Pere Domingo

Background: We evaluated the efficacy and safety of a once-daily oral two-drug regimen (2DR) combining doravirine and raltegravir in virologically suppressed people with HIV (PWH). Methods: DORAL is a multicentre, open-label, randomized phase II trial conducted in France, Italy, and Spain. Virologically suppressed adults receiving stable antiretroviral therapy (ART), naïve to doravirine and without raltegravir resistance, were randomized (2:1) either to switch immediately to doravirine (100 mg) plus raltegravir (1200 mg) or to continue baseline ART until week 48 before switching to doravirine plus raltegravir. The primary endpoint was virological failure (VF; confirmed plasma HIV-1-RNA ≥50 copies/mL) at week 48. Secondary endpoints included maintenance of virological suppression through W96, immunological outcomes, safety, and pharmacokinetics in a genital sub-study. Results: Among 114 participants (median age, 57 years; median CD4 count, 700 cells/mm3; median duration of virological suppression, 10 years), one VF occurred by week 48 in the immediate-switch group (1.3%; 95% CI, 0.0–6.9); none occurred in the delayed-switch group. No additional VF was observed through week 96. Immunological parameters remained stable during follow-up. Three adverse events considered related to doravirine and raltegravir led to treatment discontinuation. One grade 3 adverse event (anxiety), considered related to study treatment, was reported. In the genital sub-study, drug concentrations exceeded inhibitory thresholds in most samples, with infrequent detection of low-level seminal HIV-1-RNA. Conclusions: This proof-of-concept phase II switch trial supports the feasibility of a once-daily doravirine plus raltegravir 2DR in selected PWH, particularly when minimizing drug-drug interactions or avoiding NRTI exposure is a priority.

Background: Prior to the COVID‐19 pandemic, antiretroviral therapy (ART) coverage and viral suppression were improving across Europe; however, the impact of the pandemic on HIV care remains uncertain. Methods: In‐person visits, ART coverage and viral suppression among those on ART were described in the EuroSIDA cohort for each calendar year from 2016 to 2022 and compared across five European regions. Multivariable logistic regression was used to assess factors associated with having an in‐person visit and with viral suppression. Results: Among 6740 participants, 71.9% were men, 34.9% were MSM, and the median age was 50 years (IQR: 42–56) at baseline (2016). The proportion of in‐person visits dropped from 75.0% in 2019 to 67.8% in 2020, increased to 74.5% in 2021 and was 72.3% in 2022. We observed a consistent increase in ART uptake over the years and a slight increase in missing HIV‐RNA data in 2020. The odds of attending clinic in person were lower in 2020 compared with 2016 (aOR: 0.81, 95% CI 0.75–0.87) but not in 2021 or 2022, while viral suppression increased over calendar time ( p < 0.0001). Compared to Central‐Western Europe, the other regions had lower odds of in‐person visits ( p < 0.0001, most prominently for Southern Europe, aOR: 0.18) and viral suppression ( p < 0.0001, most prominently for Eastern Europe, aOR: 0.07). Conclusions: Our study confirmed the resilience of HIV care across Europe during the COVID‐19 pandemic, whereas the regional and country differences in clinic attendance and viral suppression highlighted the need to address persisting gaps in HIV care on a national level.

Community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality worldwide, affecting individuals outside health care settings. Streptococcus pneumoniae is the predominant pathogen, although regional and socioeconomic factors significantly influence epidemiology, resistance patterns, and outcomes. Diagnosis relies on clinical evaluation supported by imaging, microbiology, and biomarkers, yet presentations are highly variable across age groups and comorbidities. Chest radiography remains the cornerstone for initial assessment, while high-resolution CT (HRCT) offers superior sensitivity for early detection and complications. Typical bacterial pathogens (eg, S. pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae ) produce lobar or bronchopneumonic consolidations, whereas atypical organisms ( Mycoplasma, Chlamydia, Legionella ) and viruses often yield diffuse ground-glass or interstitial patterns. Fungal and mycobacterial infections must also be considered, particularly in endemic regions. Radiologic-pathologic correlation is essential to differentiate CAP etiologies, guide management, and identify complications such as cavitation, empyema, or necrosis. Understanding these imaging patterns within global and clinical contexts is critical for improving diagnostic accuracy and optimizing patient outcomes.

The spectrum of diseases in individuals with human immunodeficiency virus (HIV) receiving successful antiretroviral therapy has evolved over time. In the past, they developed opportunistic infections and malignancies, whereas today, cardiovascular disease is among the most common causes of illness and premature death. Traditional risk factors for atherosclerosis (hypertension, hyperlipidemia, smoking, diabetes, family history of heart disease) are more prevalent in people with HIV than in the general population. However, it is well established that HIV itself causes increased immune activation, chronic inflammation, vascular dysfunction, and a cluster of metabolic abnormalities that contribute to a faster-than-usual rate of biological aging and a higher risk of developing atherosclerosis, a risk not fully captured by current risk models. In the REPRIEVE study, treatment with pitavastatin was shown to reduce the rate of first cardiovascular events among individuals with HIV receiving antiretroviral therapy. Importantly, the beneficial effects of statins on atherosclerosis likely extend beyond lowering cholesterol to include effects on vascular function and on immune and metabolic systems altered by HIV. Even among individuals on statins, a considerable risk of cardiovascular disease remains. Here, We provide a narrative review of current evidence and an expert perspective on emerging approaches to residual cardiovascular risk after REPRIEVE. We review the current understanding of atherosclerosis pathogenesis in individuals with HIV, focusing on recent findings from the REPRIEVE trial. We outline current approaches to improving cardiovascular risk assessment across clinical, biological, and computational levels. We also examine a growing number of therapeutic options that address residual inflammation and atherogenic metabolic disturbance in individuals with HIV on long-term, effective antiretroviral therapy. Significantly, after REPRIEVE, we must move from prescribing statins to all individuals with HIV toward more individualized cardiovascular disease prevention strategies, integrating clinical information, a variety of biomarkers, imaging studies, and even molecular information to generate optimal individualized cardiovascular disease prevention regimens that reflect the complexity of this outcome in naturally diverse individuals.

Background: VH4524184 (VH-184) is an emerging third-generation integrase strand transfer inhibitor (INSTI) with an enhanced in vitro resistance profile compared with second-generation INSTIs being developed as a long-acting antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1). We present data from a proof-of-concept phase 2a trial of VH-184 in people with HIV-1. Methods: This randomized, double-blind, placebo-controlled trial evaluated oral VH-184 monotherapy in adults naive to ART with HIV-1 RNA ≥ 3000 copies/mL. Participants received oral VH-184 10, 50, or 300 mg or placebo on days 1 (baseline), 4, and 7. On day 10, participants initiated standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through day 10. Secondary endpoints included safety, tolerability, exposure–response relationship, CD4+ cell effects, and treatment-emergent resistance. Results: Of 22 participants enrolled (VH-184, n = 19; placebo, n = 3), 86% were male, 68% were White, and median age was 32 years. Mean maximum change from baseline through day 10 in HIV-1 RNA was −1.17, −2.15, and −2.31 log10 copies/mL for VH-184 10, 50, and 300 mg, respectively. No adverse events (AEs) leading to withdrawal, treatment-emergent serious AEs, or deaths occurred. There were no clinically relevant changes in safety laboratory parameters, electrocardiograms, or vital signs. No VH-184 genotypic or phenotypic resistance was detected through day 10. Conclusions: Monotherapy with VH-184 demonstrated rapid and potent antiviral activity and a favorable safety and tolerability profile. The established exposure–response model and efficacy and safety results support further development of VH-184 as the core agent in complete ART regimens for HIV-1 (ClinicalTrials.gov, NCT06214052).

In a multicenter cross-sectional study of 1308 people with human immunodeficiency virus (HIV) and chronic hepatitis B, adherence to hepatocellular carcinoma surveillance guidelines was 28% among 1142 eligible individuals. Adherence was higher in those with cirrhosis (66%) than in noncirrhotic high-risk individuals (24%), highlighting the need to integrate liver surveillance into HIV care.

Late presentation of HIV-1 infection is linked to gut dysbiosis, impaired immune reconstitution, excess inflammation, immune activation, and increased morbidity and mortality. It is unclear if antiretroviral therapy initiation can reverse HIV-associated gut dysbiosis at all, or if specific antiretroviral regimens are more effective in restoring the gut microbiota than others. This has important implications for the long-term health of individuals with HIV. In this multicenter, open-label, randomized clinical trial (NCT02337322), 88 antiretroviral-naïve individuals with advanced HIV-1 infection (median CD4+ T cells of 34 cells/mm³) were randomized (1:1) to initiate lamivudine/abacavir plus either dolutegravir or ritonavir-boosted darunavir, and were followed for 2 years. Both groups had similar HIV-1 suppression rates and recovery of CD4+ T cells. However, treatment with dolutegravir led to increased gut microbial richness and diversity and enrichment of specific microbial taxa and metabolic pathways. These changes were associated with reduced inflammation and lower immune activation, outcomes that did not occur with darunavir/ritonavir. After two years, participants on dolutegravir-based therapy had gut microbiota profiles more closely resembling those of people without HIV, compared to individuals taking darunavir/ritonavir. In summary, dolutegravir-based therapy restores the gut microbiota more effectively than darunavir/ritonavir in patients who present late with HIV.

Background/Objectives: Whilst cancer is a leading cause of death in people with HIV, less is known about clinical outcomes after cancer. Methods: Participants from the RESPOND and D:A:D cohorts with the five most common cancers (Kaposi’s sarcoma (KS); non-Hodgkin lymphoma (NHL); and lung, anal and prostate cancers) were followed from first cancer diagnosis after 2006/2012 [D:A:D/RESPOND] until death, final follow-up or administrative censoring (2016/2021). Incidence rates (IR) were calculated for post-cancer mortality; for non-fatal events (cardiovascular disease, diabetes, another primary cancer, AIDS events) individually and as a non-fatal composite clinical outcome (CCO). Predictors or mortality and CCO were assessed using Poisson regression with generalized estimating equations. Results: Amongst 2485 participants with cancer, mortality and CCO IRs were highest after lung cancer (445.4/1000 person years [95% CI 399.7, 494.9], 117.1 [94.3, 143.8], respectively) compared to other cancers and lowest after KS (21.3 [16.9, 26.6], 43.9 [37.5, 51.3]). The most common non-fatal outcomes were AIDS events after NHL and KS, diabetes after lung and prostate cancer and another primary cancer after anal cancer. Among people with NHL and anal cancer, a diagnosis in more recent years was associated with lower mortality risk. Increasing the time-updated CD4 count reduced mortality by 15–40% (per 100 cells/µL) after NHL and anal and lung cancers and reduced CCO risk by 17–28% after KS and NHL. Smoking, low BMI and multimorbidity increased CCO risks by two to three times after KS and NHL. Conclusions: Risk of post-cancer mortality and non-fatal outcomes varies by cancer type and risk profile, suggesting the need for personalized post-cancer clinical monitoring.