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Background: The application of cardiovascular disease (CVD) risk models in people living with HIV (PLHIV) may be limited due to concerns that the models tend to underestimate risk in this population. We conducted an updated meta-analysis to assess the degree of CVD risk under prediction in PLHIV by existing CVD risk models.

Methods: We searched electronic databases and the reference lists of relevant articles. Data were abstracted using standardized forms. Calibration data included observed: expected ratios, which were graphically summarized. Discrimination data included c-statistics which were pooled using random-effects model meta-analysis.

Results: Sixteen publications reporting data on 97,945 PLHIV (mean age, 41 years; 75% male) were included. The risk scores tended to underpredict CVD risk in PLHIV, especially for individuals with lower expected risk. For PLHIV with expected 10-year CVD risk of 3%, the risk scores can underestimate risk by 71% on average. By contrast, for PLHIV with 6% and 9% expected 10-year CVD risk, the underestimation is by ∼23% and ∼7%, respectively. The risk scores had moderate performance in discrimination (pooled c-statistic values ranged from 0.71 to 0.82). There was substantial heterogeneity across studies and risk models. The 10-year models of the American Joint Societies Pooled Cohort Equation (PCE-10) and the Framingham Risk Score (FRS-10) had better calibration.

Conclusions: Extant risk scores underpredict CVD risk in PLHIV, especially for individuals with lower expected risk, suggesting a need for implementation of HIV-specific calibration factors in this population. PCE-10 and FRS-10 showed better calibration.

Objective: HIV infection may affect uric acid (UA) metabolism, but no large-scale population-based studies have investigated whether and how HIV infection affects incidence of hyperuricemia.

Design: Prospective, observational, noninterventional study.

Methods: We included 1836 people with HIV (PWH) who had normal UA level at baseline assessment and 1836 age-, sex-, and baseline UA level-matched people without HIV (PWoH) from the Comparative HIV and Aging Research in Taizhou (CHART) cohort. Hyperuricemia was defined as a serum UA level ≥7 mg/dl, following Chinese clinical guidelines. Logistic regression models were used to examine the association and potential effect modifiers. A generalized linear model (GLM) and bootstrap method were employed to assess the mediation effect.

Results: The three-year cumulative incidence of hyperuricemia was significantly lower in PWH than in PWoH overall [11.6% vs. 16.4%; adjusted odds ratio (aOR) = 0.67; 95% confidence interval (CI): 0.55, 0.82], and significantly lower in male PWH than in male PWoH (13.1% vs. 19.4%; aOR = 0.64, 95% CI: 0.52, 0.79) but comparable between female PWH and female PWoH (6.2% vs. 6.1%, aOR = 0.97, 95% CI: 0.55, 1.72). A significant additive interaction between sex and HIV infection was observed, with a relative excess risk due to interaction (RERI) of -1.18 (95% CI = -2.87, -0.13). Among males, lower BMI and albumin to globulin ratio (AGR) mediated 36% and 12% of the association between HIV infection and lower risk of hyperuricemia, respectively.

Conclusions: HIV infection was associated with a lower risk of hyperuricemia in men but not women, partially mediated by lower BMI and AGR, suggesting distinct metabolic and inflammatory profiles in male PWH.

Background: ARTISTRY-1 is an operationally seamless Phase 2/3 study evaluating the safety and efficacy of once-daily oral lenacapavir (LEN) + bictegravir (BIC) in virologically suppressed participants without known integrase strand-transfer inhibitor (INSTI) resistance, compared to a complex multi-tablet regimen.

Methods: Baseline HIV-1 resistance-associated mutations (RAMs) were assessed via historical genotypic reports (HGR) and proviral DNA genotyping (GenoSure Archive, Monogram Biosciences). The impact of baseline RAMs on Week 48 efficacy in the Phase 2 part of the study was evaluated. Post-baseline genotypic and phenotypic resistance was assessed in participants with confirmed virologic rebound (HIV-1 RNA ≥50 copies/ml; analyzed if ≥200 copies/ml).

Results: Baseline HIV-1 genotypic data from HGR and/or proviral DNA analyses were available for 98% (125/128) of participants. RAMs for nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) were found in 81%, 65%, and 46% of participants, respectively; 11% had primary INSTI RAMs by proviral DNA genotyping. Baseline RAMs had no impact Week 48 efficacy. One participant with baseline resistance to NRTIs, NNRTIs, and PIs, and detectable baseline viral load met the criteria for resistance testing. A novel capsid polymorphism (N74T) emerged in this individual, with no impact on LEN susceptibility.

Conclusions: Despite high frequencies of baseline resistance, substantial rates of viral suppression were maintained through Week 48 and no on-treatment resistance to study drugs was detected. These findings support the development of once-daily BIC + LEN STR to improve and optimize treatment options in individuals on complex ART.

Objective: Dyslipidemia is common in people with HIV (PWH) and linked to cardiometabolic disease risk. Subcutaneous adipose tissue (SAT) regulates lipid storage and release, but how SAT cellular composition might influence circulating lipids in PWH on contemporary antiretroviral therapy (ART) is not well defined.

Design: Cross-sectional, observational cohort of PWH on long-term contemporary ART with virologic suppression.

Methods: We performed untargeted fasting plasma lipidomic profiling on 127 individuals with a range of metabolic fitness (non-diabetes, prediabetes, diabetes). Adjusted logistic and linear regression models identified lipid species associated with diabetes status and HOMA2-IR, respectively. Linear regression assessed the relationship between abdominal SAT cell composition from single-cell RNA sequencing with circulating lipid classes (n = 59).

Results: The median age was 48 years, body mass index 31.5 kg/m2, and 48% self-identified as non-White, with 23% women. Diabetes as a dichotomous outcome had few differences in lipid species. In contrast, HOMA2-IR was associated with higher levels of several species of tri- and diacylglycerols and inversely associated with phosphatidylcholine, phosphatidylethanolamine species, and many of their derivatives among those without diabetes. Adipose tissue microvasculature remodeling, characterized by a reduction in capillary endothelium and decreased expression of key lipid trafficking receptors (LPL, GPIHBP1), was associated with the insulin-resistant lipidomic signature.

Conclusions: Adipose tissue microvasculature remodeling in PWH on contemporary ART was associated with changes in several plasma lipid species, which are also linked to insulin resistance. Interventions targeting adipose tissue endothelial dysfunction may improve metabolic health in PWH on long-term ART.

Introduction: In Australia, cross-sectional estimates suggest that over 95% of people with HIV are virally suppressed; however, these measures reflect only the most recent viral load. Sustained viral suppression (SVS) is essential for optimising health and preventing transmission. This study describes SVS among people with HIV who are engaged in care in Australia and factors associated with SVS.

Methods: We analysed national data from the ACCESS sentinel surveillance system. Eligible participants attended an ACCESS clinic in 2023, received continuous antiretroviral therapy (ART; ≥1 prescription per calendar year), and had at least two viral load tests in the preceding three years (median:6; IQR: 5-7). SVS was defined as all viral load results <200 copies/mL. Multivariable logistic regression identified factors associated with SVS.

Results: Of 6,036 eligible participants (95% male; median age 54 years), 5,751 (95.3%) achieved SVS, while 99.1% were suppressed based on their last test. Older age (adjusted odds ratio [aOR]:1.01; 95% CI:1.002-1.03), residence in more socioeconomically advantaged areas (aOR:1.06; 1.01-1.12), and higher mean CD4 count (aOR:1.00; 1.001-1.002) were associated with higher odds of SVS. Receiving care at publicly funded sexual health/hospital-based clinics (aOR:0.64; 0.48-0.86), more diagnoses of gonorrhoea (aOR:0.81; 0.67-0.96) or infectious syphilis in the last three years (aOR:0.85; 0.73-0.98), and co-infection with hepatitis C in the last three years (aOR:0.56; 0.36-0.87) were associated with lower SVS.

Conclusions: More than 95% of people with HIV receiving ART and engaged in ongoing care achieved SVS. Strengthened, person-centred support for groups with lower SVS may enhance clinical outcomes and sustain Australia's progress toward HIV elimination goals.

Objectives: To evaluate real-world persistence with long-acting cabotegravir plus rilpivirine (CAB+RPV LA) in a nationwide cohort of virologically suppressed adults, describe the main clinical and structural reasons for discontinuation, and identify predictors of early interruption in routine practice.

Design: Ambispective, multicenter cohort study assessing the durability, safety, adherence, and virological outcomes of CAB+RPV LA implementation across 58 Spanish healthcare settings.

Methods: Adults initiating CAB+RPV LA therapy were enrolled using standardized electronic tools. Baseline demographics, comorbidities, HIV and virological variables, and injection timing were recorded. Permanent discontinuations were attributed to systemic adverse events, injection-site reactions, virological failure (VF), or nonclinical causes. Virological endpoints followed the CONSENSUS-LAI criteria. Kaplan-Meier curves and multivariate Cox models were used to identify the independent predictors.

Results: Among 3146 virologically suppressed participants, 199 (6.3%) permanently discontinued therapy over a median 13.8-month follow-up. Discontinuation was more frequent among women (21.6 vs. 14.4%; P = 0.007), foreign-born individuals (42.9 vs. 29.5%; P  < 0.001), those with a higher BMI, and those with shorter prior suppression periods. injection-site reaction- and systemic adverse event-related discontinuations were rare (1.2 and 0.7%, respectively), whereas structural reasons accounted for 3.5%. VF occurred in 20 participants (0.6%). Adjusted analyses showed that age ≥70 years [hazard ratio (HR) 5.41; 95% confidence interval (CI) 1.91-15.32] and foreign nationality (HR 2.06; 95% CI 1.48-2.86) independently increased discontinuation risk, whereas male sex (HR 0.65; 95% CI 0.44-0.96) and longer suppression (HR/day 0.99; P  = 0.036) were protective.

Conclusions: In this large national cohort, CAB+RPV LA demonstrated strong persistence, excellent tolerability, and very low rates of VF. Discontinuations were mainly structural, highlighting the need to reinforce continuity-of-care pathways and system-level support for optimal CAB+RPV LA scale-up.

Objective: Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) under development for HIV-1 treatment. We aimed to evaluate the pharmacokinetics (PK) of islatravir and its active form, islatravir-triphosphate, in blood and mucosal tissues.

Design: This was an exploratory substudy of a randomized, double-blind, placebo-controlled, multicenter, Phase 2a study of once-monthly islatravir in adults at low likelihood of HIV-1 exposure (NCT04003103).

Methods: Participants were randomly assigned 2:2:1 to receive 6 once-monthly oral doses of islatravir 60 mg, islatravir 120 mg, or placebo. Plasma, peripheral blood mononuclear cell (PBMC), and cervical, vaginal, and rectal tissue samples were collected at Weeks 1, 4, 24, and 32. Samples were assayed by liquid chromatography with tandem mass spectrometry. Intercompartmental ratios and regression analyses were assessed.

Results: The analyses included 44 participants who received islatravir 60 mg or 120 mg (73% assigned female at birth; median age 30 years). Following 6 once-monthly doses, islatravir-triphosphate trough concentrations were comparable across homogenized mucosal tissue samples and isolated rectal cells. Median venous whole blood islatravir (total of islatravir and key anabolites) to mucosal tissue islatravir-triphosphate concentration ratios ranged from 0.565 to 1.490 four weeks after the sixth islatravir dose. Adjusted R2 coefficients between islatravir concentrations in venous whole blood and islatravir-triphosphate concentrations in rectal, cervical, and vaginal tissues across sampling times were 0.67, 0.76, and 0.75, respectively.

Conclusions: The favorable tissue distribution of islatravir and islatravir-triphosphate following oral administration supports the evaluation of NRTTIs for HIV-1 pre-exposure prophylaxis.

Objective: Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has not been fully characterized in people with HIV (PWH) in different categories of disease.

Design: Retrospectively, we determined levels of β2M, neopterin, HIV RNA, albumin ratio, IgG index, CD4+ T cell count, neurofilament light chain protein (NfL), and leukocyte counts (WBC), in CSF and blood in PWH with and without antiretroviral treatment (ART). Persons without HIV served as controls.

Methods: Participants were grouped as: 1) neuroasymptomatic HIV (NA), 2) NA CSF escape, 3) symptomatic CSF escape, 4) secondary CSF escape, 5) HIV-associated dementia (HAD), 6) opportunistic infections in the central nervous system (CNS) (OI), and 7) elite controllers.

Results: We included 638 individuals: NA (N = 556); NA CSF escape (N = 33); symptomatic CSF escape (N = 4); secondary CSF escape (N = 5); HAD (N = 16); OI (N = 18); elite controllers (N = 6) and 59 controls. Highest CSF β2M levels were found in HAD, OI and symptomatic CSF escape. In 112 longitudinally followed NA participants, elevated CSF β2M levels (89%) were found at baseline, and (96%) for CSF neopterin. After ART initiation CSF β2M levels decreased by 10% per month and CSF neopterin by 17%. After three years 39% had CSF β2M and 44% had CSF neopterin levels above the reference values, similar to the controls (39%).

Conclusion: CSF β2M levels were elevated in the majority of individuals across HIV stages. Suppressive ART decreases β2M toward control levels, although neuroinflammation persists, most likely driven by non-HIV factors.

Objectives: To examine changes in weight after initiating different dolutegravir-based second-line antiretroviral regimens and to measure the impact of observed weight change on blood pressure and serum lipids.

Design: Secondary analysis of the D2EFT trial, a randomised open-label trial in people with HIV.

Methods: In D2EFT, ritonavir-boosted darunavir plus dolutegravir (DTG + DRV/r) and dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine (DTG + TDF/XTC) were compared to ritonavir-boosted darunavir plus two nucleoside reverse transcriptase inhibitors (DRV/r + 2NRTIs). We used linear mixed effects models for weight, blood pressure and lipid changes and generalized estimating equations for ≥5% weight gain.

Results: 826 participants were included. Significantly greater body weight and BMI gains at 48 and 96 weeks were observed in individuals taking DTG + DRV/r or DTG + TDF/XTC than in individuals taking DRV/r + 2NRTIs. Treatment arm (DTG + DRV/r and DTG + TDF/XTC), female gender, Black and Hispanic/Latino ethnicity, lower baseline CD4 count, and higher baseline HIV RNA were all associated with weight gain in multivariable analysis. There was no significant difference between treatment arms in blood pressure changes at 96 weeks after adjustment for weight gain. Both darunavir containing arms demonstrated greater increases in LDL cholesterol than DTG + TDF/XTC, with the greatest increase in the non-NRTI containing arm.

Conclusions: Dolutegravir-based second-line regimens were associated with weight gain, which was further influenced by gender, ethnicity and HIV-related factors. DTG-based second-line regimens had no significant effect on blood pressure at 96 weeks; DTG + TDF/XTC was associated with a more favourable lipid profile than darunavir-containing regimens.

Clinical trial registration number: NCT03017872.