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Abstract Background New York City (NYC) was the first COVID-19 epicenter in the United States and home to one of the country’s largest contact tracing programs, NYC Test & Trace (T2). Understanding points of attrition along the stages of program implementation and follow-up can inform contact tracing efforts for future epidemics or pandemics. The objective of this study was to evaluate the completeness and timeliness of T2 case and contact notification and monitoring using a “cascade of care” approach. Methods This cross-sectional study included all SARS-CoV-2 cases and contacts reported to T2 from May 31, 2020 to January 1, 2022. Attrition along the “cascade of care” was defined as: (1) attempted, (2) reached, (3) completed intake (main outcome), (4) eligible for monitoring, and (5) successfully monitored. Timeliness was assessed: (1) by median days from a case’s date of testing until their positive result was reported to T2, (2) from result until the case was notified by T2, and (3) from a case report of a contact until notification of the contact. Results A total of 1.45 million cases and 1.38 million contacts were reported to T2 during this period. For cases, attrition occurred evenly across the first three cascade steps (~-12%) and did not change substantially until the Omicron wave in December 2021. During the Omicron wave, the proportion of cases attempted dropped precipitously. For contacts, the largest attrition occurred between attempting and reaching (-27%), and attrition rose with each COVID-19 wave as contact volumes increased. Attempts to reach contacts discontinued entirely during the Omicron wave. Overall, 67% of cases and 49% of contacts completed intake interviews (79% and 57% prior to Omicron). T2 was timely, with a median of 1 day to receive lab results, 2 days to notify cases, and

Abstract Background Mathematical models are increasingly used to inform HIV policy and planning. Comparing estimates obtained using different mathematical models can test the robustness of estimates and highlight research gaps. As part of a larger project aiming to determine the optimal allocation of funding for HIV services, in this study we compare projections from five mathematical models of the HIV epidemic in South Africa: EMOD-HIV, Goals, HIV-Synthesis, Optima, and Thembisa. Methods The five modelling groups produced estimates of the total population, HIV incidence, HIV prevalence, proportion of people living with HIV who are diagnosed, ART coverage, proportion of those on ART who are virally suppressed, AIDS-related deaths, total deaths, and the proportion of adult males who are circumcised. Estimates were made under a “status quo” scenario for the period 1990 to 2040. For each output variable we assessed the consistency of model estimates by calculating the coefficient of variation and examining the trend over time. Results For most outputs there was significant inter-model variability between 1990 and 2005, when limited data was available for calibration, good consistency from 2005 to 2025, and increasing variability towards the end of the projection period. Estimates of HIV incidence, deaths in people living with HIV, and total deaths displayed the largest long-term variability, with standard deviations between 35 and 65% of the cross-model means. Despite this variability, all models predicted a gradual decline in HIV incidence in the long-term. Projections related to the UNAIDS 95–95-95 targets were more consistent, with the coefficients of variation below 0.1 for all groups except children. Conclusions While models produced consistent estimates for several outputs, there are areas of variability that should be investigated. This is important if projections are to be used in subsequent cost-effectiveness studies.

Abstract Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)‐approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well‐established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID‐19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease‐related consequences of SARS‐CoV‐2 infection/COVID‐19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS‐CoV‐2 infection/COVID‐19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS‐CoV‐2(−)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS‐CoV‐2(−)/(+)participants, and incorporating COVID‐19‐associated changes in cytochrome P450 activity did not further improve model performance for the SARS‐CoV‐2(+) population.

Introduction In sub-Saharan Africa, HIV/AIDS remains a leading cause of death. The UNAIDS established the ‘95-95-95’ targets to improve HIV care continuum outcomes. Using geospatial data from the Zambia Population-based HIV Impact Assessment (ZAMPHIA), this study aims to investigate geospatial patterns in the ‘95-95-95’ indicators and individual-level determinants that impede HIV care continuum in vulnerable communities, providing insights into the factors associated with gaps.Methods This study used data from the 2016 ZAMPHIA to investigate the geospatial distribution and individual-level determinants of engagement across the HIV care continuum in Zambia. Gaussian kernel interpolation and optimised hotspot analysis were used to identify geospatial patterns in the HIV care continuum, while geospatial k-means clustering was used to partition areas into clusters. The study also assessed healthcare availability, access and social determinants of healthcare utilisation. Multiple logistic regression models were used to examine the association between selected sociodemographic and behavioural covariates and the three main outcomes of study.Results Varied progress towards the ‘95-95-95’ targets were observed in different regions of Zambia. Each ‘95’ displayed a unique geographical pattern, independent of HIV prevalence, resulting in four distinct geographical clusters. Factors associated with gaps in the ‘95s’ include younger age, male sex, and low wealth, with younger individuals having higher odds of not being on antiretroviral therapy and having detectable viral loads.Conclusions Our study revealed significant spatial heterogeneity in the HIV care continuum in Zambia, with different regions exhibiting unique geographical patterns and levels of performance in the ‘95-95-95’ targets, highlighting the need for geospatial tailored interventions to address the specific needs of different subnational regions. These findings underscore the importance of addressing differential regional gaps in HIV diagnosis, enhancing community-level factors and developing innovative strategies to improve local HIV care continuum outcomes.

Abstract Background Prioritization of higher-risk people for COVID-19 vaccination could prevent more deaths, but could slow vaccination speed. We used mathematical modeling to examine the trade-off between vaccination speed and prioritization for individuals age 65+ and essential workers. Methods We used a stochastic, discrete-time susceptible-exposed-infected-recovered (SEIR) model with age- and comorbidity-adjusted COVID-19 outcomes (infections, hospitalizations, and deaths). The model was calibrated to COVID-19 hospitalizations, ICU census, and deaths in NYC. We assumed 10,000 vaccinations per day, initially restricted to healthcare workers and nursing home populations, and subsequently expanded to other populations at alternative times (4, 5, or 6 weeks after vaccine launch) and speeds (20,000, 50,000, 100,000, or 150,000 vaccinations per day), as well as prioritization options (+/− prioritization of people age 65+ and essential workers). In sensitivity analyses, we examined the effect of a SARS-COV-2 variant with greater transmissibility. Results To be beneficial, prioritization must not create a bottleneck that decreases vaccination speed by > 50% without a more transmissible variant, or by > 33% with the emergence of the more transmissible variant. More specifically, prioritizing people age 65+ and essential workers increased the number of lives saved per vaccine dose delivered: 3000 deaths could be averted by delivering 83,000 vaccinations per day without prioritization or 50,000 vaccinations per day with prioritization. Other tradeoffs involve vaccination speed and timing. Compared to the slowest-examined vaccination speed of 20,000 vaccinations per day, achieving the fastest-examined vaccination speed of 150,000 vaccinations per day would avert additional 313,700 (28.6%) infections and 1693 (24.1%) deaths. Emergence of a more transmissible variant would double COVID-19 infections, hospitalizations, and deaths over the first 6 months of vaccination. The fastest-examined vaccination speed could only offset the harm of the more transmissible variant if achieved within 5 weeks of vaccine launch. Conclusions Faster vaccination speed with sooner vaccination expansion would save more lives. Prioritization of COVID-19 vaccines to higher-risk populations would be more beneficial only if it does not create an excessive vaccine delivery bottleneck.

HIV/AIDS and maternal mortality are the two leading causes of death among women of reproductive age in sub-Saharan Africa. A growing body of research investigates opportunities for multipurpose prevention technologies (MPTs) that prevent unintended pregnancy, HIV, and/or other sexually transmitted infections (STIs) with a single product. More than two dozen MPTs are currently in development, most of them combining contraception with HIV pre-exposure prophylaxis, with or without protection from other STIs. If successful, such MPTs could offer women benefits at multiple levels: greater motivation for effective use; lower product administration burden; accelerated integration of HIV, STI, and reproductive health services; and opportunities to circumvent stigma by using contraception as a “fig leaf” for HIV and/or STI prevention. However, even if women find respite from product burden, lack of motivation, and/or stigma in contraceptive-containing MPTs, their use of MPTs will be interrupted, often multiple times, over the reproductive lifecourse due to desire for pregnancy, pregnancy and breastfeeding, menopause, and changes in risk. Interruptions to the benefits of MPTs could be avoided by combining HIV/STI prevention with other life-stage-appropriate reproductive health products. New product concepts could include combining prenatal supplements with HIV and STI prevention, emergency contraception with HIV post-exposure prophylaxis, or hormone replacement therapies for menopause with HIV and STI prevention. Research is needed to optimize the MPT pipeline based on the populations underserved by available options and the capacity of resource-constrained health systems to deliver novel preventative healthcare products.

IntroductionWomen in sub-Saharan Africa (SSA) experience the world's highest rates of both HIV infection and unintended pregnancy. The Dual Prevention Pill (DPP) is a novel multipurpose prevention technology (MPT) that co-formulates HIV pre-exposure prophylaxis (PrEP) and combined hormonal oral contraception into a single daily pill. As a dual indication product, the DPP may be preferred by women facing these overlapping health risks. However, most SSA countries face severe healthcare resource constraints. Research is needed to assess whether, in what populations, and in what use cases the DPP would be cost-effective.MethodsWe augmented an agent-based SSA HIV model with maternal health parameters including unintended pregnancy, abortion, and maternal mortality. Based on a previous market analysis, we assumed a primary DPP user population of current oral contraceptive users ages 25–49, and alternative user populations in different risk groups (age 15–24, sex workers, HIV-serodiscordant couples) and baseline product use profiles (unmet need for contraception, oral PrEP use, condom use). In three geographies (western Kenya, Zimbabwe, South Africa), we estimated HIV infections averted, pregnancies averted, disability-adjusted life-years (DALYs) averted, and the incremental cost-effectiveness ratio (ICER) over a 30-year time horizon, assuming equivalent adherence to the DPP as to oral contraceptives, higher adherence, or lower adherence.ResultsThe DPP is likely to be a cost-effective alternative to oral PrEP among users in need of contraception. Among women not already using PrEP, the DPP is likely to be cost-saving in sex workers and serodiscordant couples. The DPP is unlikely to be cost-effective in oral contraceptive users in the general population. Switching from oral contraception to the DPP could be net harmful in some settings and populations if it were to substantially reduces adherence to oral contraception. Results were robust to a range of time horizons or discount rates.ConclusionThe DPP has the potential to be cost-effective and cost-saving in populations at substantial HIV risk. Outcomes are sensitive to adherence, implying that effective counseling and decision-making tools for users considering the DPP will be essential. More research is needed to understand real-life adherence patterns and ensure health benefits achieved from contraception alone are not lost.

Abstract Stay-at-home restrictions such as closure of non-essential businesses were effective at reducing SARS-CoV-2 transmission in New York City (NYC) in the spring of 2020. Relaxation of these restrictions was desirable for resuming economic and social activities, but could only occur in conjunction with measures to mitigate the expected resurgence of new infections, in particular social distancing and mask-wearing. We projected the impact of individuals’ adherence to social distancing and mask-wearing on the duration, frequency, and recurrence of stay-at-home restrictions in NYC. We applied a stochastic discrete time-series model to simulate community transmission and household secondary transmission in NYC. The model was calibrated to hospitalizations, ICU admissions, and COVID-attributable deaths over March–July 2020 after accounting for the distribution of age and chronic health conditions in NYC. We projected daily new infections and hospitalizations up to May 31, 2021 under the different levels of adherence to social distancing and mask-wearing after relaxation of stay-at-home restrictions. We assumed that the relaxation of stay-at-home policies would occur in the context of adaptive reopening, where a new hospitalization rate of ≥ 2 per 100,000 residents would trigger reinstatement of stay-at-home restrictions while a new hospitalization rate of ≤ 0.8 per 100,000 residents would trigger relaxation of stay-at-home restrictions. Without social distancing and mask-wearing, simulated relaxation of stay-at-home restrictions led to epidemic resurgence and necessary reinstatement of stay-at-home restrictions within 42 days. NYC would have stayed fully open for 26% of the time until May 31, 2021, alternating reinstatement and relaxation of stay-at-home restrictions in four cycles. At a low (50%) level of adherence to mask-wearing, NYC would have needed to implement stay-at-home restrictions between 8% and 32% of the time depending on individual adherence to social distancing. At moderate to high levels of adherence to mask-wearing without social distancing, NYC would have needed to implement stay-at-home restrictions. In threshold analyses, avoiding reinstatement of stay-at-home restrictions required a minimum of 60% adherence to mask-wearing at 50% adherence to social distancing. With low adherence to mask-wearing and social distancing, reinstatement of stay-at-home restrictions in NYC was inevitable. High levels of adherence to social distancing and mask-wearing could have attributed to avoiding recurrent surges without reinstatement of stay-at-home restrictions.

We reviewed the timeline of key policies for control of the coronavirus disease epidemic and determined their impact on the epidemic and hospital burden in South Korea. Using a discrete stochastic transmission model, we estimated that multilevel policies, including extensive testing, contact tracing, and quarantine, reduced contact rates by 90% and rapidly decreased the epidemic in Daegu and nationwide during February‒March 2020. Absence of these prompt responses could have resulted in a >10-fold increase in infections, hospitalizations, and deaths by May 15, 2020, relative to the status quo. The model suggests that reallocation of persons who have mild or asymptomatic cases to community treatment centers helped avoid overwhelming hospital capacity and enabled healthcare workers to provide care for more severely and critically ill patients in hospital beds and negative-pressure intensive care units. As small outbreaks continue to occur, contact tracing and maintenance of hospital capacity are needed.

Abstract Objectives Primary Objective • To test the efficacy of Hydroxychloroquine (HCQ) (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection Secondary objectives • To determine the safety and tolerability of HCQ as SARS-CoV-2 Post-exposure Prophylaxis (PEP) in adults • To test the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection 2 weeks after completing therapy, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection • To test the efficacy of HCQ to shorten the duration of SARS-CoV-2 shedding among those with SARS-CoV-2 infection in the HCQ PEP group • To test the efficacy of HCQ to prevent incident COVID-19 Trial design This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the virus. Participants This study will enroll up to 2000 asymptomatic adults 18 to 80 years of age (inclusive) at baseline who are close contacts of persons with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. This multisite trial will be conducted at seven sites in Seattle (UW), Los Angeles (UCLA), New Orleans (Tulane), Baltimore (UMB), New York City (NYU), Syracuse (SUNY-Upstate), and Boston (BMC). Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply: 1. Men or women 18 to 80 years of age inclusive, at the time of signing the informed consent 2. Willing and able to provide informed consent 3. Had a close contact of a person (index) with known PCR-confirmed SARS-CoV-2 infection or index who is currently being assessed for COVID-19 Close contact is defined as: a. Household contact (i.e., residing with the index case in the 14 days prior to index diagnosis or prolonged exposure within a residence/vehicle/enclosed space without maintaining social distance) b. Medical staff, first responders, or other care persons who cared for the index case without personal protection (mask and gloves) 4. Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 infection) to the index case 5. Access to device and internet for Telehealth visits 6. Not planning to take HCQ in addition to the study medication Exclusion criteria Participants are excluded from the study if any of the following criteria apply: 1. Known hypersensitivity to HCQ or other 4-aminoquinoline compounds 2. Currently hospitalized 3. Symptomatic with subjective fever, cough, or shortness of breath 4. Current medications exclude concomitant use of HCQ 5. Concomitant use of other anti-malarial treatment or chemoprophylaxis, including chloroquine, mefloquine, artemether, or lumefantrine. 6. History of retinopathy of any etiology 7. Psoriasis 8. Porphyria 9. Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes

Abstract Background Despite policies for universal HIV testing and treatment (UTT) regardless of CD4 count, there are still 1.8 million new HIV infections and 1 million AIDS-related deaths annually. The UNAIDS 90-90-90 goals target suppression of HIV viral load in 73% of all HIV-infected people worldwide by 2030. However, achieving these targets may not lead to expected reductions in HIV incidence if the remaining 27% (persons with unsuppressed viral load) are the drivers of HIV transmission through high-risk behaviors. We aim to conduct a systematic review and meta-analysis to understand the demographics, mobility, geographic distribution, and risk profile of adults who are not virologically suppressed in sub-Saharan Africa in the era of UTT. Methods We will review the published and grey literature for study sources that contain data on demographic and behavioral strata of virologically suppressed and unsuppressed populations since 2014. We will search PubMed and Embase using four sets of search terms tailored to identify characteristics associated with virological suppression (or lack thereof) and each of the individual 90-90-90 goals. Record screening and data abstraction will be done independently and in duplicate. We will use random effects meta-regression analyses to estimate the distribution of demographic and risk features among groups not virologically suppressed and for each individual 90-90-90 goal. Discussion The results of our review will help elucidate factors associated with failure to achieve virological suppression in sub-Saharan Africa, as well as factors associated with failure to achieve each of the 90-90-90 goals. These data will help quantify the population-level effects of current HIV treatment interventions to improve strategies for maximizing virological suppression and ending the HIV epidemic. Systematic review registration PROSPERO CRD42018089505.

Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4–6) in HCQ, 6 days (95% CI=4–8) in HCQ/AZ, and 8 days (95% CI=6–10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01–2.60, p = 0.047) but not HCQ/AZ (HR=1.25, p = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63–1.64, p = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57–1.45, p = 0.70). Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.Trial registration ClinicalTrials.gov number NCT04354428

Background: South Africa began offering medical male circumcision (MMC) in 2010. We evaluated the current and future impact of this program to see if it is effective in preventing new HIV infections. Methods: The Thembisa, Goals and Epidemiological Modeling Software (EMOD) HIV transmission models were calibrated to South Africa’s HIV epidemic, fitting to household survey data on HIV prevalence, risk behaviors, and proportions of men circumcised, and to programmatic data on intervention roll-out including program-reported MMCs over 2009-2017. We compared the actual program accomplishments through 2017 and program targets through 2021 with a counterfactual scenario of no MMC program. Results: The MMC program averted 71,000-83,000 new HIV infections from 2010 to 2017. The future benefit of the circumcision already conducted will grow to 496,000-518,000 infections (6-7% of all new infections) by 2030. If program targets are met by 2021 the benefits will increase to 723,000-760,000 infections averted by 2030. The cost would be $1,070-1,220 per infection averted relative to no MMC. The savings from averted treatment needs would become larger than the costs of the MMC program around 2034-2039. In the Thembisa model, when modelling South Africa’s 9 provinces individually, the 9-provinces-aggregate results were similar to those of the single national model. Across provinces, projected long-term impacts were largest in Free State, KwaZulu-Natal and Mpumalanga (23-27% reduction over 2017-2030), reflecting these provinces’ greater MMC scale-up. Conclusions: MMC has already had a modest impact on HIV incidence in South Africa and can substantially impact South Africa’s HIV epidemic in the coming years.

IntroductionThe COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services.MethodsWe used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics.ResultsMaintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19-146 discounted deaths per 10,000 clients.DiscussionWhile there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.

BackgroundPre-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.MethodsWe 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").ResultsThe 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.ConclusionsProviding 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.

Western Kenya suffers a highly endemic and also very heterogeneous epidemic of human immunodeficiency virus (HIV). Although female sex workers (FSW) and their male clients are known to be at high risk for HIV, HIV prevalence across regions in Western Kenya is not strongly correlated with the fraction of women engaged in commercial sex. An agent-based network model of HIV transmission, geographically stratified at the county level, was fit to the HIV epidemic, scale-up of interventions, and populations of FSW in Western Kenya under two assumptions about the potential mobility of FSW clients. In the first, all clients were assumed to be resident in the same geographies as their interactions with FSW. In the second, some clients were considered non-resident and engaged only in interactions with FSW, but not in longer-term non-FSW partnerships in these geographies. Under both assumptions, the model successfully reconciled disparate geographic patterns of FSW and HIV prevalence. Transmission patterns in the model suggest a greater role for FSW in local transmission when clients were resident to the counties, with 30.0% of local HIV transmissions attributable to current and former FSW and clients, compared to 21.9% when mobility of clients was included. Nonetheless, the overall epidemic drivers remained similar, with risky behavior in the general population dominating transmission in high-prevalence counties. Our modeling suggests that co-location of high-risk populations and generalized epidemics can further amplify the spread of HIV, but that large numbers of formal FSW and clients are not required to observe or mechanistically explain high HIV prevalence in the general population.

Poor adherence to daily antiretrovirals can significantly affect treatment efficacy, but oral long-acting antiretrovirals are currently lacking. Here, the authors develop a once-weekly oral dosage form for anti-HIV drugs, assess its pharmacokinetics in pigs, and model its impact on viral resistance and disease epidemics.

Background: Mathematical models are widely used to simulate the effects of interventions to control HIV and to project future epidemiological trends and resource needs. We aimed to validate past model projections against data from a large household survey done in South Africa in 2012. Methods: We compared ten model projections of HIV prevalence, HIV incidence, and antiretroviral therapy (ART) coverage for South Africa with estimates from national household survey data from 2012. Model projections for 2012 were made before the publication of the 2012 household survey. We compared adult (age 15–49 years) HIV prevalence in 2012, the change in prevalence between 2008 and 2012, and prevalence, incidence, and ART coverage by sex and by age groups between model projections and the 2012 household survey. Findings: All models projected lower prevalence estimates for 2012 than the survey estimate (18·8%), with eight models' central projections being below the survey 95% CI (17·5–20·3). Eight models projected that HIV prevalence would remain unchanged (n=5) or decline (n=3) between 2008 and 2012, whereas prevalence estimates from the household surveys increased from 16·9% in 2008 to 18·8% in 2012 (difference 1·9, 95% CI −0·1 to 3·9). Model projections accurately predicted the 1·6 percentage point prevalence decline (95% CI −0·3 to 3·5) in young adults aged 15–24 years, and the 2·2 percentage point (0·5 to 3·9) increase in those aged 50 years and older. Models accurately represented the number of adults on ART in 2012; six of ten models were within the survey 95% CI of 1·54–2·12 million. However, the differential ART coverage between women and men was not fully captured; all model projections of the sex ratio of women to men on ART were lower than the survey estimate of 2·22 (95% CI 1·73–2·71). Interpretation: Projections for overall declines in HIV epidemics during the ART era might have been optimistic. Future treatment and HIV prevention needs might be greater than previously forecasted. Additional data about service provision for HIV care could help inform more accurate projections. Funding: Bill & Melinda Gates Foundation.

Background: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. Methods: We used several independent mathematical models in four settings—South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)—to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. Findings: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective. Interpretation: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets. Funding: Bill & Melinda Gates Foundation, WHO.

Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART.Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results.Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.

Biocompatible oils are used in a variety of medical applications ranging from vaccine adjuvants to vehicles for oral drug delivery. To enable such nonpolar organic phases to serve as reservoirs for delivery of hydrophilic compounds, we explored the ability of block copolymer micelles in organic solvents to sequester proteins for sustained release across an oil−water interface. Self-assembly of the block copolymer, poly(ϵ-caprolactone)-block-poly(2-vinyl pyridine) (PCL-b-P2VP), was investigated in toluene and oleic acid, a biocompatible naturally occurring fatty acid. Micelle formation in toluene was characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM) imaging of micelles cast onto silicon substrates. Cryogenic transmission electron microscopy confirmed a spherical morphology in oleic acid. Studies of homopolymer solubility implied that micelles in oleic acid consist of a P2VP corona and a PCL core, while P2VP formed the core of micelles assembled in toluene. The loading of two model proteins (ovalbumin (ova) and bovine serum albumin (BSA)) into micelles was demonstrated with loadings as high as 7.8% wt of protein per wt of P2VP in oleic acid. Characterization of block copolymer morphology in the two solvents after protein loading revealed spherical particles with similar size distributions to the as-assembled micelles. Release of ova from micelles in oleic acid was sustained for 12−30 h upon placing the oil phase in contact with an aqueous bath. Unique to the situation of micelle assembly in an oily phase, the data suggest protein is sequestered in the P2VP coronablock of PCL-b-P2VP micelles in oleic acid. More conventionally, protein loading occurs in the P2VP coreof micelles assembled in toluene. [ABSTRACT FROM AUTHOR]

Objective: EMOD-HIV v0.8 has been used to estimate the potential impact of expanding treatment guidelines to allow earlier initiation of antiretroviral therapy (ART) in sub-Saharan Africa with current or improved treatment coverage. In generating these results, a model must additionally make assumptions about the rates of dropout and re-initiation into ART programs before and after the program change, about which little is known. The objective of this work is to rigorously analyze modeling assumptions and the sensitivity of model results with respect to relevant mechanisms and parameters., Methods: We varied key model assumptions pertaining to ART dropout and re-enrollment to analyze their effect on the cost, impact, and cost-effectiveness of expanding treatment guidelines, and of expanding coverage via improved testing and linkage to care. Additionally, we performed a sensitivity analysis of 17 relevant model parameters., Setting: South Africa., Results: Allowing re-initiation of ART irrespective of prior treatment doubled the cost and impact of expanding treatment guidelines, as compared with a scenario in which re-initiation could only be triggered by a health event (AIDS symptoms, diagnosis of a partner, or an antenatal care visit). Increasing the probability of 'voluntary' re-initiation (not triggered by a health event) was the most cost-effective way to improve the treatment program, especially in the short term because it provided immediate benefits to those who would otherwise have delayed re-initiation until the onset of AIDS symptoms. However, the maximum impact of this change was limited compared with expanding coverage through improvements in testing and linkage to care. Beyond improvements in coverage and re-initiation, further gains could be made by improving retention in care. Only with optimal retention in care was expansion of guidelines cost-saving after 20 years due to reductions in transmission. Re-initiation did not reduce transmission sufficiently to make a guideline change cost-effective due to transmission that occurred while patients were away from care. Sensitivity analysis suggested that enormous health benefits could be attained by improving treatment regimens to have higher efficacy at preventing transmission, increasing the proportion of the population with access to improved healthcare, and reducing 'leaks' in the 'cascade of care.' Increasing the proportion of individuals who receive CD4 cell results was particularly cost-effective at baseline levels of coverage, and increasing retention on ART was particularly cost-effective with expanded coverage., Conclusion: This analysis provides a sense of the magnitude of uncertainty in program cost and impact that policy-makers could anticipate in the face of uncertain future programmatic changes. Our findings suggest that increasing re-initiation is the most cost-effective means of initial program improvement, especially in the short term, but that improvements in retention are necessary in order to reap the full transmission-blocking benefits of a test-and-treat program in the long term.