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BackgroundHIV testing rates among South African men lag behind rates for women and national targets. Community-based HIV self-screening (HIVSS) distribution and follow-up by community health workers (CHWs) is a scalable option to increase testing coverage, diagnosis, and treatment initiation. We provided HIVSS and assisted linkage to care to men not recently tested (within the past 12 months) residing in high-HIV-burden areas of Johannesburg.MethodsCHWs distributed HIVSS in 6 clinic catchment areas. Follow-up to encourage confirmatory testing and antiretroviral therapy initiation was conducted through personal support (PS) or an automated short message service (SMS) follow-up and linkage system in 3 clinic areas each. Using a quasi-experimental pre-post design, we compared differences in the proportion of men testing in the clinic catchment areas during the HIVSS campaign (June-August 2019) to the 3 months prior (March-May 2019) and compared treatment initiations by assisted linkage strategy.ResultsAmong 4793 participants accepting HIVSS, 62% had never tested. Among 3993 participants with follow-up data, 90.6% reported using their HIVSS kit. Testing coverage among men increased by 156%, from under 4% when only clinic-based HIV testing services were available to 9.5% when HIVSS and HIV testing services were available (z = -11.6; P < 0.01). Reported test use was higher for men followed through PS (99% vs. 68% in SMS); however, significantly more men reported reactive self-test results in the SMS group compared with PS (6.4% vs. 2.0%), resulting in more antiretroviral therapy initiations in the SMS group compared with PS (23 vs. 9; P < 0.01).ConclusionsCHW HIVSS distribution significantly increases testing among men. While PS enabled personalized follow-up, reporting differences indicate SMS is more acceptable and better aligned with expectations of privacy associated with HIVSS.

ObjectivePeople with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DL CO ), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DL CO . However, the underpinning molecular mechanisms of HIV-associated impaired DL CO are largely unknown.DesignCross-sectional pilot study with PWH with normal DL CO (values greater than or equal to the lower limit of normal, DL CO  ≥ LLN, N = 9) or abnormal DL CO (DL CO

Language barriers are major obstacles that Asian American immigrants face when accessing health care in the USA. This study was conducted to explore the impact of language barriers and facilitators on the health care of Asian Americans. Qualitative, in-depth interviews and quantitative surveys were conducted with 69 Asian Americans (Chinese, Filipino, Japanese, Malaysian, Indonesian, Vietnamese, and mixed Asian backgrounds) living with HIV (AALWH) in three urban areas (New York, San Francisco, and Los Angeles) in 2013 and from 2017 to 2020. The quantitative data indicate that language ability is negatively associated with stigma. Major themes emerged related to communication, including the impact of language barriers on HIV care and the positive impact of language facilitators-family members/friends, case managers, or interpreters-who can communicate with healthcare providers in the AALWH's native language. Language barriers negatively impact access to HIV-related services and thus result in decreased adherence to antiretroviral therapy, increased unmet healthcare needs, and increased HIV-related stigma. Language facilitators enhanced the connection between AALWH and the healthcare system by facilitating their engagement with health care providers. Language barriers experienced by AALWH not only impact their healthcare decisions and treatment choices but also increase levels of external stigma which may influence the process of acculturation to the host country. Language facilitators and barriers to health services for AALWH represent a target for future interventions in this population.

Across sub-Saharan Africa, men are less likely to know their HIV status than women, leading to later treatment initiation. Little is known about how experiences with general health services affect men's use of HIV testing. We used data from a 2019 community-representative survey of men in Malawi to understand frequency and cause of men's negative health service experiences (defined as men reporting they "would not recommend" a facility) and their association with future HIV testing. We conducted univariable and multivariable logistic regressions to determine which aspects of health facility visits were associated with would-not-recommend experiences and to determine if would-not-recommend experiences 12-24 months prior to the survey were associated with HIV testing in the 12 months prior to the survey. Among 1,098 men eligible for HIV testing in the 12 months prior to the survey, median age was 34 years; 9% of men reported at least one would-not-recommend experience, which did not differ by sociodemographics, gender norm beliefs, or HIV stigma beliefs. The factors most strongly associated with would-not-recommend experiences were cost (aOR 5.8, 95%CI 2.9-11.4), cleanliness (aOR 4.2, 95%CI 1.8-9.9), medicine availability (aOR 3.3, 95%CI 1.7-6.4), and wait times (aOR 2.7, 95%CI 1.5-5.0). Reporting a would-not-recommend experience 12-24 months ago was associated with a 59% decrease in likelihood of testing for HIV in the last 12 months (aOR 0.41; 95% CI:0.17-0.96). Dissatisfaction with general health services was strongly associated with reduced HIV testing. Coverage of high-priority screening services like HIV testing may benefit from improving overall health system quality.

ObjectivesSome drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses.DesignTo investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals.MethodsWe tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay).ResultsObatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects.ConclusionObatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.

Continuum of care is a concept that has been widely applied in HIV prevention and treatment studies. However, measuring care continuum can be challenging because it involves multiple stages and multiple components or domains at each stage of care. In this study, we introduced an analytical framework to (1) estimate intervention effects overall and by domain using a multi-level modeling approach, and (2) learn possible patterns of domains over time utilizing a multi-layer heatmap visualization. Longitudinal data from an intervention study conducted among people who use drugs in Vietnam were used to construct Seek, Test, Treat, and Retain (STTR) domain and overall scores. Findings from the adjusted analysis showed that people who use drugs in the intervention exhibited a significantly greater improvement in the overall STTR score than those in the control (p-values < .0001). The multi-layer heatmap revealed different patterns of the individual domains over time and the inter-relationships among the individual domains. This study demonstrates the feasibility of constructing a general fulfillment score and domain specific scores to measure care continuum among people who use drugs. The analytical framework can be readily extended to evaluate service fulfillment outcomes in health services and treatment studies for other key populations.

IntroductionIdentifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models.MethodsIn-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes.ResultsIndividuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure.ConclusionsDiverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

IntroductionThere is little HIV counselling that directly meets the needs of men in Eastern and Southern Africa, limiting men's knowledge about the benefits of HIV treatment and how to overcome barriers to engagement, contributing to poorer HIV-related outcomes than women. Male-specific approaches are needed to improve men's outcomes but may be difficult for healthcare workers (HCWs) to implement with fidelity and quality in low-resource settings. We developed a male-specific counselling curriculum which was implemented by male HCWs and then conducted a mixed-methods quality assessment.MethodsWe audio-recorded counselling sessions to assess the quality of implementation (n = 50) by male HCWs from two cadres (nurse, n = 10 and lay cadre, n = 10) and conducted focus group discussions (FGDs) with HCWs at 6 and 9 months after rollout to understand barriers and facilitators to implementation. Counselling sessions and FGDs were translated, transcribed and analysed using thematic analysis adapted from WHO Quality Counselling Guidelines. We assessed if sessions were respectful, informative, interactive, motivating and included tailored action plans for overcoming barriers to care. All data were collected September 2021-June 2022.ResultsAll sessions used respectful, non-judgemental language. Sessions were highly interactive with most HCWs frequently asking open-ended questions (n = 46, 92%) and often incorporating motivational explanations of how antiretroviral therapy contributes to life goals (n = 42, 84%). Few sessions included individually tailored action plans for clients to overcome barriers to care (n = 9, 18%). New counselling themes were well covered; however, occasionally themes of self-compassion and safe sex were not covered during sessions (n = 16 and n = 11). HCWs believed that having male HCWs conduct counselling, ongoing professional development and keeping detailed counselling notes facilitated quality implementation. Perceived barriers included curriculum length and client hesitancy to participate in action plan development. Findings were similar across cadres.ConclusionsImplementing high-quality male-specific counselling using male nurses and/or lay cadre is feasible. Efforts to utilize lay cadres should be prioritized, particularly in low-resource settings. Programmes should provide comprehensive job aids to support HCWs. Ongoing training and professional development are needed to (1) improve HCWs' skills in tailored action plans, and (2) sensitize HCWs to the need for self-compassion within male clients to promote holistic sexual health.

ObjectiveHIV treatment regimen during pregnancy was associated with preterm delivery (PTD) in the PROMISE 1077 BF trial. Systemic inflammation among pregnant women with HIV could help explain differences in PTD by treatment regimen. We assessed associations between inflammation, treatment regimen, and PTD.Design/methodsA nested 1 : 1 case-control study ( N  = 362) was conducted within a multicountry randomized trial comparing three HIV regimens in pregnant women: zidovudine alone, or combination antiretroviral therapy (ART) with lopinavir/ritonavir and either zidovudine or tenofovir. Cases were women with PTD (

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

BACKGROUNDEarly antiretroviral therapy initiation (ARTi) in HIV-1 restricts reservoir size and diversity while preserving immune function, potentially improving opportunities for immunotherapeutic cure strategies. For antibody-based cure approaches, the development of autologous neutralizing antibodies (anAbs) after acute/early ARTi is relevant but is poorly understood.METHODSWe characterized antibody responses in a cohort of 23 participants following ARTi in acute HIV (

IntroductionAdverse sexual and reproductive health (SRH) outcomes, such as unplanned pregnancies and HIV infection, disproportionately affect adolescent girls and young women (AGYW; aged 15-24 years) in east Africa. Increasing uptake of preventive SRH services via innovative, youth-centred interventions is imperative to addressing disparities in SRH outcomes.Methods and analysisFrom 2018 to 2019, we used human-centred design to co-develop a theoretically driven HIV and pregnancy prevention intervention for AGYW at private drug shops called Accredited Drug Dispensing Outlets (ADDOs) in Tanzania. The result, Malkia Klabu (Queen Club), was a customer loyalty programme designed to strengthen ADDOs' role as SRH providers while encouraging uptake of critical SRH prevention products among AGYW. Malkia Klabu members had access to free contraceptives and oral HIV self-test (HIVST) kits and earned punches on a loyalty card for other shop purchases; punches were redeemable for small prizes. Our pilot among 40 shops showed that intervention ADDOs had higher AGYW patronage and distributed more HIVST kits and contraceptives to AGYW relative to business-as-usual (ie, client purchasing) comparison shops. We will conduct a cluster-randomised controlled trial (c-RCT) among 120-140 ADDOs in 40 health catchment areas in Shinyanga and Mwanza Regions (Lake Zone), Tanzania. ADDO shop recruitment includes a 1-month run-in with a tablet-based electronic inventory management system for tracking shop transactions, followed by enrolment, randomisation and a 24-month trial period. Our c-RCT evaluating the human-centred design-derived intervention will assess population impact on the primary outcomes of HIV diagnoses and antenatal care registrations, measured with routine health facility data. We will also assess secondary outcomes focusing on mechanisms of action, evaluate programme exposure and AGYW behaviour change in interviews with AGYW, and assess shop-level implementation strategies and fidelity.Ethics and disseminationEthical approval was granted from both the University of California, San Francisco and the Tanzanian National Institute for Medical Research. Study progress and final outcomes will be posted annually to the National Clinical Trials website; study dissemination will occur at conferences, peer-reviewed manuscripts and local convenings of stakeholders.Trial registration numberNCT05357144.

IntroductionGlobally, transgender ('trans') women experience extreme social and economic marginalisation due to intersectional stigma, defined as the confluence of stigma that results from the intersection of social identities and positions among those who are oppressed multiple times. Among trans women, gender-based stigma intersects with social positions such as engagement in sex work and substance use, as well as race-based stigma to generate a social context of vulnerability and increased risk of HIV acquisition. In Brazil, trans women are the 'most at-risk' group for HIV, with 55 times higher estimated odds of HIV infection than the general population; further, uptake of HIV testing and pre-exposure prophylaxis (PrEP) among trans women is significantly lower than other at-risk groups. Through extensive formative work, we developed Manas por Manas, a multilevel intervention using HIV prevention strategies with demonstrated feasibility and acceptability by trans women in Brazil, to address intersectional stigma and increase engagement in the HIV prevention continuum.Methods and analysisWe are conducting a two-arm randomised wait-list controlled trial of the intervention's efficacy in São Paulo, Brazil, to improve uptake of HIV testing and PrEP among transgender women (N=400). The primary outcomes are changes in HIV testing (self-testing and clinic based), changes in PrEP uptake and changes in PrEP persistence at baseline and follow-up assessment for 12 months at 3-month intervals.Ethics and disseminationThis study was approved by University of California, San Francisco Institutional Review Board (15-17910) and Comissão Nacional de Ética em Pesquisa (Research Ethics National Commission, CAAE: 25215219.8.0000.5479) in Brazil. Participants provided informed consent before enrolment. We are committed to collaboration with National Institutes of Health officials, other researchers, and health and social services communities for rapid dissemination of data and sharing of materials. The results will be published in peer-reviewed academic journals and scientific presentations.Trial registration numberNCT03081559.

Purpose of reviewCannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV.Recent findingsResults revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.

Developmental assets are critical to the health and wellbeing of youth. The current study examines the influence of developmental assets on PrEP use and HIV testing among YBMSM ages 18-24. Using a cross-sectional survey of YBMSM (N = 225), this study explored the role of external (e.g., family support, other adult support) and internal (e.g., personal responsibility) assets in explaining HIV prevention behaviors. Participants were recruited from Mechanical Turk (M-Turk) internet-based platform, social media sites, and community-based organizations. A path analysis was conducted to investigate the direct/indirect effects of internal and external assets on PrEP use and HIV testing. Family support (β = 0.40, p

Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.

BackgroundLong-acting (LA) antiretrovirals may provide meaningful benefit to people who use drugs and people experiencing homelessness (PEH) who face disproportionate structural and psychosocial barriers in adhering to daily oral HIV antiretroviral therapy or pre-exposure prophylaxis (PrEP), but their use in these populations has not been studied.SettingThe Maria X. Martinez Health Resource Center is a low-barrier (eg, no appointment) community-based clinic serving San Francisco PEH.MethodsA multidisciplinary care model with robust monitoring and outreach support was developed to provide LA antiretroviral therapy (ART) and LA-PrEP to eligible patients experiencing difficulties adhering to oral antiretrovirals. Feasibility was assessed by evaluating the rates of HIV viremia and on-time injections among patients receiving LA antiretrovirals over the first 24 months of program implementation.ResultsBetween November 2021 and November 2023, 33 patients initiated LA-ART or LA-PrEP (median age, 37 years; 27% transgender/nonbinary; 73% non-White; 27% street homeless; 52% sheltered homeless; 30% with opioid use disorder; 82% with methamphetamine use disorder). Among 18 patients with HIV, 14 initiated LA-ART injections with detectable viremia (median CD4 count, 340 cells/mm 3 ; mean log 10 viral load, 3.53; SD, 1.62), 8 had never previously been virally suppressed, and all but 1 achieved or maintained virologic suppression (mean, 9.67 months; SD, 8.30). Among 15 LA-PrEP patients, all remained HIV negative (mean, 4.73 months; SD, 2.89). Of 224 total injections administered, 8% were delayed >7 days.DiscussionThe implementation of LA antiretrovirals is feasible in low-barrier, highly supportive clinical settings serving vulnerable PEH. Expansion of such programs will be critical in ending the HIV epidemic.

BackgroundPregnant and postpartum women in Sub-Saharan Africa are at high risk of HIV acquisition. We evaluated a person-centered dynamic choice intervention for HIV prevention (DCP) among women attending antenatal and postnatal care.SettingRural Kenya and Uganda.MethodsWomen (aged 15 years or older) at risk of HIV acquisition seen at antenatal and postnatal care clinics were individually randomized to DCP vs. standard of care (SEARCH; NCT04810650). The DCP intervention included structured client choice of product (daily oral pre-exposure prophylaxis or postexposure prophylaxis), service location (clinic or out of facility), and HIV testing modality (self-test or provider-administered), with option to switch over time and person-centered care (phone access to clinician, structured barrier assessment and counseling, and provider training). The primary outcome was biomedical prevention coverage-proportion of 48-week follow-up with self-reported pre-exposure prophylaxis or postexposure prophylaxis use, compared between arms using targeted maximum likelihood estimation.ResultsBetween April and July 2021, we enrolled 400 women (203 intervention and 197 control); 38% were pregnant, 52% were aged 15-24 years, and 94% reported no pre-exposure prophylaxis or postexposure prophylaxis use for ≥6 months before baseline. Among 384/400 participants (96%) with outcome ascertained, DCP increased biomedical prevention coverage 40% (95% CI: 34% to 47%; P < 0.001); the coverage was 70% in intervention vs. 29% in control. DCP also increased coverage during months at risk of HIV (81% in intervention, 43% in control; 38% absolute increase; 95% CI: 31% to 45%; P < 0.001).ConclusionA person-centered dynamic choice intervention that provided flexibility in product, testing, and service location more than doubled biomedical HIV prevention coverage in a high-risk population already routinely offered access to biomedical prevention options.

During HIV infection of CD4+ T cells, ubiquitin pathways are essential to viral replication and host innate immune response; however, the role of specific E3 ubiquitin ligases is not well understood. Proteomics analyses identified 116 single-subunit E3 ubiquitin ligases expressed in activated primary human CD4+ T cells. Using a CRISPR-based arrayed spreading infectivity assay, we systematically knocked out 116 E3s from activated primary CD4+ T cells and infected them with NL4-3 GFP reporter HIV-1. We found 10 E3s significantly positively or negatively affected HIV infection in activated primary CD4+ T cells, including UHRF1 (pro-viral) and TRAF2 (anti-viral). Furthermore, deletion of either TRAF2 or UHRF1 in three JLat models of latency spontaneously increased HIV transcription. To verify this effect, we developed a CRISPR-compatible resting primary human CD4+ T cell model of latency. Using this system, we found that deletion of TRAF2 or UHRF1 initiated latency reactivation and increased virus production from primary human resting CD4+ T cells, suggesting these two E3s represent promising targets for future HIV latency reversal strategies.ImportanceHIV, the virus that causes AIDS, heavily relies on the machinery of human cells to infect and replicate. Our study focuses on the host cell's ubiquitination system which is crucial for numerous cellular processes. Many pathogens, including HIV, exploit this system to enhance their own replication and survival. E3 proteins are part of the ubiquitination pathway that are useful drug targets for host-directed therapies. We interrogated the 116 E3s found in human immune cells known as CD4+ T cells, since these are the target cells infected by HIV. Using CRISPR, a gene-editing tool, we individually removed each of these enzymes and observed the impact on HIV infection in human CD4+ T cells isolated from healthy donors. We discovered that 10 of the E3 enzymes had a significant effect on HIV infection. Two of them, TRAF2 and UHRF1, modulated HIV activity within the cells and triggered an increased release of HIV from previously dormant or "latent" cells in a new primary T cell assay. This finding could guide strategies to perturb hidden HIV reservoirs, a major hurdle to curing HIV. Our study offers insights into HIV-host interactions, identifies new factors that influence HIV infection in immune cells, and introduces a novel methodology for studying HIV infection and latency in human immune cells.

Purpose: We assessed whether anticipated stigma (i.e., fear of public mistreatment due to gender identity) impacts communication between transgender women (TGW) living with HIV and health care providers. Methods: This is a secondary analysis of baseline data from Trans Amigas, a study conducted in Brazil, 2018. The study population consisted of TGW living with HIV, older than 18 years, residing in the São Paulo metropolitan area. We used multivariable logistic regression (α = 0.05), mediation, and bootstrapping for the analysis. Results: One hundred and thirteen participants completed the study. Fear of public mistreatment had an adjusted odds ratio (aOR) of 7.42 (p = 0.003) for difficulty reporting new symptoms to providers. Concerning fear of public mistreatment, we found that unemployment had an aOR of 3.62 (p = 0.036); sex work, an aOR of 2.95 (p = 0.041); and issues related to name change in documents, an aOR of 2.71 (p = 0.033). For the indirect effect on difficulty reporting new symptoms, mediated by fear of public mistreatment, unemployment had an aOR of 1.52 (confidence interval [CI] = 0.88-2.24); sex work, an aOR of 1.48 (CI = 0.81-2.52); and name change issues, an aOR of 1.47 (CI = 0.96-2.43). Conclusions: Anticipated stigma was associated with communication difficulties between TGW living with HIV and providers. Our data suggest that structural factors associated with anticipated stigma could indirectly impact on difficulty reporting new symptoms. These findings indicate the importance of considering social contexts that intersect with individual experiences when analyzing communication barriers between providers and patients, and the need to strengthen social policies for TGW in Brazil. Clinical Trial Registration number: R34MH112177.

Unhealthy alcohol use, which encompasses heavy episodic drinking to alcohol use disorder, has been identified as a modifiable barrier to optimal HIV care continuum outcomes. Despite the demonstrated efficacy of couples-based interventions for addressing unhealthy alcohol use, there are no existing couples-based alcohol interventions designed specifically for people living with HIV. This study presents the development and refinement of a three-session couples-based motivational intervention (ReACH2Gether) to address unhealthy alcohol use among a sample of 17 sexual minority men living with HIV and their partners living in the United States. To increase potential population reach, the intervention was delivered entirely remotely. Throughout an original and a modified version, results indicated that the ReACH2Gether intervention was acceptable and there were no reports of intimate partner violence or adverse events. Session engagement and retention were high. In pre-post-test analyses, the ReACH2Gether intervention showed trends in reducing Alcohol Use Disorder Identification Test scores and increasing relationship-promoting dynamics, such as positive support behaviors and goal congruence around alcohol use. Results support the need for continued work to evaluate the ReACH2Gether intervention.

ObjectiveSexual and physical abuse predict cardiovascular disease (CVD) among women in the general population. Women living with HIV (WLWH) report more abuse and have higher CVD risk compared with other women, yet associations between abuse history and CVD have not been considered among WLWH. This study fills this gap, and describes possible pathways linking abuse to CVD risk among WLWH and women living without HIV (WLWOH).MethodsUsing 25 years of data from the Women's Interagency HIV Study (WIHS; n  = 2734; WLWH n  = 1963; WLWOH n  = 771), we used longitudinal generalized estimating equations (GEE) to test associations between sexual and physical abuse with CVD risk. Framingham (FRS-H) and the American College of Cardiology/American Heart Association-Pooled Cohort Equation (ACC/AHA-PCE) scores were examined. Analyses were stratified by HIV-serostatus.ResultsAmong WLWH, childhood sexual abuse was associated with higher CVD risk ( βFRS-H  = 1.25, SE = 1.08, P  = 0.005; βACC/AHA-PCE  = 1.14, SE = 1.07, P  = 0.04) compared with no abuse. Adulthood sexual abuse was associated with higher CVD risk for WLWH ( βFRS-H  = 1.39, SE = 1.08, P

ObjectivePregnant and postpartum women (PPW) in Southern Africa are at increased risk of acquiring HIV and curable sexually transmitted infections (STIs). Oral pre-exposure prophylaxis (PrEP) is safe and effective to use during pregnancy to reduce HIV acquisition and vertical transmission. Point-of-care (POC) STI testing can identify PPW at risk of HIV and facilitate risk-differentiated and person-centred counselling to improve PrEP initiation, persistence and adherence. We evaluated the impact of POC STI testing compared with STI syndromic management on PrEP outcomes among PPW in Cape Town, South Africa.MethodsThe STI and PrEP in Pregnancy Study enrolled PPW without HIV and ≤34 weeks pregnant at their regular antenatal care visit with follow-up after 1 month. PPW were randomised to receive POC STI testing or STI syndromic management. PPW randomised to POC STI testing self-collected vaginal swabs for Chlamydia trachomatis, Neisseria gonorhoeae and Trichomonas vaginalis (Cepheid GeneXpert) testing and were offered same-day treatment if diagnosed. We compared PrEP initiation at baseline, PrEP prescription refill at 1 month (persistence) and adherence through tenofovir-diphosphate detection in dried blood spots by randomisation arm. In a secondary analysis, we evaluated the association between an STI diagnosis (positive STI test or reporting STI symptoms) with PrEP outcomes.ResultsWe enrolled and randomised 268 pregnant women. Twenty-eight per cent of women were diagnosed with ≥1 STI. Overall, 65% of women initiated and 79% persisted on PrEP with no significant differences by randomisation arm. Secondary analysis demonstrated that an STI diagnosis (positive STI test or reporting STI symptoms) was associated with higher PrEP initiation (adjusted relative risk=1.28; 95% CI 1.08 to 1.52), controlling for arm, maternal and gestational age.ConclusionsPOC STI testing was not associated with PrEP initiation or persistence relative to syndromic management. However, improving STI diagnosis by supplementing syndromic management with POC STI testing could improve PrEP initiation among PPW.Trial registration numberNCT03902418; Clinical Trials.gov; 1 April 2019.

BackgroundPrEP, a biomedical HIV prevention option, continues to be underutilized among transgender women who could benefit from sustained use, especially women of color and those who identify as Latina and/or reside in the southeastern US.ObjectiveWe explored the barriers and facilitators experienced by transgender women who live in Florida regarding accessing, using, and/or staying on PrEP.MethodsIn-depth interviews and focus groups were conducted in either Spanish or English with adult transgender women living in Florida (N = 22). The interviews were audio-recorded, transcribed, and coded in ATLAS.ti using thematic analyses.ResultsThe mean age of the participants was 42.2 years. Among the participants, 73% were Hispanic/Latina, 59% were foreign-born, and approximately one-third were living with HIV (but had past experience with PrEP). Transgender women cited the following barriers to accessing or considering PrEP: (1) costs and benefits of PrEP use; (2) under-representation in clinical trials resulting in unknown or misinformation regarding PrEP side effects; (3) chronic poverty; and (4) trauma and discrimination. Other stressors, such as behavioral healthcare needs, were identified.ConclusionsOur analysis revealed interlocking systems of oppression like transphobia, discrimination, and misgendering, which were common barriers experienced by our participants. These synergistically epidemic (i.e., syndemic) barriers contributed to their feelings of being systematically excluded in social spaces, research, public health planning and policies, laws, and social programs related to PrEP. These structural barriers are impediments to HIV preventive care but also act as a source of stress that contributes to mental health problems, financial vulnerability, substance abuse, and other deleterious health outcomes.

Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA  LLQ) and with CSF/plasma discordance (CSF > plasma HIV RNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood-brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p

PurposeGay, bisexual, and other cisgender men who have sex with men, and racial minority youth are at elevated risk of acquiring HIV infection. The Adolescent Trials Network 147 recruited youth with acute/recent HIV-infection for early antiretroviral treatment. The cohort make-up is described here.MethodsTreatment-naïve, recently identified HIV + youth, aged 12-24 years, from Los Angeles and New Orleans were recruited from community centers, clinics, social media, and a high-risk seronegative cohort (n = 1,727, the Adolescent Trials Network 149) using point-of-care assays. Acute HIV infection was determined by Fiebig staging. HIV RNA viral load (VL) and CD4 cell counts, along with demographic and behavioral data were assessed at enrollment.ResultsBetween July 2017 and July 2021, 103 newly diagnosed youth were enrolled, initiating antiretroviral treatment within a week. Mean age was 20.8 years (standard deviation: 2.4); 90.3% identified as cis male, 83.5% were single or in casual relationships, 71.8% were gay, bisexual, and other cisgender men who have sex with men; 60.2% were Black. One-fourth (24.3%) reported homelessness ever; 10.7% within last 4 months. At enrollment, median plasma VL was 37,313 HIV RNA copies/ml (interquartile range: 5,849-126,162) and median CD4 count 445.5 cells/mm3 (interquartile range: 357-613). 40% of youth reported acute retroviral symptoms before or at enrollment. Acutely infected, seroconverting youth had the highest VL. Sexually transmitted coinfections were present at enrollment in 56% of the cohort, with syphilis being most frequent (39%).DiscussionEarly identification and treatment of HIV can increase positive HIV outcomes. A high sexually transmitted infection burden was present in recently HIV-infected youth. Acute retroviral symptoms were not reported by most participants, demonstrating that broad universal HIV screening is needed for identification of recent infection in youth.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Pharmacokinetic (PK) studies in children are usually small and have ethical constraints due to the medical complexities of drawing blood in this special population. Often, population PK models for the drug(s) of interest are available in adults, and these models can be extended to incorporate the expected deviations seen in children. As a consequence, there is increasing interest in the use of optimal design methodology to design PK sampling schemes in children that maximize information using a small sample size and limited number of sampling times per dosing period. As a case study, we use the novel tuberculosis drug delamanid, and show how applications of optimal design methodology can result in highly efficient and model-robust designs in children for estimating PK parameters using a limited number of sampling measurements. Using developed population PK models based on available data from adults living with and without HIV, and limited data on children without HIV, competing designs for children living with HIV were derived and assessed based on robustness to model uncertainty.

BackgroundFacility HIV self-testing (HIVST) in outpatient departments can dramatically increase testing among adult outpatients. However, it is still unclear why populations opt out of facility HIVST and reasons for opt outing. Using data from a parent facility HIVST trial, we sought to understand individual characteristics associated with opting out of facility HIVST and reported reasons for not testing.MethodsExit surveys were conducted with outpatients aged ≥15 years at 5 facilities in Central and Southern Malawi randomized to the facility HIVST arm of the parent trial. Outpatients were eligible for our substudy if they were offered HIVST and eligible for HIV testing (ie, never previously tested HIV positive and tested ≥12 months ago or never tested). Summary statistics and multivariate regression models were used.ResultsSeven hundred seventy-one outpatients were included in the substudy. Two hundred sixty-three (34%) opted out of HIVST. Urban residency (adjusted risk ratios [aRR] 3.48; 95% CI: 1.56 to 7.76) and self-reported poor health (aRR 1.86; 95% CI: 1.27 to 2.72) were associated with an increased risk of opting out. Male participants had a 69% higher risk of opting out (aRR 1.69; 95% CI: 1.14 to 2.51), with risk being 38% lower among working male participants. Primary reasons for not testing were feeling unprepared to test (49·4%) and perceived low risk of HIV infection (30·4%)-only 2.6% believed that HIVST instructions were unclear, and 1.7% were concerned about privacy.ConclusionWorking, risky sexual behavior, rural residence, and good self-rated health were positively associated with opting out of HIVST among outpatients. Strategies to address internalized barriers, such as preparedness to test and perceived need to test, should be incorporated into facility HIVST interventions.

RationaleHIV and cardiometabolic disorders including hypertension and diabetes pose a serious double threat in Malawi. Supportive couple relationships may be an important resource for managing these conditions. According to the theory of communal coping, couples will more effectively manage illness if they view the illness as "our problem" (shared illness appraisal) and are united in shared behavioral efforts.MethodsThis study qualitatively investigated communal coping of 25 couples living with HIV and hypertension or diabetes in Zomba, Malawi. Partners were interviewed separately regarding relationship quality, shared illness appraisal, communal coping, and dyadic management of illness.ResultsMost participants (80%) were living with HIV, and more than half were also living with hypertension. Most participants expressed high levels of unity and the view that illness was "our problem." In some couples, partners expected but did not extend help and support and reported little collaboration. Communal coping and dyadic management were strongly gendered. Some women reported a one-sided support relationship in which they gave but did not receive support. Women were also more likely to initiate support interactions and offered more varied support than men. In couples with poor relationship quality and weak communal coping, dyadic management of illness was also weak. Partner support was particularly crucial for dietary changes, as women typically prepared meals for the entire family. Other lifestyle changes that could be supported or hindered by a partner included exercise, stress reduction, and medication adherence.ConclusionWe conclude that gendered power imbalances may influence the extent to which couple-level ideals translate into actual communal coping and health behaviors. Given that spouses and families of patients are also at risk due to shared environments, we call for a shift from an illness management paradigm to a paradigm of optimizing health for spouses and families regardless of diabetes or hypertension diagnosis.

BackgroundElicitation of broad immune responses is understood to be required for an efficacious preventative HIV vaccine. This Phase 1 randomized controlled trial evaluated whether administration of vaccine antigens separated at multiple injection sites vs combined, fractional delivery at multiple sites affected T-cell breadth compared to standard, single site vaccination.MethodsWe randomized 90 participants to receive recombinant adenovirus 5 (rAd5) vector with HIV inserts gag, pol and env via three different strategies. The Standard group received vaccine at a single anatomic site (n = 30) compared to two polytopic (multisite) vaccination groups: Separated (n = 30), where antigens were separately administered to four anatomical sites, and Fractioned (n = 30), where fractions of each vaccine component were combined and administered at four sites. All groups received the same total dose of vaccine.FindingsCD8 T-cell response rates and magnitudes were significantly higher in the Fractioned group than Standard for several antigen pools tested. CD4 T-cell response magnitudes to Pol were higher in the Separated than Standard group. T-cell epitope mapping demonstrated greatest breadth in the Fractioned group (median 8.0 vs 2.5 for Standard, Wilcoxon p = 0.03; not significant after multiplicity adjustment for co-primary endpoints). IgG binding antibody response rates to Env were higher in the Standard and Fractioned groups vs Separated group.InterpretationThis study shows that the number of anatomic sites for which a vaccine is delivered and distribution of its antigenic components influences immune responses in humans.FundingNational Institute of Allergy and Infectious Diseases, NIH.

IntroductionThe Last Gift study at the University of California San Diego (UCSD), United States enrolls terminally ill people with HIV (PWH) in HIV cure research.MethodsFrom 2017 to 2022, we conducted surveys with Last Gift participants and their next-of-kin/loved ones to evaluate willingness to participate in different types of HIV cure research at the end of life (EOL). We analyzed willingness data descriptively.ResultsWe surveyed 17 Last Gift participants and 17 next-of-kin/loved ones. More than half of Last Gift participants ( n  = 10; 58.8%) expressed willingness to participate in studies involving totally new treatments or approaches ('first-in-human' studies), a combination of different approaches, the use of unique antibodies, proteins or molecules, or therapeutic vaccines. Under one-quarter of Last Gift participants ( n  = 4; 23.5%) expressed willingness to participate in research involving interventions that may shorten their life expectancy to benefit medical research. Most Last Gift participants and their next-of-kin/loved ones also expressed high acceptance for various types of donations and biopsies at the EOL (e.g. hair donations and skin, lymph node or gut biopsies).DiscussionKnowing whether people would be willing to participate in different types of EOL HIV cure research can help inform the design of future innovative studies. As a research community, we have a duty to design studies with adequate safeguards to preserve the public trust in research and honor PWH's important gift to humanity.

BackgroundThere is limited systematic information available about the perspectives of participants enrolled in intensive combination HIV cure-related trials inclusive of an extended analytical treatment interruption (ATI).ObjectiveTo assess and understand experiences of people with HIV involved in a combination HIV cure-related trial with an extended ATI.MethodsThe trial included five interventions and was followed by an ATI lasting up to 52 wk. From 2022 - 2023, we conducted in-depth interviews with study participants following their extended ATIs. Interviews were audio-recorded, transcribed, and analyzed via conventional thematic analysis.ResultsWe interviewed seven participants. The majority were male, White, and non-Hispanic, with a median age of 37 years. Trust in the research team, scientific altruism and hope of becoming a post-intervention controller were key motivators for joining the trial. Interviewees reported being satisfied with their decision to participate in the trial and the extended ATI. Most recounted feelings of worry related to viral rebound during the ATI. Participants reported both defeat and relief with ART restart. Four faced challenges with protecting partners from HIV during their ATI, such as trying to find out if their partner(s) were using pre-exposure prophylaxis.ConclusionsOur findings demonstrate potential improvements for future ATI trial participant experiences, such as more robust resources for psychosocial support and partner protections. Dedicating greater effort to understanding participant ATI experiences can inform the design of future participant-centered HIV cure trial protocols.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children

Background: Many clinical and population-based research studies pivoted from in-person assessments to phone-based surveys due to the COVID-19 pandemic. The impact of these transitions on survey response remains understudied, especially for people living with HIV. Given that there are gender-specific trends in alcohol and substance use, it is particularly important to capture these data for women.Objective: Identify factors associated with responding to an alcohol and substance use phone survey administered during the COVID-19 pandemic in the Women's Interagency HIV Study, a multicenter US prospective cohort of women living with and without HIV.Methods: We used multivariable logistic regression to assess for associations of pre-pandemic (April-September 2019) sociodemographic factors, HIV status, housing status, depressive symptoms, alcohol use, and substance use with response to an early-pandemic (August-September 2020) phone survey.Results: Of 1,847 women who attended an in-person visit in 2019, 78% responded to a phone survey during the pandemic. The odds of responding were lower for women of Hispanic ethnicity (aOR 0.47 95% CI 0.33-0.66, ref=Black/African American) and those who reported substance use (aOR 0.63 95% CI 0.41-0.98). By contrast, the odds were higher for White women (aOR 1.64 95% CI 1.02-2.70, ref=Black/African American) and those with stable housing (aOR 1.74 95% CI 1.24-2.43).Conclusions: Pivoting from an in-person to phone-administered alcohol and substance use survey may lead to underrepresentation of key subpopulations of women who are often neglected in substance use and HIV research. As remote survey methods become more common, investigators need to ensure that the study population is representative of the target population.

Black and Latinx transgender women in the United States (U.S.) are at disproportionately high risk for HIV. Although HIV pre-exposure prophylaxis (PrEP) reduces the risk of HIV infection, uptake and persistence (i.e., ability to continue taking PrEP over time) can be a challenge for Black and Latinx transgender women due to myriad social and structural forces. In this qualitative study, we present unique data on the facilitators of PrEP persistence from Black and Latinx transgender women who initiated PrEP and exhibited varying levels of persistence during a demonstration project in Southern California. PrEP persistence was assessed by collecting quantitative intracellular tenofovir-diphosphate (TFV-DP) levels on dried blood spot (DBS) samples collected at weeks 12 and 48. Informed by the socioecological framework, we conducted and analyzed interviews using qualitative content analysis to determine themes on the facilitators of PrEP persistence. Individual-level facilitators included the use of reminders, having high individual-level HIV risk perception, feeling empowered to take PrEP, and reporting having improved peace of mind and mental health because of taking PrEP. Interpersonal/Community-level facilitators included feeling motivation to prevent HIV in the community, motivation to prevent HIV in the context of sex work, and having high community-level risk perception. Structural-level facilitators included having positive experiences in affirming healthcare settings and having PrEP visits combined with other gender-related healthcare visits. Interventions aiming to increase PrEP uptake and persistence among Black and Latinx transgender women in the U.S. should harness the multiple levels of support exhibited by those who were able to start and persist on PrEP in the face of the myriad social and structural barriers.

As a proposed mediator between stigma-related stressors and negative mental health outcomes, HIV-related shame has been predictive of increased rates of substance use and difficulties adhering to antiretroviral treatment among people with HIV. These downstream manifestations have ultimately impeded progress toward national goals to End the HIV Epidemic, in part due to limited success of conventional psychotherapies in addressing HIV-related shame. In a pilot clinical trial (N = 12), receipt of psilocybin-assisted group therapy was associated with a large pre-post decrease in HIV-related shame as measured by the HIV and Abuse Related Shame Inventory, with a median (IQR) change of - 5.5 (- 6.5, - 3.5) points from baseline to 3-months follow-up (Z = - 2.6, p = 0.009, r = - 0.75). A paradoxical exacerbation of sexual abuse-related shame experienced by two participants following receipt of psilocybin raises critical questions regarding the use of psilocybin therapy among patients with trauma. These preliminary findings carry potential significance for the future of HIV care.

BackgroundImplementation science frameworks situate intervention implementation and sustainment within the context of the implementing organization and system. Aspects of organizational context such as leadership have been defined and measured largely within US health care settings characterized by decentralization and individual autonomy. The relevance of these constructs in other settings may be limited by differences like collectivist orientation, resource constraints, and hierarchical power structures. We aimed to adapt measures of organizational context in South African primary care clinics.MethodsWe convened a panel of South African experts in social science and HIV care delivery and presented implementation domains informed by existing frameworks and prior work in South Africa. Based on panel input, we selected contextual domains and adapted candidate items. We conducted cognitive interviews with 25 providers in KwaZulu-Natal Province to refine measures. We then conducted a cross-sectional survey of 16 clinics with 5-20 providers per clinic (N = 186). We assessed reliability using Cronbach's alpha and calculated interrater agreement (awg) and intraclass correlation coefficient (ICC) at the clinic level. Within clinics with moderate agreement, we calculated correlation of clinic-level measures with each other and with hypothesized predictors - staff continuity and infrastructure - and a clinical outcome, patient retention on antiretroviral therapy.ResultsPanelists emphasized contextual factors; we therefore focused on elements of clinic leadership, stress, cohesion, and collective problem solving (critical consciousness). Cognitive interviews confirmed salience of the domains and improved item clarity. After excluding items related to leaders' coordination abilities due to missingness and low agreement, all other scales demonstrated individual-level reliability and at least moderate interrater agreement in most facilities. ICC was low for most leadership measures and moderate for others. Measures tended to correlate within facility, and higher stress was significantly correlated with lower staff continuity. Organizational context was generally more positively rated in facilities that showed consistent agreement.ConclusionsAs theorized, organizational context is important in understanding program implementation within the South African health system. Most adapted measures show good reliability at individual and clinic levels. Additional revision of existing frameworks to suit this context and further testing in high and low performing clinics is warranted.

BackgroundRecently-updated global guidelines for cervical cancer screening incorporated new technologies-most significantly, the inclusion of HPV DNA detection as a primary screening test-but leave many implementation decisions at countries' discretion. We sought to develop recommendations for Malawi as a test case since it has the second-highest cervical cancer burden globally and high HIV prevalence. We incorporated updated epidemiologic data, the full range of ablation methods recommended, and a more nuanced representation of how HIV status intersects with cervical cancer risk and exposure to screening to model outcomes of different approaches to screening.MethodsUsing a Markov model, we estimate the relative health outcomes and costs of different approaches to cervical cancer screening among Malawian women. The model was parameterized using published data, and focused on comparing "triage" approaches-i.e., lesion treatment (cryotherapy or thermocoagulation) at differing frequencies and varying by HIV status. Health outcomes were quality-adjusted life years (QALYs) and deaths averted. The model was built using TreeAge Pro software.ResultsThermocoagulation was more cost-effective than cryotherapy at all screening frequencies. Screening women once per decade would avert substantially more deaths than screening only once per lifetime, at relatively little additional cost. Moreover, at this frequency, it would be advisable to ensure that all women who screen positive receive treatment (rather than investing in further increases in screening frequency): for a similar gain in QALYs, it would cost more than four times as much to implement once-per-5 years screening with only 50% of women treated versus once-per-decade screening with 100% of women treated. Stratified screening schedules by HIV status was found to be an optimal approach.ConclusionsThese results add new evidence about cost-effective approaches to cervical cancer screening in low-income countries. At relatively infrequent screening intervals, if resources are limited, it would be more cost-effective to invest in scaling up thermocoagulation for treatment before increasing the recommended screening frequency. In Malawi or countries in a similar stage of the HIV epidemic, a stratified approach that prioritizes more frequent screening for women living with HIV may be more cost-effective than population-wide recommendations that are HIV status neutral.

BackgroundCisgender women account for 1 in 5 new HIV infections in the United States, yet remain under-engaged in HIV prevention. Women experiencing violence face risk for HIV due to biological and behavioral mechanisms, and barriers to prevention, such as challenges to Pre-Exposure Prophylaxis for HIV Prevention (PrEP) adherence. In this analysis, we aim to characterize intimate partner violence (IPV) among cisgender heterosexual women enrolled in a PrEP demonstration project and assess the associations with PrEP adherence.MethodsAdherence Enhancement Guided by Individualized Texting and Drug Levels (AEGiS) was a 48-week single-arm open-label study of PrEP adherence in HIV-negative cisgender women in Southern California (N = 130) offered daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). From 6/2016 to 10/2018, women completed a survey reporting HIV risk behavior and experiences of any IPV (past 90-days) and IPV sub-types (past-year, lifetime) and biological testing for HIV/STIs at baseline, and concentrations of tenofovir-diphosphate (TFV-DP) in dried blood spots at weeks 4, 12, 24, 36, and 48. Outcomes were TFV-DP concentrations consistent with ≥ 4 or ≥ 6 doses/week at one or multiple visits. Multivariable logistic regression models were conducted to examine associations.ResultsPast-90-day IPV was reported by 34.4% of participants, and past-year and lifetime subtypes reported by 11.5-41.5%, and 21.5-52.3%, respectively. Women who engaged in sex work and Black women were significantly more likely to report IPV than others. Lifetime physical IPV was negatively associated with adherence at ≥ 4 doses/week at ≥ 3 of 5 visits, while other relationships with any IPV and IPV sub-types were variable.ConclusionIPV is an indication for PrEP and important indicator of HIV risk; our findings suggest that physical IPV may also negatively impact long-term PrEP adherence.Clinical trials registrationNCT02584140 (ClinicalTrials.gov), registered 15/10/2015.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aβ42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

BackgroundEstimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. The objective of our study was to forecast the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the United States (US) through 2030.Methods and findingsUsing the PEARL model-an agent-based simulation of PWH who have initiated ART in the US-the prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV) were forecasted through 2030. Simulations were informed by the US CDC HIV surveillance data of new HIV diagnosis and the longitudinal North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data on risk of comorbidities from 2009 to 2017. The simulated population represented 15 subgroups of PWH including Hispanic, non-Hispanic White (White), and non-Hispanic Black/African American (Black/AA) men who have sex with men (MSM), men and women with history of injection drug use and heterosexual men and women. Simulations were replicated for 200 runs and forecasted outcomes are presented as median values (95% uncertainty ranges are presented in the Supporting information). In 2020, PEARL forecasted a median population of 670,000 individuals receiving ART in the US, of whom 9% men and 4% women with history of injection drug use, 60% MSM, 8% heterosexual men, and 19% heterosexual women. Additionally, 44% were Black/AA, 32% White, and 23% Hispanic. Along with a gradual rise in population size of PWH receiving ART-reaching 908,000 individuals by 2030-PEARL forecasted a surge in prevalence of most comorbidities to 2030. Depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension decreased while dyslipidemia, diabetes, CKD, and MI increased. There was little change in prevalence of cancer and ESLD. The forecasted multimorbidity among PWH receiving ART increased from 63% in 2020 to 70% in 2030. There was heterogeneity in trends across subgroups. Among Black women with history of injection drug use in 2030 (oldest demographic subgroup with median age of 66 year), dyslipidemia, CKD, hypertension, diabetes, anxiety, and depression were most prevalent, with 92% experiencing multimorbidity. Among Black MSM in 2030 (youngest demographic subgroup with median age of 42 year), depression and CKD were highly prevalent, with 57% experiencing multimorbidity. These results are limited by the assumption that trends in new HIV diagnoses, mortality, and comorbidity risk observed in 2009 to 2017 will persist through 2030; influences occurring outside this period are not accounted for in the forecasts.ConclusionsThe PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support extended clinical capacity to meet the healthcare needs of people aging with HIV.

BackgroundHIV molecular epidemiology (HIV ME) can support the early detection of emerging clusters of new HIV infections by combining HIV sequence data routinely obtained during the clinical treatment of people living with HIV with behavioral, geographic, and sociodemographic information. While information about emerging clusters promises to facilitate HIV prevention and treatment efforts, the use of this data also raises several ethical concerns. We sought to assess how those working on the frontlines of HIV ME, specifically public health practitioners (PHPs) and researchers, prioritized these issues.MethodsEthical issues were identified through literature review, qualitative in-depth interviews, and stakeholder engagement. PHPs and researchers using HIV ME prioritized the issues using best-worst scaling (BWS). A balanced incomplete block design was used to generate 11 choice tasks each consisting of a sub-set of 5 ethical concerns. In each task, respondents were asked to assess the most and least concerning issue. Data were analyzed using conditional logit, with a Swait-Louviere test of poolability. Latent class analysis was then used to explore preference heterogeneity.ResultsIn total, 57 respondents completed the BWS experiment May-June 2023 with the Swait-Louviere test indicating that researchers and PHPs could be pooled (p = 0.512). Latent class analysis identified two classes, those highlighting "Harms" (n = 29) (prioritizing concerns about potential risk of legal prosecution, individual harm, and group stigma) and those highlighting "Utility" (n = 28) (prioritizing concerns about limited evidence, resource allocation, non-disclosure of data use for HIV ME, and the potential to infer the directionality of HIV transmission). There were no differences in the characteristics of members across classes.ConclusionsThe ethical issues of HIV ME vary in importance among stakeholders, reflecting different perspectives on the potential impact and usefulness of the data. Knowing these differences exist can directly inform the focus of future deliberations about the policies and practices of HIV ME in the United States.

ObjectiveMany persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood.Method and participantsStudy participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time.ResultsHPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14.ConclusionsWorsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation.

BackgroundThere has been a longstanding effort to integrate behavioral health and HIV care for people with comorbid HIV and behavioral health needs, including those with severe mental illness (SMI). As this population frequents both behavioral health and HIV care settings, they were likely to experience new obstacles to the quality and availability of care during the COVID-19 pandemic. This study aims to describe how clinics for HIV services or behavioral healthcare-as well as co-located sites providing both-sought to rapidly shift protocols to maintain a standard of patient care for people with comorbid HIV and SMI while adapting to the unprecedented circumstances of the pandemic.MethodsWe interviewed HIV and behavioral healthcare providers, clinic leaders, and support service agencies that served clients impacted by both HIV and SMI. Seventeen key informants across three settings (HIV care settings, behavioral health care settings, and integrated or co-located care settings) were interviewed in 2022. Interviews focused on changes in clinical services, protocols, and care provision strategies during and at the onset of the COVID-19 pandemic. Interviews were transcribed and coded using thematic analysis.ResultsCommonly endorsed themes included both positive and negative changes in care and care provision during the pandemic. Negative impacts of the pandemic included the loss of physical space, exacerbated mental health needs and disengagement in HIV care, patient barriers to telehealth and the digital divide, and increased healthcare workforce burnout. Positive changes included improved healthcare delivery and care engagement through telehealth, new opportunities to provide a wide range of social services, paradoxical increases in engagement in HIV care for certain patients, and broad institution of workforce wellness practices.ConclusionsThough COVID-19 presented several complex barriers to care for providers serving patients with comorbid HIV and SMI, the increased flexibility afforded by telehealth and a greater focus on collaborative approaches to patient care may benefit this patient population in the future. Additionally, the focus on workforce wellness may serve to increase retention and avoid burnout among providers. The strategies and lessons learned through adapting to COVID-19 may be invaluable moving forward as healthcare systems respond to future pandemics.

BackgroundInterleukin-17-producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with human immunodeficiency virus (HIV) disproportionately affects distinct Th17-cell subsets that respond to Mtb is incompletely defined.MethodsWe performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by liquid chromatography-mass spectrometry (LC/MS) on plasma and tested the hypothesis that tryptophan catabolism influences Th17-cell frequencies in this context.ResultsWe identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in latent tuberculosis infection (LTBI) with HIV-ART, yet Mtb-responsive IL-17-producing CD4 T cells were preserved; we found that IL-17-producing CD4 T cells dominate the response to Mtb antigen but not cytomegalovirus (CMV) antigen or staphylococcal enterotoxin B (SEB), and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17-cell frequencies.ConclusionsWe found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL-17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.

Polygamy is the practice of marriage to multiple partners. Approximately 6-11% of households in Uganda and 4-11% of households in Kenya are polygamous. The complex families produced by polygamous marriage customs give rise to additional considerations for healthcare providers and public health messaging around HIV care. Using 27 in-depth, semi-structured qualitative interviews with participants in two studies in rural Kenya and Uganda, we analysed challenges and opportunities that polygamous families presented in the diagnosis, treatment and prevention of HIV, and provider roles in improving HIV outcomes in these families. Overall, prevention methods seemed more justifiable to families where co-wives live far apart than when all members live in the same household. In treatment, diagnosis of one member did not always lead to disclosure to other members, creating an adverse home environment; but sometimes diagnosis of one wife led not only to diagnosis of the other, but also to greater household support.

BackgroundPeople living with HIV (PLWH) are at increased risk of cardiometabolic disorders (CMD). Adequate access to care for both HIV and CMD is crucial to improving health outcomes; however, there is limited research that have examined couples' experiences accessing such care in resource-constrained settings. We aimed to identify barriers to accessing CMD care among PLWH in Malawi and the role of partners in mitigating these barriers.MethodsWe conducted a qualitative investigation of barriers to CMD care among 25 couples in Malawi. Couples were eligible if at least one partner was living with HIV and had hypertension or diabetes (i.e., the index patient). Index patients were recruited from HIV care clinics in the Zomba district, and their partners were enrolled thereafter. Interviews were conducted separately with both partners to determine barriers to CMD care access and how partners were involved in care.ResultsParticipants framed their experiences with CMD care by making comparisons to HIV treatment, which was free and consistently available. The main barriers to accessing CMD care included shortage of medications, cost of tests and treatments, high cost of transportation to health facilities, lengthy wait times at health facilities, faulty or unavailable medical equipment and supplies, inadequate monitoring of patients' health conditions, some cultural beliefs about causes of illness, use of herbal therapies as an alternative to prescribed medicine, and inadequate knowledge about CMD treatments. Partners provided support through decision-making on accessing medical care, assisting partners in navigating the healthcare system, and providing financial assistance with transportation and treatment expenses. Partners also helped manage care for CMD, including communicating health information to their partners, providing appointment reminders, supporting medication adherence, and supporting recommended lifestyle behaviors.ConclusionsCouples identified many barriers to CMD care access, which were perceived as greater challenges than HIV care. Partners provided critical forms of support in navigating these barriers. With the rise of CMD among PLWH, improving access to CMD care should be prioritized, using lessons learned from HIV and integrated care approaches. Partner involvement in CMD care may help mitigate most barriers to CMD care.