Search

Background The SEARCH study provided community-based HIV and multi-disease testing and antiretroviral therapy (ART) to 32 communities in East Africa and reported no statistically significant difference in three-year HIV incidence. We used mathematical modelling to estimate the effect of control arm viral suppression and community mixing on SEARCH trial outcomes. Setting Uganda and Kenya. Methods Using the individual-based HIV modeling software EMOD-HIV, we configured a new model of SEARCH communities. The model was parameterized using demographic, HIV prevalence, male circumcision, and viral suppression data, and calibrated to HIV prevalence, ART coverage, and population size. Using assumptions about ART scale-up in the control arm, degree of community mixing, and effect of baseline testing, we estimated comparative HIV incidence under multiple scenarios. Results Prior to the trial results, we predicted that SEARCH would report a 4-40% reduction between arms, depending on control arm ART linkage rates and community mixing. With universal baseline testing followed by rapidly expanded ART eligibility and uptake, modelled effect sizes were smaller than the study was powered to detect. Using interim viral suppression data, we estimated three-year cumulative incidence would have been reduced by up to 27% in the control arm and 43% in the intervention arm compared to a counterfactual without universal baseline testing. Conclusions Our model suggests that the active control arm substantially reduced expected effect size and power of the SEARCH study. However, compared to a counterfactual "true control" without increased ART linkage due to baseline testing, SEARCH reduced HIV incidence by up to 43%.

Summary Background The number of people on antiretroviral therapy (ART) requiring treatment monitoring in low-resource settings is rapidly increasing. Point-of-care (POC) testing for ART monitoring might alleviate burden on centralised laboratories and improve clinical outcomes, but its cost-effectiveness is unknown. Methods We used cost and effectiveness data from the STREAM trial in South Africa (February, 2017–October, 2018), which evaluated POC testing for viral load, CD4 count, and creatinine, with task shifting from professional to lower-cadre registered nurses compared with laboratory-based testing without task shifting (standard of care). We parameterised an agent-based network model, EMOD-HIV, to project the impact of implementing this intervention in South Africa over 20 years, simulating approximately 175 000 individuals per run. We assumed POC monitoring increased viral suppression by 9 percentage points, enrolment into community-based ART delivery by 25 percentage points, and switching to second-line ART by 1 percentage point compared with standard of care, as reported in the STREAM trial. We evaluated POC implementation in varying clinic sizes (10–50 patient initiating ART per month). We calculated incremental cost-effectiveness ratios (ICERs) and report the mean and 90% model variability of 250 runs, using a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted for our main analysis. Findings POC testing at 70% coverage of patients on ART was projected to reduce HIV infections by 4·5% (90% model variability 1·6 to 7·6) and HIV-related deaths by 3·9% (2·0 to 6·0). In clinics with 30 ART initiations per month, the intervention had an ICER of $197 (90% model variability –27 to 863) per DALY averted; results remained cost-effective when varying background viral suppression, ART dropout, intervention effectiveness, and reduction in HIV transmissibility. At higher clinic volumes (≥40 ART initiations per month), POC testing was cost-saving and at lower clinic volumes (20 ART initiations per month) the ICER was $734 (93 to 2569). A scenario that assumed POC testing did not increase enrolment into community ART delivery produced ICERs that exceeded the cost-effectiveness threshold for all clinic volumes. Interpretation POC testing is a promising strategy to cost-effectively improve patient outcomes in moderately sized clinics in South Africa. Results are most sensitive to changes in intervention impact on enrolment into community-based ART delivery. Funding National Institutes of Health.

Seung Heon Lee,1 So-Youn Park,2 Jeong-Yeon Seon,3 Woo-Hwi Jeon,3 Sung-Il Nam,4 Jong-Hak Park,5 Jae Seok Park,6 Hae-Young Kim,7 Niket Thakkar,8 Prashanth Selvaraj,8 Anna Bershteyn,7 In-Hwan Oh3 1Division of Pulmonary, Sleep, and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea; 2Department of Medical Education and Humanities, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; 3Department of Preventive Medicine, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; 4Department of Otolaryngology-Head & Neck Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea; 5Department of Emergency Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea; 6Division of Pulmonology, Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea; 7Department of Population Health, New York University Grossman School of Medicine, New York, NY, USA; 8Institute for Disease Modeling, Seattle, WA, USACorrespondence: In-Hwan Oh Department of Preventive MedicineSchool of Medicine, Kyung Hee University, Seoul, Republic of KoreaFax +82-2-969-0792Email ihoh@khu.ac.krObjective: To identify risk factors for intensive care unit (ICU) admission and mechanical ventilator usage among confirmed coronavirus disease (COVID-19) patients and estimate the effects of mitigation efforts on ICU capacity in Korea.Patients and Methods: Data on profiles and medical history of all confirmed COVID-19 patients in the past 1 year were extracted from the Korean National Health Insurance System’s claims database to assess risk factors for ICU admission and ventilator use. We used a time-series epidemic model to estimate the ICU census in Daegu from the reported hospital data.Findings: Multivariate regression analysis revealed male sex, old age, and residing in Daegu city as significant risk factors for ICU admission. The number of patients requiring ICU admission exceeded the bed capacity across all Daegu hospitals before March 9, 2020, and therefore, critically ill patients were transferred to nearby hospitals outside Daegu. This finding was consistent with our prediction that the ICU census in Daegu would peak on March 16, 2020, at 160 through mitigation efforts, without which it would have reached 300 by late March 2020.Conclusion: Older age and male sex were risk factors for ICU admission. In addition, the geographic location of the hospital seems to contribute to the severity of the COVID-19 patients admitted to the ICU and to the ICU capacity.Keywords: COVID-19 pandemic, ICU admission, Korea, risk factors

Summary Background The COVID-19 pandemic could lead to disruptions to provision of HIV services for people living with HIV and those at risk of acquiring HIV in sub-Saharan Africa, where UNAIDS estimated that more than two-thirds of the approximately 38 million people living with HIV resided in 2018. We aimed to predict the potential effects of such disruptions on HIV-related deaths and new infections in sub-Saharan Africa. Methods In this modelling study, we used five well described models of HIV epidemics (Goals, Optima HIV, HIV Synthesis, an Imperial College London model, and Epidemiological MODeling software [EMOD]) to estimate the effect of various potential disruptions to HIV prevention, testing, and treatment services on HIV-related deaths and new infections in sub-Saharan Africa lasting 6 months over 1 year from April 1, 2020. We considered scenarios in which disruptions affected 20%, 50%, and 100% of the population. Findings A 6-month interruption of supply of antiretroviral therapy (ART) drugs across 50% of the population of people living with HIV who are on treatment would be expected to lead to a 1·63 times (median across models; range 1·39–1·87) increase in HIV-related deaths over a 1-year period compared with no disruption. In sub-Saharan Africa, this increase amounts to a median excess of HIV deaths, across all model estimates, of 296 000 (range 229 023–420 000) if such a high level of disruption occurred. Interruption of ART would increase mother-to-child transmission of HIV by approximately 1·6 times. Although an interruption in the supply of ART drugs would have the largest impact of any potential disruptions, effects of poorer clinical care due to overstretched health facilities, interruptions of supply of other drugs such as co-trimoxazole, and suspension of HIV testing would all have a substantial effect on population-level mortality (up to a 1·06 times increase in HIV-related deaths over a 1-year period due to disruptions affecting 50% of the population compared with no disruption). Interruption to condom supplies and peer education would make populations more susceptible to increases in HIV incidence, although physical distancing measures could lead to reductions in risky sexual behaviour (up to 1·19 times increase in new HIV infections over a 1-year period if 50% of people are affected). Interpretation During the COVID-19 pandemic, the primary priority for governments, donors, suppliers, and communities should focus on maintaining uninterrupted supply of ART drugs for people with HIV to avoid additional HIV-related deaths. The provision of other HIV prevention measures is also important to prevent any increase in HIV incidence. Funding Bill & Melinda Gates Foundation.

Summary Background The rapid scale-up of antiretroviral therapy (ART) towards the UNAIDS 90-90-90 goals over the last decade has sparked considerable debate as to whether universal test and treat can end the HIV-1 epidemic in sub-Saharan Africa. We aimed to develop a network transmission model, calibrated to capture age-specific and sex-specific gaps in the scale-up of ART, to estimate the historical and future effect of attaining and surpassing the UNAIDS 90-90-90 treatment targets on HIV-1 incidence and mortality, and to assess whether these interventions will be enough to achieve epidemic control (incidence of 1 infection per 1000 person-years) by 2030. Methods We used eSwatini (formerly Swaziland) as a case study to develop our model. We used data on HIV prevalence by 5-year age bins, sex, and year from the 2007 Swaziland Demographic Health Survey (SDHS), the 2011 Swaziland HIV Incidence Measurement Survey, and the 2016 Swaziland Population Health Impact Assessment (PHIA) survey. We estimated the point prevalence of ART coverage among all HIV-infected individuals by age, sex, and year. Age-specific data on the prevalence of male circumcision from the SDHS and PHIA surveys were used as model inputs for traditional male circumcision and scale-up of voluntary medical male circumcision (VMMC). We calibrated our model using publicly available data on demographics; HIV prevalence by 5-year age bins, sex, and year; and ART coverage by age, sex, and year. We modelled the effects of five scenarios (historical scale-up of ART and VMMC [status quo], no ART or VMMC, no ART, age-targeted 90-90-90, and 100% ART initiation) to quantify the contribution of ART scale-up to declines in HIV incidence and mortality in individuals aged 15–49 by 2016, 2030, and 2050. Findings Between 2010 and 2016, status-quo ART scale-up among adults (aged 15–49 years) in eSwatini (from 34·0% in 2010 to 74·1% in 2016) reduced HIV incidence by 43·57% (95% credible interval 39·71 to 46·36) and HIV mortality by 56·17% (54·06 to 58·92) among individuals aged 15–49 years, with larger reductions in incidence among men and mortality among women. Holding 2016 ART coverage levels by age and sex into the future, by 2030 adult HIV incidence would fall to 1·09 (0·87 to 1·29) per 100 person-years, 1·42 (1·13 to 1·71) per 100 person-years among women and 0·79 (0·63 to 0·94) per 100 person-years among men. Achieving the 90-90-90 targets evenly by age and sex would further reduce incidence beyond status-quo ART, primarily among individuals aged 15–24 years (an additional 17·37% [7·33 to 26·12] reduction between 2016 and 2030), with only modest additional incidence reductions in adults aged 35–49 years (1·99% [–5·09 to 7·74]). Achieving 100% ART initiation among all people living with HIV within an average of 6 months from infection—an upper bound of plausible treatment effect—would reduce adult HIV incidence to 0·73 infections (0·55 to 0·92) per 100 person-years by 2030 and 0·46 (0·33 to 0·59) per 100 person-years by 2050. Interpretation Scale-up of ART over the last decade has already contributed to substantial reductions in HIV-1 incidence and mortality in eSwatini. Focused ART targeting would further reduce incidence, especially in younger individuals, but even the most aggressive treatment campaigns would be insufficient to end the epidemic in high-burden settings without a renewed focus on expanding preventive measures. Funding Global Good Fund and the Bill & Melinda Gates Foundation.

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.

ImportanceSARS-CoV-2 viral trajectory has not been well-characterized in documented incident infections. These data will inform SARS-CoV-2 natural history, transmission dynamics, prevention practices, and therapeutic development.ObjectiveTo prospectively characterize early SARS-CoV-2 viral shedding in persons with incident infection.DesignProspective cohort study.SettingSecondary data analysis from a multicenter study in the U.S.ParticipantsThe samples derived from a randomized controlled trial of 829 community-based asymptomatic participants recently exposed (ExposureLaboratory-confirmed SARS-CoV-2 infection.Main outcomes and measuresThe observed SARS-CoV-2 viral shedding characteristics were summarized and shedding trajectories were examined using a piece-wise linear mixed-effects modeling. Whole viral genome sequencing was performed on samples with cycle threshold (Ct)ResultsNinety-seven persons (57% women, median age 37-years) developed incident infections during 14-days of follow-up. Two-hundred fifteen sequenced samples were assigned to 15 lineages that belonged to the G614 variant. Forty-two (43%), 18(19%), and 31(32%) participants had viral shedding for 1 day, 2-6 days, and ≥7 days, with median peak viral load Ct of 38.5, 36.7, and 18.3, respectively. Six (6%) participants had 1–6 days of observed viral shedding with censored duration. The peak average viral load was observed on day 3 of viral shedding. The average Ct value was lower, indicating higher viral load, in persons reporting COVID-19 symptoms than asymptomatic. Using the statistical model, the median time from shedding onset to peak viral load was 1.4 days followed by a median of 9.7 days before clearance.Conclusions and RelevanceIncident SARS-CoV-2 G614 infection resulted in a rapid viral load peak followed by slower decay and positive correlation between peak viral load and shedding duration; duration of shedding was heterogeneous. This longitudinal evaluation of the SARS-CoV-2 G614 variant with frequent molecular testing may serve as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.KEY POINTSQuestionWhat are the early SARS-CoV-2 G614 viral shedding characteristics in persons with incident infection?FindingsIn this prospective cohort of 97 community-based participants who collected daily mid-turbinate swabs for SARS-CoV-2 detection after recent exposure to SARS-CoV-2, viral trajectory was characterized by a rapid peak followed by slower decay. Peak viral load correlated positively with symptoms. The duration of shedding was heterogeneous.MeaningA detailed description of the SARS-CoV-2 G614 viral shedding trajectory serves as baseline for comparison to new viral variants of concern and inform models for the planning of clinical trials and transmission dynamics to end this pandemic.

IntroductionNew York City (NYC) was a global epicenter of COVID-19. Vaccines against COVID-19 became available in December 2020 with limited supply, resulting in the need for policies regarding prioritization. The next month, SARS-CoV-2 variants were detected that were more transmissible but still vaccine-susceptible, raising scrutiny of these policies. In particular, prioritization of higher-risk people could prevent more deaths per dose of vaccine administered but could also delay herd immunity if the prioritization introduced bottlenecks that lowered vaccination speed (the number of doses that could be delivered per day). We used mathematical modeling to examine the trade-off between prioritization and the vaccination speed.MethodsA stochastic, discrete-time susceptible-exposed-infected-recovered (SEIR) model with age- and comorbidity-adjusted COVID-19 outcomes (infections, hospitalizations, and deaths by July 1, 2021) was used to examine the trade-off between vaccination speed and whether or not vaccination was prioritized to individuals age 65+ and “essential workers,” defined as including first responders and healthcare, transit, education, and public safety workers. The model was calibrated to COVID-19 hospital admissions, hospital census, ICU census, and deaths in NYC. Vaccination speed was assumed to be 10,000 doses per day starting December 15th, 2020 targeting healthcare workers and nursing home populations, and to subsequently expand at alternative starting times and speeds. We compared COVID-outcomes across alternative expansion starting times (January 15th, January 21st, or February 1st) and speeds (20,000, 30,000, 50,000, 100,000, 150,000, or 200,000 doses per day for the first dose), as well as alternative prioritization options (“yes” versus “no” prioritization of essential workers and people age 65+). Model projections were produced with and without considering the emergence of a SARS-COV-2 variant with 56% greater transmissibility over January and February, 2021.ResultsIn the absence of a COVID-19 vaccine, the emergence of the more transmissible variant would triple the peak in infections, hospitalizations, and deaths and more than double cumulative infections, hospitalizations, and deaths. To offset the harm from the more transmissible variant would require reaching a vaccination speed of at least 100,000 doses per day by January 15th or 150,000 per day by January 21st. Prioritizing people ages 65+ and essential workers increased the number of lives saved per vaccine dose delivered: with the emergence of a more transmissible variant, 8,000 deaths could be averted by delivering 115,000 doses per day without prioritization or 71,000 doses per day with prioritization. If prioritization were to cause a bottleneck in vaccination speed, more lives would be saved with prioritization only if the bottleneck reduced vaccination speed by less than one-third of the maximum vaccine delivery capacity. These trade-offs between vaccination speed and prioritization were robust over a wide range of delivery capacity.ConclusionsThe emergence of a more transmissible variant of SARS-CoV-2 has the potential to triple the 2021 epidemic peak and more than double the 2021 COVID-19 burden in NYC. Vaccination could only offset the harm of the more transmissible variant if high speed were achieved in mid-to late January. Prioritization of COVID-19 vaccines to higher-risk populations saves more lives only if it does not create an excessive vaccine delivery bottleneck.

Background Prevention interventions for coronavirus disease (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are currently limited to non-pharmaceutical strategies. Observational and laboratory data suggested that hydroxychloroquine (HCQ) had biologic activity against SARS-CoV-2. A blinded trial of HCQ in persons with confirmed exposure and virologic and clinical endpoints is needed. Methods We conducted a national, householdrandomized, double-blind, controlled trial of HCQ post-exposure prophylaxis, with entirely remote study procedures. We enrolled close contacts exposed to persons with SARS-CoV-2 infection in the past 96 hours. Participants were randomized to either HCQ (400 mg daily for three days followed by 200 mg daily for eleven days) or ascorbic acid (500 mg followed by 250 mg daily), as a placebo-equivalent control. Participants self-collected mid-turbinate swabs daily (days 1–14) for SARS-CoV-2 PCR testing. The primary outcome was PCR-confirmed, incident SARS-CoV-2 infection among persons SARS-CoV-2 negative at enrollment. Symptoms were assessed using criteria from the US CDC. Results From March-August 2020, 623 households were randomized; 311 households (381 participants) to the HCQ group and 312 households (400 participants) to the control group. Ninety- one percent of participants were retained up to day 14 and 9,595 of 10,588 (91%) of swabs were tested. Among participants who were SARS-CoV-2 negative at baseline (n=626/781, 80%), the cumulative incidence of SARS-CoV-2 was 14.5% (95% CI: 11.6–17.4) and the cumulative incidence of COVID-19 symptoms was 11.6% (95% CI: 8.9–14.2) at day 14. By day 14, there was no difference between the HCQ group and control group in SARS-CoV-2 acquisition (46 vs. 43 events, aHR= 0.99, 95% CI 0.64–1.52, p=0.95) or symptomatic disease (40 vs. 32 events, aHR= 1.23, 95% CI: 0.76–1.99, p=0.40). The adverse event frequency was similar between groups (59 [15.5%] participants in the HCQ and 45 [11.3%] in the control group, p=0.092). Cumulative incidence of RT-PCR-confirmed SARS-CoV-2 infection among close contacts of diagnosed cases, by study group Conclusion This randomized, double-blind, controlled trial among persons with recent exposure and high incidence of SAR-CoV2 provides strong evidence that HCQ post-exposure prophylaxis did not prevent SARS-CoV-2 infection or modify clinical disease. Disclosures Anna Bershteyn, PhD, Bill and Melinda Gates Foundation (Grant/Research Support)Gates Ventures (Consultant)National Institutes of Health (Grant/Research Support) Kristopher M. Paolino, MD, MTM&H, Nothing to disclose Raphael J. Landovitz, MD, MSc, Gilead (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Other Financial or Material Support, Speaker Honoraria) Anna Wald, MD, MPH, Aicuris (Individual(s) Involved: Self): Consultant; Gilead (Individual(s) Involved: Self): Consultant; GlaxoSmithKline (Individual(s) Involved: Self): Scientific Research Study Investigator; Merck (Individual(s) Involved: Self): DSMB participation; provision of vaccine for a study, Other Financial or Material Support; Sanofi (Individual(s) Involved: Self): Scientific Research Study Investigator; X-Vax (Individual(s) Involved: Self): Consultant Helen Y. Chu, MD MPH, Cepheid (Grant/Research Support)Ellume (Grant/Research Support)Glaxo Smith Kline (Consultant)Merck (Consultant)Sanofi-Pasteur (Grant/Research Support)

This is the accepted manuscript version of the work published in its final form asBershteyn, A., Schwartz, M. D., Thorpe, L. E., Paasche-orlow, M. K., Kissinger, P., Karita, H. C. S., Laufer, M. K., Hoffman, R. M., Landovitz, R. J., Paolino, K., & Ruanne V. Barnabas. (2021). Taking a stand against the politicization of medical research: How 'swinging the pendulum' poses a hazard to clinical trials, study participants, and the progress of science.Expert Review of Clinical Immunology,17(1), 101-103. https://doi.org/10.1080/1744666x.2020.1860758 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org. &nbsp

Clinical trials have ruled out a role of hydroxychloroquine in the treatment of COVID-19, but it has been hypothesized that hydroxychloroquine's activity against SARS-CoV-2 in the laboratory suggests a role in prevention. This randomized controlled trial tests hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection., Visual Abstract. Postexposure Hydroxychloroquine Prophylaxis to Prevent SARS-CoV-2 Infection Clinical trials have ruled out a role of hydroxychloroquine in the treatment of COVID-19, but it has been hypothesized that hydroxychloroquine's activity against SARS-CoV-2 in the laboratory suggests a role in prevention. This randomized controlled trial tests hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection. Visual Abstract. Postexposure Hydroxychloroquine Prophylaxis to Prevent SARS-CoV-2 Infection Clinical trials have ruled out a role of hydroxychloroquine in the treatment of COVID-19, but it has been hypothesized that hydroxychloroquine's activity against SARS-CoV-2 in the laboratory suggests a role in prevention. This randomized controlled trial tests hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection., Background: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention. Objective: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection. Design: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961) Setting: National U.S. multicenter study. Participants: Close contacts recently exposed ( 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026). Limitation: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days. Conclusion: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection. Primary Funding Source: Bill & Melinda Gates Foundation.

IntroductionNew York City (NYC) has the largest public school system in the United States (US). During the SARS-CoV-2 pandemic, NYC was the first major US city to open schools for in-person learning in the 2020-2021 academic year. Several policies were implemented to reduce the risk of in-school transmission, including infection control measures (facemasks, physical distancing, enhanced indoor ventilation, cohorting of small groups, and hand hygiene), option of all-remote instruction, alternative options for how class schedules would rotate in-person and remote instruction, daily symptom screening, and testing 10-20% of students and staff weekly or monthly depending on local case rates. We sought to determine which of these policies had the greatest impact on reducing the risk of in-school transmission.MethodsWe evaluated the impact of each policy by referring to global benchmarks for the secondary attack rate (SAR) of SARS-CoV-2 in school settings and by simulating the potential for transmission in NYC’s rotating cohort schedules, in which teachers could act as “bridges” across rotating cohorts. We estimated the impact of (1) infection control measures, (2) providing an option of all-remote instruction, (3) choice of class scheduling for in-person learners, (4) daily symptom screening, (5) testing to curtail transmission, and (6) testing to identify school outbreaks. Each policy was assessed independently of other policies, with the exception of symptom screening and random testing, which were assessed both independently and jointly.ResultsAmong the policies analyzed, the greatest transmission reduction was associated with the infection control measures, followed by small class cohorts with an option for all-remote instruction, symptom screening, and finally randomly testing 10-20% of school attendees. Assuming adult staff are the primary source of within-school SARS-CoV-2 transmission, weekly testing of staff could be at least as effective as symptom screening, and potentially more so if testing days occur in the beginning of the workweek with results available by the following day. A combination of daily symptom screening and testing on the first workday of each week could reduce transmission by 70%.ConclusionsAdherence to infection control is the highest priority for safe school re-opening. Further transmission reduction can be achieved through small rotating class cohorts with an option for remote learning, widespread testing at the beginning of the work week, and daily symptom screening and self-isolation. Randomly testing 10-20% of attendees weekly or monthly does not meaningfully curtail transmission and may not detect outbreaks before they have spread beyond a handful of individuals. School systems considering re-opening during the SARS-CoV-2 pandemic or similarly virulent respiratory disease outbreaks should consider these relative impacts when setting policy priorities.

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.

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.

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: Men or women 18 to 80 years of age inclusive, at the time of signing the informed consentWilling and able to provide informed consentHad 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: 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)Medical staff, first responders, or other care persons who cared for the index case without personal protection (mask and gloves)Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 infection) to the index caseAccess to device and internet for Telehealth visitsNot 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: Known hypersensitivity to HCQ or other 4-aminoquinoline compoundsCurrently hospitalizedSymptomatic with subjective fever, cough, or shortness of breathCurrent medications exclude concomitant use of HCQConcomitant use of other anti-malarial treatment or chemoprophylaxis, including chloroquine, mefloquine, artemether, or lumefantrine.History of retinopathy of any etiologyPsoriasisPorphyriaKnown bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifenKnown moderate or severe liver diseaseKnown long QT syndromeSevere renal impairmentUse of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of the study drugs or planned use during the study period Intervention and comparator Households will be randomized 1:1 (at the level of household), with close contact participants receiving one of the following therapies: •HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days •Placebo-like control (ascorbic acid) 500 mg orally daily for 3 days then 250 mg orally daily for 11 days Main outcomes The primary outcome of the study is the incidence of SARS-CoV-2 infection through day 14 among participants who are SARS-CoV-2 negative at baseline by randomization group. Randomisation Participants will be randomized in a 1:1 ratio to HCQ or ascorbic acid at the level of the household (all eligible participants in 1 household will receive the same intervention). The randomization code and resulting allocation list will be generated and maintained by the Study Statistician. The list will be blocked and stratified by site and contact type (household versus healthcare worker). Blinding (masking) This is a blinded study. HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be bitter and ascorbic acid will be sour. The participants will be blinded to their randomization group once assigned. Study team members, apart from the Study Pharmacist and the unblinded statistical staff, will be blinded. Laboratory staff are blinded to the group allocation. Numbers to be randomised (sample size) The sample size for the study is N=2 000 participants randomized 1:1 to either HCZ (n=1 000) and ascorbic acid (n=1 000). Trial status Protocol version: 1.2 05 April 2020 Recruitment is ongoing, started March 31 and anticipated end date is September 30, 2020. Trial registration ClinicalTrials.gov, Protocol Registry Number: NCT04328961 Date of registration: April 1, 2020, retrospectively registered Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Introduction Heterogeneity of sociodemographics and risk behaviours across the HIV treatment cascade could influence the public health impact of universal ART in sub‐Saharan Africa if those not virologically suppressed are more likely to be part of a risk group contributing to onward infections. Sociodemographic and risk heterogeneity across the treatment cascade has not yet been comprehensively described or quantified and we seek to systematically review and synthesize research on this topic among adults in Africa. Methods We conducted a systematic review of peer‐reviewed literature in Embase and MEDLINE databases as well as grey literature sources published in English between 2014 and 2018. We included studies that included people living with HIV (PLHIV) aged ≥15 years, and reported a 90‐90‐90 outcome: awareness of HIV‐positive status, ART use among those diagnosed or viral suppression among those on ART. We summarized measures of association between sociodemographics, within each outcome, and as a composite measure of population‐wide viral suppression. Results and discussion From 3533 screened titles, we extracted data from 92 studies (50 peer‐reviewed, 42 grey sources). Of included studies, 32 reported on awareness, 53 on ART use, 32 on viral suppression and 23 on population‐wide viral suppression. The majority of studies were conducted in South Africa, Uganda, and Malawi and reported data for age and gender. When stratified, PLHIV ages 15 to 24 years had lower median achievement of the treatment cascade (60‐49‐81), as compared to PLHIV ≥25 years (70‐63‐91). Men also had lower median achievement of the treatment cascade (66‐72‐85), compared to women (79‐76‐89). For population‐wide viral suppression, women aged ≥45 years had achieved the 73% target, while the lowest medians were among 15‐ to 24‐year‐old men (37%) and women (49%). Conclusions Considerable heterogeneity exists by age and gender for achieving the HIV 90‐90‐90 treatment goals. These results may inform delivery of HIV testing and treatment in sub‐Saharan Africa, as targeting youth and men could be a strategic way to maximize the population‐level impact of ART.

Summary Background Community-based delivery of antiretroviral therapy (ART) for HIV, including ART initiation, clinical and laboratory monitoring, and refills, could reduce barriers to treatment and improve viral suppression, reducing the gap in access to care for individuals who have detectable HIV viral load, including men who are less likely than women to be virally suppressed. We aimed to test the effect of community-based ART delivery on viral suppression among people living with HIV not on ART. Methods We did a household-randomised, unblinded trial (DO ART) of delivery of ART in the community compared with the clinic in rural and peri-urban settings in KwaZulu-Natal, South Africa and the Sheema District, Uganda. After community-based HIV testing, people living with HIV were randomly assigned (1:1:1) with mobile phone software to community-based ART initiation with quarterly monitoring and ART refills through mobile vans; ART initiation at the clinic followed by mobile van monitoring and refills (hybrid approach); or standard clinic ART initiation and refills. The primary outcome was HIV viral suppression at 12 months. If the difference in viral suppression was not superior between study groups, an a-priori test for non-inferiority was done to test for a relative risk (RR) of more than 0·95. The cost per person virally suppressed was a co-primary outcome of the study. This study is registered with ClinicalTrials.gov, NCT02929992. Findings Between May 26, 2016, and March 28, 2019, of 2479 assessed for eligibility, 1315 people living with HIV and not on ART with detectable viral load at baseline were randomly assigned; 666 (51%) were men. Retention at the month 12 visit was 95% (n=1253). At 12 months, community-based ART increased viral suppression compared with the clinic group (306 [74%] vs 269 [63%], RR 1·18, 95% CI 1·07–1·29; psuperiority=0·0005) and the hybrid approach was non-inferior (282 [68%] vs 269 [63%], RR 1·08, 0·98–1·19; pnon-inferiority=0·0049). Community-based ART increased viral suppression among men (73%, RR 1·34, 95% CI 1·16–1·55; psuperiority

Background: The scale-up of “HIV test and treat” has rapidly increased the number of persons on antiretroviral therapy (ART) requiring treatment monitoring in low-resource settings. Decentralized point-of-care (POC) testing for ART monitoring may alleviate burden on centralized laboratories and improve clinical outcomes, but its cost-effectiveness is unknown. Methods: We used primary cost and effectiveness data from the STREAM trial in South Africa, which assessed the impact of POC testing for viral load, CD4 count, and creatinine, with task-shifting from professional to lower-cadre registered nurses compared to laboratory-based testing without task-shifting. We parameterized an agent-based network model, EMOD-HIV, to project the impact of implementing this intervention in South Africa. We assumed POC monitoring increased viral suppression by 9%, enrollment into community-based ART delivery by 25%, and switching to second-line ART by 1%, as reported in STREAM. We evaluated POC scale-up in varying clinic sizes (10-50 patient initiating ART/month) over a 20-year time horizon. We used a cost-effectiveness threshold of $500 USD/disability adjusted life year (DALY) averted for our main analysis. Results: Implementing POC testing at 70% coverage of ART patients was projected to reduce HIV infections by 4.5% and HIV-related deaths by 3.9%. In clinics with 30 ART initiations/month, the intervention was associated with an incremental cost-effectiveness ratio (ICER) of $197/DALY averted; results remained cost-effective when varying background viral suppression, ART dropout, and intervention effectiveness within the 95% confidence bound of the trial results. Assuming POC testing did not increase enrollment into community ART delivery produced an ICER of $1,149, exceeding the cost-effectiveness threshold. At higher clinic volumes (≥40 ART initiations/month), POC testing was cost-saving compared to standard-of-care. At lower clinic volumes (20 patients initiated on ART/month) the ICER was $734/DALY averted. Conclusions: POC testing for ART monitoring with task-shifting is projected to be cost-effective in moderately-sized clinics in South Africa. Funding Statement: This study was funded by the U.S. National Institute of Allergy and Infectious Diseases (R21AI124719 and R01AI147752). MS received support from NIMH K01MH115789 Declaration of Interests: Dr. Paul Drain reports receiving consulting or speaking fees from Gilead Science and Cepheid, and research support from the NIH, CDC, Gilead Sciences, and the Bill and Melinda Gates Foundation, during the conduct of the study. Dr. Abdool Karim reports grants from the NIH during the conduct of the study. All authors declare that they have no competing interests. Ethics Approval Statement: Missing.

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 control trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive HCQ (400mg BID x1day, followed by 200mg BID x9days) or placebo-equivalent (ascorbic acid) and AZ (500mg, then 250mg daily x4days) or placebo-equivalent (folic acid), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected mid-turbinate nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs 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. Incident LRTI occurred in six participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in nine (four control, two HCQ, three HCQ/AZ). There were no deaths. 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. HCQ but not HCQ/AZ had faster time to viral clearance (HR=1.62, 95% CI=1.01-2.60, p=0.047 & HR=1.25, 95% CI=0.75-2.07, 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. 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. Trial Registration Number: ClinicalTrials.gov: NCT04354428 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. Conflict of Interest: Declaration of interests: CJ reports grants from BMGF for conduct of the study, and grants from CDC and NIH outside of the submitted work. HSK reports funding from NIH. PAN and MJA have a potential financial relationship with AliveCor related to QT assessment using the device, however the investigators would receive no financial benefit for use of the technology for patients at Mayo Clinic or for its use in the current study. AB reports consulting for Gates Ventures and grants from BMGF and NIH outside of the submitted work. HYC reports consulting for BMGF, Pfizer, Ellume, and Merck, and grants from Gates Ventures, NIH, CDC, BMGF, DARPA, Apple Inc., Sanofi-Pasteur, and Roche-Genentech, outside of the submitted work. Ethical Approval: Study visits were conducted via Health Insurance Portability and Accountability Act (HIPAA)-compliant telemedicine. The Western Institutional Review Board (WIRB) approved this study with reliance agreements with collaborating institutions.

Introduction The 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. Methods We 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. Results Maintaining 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. Discussion While 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.

Objective: To quantify the contribution of specific sexual partner age groups to the risk of HIV acquisition in men and women in a hyperendemic region of South Africa. Design: We conducted a population-based cohort study among women (15–49 years of age) and men (15–55 years of age) between 2004 and 2015 in KwaZulu-Natal, South Africa. Methods: Generalized additive models were used to estimate smoothed HIV incidence rates across partnership age pairings in men and women. Cox proportional hazards regression was used to estimate the relative risk of HIV acquisition by partner age group. Results: A total of 882 HIV seroconversions were observed in 15 935 person-years for women, incidence rate = 5.5 per 100 person-years [95% confidence interval (CI), 5.2–5.9] and 270 HIV seroconversions were observed in 9372 person-years for men, incidence rate = 2.9 per 100 person-years (95% CI, 2.6–3.2). HIV incidence was highest among 15–24-year-old women reporting partnerships with 30–34-year-old men, incidence rate = 9.7 per 100 person-years (95% CI, 7.2–13.1). Risk of HIV acquisition in women was associated with male partners aged 25–29 years (adjusted hazard ratio; aHR = 1.44, 95% CI, 1.02–2.04) and 30–34 years (aHR = 1.50, 95% CI, 1.08–2.09) relative to male partners aged 35 and above. Risk of HIV acquisition in men was associated with 25–29-year-old (aHR = 1.72, 95% CI, 1.02–2.90) and 30–34-year-old women (aHR = 2.12, 95% CI, 1.03–4.39) compared to partnerships with women aged 15–19 years. Conclusion: Age of sexual partner is a major risk factor for HIV acquisition in both men and women, independent of one's own age. Partner age pairings play a critical role in driving the cycle of HIV transmission.

The global public health community has set ambitious treatment targets to end the HIV/AIDS pandemic. With the notable absence of a cure, the goal of HIV treatment is to achieve sustained suppression of an HIV viral load, which allows for immunological recovery and reduces the risk of onward HIV transmission. Monitoring HIV viral load in people living with HIV is therefore central to maintaining effective individual antiretroviral therapy as well as monitoring progress toward achieving population targets for viral suppression. The capacity for laboratory-based HIV viral load testing has increased rapidly in low- and middle-income countries, but implementation of universal viral load monitoring is still hindered by several barriers and delays. New devices for point-of-care HIV viral load testing may be used near patients to improve HIV management by reducing the turnaround time for clinical test results. The implementation of near-patient testing using these new and emerging technologies may be an essential tool for ensuring a sustainable response that will ultimately enable an end to the HIV/AIDS pandemic. In this report, we review the current and emerging technology, the evidence for decentralized viral load monitoring by non-laboratory health care workers, and the additional considerations for expanding point-of-care HIV viral load testing.

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. Electronic supplementary material The online version of this article (10.1186/s13643-019-1024-6) contains supplementary material, which is available to authorized users.

BackgroundRV144 is to date the only HIV vaccine trial to demonstrate efficacy, albeit rapidly waning over time. The HVTN 702 trial is currently evaluating in South Africa a similar vaccine formulation to that of RV144 for subtype C HIV with additional boosters (pox-protein regimen). Using a detailed stochastic individualbased network model of disease transmission calibrated to the HIV epidemic, we investigate population-level impact and maximum cost of an HIV vaccine to remain cost-effective.MethodsConsistent with the original pox-protein regimen, we model a primary series of five vaccinations meeting the goal of 50% cumulative efficacy 24 months after the first dose and include two-yearly boosters that maintain durable efficacy over 10 years. We simulate vaccination programs in South Africa starting in 2027 under various vaccine targeting and HIV treatment and prevention assumptions.ResultsOur analysis shows that this partially effective vaccine could prevent, at catchup vaccination with 60% coverage, up to 941,000 (15.6%) new infections between 2027 and 2047 assuming current trends of antiretroviral treatment. An impact of up to 697,000 (11.5%) infections prevented could be achieved by targeting age cohorts of highest incidence. Economic evaluation indicates that, if treatment scale-up was achieved, vaccination could be cost-effective at a total cost of less than $385 and $62 per 10-year series (cost-effectiveness thresholds of $5,691 and $750).ConclusionsWhile a partially effective, rapidly waning vaccine could help to prevent HIV infections, it will not eliminate HIV as a public health priority in sub-Saharan Africa. Vaccination is expected to be most effective under targeted delivery to age groups of highest HIV incidence. Awaiting results of trial, the introduction of vaccination should go in parallel with continued innovation in HIV prevention, including studies to determine the costs of delivery and feasibility and further research into products with greater efficacy and durability.

ObjectivesMathematical models have unanimously predicted that a first-generation HIV vaccine would be useful and cost-effective to roll out, but that its overall impact would be insufficient to reverse the epidemic. Here, we explore what factors contribute most to limiting the impact of such a vaccine.MethodsRanging from a theoretical ideal to a more realistic regimen, mirroring the one used in the currently ongoing trial in South Africa (HVTN 702), we model a nested hierarchy of vaccine attributes such as speed of roll-out, efficacy, and retention of booster doses.ResultsThe predominant reasons leading to a substantial loss of vaccine impact on the HIV epidemic are the time required to scale up mass vaccination, limited durability and waning of efficacy.ConclusionsA partially effective HIV vaccine will be a critical milestone for the development of a highly effective, durable, and scalable next-generation vaccine. Accelerated development, expedited vaccine availability, and improved immunogenicity are the main attributes of a vaccine that could dramatically reverse the course of the epidemic in highly endemic countries.

Background: The rapid scale-up of antiretroviral therapy (ART) over the last decade has sparked considerable debate as to whether universal test and treat (UTT) can end the HIV epidemic in sub-Saharan Africa (SSA). Methods: Using the Kingdom of Eswatini as a case study, we developed a network transmission model, calibrated to capture age and gender-specific gaps in the scale-up of ART, to estimate the impact of attaining and surpassing the 90-90-90 treatment targets on HIV incidence and mortality. We compared different ART coverage scenarios to estimate reductions in incidence and mortality over time and to evaluate the potential to drive annual incidence below an epidemic control threshold of 0.1%. Findings: ART scale-up reduced HIV incidence by 43.5% (95% credible interval, 39.7 - 46.4%) and HIV mortality by 56.2% (95% CI, 54.1 - 58.9%) among adults 15-49 years of age between 2010 and 2016, with larger reductions in incidence among men and mortality among women. Holding 2016 ART coverage levels by age and gender, adult HIV incidence would fall to 1.1% (95% CI: 0.87 - 1.3%), 2.0% (95% CI: 1.5 - 2.5%) among women, and 0.9% (95% CI: 0.7 - 1.2%) among men by 2030. Achieving the 90-90-90 targets by age and gender would further reduce incidence in individuals 15-24 years of age, 17.4% (95% CI, 7.3 - 26.1%) additional incidence reduction between 2016 and 2013, with only modest additional reductions in adults overall. Achieving 100% ART initiation, an upper bound of treatment effect, would reduce adult HIV incidence to 0.7% (95% CI: 0.6 - 0.9%) by 2030 and 0.5% (95% CI: 0.3 - 0.6%) by 2050. Interpretation: Scale-up of ART over the last decade has already contributed to substantial reductions in HIV incidence and mortality. Focused ART targeting would further reduce incidence, especially in younger individuals, but even the most aggressive treatment campaigns would be insufficient to end the epidemic in high-burden settings without a renewed focus on expanding preventive measures. Funding Statement: Support provided from the Global Good Fund and the Bill and Melinda Gates Foundation. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Not required.

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.

Background Generalized HIV epidemics propagate to future generations according to the age patterns of transmission. We hypothesized that future generations could be protected from infection using age-targeted prevention, analogous to the ring-fencing strategies used to control the spread of smallpox. Methods We modeled age-targeted or cohort-targeted outreach with HIV treatment and/or prevention using EMOD-HIV v0·8, an individual-based network model of HIV transmission in South Africa. Results Targeting ages 20 to 30 with intensified outreach, linkage, and eligibility for antiretroviral therapy (ART) averted 45% as many infections as universal outreach for approximately one-fifth the cost beyond existing HIV services. Though cost-effective, targeting failed to eliminate all infections to those under 20 due to vertical and inter-generational transmission. Cost-effectiveness of optimal prevention strategies included US$6238 per infection averted targeting ages 10-30, US$5031 targeting 20-30, US$4279 targeting 22-27, and US$3967 targeting 25-27, compared to US$10 812 for full-population test-and-treat. Minimizing burden (disability-adjusted life years [DALYs]) rather than infections resulted in older target age ranges because older adults were more likely to receive a direct health benefit from treatment. Conclusions Age-targeted treatment for HIV prevention is unlikely to eliminate HIV epidemics, but is an efficient strategy for reducing new infections in generalized epidemics settings.

IntroductionSEARCH is one of four randomized-controlled trials (RCTs) investigating the strategy of community-based treatment-as-prevention (TasP) for the reduction of HIV incidence in sub-Saharan Africa. SEARCH takes place among 32 pair-matched rural communities in three regions of East Africa and exceeded the UNAIDS 90-90-90 targets for HIV testing, linkage to care, and viral suppression in the intervention arm. We used mathematical modeling to estimate expected 3-year cumulative HIV incidence in both arms of the trial, using different assumptions about two main sources of uncertainty: scale-up of antiretroviral therapy (ART) in the control arm, and the degree of mixing between SEARCH residents and non-residents.MethodsWe used the HIV modelling software EMOD-HIV to configure and calibrate a new model of the SEARCH communities. The 32 trial communities were clustered into six nodes (three for the control arm and three for the intervention arm) using k-means clustering based on community HIV prevalence, male circumcision rates, mobility, and geographic region. The model was parameterized using data on demographics, HIV prevalence, male circumcision rates, and viral suppression data collected at trial baseline in 2013, and calibrated to nodespecific and age-specific HIV prevalence, ART coverage, and population size. Using data on ART scale-up in subsequent follow-up years in the trial, we varied linkage to ART in the control arm and the degree of external mixing between SEARCH residents and non-residents.ResultsIf no external mixing and no additional control arm ART linkage occurred, we estimate the trial would report a relative risk (RR) of 0.60 (95% CI 0.54-0.67, pConclusionThe SEARCH trial is predicted to show a 4-40% reduction in cumulative 3-year incidence, but between 18-72% of simulations were non-significant if either or both ART linkage in the control arm and external mixing are substantial. Despite achieving the 90-90-90 targets, our “best guess” is that the SEARCH trial has an equal probability of reporting a non-significant reduction in HIV incidence as it does a significant reduction.

Individual-based models provide modularity and structural flexibility necessary for modeling of infectious diseases at the within-host and population levels, but are challenging to implement. Levels of complexity can exceed the capacity and timescales for students and trainees in most academic institutions. Here we describe the process and advantages of a multi-disease framework approach developed with formal software support. The epidemiological modeling software, EMOD, has undergone a decade of software development. It is structured so that a majority of code is shared across disease modeling including malaria, HIV, tuberculosis, dengue, polio and typhoid. In additional to implementation efficiency, the sharing increases code usage and testing. The freely available codebase also includes hundreds of regression tests, scientific feature tests and component tests to help verify functionality and avoid inadvertent changes to functionality during future development. Here we describe the levels of detail, flexible configurability and modularity enabled by EMOD and the role of software development principles and processes in its development., To address multi-scale questions in infectious disease transmission, a multi-disease modeling platform EMOD has been developed with modularity, code sharing across diseases, and formal software development and testing processes.

Background Migrant populations such as mine workers contributed to the spread of HIV in sub-Saharan Africa. We used a mathematical model to estimate the community-wide impact of targeting treatment and prevention to male migrants. Methods We augmented an individual-based network model, EMOD-HIV v0.8, to include an age-dependent propensity for males to migrate. Migrants were exposed to HIV outside their home community, but continued to participate in HIV transmission in the community during periodic visits. Results Migrant-targeted interventions would have been transformative in the 1980s to 1990s, but post-2015 impacts were more modest. When targetable migrants comprised 2% of adult males, workplace HIV prevention averted 3.5% of community-wide infections over 20 years. Targeted treatment averted 8.5% of all-cause deaths among migrants. When migrants comprised 10% of males, workplace prevention averted 16.2% of infections in the community, one-quarter of which were among migrants. Workplace prevention and treatment acted synergistically, averting 17.1% of community infections and 11.6% of deaths among migrants. These estimates do not include prevention of secondary spread of HIV or tuberculosis at the workplace. Conclusions Though cost-effective, targeting migrants cannot collapse generalized epidemics in their home communities. Such a strategy would only have been possible prior to the early 1990s. However, migrant-targeted interventions synergize with general-population expansion of HIV services.

Contains fulltext : 138145.pdf (Publisher’s version ) (Open Access) BACKGROUND: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per muL 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 muL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per muL 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 muL 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 muL 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 muL 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.

Cell therapy is a rapidly expanding field in translational medicine as a targeted cancer treatment modality. While allogeneic bone marrow transplantations have been in clinical practice for decades to treat hematological malignancies, a plethora of new cell-based cancer treatment formats are in early clinical trials infusing large numbers of autologous T lymphocytes with high avidity for tumor antigens (1). Notably, following cell transfer, therapeutic cells often rely on the co-delivery of adjuvant drugs. These agents are designed to maximize donor cell efficacy and in vivo persistence, offset suppressive and adverse molecules at cell homing sites, or promote the differentiation of transferred cells into a therapeutically desirable cellular phenotype. Examples include administration of γc receptor cytokines, including interleukin (IL-) 2, IL-7, IL-21 and IL-15 in adoptive T-cell therapy (2), the blockade of immunosuppressive transforming growth factor-beta (TGF-β) in the tumor microenvironment (3), or the use of small-molecule drugs to boost immune reconstitution following HSC transplants (4). However, these agents often require high and sustained systemic doses to achieve the desired therapeutic effect, leading to dose-limiting toxicities due to the generally pleiotropic nature of these drugs, which has restricted their clinical use. One approach to focus adjuvant drug action on the transferred cell population is to genetically engineer donor cells to secrete their own supporting factors. However, regulatory and cost barriers of large-scale clinical grade vector production and safety testing, costly and lengthy cell culture, and technical challenges of high gene transfer hinder the implementation of clinical gene transfer protocols. More importantly, several emerging adjuvant therapies are based on small-molecule drugs that cannot be genetically encoded. We present a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles directly onto the plasma membrane of therapeutic cells. Using this method to provide sustained pseudo-autocrine stimulation to donor cells, we elicited dramatic enhancements in tumor elimination in a model of adoptive T-cell therapy for cancer and increased the in vivo repopulation rate of hematopoietic stem cell grafts, using very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a facile and generalizable strategy to augment cytoreagents while minimizing systemic side effects of adjuvant drugs. Based on the wealth of available NP-formulations tailored to deliver small molecule drugs, proteins, or siRNA, the range of therapeutic or diagnostic cargos that can be attached to therapeutic cells extends far beyond the small molecules and recombinant proteins tested in our studies. In addition, our results suggest therapeutic cells are promising vectors for actively targeted drug delivery. References 1. Morgan, R.A., et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126-129 (2006). 2. June, C.H. Adoptive T cell therapy for cancer in the clinic. The Journal of clinical investigation 117, 1466-1476 (2007). 3. Wallace, A., et al. Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. Clin Cancer Res 14, 3966-3974 (2008). 4. Trowbridge, J.J., Xenocostas, A., Moon, R.T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med 12, 89-98 (2006). Citation Format: Matthias Stephan, James J. Moon, Soong Ho Um, Anna Bershteyn, Darrell J. Irvine. Therapeutic cell engineering using surface-conjugated synthetic nanoparticles [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SSY01-05

The South African government is currently discussing various alternative approaches to the further expansion of antiretroviral treatment (ART) in public-sector facilities. Alternatives under consideration include the criteria under which a patient would be eligible for free care the level of coverage with testing and care how much of the care will be delivered in small facilities located closer to the patients and how to assure linkage to care and subsequent adherence by ART patients. We used the EMOD-HIV model to generate 12 epidemiological scenarios. The EMOD-HIV model is a model of HIV transmission which projects South African HIV incidence and prevalence and ARV treatment by age group for alternative combinations of treatment eligibility criteria and testing. We treat as sunk costs the projected future cost of one of these 12 scenarios the baseline scenario characterizing South Africa’s 2013 policy to treat people with CD4 counts less than 350. We compute the cost and benefits of the other 11 scenarios relative to this baseline. Starting with our own bottom-up cost analyses in South Africa we separate outpatient cost into non-scale-dependent costs (drugs and laboratory tests) and scale-dependent cost (staff space equipment and overheads) and model the cost of production according to the expected future number and size of clinics. On the demand side we include the cost of creating and sustaining the projected incremental demand for testing and treatment. Previous research with EMOD-HIV has shown that more vigorous recruitment of patients with CD4 counts less than 350 appears to be an advantageous policy over a five-year horizon. Over 20 years however the model assumption that a person on treatment is 92 percent less infectious improves the cost-effectiveness of higher eligibility thresholds over more vigorous recruitment at the lower threshold of 350 averting HIV infections for between $1700 and $2800 (under our central assumptions) while more vigorous expansion under the current guidelines would cost more than $7500 per incremental HIV infection averted. Granular spatial models of demand and cost facilitate the optimal targeting of new facility construction and outreach services. Based on analysis of the sensitivity of the results to 1728 alternative parameter combinations at each of four discount rates we conclude that better knowledge of the behavioral elasticities would be valuable reducing the uncertainty of cost estimates by a factor of 4 to 10.

Voluntary Medical Male Circumcision (VMMC) for human immunodeficiency virus (HIV) prevention has scaled up rapidly among young men in western Kenya since 2008. Whether the program has successfully reached uncircumcised men evenly across the region is largely unknown. Using data from two cluster randomized surveys from the 2008 and 2014 Kenyan Demographic Health Survey (KDHS), we mapped the continuous spatial distribution of circumcised men by age group across former Nyanza Province to identify geographic areas where local circumcision prevalence is lower than the overall, regional prevalence. The prevalence of self-reported circumcision among men 15 to 49 across six counties in former Nyanza Province increased from 45.6% (95% CI = 33.2–58.0%) in 2008 to 71.4% (95% CI = 67.4–75.0%) in 2014, with the greatest increase in men 15 to 24 years of age, from 40.4% (95% CI = 27.7–55.0%) in 2008 to 81.6% (95% CI = 77.2–85.0%) in 2014. Despite the dramatic scale-up of VMMC in western Kenya, circumcision coverage in parts of Kisumu, Siaya, and Homa Bay counties was lower than expected (P

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.

Background 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. Methods and Findings 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. Conclusions 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. Please see later in the article for the Editors' Summary, Editors' Summary Background Following the first reported case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, increased rapidly. In recent years, the number of people becoming newly infected has declined slightly, but the virus continues to spread at unacceptably high levels. In 2010 alone, 2.7 million people became HIV-positive. HIV, which is usually transmitted through unprotected sex, destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, half of HIV-infected people died within eleven years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and, for people living in affluent countries, HIV/AIDS gradually became considered a chronic condition. But because ART was expensive, for people living in developing countries HIV/AIDS remained a fatal condition. Roll-out of ART in developing countries first started in the early 2000s. In 2006, the international community set a target of achieving universal ART coverage by 2010. Although this target has still not been reached, by the end of 2010, 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving ART. Why Was This Study Done? Several studies suggest that ART, in addition to reducing illness and death among HIV-positive people, reduces HIV transmission. Consequently, there is interest in expanding the provision of ART as a strategy for reducing the spread of HIV (“HIV treatment as prevention"), particularly in sub-Saharan Africa, where one in 20 adults is HIV-positive. It is important to understand exactly how ART might contribute to averting HIV transmission. Several mathematical models that simulate HIV infection and disease progression have been developed to investigate the impact of expanding access to ART on the incidence of HIV (the number of new infections occurring in a population over a year). But, although all these models predict that increased ART coverage will have epidemiologic (population) benefits, they vary widely in their estimates of the magnitude of these benefits. In this study, the researchers systematically compare the predictions of 12 mathematical models of the HIV epidemic in South Africa, simulating the same ART intervention programs to determine the extent to which different models agree about the impact of expanded ART. What Did the Researchers Do and Find? The researchers invited groups who had previously developed mathematical models of the epidemiological impact of expanded access to ART in South Africa to participate in a systematic comparison exercise in which their models were used to simulate ART scale-up scenarios in which the CD4 count threshold for treatment eligibility, access to treatment, and retention on treatment were systematically varied. To exclude variation resulting from different model assumptions about the past and current ART program, it was assumed that ART is introduced into the population in the year 2012, with no treatment provision prior to this, and interventions were evaluated in comparison to an artificial counterfactual scenario in which no treatment is provided. A standard scenario based on the World Health Organization's recommended threshold for initiation of ART, although unrepresentative of current provision in South Africa, was used to compare the models. In this scenario, 80% of HIV-infected individuals received treatment, they started treatment on average a year after their CD4 count dropped below 350 cells per microliter of blood, and 85% remained on treatment after three years. The models predicted that, with a start point of 2012, the HIV incidence would be 35%–54% lower in 2020 and 32%–74% lower in 2050 compared to a counterfactual scenario where there was no ART. Estimates of the number of person-years of ART needed per infection averted (the efficiency with which ART reduced new infections) ranged from 6.3–18.7 and from 4.5–20.2 over the periods 2012–2020 and 2012–2050, respectively. Finally, estimates of the impact of ambitious interventions (for example, immediate treatment of all HIV-positive individuals) varied widely across the models. What Do These Findings Mean? Although the mathematical models used in this study had different characteristics, all 12 predict that ART, at high levels of access and adherence, has the potential to reduce new HIV infections. However, although the models broadly agree about the short-term epidemiologic impact of treatment scale-up, their longer-term projections (including whether ART alone can eliminate HIV infection) and their estimates of the efficiency with which ART can reduce new infections vary widely. Importantly, it is possible that all these predictions will be wrong—all the models may have excluded some aspect of HIV transmission that will be found in the future to be crucial. Finally, these findings do not aim to indicate which specific ART interventions should be used to reduce the incidence of HIV. Rather, by comparing the models that are being used to investigate the feasibility of “HIV treatment as prevention," these findings should help modelers and policy-makers think critically about how the assumptions underlying these models affect the models' predictions. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001245. This study is part of the July 2012 PLoS Medicine Collection, Investigating the Impact of Treatment on New HIV Infections Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, on HIV treatment as prevention, and on HIV/AIDS in South Africa (in English and Spanish) The World Health Organization provides information about universal access to AIDS treatment (in English, French, and Spanish); its 2010 ART guidelines can be downloaded The HIV Modelling Consortium aims to improve scientific support for decision-making by coordinating mathematical modeling of the HIV epidemic Patient stories about living with HIV/AIDS are available through Avert; the charity website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs

Contains fulltext : 154578.pdf (Publisher’s version ) (Open Access) 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.