Sex Differences in Human Immunodeficiency Virus Persistence and Reservoir Size During Aging.

BACKGROUND: Sex differences in human immunodeficiency virus (HIV) reservoir dynamics remain underexplored. METHODS: Longitudinal samples from virally suppressed midlife women (n = 59, median age 45 years) and age-matched men (n = 31) were analyzed retrospectively. At each time point, we measured sex hormones (by means of enzyme-linked immunosorbent assay) and cellular HIV DNA and RNA (by means of digital droplet polymerase chain reaction). Number of inducible HIV RNA+ cells, which provides an upper estimate of the replication-competent reservoir, was quantified longitudinally in a different subset of 14 women, across well-defined reproductive stages. Mixed-effects models included normalized reservoir outcomes and sex, time since antiretroviral therapy (ART) initiation, and the sex-by-time interaction as predictors. RESULTS: At ART initiation, women and men had median (interquartile range [IQR]) CD4+ T-cell counts of 204/µL (83-306/µL) versus 238/µL (120-284/µL), respectively; median ages of 45 (42-48) versus 47 (43-51) years; and median follow-up times of 79.2/µL (60.5-121.1/µL) versus 66.2/µL (43.2-80.6/µL) months. We observed a significant decline of total HIV DNA over time in both men and women (P < .01). However, the rates of change differed significantly between the sexes (P < .01), with women having a significantly slower rate of decline than men, more pronounced with age. By contrast, the levels of inducible HIV RNA increased incrementally over time in women during reproductive aging (P < .01). CONCLUSIONS: In contrast to men, in whom the HIV reservoir steadily declines with aging, the HIV reservoir in women is more dynamic. Total HIV DNA (including intact and defective genomes) declines more slowly in women than in men, while the inducible HIV RNA+ reservoir, which is highly enriched in replication-competent virus, increases in women after menopause.

Rapid Antiretroviral Therapy Among Individuals With Acute and Early HIV.

HIV transmission is increased during acute and early HIV (AEH). Rapid antiretroviral therapy may shorten the duration of infectivity. We show rapid antiretroviral therapy in AEH is acceptable and effective, with 69.0% of participants starting ART within 7 days of HIV diagnosis disclosure, and 88.1% achieving suppression by 48 weeks.

Effective Human Immunodeficiency Virus Molecular Surveillance Requires Identification of Incident Cases of Infection.

BACKGROUND: Ending the human immunodeficiency virus (HIV) epidemic requires knowledge of key drivers of spread of HIV infection. METHODS: Between 1996 and 2018, 1119 newly and previously diagnosed, therapy-naive persons with HIV (PWH) from San Diego were followed. A genetic distance-based network was inferred using pol sequences, and genetic clusters grew over time through linkage of sequences from newly observed infections. Cox proportional hazards models were used to identify factors associated with the rate of growth. These results were used to predict the impact of a hypothetical intervention targeting PWH with incident infection. Comparison was made to the Centers for Disease Control and Prevention (CDC) Ending the HIV Epidemic (EHE) molecular surveillance strategy, which prioritizes clusters recently linked to all new HIV diagnoses and does not incorporate data on incident infections. RESULTS: Overall, 219 genetic linkages to incident infections were identified over a median follow-up of 8.8 years. Incident cluster growth was strongly associated with proportion of PWH in the cluster who themselves had incident infection (hazard ratio, 44.09 [95% confidence interval, 17.09-113.78]). The CDC EHE molecular surveillance strategy identified 11 linkages to incident infections a genetic distance threshold of 0.5%, and 24 linkages at 1.5%. CONCLUSIONS: Over the past 2 decades, incident infections drove incident HIV cluster growth in San Diego. The current CDC EHE molecular detection and response strategy would not have identified most transmission events arising from those with incident infection in San Diego. Molecular surveillance that includes detection of incident cases will provide a more effective strategy for EHE.

Subclinical Cytomegalovirus and Epstein-Barr Virus Shedding Is Associated with Increasing HIV DNA Molecular Diversity in Peripheral Blood during Suppressive Antiretroviral Therapy.

Cytomegalovirus (CMV) almost universally infects persons with HIV (PWH), and it is a driver of persistent inflammation and HIV persistence. The mechanisms underlying the association between CMV (and possibly other herpesviruses) and HIV persistence are unclear. Serially collected blood samples were obtained from men who have sex with men (MSM) who started antiretroviral therapy (ART) within 1 year of their estimated date of HIV infection (EDI). Total CMV and Epstein-Barr virus (EBV) DNA were quantified in peripheral blood mononuclear cells by droplet digital PCR (ddPCR). Deep sequencing of the HIV DNA partial env gene was performed, and the dynamics of viral diversity over time were analyzed in relation to CMV and EBV shedding status. In total, 37 MSM PWH were included and followed for a median of 23 months (IQR, 22 to 28). Participants started ART within a median of 3.1 months (IQR, 1.5 to 6.5) after EDI and remained virally suppressed thereafter. A total of 18 participants (48.6%) were classified as high EBV shedders, while 19 (51.4%) were classified as CMV shedders. In longitudinal analyses, normalized molecular diversity levels tended to increase over time among participants with detectable CMV and high EBV DNA (0.03 ± 0.02, P = 0.08), while they significantly declined among participants with no/low viral shedding (-0.04 ± 0.02, P = 0.047, interaction P < 0.01). Subclinical CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART. Whether persistent CMV/EBV replication could be targeted as a strategy to reduce the size of the latent HIV reservoir is an avenue that should be explored.IMPORTANCE As part of this study, we evaluated the molecular characteristics of the HIV DNA reservoir over time during antiretroviral treatment (ART) in relation to those of other chronic viral infections (i.e., cytomegalovirus [CMV] and Epstein-Barr virus [EBV]). We demonstrated that the presence of CMV and high-level EBV DNA in peripheral blood cells was associated with changes in HIV DNA molecular diversity. Specifically, HIV DNA molecular diversity increased over time among participants with detectable CMV and high-level EBV DNA, while it significantly declined among participants with no/low viral shedding. Although the current study design does not allow causality to be inferred, it does support the theory that persistent CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART, even when ART is initiated during the earliest phases of HIV infection.

Effect of Cannabis Use on Human Immunodeficiency Virus DNA During Suppressive Antiretroviral Therapy.

Cannabis use is frequent among people living with human immunodeficiency virus (HIV) and is associated with reduced systemic inflammation. We observed a faster HIV DNA decay during antiretroviral therapy among cannabis users, compared to those with no drug use. No cannabis effect was observed on cellular HIV RNA transcription.

Subclinical Cytomegalovirus DNA Is Associated with CD4 T Cell Activation and Impaired CD8 T Cell CD107a Expression in People Living with HIV despite Early Antiretroviral Therapy.

Most people living with HIV (PLWH) are coinfected with cytomegalovirus (CMV). Subclinical CMV replication is associated with immune dysfunction and with increased HIV DNA in antiretroviral therapy (ART)-naive and -suppressed PLWH. To identify immunological mechanisms by which CMV could favor HIV persistence, we analyzed 181 peripheral blood mononuclear cell (PBMC) samples from 64 PLWH starting ART during early HIV infection with subsequent virologic suppression up to 58 months. In each sample, we measured levels of CMV and Epstein-Barr virus (EBV) DNA by droplet digital PCR (ddPCR). We also measured expression of immunological markers for activation (HLA-DR+ CD38+), cycling (Ki-67+), degranulation (CD107a+), and the immune checkpoint protein PD-1 on CD4+ and CD8+ T cell memory subsets. Significant differences in percentages of lymphocyte markers by CMV/EBV shedding were identified using generalized linear mixed-effects models. Overall, CMV DNA was detected at 60/181 time points. At the time of ART initiation, the presence of detectable CMV DNA was associated with increased CD4+ T cell activation and CD107a expression and with increased CD8+ T cellular cycling and reduced CD107a expression on CD8+ T cells. While some effects disappeared during ART, greater CD4+ T cell activation and reduced CD107a expression on CD8+ T cells persisted when CMV was present (P < 0.01). In contrast, EBV was not associated with any immunological differences. Among the covariates, peak HIV RNA and CD4/CD8 ratio had the most significant effect on the immune system. In conclusion, our study identified immune differences in PLWH with detectable CMV starting early ART, which may represent an additional hurdle for HIV cure efforts.IMPORTANCE Chronic viral infections such as with HIV and CMV last a lifetime and can continually antagonize the immune system. Both viruses are associated with higher expression of inflammation markers, and recent evidence suggests that CMV may complicate efforts to deplete HIV reservoirs. Our group and others have shown that CMV shedding is associated with a larger HIV reservoir. Subclinical CMV replication could favor HIV persistence via bystander effects on our immune system. In this study, we collected longitudinal PBMC samples from people starting ART and measured immune changes associated with detectable CMV. We found that when CMV was detectable, CD4+ T cell activation was higher and CD8+ T cell degranulation was lower. Both results may contribute to the slower decay of the size of the reservoir during CMV replication, since activated CD4+ T cells are more vulnerable to HIV infection, while the loss of CD8+ T cell degranulation may impede the proper killing of infected cells.

Herd Immunity Likely Protected the Men Who Have Sex With Men in the Recent Hepatitis A Outbreak in San Diego, California.

A high seroprevalence of hepatitis A virus (81%) among human immunodeficiency virus-negative high-risk men who have sex with men is likely why this community was largely spared from a recent hepatitis A virus outbreak in San Diego, California.

Molecular Features of the V1-V4 Coding Region of Sexually Transmitted Human Immunodeficiency Virus Type 1.

Background: Investigations into which human immunodeficiency virus type 1 (HIV-1) sequence features may be selected for transmission during sexual exposure have been hampered by the small number of characterized transmission pairs in individual studies. Methods: To boost statistical power to detect differences in glycosylation, length, and electrical charge in the HIV-1 V1-V4 coding region, we reanalyzed all available 2485 env sequences derived from 114 subjects representing 58 transmission pairs from previous studies using mixed-effects linear regression and an approach to approximate the unobserved transmitted virus. Results: The recipient partner had a shorter V1-V4 region and fewer potential N-linked glycosylation sites (PNGS) than sequences from the source partner. We also detected a trend toward more PNGS and lower isoelectric points in transmitted sequences with source partner and the evolutionary tendency to shorten V1-V4 sequences, reduce the number of PNGS, and lower isoelectric points in the recipient following transmission. Conclusions: By using all available well-characterized env sequences from transmission pairs via sexual exposure, we were able to identify several important virologic factors that may be important in the development of biomedical preventive interventions.

Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection.

UNLABELLED: Asymptomatic replication of human herpesviruses (HHV) is frequent in HIV-infected men and is associated with increased T-cell activation and HIV disease progression. We hypothesized that the presence of replication of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) (the most frequently detected HHV) might influence HIV DNA decay during antiretroviral therapy (ART). We investigated 607 peripheral blood mononuclear cell (PBMC) samples from 107 CMV-seropositive, HIV-infected men who have sex with men, who started ART within a median of 3 months from their estimated date of infection (EDI) and were monitored for a median of 19 months thereafter. Levels of HIV, CMV, and EBV DNA and cellular HIV RNA were measured by droplet digital PCR (ddPCR) for each time point. Using a general linear mixed-effect regression model, we evaluated associations between the presence of detectable CMV DNA and EBV DNA levels and HIV DNA decay and cellular HIV RNA levels, while adjusting for peak HIV RNA, nadir CD4(+)count, CD4/CD8 ratio, CMV IgG levels, time from EDI to ART initiation, time from ART initiation to virologic suppression, detectable CMV DNA pre-ART, and age. The presence of intermittent CMV DNA in PBMC during ART was significantly associated with slower decay of HIV DNA (P= 0.011) but not with increased cellular HIV RNA transcription or more detectable 2-long terminal repeat circles. Higher levels of EBV DNA were also associated with higher levels of HIV DNA (P< 0.001) and increased unspliced cellular HIV RNA transcription (P= 0.010). These observations suggest that replication of HHV may help maintain a larger HIV DNA reservoir, but the underlying mechanisms remain unclear. IMPORTANCE: Over three-fourths of HIV-infected men have at least one actively replicating human herpesvirus (HHV) in their mucosal secretions at any one time. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the most common, and although it is often asymptomatic, such CMV and EBV replication is associated with higher levels of immune activation and HIV disease progression. We hypothesized that HHV-associated activation of HIV-infected CD4(+)T cells might lead to increased HIV DNA. This study found that detectable CMV in blood cells of HIV-infected men was associated with slower decay of HIV DNA even during antiretroviral therapy (ART) that was started during early HIV infection. Similarly, levels of EBV DNA were associated with higher levels of HIV DNA during ART. If this observation points to a causal pathway, interventions that control CMV and EBV replication may be able to reduce the HIV reservoir, which might be relevant to current HIV cure efforts.

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment.

BACKGROUND: A low CD4/CD8 ratio in human immunodeficiency virus (HIV)-infected individuals is associated with inflammation and higher risk of non-AIDS morbidity and mortality. In this study, we investigated the effect of subclinical cytomegalovirus (CMV) and Epstein-Barr virus (EBV) replication on CD4+ and CD8+ T-cell dynamics when antiretroviral therapy (ART) is started during early infection. METHODS: We investigated 604 peripheral blood mononuclear cell samples from 108 CMV- and EBV-seropositive HIV-infected men who have sex with men, who started ART within a median of 4 months from their estimated date of infection and were followed for a median of 29.1 months thereafter. Levels of CMV and EBV DNA were measured at each timepoint. Mixed-effects asymptotic regression models were applied to characterize CD4+ and CD8+ T-cell dynamics, and Bayesian hierarchical models were used to quantify individual differences in CMV and EBV DNA replication. RESULTS: Higher levels of subclinical CMV replication were associated with lower predicted maximum levels of CD4/CD8 ratio (P < .05), which was driven by higher levels of CD8+ T-cell counts (P < .05), without affecting CD4+ T-cell counts (P > .1). Age was negatively associated with CD4/CD8 levels (P < .05), and this effect was independent of the CMV association (P < .05 for both CMV and age in a multivariate model). CONCLUSIONS: Subclinical CMV replication in blood cells during early HIV infection and younger age were associated with lower CD4/CD8 ratios during suppressive ART. These findings suggest that active CMV infection in the setting of treated HIV may represent an attractive potential target for therapeutic intervention.

Using HIV Sequence and Epidemiologic Data to Assess the Effect of Self-referral Testing for Acute HIV Infection on Incident Diagnoses in San Diego, California.

BACKGROUND: Because recently infected individuals disproportionately contribute to the spread of human immunodeficiency virus (HIV), we evaluated the impact of a primary HIV screening program (the Early Test) implemented in San Diego. METHODS: The Early Test program used combined nucleic acid and serology testing to screen for primary infection targeting local high-risk individuals. Epidemiologic, HIV sequence, and geographic data were obtained from the San Diego County Department of Public Health and the Early Test program. Poisson regression analysis was performed to determine whether the Early Test program was temporally and geographically associated with changes in incident HIV diagnoses. Transmission chains were inferred by phylogenetic analysis of sequence data. RESULTS: Over time, a decrease in incident HIV diagnoses was observed proportional to the number primary HIV infections diagnosed in each San Diego region (P < .001). Molecular network analyses also showed that transmission chains were more likely to terminate in regions where the program was marketed (P = .002). Although, individuals in these zip codes had infection diagnosed earlier (P = .08), they were not treated earlier (P = .83). CONCLUSIONS: These findings suggests that early HIV diagnoses by this primary infection screening program probably contributed to the observed decrease in new HIV diagnoses in San Diego, and they support the expansion and evaluation of similar programs.

Development and validation of the San Diego Early Test Score to predict acute and early HIV infection risk in men who have sex with men.

BACKGROUND: Although men who have sex with men (MSM) represent a dominant risk group for human immunodeficiency virus (HIV), the risk of HIV infection within this population is not uniform. The objective of this study was to develop and validate a score to estimate incident HIV infection risk. METHODS: Adult MSM who were tested for acute and early HIV (AEH) between 2008 and 2014 were retrospectively randomized 2:1 to a derivation and validation dataset, respectively. Using the derivation dataset, each predictor associated with an AEH outcome in the multivariate prediction model was assigned a point value that corresponded to its odds ratio. The score was validated on the validation dataset using C-statistics. RESULTS: Data collected at a single HIV testing encounter from 8326 unique MSM were analyzed, including 200 with AEH (2.4%). Four risk behavior variables were significantly associated with an AEH diagnosis (ie, incident infection) in multivariable analysis and were used to derive the San Diego Early Test (SDET) score: condomless receptive anal intercourse (CRAI) with an HIV-positive MSM (3 points), the combination of CRAI plus ≥5 male partners (3 points), ≥10 male partners (2 points), and diagnosis of bacterial sexually transmitted infection (2 points)-all as reported for the prior 12 months. The C-statistic for this risk score was >0.7 in both data sets. CONCLUSIONS: The SDET risk score may help to prioritize resources and target interventions, such as preexposure prophylaxis, to MSM at greatest risk of acquiring HIV infection. The SDET risk score is deployed as a freely available tool at http://sdet.ucsd.edu.

Repeat HIV-testing is associated with an increase in behavioral risk among men who have sex with men: a cohort study.

BACKGROUND: The Center for Disease Control and Prevention recommends that high-risk groups, like sexually active men who have sex with men (MSM), receive HIV testing and counseling at least annually. The objective of this study was to investigate the relationship between voluntary repeat HIV testing and sexual risk behavior in MSM receiving rapid serologic and nucleic acid amplification testing. METHODS: We performed a cohort study to analyze reported risk behavior among MSM receiving the "Early Test", a community-based, confidential acute and early HIV infection screening program in San Diego, California, between April 2008 and July 2014. The study included 8,935 MSM receiving 17,333 "Early Tests". A previously published risk behavior score for HIV acquisition in MSM (i.e. Menza score) was chosen as an outcome to assess associations between risk behaviors and number of repeated tests. RESULTS: At baseline, repeat-testers (n = 3,202) reported more male partners and more condomless receptive anal intercourse (CRAI) when compared to single-testers (n = 5,405, all P <0.001). In 2,457 repeat testers there was a strong association observed between repeated HIV tests obtained and increased risk behavior, with number of male partners, CRAI with high risk persons, non-injection stimulant drug use, and sexually transmitted infections all increasing between the first and last test. There was also a linear increase of risk (i.e. high Menza scores) with number of tests up to the 17th test. In the multivariable mixed effects model, more HIV tests (OR = 1.18 for each doubling of the number of tests, P <0.001) and younger age (OR = 0.95 per 5-year increase, P = 0.006) had significant associations with high Menza scores. CONCLUSIONS: This study found that the highest risk individuals for acquiring HIV (e.g. candidates for antiretroviral pre-exposure prophylaxis) can be identified by their testing patterns. Future studies should delineate causation versus association to improve prevention messages delivered to repeat testers during HIV testing and counseling sessions.

Are we prepped for preexposure prophylaxis (PrEP)? Provider opinions on the real-world use of PrEP in the United States and Canada.

BACKGROUND: Preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (Truvada) has demonstrated efficacy in placebo-controlled clinical trials involving men who have sex with men, high-risk heterosexuals, serodiscordant couples, and intravenous drug users. To assist in the real-world provision of PrEP, the Centers for Disease Control and Prevention (CDC) has released guidance documents for PrEP use. METHODS: Adult infectious disease physicians were surveyed about their opinions and current practices of PrEP through the Emerging Infections Network (EIN). Geographic information systems analysis was used to map out provider responses across the United States. RESULTS: Of 1175 EIN members across the country, 573 (48.8%) responded to the survey. A majority of clinicians supported PrEP but only 9% had actually provided it. Despite CDC guidance, PrEP practices were variable and clinicians reported many barriers to its real-world provision. CONCLUSIONS: The majority of adult infectious disease physicians across the United States and Canada support PrEP but have vast differences of opinion and practice, despite the existence of CDC guidance documents. The success of real-world PrEP will likely require multifaceted programs addressing barriers to its provision and will be assisted with the development of comprehensive guidelines for real-world PrEP.

Cytomegalovirus DNA in semen and blood is associated with higher levels of proviral HIV DNA.

Over three-fourths of human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) have at least one herpesvirus detected in their semen, and cytomegalovirus (CMV) is the most prevalent. The presence of CMV is associated with higher T-cell immune activation and with HIV disease progression in treated and untreated individuals. In this study of 113 antiretroviral (ART)-naive HIV-infected MSM, we found that CMV replication in blood and semen was associated with higher levels of HIV DNA in peripheral blood mononuclear cells. These observations suggest that interventions aimed to reduce CMV replication and, thus, systemic immune activation could decrease the size of the latent HIV reservoir.

Randomized Controlled Trial of 60 minutes for Health With Rapid Antiretroviral Therapy to Reengage Persons With HIV Who Are Out of Care.

BACKGROUND: Many persons with HIV remain out of care (PWH-OOC). We evaluated InstaCare, a complex intervention integrating the brief behavioral intervention 60 minutes for Health with the rapid restart of antiretroviral therapy (rapid ART). SETTING: Prospective open-label randomized controlled trial among PWH-OOC in San Diego, USA. METHODS: PWH-OOC were randomized 1:1 to InstaCare or a time-and-attention control integrating a diet-and-nutrition behavioral intervention also with rapid ART initiation (restart ≤7 days from enrollment). All participants had access to support services (free transport, HIV peer navigation, adherence counseling, and linkage to care) and primary care services (mental health, case management, social work, medication-assisted treatment, and specialist pharmacy). The primary outcomes were viral suppression (<50 copies/mL) and re-engagement with care (≥2 HIV care visits >90 days apart) by 24 weeks. Outcomes were reported on an intention-to-treat basis. RESULTS: Between November 2020 and August 2022, 52 PWH-OOC were enrolled. Baseline substance use in the preceding month (49%), unstable housing (51%), moderate/severe depression (49%), and moderate/severe anxiety (41.7%) were prevalent. Rapid ART was provided for all participants. At week 24, the proportion with HIV viral load <50 copies/mL was 37.3% (19/51) (InstaCare 28.0%, control 46.2%, P = 0.25). Fourteen (27.5%) were engaged with care (InstaCare 7/25 [28.0%], control 7/26 [26.9%], P = 1.00). Most participants (94%) reported low or very low emotional distress associated with rapid ART. Study lost to follow-up by week 24 was high (23/51, 45%). CONCLUSIONS: The InstaCare complex intervention did not improve viral suppression or reengagement with care among PWH-OOC. Investigation of high-intensity, individually adapted interventions is needed among PWH-OOC.

Impact of influenza and pneumococcal vaccines on HIV persistence and immune dynamics during suppressive antiretroviral therapy.

OBJECTIVE: We sought to determine if standard influenza and pneumococcal vaccines can be used to stimulate HIV reservoirs during antiretroviral therapy (ART). DESIGN: A prospective, randomized, double-blinded, placebo-controlled, crossover trial of two clinically recommended vaccines (influenza and pneumococcal). METHODS: Persons with HIV on ART ( N  = 54) were enrolled in the clinical trial. Blood was collected at baseline and days 2,4,7,14, and 30 postimmunizations. Levels of cellular HIV RNA and HIV DNA were measured by ddPCR. Expression of immunological markers on T cell subsets was measured by flow cytometry. Changes in unspliced cellular HIV RNA from baseline to day 7 postinjection between each vaccine and placebo was the primary outcome. RESULTS: Forty-seven participants completed at least one cycle and there were no serious adverse events related to the intervention. We observed no significant differences in the change in cellular HIV RNA after either vaccine compared with placebo at any timepoint. In secondary analyses, we observed a transient increase in total HIV DNA levels after influenza vaccine, as well as increased T cell activation and exhaustion on CD4 + T cells after pneumococcal vaccine. CONCLUSION: Clinically recommended vaccines were well tolerated but did not appear to stimulate the immune system strongly enough to elicit significantly noticeable HIV RNA transcription during ART.Clinicaltrials.gov identifier: NCT02707692.

Assessing the reliability of the CD4 depletion model in the presence of Ending the HIV Epidemic initiatives.

BACKGROUND: Accurate estimates of HIV incidence are necessary to monitor progress towards Ending the HIV Epidemic (EHE) initiative targets (90% decline by 2030). U.S. incidence estimates are derived from a CD4 depletion model (CD4 model). We performed simulation-based analyses to investigate the ability of this model to estimate HIV incidence when implementing EHE interventions that have the potential to shorten the duration between HIV infection and diagnosis (diagnosis delay). METHODS: Our simulation study evaluates the impact of three parameters on the accuracy of incidence estimates derived from the CD4 model: rate of HIV incidence decline, length of diagnosis delay, and sensitivity of using CD4 + cell counts to identify new infections (recency error). We model HIV incidence and diagnoses after the implementation of a theoretical prevention intervention and compare HIV incidence estimates derived from the CD4 model to simulated incidence. RESULTS: Theoretical interventions that shortened the diagnosis delay (10-50%) result in overestimation of HIV incidence by the CD4 model (10-92%) in the first year and by more than 10% for the first 6 years after implementation of the intervention. Changes in the rate of HIV incidence decline and the presence of recency error had minimal impact on the accuracy of incidence estimates derived from the CD4 model. CONCLUSION: In the setting of EHE interventions to identify persons with HIV earlier during infection, the CD4 model overestimates HIV incidence. Alternative methods to estimate incidence based on objective measures of incidence are needed to assess and monitor EHE interventions.

Predictors of Human Immunodeficiency Virus Pre-Exposure Prophylaxis (PrEP) Uptake in a Sexual Health Clinic With Rapid PrEP Initiation.

Background: Improved pre-exposure prophylaxis (PrEP) uptake is essential for human immunodeficiency virus (HIV) prevention initiatives. Offering PrEP at the time of HIV and sexually transmitted infection (STI) testing can improve uptake. We offered rapid PrEP initiation in a sexual health clinic and assessed predictors of PrEP interest, initiation, linkage, and retention. Methods: Between November 2018 and February 2020, PrEP-eligible individuals who presented to a sexual health clinic were offered a free 30-day supply of PrEP plus linkage to continued PrEP care. Univariable and multivariable analyses of demographic and HIV risk data were conducted to determine predictors of PrEP uptake. Results: Of 1259 adults who were eligible for PrEP (99.7% male, 42.7% White, 36.2% Hispanic), 456 were interested in PrEP, 249 initiated PrEP, 209 were linked, and 67 were retained in care. Predictors of PrEP interest included younger age (P < .01), lower monthly income (P = .01), recreational drug use (P = .02), and a greater number of sexual partners (P < .01). Negative predictors of PrEP initiation included lower monthly income (P = .04), testing positive for chlamydia (P = .04), and exchanging money for sex (P = .01). Negative predictors of linkage included self-identifying as Black (P = .03) and testing positive for an STI (P < .01). Having health insurance positively predicted both linkage (P < .01) and retention (P < .03). Conclusions: A minority of PrEP-eligible HIV and STI testers initiated PrEP when offered, suggesting that easy PrEP access in sexual health clinics alone may not improve uptake. Predictors of uptake included established HIV risk factors and markers of higher socioeconomic status, suggesting that those aware of their risk and with the means to utilize health services engaged best with this model.

Cost savings associated with testing of antibodies, antigens, and nucleic acids for diagnosis of acute HIV infection.

Efforts to identify all persons infected with HIV in the United States are driven by the hope that early diagnosis will lower risk behaviors and decrease HIV transmission. Identification of HIV-infected people earlier in the course of their infection with HIV antigen/antibody (Ag/Ab) combination assays (4th-generation HIV assays) should help achieve this goal. We compared HIV RNA nucleic acid test (NAT) results to the results of a 4th-generation Ag/Ab assay (Architect HIV Ag/Ab Combo [HIV Combo] assay; Abbott Diagnostics) in 2,744 HIV antibody-negative samples. Fourteen people with acute HIV infection (HIV antibody negative/NAT positive) were identified; the HIV Combo assay detected nine of these individuals and was falsely negative in the remaining five. All five persons missed by the HIV Combo assay were in the stage of exponential increase in plasma virus associated with acute HIV infection (3, 7, 20, 35, 48). In contrast, most acutely infected persons detected by the HIV Combo assay demonstrated either a plateauing or decreasing plasma viral load. The HIV Combo assay also classified as positive five other samples which were negative by NAT. Taken together, the HIV Combo assay had a sensitivity of 73.7% and a specificity of 99.8%. Using published data, we estimated secondary transmission events had HIV infection in these five individuals remained undiagnosed. Screening of our population with NAT cost more than screening with the HIV Combo assay but achieved new diagnoses that we predict resulted in health care savings that far exceed screening costs. These findings support the use of more sensitive assays, like NAT, in HIV screening of populations with a high prevalence of acute HIV infection.