Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy.

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA).

The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in HIV-1 remission trials.

Undetectable equals untransmittable (U = U): awareness and associations with health outcomes among people living with HIV in 25 countries.

OBJECTIVES: 'Undetectable equals Untransmittable' (U=U) is an empowering message that may enable people living with HIV (PLHIV) to reach and maintain undetectability. We estimated the percentage of PLHIV who ever discussed U=U with their main HIV care provider, and measured associations with health-related outcomes. Secondarily, we evaluated whether the impact of the U=U message varied between those who heard it from their healthcare provider (HCP) vs from elsewhere. METHODS: Data were from the 25-country 2019 Positive Perspectives Survey of PLHIV on treatment (n=2389). PLHIV were classified as having discussed U=U with their HCP if they indicated that their HCP had ever told them about U=U. Those who had not discussed U=U with their HCP but were nonetheless aware that 'My HIV medication prevents me from passing on HIV to others' were classified as being made aware of U=U from non-HCP sources. Multivariable logistic regression was used to measure associations between exposure to U=U messages and health outcomes. RESULTS: Overall, 66.5% reported ever discussing U=U with their HCP, from 38.0% (South Korea) to 87.3% (Switzerland). Prevalence was lowest among heterosexual men (57.6%) and PLHIV in Asia (51.3%). Compared with those unaware of U=U, those reporting U=U discussions with their HCP had lower odds of suboptimal adherence (AOR=0.59, 95% CI 0.44 to 0.78) and higher odds of self-reported viral suppression (AOR=2.34, 95% CI 1.72 to 3.20), optimal sexual health (AOR=1.48, 95% CI 1.14 to 1.92) and reporting they 'always shared' their HIV status (AOR=2.99, 95% CI 1.42 to 6.28). While exposure to U=U information from non-HCP sources was beneficial too, the observed associations were attenuated relative to those seen with reported discussions with HCPs. CONCLUSION: HCP discussion of U=U with PLHIV was associated with favourable health outcomes. However, missed opportunities exist since a third of PLHIV reported not having any U=U discussion with their HCP. U=U discussions with PLHIV should be considered as a standard of care in clinical guidelines.

Physical, Emotional, and Psychosocial Challenges Associated with Daily Dosing of HIV Medications and Their Impact on Indicators of Quality of Life: Findings from the Positive Perspectives Study.

To assess challenges with daily oral antiretroviral therapy (ART), we analyzed data for 2389 participants in the 2019 Positive Perspectives survey of people living with HIV in 25 countries. ART-related challenges reported included difficulty swallowing pills (33.1% [790/2389]); stress from daily dosing routine (33.3% [795/2389]); bad memories from daily intake of HIV medication (35.1%[839/2389]), and concern "that having to take pills every day means a greater chance of revealing my HIV status to others" (37.9% [906/2389]). Individuals who felt empowered by daily oral dosing ["taking my pill(s) every day reassures me that my HIV is being kept under control"] had 69% higher odds of optimal overall health (AOR 1.69, 95% CI 1.40-2.04). Conversely, odds of optimal overall health were lower among those who felt daily pill intake "limits my day-to-day life" (AOR 0.53, 95% CI 0.44-0.64). These findings show that there is need for increased flexibility of ART delivery to meet diverse patient needs.

Regional differences in perceived treatments needs and priorities in relation to antiretroviral therapy among people living with HIV in 25 countries.

While geographic differences in HIV burden are well documented, less is known about regional differences in perceived treatment needs. To fill this gap, the 2019 Positive Perspectives study of people living with HIV (PLHIV) was conducted in 25 countries across Northern America, Latin America, the Asian region, Europe (EU/Schengen countries), Russia, Australia, and South Africa (n = 2389). Overall mean duration of HIV was 10.1 (SD = 9.6) years. The perception that HIV had a negative impact on day-to-day life was lowest among participants from South Africa (14.0%[25/179]) and highest among participants from the Asian region (55.2%[127/230]). Most of the regional gap in the perception that HIV had a negative impact on daily life was explained by regional differences in medication-related unmet needs, stigma, demographic factors, and comorbidities. The percentage who felt they understood their treatment was highest among participants from Australia (87.5%[105/120]) and lowest among those from Russia (62.0%[93/150]), the Asian region (62.2%[143/230]), and South Africa (62.6%[112/179]). Among participants from Northern America, Europe, and Latin America, the treatment goals with the largest absolute increase in perceived importance, from time of starting treatment to time of survey among those diagnosed for ≥1 year, were minimizing the long term impact of antiretroviral treatment and keeping the number of medicines in their antiretroviral regimen at a minimum. Tailored approaches to care of PLHIV are needed as different regions have different disease burden and treatment needs. Equitable approaches to HIV care are needed across and within regions to ensure that patients' unmet needs and preferences are addressed to improve their overall wellbeing and health-related quality of life.

Metabolic factors and post-traumatic arthritis may influence the increased rate of surgical site infection in patients with human immunodeficiency virus following total hip arthroplasty.

BACKGROUND: The impact of CD4+ T-cell count and highly active antiretroviral therapy (HAART) on the rate of surgical site infection (SSI) in patients with human immunodeficiency virus (HIV) undergoing total hip arthroplasty is still unclear. The goals of this study were to assess the rate of perioperative infection at a large tertiary care referral center and to identify risk factors in HIV+ patients undergoing total hip arthroplasty (THA). METHODS: This study was a prospective, observational study at a single medical center from 2000-2017. Patients who were HIV+ and underwent THA were followed from the preoperative assessment period, through surgery and for a 2-year follow-up period. RESULTS: Sixteen of 144 HIV+ patients (11%) undergoing THA developed perioperative surgical site infections. Fourteen patients (10%) required revision THA within a range of 12 to 97 days after the initial surgery. The patients' mean age was 49.6 ± 4.5 years, and the most common diagnosis prompting THA was osteonecrosis (96%). Patients who developed SSI had a lower waist-hip ratio (0.86 vs. 0.93, p = 0.047), lower high density lipoprotein cholesterol (45.8 vs. 52.5, p = 0.015) and were more likely to have post-traumatic arthritis (12.5% vs. 0%, p = 0.008). Logistic regression analysis demonstrated that current alcohol use and higher waist-hip ratio were significant protectors against infection (p < 0.05). No other demographic, medical, immunologic parameters, or specific HAART regimens were associated with perioperative infection. CONCLUSIONS: Immunologic status as measured by CD4+ cell count, HIV viral load, and medical therapy do not appear to influence the development of SSI in HIV+ patients undergoing THA. Metabolic factors and post-traumatic arthritis may influence the increased rate of infection in HIV+ patients following THA.

Prevalence, determinants, and impact of suboptimal adherence to HIV medication in 25 countries.

Modern antiretroviral therapy (ART) has improved the lives of people living with HIV (PLHIV) but currently requires daily adherence. We assessed prevalence and correlates of suboptimal adherence, and measured associations with self-reported health outcomes. Data were from web-based surveys of confirmed HIV+ adults on antiretroviral treatment within 25 countries during 2019 (n = 2389). Suboptimal adherence was a report of ≥1 reason for missing ART ≥5 times within the past month. Multivariable logistic regression examined associations between suboptimal adherence and self-reported overall health and virologic suppression. Overall, 24.1% (575/2389) reported suboptimal adherence, from 10.0% (5/50) in Austria, to 62.0% (31/50) in China. The most common reasons for missing ART ≥5 times in the overall population were feeling depressed/overwhelmed (7.4%, 176/2389), trying to forget about HIV (7.0%, 168/2389), and work (6.1%, 145/2389). Correlates of suboptimal adherence included being heterosexual, <50 years old, ≤high school, having gastrointestinal treatment side effects, and privacy concerns. Odds of suboptimal overall health were 1.41 (95%CI, 1.11-1.80), 2.10 (95%CI, 1.65-2.68), and 2.55 (95%CI, 2.00-3.25) among those who reported the maximum number of times missed ART for any reason within the past month as 1, 2-4, or ≥5 times respectively, vs not missing at all. Odds of virologic nonsuppression were 1.80 (95%CI, 1.33-2.45), and 2.24 (95%CI, 1.66-3.02) for 2-4, or ≥5 times of missed ART respectively, vs not missing at all; missing for only 1 time was not significantly associated with virologic nonsuppression. Novel ART strategies designed to improve adherence along with interventions to empower PLHIV and support self-medication may improve health outcomes and quality of life.

A Call to Action: The Role of Antiretroviral Stewardship in Inpatient Practice, a Joint Policy Paper of the Infectious Diseases Society of America, HIV Medicine Association, and American Academy of HIV Medicine.

Persons living with human immunodeficiency virus (HIV) and others receiving antiretrovirals are at risk for medication errors during hospitalization and at transitions of care. These errors may result in adverse effects or viral resistance, limiting future treatment options. A range of interventions is described in the literature to decrease the occurrence or duration of medication errors, including review of electronic health records, clinical checklists at care transitions, and daily review of medication lists. To reduce the risk of medication-related errors, antiretroviral stewardship programs (ARVSPs) are needed to enhance patient safety. This call to action, endorsed by the Infectious Diseases Society of America, the HIV Medicine Association, and the American Academy of HIV Medicine, is modeled upon the success of antimicrobial stewardship programs now mandated by the Joint Commission. Herein, we propose definitions of ARVSPs, suggest resources for ARVSP leadership, and provide a summary of published, successful strategies for ARVSP that healthcare facilities may use to develop locally appropriate programs.

Despite early Medicaid expansion, decreased durable virologic suppression among publicly insured people with HIV in Washington, DC: a retrospective analysis.

BACKGROUND: Despite widely available access to HIV care in Washington, DC, inequities in HIV outcomes persist. We hypothesized that laboratory monitoring and virologic outcomes would not differ significantly based on insurance type. METHODS: We compared HIV monitoring with outcomes among people with HIV (PWH) with private (commercial payer) versus public (Medicare, Medicaid) insurance receiving care at community and hospital clinics. The DC Cohort follows over 8000 PWH from 14 clinics. We included those ≥18 years old enrolled between 2011 and 2015 with stable insurance. Outcomes included frequency of CD4 count and HIV RNA monitoring (> 2 lab measures/year, > 30 days apart) and durable viral suppression (VS; HIV RNA < 50 copies/mL at last visit and receiving antiretroviral therapy (ART) for ≥12 months). Multivariable logistic regression models examined impact of demographic and clinical factors. RESULTS: Among 3908 PWH, 67.9% were publicly-insured and 58.9% attended community clinics. Compared with privately insured participants, a higher proportion of publicly insured participants had the following characteristics: female sex, Black race, heterosexual, unemployed, and attending community clinics. Despite less lab monitoring, privately-insured PWH had greater durable VS than publicly-insured PWH (ART-naïve: private 70.0% vs public 53.1%, p = 0.03; ART-experienced: private 80.2% vs public 69.4%, p < 0.0001). Privately-insured PWH had greater durable VS than publicly-insured PWH at hospital clinics (AOR = 1.59, 95% CI: 1.20, 2.12; p = 0.001). CONCLUSIONS: Paradoxical differences between HIV monitoring and durable VS exist among publicly and privately-insured PWH in Washington, DC. Programs serving PWH must improve efforts to address barriers creating inequity in HIV outcomes.

BCL-2 antagonism sensitizes cytotoxic T cell-resistant HIV reservoirs to elimination ex vivo.

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4+ T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets in ex vivo CD4+ T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.

Integrated Assessment of Viral Transcription, Antigen Presentation, and CD8+ T Cell Function Reveals Multiple Limitations of Class I-Selective Histone Deacetylase Inhibitors during HIV-1 Latency Reversal.

Clinical trials investigating histone deacetylase inhibitors (HDACi) to reverse HIV-1 latency aim to expose reservoirs in antiretroviral (ARV)-treated individuals to clearance by immune effectors, yet have not driven measurable reductions in the frequencies of infected cells. We therefore investigated the effects of the class I-selective HDACi nanatinostat and romidepsin on various blocks to latency reversal and elimination, including viral splicing, antigen presentation, and CD8+ T cell function. In ex vivo CD4+ T cells from ARV-suppressed individuals, both HDACi significantly induced viral transcription, but not splicing nor supernatant HIV-1 RNA. In an HIV-1 latency model using autologous CD8+ T cell clones as biosensors of antigen presentation, neither HDACi-treated CD4+ T cell condition induced clone degranulation. Both HDACi also impaired the function of primary CD8+ T cells in viral inhibition assays, with nanatinostat causing less impairment. These findings suggest that spliced or cell-free HIV-1 RNAs are more indicative of antigen expression than unspliced HIV-RNAs and may help to explain the limited abilities of HDACi to generate CD8+ T cell targets in vivoIMPORTANCE Antiretroviral (ARV) drug regimens suppress HIV-1 replication but are unable to cure infection. This leaves people living with HIV-1 burdened by a lifelong commitment to expensive daily medication. Furthermore, it has become clear that ARV therapy does not fully restore health, leaving individuals at elevated risk for cardiovascular disease, certain types of cancers, and neurocognitive disorders, as well as leaving them exposed to stigma. Efforts are therefore under way to develop therapies capable of curing infection. A key focus of these efforts has been on a class of drugs called histone deacetylase inhibitors (HDACi), which have the potential of exposing hidden reservoirs of HIV-1 to elimination by the immune system. Unfortunately, clinical trial results with HDACi have thus far been disappointing. In the current study, we integrate a number of experimental approaches to build a model that provides insights into the limited activity of HDACi in clinical trials and offers direction for future approaches.

Transgender and Nontrans Patients Do Not Receive Statistically Different Quality Primary Care at Whitman-Walker Health, 2008-2016.

Purpose: Washington, DC, has the highest prevalence of transgender persons in the United States at 2.8%. Transgender persons in DC have lower income, less stable housing, and more HIV infection than nontrans persons. Data are scarce regarding primary care quality among trans persons. We provide a detailed analysis of transgender patients at Whitman-Walker Health, an HIV- and LGBT-focused community health center. Methods: We performed a retrospective electronic medical record review of transgender patients ≥18 years of age from 2008 to 2016, evaluating demographic factors, HIV status, gender-affirming care, and primary care quality indicators. Results: Of 20,097 patients, 1822 (9.0%) self-identify as transgender (62.9% trans female and 37.2% trans male), and 18,275 were nontransgender. Transgender patients are more likely to be young, white, HIV negative, and reside outside Washington, DC, than nontrans patients. Transgender patients are more likely to engage in primary care and have a similar likelihood of mammogram and colonoscopy screening than nontrans patients. Trans males are more likely to be privately insured, have lower rates of HIV testing than nontrans patients, and have higher rates of cervical Pap smears than cis females. Trans females have a high prevalence of HIV infection (26.6%). Conclusion: This is the largest single-center U.S. transgender cohort to date. Over a quarter of trans females are HIV positive, consistent with a national prevalence of 27.7%. Transgender and nontrans patients do not receive statistically different quality of primary care. Trans patients' high engagement in primary care may result from providing hormone therapy and primary care within a single provider visit.

Spectrum of Diversity in Today's Infectious Diseases Workforce: It's Much Broader and Brighter Than You Think.

The spectrum of inclusion, diversity, access, and equity among the Infectious Diseases (ID) workforce is ever-growing, ever-evolving, and continuously benefiting from the contributions made by the unique differences among our workforce which make us stronger, smarter, and better prepared to respond to whatever emerging ID challenge we will encounter next.

A Gap Between Willingness and Uptake: Findings From Mixed Methods Research on HIV Prevention Among Black and Latina Transgender Women.

BACKGROUND: Black and Latina transgender women (BLTW) face significant HIV disparities with estimated HIV prevalence up to 50% and annual incidence rates as high as 2.8 per 100 person-years. However, few studies have evaluated the acceptability and uptake of high-impact HIV prevention interventions among BLTW. SETTING: Data collection took place in Baltimore, MD and Washington, DC from May 2015 to May 2017. METHODS: This mixed methods study included quantitative interviewer-administered surveys, key informant interviews, and focus group discussions. Rapid HIV testing followed each survey. Logistic regression models tested associations between legal gender affirmation (ie, desired name and gender marker on identity documents), transgender pride, history of exchange sex, HIV risk perception, and willingness to take pre-exposure prophylaxis (PrEP). Transcripts of qualitative data were coded to identify common themes related to engagement in HIV prevention. RESULTS: Among 201 BLTW, 56% tested HIV-positive and 87% had heard of PrEP. Only 18% who had heard of PrEP had ever taken it. Of the 72 self-reported HIV-negative or status-unknown BLTW who had never taken PrEP, 75% were willing to take it. In multivariable analyses, history of exchange sex was associated with willingness to take PrEP, whereas greater HIV knowledge and transgender pride were associated with lower likelihood of willingness to take PrEP. Concern about drug interactions with hormone therapy was the most frequently reported barrier to PrEP uptake. CONCLUSIONS: Noting the disconnect between PrEP willingness and uptake among BLTW, HIV prevention programs could bridge this gap by responding to identified access barriers and incorporating community-derived strategies.

Serological Assessment of 18 Pathogens and Risk of AIDS-Associated Non-Hodgkin Lymphoma.

BACKGROUND: HIV infection is associated with increased susceptibility to common pathogens, which may trigger chronic antigenic stimulation and hyperactivation of B cells, events known to precede the development of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL). METHODS: To explore whether cumulative exposure to infectious agents contributes to AIDS-NHL risk, we tested sera from 199 AIDS-NHL patients (pre-NHL, average lead time 3.9 years) and 199 matched HIV-infected controls from the Multicenter AIDS Cohort Study, for anti-IgG responses to 18 pathogens using multiplex serology. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models. RESULTS: We found no association between cumulative exposure to infectious agents and AIDS-NHL risk (OR 1.01, 95% CI: 0.91 to 1.12). However, seropositivity for trichodysplasia spinulosa polyomavirus (TSPyV), defined as presence of antibodies to TSPyV capsid protein VP1, was significantly associated with a 1.6-fold increase in AIDS-NHL risk (OR 1.62, 95% CI: 1.02 to 2.57). High Epstein-Barr virus (EBV) anti-VCA p18 antibody levels closer to the time of AIDS-NHL diagnosis (<4 years) were associated with a 2.6-fold increase in AIDS-NHL risk (OR 2.59, 95% CI: 1.17 to 5.74). In addition, high EBV anti-EBNA-1 and anti-ZEBRA antibody levels were associated with 2.1-fold (OR 0.47, 95% CI: 0.26 to 0.85) and 1.6-fold (OR 0.57, 95% CI: 0.35 to 0.93) decreased risk of AIDS-NHL, respectively. CONCLUSIONS: Our results do not support the hypothesis that cumulative exposure to infectious agents contributes to AIDS-NHL development. However, the observed associations with respect to TSPyV seropositivity and EBV antigen antibody levels offer additional insights into the pathogenesis of AIDS-NHL.

Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus-Seropositive Patients.

Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus-accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation.