequent exams (multivariable-adjusted incidence rate difference per SD of natural logarithm [SWCS] per 100 person-years 1.68 [95% CI, 1.03-2.33]; P0 at repeat computed tomography scanning at later exams. SWCS has predictive validity as a subclinical phenotype and marker of CHD risk in individuals with Agatston CAC=0.

ObjectiveWe aimed to determine if the dapivirine vaginal ring and the ring device alone (flexible silicone matrix polymer) was associated with the development of cervical cytology abnormalities.DesignSecondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (MTN-020/ASPIRE and MTN-003/VOICE).MethodsData from ASPIRE, a phase III, placebo-controlled trial of the dapivirine vaginal ring, were used in this analysis. Cervical cytology smears were evaluated at baseline and at the final visit with product use. We compared cytology results between women randomized to dapivirine versus placebo vaginal ring. We further assessed for the effect of the vaginal ring device on cervical cytology by comparing results with data from the oral placebo arm of VOICE, a prior HIV-1 prevention trial conducted in a similar population.ResultsCervical cytology results for 2394 women from ASPIRE (1197 per study arm) were used in this analysis; median time between baseline and final visit with product use was 22.1 months. Cytology smear findings were comparable between dapivirine and placebo vaginal ring arms: at final visit, normal: 90.6 versus 91.5%, ASC-US//LSIL: 7.8 versus 7.4%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 1.7 versus 1.1%, P = 0.44. Cytology data from VOICE had findings (normal: 87.8%, ASC-US/LSIL: 9.8%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 2.4%) comparable with that of both dapivirine (P = 0.93) and placebo vaginal ring arms (P = 0.24).ConclusionThese findings indicate that neither use of the dapivirine vaginal ring nor the vaginal ring device alone, over a period of 2 years, is associated with development of cervical cytology abnormalities that could lead to precancerous or cancerous lesions.

BackgroundAntiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection.MethodsWe conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe.ResultsAmong the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P

The university participant pool is a key resource for behavioral research, and data quality is believed to vary over the course of the academic semester. This crowdsourced project examined time of semester variation in 10 known effects, 10 individual differences, and 3 data quality indicators over the course of the academic semester in 20 participant pools (N = 2696) and with an online sample (N = 737). Weak time of semester effects were observed on data quality indicators, participant sex, and a few individual differences—conscientiousness, mood, and stress. However, there was little evidence for time of semester qualifying experimental or correlational effects. The generality of this evidence is unknown because only a subset of the tested effects demonstrated evidence for the original result in the whole sample. Mean characteristics of pool samples change slightly during the semester, but these data suggest that those changes are mostly irrelevant for detecting effects.

VOICE-a phase 2B, placebo-controlled, randomized trial testing daily use of an antiretroviral tablet (tenofovir or Truvada) or daily use of tenofovir gel in 5029 women from South Africa, Uganda, and Zimbabwe-found none of the drug regimens effective in reducing HIV-1 acquisition in the intent-to-treat analysis. More than half of women assigned to active products in a case cohort sample had no drug detected in any plasma specimens tested during the trial. Yet, in response to questions asked of participants during the trial, ≥90 % of doses were reportedly taken. To explore factors associated with low adherence, a behavioral termination visit questionnaire was developed after early closure of the oral tenofovir and vaginal gel arms. We hypothesized that participants would be more forthcoming about nonuse after they exited the trial than during monthly/quarterly follow-up visits. Comparison of adherence reporting at routine follow-up visits with reporting at trial termination, however, indicates that disclosure of product nonadherence did not increase at the termination visit as anticipated. In resource-limited settings where women value the ancillary benefits provided by trial participation and are concerned that disclosure of nonuse may jeopardize trial participation, objective measures of adherence may yield more meaningful data regarding the inability or reluctance to use than measures of product use derived from self-report.

Introduction: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women's risk of sexually acquiring HIV-1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use. Methods: We measured the amount of dapivirine in returned rings from a placebo-controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and [less than or equal to]0.9 mg released suggested non-use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time-dependent covariate for HIV-1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV-1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence. Results: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV-1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV-1 acquisition estimated 75% to 91% HIV-1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women Conclusions: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV-1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long-acting, woman-initiated approach for discreet HIV-1 prevention. Keywords: adherence; clinical trials; HIV prevention; women; HIV prevention trials; Africa, 1 | INTRODUCTION Worldwide, nearly 870 000 women and girls are infected with HIV-1 every year [1] , with the vast majority of infections occurring in sub-Saharan Africa. New, effective [...]

ObjectiveTo assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial.Study designThis is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition.ResultsThe analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person-years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HIV acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (CI) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55).ConclusionIn this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organization's recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures.ImplicationsAmong Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential.

BackgroundExtent of atherosclerosis measured by amount of coronary artery calcium (CAC) in computed tomography (CT) has been traditionally assessed using thresholded scoring methods, such as the Agatston score (AS). These thresholded scores have value in clinical prediction, but important information might exist below the threshold, which would have important advantages for understanding genetic, environmental, and other risk factors in atherosclerosis. We developed a semi-automated threshold-free scoring method, the spatially weighted calcium score (SWCS) for CAC in the Multi-Ethnic Study of Atherosclerosis (MESA).MethodsChest CT scans were obtained from 6814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The SWCS and the AS were calculated for each of the scans. Cox proportional hazards models and linear regression models were used to evaluate the associations of the scores with CHD events and CHD risk factors. CHD risk factors were summarized using a linear predictor.ResultsAmong all participants and participants with AS > 0, the SWCS and AS both showed similar strongly significant associations with CHD events (hazard ratios, 1.23 and 1.19 per doubling of SWCS and AS; 95% CI, 1.16 to 1.30 and 1.14 to 1.26) and CHD risk factors (slopes, 0.178 and 0.164; 95% CI, 0.162 to 0.195 and 0.149 to 0.179). Even among participants with AS = 0, an increase in the SWCS was still significantly associated with established CHD risk factors (slope, 0.181; 95% CI, 0.138 to 0.224). The SWCS appeared to be predictive of CHD events even in participants with AS = 0, though those events were rare as expected.ConclusionsThe SWCS provides a valid, continuous measure of CAC suitable for quantifying the extent of atherosclerosis without a threshold, which will be useful for examining novel genetic and environmental risk factors for atherosclerosis.

AbstractBackgroundExtent of atherosclerosis measured by amount of coronary artery calcium (CAC) in computed tomography (CT) has been traditionally assessed using thresholded scoring methods, such as the Agatston score (AS). These thresholded scores have value in clinical prediction, but important information might exist below the threshold, which would have important advantages for understanding genetic, environmental, and other risk factors in atherosclerosis. We developed a semi-automated threshold-free scoring method, the spatially weighted calcium score (SWCS) for CAC in the Multi-Ethnic Study of Atherosclerosis (MESA).MethodsChest CT scans were obtained from 6814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The SWCS and the AS were calculated for each of the scans. Cox proportional hazards models and linear regression models were used to evaluate the associations of the scores with CHD events and CHD risk factors. CHD risk factors were summarized using a linear predictor.ResultsAmong all participants and participants with AS > 0, the SWCS and AS both showed similar strongly significant associations with CHD events (hazard ratios, 1.23 and 1.19 per doubling of SWCS and AS; 95% CI, 1.16 to 1.30 and 1.14 to 1.26) and CHD risk factors (slopes, 0.178 and 0.164; 95% CI, 0.162 to 0.195 and 0.149 to 0.179). Even among participants with AS = 0, an increase in the SWCS was still significantly associated with established CHD risk factors (slope, 0.181; 95% CI, 0.138 to 0.224). The SWCS appeared to be predictive of CHD events even in participants with AS = 0, though those events were rare as expected.ConclusionsThe SWCS provides a valid, continuous measure of CAC suitable for quantifying the extent of atherosclerosis without a threshold, which will be useful for examining novel genetic and environmental risk factors for atherosclerosis.

The contributing role of stereotype threat (ST) to learning and performance decrements for stigmatized students in highly evaluative situations has been vastly documented and is now widely known by educators and policy makers. However, recent research illustrates that underrepresented and stigmatized students' academic and career motivations are influenced by ST more broadly, particularly through influences on achievement orientations, sense of belonging, and intrinsic motivation. Such a focus moves conceptualizations of ST effects in education beyond the influence on a student's performance, skill level, and feelings of self-efficacy per se to experiencing greater belonging uncertainty and lower interest in stereotyped tasks and domains. These negative experiences are associated with important outcomes such as decreased persistence and domain identification, even among students who are high in achievement motivation. In this vein, we present and review support for the Motivational Experience Model of ST, a self-regulatory model framework for integrating research on ST, achievement goals, sense of belonging, and intrinsic motivation to make predictions for how stigmatized students' motivational experiences are maintained or disrupted, particularly over long periods of time.