When does humoral memory enhance infection?

Antibodies and humoral memory are key components of the adaptive immune system. We consider and computationally model mechanisms by which humoral memory present at baseline might increase rather than decrease infection load; we refer to this effect as EI-HM (enhancement of infection by humoral memory). We first consider antibody dependent enhancement (ADE) in which antibody enhances the growth of the pathogen, typically a virus, and typically at intermediate 'Goldilocks' levels of antibody. Our ADE model reproduces ADE in vitro and enhancement of infection in vivo from passive antibody transfer. But notably the simplest implementation of our ADE model never results in EI-HM. Adding complexity, by making the cross-reactive antibody much less neutralizing than the de novo generated antibody or by including a sufficiently strong non-antibody immune response, allows for ADE-mediated EI-HM. We next consider the possibility that cross-reactive memory causes EI-HM by crowding out a possibly superior de novo immune response. We show that, even without ADE, EI-HM can occur when the cross-reactive response is both less potent and 'directly' (i.e. independently of infection load) suppressive with regard to the de novo response. In this case adding a non-antibody immune response to our computational model greatly reduces or completely eliminates EI-HM, which suggests that 'crowding out' is unlikely to cause substantial EI-HM. Hence, our results provide examples in which simple models give qualitatively opposite results compared to models with plausible complexity. Our results may be helpful in interpreting and reconciling disparate experimental findings, especially from dengue, and for vaccination.

How Can Progress Toward Ending the Human Immunodeficiency Virus Epidemic in the United States Be Monitored?

The plan for Ending the HIV (human immunodeficiency virus) Epidemic (EHE) in the United States aims to reduce new infections by 75% by 2025 and by 90% by 2030. For EHE to be successful, it is important to accurately measure changes in numbers of new HIV infections after 5 and 10 years (to determine whether the EHE goals have been achieved) but also over shorter timescales (to monitor progress and intensify prevention efforts if required). In this viewpoint, we aim to demonstrate why the method used to monitor progress toward the EHE goals must be carefully considered. We briefly describe and discuss different methods to estimate numbers of new HIV infections based on longitudinal cohort studies, cross-sectional incidence surveys, and routine surveillance data. We particularly focus on identifying conditions under which unadjusted and adjusted estimates based on routine surveillance data can be used to estimate changes in new HIV infections.

Dynamics and turnover of memory CD8 T cell responses following yellow fever vaccination.

Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models were first fit to the frequency of YFV-specific memory CD8 T cells and deuterium enrichment in those cells 42 days to 1 year post-vaccination. A different dataset, on the loss of YFV-specific CD8 T cells over three decades, was used to assess out of sample predictions of our models. The commonly used exponential and bi-exponential decline models performed relatively poorly. Models with the cell loss following a power law (exactly or approximately) were most predictive. Notably, using only the first year of data, these models accurately predicted T cell frequencies up to 30 years post-vaccination. Our analyses suggest that division rates of these cells drop and plateau at a low level (0.1% per day, ∼ double the estimated values for naive T cells) within one year following vaccination, whereas death rates continue to decline for much longer. Our results show that power laws can be predictive for T cell memory, a finding that may be useful for vaccine evaluation and epidemiological modeling. Moreover, since power laws asymptotically decline more slowly than any exponential decline, our results help explain the longevity of immune memory phenomenologically.

Estimating vaccine efficacy during open-label follow-up of COVID-19 vaccine trials based on population-level surveillance data.

While rapid development and roll out of COVID-19 vaccines is necessary in a pandemic, the process limits the ability of clinical trials to assess longer-term vaccine efficacy. We leveraged COVID-19 surveillance data in the U.S. to evaluate vaccine efficacy in U.S. Government-funded COVID-19 vaccine efficacy trials with a three-step estimation process. First, we used a compartmental epidemiological model informed by county-level surveillance data, a "population model", to estimate SARS-CoV-2 incidence among the unvaccinated. Second, a "cohort model" was used to adjust the population SARS-CoV-2 incidence to the vaccine trial cohort, taking into account individual participant characteristics and the difference between SARS-CoV-2 infection and COVID-19 disease. Third, we fit a regression model estimating the offset between the cohort-model-based COVID-19 incidence in the unvaccinated with the placebo-group COVID-19 incidence in the trial during blinded follow-up. Counterfactual placebo COVID-19 incidence was estimated during open-label follow-up by adjusting the cohort-model-based incidence rate by the estimated offset. Vaccine efficacy during open-label follow-up was estimated by contrasting the vaccine group COVID-19 incidence with the counterfactual placebo COVID-19 incidence. We documented good performance of the methodology in a simulation study. We also applied the methodology to estimate vaccine efficacy for the two-dose AZD1222 COVID-19 vaccine using data from the phase 3 U.S. trial (ClinicalTrials.gov # NCT04516746). We estimated AZD1222 vaccine efficacy of 59.1% (95% uncertainty interval (UI): 40.4%-74.3%) in April, 2021 (mean 106 days post-second dose), which reduced to 35.7% (95% UI: 15.0%-51.7%) in July, 2021 (mean 198 days post-second-dose). We developed and evaluated a methodology for estimating longer-term vaccine efficacy. This methodology could be applied to estimating counterfactual placebo incidence for future placebo-controlled vaccine efficacy trials of emerging pathogens with early termination of blinded follow-up, to active-controlled or uncontrolled COVID-19 vaccine efficacy trials, and to other clinical endpoints influenced by vaccination.

Estimating benefits of using on-demand oral prep by MSM: A comparative modeling study of the US and Thailand.

Background: Daily and on-demand pre-exposure prophylaxis (PrEP) are effective at preventing HIV acquisition among men who have sex with men (MSM), but only daily PrEP is approved in the US. On-demand PrEP may improve uptake and adherence. We identify sub-groups of MSM who would benefit from on-demand PrEP and determine effectiveness achieved if individuals used their optimal regimens. Methods: Using data from the HPTN 067 study (study period 2012-2014), we created an individual-based stochastic model of HIV risk in two synthetic MSM populations with parameters separately estimated using data from Harlem, US, and Bangkok, Thailand. Agents were assigned daily and on-demand PrEP for six months each. Two personalized PrEP assignments: optimal, based on improved predicted effectiveness and reduced pill burden, and adherence-based, using daily PrEP adherence, were simulated for another six months. Findings: Simulated on-demand PrEP was optimal for approximately one-third of MSM. It was assigned mainly to those with low daily PrEP adherence (88% (Harlem), 95% (Bangkok) of MSM with daily PrEP adherence <40%). Mean effectiveness was slightly higher in the full synthetic population with optimal PrEP assignment compared to universal daily PrEP. Among MSM for whom on-demand PrEP was optimal, mean effectiveness improved by 18 (Harlem) and 7 percentage points (Bangkok). Comparable predicted effectiveness was achieved if on-demand PrEP was assigned to the population with daily PrEP adherence <50%. There was no advantage in assigning on-demand PrEP by sex act frequency. Interpretation: On-demand PrEP could benefit many MSM by increasing effectiveness or decreasing pill burden with similar effectiveness. On-demand PrEP may be an effective alternative to daily PrEP for individuals with difficulty taking daily PrEP consistently. Results were similar for Harlem and Bangkok, indicating that these conclusions were robust in populations with different overall adherence levels and may inform future public-health policies. Funding: US NIH grant UM1 AI068617.

Estimating the impact of HIV PrEP regimens containing long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate/emtricitabine among men who have sex with men in the United States: a mathematical modelling study for HPTN 083.

Background: The HPTN 083 trial demonstrated superiority of HIV pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB) to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) among men who have sex with men (MSM). We compared the potential population-level impact of TDF/FTC and CAB among MSM in Atlanta, Georgia. Methods: An MSM HIV transmission model was calibrated to Atlanta-specific data on HIV prevalence and PrEP usage (percentage of uninfected MSM on PrEP), assuming only PrEP-indicated MSM used PrEP. CAB effectiveness (efficacy × adherence) of 91% was estimated using data from HPTN 083 and previous TDF/FTC trials. We estimated HIV infections averted over 5/10 years if TDF/FTC use were maintained, or if all TDF/FTC users switched to CAB in January 2022 (vs. no PrEP or continued TDF/FTC use). CAB scenarios with 10%/20% more users were also considered. Progress towards Ending the HIV Epidemic (EHE) goals (75%/90% fewer HIV infections in 2025/2030 vs. 2017) was estimated. Findings: We predicted TDF/FTC at current usage (∼28%) would avert 36.3% of new HIV infections (95% credible interval 25.6-48.7%) among all Atlanta MSM over 2022-2026 vs. no PrEP. Switching to CAB with similar usage may prevent 44.6% (33.2-56.6%) infections vs. no PrEP and 11.9% (5.2-20.2%) infections vs. continued TDF/FTC. Increasing CAB usage 20% could increase the incremental impact over TDF/FTC to 30.0% over 2022-2026, getting ∼60% towards reaching EHE goals (47%/54% fewer infections in 2025/2030). Reaching the 2030 EHE goal would require 93% CAB usage. Interpretation: If CAB effectiveness were like HPTN 083, CAB could prevent more infections than TDF/FTC at similar usage. Increased CAB usage could contribute substantially towards reaching EHE goals, but the usage required to meet EHE goals is unrealistic. Funding: NIH, MRC.

Efficacy estimates of oral pre-exposure prophylaxis for HIV prevention in cisgender women with partial adherence.

Pre-exposure prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate and emtricitabine administered orally daily is effective in preventing human immunodeficiency virus (HIV) acquisition in both men and women with sufficient adherence; however, the adherence-efficacy relationship in cisgender women has not been well established. We calculated the adherence-efficacy curve for cisgender women by using HIV incidence and plasma TFV concentration data from three trials (FEM-PrEP, VOICE and Partners PrEP). We imputed TFV diphosphate (TFV-DP) concentrations, a measure of long-term adherence, from TFV quantification by using data from the HIV Prevention Trials Network 082 study, which measured both TFV-DP and TFV concentrations. Two, four and seven pills per week reduced HIV incidence by 59.3% (95% credible interval (CrI) 29.9-95.8%), 83.8% (95% CI 51.7-99.8%) and 95.9% (95% CI 72.6-100%), respectively. Our adherence-efficacy curve can be validated and updated by HIV prevention studies that directly measure TFV-DP concentrations. The curve suggests that high adherence confers high protection in cisgender women. However, the lower efficacy with partial adherence highlights the need for new PrEP products and interventions to increase adherence.

Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis.

INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics. METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only. RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively. CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands).

Improving vaccination coverage and offering vaccine to all school-age children allowed uninterrupted in-person schooling in King County, WA: Modeling analysis.

The rapid spread of highly transmissible SARS-CoV-2 variants combined with slowing pace of vaccination in Fall 2021 created uncertainty around the future trajectory of the epidemic in King County, Washington, USA. We analyzed the benefits of offering vaccination to children ages 5-11 and expanding the overall vaccination coverage using mathematical modeling. We adapted a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington, to simulate scenarios of vaccinating children aged 5-11 with different starting dates and different proportions of physical interactions (PPI) in schools being restored. Dynamic social distancing was implemented in response to changes in weekly hospitalizations. Reduction of hospitalizations and estimated time under additional social distancing measures are reported over the 2021-2022 school year. In the scenario with 85% vaccination coverage of 12+ year-olds, offering early vaccination to children aged 5-11 with 75% PPI was predicted to prevent 756 (median, IQR 301-1434) hospitalizations cutting youth hospitalizations in half compared to no vaccination and largely reducing the need for additional social distancing measures over the school year. If, in addition, 90% overall vaccination coverage was reached, 60% of remaining hospitalizations would be averted and the need for increased social distancing would almost certainly be avoided. Our work suggests that uninterrupted in-person schooling in King County was partly possible because reasonable precaution measures were taken at schools to reduce infectious contacts. Rapid vaccination of all school-aged children provides meaningful reduction of the COVID-19 health burden over this school year but only if implemented early. It remains critical to vaccinate as many people as possible to limit the morbidity and mortality associated with future epidemic waves.

Bayesian validation framework for dynamic epidemic models.

Complex models of infectious diseases are used to understand the transmission dynamics of the disease, project the course of an epidemic, predict the effect of interventions and/or provide information for power calculations of community level intervention studies. However, there have been relatively few opportunities to rigorously evaluate the predictions of such models till now. Indeed, while there is a large literature on calibration (fitting model parameters) and validation (comparing model outputs to data) of complex models based on empirical data, the lack of uniformity in accepted criteria for such procedures for models of infectious diseases has led to simple procedures being prevalent for such steps. However, recently, several community level randomized trials of combination HIV intervention have been planned and/or initiated, and in each case, significant epidemic modeling efforts were conducted during trial planning which were integral to the design of these trials. The existence of these models and the (anticipated) availability of results from the related trials, provide a unique opportunity to evaluate the models and their usefulness in trial design. In this project, we outline a framework for evaluating the predictions of complex epidemiological models and describe experiments that can be used to test their predictions.

Widespread testing, case isolation and contact tracing may allow safe school reopening with continued moderate physical distancing: A modeling analysis of King County, WA data.

BACKGROUND: In late March 2020, a "Stay Home, Stay Healthy" order was issued in Washington State in response to the COVID-19 pandemic. On May 1, a 4-phase reopening plan began. We investigated whether adjunctive prevention strategies would allow less restrictive physical distancing to avoid second epidemic waves and secure safe school reopening. METHODS: We developed a mathematical model, stratifying the population by age, infection status and treatment status to project SARS-CoV-2 transmission during and after the reopening period. The model was parameterized with demographic and contact data from King County, WA and calibrated to confirmed cases, deaths and epidemic peak timing. Adjunctive prevention interventions were simulated assuming different levels of pre-COVID physical interactions (pC_PI) restored. RESULTS: The best model fit estimated ~35% pC_PI under the lockdown which prevented ~17,000 deaths by May 15. Gradually restoring 75% pC_PI for all age groups between May 15-July 15 would have resulted in ~350 daily deaths by early September 2020. Maintaining <45% pC_PI was required with current testing practices to ensure low levels of daily infections and deaths. Increased testing, isolation of symptomatic infections, and contact tracing permitted 60% pC_PI without significant increases in daily deaths before November and allowed opening of schools with <15 daily deaths. Inpatient antiviral treatment was predicted to reduce deaths significantly without lowering cases or hospitalizations. CONCLUSIONS: We predict that widespread testing, contact tracing and case isolation would allow relaxation of physical distancing, as well as opening of schools, without a surge in local cases and deaths.

COVID-19 vaccines that reduce symptoms but do not block infection need higher coverage and faster rollout to achieve population impact.

Trial results for two COVID-19 vaccines suggest at least 90% efficacy against symptomatic disease (VEDIS). It remains unknown whether this efficacy is mediated by lowering SARS-CoV-2 infection susceptibility (VESUSC) or development of symptoms after infection (VESYMP). We aim to assess and compare the population impact of vaccines with different efficacy profiles (VESYMP and VESUSC) satisfying licensure criteria. We developed a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington. Rollout scenarios starting December 2020 were simulated with combinations of VESUSC and VESYMP resulting in up to 100% VEDIS. We assumed no reduction of infectivity upon infection conditional on presence of symptoms. Proportions of cumulative infections, hospitalizations and deaths prevented over 1 year from vaccination start are reported. Rollouts of 1 M vaccinations (5000 daily) using vaccines with 50% VEDIS are projected to prevent 23-46% of infections and 31-46% of deaths over 1 year. In comparison, vaccines with 90% VEDIS are projected to prevent 37-64% of infections and 46-64% of deaths over 1 year. In both cases, there is a greater reduction if VEDIS is mediated mostly by VESUSC. The use of a "symptom reducing" vaccine will require twice as many people vaccinated than a "susceptibility reducing" vaccine with the same 90% VEDIS to prevent 50% of the infections and death over 1 year. Delaying the start of the vaccination by 3 months decreases the expected population impact by more than 50%. Vaccines which prevent COVID-19 disease but not SARS-CoV-2 infection, and thereby shift symptomatic infections to asymptomatic infections, will prevent fewer infections and require larger and faster vaccination rollouts to have population impact, compared to vaccines that reduce susceptibility to infection. If uncontrolled transmission across the U.S. continues, then expected vaccination in Spring 2021 will provide only limited benefit.

The potential effect of COVID-19-related disruptions on HIV incidence and HIV-related mortality among men who have sex with men in the USA: a modelling study.

BACKGROUND: During the COVID-19 pandemic, men who have sex with men (MSM) in the USA have reported similar or fewer sexual partners and reduced HIV testing and care access compared with before the pandemic. Pre-exposure prophylaxis (PrEP) use has also declined. We aimed to quantify the potential effect of COVID-19 on HIV incidence and HIV-related mortality among US MSM. METHODS: We used a calibrated, deterministic, compartmental HIV transmission model for MSM in Baltimore (MD, USA) and available data on COVID-19-related disruptions to HIV services to predict effects of reductions in sexual partners (0%, 25%, 50%), condom use (5%), HIV testing (20%), viral suppression (10%), PrEP initiations (72%), PrEP adherence (9%), and antiretroviral therapy (ART) initiations (50%). In our main analysis, we modelled disruptions due to COVID-19 starting Jan 1, 2020, and lasting 6 months. We estimated the median change in cumulative new HIV infections and HIV-related deaths among MSM over 1 and 5 years, compared with a base case scenario without COVID-19-related disruptions. FINDINGS: A 25% reduction in sexual partners for 6 months among MSM in Baltimore, without HIV service changes, could reduce new HIV infections by median 12·2% (95% credible interval 11·7 to 12·8) over 1 year and median 3·0% (2·6 to 3·4) over 5 years. In the absence of changes in sexual behaviour, the 6-month estimated reductions in condom use, HIV testing, viral suppression, PrEP initiations, PrEP adherence, and ART initiations combined are predicted to increase new HIV infections by median 10·5% (5·8 to 16·5) over 1 year, and by median 3·5% (2·1 to 5·4) over 5 years. Disruptions to ART initiations and viral suppression are estimated to substantially increase HIV-related deaths (ART initiations by median 1·7% [0·8 to 3·2], viral suppression by median 9·5% [5·2 to 15·9]) over 1 year, with smaller proportional increases over 5 years. The other individual disruptions (to HIV testing, PrEP and condom use, PrEP initiation, and partner numbers) were estimated to have little effect on HIV-related deaths (<1% change over 1 or 5 years). A 25% reduction in sexual partnerships is estimated to offset the effect of the combined service disruptions on new HIV infections (change over 1 year: median -3·9% [-7·4 to 1·0]; over 5 years: median 0·0% [-0·9 to 1·4]), but not on HIV deaths (change over 1 year: 11·0% [6·2 to 17·7]; over 5 years: 2·6% [1·5 to 4·3]). INTERPRETATION: Maintaining access to ART and adherence support is of the utmost importance to maintain viral suppression and minimise excess HIV-related mortality due to COVID-19 restrictions in the USA, even if disruptions to services are accompanied by reductions in sexual partnerships. FUNDING: National Institutes of Health.

Mathematical Modeling of Vaccines That Prevent SARS-CoV-2 Transmission.

SARS-CoV-2 vaccine clinical trials assess efficacy against disease (VEDIS), the ability to block symptomatic COVID-19. They only partially discriminate whether VEDIS is mediated by preventing infection completely, which is defined as detection of virus in the airways (VESUSC), or by preventing symptoms despite infection (VESYMP). Vaccine efficacy against transmissibility given infection (VEINF), the decrease in secondary transmissions from infected vaccine recipients, is also not measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna (mRNA-1273QS) and Pfizer-BioNTech (BNT162b2) vaccines, which demonstrated VEDIS > 90% in clinical trials, mediate VEDIS by VESUSC, then a limited fourth epidemic wave of infections with the highly infectious B.1.1.7 variant would have been predicted in spring 2021 assuming rapid vaccine roll out. If high VEDIS is explained by VESYMP, then high VEINF would have also been necessary to limit the extent of this fourth wave. Vaccines which completely protect against infection or secondary transmission also substantially lower the number of people who must be vaccinated before the herd immunity threshold is reached. The limited extent of the fourth wave suggests that the vaccines have either high VESUSC or both high VESYMP and high VEINF against B.1.1.7. Finally, using a separate intra-host mathematical model of viral kinetics, we demonstrate that a 0.6 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve 50% VEINF, which suggests that human challenge studies with a relatively low number of infected participants could be employed to estimate all three vaccine efficacy metrics.

Identifying Regions of Greatest Need for Ending the HIV Epidemic: A Plan for America.

BACKGROUND: In the 2019 State of the Union Address, President Trump announced a plan for "Ending the HIV Epidemic" in the United States, with a goal to reduce new HIV infections by 90% by 2030. Phase I of the plan set an intermediate goal of a 75% reduction within 5 years, focusing on select states and counties. METHODS: We assessed the feasibility of the first phase of the plan by estimating the fraction of HIV diagnoses that occur within the targeted region, using a statistical model to predict new HIV cases in each county. We suggested new areas that should be added to the current plan, prioritizing by both a "Density Metric" of new HIV cases and a "Gap Metric" quantifying shortcomings in antiretroviral therapy and pre-exposure prophylaxis uptake. RESULTS: We found the current plan targets less than 60% of new diagnoses. The plan should be expanded to Puerto Rico, Florida, Georgia, Louisiana, and Maryland as well as parts of New York, North Carolina, Texas, and Virginia, areas which were prioritized by both metrics. CONCLUSION: Many of the highest priority areas, both by density of HIV cases and by lack of viral suppression and pre-exposure prophylaxis use, were not covered by the original plan, particularly in the South. The current plan to end the HIV epidemic must be expanded to these areas to feasibly allow for a 75% reduction in new HIV cases within 5 years.

Assessing the use of surveillance data to estimate the impact of prevention interventions on HIV incidence in cluster-randomized controlled trials.

BACKGROUND: In cluster-randomized controlled trials (C-RCTs) of HIV prevention strategies, HIV incidence is expensive to measure directly. Surveillance data on HIV diagnoses or viral suppression could provide cheaper incidence estimates. We used mathematical modelling to evaluate whether these measures can replace HIV incidence measurement in C-RCTs. METHODS: We used a US HIV transmission model to simulate C-RCTs of expanded antiretroviral therapy(ART), pre-exposure prophylaxis(PrEP) and HIV testing, together or alone. We tested whether modelled reductions in total new HIV diagnoses, diagnoses with acute infection, diagnoses with early infection(CD4 > 500 cells/µl), diagnoses adjusted for testing volume, or the proportion virally non-suppressed, reflected HIV incidence reductions. RESULTS: Over a two-year trial expanding PrEP alone, modelled reductions in total diagnoses underestimated incidence reductions by a median six percentage points(pp), with acceptable variability(95 % credible interval -14,-2pp). For trials expanding HIV testing alone or alongside ART + PrEP, greater, highly variable bias was seen[-20pp(-128,-1) and -30pp(-134,-16), respectively]. Acceptable levels of bias were only seen over longer trial durations when levels of awareness of HIV-positive status were already high. Expanding ART alone, only acute and early diagnoses reductions reflected incidence reduction well, with some bias[-3pp(-6,-1) and -8pp(-16,-3), respectively]. Early and adjusted diagnoses also reliably reflected incidence when scaling up PrEP alone[bias -5pp(-11,1) and 10pp(3,18), respectively]. For trials expanding testing (alone or with ART + PrEP), bias for all measures explored was too variable for them to replace direct incidence measures, unless using diagnoses when HIV status awareness was already high. CONCLUSIONS: Surveillance measures based on HIV diagnoses may sometimes be adequate surrogates for HIV incidence reduction in C-RCTs expanding ART or PrEP only, if adjusted for bias. However, all surveillance measures explored failed to approximate HIV incidence reductions for C-RCTs expanding HIV testing, unless levels of awareness of HIV-positive status were already high.

Estimating the potential impact of COVID-19-related disruptions on HIV incidence and mortality among men who have sex with men in the United States: a modelling study.

BACKGROUND: During the COVID-19 pandemic, gay and other men who have sex with men (MSM) in the United States (US) report similar or fewer sexual partners and reduced HIV testing and care access. Pre-exposure prophylaxis (PrEP) use has declined. We estimated the potential impact of COVID-19 on HIV incidence and mortality among US MSM. METHODS: We used a calibrated HIV transmission model for MSM in Baltimore, Maryland, and available data on COVID-19-related disruptions to predict impacts of data-driven reductions in sexual partners(0%,25%,50%), condom use(5%), HIV testing(20%), viral suppression(10%), PrEP initiations(72%), PrEP use(9%) and ART initiations(50%), exploring different disruption durations and magnitudes. We estimated the median (95% credible interval) change in cumulative new HIV infections and deaths among MSM over one and five years, compared with a scenario without COVID-19-related disruptions. FINDINGS: A six-month 25% reduction in sexual partners among Baltimore MSM, without HIV service changes, could reduce new HIV infections by 12·2%(11·7,12·8%) and 3·0%(2·6,3·4%) over one and five years, respectively. In the absence of changes in sexual behaviour, the six-month data-driven disruptions to condom use, testing, viral suppression, PrEP initiations, PrEP use and ART initiations combined were predicted to increase new HIV infections by 10·5%(5·8,16·5%) over one year, and by 3·5%(2·1,5·4%) over five years. A 25% reduction in partnerships offsets the negative impact of these combined service disruptions on new HIV infections (overall reduction 3·9%(-1·0,7·4%), 0·0%(-1·4,0·9%) over one, five years, respectively), but not on HIV deaths (corresponding increases 11·0%(6·2,17·7%), 2·6%(1·5,4·3%)). The predicted impacts of reductions in partnerships or viral suppression doubled if they lasted 12 months or if disruptions were twice as large. INTERPRETATION: Maintaining access to ART and adherence support is of the utmost importance to minimise excess HIV-related mortality due to COVID-19 restrictions in the US, even if accompanied by reductions in sexual partnerships. FUNDING: NIH. RESEARCH IN CONTEXT: Evidence before this study: The COVID-19 pandemic and responses to it have disrupted HIV prevention and treatment services and led to changes in sexual risk behaviour in the United States, but the overall potential impact on HIV transmission and HIV-related mortality is not known. We searched PubMed for articles documenting COVID-related disruptions to HIV prevention and treatment and changes in sexual risk behaviour in the United States, published between 1 st January and 7 th October 2020, with no language restrictions, using the terms COVID* AND (HIV OR AIDS) AND ("United States" OR US). We identified three cross-sectional surveys assessing changes in sexual risk behaviour among men who have sex with men (MSM) in the United States, one finding a reduction, one a slight increase, and one no change in partner numbers during COVID-19 restrictions. Two of these studies also found reductions in reported HIV testing, HIV care and/or access to pre-exposure prophylaxis (PrEP) among MSM due to COVID-19. A separate study from a San Francisco clinic found declines in viral suppression among its clients during lockdown. We searched PubMed for articles estimating the impact of COVID-related disruptions on HIV transmission and mortality published between 1 st January 2020 and 12 th October 2020, with no language restrictions, using the following terms: COVID* AND model* AND (HIV OR AIDS). We identified two published studies which had used mathematical modelling to estimate the impact of hypothetical COVID-19-related disruptions to HIV programmes on HIV-related deaths and/or new HIV infections in Africa, another published study using modelling to estimate the impact of COVID-19-related disruptions and linked HIV and SARS-CoV-2 testing on new HIV infections in six cities in the United States, and a pre-print reporting modelling of the impact of COVID-19-related disruptions on HIV incidence among men who have sex with men in Atlanta, United States. None of these studies were informed by data on the size of these disruptions. The two African studies and the Atlanta study assessed the impact of disruptions to different healthcare disruptions separately, and all found that the greatest negative impacts on new HIV infections and/or deaths would arise from interruptions to antiretroviral therapy. They all found smaller effects on HIV-related mortality and/or incidence from other healthcare disruptions, including HIV testing, PrEP use and condom supplies. The United States study assessing the impact of linked HIV and SARS-CoV-2 testing estimated that this could substantially reduce HIV incidence. Added value of this study: We used mathematical modelling to derive estimates of the potential impact of the COVID-19 pandemic and associated restrictions on HIV incidence and mortality among MSM in the United States, directly informed by data from the United States on disruptions to HIV testing, antiretroviral therapy and pre-exposure prophylaxis services and reported changes in sexual risk behaviour during the COVID-19 pandemic. We also assessed the impact of an HIV testing campaign during COVID-19 lockdown.Implications of all the available evidence: In the United States, maintaining access to antiretroviral therapy and adherence support for both existing and new users will be crucial to minimize excess HIV-related deaths arising from the COVID-19 pandemic among men who have sex with men. While reductions in sexual risk behaviour may offset increases in new HIV infections arising from disruptions to HIV prevention and treatment services, this will not offset the additional HIV-related deaths which are also predicted to occur. There are mixed findings on the impact of an HIV testing campaign among US MSM during COVID-19 lockdown. Together, these studies highlight the importance of maintaining effective HIV treatment provision during the COVID-19 pandemic.