Showing papers by "Deborah Donnell published in 2020"

COVID-19 vaccines that reduce symptoms but do not block infection need higher coverage and faster rollout to achieve population impact

Abstract: Background Several COVID-19 vaccine candidates are in the final stage of testing. Interim trial results for two vaccines suggest at least 90% efficacy against symptomatic disease (VEDIS). It remains unknown whether this efficacy is mediated predominately by lowering SARS-CoV-2 infection susceptibility (VESUSC) or development of symptoms after infection (VESYMP). A vaccine with high VESYMP but low VESUSC has uncertain population impact. Methods We developed a mathematical model of SARS-CoV-2 transmission, calibrated to demographic, physical distancing and epidemic data from King County, Washington. Different rollout scenarios starting December 2020 were simulated assuming different combinations of VESUSC and VESYMP resulting in up to 100% VEDIS with constant vaccine effects over 1 year. We assumed no further increase in physical distancing despite expanding case numbers and no reduction of infectivity upon infection conditional on presence of symptoms. Proportions of cumulative infections, hospitalizations and deaths prevented over 1 year from vaccination start are reported. Results Rollouts of 1M vaccinations (5,000 daily) using vaccines with 50% VEDIS are projected to prevent 30%-58% of infections and 38%-58% of deaths over one year. In comparison, vaccines with 90% VEDIS are projected to prevent 47%-78% of the infections and 58%-77% of deaths over one year. In both cases, there is a greater reduction if VEDIS is mediated mostly by VESUSC. The use of a “symptom reducing” vaccine will require twice as many people vaccinated than a “susceptibility reducing” vaccine with the same 90% VEDIS to prevent 50% of the infections and death over one year. Delaying the start of the vaccination by 3 months decreases the expected population impact by approximately 40%. Conclusions Vaccines which prevent COVID-19 disease but not SARS-CoV-2 infection, and thereby shift symptomatic infections to asymptomatic infections, will prevent fewer infections and require larger and faster vaccination rollouts to have population impact, compared to vaccines that reduce susceptibility to infection. If uncontrolled transmission across the U.S. continues, then expected vaccination in Spring 2021 will provide only limited benefit.

Integrating oral PrEP delivery among African women in a large HIV endpoint-driven clinical trial.

Abstract: INTRODUCTION Global guidelines emphasize the ethical obligation of investigators to help participants in HIV-endpoint trials reduce HIV risk by offering an optimal HIV prevention package. Oral pre-exposure prophylaxis (PrEP) has increasingly become part of state-of-the-art HIV prevention. Here we describe the process of integrating oral PrEP delivery into the HIV prevention package of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS ECHO was an open-label randomized clinical trial that compared HIV incidence among women randomized to one of three effective contraceptives. In total, 7830 women aged 16 to 35 years from 12 sites in four African countries (Eswatini, Kenya, South Africa and Zambia) were enrolled and followed for 12 to 18 months, from 2015 to 2018. Part-way through the course of the trial, oral PrEP was provided to study participants either off-site via referral or on site via trained trial staff. PrEP uptake was compared between different contraceptive users using Chi-squared tests or t-tests. HIV seroincidence rates were compared between participants who never versus ever initiated PrEP using exact Poisson regression. RESULTS PrEP access in ECHO began through public availability in Kenya in May 2017 and was available at all sites by June 2018. When PrEP became available, 3626 (46.3%) eligible women were still in follow-up in the study, and of these, 622 (17.2%) initiated PrEP. Women initiating PrEP were slightly older; more likely to be unmarried, not living with their partner, having multiple partners; and less likely to be earning their own income and receiving financial support from partners (all p < 0.05). PrEP initiation did not differ across study randomized groups (p = 0.7). Two-thirds of PrEP users were continuing PrEP at study exit. CONCLUSIONS There is a need for improved HIV prevention services in clinical trials with HIV endpoints, especially trials among African women. PrEP as a component of a comprehensive HIV prevention package provided to women in a large clinical trial is practical and feasible. Provision of PrEP within clinical trials with HIV outcomes should be standard of prevention.

HIV Stigma and Viral Suppression Among People Living With HIV in the Context of Universal Test and Treat: Analysis of Data From the HPTN 071 (PopART) Trial in Zambia and South Africa.

Abstract: BACKGROUND: The impact of HIV stigma on viral suppression among people living with HIV (PLHIV) is not well characterized. SETTING: Twenty-one communities in Zambia and South Africa, nested within the HPTN 071 (PopART) trial. METHODS: We analyzed data on viral suppression (<400 copies HIV RNA/mL) among 5662 laboratory-confirmed PLHIV aged 18-44 years who were randomly sampled within the PopART trial population cohort 24 months after enrolment (PC24). We collected data on experiences and internalization of stigma from those PLHIV who self-reported their HIV status (n = 3963/5662) and data on perceptions of stigma from a 20% random sample of all PLHIV (n = 1154/5662). We also measured stigma at the community-level among PLHIV, community members, and health workers. We analyzed the association between individual- and community-level measures of HIV stigma and viral suppression among PLHIV, adjusting for confounding. RESULTS: Of all 5662 PLHIV, 69.1% were virally suppressed at PC24. Viral suppression was highest among those 3963 cohort participants who self-reported living with HIV and were on ART (88.3%), and lower among those not on treatment (37.5%). Self-identifying PLHIV who reported internalized stigma were less likely to be virally suppressed (75.0%) than those who did not (80.7%; adjusted risk ratio, 0.94 95% CI: 0.89 to 0.98). Experiences, perceptions, and community-level measures of stigma were not associated with viral suppression. CONCLUSION: Internalized stigma among PLHIV was associated with a lower level of viral suppression; other dimensions of stigma were not. Stigma reduction approaches that address internalized stigma should be an integral component of efforts to control the HIV epidemic.

Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials

Abstract: Background: Several candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known. Methods: Following vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the benefit of vaccination over time has the same profile for the original vaccine recipients and the placebo crossovers. This reconstruction allows estimation of both vaccine durability and potential vaccine-associated enhanced disease. Results: Post-crossover estimates of vaccine efficacy can provide insights about durability, identify waning efficacy, and identify late enhancement of disease, but are less reliable estimates than those obtained by a standard trial where the placebo cohort is maintained. As vaccine efficacy estimates for post-crossover periods depend on prior vaccine efficacy estimates, longer pre-crossover periods with higher case counts provide better estimates of late vaccine efficacy. Further, open-label crossover may lead to riskier behavior in the immediate crossover period for the unblinded vaccine arm, confounding vaccine efficacy estimates for all post-crossover periods. Conclusions: We advocate blinded crossover and continued follow-up of trial participants to best assess vaccine durability and potential delayed enhancement of disease. This approach allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain participants on placebo, yet still allows important insights about immunological and clinical effectiveness over time.

Association between HIV-stigma and antiretroviral therapy adherence among adults living with HIV: Baseline findings from the HPTN 071 (PopART) trial in Zambia and South Africa.

Abstract: OBJECTIVES: Adherence to antiretroviral therapy (ART) leads to viral suppression for people living with HIV (PLHIV) and is critical for both individual health and reducing onward HIV transmission. HIV stigma is a risk factor that can undermine adherence. We explored the association between HIV stigma and self-reported ART adherence among PLHIV in 21 communities in the HPTN 071 (PopART) trial in Zambia and the Western Cape of South Africa. METHODS: We conducted a cross-sectional analysis of baseline data collected between 2013 and 2015, before the roll-out of trial interventions. Questionnaires were conducted, and consenting participants provided a blood sample for HIV testing. Poor adherence was defined as self-report of not currently taking ART, missing pills over the previous 7 days or stopping treatment in the previous 12 months. Stigma was categorised into three domains: community, health setting and internalised stigma. Multivariable logistic regression was used for analysis. RESULTS: Among 2020 PLHIV self-reporting ever taking ART, 1888 (93%) were included in multivariable analysis. Poor ART adherence was reported by 15.8% (n = 320) of participants, and 25.7% (n = 519) reported experiencing community stigma, 21.5% (n = 434) internalised stigma, and 5.7% (n = 152) health setting stigma. PLHIV who self-reported previous experiences of community and internalised stigma more commonly reported poor ART adherence than those who did not (aOR 1.63, 95% CI 1.21 -2.19, P = 0.001 and aOR 1.31, 95% CI 0.96-1.79, P = 0.09). CONCLUSIONS: HIV stigma was associated with poor ART adherence. Roll-out of universal treatment will see an increasingly high proportion of PLHIV initiated on ART. Addressing HIV stigma could make an important contribution to supporting lifelong ART adherence.

Understanding the HIV Epidemic Among MSM in Baltimore: A Modeling Study Estimating the Impact of Past HIV Interventions and Who Acquired and Contributed to Infections.

Abstract: Introduction Men who have sex with men (MSM) in the United States are disproportionately affected by HIV. We estimated the impact of past interventions and contribution of different population groups to incident MSM HIV infections. Setting Baltimore, US. Methods We used a deterministic model, parameterized and calibrated to demographic and epidemic Baltimore MSM data, to estimate the fraction of HIV infections among MSM averted by condoms and antiretroviral therapy (ART) over 1984-2017 and the fraction of infections acquired and transmission contributed by MSM from different demographic groups and disease and care continuum stages over 10-year periods from 1988 to 2017, using population attributable fractions. Results Condom use and ART averted 19% (95% uncertainty interval: 14%-25%) and 23% (15%-31%) of HIV infections that would have occurred since 1984 and 1996, respectively. Over 2008-2017, 46% (41%-52%) of incident infections were acquired by and 35% (27%-49%) of transmissions contributed by MSM aged 18-24 years (who constitute 27% of all MSM, 19% of HIV+ MSM). MSM with undiagnosed HIV infection, those with diagnosed infection but not in care, and those on ART contributed to 41% (31%-54%), 46% (25%-56%), and 14% (7%-28%) of transmissions, respectively. Conclusion Condoms and ART have modestly impacted the HIV epidemic among Baltimore MSM to date. Interventions reaching MSM with diagnosed infection who are not in care should be implemented because the largest percentage of HIV transmissions among Baltimore MSM is attributed to this group.

The effect of universal testing and treatment on HIV stigma in 21 communities in Zambia and South Africa.

Abstract: OBJECTIVES: To assess the impact of a combination HIV prevention intervention including universal testing and treatment (UTT) on HIV stigma among people living with HIV, and among community members and health workers not living with HIV. DESIGN: This HIV stigma study was nested in the HPTN 071 (PopART) trial, a three-arm cluster randomised trial conducted between 2013 and 2018 in 21 urban/peri-urban communities (12 in Zambia and nine in South Africa). METHODS: Using an adjusted two-stage cluster-level analysis, controlling for baseline imbalances, we compared multiple domains of stigma between the trial arms at 36 months. Different domains of stigma were measured among three cohorts recruited across all study communities: 4178 randomly sampled adults aged 18-44 who were living with HIV, and 3487 randomly sampled adults and 1224 health workers who did not self-report living with HIV. RESULTS: Prevalence of any stigma reported by people living with HIV at 36 months was 20.2% in arm A, 26.1% in arm B, and 19.1% in arm C (adjusted prevalence ratio, A vs. C 1.01 95% CI 0.49-2.08, B vs. C 1.34 95% CI 0.65-2.75). There were no significant differences between arms in any other measures of stigma across all three cohorts. All measures of stigma reduced over time (0.2--4.1% reduction between rounds) with most reductions statistically significant. CONCLUSION: We found little evidence that UTT either increased or decreased HIV stigma measured among people living with HIV, or among community members or health workers not living with HIV. Stigma reduced over time, but slowly. CLINICALTRIALS. GOV NUMBER: NCT01900977.

Sample Size Calculation for Active-Arm Trial with Counterfactual Incidence Based on Recency Assay.

Abstract: The past decade has seen tremendous progress in the development of biomedical agents that are effective as pre-exposure prophylaxis (PrEP) for HIV prevention. To expand the choice of products and delivery methods, new medications and delivery methods are under development. Future trials of non-inferiority, given the high efficacy of ARV-based PrEP products as they become current or future standard of care, would require a large number of participants and long follow-up time that may not be feasible. This motivates the construction of a counterfactual estimate that approximates incidence for a randomized concurrent control group receiving no PrEP. We propose an approach that is to enroll a cohort of prospective PrEP users and augment screening for HIV with laboratory markers of duration of HIV infection to indicate recent infections. We discuss the assumptions under which these data would yield an estimate of the counterfactual HIV incidence and develop sample size and power calculations for comparisons to incidence observed on an investigational PrEP agent.

Model-Based Predictions of HIV Incidence Among African Women Using HIV Risk Behaviors and Community-Level Data on Male HIV Prevalence and Viral Suppression.

Abstract: Background Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical "placebo arm" for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP. Methods Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study. Results Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over 1 year of follow-up in the placebo groups of 4 completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% confidence interval: 3.2 to 4.2) among HIV Prevention Trials Network 082 participants in the absence of PrEP and other risk reduction interventions. Conclusions We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.

Predicted Effectiveness of Daily and Nondaily Preexposure Prophylaxis for Men Who Have Sex With Men Based on Sex and Pill-taking Patterns From the Human Immuno Virus Prevention Trials Network 067/ADAPT Study

Abstract: Background The HIV Prevention Trials Network (HPTN) 067/Alternative Dosing to Augment PrEP Pill Taking (ADAPT) Study evaluated the feasibility of daily and nondaily human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. Methods An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the preexposure prophylaxis initiative (iPrEx) trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. Results We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85%, and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens. Conclusions Our analysis suggests that PrEP was more effective among MSM in Thailand than in the United States as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, nondaily PrEP was less effective than daily PrEP, especially in the United States where the sex act coverage associated with daily use was substantially higher.

PopART-IBM, a highly efficient stochastic individual-based simulation model of generalised HIV epidemics developed in the context of the HPTN 071 (PopART) trial

Abstract: Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HIV transmission occurs. An individual-based model, which explicitly models sexual partnerships, is thus often the most natural type of model to choose. In this paper we present PopART-IBM, a computationally efficient individual-based model capable of simulating 50 years of an HIV epidemic in a large, high-prevalence community in under a minute. We show how the model calibrates within a Bayesian inference framework to detailed age- and sex-stratified data from multiple sources on HIV prevalence, awareness of HIV status, ART status, and viral suppression for an HPTN 071 (PopART) study community in Zambia, and present future projections of HIV prevalence and incidence for this community in the absence of trial intervention.

Determination of HIV status and identification of incident HIV infections in a large, community-randomized trial: HPTN 071 (PopART).

Abstract: Introduction The HPTN 071 (PopART) trial evaluated the impact of an HIV combination prevention package that included "universal testing and treatment" on HIV incidence in 21 communities in Zambia and South Africa during 2013-2018. The primary study endpoint was based on the results of laboratory-based HIV testing for> 48,000 participants who were followed for up to three years. This report evaluated the performance of HIV assays and algorithms used to determine HIV status and identify incident HIV infections in HPTN 071, and assessed the impact of errors on HIV incidence estimates. Methods HIV status was determined using a streamlined, algorithmic approach. A single HIV screening test was performed at centralized laboratories in Zambia and South Africa (all participants, all visits). Additional testing was performed at the HPTN Laboratory Center using antigen/antibody screening tests, a discriminatory test and an HIV RNA test. This testing was performed to investigate cases with discordant test results and confirm incident HIV infections. Results HIV testing identified 978 seroconverter cases. This included 28 cases where the participant had acute HIV infection at the first HIV-positive visit. Investigations of cases with discordant test results identified cases where there was a participant or sample error (mixups). Seroreverter cases (errors where status changed from HIV infected to HIV uninfected, 0.4% of all cases) were excluded from the primary endpoint analysis. Statistical analysis demonstrated that exclusion of those cases improved the accuracy of HIV incidence estimates. Conclusions This report demonstrates that the streamlined, algorithmic approach effectively identified HIV infections in this large cluster-randomized trial. Longitudinal HIV testing (all participants, all visits) and quality control testing provided useful data on the frequency of errors and provided more accurate data for HIV incidence estimates.

Brief Report: Bacterial Vaginosis and Risk of HIV Infection in the Context of CD101 Gene Variation.

Abstract: Author(s): Wanga, Valentine; Mackelprang, Romel D; Thomas, Katherine K; Donnell, Deborah; Cohen, Craig R; Mugo, Nelly R; Bukusi, Elizabeth A; de Bruyn, Guy; Irungu, Elizabeth; Celum, Connie; Baeten, Jared M; Lingappa, Jairam R; Partners in Prevention HSV/HIV Transmission Study and the Partners PrEP Study | Abstract: BackgroundWhether bacterial vaginosis (BV) and CD101 immunoglobulin-like (Ig-like) variants independently increase HIV risk through mucosal inflammation is not well understood. We evaluated whether the impact of BV on HIV acquisition in women differs by the presence or absence of candidate CD101 Ig-like variants.MethodsWe used data from 2 studies of HIV serodiscordant couples in east (Kenya, Tanzania, and Uganda) and southern (Botswana, South Africa, and Zambia) Africa, which longitudinally assessed HIV acquisition (by ELISA) and BV (by Nugent score ≥7). We used previously generated CD101 sequence data for each case and control participant to create a binary variable indicating the presence/absence of any of 5 CD101 Ig-like variants.ResultsConfirming previously shown results in this cohort, Ig-like variants increased HIV-infection risk (adjusted hazard ratio [aHR], = 2.63; 95% confidence interval [CI], 1.41 to 4.89). BV was associated with 2.5-fold higher HIV-infection risk only in the absence of Ig-like variants (aHR = 2.47; 95% CI, 0.99 to 6.15; P = 0.052), whereas in the presence of Ig-like variants, BV was not associated with higher HIV-infection risk (aHR = 0.87; 95% CI, 0.35 to 2.15; P = 0.765); however, a test for interaction was nonsignificant (P = 0.116).ConclusionsWe hypothesized that both BV and CD101 Ig-like variants facilitate HIV acquisition by augmenting similar genital inflammation pathways. Our findings indicate that inflammatory mucosal effects of Ig-like variants may influence the impact of BV on HIV risk. Host-defined inflammatory pathways may be useful targets for HIV prevention.

Sexual Behaviors After PrEP Discontinuation Among HIV Serodiscordant Couples in Kenya and Uganda.

Abstract: Background A strategy of pre-exposure prophylaxis (PrEP) transitioning to treatment as prevention is highly efficacious and cost effective for prevention of HIV transmission within HIV serodiscordant couples. We assessed whether couples who adopted this strategy experienced changes in sexual behaviors after HIV-negative partners discontinued PrEP and transitioned to rely primarily on their partner's adherence to antiretroviral therapy (ART) for prevention. Setting Kenya and Uganda. Methods Data are from the Partners Demonstration Project, a prospective, open-label evaluation of PrEP and ART use for HIV prevention. Using zero-inflated negative binomial models, we assessed changes in the level (ie, intercept) and trend over time (ie, slope) in total and condomless sex acts reported after PrEP discontinuation by HIV-negative partners. We conducted subgroup analyses based on HIV-negative partners' age and sex. Results We included 567 couples where the HIV-negative partner discontinued PrEP because of their partner with HIV using ART for ≥6 months. HIV-negative partners were women in 32.6% of couples and had a median age of 30 years. We observed no change in the level or trend over time in total sex acts [level adjusted rate ratio (aRR) = 0.95, 95% confidence interval (CI): 0.87 to 1.04; trend aRR = 1.00, 95% CI: 0.99 to 1.01] or condomless sex acts (level aRR = 0.97, 95% CI: 0.81 to 1.17; trend aRR = 1.00, 95% CI: 0.98 to 1.03) reported after PrEP discontinuation versus prediscontinuation. No significant changes in behaviors were observed in age and sex subgroups. Conclusions PrEP discontinuation seems to result in no significant changes in couples' sexual behaviors. These data further support a strategy of time-limited PrEP use by serodiscordant couples.