Faculty Bibliography

Importance:The SARS-CoV-2 viral trajectory has not been well characterized in incident infections. These data are needed to inform natural history, prevention practices, and therapeutic development. Objective:To characterize early SARS-CoV-2 viral RNA load (hereafter referred to as viral load) in individuals with incident infections in association with COVID-19 symptom onset and severity. Design, Setting, and Participants:This prospective cohort study was a secondary data analysis of a remotely conducted study that enrolled 829 asymptomatic community-based participants recently exposed (<96 hours) to persons with SARS-CoV-2 from 41 US states from March 31 to August 21, 2020. Two cohorts were studied: (1) participants who were SARS-CoV-2 negative at baseline and tested positive during study follow-up, and (2) participants who had 2 or more positive swabs during follow-up, regardless of the initial (baseline) swab result. Participants collected daily midturbinate swab samples for SARS-CoV-2 RNA detection and maintained symptom diaries for 14 days. Exposure:Laboratory-confirmed SARS-CoV-2 infection. Main Outcomes and Measures:The observed SARS-CoV-2 viral load among incident infections was summarized, and piecewise linear mixed-effects models were used to estimate the characteristics of viral trajectories in association with COVID-19 symptom onset and severity. Results:A total of 97 participants (55 women [57%]; median age, 37 years [IQR, 27-52 years]) developed incident infections during follow-up. Forty-two participants (43%) had viral shedding for 1 day (median peak viral load cycle threshold [Ct] value, 38.5 [95% CI, 38.3-39.0]), 18 (19%) for 2 to 6 days (median Ct value, 36.7 [95% CI, 30.2-38.1]), and 31 (32%) for 7 days or more (median Ct value, 18.3 [95% CI, 17.4-22.0]). The cycle threshold value has an inverse association with viral load. Six participants (6%) had 1 to 6 days of viral shedding with censored duration. The peak mean (SD) viral load was observed on day 3 of shedding (Ct value, 33.8 [95% CI, 31.9-35.6]). Based on the statistical models fitted to 129 participants (60 men [47%]; median age, 38 years [IQR, 25-54 years]) with 2 or more SARS-CoV-2-positive swab samples, persons reporting moderate or severe symptoms tended to have a higher peak mean viral load than those who were asymptomatic (Ct value, 23.3 [95% CI, 22.6-24.0] vs 30.7 [95% CI, 29.8-31.4]). Mild symptoms generally started within 1 day of peak viral load, and moderate or severe symptoms 2 days after peak viral load. All 535 sequenced samples detected the G614 variant (Wuhan strain). Conclusions and Relevance:This cohort study suggests that having incident SARS-CoV-2 G614 infection was associated with a rapid viral load peak followed by slower decay. COVID-19 symptom onset generally coincided with peak viral load, which correlated positively with symptom severity. This longitudinal evaluation of the SARS-CoV-2 G614 with frequent molecular testing serves as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.

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.

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/METHODS: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%.

Recent declines in adult HIV-1 incidence have followed the large-scale expansion of antiretroviral therapy and primary HIV prevention across high-burden communities of sub-Saharan Africa. Mathematical modeling suggests that HIV risk will decline disproportionately in younger adult age-groups as interventions scale, concentrating new HIV infections in those >age 25 over time. Yet, no empirical data exist to support these projections. We conducted a population-based cohort study over a 16-y period (2004 to 2019), spanning the early scale-up of antiretroviral therapy and voluntary medical male circumcision, to estimate changes in the age distribution of HIV incidence in a hyperepidemic region of KwaZulu-Natal, South Africa, where adult HIV incidence has recently declined. Median age of HIV seroconversion increased by 5.5 y in men and 3.0 y in women, and the age of peak HIV incidence increased by 5.0 y in men and 2.0 y in women. Incidence declined disproportionately among young men (64% in men 15 to 19, 68% in men 20 to 24, and 46% in men 25 to 29) and young women (44% in women 15 to 19, 24% in women 20 to 24) comparing periods pre- versus post-universal test and treat. Incidence was stable (<20% change) in women aged 30 to 39 and men aged 30 to 34. Age shifts in incidence occurred after 2012 and were observed earlier in men than in women. These results provide direct epidemiological evidence of the changing demographics of HIV risk in sub-Saharan Africa in the era of large-scale treatment and prevention. More attention is needed to address lagging incidence decline among older individuals.

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/RESULTS: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/CONCLUSIONS: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/BACKGROUND:National Institutes of Health.

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 (<96 hours) to persons with diagnosed SARS-CoV-2 infection. INTERVENTION:Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control. MEASUREMENTS:Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment. RESULTS: = 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.

Background/UNASSIGNED:Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. Methods/UNASSIGNED:In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. Findings/UNASSIGNED: = 0.70). Interpretation/UNASSIGNED:Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. Funding/UNASSIGNED:ClinicalTrials.gov number NCT04354428.

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

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.