Identifying risk factors for anal cancer in people with HIV in Spain: a multicentre retrospective cohort study nested in the PISCIS cohort.

BACKGROUND: People with HIV have a substantially higher risk of anal cancer than the general population. We aimed to identify risk factors associated with the development of anal cancer among people with HIV to implement more effective and targeted screening strategies. METHODS: We conducted a multicentre retrospective cohort study in 16 hospitals across Catalonia and the Balearic Islands, Spain, between Jan 1, 1998, and Dec 31, 2022. Treatment-naive people with HIV nested in the PISCIS cohort aged 16 years and older with biopsy-proven squamous cell carcinoma of the anus or anal canal were eligible for inclusion. Data were retrieved from every hospital registry and were centrally validated in the PISCIS cohort and the Public Data Analysis for Health Research and Innovation Program. The primary outcome was the incidence rate (IR) of histologically confirmed anal cancer. We used Poisson regression to examine the association between the following risk factors and incidence of anal cancer: age, mode of HIV transmission, nadir CD4 cell count, and time period of HIV diagnosis. FINDINGS: Among 14 238 people with HIV, 107 (0·8%) developed anal cancer, with an overall IR of 72·5 cases per 100 000 person-years (95% CI 59·4-87·6) and median follow-up of 9·5 years (IQR 4·4-15·7). Of these patients with anal cancer, 37 (34·6%) died, of which 24 (64·9%) deaths were related to anal cancer. Incidence was highest among people with HIV with historical nadir CD4 counts of less than 200 cells per µL (IR 105·0 person-years, 95% CI 82·0-132·5) and lowest among those with counts of more than 350 cells per µL (2·9 person-years, 0·1-16·0). Among men who have sex with men (MSM), the IR was 211·5 person-years (95% CI 151·1-211·7) among those with a CD4 count of less than 200 cells per µL, 37·6 person-years (16·2-74·1) among those with a count of 200-350 cells per µL, and 4·8 person-years (0·1-26·9) among those with a count of more than 350 cells per µL. Among people with HIV younger than 30 years, there were no cases of anal cancer among women or men who do not have sex with men, and one case among MSM with a nadir CD4 count of more than 350 cells per µL (IR 4·8 person-years, 95% CI 0·1-26·9). In the multivariable analysis, people with HIV with nadir CD4 counts of more than 350 cells per µL had the lowest risk of developing anal cancer, compared with people with HIV with counts of less than 200 cells per µL (adjusted IR ratio 0·03, 95% CI 0·00-0·25; p=0·0010) or 200-350 cells per µL (0·30, 0·17-0·55; p<0·0001). Compared with people with HIV younger than 30 years, people with HIV aged 60 years and older had an adjusted IR ratio of 27·6 (3·7-206·9; p=0·0010) and people with HIV aged 45-59 years of 21·6 (3·0-156·4; p=0·0020). Compared with individuals diagnosed after 2015, a diagnosis of HIV before 1998 had an adjusted IR ratio of 33·0 (7·9-137·5; p<0·0001). INTERPRETATION: A nadir CD4 count threshold below 350 cells per µL, particularly less than 200 cells per µL, has the potential to identify people with HIV at heightened risk of developing anal cancer. Customised screening strategies that prioritise screening for individuals at high risk with this surrogate marker could maximise available resources. External validation of these data with other cohorts is required before screening recommendations can be updated. FUNDING: Catalan Health Department, Generalitat de Catalunya.

Evolving trends in neuropsychological profiles of post COVID-19 condition: A 1-year follow-up in individuals with cognitive complaints.

Cognitive difficulties are reported as lasting sequelae within post COVID-19 condition. However, the chronicity of these difficulties and related factors of fatigue, mood, and perceived health have yet to be fully determined. To address this, the current longitudinal study aimed to clarify the trends of cognitive test performance and cognitive domain impairment following COVID-19 onset, and whether hospitalization influences outcomes. 57 participants who reported subjective cognitive difficulties after confirmed COVID-19 infection were assessed at baseline (~6 months post COVID-19) and follow-up (~15 months later) visits. Assessments included measures across multiple cognitive domains and self-report questionnaires of fatigue, mood, and overall health. Analyses were conducted in three stages: at the test score level (raw and adjusted scores), at the cognitive domain level, and stratified by hospitalization status during infection. Results at the test-score level indicate that cognitive performance remains relatively stable across assessments at the group level, with no significant improvements in any adjusted test scores at follow-up. Cognitive domain analyses indicate significant reductions in attention and executive functioning impairment, while memory impairment is slower to resolve. On self-report measures, there was a significant improvement in overall health ratings at follow-up. Finally, those hospitalized during infection performed worse on timed cognitive measures across visits and accounted for a larger proportion of cases with short-term and working memory impairment at follow-up. Overall, our findings indicate that cognitive difficulties persist both at test score and cognitive domain levels in many cases of post COVID-19 condition, but evidence suggests some improvement in global measures of attention, executive functioning and overall self-rated health. Furthermore, an effect of hospitalization on cognitive symptoms post COVID-19 may be more discernible over time.

Discrimination of the Veterans Aging Cohort Study Index 2.0 for Predicting Cause-specific Mortality Among Persons With HIV in Europe and North America.

Background: Predicting cause-specific mortality among people with HIV (PWH) could facilitate targeted care to improve survival. We assessed discrimination of the Veterans Aging Cohort Study (VACS) Index 2.0 in predicting cause-specific mortality among PWH on antiretroviral therapy (ART). Methods: Using Antiretroviral Therapy Cohort Collaboration data for PWH who initiated ART between 2000 and 2018, VACS Index 2.0 scores (higher scores indicate worse prognosis) were calculated around a randomly selected visit date at least 1 year after ART initiation. Missingness in VACS Index 2.0 variables was addressed through multiple imputation. Cox models estimated associations between VACS Index 2.0 and causes of death, with discrimination evaluated using Harrell's C-statistic. Absolute mortality risk was modelled using flexible parametric survival models. Results: Of 59 741 PWH (mean age: 43 years; 80% male), the mean VACS Index 2.0 at baseline was 41 (range: 0-129). For 2425 deaths over 168 162 person-years follow-up (median: 2.6 years/person), AIDS (n = 455) and non-AIDS-defining cancers (n = 452) were the most common causes. Predicted 5-year mortality for PWH with a mean VACS Index 2.0 score of 38 at baseline was 1% and approximately doubled for every 10-unit increase. The 5-year all-cause mortality C-statistic was .83. Discrimination with the VACS Index 2.0 was highest for deaths resulting from AIDS (0.91), liver-related (0.91), respiratory-related (0.89), non-AIDS infections (0.87), and non-AIDS-defining cancers (0.83), and lowest for suicides/accidental deaths (0.65). Conclusions: For deaths among PWH, discrimination with the VACS Index 2.0 was highest for deaths with measurable physiological causes and was lowest for suicide/accidental deaths.

CD66b+/CD68+ circulating extracellular vesicles, lactate dehydrogenase and neutrophil-to-lymphocyte ratio can differentiate coronavirus disease 2019 severity during and after infection.

Coronavirus disease 2019 (COVID-19) has been a major public health burden. We hypothesised that circulating extracellular vesicles (cEVs), key players in health and disease, could trace the cell changes during COVID-19 infection and recovery. Therefore, we studied the temporal trend of cEV and inflammatory marker levels in plasma samples of COVID-19 patients that were collected within 24 h of patient admission (baseline, n = 80) and after hospital discharge at day-90 post-admission (n = 59). Inflammatory markers were measured by standard biochemical methods. cEVs were quantitatively and phenotypically characterized by high-sensitivity nano flow cytometry. In patients recovered from COVID-19 lower levels of inflammatory markers were detected. cEVs from vascular (endothelial cells) and blood (platelets, distinct immune subsets) cells were significantly reduced at day-90 compared to admission levels, a pattern also observed for cEVs from progenitor, perivascular and epithelial cells. The best discriminatory power for COVID-19 severity was found for inflammatory markers lactate dehydrogenase and neutrophil-to-lymphocyte ratio and for granulocyte/macrophage-released CD66b+/CD68+-cEVs. Albeit inflammatory markers were good indicators of systemic inflammatory response and discriminators of COVID-19 remission, they do not completely reveal cell stress and organ damage states. cEVs reaching baseline pre-infection levels at 90 days post-infection in recovered patients discriminate parental cells affected by disease.

Mitochondrial Haplogroups and Weight Gain After Initiating ART in Patients With HIV.

We studied the association of mitochondrial DNA (mtDNA) haplogroups with weight and body mass index (BMI) gain at 96 weeks in 1019 treatment-naive persons with HIV (PWH) who initiated first-line antiretroviral therapy (ART) since 2014. The mean increase in weight and BMI over the study period was 2.90 kg and 0.98 kg/m2, respectively. We found a significant adjusted association between the major UK mtDNA haplogroup and lower weight and BMI increase at 96 weeks after ART initiation. Our findings reveal a potential role for mitochondrial genetics in the complex phenomenon of weight gain after initial ART in PWH.

Evolving AIDS- and non-AIDS Mortality and Predictors in the PISCIS Cohort of People Living With HIV in Catalonia and the Balearic Islands (Spain), 1998-2020.

Background: Effective antiretroviral therapy (ART) has substantially reduced acquired immunodeficiency syndrome (AIDS)-related deaths, shifting the focus to non-AIDS conditions in people living with human immunodeficiency virus (HIV) (PLWH). We examined mortality trends and predictors of AIDS- and non-AIDS mortality in the Population HIV Cohort from Catalonia and Balearic Islands (PISCIS) cohort of PLWH from 1998 to 2020. Methods: We used a modified Coding Causes of Death in HIV protocol, which has been widely adopted by various HIV cohorts to classify mortality causes. We applied standardized mortality rates (SMR) to compare with the general population and used competing risks models to determine AIDS-related and non-AIDS-related mortality predictors. Results: Among 30 394 PLWH (81.5% male, median age at death 47.3), crude mortality was 14.2 per 1000 person-years. All-cause standardized mortality rates dropped from 9.6 (95% confidence interval [CI], 8.45-10.90) in 1998 through 2003 to 3.33 (95% CI, 3.14-3.53) in 2015 through 2020, P for trend = .0001. Major causes were AIDS, non-AIDS cancers, cardiovascular disease, AIDS-defining cancers, viral hepatitis, and nonhepatitis liver disease. Predictors for AIDS-related mortality included being aged ≥40 years, not being a man who have sex with men, history of AIDS-defining illnesses, CD4 < 200 cells/µL, ≥2 comorbidities, and nonreceipt of ART. Non-AIDS mortality increased with age, injection drug use, heterosexual men, socioeconomic deprivation, CD4 200 to 349 cells/µL, nonreceipt of ART, and comorbidities, but migrants had lower risk (adjusted hazard risk, 0.69 [95% CI, .57-.83]). Conclusions: Mortality rates among PLWH have significantly decreased over the past 2 decades, with a notable shift toward non-AIDS-related causes. Continuous monitoring and effective management of these non-AIDS conditions are essential to enhance overall health outcomes.

Multiomics plasma effects of switching from triple antiretroviral regimens to dolutegravir plus lamivudine.

INTRODUCTION: The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48 weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters. METHODS: Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48 weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48 weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms. RESULTS: Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR. CONCLUSIONS: Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences.

Major cardiovascular events after COVID-19 in people with HIV.

OBJECTIVES: To assess the effect of COVID-19 on the postacute risk of cardiovascular events (CVEs) among people with HIV (PWH). METHODS: Population-based matched cohort, including all PWH ≥16 years in the Catalan PISCIS HIV cohort. We estimated the incidence rate of the first CVE after COVID-19, analysed it a composite outcome (2020-2022). We adjusted for baseline differences using inverse probability weighting and used competing risk analysis. RESULTS: We included 4199 PWH with and 14 004 PWH without COVID-19. The median follow-up was 243 days (interquartile range [IQR]: 93-455), 82% (14 941/18 203) were men, with a median age of 47 years. Overall, 211 PWH with COVID-19 and 621 without developed CVE, with an incidence rate of 70.2 and 56.8/1000 person-years, respectively. During COVID-19 infection, 7.6% (320/4199) required hospitalization and 0.6% (25/4199) intensive care unit admission, 97% (4079/4199) had CD4+T-cell ≥200 cells/µL, 90% (3791/4199) had HIV-RNA<50 copies/mL and 11.8% (496/4199) had previous CVE at baseline. The cumulative CVE incidence was higher among PWH after COVID-19 compared with PWH without COVID-19 during the first year (log-rank p=0.011). The multivariable analysis identified significantly increased CVE risk with age, heterosexual men, previous cardiovascular disease (CVD), and chronic kidney or liver disease. COVID-19 was associated with increased subsequent risk of CVE (adjusted hazard ratio 1.30 [95% CI, 1.09-1.55]), also when only including individuals without previous CVD (1.60 [95% CI, 1.11-2.29]) or nonhospitalized patients (1.34 [95% CI, 1.11-1.62]). DISCUSSION: COVID-19 was associated with a 30% increased risk of major CVE in PWH during the subsequent year, suggesting that COVID-19 should be considered an additional CVD risk in PWH in the short term.

The impact of the COVID-19 pandemic on healthcare services utilization among people living with HIV in Catalonia, Spain: A population-based cohort study.

BACKGROUND: The COVID-19 pandemic disrupted healthcare services usage. We estimated the impact of the COVID-19 pandemic on healthcare services utilization among people living with HIV (PLWH) in Catalonia, Spain. METHODS: We accessed public healthcare usage in HIV units, primary care, hospitals, and emergency departments among 17,738 PLWH in the PISCIS cohort from January 1, 2017, to December 31, 2020. We performed an interrupted time series analysis using the autoregressive integrated moving average to estimate the effect of COVID-19 on medical visits and HIV monitoring among PLWH. RESULTS: A non-significant decrease of 17.1% (95% CI: [-29.4, 0.4]) in overall medical visits was observed during the lockdown, followed by a steady resumption until the end of 2020. Three health facilities presented statistically significant declines in visits during the lockdown: HIV units (-44.8% [-56.7, -23.6]), hospitals (-40.4% [-52.8, -18.1]), and emergency departments (-36.9% [-47.0, -21.9]); thereafter, the visits have begun to increase steadily but not to previous levels as of December 2020. In contrast, primary care visits remained unchanged during the lockdown by 1.9% (95% CI: -13.5, 23.9). CD4 cell (54.2% [95% CI: -64.4, -36.0]) and HIV RNA viral load (53.1% [95% CI: -62.9, -36.1]) laboratory monitoring reduced significantly during the lockdown. CONCLUSION: COVID-19 lockdowns significantly disrupted in-person healthcare services usage among PLWH. The reduction in healthcare utilization however did not affect primary care services. Despite services gradually rebounding to pre-pandemic levels, it is imperative to effectively prepare for future pandemics and implement measures to ensure continuous provision of care to PLWH during pandemic lockdowns.

Disparities in Coronavirus Disease 2019 Clinical Outcomes and Vaccination Coverage Among Migrants With Human Immunodeficiency Virus in the PISCIS Cohort: A Population-Based Propensity Score-Matched Analysis.

Background: Coronavirus disease 2019 (COVID-19) disproportionately affects migrants and ethnic minorities, including those with human immunodeficiency virus (HIV). Comprehensive studies are needed to understand the impact and risk factors. Methods: Using data from the PISCIS cohort of people with HIV (PWH) in Catalonia, Spain, we investigated COVID-19 outcomes and vaccination coverage. Among 10 640 PWH we compared migrants and non-migrants assessing rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, diagnosis, and associated clinical outcomes through propensity score matching and multivariable Cox regression. Results: The cohort (mean age, 43 years; 83.5% male) included 57.4% (3053) Latin American migrants. Migrants with HIV (MWH) had fewer SARS-CoV-2 tests (67.8% vs 72.1%, P < .0001) but similar COVID-19 diagnoses (29.2% vs 29.4%, P = .847) compared to Spanish natives. Migrants had lower complete vaccination (78.9% vs 85.1%, P < .0001) and booster doses (63.0% vs 65.5%, P = .027). COVID-19 hospitalizations (8.1% vs 5.1%, P < .0001) and intensive care unit (ICU) admissions (2.9% vs 1.2%, P < .0001) were higher among migrants, with similar hospitalization duration (5.5 vs 4.0 days, P = .098) and mortality (3 [0.2%] vs 6 [0.4%], P = .510). Age ≥40 years, CD4 counts <200 cells/µL, ≥2 comorbidities, and incomplete/nonreception of the SARS-CoV-2 vaccine increased the risk of severe COVID-19 among migrants. Conclusions: MWH had lower rates of SARS-CoV-2 testing and vaccination coverage, although the rates of COVID-19 diagnosis were similar between migrants and non-migrants. Rates of COVID-19-associated hospitalizations and ICU admissions were higher among migrants in comparison with non-migrants, with similar hospitalization duration and mortality. These findings can inform policies to address disparities in future pandemic responses for MWH.

Heavy antiretroviral exposure and exhausted/limited antiretroviral options: predictors and clinical outcomes.

OBJECTIVES: People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort. METHODS: Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]). RESULTS: Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4 + cell count of 350 cells/µl or less (vs. 351-500 cells/µl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05). CONCLUSION: Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.

Mpox: Clinical Outcomes and Impact of Vaccination in People with and without HIV: A Population-Wide Study.

We investigated differences in mpox clinical outcomes in people with HIV (PWH) and without HIV (PWoH) and the impact of vaccination in Catalonia, Spain. We used surveillance data and the PISCIS HIV cohort. We included all confirmed mpox cases (May-December 2022). Of 2122 mpox cases, the majority had mild disease, 56% were Spanish, and 24% were from Latin America. A total of 40% were PWH, with a median CD4+T-cell of 715 cells/µL; 83% had HIV-RNA < 50 copies/mL; and 1.8% CD4+T-cell < 200 cells/µL. PWH had no increased risk for complications, except those with CD4+T-cell < 200 cells/µL. PWH with CD4+T-cell < 200 cells/µL were more likely to be from Latin America, had more generalized exanthema, and required hospitalization more frequently (p = 0.001). Diagnosis of other sexually transmitted infections (STIs) was common, both at mpox diagnosis (17%) and two years before (43%). Dose-sparing smallpox intradermal vaccination was accompanied by a sharp decrease in mpox incidence in both populations (p < 0.0001). In conclusion, unless immunosuppressed, PWH were not at increased risk of severe disease or hospitalization. Mpox is a marker of high-risk sexual behavior and was associated with high HIV and STI rates, supporting the need for screening in all mpox cases. Ethnicity disparities demonstrate the need for interventions to ensure equitable healthcare access. Dose-sparing smallpox vaccination retained effectiveness.

A Randomized Trial of Dolutegravir Plus Darunavir/Cobicistat as a Switch Strategy in HIV-1-Infected Patients With Resistance to at Least 2 Antiretroviral Classes.

Background: Suppressed patients with drug-resistant HIV-1 require effective and simple antiretroviral therapy to maintain treatment adherence and viral suppression. Methods: This randomized, open-label, noninferiority, multicenter pilot study involved HIV-infected adults who met the following criteria: confirmed HIV-1 RNA <50 copies/mL for ≥6 months preceding the study randomization, treatment with at least 3 antiretroviral drugs, and a history of drug resistance mutations against at least 2 antiretroviral classes but remaining fully susceptible to darunavir (DRV) and integrase inhibitors. Participants were randomized 1:1 to switch to dolutegravir (DTG; 50 mg once per day) plus DRV boosted with cobicistat (DRV/c; 800/150 mg once per day; 2D group) or continue with their baseline regimen (standard-of-care [SOC] group). The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at week 48 relative to time to loss of virologic response, with a noninferiority margin set at -12.5%. Virologic failure was defined as confirmed HIV-1 RNA ≥50 copies/mL or a single determination of HIV-1 RNA >50 copies/mL followed by antiretroviral therapy discontinuation. Results: Forty-five participants were assigned to the 2D group and 44 to the SOC group. Time to loss of virologic response showed no difference in the proportion maintaining HIV-1 RNA <50 copies/mL at week 48: 39 of 45 (86.7%; 95% CI, 73.21%-94.95%) in the 2D group vs 42 of 44 (95.4%; 95% CI, 84.53%-99.44%) in the SOC group (log-rank P = .159) with an estimated difference of -8.7 (95% CI, -22.72 to 5.14). Only 2 (4.5%) in the SOC group experienced virologic failure, and 3 participants from the 2D group experienced adverse events leading to treatment discontinuation. Conclusions: In suppressed patients with at least 2 resistant antiretroviral classes, noninferiority could not be demonstrated by fully active DRV/c plus DTG. Nevertheless, there were no unexpected adverse events or virologic failure. DRV/c plus DTG may be considered a once-daily therapy option only for well-selected patients. Clinical Trials Registration. ClinicalTrials.gov (NCT03683524).

Long-term effects on subclinical cardiovascular disease of switching from boosted protease inhibitors to dolutegravir.

BACKGROUND: In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. METHODS: PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. RESULTS: Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. DISCUSSION: After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.

Decay of HIV RNA in Seminal Plasma and Rectal Fluid in Treatment-Naive Adults Starting Antiretroviral Therapy With Dolutegravir Plus Lamivudine or Bictegravir/Emtricitabine/Tenofovir Alafenamide.

BACKGROUND: Decay of HIV in seminal plasma (SP) and rectal fluid (RF) has not yet been described for the antiretroviral combination of dolutegravir (DTG) + lamivudine (3TC). METHODS: In this randomized multicenter pilot trial, males who were antiretroviral naive were randomized (2:1) to DTG + 3TC or bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). HIV-1 RNA was measured in blood plasma (BP), SP, and RF at baseline; days 3, 7, 14, and 28; and weeks 12 and 24. RESULTS: Of 25 individuals enrolled, 24 completed the study (DTG + 3TC, n = 16; BIC/FTC/TAF, n = 8). No significant differences were observed between groups for median decline in HIV-1 RNA from baseline at each time point or median time to achieve HIV-1 RNA <20 copies/mL in BP and SP and <20 copies/swab in RF. HIV-1 RNA decay patterns were compared in individuals receiving DTG + 3TC. Despite significantly higher percentages for changes from baseline in BP, median (IQR) times to HIV-1 RNA suppression were shorter in SP (7 days; 0-8.75) and RF (10.5 days; 3-17.5) than in BP (28 days; 14-84; P < .001). CONCLUSIONS: Comparable HIV-1 RNA decay in BP, SP, and RF was observed between DTG + 3TC and BIC/FTC/TAF. As shown with triple-drug integrase inhibitor-based regimens, rapid HIV-1 RNA suppression in SP and RF is achieved with DTG + 3TC, despite decay patterns differing from those of BP. CLINICAL TRIALS REGISTRATION: EudraCT 2019-004109-28.

Cardiovascular events in delayed presentation of HIV: the prospective PISCIS cohort study.

Objectives: People with HIV (PWH) have a higher cardiovascular risk than the general population. It remains unclear, however, whether the risk of cardiovascular disease (CVD) is higher in late HIV presenters (LP; CD4 ≤ 350 cells/µL at HIV diagnosis) compared to PWH diagnosed early. We aimed to assess the rates of incident cardiovascular events (CVEs) following ART initiation among LP compared to non-LP. Methods: From the prospective, multicentre PISCIS cohort, we included all adult people with HIV (PWH) initiating antiretroviral therapy (ART) between 2005 and 2019 without prior CVE. Additional data were extracted from public health registries. The primary outcome was the incidence of first CVE (ischemic heart disease, congestive heart failure, cerebrovascular, or peripheral vascular disease). The secondary outcome was all-cause mortality after the first CVE. We used Poisson regression. Results: We included 3,317 PWH [26 589.1 person/years (PY)]: 1761 LP and 1556 non-LP. Overall, 163 (4.9%) experienced a CVE [IR 6.1/1000PY (95%CI: 5.3-7.1)]: 105 (6.0%) LP vs. 58 (3.7%) non-LP. No differences were observed in the multivariate analysis adjusting for age, transmission mode, comorbidities, and calendar time, regardless of CD4 at ART initiation [aIRR 0.92 (0.62-1.36) and 0.84 (0.56-1.26) in LP with CD4 count <200 and 200- ≤ 350 cells/µL, respectively, compared to non-LP]. Overall mortality was 8.5% in LP versus 2.3% in non-LP (p < 0.001). Mortality after the CVE was 31/163 (19.0%), with no differences between groups [aMRR 1.24 (0.45-3.44)]. Women vs. MSM and individuals with chronic lung and liver disease experienced particularly high mortality after the CVE [aMRR 5.89 (1.35-25.60), 5.06 (1.61-15.91), and 3.49 (1.08-11.26), respectively]. Sensitivity analyses including only PWH surviving the first 2 years yielded similar results. Conclusion: CVD remains a common cause of morbidity and mortality among PWH. LP without prior CVD did not exhibit an increased long-term risk of CVE compared with non-LP. Identifying traditional cardiovascular risk factors is essential for CVD risk reduction in this population.

Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study.

Introduction: Second-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients. Methods: Real-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) ≥200 copies/mL at 24 weeks or as a single determination of VL ≥1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated. Results: Virological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir <100 cells/µL were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerability were consistent with expected safety profiles. Discussion: Whereas second-generation INSTIs are preferred treatment options worldwide, and DTG is one of the treatment of choices in resource-limited settings, first-generation INSTIs may still provide high virological and immunological effectiveness when DTG is not available.

Acute Bacterial Meningitis in Healthy Adult Patients: A Prospective Cohort Study.

Spontaneous bacterial meningitis (BM) is more common among patients with underlying conditions, but its characteristics in previously healthy patients are not well described. We analyzed the time trends of BM in terms of characteristics, and outcomes in patients without comorbidities. PATIENTS AND METHODS: Single-center, prospective observational cohort study of 328 adults with BM hospitalized in a tertiary university hospital in Barcelona (Spain). We compared the features of infections diagnosed in 1982-2000 and 2001-2019. The main outcome measure was in-hospital mortality. RESULTS: The median age of the patients increased from 37 to 45 years. Meningococcal meningitis significantly diminished (56% versus 31%, p < 0.000) whereas listerial meningitis increased (1.2% versus 8%, p = 0.004). Systemic complications were more common in the second period, although mortality did not vary significantly between periods (10.4% versus 9.2%). However, after adjusting for relevant variables, infection in the second period was associated with lower risk death. CONCLUSIONS: Adult patients without underlying comorbidities that developed BM in recent years were older and more likely to have pneumococcal or listerial infections and systemic complications. In-hospital death was less likely in the second period, after adjusting for risk factors of mortality.

Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning.

Adipose tissue from pheochromocytoma patients acquires brown fat features, making it a valuable model for studying the mechanisms that control thermogenic adipose plasticity in humans. Transcriptomic analyses revealed a massive downregulation of splicing machinery components and splicing regulatory factors in browned adipose tissue from patients, with upregulation of a few genes encoding RNA-binding proteins potentially involved in splicing regulation. These changes were also observed in cell culture models of human brown adipocyte differentiation, confirming a potential involvement of splicing in the cell-autonomous control of adipose browning. The coordinated changes in splicing are associated with a profound modification in the expression levels of splicing-driven transcript isoforms for genes involved in the specialized metabolism of brown adipocytes and those encoding master transcriptional regulators of adipose browning. Splicing control appears to be a relevant component of the coordinated gene expression changes that allow human adipose tissue to acquire a brown phenotype.

Incidence of Hypertension and Blood Pressure Changes in Persons With Human Immunodeficiency Virus at High Risk for Cardiovascular Disease Switching From Boosted Protease Inhibitors to Dolutegravir: A Post-hoc Analysis of the 96-week Randomised NEAT-022 Trial.

BACKGROUND: Integrase inhibitors have been recently linked to a higher risk for hypertension. In NEAT022 randomized trial, virologically suppressed persons with human immunodeficiency virus (HIV, PWH) with high cardiovascular risk switched from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D). METHODS: Primary endpoint was incident hypertension at 48 weeks. Secondary endpoints were changes in systolic (SBP) and diastolic (DBP) blood pressure; adverse events and discontinuations associated with high blood pressure; and factors associated with incident hypertension. RESULTS: At baseline, 191 (46.4%) participants had hypertension and 24 persons without hypertension were receiving antihypertensive medications for other reasons. In the 197 PWH (n = 98, DTG-I arm; n = 99, DTG-D arm) without hypertension or antihypertensive agents at baseline, incidence rates per 100 person-years were 40.3 and 36.3 (DTG-I) and 34.7 and 52.0 (DTG-D) at 48 (P = .5755) and 96 (P = .2347) weeks. SBP or DBP changes did not differed between arms. DBP (mean, 95% confidence interval) significantly increased in both DTG-I (+2.78 mmHg [1.07-4.50], P = .0016) and DTG-D (+2.29 mmHg [0.35-4.23], P = .0211) arms in the first 48 weeks of exposure to dolutegravir. Four (3 under dolutegravir, 1 under protease inhibitors) participants discontinued study drugs due to adverse events associated with high blood pressure. Classical factors, but not treatment arm, were independently associated with incident hypertension. CONCLUSIONS: PWH at high risk for cardiovascular disease showed high rates of hypertension at baseline and after 96 weeks. Switching to dolutegravir did not negatively impact on the incidence of hypertension or blood pressure changes relative to continuing protease inhibitors.