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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may trigger autoimmune disease (AD) through initial innate immune activation with subsequent aberrations in adaptive immune cells leading to AD. While there are multiple reports of incident AD diagnosed after COVID-19, the risk in the context of key circulating strains is unknown. TriNetX, a global, federated, health research network providing access to electronic medical records across 74 healthcare organizations, was utilized to define an adult cohort between January 1, 2020, and March 3, 2023. Exposure was defined as COVID-19 diagnosis (ICD-10 code or positive laboratory test). Age- and sex-propensity score-matched controls never had COVID-19 diagnosed. Outcomes were assessed 1 month to 1 year after the index date. Patients with AD prior to or within 1 month after the index date were excluded from the primary analysis. Incidence and risk ratios of each AD were assessed. A total of 3,908,592 patients were included. Of 24 AD patients assessed, adjusted risk ratios for eight AD patients who had COVID-19 were higher compared to those who had no COVID-19. Cutaneous vasculitis (adjusted hazard ratio (aHR): 1.82; 95% CI 1.55-2.13), polyarteritis nodosa (aHR: 1.76; 95% CI 1.15-2.70), and hypersensitivity angiitis (aHR: 1.64; 95% CI 1.12-2.38) had the highest risk ratios. Overall, psoriasis (0.15%), rheumatoid arthritis (0.14%), and type 1 diabetes (0.13%) had the highest incidence during the study period, and of these, psoriasis and diabetes were more likely after COVID-19. The risk of any AD was lower if COVID-19 was diagnosed when Omicron variants were the predominant circulating strains. A positive antinuclear antibody was more likely and predictive of AD after COVID-19. SARS-CoV-2 may be a potential trigger for some AD, but the risk for AD may decrease with time given the apparent lower risk after infection with Omicron variants.

Purpose of ReviewThis review focuses on the differential effects of contemporary antiretrovirals on systemic inflammation as heightened immune activation is linked to important co-morbidities and mortality with HIV infection.Recent FindingsAntiretroviral therapy (ART) reduces dramatically systemic inflammation and immune activation, but not to levels synchronous with HIV-uninfected populations. In one ART initiation trial, integrase inhibitors appear to reduce inflammation to a greater degree than non-nucleoside reverse transcriptase inhibitors (NNRTIs); however, it is not clear that there are beneficial effects on inflammation resulting from treatment with integrase inhibitors compared to PIs, between PIs and NNRTIs, between specific nucleoside reverse transcriptase inhibitors, or with maraviroc in ART-naïve patients. In ART switch studies, changing to an integrase inhibitor from a PI-, NNRTI-, or enfuvirtide-containing regimen has resulted in improvement in several markers of inflammation.SummaryAdditional research is needed to conclusively state whether there are clear differences in effects of specific antiretrovirals on inflammation and immune activation in HIV.

Reciprocal innovation, a model of sustained, multidirectional exchange in which health strategies are adapted, revisited, and refined across contexts, offers a compelling framework to rethink how implementation science can support global health equity by enabling dynamic, multidirectional learning across different contexts. Drawing on the EXTRA-CVD trial, a nurse-led cardiovascular disease prevention intervention designed to extend the HIV treatment cascade in United States (U.S.) HIV clinics, which adapted strategies informed by implementation research in Kenya and the U.S. Veterans Affairs health system, this perspective examines how reciprocal innovation can begin to emerge within existing research structures, as well as where opportunities for deeper exchange remain limited. We identify four operational domains of reciprocal innovation: care delivery strategies, end-user engagement, research methodologies, and research leadership and partnership. Across these domains, we describe how cross-context learning shaped intervention adaptation and site-level implementation in EXTRA-CVD, as well as missed opportunities where more intentional feedback, shared leadership, and methodological exchange could have strengthened multidirectional learning. Taken together, this work highlights both the potential and the practical challenges of reciprocal innovation in implementation research, emphasizing its role in moving beyond unidirectional knowledge transfer toward iterative, context-responsive learning. By embedding structures for iterative feedback, equity-centered governance, and multidirectional learning systems within research and implementation systems, future global partnerships can foster more inclusive, responsive, and sustainable health interventions.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36–0.79 and 0.66, 95% CI 0.45–0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (β) = 0.15, 95% CI 0.02–0.29; FTL-by-sex βinteraction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (FTL: rho = −0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms.

Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH.

Background People with HIV (PWH) experience increased cardiovascular disease (CVD) risk. Many PWH in the USA receive their primary medical care from infectious disease specialists in HIV clinics. HIV care teams may not be fully prepared to provide evidence-based CVD care. We sought to describe local context for HIV clinics participating in an NIH-funded implementation trial and to identify facilitators and barriers to integrated CVD preventive care for PWH. Methods Data were collected in semi-structured interviews and focus groups with PWH and multidisciplinary healthcare providers at three academic medical centers. We used template analysis to identify barriers and facilitators of CVD preventive care in three HIV specialty clinics using the Theoretical Domains Framework (TDF). Results Six focus groups were conducted with 37 PWH. Individual interviews were conducted with 34 healthcare providers and 14 PWH. Major themes were captured in seven TDF domains. Within those themes, we identified nine facilitators and 11 barriers to CVD preventive care. Knowledge gaps contributed to inaccurate CVD risk perceptions and ineffective self-management practices in PWH. Exclusive prioritization of HIV over CVD-related conditions was common in PWH and their providers. HIV care providers assumed inconsistent roles in CVD prevention, including for PWH with primary care providers. HIV providers were knowledgeable of HIV-related CVD risks and co-located health resources were consistently available to support PWH with limited resources in health behavior change. However, infrequent medical visits, perceptions of CVD prevention as a primary care service, and multiple co-location of support programs introduced local challenges to engaging in CVD preventive care. Conclusions Barriers to screening and treatment of cardiovascular conditions are common in HIV care settings and highlight a need for greater primary care integration. Improving long-term cardiovascular outcomes of PWH will likely require multi-level interventions supporting HIV providers to expand their scope of practice, addressing patient preferences for co-located CVD preventive care, changing clinic cultures that focus only on HIV to the exclusion of non-AIDS multimorbidity, and managing constraints associated with multiple services co-location. Trial registration ClinicalTrials.gov , NCT03643705

We sought to understand how no, single, and polysubstance use correlate with social drivers of health (SDOH) and mental health symptoms in persons with HIV (PWH). Cross-sectional analysis of PWH who use and do not use illicit substances and marijuana. Substance use was defined by self-report and toxicology (urine and hair). Surveys evaluated SDOH and mental health domains. Linear and logistic regression were used to assess the associations of polysubstance and single substance use with SDOH domains at risk and presence of mental health symptom domains compared to controls (no substance use). A total of 171 participants were enrolled (67 polysubstance, 68 single substance, and 36 controls): 75% were male, 61% were Black, and 13% were of Hispanic ethnicity. Substance using groups were younger, had more transgender women, and higher proportion with income ≤$20 000/year. Ninety-one percent had HIV-1 RNA ≤200 copies/mL. Participants in the polysubstance group reported the most SDOH domains at risk. With adjustment, odds of transportation needs and food insecurity were 2 to 5 times higher for the substance using groups than controls. Odds of mental health symptom domains (depression, mania, anxiety, and posttraumatic stress disorder) were significantly higher in substance using groups than controls. Substance use is strongly associated with SDOH domains at risk and mental health symptom domains in PWH. Polysubstance use appears to be an important correlate for SDOH domains at risk and this suggests more attention in both future research and clinical care is necessary to determine interventions that will improve SDOH and health-related outcomes.

Abstract Background Injectable cabotegravir (CAB)/rilpivirine (RPV) is the only combination long-acting (LA) antiretroviral regimen approved for HIV. RPV may not be effective among individuals with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, which has >10% prevalence in many countries. Lenacapavir (LEN) is an LA capsid inhibitor given every 6 months, but has not been studied in combination with other LA agents. Methods We assembled a case series from 4 US academic medical centers where patients with adherence challenges were prescribed LEN subcutaneously every 26 weeks/CAB (+/− RPV) intramuscularly every 4 or 8 weeks. Descriptive statistics, including viral load (VL) outcomes, were summarized. Results All patients (n = 34: 76% male; 24% cis/trans female; 41% Black; 38% Latino/a; median age [range], 47 [28–75] years; 29% and 71% on CAB every 4 or 8 weeks) reported challenges adhering to oral ART. The reasons for using LEN/CAB with or without RPV were documented or suspected NNRTI mutations (n = 21, 59%), integrase mutations (n = 5, 15%), high VL (n = 6, 18%), or continued viremia on CAB/RPV alone (n = 4, 12%). Injection site reactions on LA LEN were reported in 44% (32% grade I, 12% grade 2). All patients but 2 (32/34; 94%) were suppressed (VL <75 copies/mL) after starting LEN at a median (range) of 8 (4–16) weeks, with 16/34 (47%) suppressed at baseline. Conclusions In this case series of 34 patients on LEN/CAB, high rates of virologic suppression (94%) were observed. Reasons for using LEN/CAB included adherence challenges and underlying resistance, mostly to NNRTIs. These data support a clinical trial of LEN/CAB among persons with NNRTI resistance. Due to the prevalence of NNRTI-resistance worldwide, LA ART with CAB/RPV is not endorsed for low-and-middle-income-countries. This is the first case series examining LA-LEN/CAB to treat HIV in mostly NNRTI-resistant patients, serving as a call for a trial of this regimen.

Background. Little is known about how different antiretrovirals effect inflammation and monocyte activation in human immunodeficiency virus (HIV) infection. Methods. We examined plasma specimens obtained during a randomized, double-blinded trial in antiretroviral therapy (ART)-naive HIV-infected adults which compared the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) with that of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). From a random sample achieving an HIV type 1 RNA load of < 50 copies/mL by week 48, changes over 24 and 48 weeks in levels of biomarkers of monocyte activation (soluble CD14 [sCD14] and soluble CD163 [sCD163]), systemic inflammation (soluble tumor necrosis factor α receptor I [sTNF-RI], interleukin 6 [IL-6], and high-sensitivity C-reactive protein [hsCRP]), and vascular inflammation (lipoprotein-associated phospholipase A₂[Lp-PLA₂]) were compared. Multivariable linear regression was used. Results. A total of 200 participants were included. Significant differences favoring EVG/c/FTC/TDF were noted for changes in sCD14, hsCRP, and Lp-PLA₂ levels. Factors independently associated with a larger decrease in the sCD14 level included random assignment to receive EVG/c/FTC/TDF, higher baseline sCD14 level, and larger decreases in hsCRP and sCD163 levels; factors associated with a larger Lp-PLA₂ decrease included higher baseline Lp-PLA₂ and IL-6 levels, smaller increases in total cholesterol and triglycerides levels, a larger decrease in the sCD14 level, and a smaller decrease in the sCD163 level. Conclusions. EVG/c/FTC/TDF led to greater decreases in sCD14, hsCRP, and Lp-PLA₂ levels, compared with EFV/FTC/TDF. Randomization group independently predicted the change in sCD14 level, and changes in monocyte activation independently predicted the change in Lp-PLA₂ level. There appears to be a more favorable effect of the integrase inhibitor EVG over efavirenz on immune activation, which may affect vascular inflammation.

Purpose of Review Advances in HIV testing, prevention, and treatment, alongside increased awareness and harm reduction efforts for substance use disorder (SUD) have improved care and treatment access over the past decade. However, racial and ethnic minorities with SUD and HIV or at risk for HIV still face disproportionately high health disparities. Understanding and addressing the reasons behind these disparities is crucial. Recent Findings Structural and systemic barriers continue to negatively impact minoritized communities, due to lack of access to care, mistrust, and feelings of ostracization. Disconnected systems for HIV and SUD treatment complicate combined care. Delays in HIV diagnosis and viral suppression reduce life expectancy for minority populations by around 10 years. Summary Healthcare systems need to become more integrated, accessible, and culturally welcoming to marginalized communities. Promising interventions utilizing technology, harm reduction, and mobile service delivery can reduce barriers and improve outcomes for minority individuals.