Faculty Bibliography

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

BACKGROUND:Voluntary medical male circumcision (VMMC) has been a recommended HIV prevention strategy in sub-Saharan Africa since 2007, particularly in countries with high HIV prevalence. However, given the scale-up of antiretroviral therapy programmes, it is not clear whether VMMC still represents a cost-effective use of scarce HIV programme resources. METHODS:Using five existing well described HIV mathematical models, we compared continuation of VMMC for 5 years in men aged 15 years and older to no further VMMC in South Africa, Malawi, and Zimbabwe and across a range of setting scenarios in sub-Saharan Africa. Outputs were based on a 50-year time horizon, VMMC cost was assumed to be US$90, and a cost-effectiveness threshold of US$500 was used. FINDINGS/RESULTS:In South Africa and Malawi, the continuation of VMMC for 5 years resulted in cost savings and health benefits (infections and disability-adjusted life-years averted) according to all models. Of the two models modelling Zimbabwe, the continuation of VMMC for 5 years resulted in cost savings and health benefits by one model but was not as cost-effective according to the other model. Continuation of VMMC was cost-effective in 68% of setting scenarios across sub-Saharan Africa. VMMC was more likely to be cost-effective in modelled settings with higher HIV incidence; VMMC was cost-effective in 62% of settings with HIV incidence of less than 0·1 per 100 person-years in men aged 15-49 years, increasing to 95% with HIV incidence greater than 1·0 per 100 person-years. INTERPRETATION/CONCLUSIONS:VMMC remains a cost-effective, often cost-saving, prevention intervention in sub-Saharan Africa for at least the next 5 years. FUNDING/BACKGROUND:Bill & Melinda Gates Foundation for the HIV Modelling Consortium.

PURPOSE OF REVIEW/OBJECTIVE:Voluntary male medical circumcision (VMMC) has been a cornerstone of HIV prevention in Eastern and Southern Africa (ESA) and is credited in part for declines in HIV incidence seen in recent years. However, these HIV incidence declines change VMMC cost-effectiveness and how it varies across populations. RECENT FINDINGS/RESULTS:Mathematical models project continued cost-effectiveness of VMMC in much of ESA despite HIV incidence declines. A key data gap is how demand generation cost differs across age groups and over time as VMMC coverage increases. Additionally, VMMC models usually neglect non-HIV effects of VMMC, such as prevention of other sexually transmitted infections and medical adverse events. While small compared to HIV effects in the short term, these could become important as HIV incidence declines. Evidence to date supports prioritizing VMMC in ESA despite falling HIV incidence. Updated modeling methodologies will become necessary if HIV incidence reaches low levels.

BACKGROUND:In this so-called treat-all era, antiretroviral therapy (ART) interruptions contribute to an increasing proportion of HIV infections and deaths. Many strategies to improve retention on ART cost more than standard of care. In this study, we aimed to estimate the upper-bound costs at which such interventions should be adopted. METHODS:In this combined analysis, we compared the infections averted, disability-adjusted life-years (DALYs) averted, and upper-bound costs of interventions that improve ART retention in three HIV models with diverse structures, assumptions, and baseline settings: EMOD in South Africa, Optima in Malawi, and Synthesis in sub-Saharan African low-income and middle-income countries (LMICs). We modelled estimates over a 40-year time horizon, from a baseline of Jan 1, 2022, when interventions would be implemented, to Jan 1, 2062. We varied increment of ART retention (25%, 50%, 75%, and 100% retention), the extent to which interventions could be targeted towards individuals at risk of interrupting ART, and cost-effectiveness thresholds in each setting. FINDINGS/RESULTS:Despite simulating different settings and epidemic trends, all three models produced consistent estimates of health benefit (ie, DALYs averted) and transmission reduction per increment in retention. The range of estimates was 1·35-3·55 DALYs and 0·12-0·20 infections averted over the 40-year time horizon per additional person-year retained on ART. Upper-bound costs varied by setting and intervention effectiveness. Improving retention by 25% among all people receiving ART, regardless of risk of ART interruption, gave an upper-bound cost per person-year of US$2-6 in Optima (Malawi), $43-68 in Synthesis (LMICs in sub-Saharan Africa), and $28-180 in EMOD (South Africa). A maximally targeted and effective retention intervention had an upper-bound cost per person-year of US$93-223 in Optima (Malawi), $871-1389 in Synthesis (LMICs in sub-Saharan Africa), and $1013-6518 in EMOD (South Africa). INTERPRETATION/CONCLUSIONS:Upper-bound costs that could improve ART retention vary across sub-Saharan African settings and are likely to be similar to or higher than was estimated before the start of the treat-all era. Upper-bound costs could be increased by targeting interventions to those most at risk of interrupting ART. FUNDING/BACKGROUND:Bill & Melinda Gates Foundation.

Two randomized controlled trials demonstrated no clinical benefit of hydroxychloroquine (HCQ) for either post-exposure prophylaxis (PEP) or early treatment of SARS-CoV-2 infection. Using data from these studies, we calculated time-weighted average change from baseline SARS-CoV-2 viral load and demonstrated that HCQ did not affect viral clearance. This article is protected by copyright. All rights reserved.

Health authorities encouraged the use of digital contact tracing mobile applications (apps) during the COVID-19 pandemic, but the level of adoption was low because apps offered few direct benefits to counterbalance risks to personal privacy. Adoption of such apps could improve if they provided benefits to users. NOVID (COVID-19 Radar), a smartphone app, provided users with personalized data on social proximity of COVID-19 cases and exposed contacts. We analyzed uptake of NOVID at the Georgia Institute of Technology (Georgia Tech) during the 2020-2021 academic year. Data included anonymous NOVID users who self-identified with Georgia Tech and their first- and second-degree network contacts. NOVID achieved 13%-30% adoption at Georgia Tech. Because of technical challenges, adoption waned after an initial peak. The largest increases in adoption (from 41 to 3704) followed administrative promotion of NOVID. Adoption increased modestly (from 2512 to 2661) after faculty- and student-led promotion, such as distribution of door hangers and a public seminar. Two-thirds of on-campus NOVID users were connected to a large network of other users, enabling them to receive data on social proximity of COVID-19 cases and exposed contacts. Network cohesion was observed to emerge rapidly when adoption rates passed just 10%, consistent with estimates from network theory. The key lesson learned in this case study is that top-down administrative promotion outperforms bottom-up grassroots promotion. Relatively high levels of adoption and network cohesion, despite technical challenges during the Georgia Tech pilot of NOVID, illustrate the promise of digital contact tracing when apps provide privacy and inherently beneficial personalized data to their users, especially in regions where Google Apple Exposure Notification is not available.

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

BACKGROUND:Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS:We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug $11, HIV test $4, and $14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3%, and a time horizon of 50 years. In sensitivity analyses, we considered a cost-effectiveness threshold of $100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS:In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION:Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING:US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation.

While detection of SARS-CoV-2 by diagnostic RT-PCR is highly sensitive for viral RNA, the nucleic acid amplification of subgenomic RNAs (sgRNA) that are the product of viral replication may more accurately identify replication. We characterized the diagnostic RT-PCR and sgRNA detection from nasal swabs collected daily by participants in post exposure prophylaxis or treatment studies for SARS-CoV-2. Among 1932 RT-PCR-positive swabs with sgRNA tests, 40% (767) had detectable sgRNA. Above a diagnostic PCR viral load threshold of 5.1 log10 copies/mL, 96% of samples had detectable sgRNA with viral loads that followed a linear trend. The trajectories of diagnostic and sgRNA viral loads differed, with 80% peaking on the same day but duration of sgRNA detection being shorter (8 versus 14 days). With a large sample of daily swabs we provide comparative sgRNA kinetics and a diagnostic PCR threshold that correlates with replicating virus independent of symptoms or duration of illness.