Aberrant expression of regulatory receptors programmed death-1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) is linked with dysregulation and exhaustion of T lymphocytes during chronic human immunodeficiency virus type 1 (HIV-1) infection; however, less is known about whether a similar process impacts B-lymphocyte function during HIV-1 infection. We reasoned that disruption of the peripheral B cell compartment might be associated with decreased neutralizing antibody activity. Expression of markers that indicate dysregulation (BTLA and PD-1), immune activation (CD95), and proliferation (Ki-67) was evaluated in B cells from HIV-1-infected viremic and aviremic subjects and healthy subjects, in conjunction with immunoglobulin production and CD4 T cell count. Viral load and cross-clade neutralizing activity in plasma from viremic subjects were also assessed. Dysregulation of B lymphocytes was indicated by a marked disruption of peripheral B cell subsets, increased levels of PD-1 expression, and decreased levels of BTLA expression in viremic subjects compared to aviremic subjects and healthy controls. PD-1 and BTLA were correlated in a divergent fashion with immune activation, CD4 T cell count, and the total plasma IgG level, a functional correlate of B cell dysfunction. Within viremic subjects, the total IgG level correlated directly with cross-clade neutralizing activity in plasma. The findings demonstrate that even in chronically infected subjects in which B lymphocytes display multiple indications of dysfunction, antibodies that mediate cross-clade neutralization breadth continue to circulate in plasma.

Background: Understanding the sources of HIV transmission provides a basis for prioritizing HIV prevention resources in specific geographic regions and populations. This study estimated the number, proportion, and rate of HIV transmissions attributable to individuals along the HIV care continuum within different HIV transmission risk groups in 6 US cities. Methods: We used a dynamic, compartmental HIV transmission model that draws on racial behavior-specific or ethnic behavior-specific and risk behavior-specific linkage to HIV care and use of HIV prevention services from local, state, and national surveillance sources. We estimated the rate and number of HIV transmissions attributable to individuals in the stage of acute undiagnosed HIV, nonacute undiagnosed HIV, HIV diagnosed but antiretroviral therapy (ART) naïve, off ART, and on ART, stratified by HIV transmission group for the 2019 calendar year. Results: Individuals with undiagnosed nonacute HIV infection accounted for the highest proportion of total transmissions in every city, ranging from 36.8% (26.7%-44.9%) in New York City to 64.9% (47.0%-71.6%) in Baltimore. Individuals who had discontinued ART contributed to the second highest percentage of total infections in 4 of 6 cities. Individuals with acute HIV had the highest transmission rate per 100 person-years, ranging from 76.4 (58.9-135.9) in Miami to 160.2 (85.7-302.8) in Baltimore. Conclusion: These findings underline the importance of both early diagnosis and improved ART retention for ending the HIV epidemic in the United States. Differences in the sources of transmission across cities indicate that localized priority setting to effectively address diverse microepidemics at different stages of epidemic control is necessary.

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06-0.12] than DRV, 0.04 (95%CI 0.03-0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50) in all ATV and 1 DRV-treated subjects (P<0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P=0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation.

The COVID-19 pandemic has exposed longstanding vulnerabilities in our healthcare system, and has laid bare the individuals and communities most threatened by insufficient public health support. In the U.S., persons with HIV (PWH) represent a heterogenous population with complex medical and sociobehavioral needs currently unmet by systemically-flawed care models1,2. Thriving on health disparity, COVID-19 devastates the same communities where HIV prevalence is highest3, illuminating the catastrophic synergy of poverty, policies and structural racism4. This unprecedented time demands reexamination of HIV care delivery, paving the way for a revitalized healthcare infrastructure tailored to the needs of PWH and those at-risk of HIV to realize the goals of the Ending the HIV Epidemic (EHE) initiative5.

Background: Alcohol use is common among persons living with HIV (PLWH), who often experience chronic pain, yet its impact on pain and opioid misuse is not fully characterized. Methods: We assessed associations between hazardous alcohol use and pain interference, defined as the self-reported impact of pain on daily living, pain severity, and risk for opioid misuse among PLWH who were on long-term opioid therapy (LTOT). A cohort was recruited as part of the “Targeting Effective Analgesia in Clinics for HIV” (TEACH) study, a randomized controlled trial to improve LTOT in HIV clinics. The Alcohol Use Disorders Test (AUDIT), Brief Pain Inventory (BPI) and the Current Opioid Misuse Measure (COMM) were administered at both baseline and 12-months. Linear mixed and generalized estimating equation models, incorporating data from both time points, evaluated associations between hazardous alcohol use (AUDIT ≥8) and: pain interference (0–10), pain severity (0–10), and opioid misuse risk (COMM ≥13), adjusting for age, gender, depressive symptoms, use of non-alcohol substances, time-point, and study-arm. Results: The sample was comprised of 166 participants, of which 31 (19%) reported hazardous alcohol use. The majority were male (65%), black (72%), and the mean age was 54 (range: 29–77). Hazardous alcohol use was significantly associated with higher pain interference (adjusted mean difference [AMD]: 1.02; 95% CI: 0.08, 1.96) and higher odds of opioid misuse risk (AOR: 3.73, 95% CI: 1.88–7.39), but not pain severity (AMD: 0.47, 95% CI: − 0.35, 1.29). Conclusions: Hazardous alcohol use was associated with greater functional impairment in daily living from their pain and higher odds for prescription opioid misuse in this study of PLWH on LTOT. Providers should be attentive to alcohol use among PLWH who are prescribed opioids given associations with pain and opioid misuse. Trial registration: ClinicalTrials.govNCT02564341 (Intervention, September 30, 2015) and NCT02525731 (Patient Cohort, August 17, 2015). Both prospectively registered.

One of the many challenges that has befallen the Infectious Diseases and Graduate Medical Education communities during the coronavirus disease 2019 (COVID-19) pandemic is the maintenance of continued effective education and training of the future leaders of our field. With the remarkable speed and innovation that has characterized the responses to this pandemic, educators everywhere have adapted existing robust and safe learning environments to meet the needs of our learners. This paper will review distinct aspects of education and training of the Infectious Diseases fellows we believe the COVID-19 pandemic has impacted most, including mentoring, didactics, and wellness. We anticipate that several strategies developed in this context and described herein will help to inform training and best practices during the pandemic and beyond.

Prompt antiretroviral therapy (ART) initiation after AIDS diagnosis, in the absence of certain opportunistic infections such as tuberculosis and cryptococcal meningitis, delays disease progression and death, but system barriers to inpatient ART initiation at large hospitals in the era of modern ART have been less studied. We reviewed hospitalizations for persons newly diagnosed with AIDS at Grady Memorial Hospital in Atlanta, Georgia in 2011 and 2012. Individual- and system-level variables were collected. Logistic regression models were used to estimate the odds ratios (ORs) for ART initiation prior to discharge. With Georgia Department of Health surveillance data, we estimated time to first clinic visit, ART initiation, and viral suppression. In the study population (n = 81), ART was initiated prior to discharge in 10 (12%) patients. Shorter hospital stay was significantly associated with lack of ART initiation at the time of HIV diagnosis (8 versus 24 days, OR: 1.14, 95% confidence interval: 1.04-1.25). Reducing barriers to ART initiation for newly diagnosed HIV-positive patients with short hospital stays may improve time to viral suppression.

The goal of the Ending the HIV Epidemic Initiative is to reduce new infections in the United States by 90% by 2030. Success will require fundamentally changing human immunodeficiency virus (HIV) prevention and care delivery to engage more persons with HIV and at risk of HIV in treatment. While the coronavirus disease 2019 (COVID-19) pandemic reduced in-person visits to care facilities and led to concern about interruptions in care, it also accelerated growth of alternative options, bolstered by additional funding support. These included the use of telehealth, medication delivery to the home, and increased flexibility facilitating access to Ryan White HIV/AIDS Program services. While the outcomes of these programs must be studied, many have improved accessibility during the pandemic. As the pandemic wanes, long-term policy changes are needed to preserve these options for those who benefit from them. These new care paradigms may provide a roadmap for progress for those with other chronic health issues as well.

Background: Widespread viral and serological testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present a unique opportunity to also test for human immunodeficiency virus (HIV) infection. We estimated the potential impact of adding linked, opt-out HIV testing alongside SARS-CoV-2 testing on the HIV incidence and the cost-effectiveness of this strategy in 6 US cities. Methods: Using a previously calibrated dynamic HIV transmission model, we constructed 3 sets of scenarios for each city: (1) sustained current levels of HIV-related treatment and prevention services (status quo); (2) temporary disruptions in health services and changes in sexual and injection risk behaviors at discrete levels between 0%-50%; and (3) linked HIV and SARS-CoV-2 testing offered to 10%-90% of the adult population in addition to Scenario 2. We estimated the cumulative number of HIV infections between 2020-2025 and the incremental cost-effectiveness ratios of linked HIV testing over 20 years. Results: In the absence of linked, opt-out HIV testing, we estimated a total of a 16.5% decrease in HIV infections between 2020-2025 in the best-case scenario (50% reduction in risk behaviors and no service disruptions), and a 9.0% increase in the worst-case scenario (no behavioral change and 50% reduction in service access). We estimated that HIV testing (offered at 10%-90% levels) could avert a total of 576-7225 (1.6%-17.2%) new infections. The intervention would require an initial investment of $20.6M-$220.7M across cities; however, the intervention would ultimately result in savings in health-care costs in each city. Conclusions: A campaign in which HIV testing is linked with SARS-CoV-2 testing could substantially reduce the HIV incidence and reduce direct and indirect health care costs attributable to HIV.

Gender and racial differences in CD4+ T cell counts and human immunodeficiency virus (HIV)-1 RNA levels among chronically HIV-infected persons have been shown to exist in multiple studies, and although women have significantly lower plasma HIV-1 RNA levels than men, the rate of progression to AIDS is similar among men and women. Similarly, several studies have suggested that blacks and Latinos have lower CD4+ T cell counts and higher viral loads at presentation, but this is likely due to delays in diagnosis and, thus, more advanced disease at presentation. The study by Meditz et al in this issue of the Journal confirms and extends these findings by demonstrating that gender and racial differences are present in the earliest stages of infection—in those with acute and recent HIV infection. Among untreated patients in their cohort, however, this difference disappeared after 24 weeks, and by week 104 of follow-up, women had higher viral loads than men. Their data also suggest that women report fewer symptoms associated with the …