Molnupiravir Use Among Patients with COVID-19 in Real-World Settings: A Systematic Literature Review.

INTRODUCTION: Molnupiravir (MOV) is an oral antiviral for the treatment of individuals with mild-to-moderate COVID-19 and at high risk of progression to severe disease. Our objective was to conduct a systematic literature review (SLR) of evidence on the effectiveness of MOV in reducing the risk of severe COVID-19 outcomes in real-world outpatient settings. METHODS: The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and using pre-determined population, intervention, comparison, outcome, time, and study design inclusion criteria. Eligible studies were published between January 1, 2021, and March 10, 2023, and evaluated the real-world effectiveness of MOV compared to no treatment in reducing the risk of severe COVID-19 outcomes among outpatients ≥ 18 years of age with a laboratory-confirmed diagnosis of SARS-CoV-2 infection. RESULTS: Nine studies from five countries were included in the review. The size of the MOV-treated group ranged from 359 to 7818 individuals. Omicron variants of SARS-CoV-2 were dominant in all study periods. Most studies noted differences in the baseline characteristics of the MOV-treated and untreated control groups, with the treated groups generally being older and with more comorbidities. Eight studies reported that treatment with MOV was associated with a significantly reduced risk of at least one severe COVID-19 outcome in at least one age group, with greater benefits consistently observed among older age groups. CONCLUSIONS: In this SLR study, treatment with MOV was effective in reducing the risk of severe outcomes from COVID-19 caused by Omicron variants, especially for older individuals. Differences in the ages and baseline comorbidities of the MOV-treated and control groups may have led to underestimation of the effectiveness of MOV in many observational studies. Real-world studies published to date thus provide additional evidence supporting the continued benefits of MOV in non-hospitalized adults with COVID-19.

COVID-19 continues to be a major source of morbidity and mortality. Throughout the pandemic, many countries authorized various therapies for the treatment of individuals presenting with mild-to-moderate COVID-19 and at high risk of progression to severe disease. Some of these therapies have since been rendered ineffective due to the emergence of Omicron variants in late 2021. The objective of the current study was to conduct a systematic literature review to assess real-world evidence on the effectiveness of molnupiravir, including effectiveness against COVID-19 caused by Omicron variants, to supplement the findings of the MOVe-OUT clinical trial and further inform on the potential clinical benefit and utility of this antiviral agent. Nine studies were included in the systematic literature review. We found that treatment with molnupiravir was effective in reducing the risk of severe outcomes from COVID-19 caused by Omicron variants, especially for older individuals. Differences in the ages and baseline comorbidities of the molnupiravir-treated and control groups may have led to underestimation of the effectiveness of molnupiravir in many observational studies. In summary, real-world effectiveness studies provide additional evidence supporting the continued benefits of molnupiravir in non-hospitalized adults with COVID-19.

Pfizer-BioNTech Coronavirus Disease 2019 Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Long-term Care Facility Staff With and Without Prior Infection in New York City, January-June 2021.

BACKGROUND: Evidence is accumulating of coronavirus disease 2019 (COVID-19) vaccine effectiveness among persons with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We evaluated the effect against incident SARS-CoV-2 infection of (1) prior infection without vaccination, (2) vaccination (2 doses of Pfizer-BioNTech COVID-19 vaccine) without prior infection, and (3) vaccination after prior infection, all compared with unvaccinated persons without prior infection. We included long-term care facility staff in New York City aged <65 years with weekly SARS-CoV-2 testing from 21 January to 5 June 2021. Test results were obtained from state-mandated laboratory reporting. Vaccination status was obtained from the Citywide Immunization Registry. Cox proportional hazards models adjusted for confounding with inverse probability of treatment weights. RESULTS: Compared with unvaccinated persons without prior infection, incident SARS-CoV-2 infection risk was lower in all groups: 54.6% (95% confidence interval, 38.0%-66.8%) lower among unvaccinated, previously infected persons; 80.0% (67.6%-87.7%) lower among fully vaccinated persons without prior infection; and 82.4% (70.8%-89.3%) lower among persons fully vaccinated after prior infection. CONCLUSIONS: Two doses of Pfizer-BioNTech COVID-19 vaccine reduced SARS-CoV-2 infection risk by ≥80% and, for those with prior infection, increased protection from prior infection alone. These findings support recommendations that all eligible persons, regardless of prior infection, be vaccinated against COVID-19.

Brief Report: Dapivirine Ring HIV-1 Prevention Effectiveness for Women Engaged in Vaginal and Anal Intercourse: Insights From Mathematical Modeling.

BACKGROUND: The dapivirine vaginal ring reduces the risk of HIV-1 acquisition in acts of vaginal intercourse (VI), and although it does not offer HIV-1 protection in acts of anal intercourse (AI), it may provide some overall risk reduction for women for whom most sex acts are vaginal. We estimated the protective effect of the ring among women with high ring adherence engaged in both VI and AI. METHODS: We developed a microsimulation model using data from the MTN-020/ASPIRE trial. Among women who reported any AI, we estimated the proportion of all sex acts that were AI. Model scenarios varied this proportion among women engaged in both VI and AI from 5% to 30%, including the trial-observed median proportion of 6.3% of all acts being AI. In primary analyses, dapivirine ring efficacy was model-calibrated at 70% for vaginal exposures and assumed to be 0% for anal exposures. RESULTS: Among highly adherent women for whom 6.3% of sex acts were AI, the ring reduced HIV-1 risk by 53% (interquartile range: 44, 60), with a decline to 26% (interquartile range: 16, 36) among women for whom 30% of acts were AI. Ring effectiveness was less than 40% among women for whom AI accounted for greater than 16% of all sex acts, although this represented less than 5% of all women in the ASPIRE trial. CONCLUSIONS: For most women, including those who engage in AI, because most HIV-1 risk occurs in acts of vaginal sex, the dapivirine vaginal ring can provide important HIV-1 protection.

Incremental costs of integrated PrEP provision and effective use counselling in community-based platforms for adolescent girls and young women in South Africa: an observational study.

INTRODUCTION: Adolescent girls and young women (AGYW) are a priority population for pre-exposure prophylaxis (PrEP), a highly effective HIV prevention method. However, effective PrEP use among AGYW has been low. Interventions to support PrEP effective use may improve pill-taking. Affordability of PrEP programs depends on their cost. We, therefore, evaluated the cost of community-based PrEP with effective use counselling. METHODS: Cost data from a randomized controlled trial were used to evaluate the cost of PrEP provision with effective use counselling offered to AGYW through community-based HIV testing platforms between November 2018 and November 2019. AGYW were randomized to receive (1) group-based community health club effective use counselling, (2) individualized effective use counselling or (3) community-based PrEP dispensary. Task shifting of effective use counselling from nurses to trained lay counsellors was implemented in groups 1 and 2. Personnel costs were estimated from time-and-motion observations and staff interviews. Expenditure and ingredients-based approaches were used to estimate costs for medical and non-medical supplies. RESULTS: In total, 603 AGYW initiated PrEP and accrued a total of 1280 months on PrEP. Average cost per person-month on PrEP with group-based community health club, individualized effective use counselling and community-based PrEP dispensary under the Department of Health scenario were similar and high (USD $55.32, $55.65 and $55.46, respectively) due to low PrEP client volume observed in the clinical trial. Increasing client volume (scaled Department of Health scenario) reduced cost per-person month estimates to USD $15.48, $26.40 and $13.99, respectively. CONCLUSIONS: As designed, individualized effective use counselling increased the cost of standard-of-care PrEP delivery by 89%, group-based community health effective use counselling increased the cost of standard-of-care PrEP delivery by 11%. These estimates can inform cost-effectiveness and budget impact analysis for PrEP provision with effective use counselling services.

Adapting Survey Data Collection to Respond to the COVID-19 Pandemic: Experiences From a Local Health Department.

The New York City (NYC) Department of Health and Mental Hygiene ("Health Department") conducts routine surveys to describe the health of NYC residents. During the COVID-19 pandemic, the Health Department adjusted existing surveys and developed new ones to improve our understanding of the impact of the pandemic on physical health, mental health, and social determinants of health and to incorporate more explicit measures of racial inequities. The longstanding Community Health Survey was adapted in 2020 to ask questions about COVID-19 and recruit respondents for a population-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurvey. A new survey panel, Healthy NYC, was launched in June 2020 and is being used to collect data on COVID-19, mental health, and social determinants of health. In addition, 7 Health Opinion Polls were conducted from March 2020 through March 2021 to learn about COVID-19-related knowledge, attitudes, and opinions, including vaccine intentions. We describe the contributions that survey data have made to the emergency response in NYC in ways that address COVID-19 and the profound inequities of the pandemic. (Am J Public Health. 2021;111(12):2176-2185. https://doi.org/10.2105/AJPH.2021.306515).

Low costs and opportunities for efficiency: a cost analysis of the first year of programmatic PrEP delivery in Kenya's public sector.

BACKGROUND: In 2017, the Kenyan Ministry of Health integrated provision of pre-exposure prophylaxis (PrEP) into public HIV-1 care clinics as a key component of the national HIV-1 prevention strategy. Estimates of the cost of PrEP provision are needed to inform the affordability and cost-effectiveness of PrEP in Kenya. METHODS: We conducted activity-based micro-costing from the payer perspective to estimate both the financial and economic costs of all resources and activities required to provide PrEP in Kenya's public sector. We estimated total and unit costs in 2019 United States dollars from a combination of project expense reports, Ministry of Health training reports, clinic staff interviews, time-and-motion observations, and routinely collected data from PrEP recipient files from 25 high-volume HIV-1 care clinics. RESULTS: In the first year of programmatic PrEP delivery in 25 HIV-1 care clinics, 2,567 persons initiated PrEP and accrued 8,847 total months of PrEP coverage, accounting for 2 % of total outpatient clinic visits. The total financial cost to the Ministry of Health was $91,175, translating to an average of $10.31 per person per month. The majority (69 %) of financial costs were attributable to PrEP medication, followed by administrative supplies (17 %) and training (9 %). Economic costs were higher ($188,584 total; $21.32 per person per month) due to the inclusion of the opportunity cost of staff time re-allocated to provide PrEP and a proportional fraction of facility overhead. The vast majority (88 %) of the annual $80,811 economic cost of personnel time was incurred during activities to recruit new clients (e.g., discussion of PrEP within HIV-1 testing and counselling services), while the remaining 12 % was for activities related to both initiation and maintenance of PrEP provision (e.g., client consultations, technical advising, support groups). CONCLUSIONS: Integration of PrEP provision into existing public health HIV-1 care service delivery platforms resulted in minimal additional staff burden and low incremental costs. Efforts to improve the efficiency of PrEP provision should focus on reductions in the cost of PrEP medication and extra-clinic demand creation and community sensitization to reduce personnel time dedicated to recruitment-related activities. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT03052010 . Retrospectively registered on February 14, 2017.

Cost of pre-exposure prophylaxis delivery in family planning clinics to prevent HIV acquisition among adolescent girls and young women in Kisumu, Kenya.

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is increasingly being implemented in sub-Saharan Africa. Adolescent girls and young women (AGYW) in Kenya contribute more than half of all new infections among young people aged 15-24 years, highlighting the need for evidence on the cost of PrEP in real-world implementation to inform the budget impact, cost-effectiveness, and financial sustainability of PrEP programs. METHODS: We estimated the cost of delivering PrEP to AGYW enrolled in a PrEP implementation study in two family planning clinics in Kisumu county, located in western Kenya. We derived total annual costs and the average cost per client-month of PrEP by input type (variable or fixed) and visit type (initiation or follow-up). We estimated all costs as implemented in the study, and under implementation by the Kenyan Ministry of Health (MoH), both at the program volume observed and if the facilities were delivering PrEP at full capacity (scaled-MoH). RESULTS: For the costing period between March 2018 and March 2019, 615 HIV-negative women contributed 1,128 (502 initiation and 626 follow-up) visits. The average cost per client-month of PrEP dispensed per study protocol and per the MoH scenario was $28.92 and $14.52, respectively. If the MoH scaled the program so that facilities could see PrEP clients at capacity, the average cost per client-month of PrEP was $10.88. Medication costs accounted for the largest proportion of the total annual costs (48% in MoH scenario and 65% in the scaled-MoH scenario). CONCLUSIONS: Using data from a PrEP implementation program, we found that the cost per client-month of PrEP dispensed is reduced by 62% if PrEP delivery at the two clinics is scaled up by the MoH. Our findings are valuable for informing local resource allocation and budgetary cost projections for scale-up of PrEP delivery to AGYW. Additionally, previous cost-effectiveness studies have been limited by the use of fixed assumptions of the cost of PrEP per person-month. Our study provides cost estimates from practical data which will better inform cost-effectiveness and budget impact analyses.

Risk compensation after HIV-1 vaccination may accelerate viral adaptation and reduce cost-effectiveness: a modeling study.

Pathogen populations can evolve in response to selective pressure from vaccine-induced immune responses. For HIV, models predict that viral adaptation, either via strain replacement or selection on de novo mutation, may rapidly reduce the effectiveness of an HIV vaccine. We hypothesized that behavioral risk compensation after vaccination may accelerate the transmission of vaccine resistant strains, increasing the rate of viral adaptation and leading to a more rapid decline in vaccine effectiveness. To test our hypothesis, we modeled: (a) the impact of risk compensation on rates of HIV adaptation via strain replacement in response to a partially effective vaccine; and (b) the combined impact of risk compensation and viral adaptation on vaccine-mediated epidemic control. We used an agent-based epidemic model that was calibrated to HIV-1 trends in South Africa, and includes demographics, sexual network structure and behavior, and within-host disease dynamics. Our model predicts that risk compensation can increase the rate of HIV viral adaptation in response to a vaccine. In combination, risk compensation and viral adaptation can, under certain scenarios, reverse initial declines in prevalence due to vaccination, and result in HIV prevalence at 15 years equal to or greater than prevalence without a vaccine.

"I Just Decided to Stop:" Understanding PrEP Discontinuation Among Individuals Initiating PrEP in HIV Care Centers in Kenya.

BACKGROUND: Preexposure prophylaxis (PrEP) discontinuation rates in clinical trials and demonstration projects have been well characterized; however, little is known about discontinuation in routine public health settings in sub-Saharan Africa. Understanding discontinuation in nonstudy settings is important for establishing expectations for PrEP continuation in national programs and for facilitating effective PrEP scale-up. METHODS: We conducted in-depth interviews with 46 individuals who had initiated PrEP at 25 HIV comprehensive care clinics (CCCs) in central and western Kenya and whose clinic records indicated they had discontinued. RESULTS: Many of our study participants discontinued PrEP when their perceived risk decreased (eg, hiatus or end of a sexual relationship or partner known to be living with HIV became virally suppressed). Others reported discontinuation due to side effects, daily pill burden, preference for condoms, or their partner's insistence. Participant narratives frequently described facility level factors such as stigma-related discomforts with accessing PrEP at CCCs, inconvenient clinic location or operating hours, long wait times, and short refill dates as discouraging factors, suggesting actionable areas for improving PrEP access and continuation. CONCLUSION: Clients frequently make intentional decisions to discontinue PrEP as they weigh different prevention options within the context of complex lives. Many clients will decide to discontinue PrEP when perceiving themselves to be at reduced risk and PrEP counseling must include provisions for addressing seasons of risk. PrEP will not be the right prevention method for everyone, or forever. Expanding PrEP access points and increasing sex-positive messaging may facilitate PrEP being a better option for many.

Elevated Risk of Bacterial Vaginosis Among Users of the Copper Intrauterine Device: A Prospective Longitudinal Cohort Study.

BACKGROUND: Limited evidence suggests that the nonhormonal contraceptive copper intrauterine device (Cu-IUD) may increase bacterial vaginosis (BV) risk, possibly due to increased volume and duration of menses, a common side effect of Cu-IUD use. Although increases in bleeding typically resolve within 6-12 months following initiation, evaluations of the association between Cu-IUD and BV have not included more than 6 months of follow-up. METHODS: This secondary analysis of a human immunodeficiency virus type 1 prevention trial included 2585 African women ages 18-45 followed for up to 33 months. Women reported contraceptive use each month. BV was evaluated by Nugent score in 6-monthly intervals and, if clinically indicated, by Amsel criteria. Andersen-Gill proportional hazards models were used to (1) evaluate BV risk among Cu-IUD users relative to women using no/another nonhormonal contraceptive and (2) test changes in BV frequency before, while using, and following Cu-IUD discontinuation. RESULTS: BV frequency was highest among Cu-IUD users at 153.6 episodes per 100 person-years (95% confidence interval [CI]: 145.2, 162.4). In adjusted models, Cu-IUD users experienced 1.28-fold (95% CI: 1.12, 1.46) higher BV risk relative to women using no/another nonhormonal contraception. Compared to the 6 months prior to initiation, BV risk was 1.52-fold (95% CI: 1.16, 2.00) higher in the first 6 months of Cu-IUD use and remained elevated over 18 months of use (P < .05). Among women who discontinued Cu-IUD, BV frequency was similar to pre-initiation rates within 1 year. CONCLUSIONS: Cu-IUD users experienced elevated BV risk that persisted throughout use. Women and their providers may wish to consider BV risk when discussing contraceptive options.

Individual and community-level benefits of PrEP in western Kenya and South Africa: Implications for population prioritization of PrEP provision.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV and has the potential to significantly impact the HIV epidemic. Given limited resources for HIV prevention, identifying PrEP provision strategies that maximize impact is critical. METHODS: We used a stochastic individual-based network model to evaluate the direct (infections prevented among PrEP users) and indirect (infections prevented among non-PrEP users as a result of PrEP) benefits of PrEP, the person-years of PrEP required to prevent one HIV infection, and the community-level impact of providing PrEP to populations defined by gender and age in western Kenya and South Africa. We examined sensitivity of results to scale-up of antiretroviral therapy (ART) and voluntary medical male circumcision (VMMC) by comparing two scenarios: maintaining current coverage ("status quo") and rapid scale-up to meet programmatic targets ("fast-track"). RESULTS: The community-level impact of PrEP was greatest among women aged 15-24 due to high incidence, while PrEP use among men aged 15-24 yielded the highest proportion of indirect infections prevented in the community. These indirect infections prevented continue to increase over time (western Kenya: 0.4-5.5 (status quo); 0.4-4.9 (fast-track); South Africa: 0.5-1.8 (status quo); 0.5-3.0 (fast-track)) relative to direct infections prevented among PrEP users. The number of person-years of PrEP needed to prevent one HIV infection was lower (59 western Kenya and 69 in South Africa in the status quo scenario; 201 western Kenya and 87 in South Africa in the fast-track scenario) when PrEP was provided only to women compared with only to men over time horizons of up to 5 years, as the indirect benefits of providing PrEP to men accrue in later years. CONCLUSIONS: Providing PrEP to women aged 15-24 prevents the greatest number of HIV infections per person-year of PrEP, but PrEP provision for young men also provides indirect benefits to women and to the community overall. This finding supports existing policies that prioritize PrEP use for young women, while also illuminating the community-level benefits of PrEP availability for men when resources permit.

Age-Specific Risk Scores Do Not Improve HIV-1 Prediction Among Women in South Africa.

BACKGROUND: HIV-1 risk scoring tools could help target provision of prevention modalities such as pre-exposure prophylaxis. Recent research suggests that risk scores for women aged 18-45 may not predict risk well among young women aged 18-24. We evaluated the predictive performance of age-specific risk scores compared with the existing non-age-specific VOICE risk score, developed for women aged 18-45. METHODS: We conducted a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes Trial to develop and internally validate HIV-1 risk scores for women aged 18-24 and 25-35 in South Africa. Candidate predictors included baseline demographic, clinical, behavioral, and contextual characteristics readily available in clinical settings. The VOICE risk score was applied to women aged 18-35. We evaluated predictive performance of each risk score by area under the receiver operating characteristic curve (AUC). RESULTS: Predictive performance of all risk scores was moderate, with AUC (95% confidence interval) of 0.64 (0.60 to 0.67) among women aged 18-24, 0.68 (0.62 to 0.73) among those aged 25-35, and 0.61 (0.58 to 0.65) for the VOICE risk score applied to women aged 18-35; The AUC was similar in internal validation. Among women aged 18-24, HIV-1 incidence was high even at low risk scores, at 3.9 per 100 person-years (95% confidence interval: 3.2 to 4.7). CONCLUSIONS: All risk scores were moderately predictive of HIV-1 acquisition, and age-specific risk scores performed only marginally better than the VOICE non-age-specific risk score. Approaches for targeted pre-exposure prophylaxis provision to women in South Africa may require more extensive data than are currently available to improve prediction.

Impact along the HIV pre-exposure prophylaxis "cascade of prevention" in western Kenya: a mathematical modelling study.

INTRODUCTION: Over one hundred implementation studies of HIV pre-exposure prophylaxis (PrEP) are completed, underway or planned. We synthesized evidence from these studies to inform mathematical modelling of the prevention cascade for oral and long-acting PrEP in the setting of western Kenya, one of the world's most heavily HIV-affected regions. METHODS: We incorporated steps of the PrEP prevention cascade - uptake, adherence, retention and re-engagement after discontinuation - into EMOD-HIV, an open-source transmission model calibrated to the demography and HIV epidemic patterns of western Kenya. Early PrEP implementation research from East Africa was used to parameterize prevention cascades for oral PrEP as currently implemented, delivery innovations for oral PrEP, and future long-acting PrEP. We compared infections averted by PrEP at the population level for different cascade assumptions and sub-populations on PrEP. Analyses were conducted over the 2020 to 2040 time horizon, with additional sensitivity analyses for the time horizon of analysis and the time when long-acting PrEP becomes available. RESULTS: The maximum impact of oral PrEP diminished by over 98% across all prevention cascades, with the exception of long-acting PrEP under optimistic assumptions about uptake and re-engagement after discontinuation. Long-acting PrEP had the highest population-level impact, even after accounting for possible delays in product availability, primarily because its effectiveness does not depend on drug adherence. Retention was the most significant cascade step reducing the potential impact of long-acting PrEP. These results were robust to assumptions about the sub-populations receiving PrEP, but were highly influenced by assumptions about re-initiation of PrEP after discontinuation, about which evidence was sparse. CONCLUSIONS: Implementation challenges along the prevention cascade compound to diminish the population-level impact of oral PrEP. Long-acting PrEP is expected to be less impacted by user uptake and adherence, but it is instead dependent on product availability in the short term and retention in the long term. To maximize the impact of long-acting PrEP, ensuring timely product approval and rollout is critical. Research is needed on strategies to improve retention and patterns of PrEP re-initiation.

"I just believe there is a risk" understanding of undetectable equals untransmissible (U = U) among health providers and HIV-negative partners in serodiscordant relationships in Kenya.

INTRODUCTION: Sustained HIV viral suppression resulting from antiretroviral therapy (ART) eliminates the risk of HIV transmission, a concept popularly framed as Undetectable = Untransmittable (U = U). We explored knowledge and acceptance of information around the elimination of HIV transmission risk with ART (U = U) in Kenya. METHODS: Our qualitative study was conducted within a project evaluating the use of pre-exposure prophylaxis (PrEP) integrated into ART care for HIV serodiscordant couples in public clinics in Kenya (the Partners Scale Up Project). From February 2017 to April 2019, we conducted semi-structured key informant interviews with 83 health providers and in-depth interviews with 61 HIV-negative people in serodiscordant relationships receiving PrEP services. Transcripts were coded using thematic analysis. RESULTS: Health providers reported being aware of reduced risk of HIV transmission as a result of consistent ART use and used words such as "very low," "minimal" and "like zero" to describe HIV transmission risk after viral suppression. Providers reported finding viral load results helpful when counselling clients about the risk of HIV transmission. Many lacked confidence in U = U and counselled on consistent condom use even after viral suppression while some expressed concerns that communicating this message to people living with HIV (PLHIV) would lead them to engage in multiple sexual relationships. Other providers reported that they did not counsel about the reduced risk of HIV transmission after viral suppression for fear of being blamed if HIV transmission occurred. HIV-negative partners reported being informed about U = U by providers but they did not believe nor trust the message. Even after their partners achieved viral suppression, some HIV-negative partners were unwilling to stop PrEP, while others indicated that they would use condoms if they stopped PrEP to be sure that they were protected from HIV. CONCLUSIONS: Despite awareness that effective ART use eliminates HIV transmission risk, there is both a lack of in-depth knowledge and conviction about the strategy among health providers and HIV-negative partners in serodiscordant relationships. New strategies that go beyond communicating the science of U = U to consider the local social and clinical environments could maximize the effectiveness of U = U.

Brief Report: Anal Intercourse, HIV-1 Risk, and Efficacy in a Trial of a Dapivirine Vaginal Ring for HIV-1 Prevention.

OBJECTIVES: To describe receptive anal intercourse (RAI) behaviors and correlates in a cohort of sub-Saharan African women, evaluate the association of RAI with HIV-1 risk, and evaluate whether the HIV-1 prevention efficacy of a dapivirine vaginal ring differs among women who reported RAI. DESIGN: Secondary analysis of the MTN-020/ASPIRE trial, a randomized, double-blind, placebo-controlled trial evaluating a dapivirine vaginal ring for HIV-1 prevention. METHODS: At enrollment and month 3, women reported RAI in the prior 3 months in audio computer-assisted self-interviews. We evaluated associations between RAI and participant characteristics with χ and t-tests adjusted for study site. Cox proportional hazards models stratified by study site tested the association of RAI with HIV-1 acquisition and effect modification by RAI. RESULTS: Eighteen percent of women reported any RAI at enrollment and/or month 3, with a median of 2 (interquartile range: 1-4) RAI acts in the prior 3 months, accounting for 1.5% of total sex acts. RAI prevalence was higher among women with lower educational attainment and those reporting transactional sex. In adjusted models, RAI was not associated with HIV-1 acquisition (aHR: 0.93, 95% CI: 0.57 to 1.54). The ring reduced HIV-1 risk by 27% (95% CI: -5 to 49) among women reporting no RAI and by 18% (95% CI: -57 to 57) among women reporting any RAI (interaction P-value = 0.77). CONCLUSIONS: RAI was modestly infrequent and was not associated with reduced HIV-1 protection from the ring, suggesting that, in populations with rates of RAI similar to this cohort, RAI may not appreciably reduce the population-level impact of the dapivirine vaginal ring.

Large benefits to youth-focused HIV treatment-as-prevention efforts in generalized heterosexual populations: An agent-based simulation model.

Predominantly heterosexual HIV-1 epidemics like those in sub-Saharan Africa continue to have high HIV incidence in young people. We used a stochastic, agent-based model for age-disparate networks to test the hypothesis that focusing uptake and retention of ART among youth could enhance the efficiency of treatment as prevention (TasP) campaigns. We used the model to identify strategies that reduce incidence to negligible levels (i.e., < 0.1 cases/100 person-years) 20-25 years after initiation of a targeted TasP campaign. The model was parameterized using behavioral, demographic, and clinical data from published papers and national reports. To keep a focus on the underlying age effects we model a generalized heterosexual population with average risks (i.e., no MSM, no PWIDs, no sex workers) and no entry of HIV+ people from other regions. The model assumes that most people (default 95%, range in variant simulations 60-95%) are "linkable"; i.e., could get linked to effective care given sufficient resources. To simplify the accounting, we assume a rapid jump in the number of people receiving treatment at the start of the TasP campaign, followed by a 2% annual increase that continues until all linkable HIV+ people have been treated. Under historical scenarios of CD4-based targeted ART allocation and current policies of untargeted (random) ART allocation, our model predicts that viral replication would need to be suppressed in 60-85% of infected people at the start of the TasP campaign to drive incidence to negligible levels. Under age-based strategies, by contrast, this percentage dropped by 18-54%, depending on the strength of the epidemic and the age target. For our baseline model, targeting those under age 30 halved the number of people who need to be treated. Age-based targeting also minimized total and time-discounted AIDS deaths over 25 years. Age-based targeting yielded benefits without being highly exclusive; in a model in which 60% of infected people were treated, ~87% and ~58% of those initiating therapy during a campaign targeting those <25 and <30 years, respectively, fell outside the target group. Sensitivity analyses revealed that youth-focused TasP is beneficial due to age-related risk factors (e.g. shorter relationship durations), and an age-specific herd immunity (ASHI) effect that protects uninfected adolescents entering the sexually active population. As testing rates increase in response to UNAIDS 90-90-90 goals, efforts to link all young people to care and treatment could contribute enormously to ending the HIV epidemic.

Models to predict the public health impact of vaccine resistance: A systematic review.

Pathogen evolution is a potential threat to the long-term benefits provided by public health vaccination campaigns. Mathematical modeling can be a powerful tool to examine the forces responsible for the development of vaccine resistance and to predict its public health implications. We conducted a systematic review of existing literature to understand the construction and application of vaccine resistance models. We identified 26 studies that modeled the public health impact of vaccine resistance for 12 different pathogens. Most models predicted that vaccines would reduce overall disease burden in spite of evolution of vaccine resistance. Relatively few pathogens and populations for which vaccine resistance may be problematic were covered in the reviewed studies, with low- and middle-income countries particularly under-represented. We discuss the key components of model design, as well as patterns of model predictions.

High Global Burden and Costs of Bacterial Vaginosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Bacterial vaginosis (BV) is the most common vaginal infection among women of reproductive age and is associated with important adverse health outcomes. Estimates of the burden of BV and associated costs are needed to inform research priorities. METHODS: We conducted a systematic review and meta-analysis of global BV prevalence among reproductive-aged women in the general population. We searched PubMed and Embase and used random effects models to estimate BV prevalence by global regions. We estimated the direct medical costs of treating symptomatic BV. Assuming a causal relationship, we also estimated the potential costs of BV-associated preterm births and human immunodeficiency virus cases in the United States. RESULTS: General population prevalence of BV is high globally, ranging from 23% to 29% across regions (Europe and Central Asia, 23%; East Asia and Pacific, 24%; Latin America and Caribbean, 24%; Middle East and North Africa, 25%; sub-Saharan Africa, 25%; North America, 27%; South Asia, 29%). Within North America, black and Hispanic women have significantly higher (33% and 31%, respectively) prevalence compared with other racial groups (white, 23%; Asian, 11%; P < 0.01). The estimated annual global economic burden of treating symptomatic BV is US $4.8 (95% confidence interval, $3.7-$6.1) billion. The US economic burden of BV is nearly tripled when including costs of BV-associated preterm births and human immunodeficiency virus cases. CONCLUSIONS: The BV prevalence is high globally, with a concomitant high economic burden and marked racial disparities in prevalence. Research to determine the etiology of BV and corresponding prevention and sustainable treatment strategies are urgently needed to reduce the burden of BV among women. Additionally, the exceptionally high cost of BV-associated sequelae highlights the need for research to understand potential causal linkages between BV and adverse health outcomes.

Higher prevalence of viral control in HIV-1-infected women in serodiscordant relationships.

BACKGROUND: HIV-1-discordant couples that remain discordant despite repeated exposure may differ from the general population in their distribution of transmission risk factors, including low plasma viral load (PVL) in the infected partner even in the absence of antiretroviral therapy (ART). METHODS: We followed two cohorts of HIV-1-infected Kenyan women: females in discordant couples (FDC) and female sex workers (FSW). We compared the distribution of undetectable (<150 copies/mL) and low PVL (<1,000 copies/mL) between the cohorts using bootstrap methods and exact Poisson regression. RESULTS: We evaluated 296 FDC and 220 FSW. At baseline, FDC were more likely to have undetectable (RR = 6.94, bootstrap 95% CI: 3.47, 20.81) and low PVL (RR = 3.53, bootstrap 95% CI: 2.57, 5.65) than FSW. Similarly, both repeat undetectable PVL (RR = 9.36, bootstrap 95% CI: 6.04, 10.97) and repeat low (RR = 4.99, bootstrap 95% CI: 2.33, 14.04) PVL were more likely among FDC than FSW during follow-up. DISCUSSION: We observed higher prevalence of viral control in FDC compared to FSW in the absence of ART, suggesting potentially higher prevalence of biological HIV resistance factors among discordant couples.