HIV Prevention Among Men Who Have Sex With Men: Tenofovir Alafenamide Combination Preexposure Prophylaxis Versus Placebo.

BACKGROUND: While noninferiority of tenofovir alafenamide and emtricitabine (TAF/FTC) as preexposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) has been shown, interest remains in its efficacy relative to placebo. We estimate the efficacy of TAF/FTC PrEP versus placebo for the prevention of HIV infection. METHODS: We used data from the DISCOVER and iPrEx trials to compare TAF/FTC to placebo. DISCOVER was a noninferiority trial conducted from 2016 to 2017. iPrEx was a placebo-controlled trial conducted from 2007 to 2009. Inverse probability weights were used to standardize the iPrEx participants to the distribution of demographics and risk factors in the DISCOVER trial. To check the comparison, we evaluated whether risk of HIV infection in the shared tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) arms was similar. RESULTS: Notable differences in demographics and risk factors occurred between trials. After standardization, the difference in risk of HIV infection between the TDF/FTC arms was near zero. The risk of HIV with TAF/FTC was 5.8 percentage points lower (95% confidence interval [CI], -2.0% to -9.6%) or 12.5-fold lower (95% CI, .02 to .31) than placebo standardized to the DISCOVER population. CONCLUSIONS: There was a reduction in HIV infection with TAF/FTC versus placebo across 96 weeks of follow-up. CLINICAL TRIALS REGISTRATION: NCT02842086 and NCT00458393.

CalScope: methodology and lessons learned for conducting a remote statewide SARS-CoV-2 seroprevalence study in California using an at-home dried blood spot collection kit and online survey.

BACKGROUND: To describe the methodology for conducting the CalScope study, a remote, population-based survey launched by the California Department of Public Health (CDPH) to estimate SARS-CoV-2 seroprevalence and understand COVID-19 disease burden in California. METHODS: Between April 2021 and August 2022, 666,857 randomly selected households were invited by mail to complete an online survey and at-home test kit for up to one adult and one child. A gift card was given for each completed survey and test kit. Multiple customized REDCap databases were used to create a data system which provided task automation and scalable data management through API integrations. Support infrastructure was developed to manage follow-up for participant questions and a communications plan was used for outreach through local partners. RESULTS: Across 3 waves, 32,671 out of 666,857 (4.9%) households registered, 6.3% by phone using an interactive voice response (IVR) system and 95.7% in English. Overall, 25,488 (78.0%) households completed surveys, while 23,396 (71.6%) households returned blood samples for testing. Support requests (n = 5,807) received through the web-based form (36.3%), by email (34.1%), and voicemail (29.7%) were mostly concerned with the test kit (31.6%), test result (26.8%), and gift card (21.3%). CONCLUSIONS: Ensuring a well-integrated and scalable data system, responsive support infrastructure for participant follow-up, and appropriate academic and local health department partnerships for study management and communication allowed for successful rollout of a large population-based survey. Remote data collection utilizing online surveys and at-home test kits can complement routine surveillance data for a state health department.

Evaluating the association between in-person work and the risk of SARS-CoV-2 infection through June 2021.

OBJECTIVES: Recent studies have evaluated COVID-19 outbreaks and excess mortality by occupation sectors. Studies on SARS-CoV-2 infection across occupation and occupation-related factors remain lacking. In this study, we estimate the effect of in-person work on SARS-CoV-2 infection risk and describe SARS-CoV-2 seroprevalence among working adults. METHODS: We used Wave 1 data (May to June 2021) from CalScope, a population-based seroprevalence study in California. Occupation data were coded using the National Institute for Occupational Safety and Health Industry and Occupation Computerized Coding System. Dried blood spot specimens were tested for antibodies to establish evidence of prior infection. We estimated the causal effect of in-person work on SARS-CoV-2 infection risk using the g-formula and describe SARS-CoV-2 seroprevalence across occupation-related factors. RESULTS: Among 4335 working adults, 53% worked in person. In-person work was associated with increased risk of prior SARS-CoV-2 infection (risk difference: 0.03; [95% CI: 0.02-0.04]) compared with working remotely. Workers that reported job loss or who were without medical insurance had higher evidence of prior infection. Amongst in-person workers, evidence of prior infection was highest within farming, fishing, and forestry (55%; [95% CI: 26%-81%]); installation, maintenance, and repair (23%; [12%-39%]); building and grounds cleaning and maintenance (23%; [13%-36%]); food preparation and serving related (22% [13%-35%]); and healthcare support (22%; [13%-34%]) occupations. Workers who identified as Latino, reported a household income of <$25K, or who were without a bachelor's degree also had higher evidence of prior infection. CONCLUSIONS: SARS-CoV-2 infection risk varies by occupation. Future vaccination strategies may consider prioritizing in-person workers.

Transporting Subgroup Analyses of Randomized Controlled Trials for Planning Implementation of New Interventions.

Subgroup analyses of randomized controlled trials guide resource allocation and implementation of new interventions by identifying groups of individuals who are likely to benefit most from the intervention. Unfortunately, trial populations are rarely representative of the target populations of public health or clinical interest. Unless the relevant differences between trial and target populations are accounted for, subgroup results from trials might not reflect which groups in the target population will benefit most from the intervention. Transportability provides a rigorous framework for applying results derived in potentially highly selected study populations to external target populations. The method requires that researchers measure and adjust for all variables that 1) modify the effect of interest and 2) differ between the target and trial populations. To date, applications of transportability have focused on the external validity of overall study results and understanding within-trial heterogeneity; however, this approach has not yet been used for subgroup analyses of trials. Through an example from the Iniciativa Profilaxis Pre-Exposición (iPrEx) study (multiple countries, 2007-2010) of preexposure prophylaxis for human immunodeficiency virus, we illustrate how transporting subgroup analyses can produce target-specific subgroup effect estimates and numbers needed to treat. This approach could lead to more tailored and accurate guidance for resource allocation and cost-effectiveness analyses.

Generalizability of findings from a clinical sample to a community-based sample: A comparison of ADNI and ARIC.

INTRODUCTION: Clinic-based study samples, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community-based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings. METHODS: We estimated cohort-specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates. RESULTS: The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E ε4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6). DISCUSSION: A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples.

The Role of Social Relationships in PrEP Uptake and Use Among Transgender Women and Men Who Have Sex with Men.

Qualitative studies suggest that social relationships play an important role in HIV pre-exposure prophylaxis (PrEP) use, but there have been few quantitative assessments of the role of social relationships in PrEP uptake or adherence. We examined the association between disclosure of study participation or LGBT identity and PrEP use in the 1603 HIV-negative participants enrolled in the iPrEx OLE study. We also evaluated the association between LGBT social group involvement and PrEP use. Study participation disclosure to parents and LGBT identity disclosure to anyone in a participant's social network were associated with greater PrEP uptake. Study participation disclosure to partners was associated with higher probability of having protective PrEP drug concentrations compared [risk difference 0.15 95% CI (0.01, 0.30)]. For each additional type of LGBT organization a participant was involved in, the probability of PrEP uptake and having protective drug concentrations increased by 0.04 [95% CI (0.03, 0.06)] and 0.04 (95% CI (0.02, 0.07)] respectively. Overall, social context was associated with PrEP use in iPrEx OLE, and should be taken into consideration when designing future PrEP implementation programs.

Cellular immune correlates analysis of an HIV-1 preexposure prophylaxis trial.

HIV-1-specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case-control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-γ enzyme-linked immunospot (ELISpot) assay. IFN-γ responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1-negative for Gag (P = 0.007), Integrase (P < 0.001), Vif (P < 0.001), and Nef (P < 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19-0.66 and HR = 0.52, 95% CI = 0.28-0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-γ secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ T cells. Our results show that HIV-1-specific T-cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes.

Persistent HIV Type 1 Seronegative Status Is Associated With Lower CD8+ T-Cell Activation.

We leveraged data from the Preexposure Prophylaxis Initiative (iPrEx), a global trial of preexposure chemoprophylaxis against human immunodeficiency virus type 1 (HIV-1) infection, to compare T-cell activation between those who remained negative for HIV-1 and those who became infected during the trial. The frequency of CD38(+)HLA-DR(+) CD8(+) T cells was greater in those who seroconverted, relative to the frequency in those who remained uninfected (1.30% vs 0.82%, respectively; P = .005). This translated to an odds ratio of 4.26 (95% confidence interval, 1.54-11.78) for the association between CD8(+) T-cell activation and infection with HIV-1. T-cell activation may be a biomarker for elevated HIV-1 infection risk.

The Effect of Depressive Symptoms on Adherence to Daily Oral PrEP in Men who have Sex with Men and Transgender Women: A Marginal Structural Model Analysis of The iPrEx OLE Study.

We assessed the role of depressive symptoms on adherence to daily oral FTC/TDF for HIV PrEP in cisgender men who have sex with men (MSM) and transgender women who have sex with men (TGW) using data from the iPrEx OLE study. A marginal structural logistic regression model was used to estimate the effect of time-varying CES-D scores on having protective levels of drug concentration, adjusting for confounding by sexual practices over time, prior adherence, and baseline demographic characteristics. We found a non-monotonic relationship between CES-D score and odds of protective FTC/TDF levels in MSM. We found evidence that the effect of depression on adherence varied between MSM and TGW, and that depressive symptoms did not contribute greatly to decreased adherence on a population scale. We recommend that depressive symptoms not preclude the prescription of PrEP, and that MSM and TGW be studied separately.

CalScope: Monitoring Severe Acute Respiratory Syndrome Coronavirus 2 Seroprevalence From Vaccination and Prior Infection in Adults and Children in California May 2021-July 2021.

Background: Understanding the distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies from vaccination and/or prior infection is critical to the public health response to the pandemic. CalScope is a population-based serosurvey in 7 counties in California. Methods: We invited 200 000 randomly sampled households to enroll up to 1 adult and 1 child between April 20, 2021 and June 16, 2021. We tested all specimens for antibodies against SARS-CoV-2 nucleocapsid and spike proteins, and each participant completed an online survey. We classified participants into categories: seronegative, antibodies from infection only, antibodies from infection and vaccination, and antibodies from vaccination only. Results: A total of 11 161 households enrolled (5.6%), with 7483 adults and 1375 children completing antibody testing. As of June 2021, 33% (95% confidence interval [CI], 28%-37%) of adults and 57% (95% CI, 48%-66%) of children were seronegative; 18% (95% CI, 14%-22%) of adults and 26% (95% CI, 19%-32%) of children had antibodies from infection alone; 9% (95% CI, 6%-11%) of adults and 5% (95% CI, 1%-8%) of children had antibodies from infection and vaccination; and 41% (95% CI, 37%-45%) of adults and 13% (95% CI, 7%-18%) of children had antibodies from vaccination alone. Conclusions: As of June 2021, one third of adults and most children in California were seronegative. Serostatus varied regionally and by demographic group.

Severe Acute Respiratory Syndrome Coronavirus 2 Seroprevalence and Reported Coronavirus Disease 2019 Cases in US Children, August 2020-May 2021.

BACKGROUND: Case-based surveillance of pediatric coronavirus disease 2019 (COVID-19) cases underestimates the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among children and adolescents. Our objectives were to estimate monthly SARS-CoV-2 antibody seroprevalence and calculate ratios of SARS-CoV-2 infections to reported COVID-19 cases among children and adolescents in 8 US states. METHODS: Using data from the Nationwide Commercial Laboratory Seroprevalence Survey, we estimated monthly SARS-CoV-2 antibody seroprevalence among children aged 0-17 years from August 2020 through May 2021. We calculated and compared cumulative incidence of SARS-CoV-2 infection extrapolated from population-standardized seroprevalence of antibodies to SARS-CoV-2, cumulative COVID-19 case reports since March 2020, and infection-to-case ratios among persons of all ages and children aged 0-17 years for each state. RESULTS: Of 41 583 residual serum specimens tested, children aged 0-4, 5-11, and 12-17 years accounted for 1619 (3.9%), 10 507 (25.3%), and 29 457 (70.8%), respectively. Median SARS-CoV-2 antibody seroprevalence among children increased from 8% (range, 6%-20%) in August 2020 to 37% (range, 26%-44%) in May 2021. Estimated ratios of SARS-CoV-2 infections to reported COVID-19 cases in May 2021 ranged by state from 4.7-8.9 among children and adolescents to 2.2-3.9 for all ages combined. CONCLUSIONS: Through May 2021 in selected states, the majority of children with serum specimens included in serosurveys did not have evidence of prior SARS-CoV-2 infection. Case-based surveillance underestimated the number of children infected with SARS-CoV-2 more than among all ages. Continued monitoring of pediatric SARS-CoV-2 antibody seroprevalence should inform prevention and vaccination strategies.

Brief Report: Seroadaptive Behaviors Varied Among Geographically Diverse iPrEx Participants.

BACKGROUND: Seroadaptive behaviors refer to a wide range of harm reduction practices to decrease HIV transmission risk. Effective implementation of seroadaptive behaviors is dependent on knowledge of one's own serostatus and that of one's sexual partners. Partner-level and environmental-level attributes may affect seroadaptation practices. We assessed factors associated with seroadaptive behaviors. METHODS: Men who have sex with men and transgender women were recruited from an HIV pre-exposure prophylaxis clinical trial (iPrEx) with study sites in the US, Peru, Ecuador, Brazil, Thailand, and South Africa. Partnership-level data were collected at the baseline visit for the 3 most recent partners. Participants were considered to have practiced seroadaptive behaviors if: (1) they believed their partner to be HIV-negative, that is, serosorting; or (2) no condomless receptive sex occurred with an HIV-positive or unknown status partner, that is, seropositioning. RESULTS: Of 2331 participants, 41% always practiced seroadaptive behaviors, 36% sometimes did, and 23% never did. Participants enrolled at study sites in the US (P < 0.001) and Peru/Ecuador (P < 0.001) were more likely to practice seroadaptive behaviors, whereas transgender women were less likely to do so (P < 0.001). Seroadaptive behaviors were more likely to occur in relationships with steady partners (P = 0.005) and emotionally close relationships (P = 0.013). CONCLUSIONS: Seroadaptive behaviors were more frequently observed among iPrEx participants from the US, Peru, and Ecuador study sites and among participants in relationships with partners who they were more committed to and felt emotionally close to. Our findings suggest that seroadaptive behaviors may be influenced by social norms that vary geographically and culturally.

Breaking Inertia: Movement Along the PrEP Cascade in a Longitudinal US National Cohort of Sexual Minority Individuals at Risk for HIV.

BACKGROUND: The pre-exposure prophylaxis (PrEP) cascade outlines sequential steps to maximize PrEP's impact and highlights potential intervention targets to improve PrEP implementation. We evaluate the PrEP cascade in the Together 5000 study (T5K). METHODS: T5K is an internet-based, US national cohort study of PrEP-eligible men and trans persons who have sex with men who were not taking PrEP at enrollment. Using longitudinal data from baseline (2017-2018) and year 1 follow-up (2018-2019, n = 4229), we evaluated 5 steps of the PrEP cascade-PrEP contemplation: believes they are a good candidate for PrEP; PrEParation: plans to initiate PrEP; PrEP action: speaks to a provider about PrEP; PrEP initiation: receives a prescription for PrEP; and PrEP maintenance: continues to take PrEP. We compared the cascade across geographic region and identified factors associated with gaps in the cascade. RESULTS: After 1 year, 1092 (26%) participants had initiated PrEP, 709 (17%) were still using PrEP, and 177 (4%) were no longer clinically indicated for PrEP. Participants in the South and Midwest were less likely to speak to a provider about PrEP or initiate PrEP. Baseline characteristics associated with lower odds of PrEP initiation at year 1 include: not having a college degree; earning <$20,000/year; not having health insurance; having very low food security; and not having a primary care doctor. CONCLUSIONS: Lack of health care access is a major barrier to PrEP implementation and may exacerbate disparities in PrEP uptake across geographic regions.

SARS-CoV-2 Cumulative Incidence and Period Seroprevalence: Results From a Statewide Population-Based Serosurvey in California.

BACKGROUND: California has reported the largest number of coronavirus disease 2019 (COVID-19) cases of any US state, with more than 3.5 million confirmed as of March 2021. However, the full breadth of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in California is unknown as reported cases only represent a fraction of all infections. METHODS: We conducted a population-based serosurvey, utilizing mailed, home-based SARS-CoV-2 antibody testing along with a demographic and behavioral survey. We weighted data from a random sample to represent the adult California population and estimated period seroprevalence overall and by participant characteristics. Seroprevalence estimates were adjusted for waning antibodies to produce statewide estimates of cumulative incidence, the infection fatality ratio (IFR), and the reported fraction. RESULTS: California's SARS-CoV-2 weighted seroprevalence during August-December 2020 was 4.6% (95% CI, 2.8%-7.4%). Estimated cumulative incidence as of November 2, 2020, was 8.7% (95% CrI, 6.4%-11.5%), indicating that 2 660 441 adults (95% CrI, 1 959 218-3 532 380) had been infected. The estimated IFR was 0.8% (95% CrI, 0.6%-1.0%), and the estimated percentage of infections reported to the California Department of Public Health was 31%. Disparately high risk for infection was observed among persons of Hispanic/Latinx ethnicity and people with no health insurance and who reported working outside the home. CONCLUSIONS: We present the first statewide SARS-CoV-2 cumulative incidence estimate among adults in California. As of November 2020, ~1 in 3 SARS-CoV-2 infections in California adults had been identified by public health surveillance. When accounting for unreported SARS-CoV-2 infections, disparities by race/ethnicity seen in case-based surveillance persist.

HIV preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health.

OBJECTIVE: To evaluate the effects of HIV preexposure prophylaxis (PrEP) with tenofovir disoproxial fumurate (TDF)/emtricitabine (FTC) on kidney function and kidney tubular health. DESIGN: The Iniciativa Profilaxis Pre-Exposicion open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. This study included 123 iPrEx-OLE participants who demonstrated PrEP adherence. METHODS: We compared estimated glomerular filtration rate calculated using serum creatinine (eGFRcr), serum cystatin C (eGFRcys), and in combination (eGFRcr-cys), and a panel of 14 urine biomarkers reflecting kidney tubular health before and 6 months after PrEP initiation. RESULTS: At baseline, mean eGFRcr, eGFRcys, and eGFRcr-cys were 108.3, 107.0, and 111.1 ml/min per 1.73 m, respectively. Six months after PrEP initiation, eGFRcr declined by -4% (95% CI: -5.7 to -2.4%), eGFRcys declined by -3.3% (95% CI: -8.3 to 1.9%), and eGFRcr-cys declined by -4.1% (95% CI: -7.5 to -0.7%). From the urine biomarker panel, α1-microglobulin and ß2-microglobulin increased by 22.7% (95% CI: 11.8--34.7%) and 14.1% (95% CI: -6.1 to 38.6%), whereas chitinase-3-like 1 protein and monocyte chemoattractant protein-1 decreased by -37.7% (95% CI: -53.0 to -17.3%) and -15.6% (95% CI: -31.6 to 4.2%), respectively. Ten of the 14 urine biomarkers, including albumin, had estimated changes of less than 12% with wide confidence intervals. CONCLUSION: Six months of PrEP with TDF/FTC was associated with decreases in eGFRcr and eGFRcys. We also observed for the first time changes in flour of 14 urine biomarkers reflecting kidney tubular health. These findings demonstrate that PrEP has direct effects on eGFR and the proximal tubule.

Understanding HIV Program Effects: A Structural Approach to Context Using the Transportability Framework.

BACKGROUND: Implementation science focuses on evaluating strategies for delivering evidence-based interventions to improve HIV prevention and treatment. The effectiveness of these implementation strategies is often context-dependent and reconciling the desire to produce generalizable knowledge in the face of these contextual interventions is a central challenge for implementation science researchers. METHODS: We provide an overview of the causal transportability theory and conceptualize context under this framework. We review how causal graphs can be used to illustrate the assumptions necessary to apply the results of a study to a new context, and we illustrate this approach using an example of a community adherence group intervention that aims to improve retention in HIV care. Finally, we discuss several key insights highlighted by the transportability theory that are relevant to implementation science researchers. RESULTS: By adopting causal transportability to consider how context may affect the success of an implementation strategy, researchers can formally diagnose when the results of a study are likely to generalize to a given setting. Moreover, selection diagrams can highlight what additional measurements would be needed in a target population to estimate the effect of an implementation strategy in that target population without having to repeat the initial study. CONCLUSIONS: Transportability translates intuition about context-dependent interventions and external validity into actionable and testable insight.

Mosaic effectiveness: measuring the impact of novel PrEP methods.

Various ongoing trials seek to evaluate long-acting pre-exposure prophylaxis (PrEP) agents by showing that they are non-inferior to daily oral tenofovir disoproxil fumarate and emtricitabine. Trials comparing oral PrEP to new methods examine effectiveness in a setting where only one or the other is provided; however, a new product will probably be delivered in a context where oral PrEP is also available. The effectiveness of a new PrEP product is best measured by its potential effect in a context that also includes oral tenofovir disoproxil fumarate and emtricitabine as an option. We offer an alternative standard for long-acting products-a measure of the effectiveness of the new product in addition to oral tenofovir disoproxil fumarate and emtricitabine as compared with oral PrEP alone. We term this measure mosaic effectiveness. We illustrate scenarios where a novel product can fail to show non-inferiority but show substantial mosaic effectiveness, thus implying the public health value of the novel product even if it is less effective than oral PrEP. Regulatory standards should consider mosaic effectiveness, not just comparative effectiveness. We assert that measurements that combine rigor with public health relevance can accelerate progress against the HIV epidemic.

Brief Report: HIV-1 gp120 T-Cell Responses Correspond to Infection Outcomes in the Global iPrEx Chemoprophylaxis Trial.

Association of HIV-1-specific T-cell responses to infection risk in seronegative individuals is controversial. We quantified and phenotypically characterized gp120-specific T-cell responses in HIV-1 exposed, but uninfected subjects enrolled in the global Pre-exposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. IFNγ ELISpot responses were detected in 24% of subjects irrespective of infection outcome. HIV-1 gp120 envelope-specific T-cell responses were more uniformly IFN-γ+TNF-α+Mip-1ß+ in persistently seronegative subjects relative to subjects who later seroconverted (median frequency of 76.5% and 66.5%, respectively). IFNγ responses targeted the V2 loop for subjects who remained seronegative. HIV-1 gp120 envelope V2 loop-specific CD8 T-cell responses may help to protect against HIV-1 acquisition.