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Objective: To assess final efficacy (through Week [W] 132), safety, and emergent resistance with lenacapavir-based combination regimens in the CALIBRATE study.

Design: CALIBRATE was a Phase 2, randomized, open-label study (NCT04143594).

Methods: Treatment-naive PWH were randomized (2 : 2:2 : 1) to four treatment groups (TG): TG1 and TG2 received twice-yearly subcutaneous lenacapavir plus oral daily emtricitabine/tenofovir alafenamide (F/TAF); TG3 received oral daily lenacapavir plus F/TAF; and TG4 received oral daily bictegravir/F/TAF. At W28, TG1 switched to lenacapavir plus TAF and TG2 switched to lenacapavir plus bictegravir. At W80, TG4 completed the study and TG1-3 continued assigned treatments.

Results: Overall, 182 participants received at least one dose of study drug (TG1-4, respectively: n  = 52, n  = 53, n  = 52, n  = 25). Virologic suppression (HIV-1 RNA <50 copies/ml) at W80 by FDA snapshot: 87, 75, 87, and 92% in TG1-4, respectively. When excluding missing data, virologic suppression at W132 across TG1-3 was 98-100%. Mean (95% CI) increase from baseline to W80 in CD4 cells/μl was consistent across TG1-4: 275 (214; 337), 262 (203; 320), 245 (174; 315), and 248 (155; 340), respectively. No serious treatment-related adverse events occurred. Two participants in TG1 and three in TG2 discontinued study drug due to adverse events. Injection-site reactions were mostly mild to moderate. LEN resistance-associated mutations emerged in four participants.

Conclusion: Lenacapavir-containing combinations achieved and maintained high rates of virologic suppression in treatment-naive participants through W132; lenacapavir was well tolerated. These data support future development of lenacapavir-containing regimens for HIV-1 treatment.

Background: Recent findings from the REPRIEVE study suggest statins provide greater cardiovascular protection in persons with HIV (PWH) than expected from low-density lipoprotein (LDL) cholesterol reduction alone. Statins may modulate Th1-type immune responses, including interferon-gamma (IFN-γ), neopterin, and kynurenine metabolism. We investigated if statin use in PWH was associated with suppression of Th1-type immune responses.

Methods: This cross-sectional study included PWH from the Copenhagen Comorbidity in HIV infection (COCOMO) study. Demographic and clinical variables were collected through questionnaires and physical examinations. Plasma IFN-γ, neopterin, kynurenine-to-tryptophan ratio [marker of indoleamine 2,3-dioxygenase (IDO)-1 activity], interleukin (IL)-6, IL-1β, soluble CD14, and clinical data were measured in plasma. Multivariable logistic regression models were adjusted for age, sex, waist-to-hip ratio, metabolic syndrome, physical activity, high-sensitivity C-reactive protein, and LDL cholesterol.

Results: We included 1041 of whom 130 (12.5%) received statins. Statin-treated PWH were older (60 vs. 49 years), and more frequently men (92 vs. 84%). In unadjusted analyses, odds of elevated markers of Th1 immune responses did not differ significantly between groups. After multivariable adjustment, statin exposure was associated with lower odds of high kynurenine-to-tryptophan ratio [odds ratio (OR): 0.60; 95% confidence interval (CI) 0.37-0.98], IFN-γ (OR 0.58; 95% CI 0.36-0.92), and neopterin (OR 0.58; 95% CI 0.36-0.92). No significant associations were observed for IL-6, IL-1β, or soluble CD14.

Conclusion: In PWH, statin therapy was independently associated with suppression of Th1-type immune responses. These findings support a lipid-independent, immunomodulatory mechanism by which statins may confer cardiovascular protection in HIV infection and warrant confirmation in prospective studies.

Background: Switching to an integrase strand transfer inhibitor (INSTI) during the menopausal transition has been associated with accelerated increases in visceral obesity, a risk factor for insulin resistance. Whether switching to an INSTI modifies the association of HIV and menopause with insulin resistance is unknown.

Methods: From 2006 to 2019, 389 nonpregnant women with HIV (WWH) [133 who switched to an INSTI (INSTI+); 256 who did not switch (INSTI-)] and 334 women without HIV from the Women's Interagency HIV study without diabetes or hepatitis C virus were included in the analysis. Mixed effect models evaluated the change in insulin resistance estimated through log HOMA-IR by HIV status by menopausal phase. We then compared trajectories by INSTI group. Menopausal phase was determined by anti-Müllerian hormone, a biomarker of ovarian reserve.

Results: Compared to women without HIV, INSTI+ WWH in premenopause had nonstatistically significant faster annual increases in HOMA-IR [difference in slope: 7.03%; 95% confidence interval (CI): -4.99 to 20.58] whereas INSTI- WWH had nonstatistically significantly faster annual decreases [-1.01% (95% CI: -7.34 to 5.75)]. In late perimenopause, INSTI+ and INSTI- had 4.87% (95% CI: -3.59 to 14.06) and 4.38% (95%CI: -3.10 to 12.44) nonstatistically significantly faster annual increases in HOMA-IR, respectively. In menopause, INSTI+ and INSTI- WWH had 9.18% (95% CI: 1.60 to 17.33) and 11.28% (95% CI: 3.27 to 19.91) statistically significant faster annual increases in HOMA-IR than women without HIV. There was no statistically significant difference between INSTI+ and INSTI- in any menopausal phase.

Conclusion: Regardless of switching to an INSTI or not, WWH in late perimenopause and menopause have faster increases in insulin resistance when compared to women without HIV. Diabetes screening and prevention in midlife WWH is imperative.

Background: This study identified complex, multidimensional, longitudinal biopsychosocial (BPS) phenotypes (MLBPSPs) in people with HIV (PWH) and evaluated their associations with baseline clinical characteristics.

Methods: We included 506 PWH in the multisite CHARTER study who underwent assessments at four visits, 6 months apart. Participants were enrolled in the CHARTER cohort during 2003-2010, an earlier antiretroviral thearpy (ART) era in which treatment uptake and viral suppression were lower than is typical today; a prespecified sensitivity analysis examined those with sustained plasma viral suppression across visits. Using machine learning, we identified four MLBPSP clusters based on means and nonlinear trajectories of BPS characteristics. These characteristics included neurocognition, depressed mood, self-reported cognitive symptoms, and activities of daily living at each visit.

Results: The largest MLBPSP cluster (C1, N  = 231) had the best average scores across all domains and remained stable over 18 months of follow-up. Other clusters showed varying degrees of cognitive impairment, depressed mood, and functional disability. In multivariable analyses, several baseline clinical characteristics, including chronic pulmonary disease, distal neuropathic pain, polypharmacy, and creatinine levels, significantly predicted one or more adverse MLBPSP trajectories. In the sustained-suppression subgroup, the four-phenotype trajectory structure closely resembled that of the full cohort.

Conclusion: These findings have implications for HIV care by identifying PWH at risk for future adverse trajectories. The results may lead to insights informing future personalized interventions targeted to vulnerable subpopulations of PWH. Participants were enrolled in an earlier ART era with frequent prior AIDS and lower ART uptake and viral suppression than current practice; although subgroup analyses among virally suppressed PWH showed similar directions of effect, generalizability to consistently treated contemporary cohorts may be limited and requires confirmation in modern samples.

Despite preexposure prophylaxis (PrEP) expansion in Mexico, concerns remain about equitable access. Using counterfactual prediction and propensity score matching, we compared a nonprobability sample of PrEP users with high-risk men who have sex with men (MSM) from a national survey. Findings indicate that the program may miss up to 60% of high-risk MSM based on their profile and location, with younger and less educated men particularly unlikely to access PrEP, highlighting persistent gaps in the current program.

Objective: Inequalities in the antiretroviral therapy (ART) cascade across subpopulations remain an ongoing challenge in the global HIV response. Eswatini achieved the UNAIDS 95-95-95 ART cascade targets by 2020, with differentiated programs to minimize inequalities across subpopulations, including for female sex workers (FSWs) and their clients. We sought to estimate the impacts of this achievement, through a retrospective impact evaluation of ART scale-up in Eswatini.

Design: Drawing on population-level and FSW-specific surveys, we developed a compartmental model of heterosexual HIV transmission, and calibrated it to observed HIV prevalence, incidence, and ART cascade scale-up in Eswatini.

Methods: We defined four counterfactual scenarios in which the population overall reached only 80-80-90 by 2020, but where FSW, clients, both, or neither were disproportionately left behind, reaching only 60-40-80. We estimated additional HIV infections by 2020 in counterfactual vs. observed scenarios, and identified epidemic conditions which maximized differences.

Results: Compared with observed cascade scale-up in Eswatini, leaving behind neither FSW nor their clients led to median (95% confidence interval, 95% CI) 8.8 (6.3-10.9) additional infections by 2020 vs. 14.3 (10.8-18.6) if both were left behind, a 63 (31-128) increase. The impact of leaving behind FSW and/or clients was largely determined by their population sizes and HIV incidence ratio among clients vs. men overall.

Conclusion: Inequalities in the ART cascade across subpopulations can undermine the anticipated prevention impacts of cascade scale-up. As Eswatini has shown, addressing inequalities in the ART cascade that intersect with transmission risk can maximize incidence reductions from cascade scale-up.

Background: Mental health has become an area of concern among people with HIV (PWH). We aim to assess whether the risk of schizophrenia spectrum disorders (SSD) is increased among PWH. To examine whether such risks are affected by familial factors we also accessed the risk among their siblings.

Methods: Nationwide, population-based, matched cohort study of PWH with Danish origin (1995-2021), a comparison cohort from the background population, matched on date of birth and gender, and sibling cohorts. We used cumulative incidence function and Cox regression to estimate absolute risk and hazard ratios (HR) with 95% confidence intervals (CI) of study outcomes and stratified the results according to route of HIV transmission.

Findings: We observed an increased risk of SSD among PWH [20-year cumulative incidence 3.7% vs. 1.0% and HR 4.6 (95% CI: 3.8-5.6)], especially among individuals with injection drug use (IDU) as route of HIV transmission [HR 11.3 (95% CI: 7.7-16.4)]. Among siblings increased risk of SSD was mainly observed among siblings of PWH with IDU as route of HIV transmission [HR of 2.9 (95% CI: 1.9-4.5)] and with lack of statistical power among siblings of PWH with men who have sex with men and heterosexual contact as routes of HIV transmission [HR 1.3 (95% CI: 0.9-1.7) and HR 1.2 (95% CI: 0.7-1.9)].

Interpretation: Risk of SSD is substantially increased among PWH, especially among those who report IDU as route of HIV transmission. Familial risk factors might partly contribute to this risk.

Objective: To evaluate the association between maternal gestational lipid biomarkers and cardiometabolic health indicators in children who are HIV-exposed uninfected (CHEU) and HIV-unexposed uninfected children.

Design: Prospective cohort study.

Methods: Our study randomly sampled 260 mother-child pairs from Drakenstein Child Health Study ( N  = 100 CHEU & N  = 160 HIV-unexposed uninfected). Multivariable linear regression were used to assess associations between maternal lipid biomarkers from second trimester of pregnancy with child cardiometabolic indicators at 5-8 years of age and explored potential effect modification by HIV exposure status in stratified analyses. Child cardiometabolic indicators included lipids, glucose metabolism, blood pressure, and body composition.

Results: Associations were found between maternal total cholesterol (TC) and child TC and low-density lipoprotein (LDL) [TC; mean difference [MD] 0.19, 95% CI 0.09-0.30] & [LDL; MD 0.21, 95% CI 0.12-0.31]. When stratified by HIV exposure status, the relationship between maternal TC and child TC was stronger in CHEU children than in HU children. The relationship between maternal TC and child LDL was also observed to be stronger in CHEU. Maternal high-density lipoprotein (HDL) was associated with the child HDL levels [MD 0.13, 95% CI 0.03-0.23]; when stratified, this association was only demonstrated in HIV-unexposed uninfected children. No significant associations were found between maternal lipids and child HbA1c, insulin resistance, SBP or DBP, or body composition.

Conclusion: In a birth cohort of South African CHEU and HU children, maternal gestational lipid profiles was associated with child lipid metabolism, and this relationship may differ based on in-utero HIV exposure status.