Search Results (43)

The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice) treated with the WHO/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)/tenofovir disoproxil fumarate (TDF, NRTIs)/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. HIV-1-infected and uninfected Hu-mice served as controls. After one month of infection (HIV-1_ADA), ECG intervals/segments were significantly altered. ECG changes progressively worsened as the duration of untreated infection increased. Treating HIV-1-infected animals with the DTG/TDF/FTC for eight weeks, starting four weeks after infection, prevented worsening, but did not restore ECG intervals/segments to those before infection. In hearts from DTG/TDF/FTC-treated animals, steady-state levels of the sarco-(endo) plasmic reticulum Ca²⁺ ATPase (SERCA2) were reduced by 35%. Steady-state levels of type 2 ryanodine receptor (RyR2) did not change, but its phosphorylation status at Ser2808 was 2-fold higher than that of uninfected controls, indicative of a gain-of-function. The density of perfused micro vessels and fibrosis in hearts of DTG/TDF/FTC-treated animals was not significantly different from that of HIV-1-infected and uninfected Hu-mice. These data show for the first time that HIV-1 infection is triggering abnormalities in the ECG of Hu-mice, and changes in ECG persisted with DTG/TDF/FTC treatment, independent of ischemia and/or fibrosis. They also indicate that chronic DTG/TDF/FTC treatment did not worsen ECG changes, including the QT interval. Since phosphorylation of RyR2 at Ser2808 occurs via β-adrenergic activation of protein kinase A, these new data also suggest that chronic hyperadrenergic activity may be increasing the risk of SCD via Ca²⁺ leak through RyR2. Full article

Background: Antiretroviral therapy (ART) has transformed HIV into a chronic manageable condition, yet metabolic toxicities including pancreatic enzyme alterations remain concerns. While older ART regimens have been associated with hyperamylasemia, the impact of integrase strand transfer inhibitor (INSTI)-based therapies on serum amylase levels has not been specifically examined. Purpose: This study aimed to compare longitudinal patterns of serum amylase levels between people living with HIV receiving INSTI-based versus NNRTI/PI-based ART regimens. Methods: This retrospective observational study analyzed 99 HIV-positive patients at Kaplan Medical Centre, Israel (2002–2023). Participants received either INSTI-based (n = 49) or NNRTI/PI-based (n = 50) regimens for ≥24 months. Serum amylase, viral load, CD4 counts, and metabolic parameters were measured at baseline, one year, and two years. Repeated-measures ANOVA assessed longitudinal changes. Results: NNRTI/PI-treated patients maintained significantly higher mean amylase levels throughout follow-up (baseline: 122.9 ± 42.1 U/L; two years: 129.6 ± 38.0 U/L) compared to INSTI-treated patients (baseline: 78.7 ± 32.3 U/L; two years: 68.4 ± 23.4 U/L; p < 0.0001 at all timepoints). A significant linear time-by-group interaction (p = 0.037) demonstrated divergent trajectories. No clinical pancreatitis was observed in either treatment group during the follow-up period, and all observed variations in serum amylase were biochemical and asymptomatic. While these findings are reassuring regarding acute pancreatic toxicity, the clinical significance of chronic subclinical enzyme elevations remains uncertain. Conclusion: INSTI-based antiretroviral regimens suggest a favorable pancreatic and metabolic safety profile compared with NNRTI/PI-based therapies. Full article

Emerging evidence indicates a high rate (>10%) of drug resistance (DR) associated with integrase strand transfer inhibitors (INSTIs) in developed countries, although there is limited information on DR during INSTI treatment in Uganda. With the increased use of INSTIs as standard first-line treatment, monitoring for DR using next-generation sequencing (NGS) has become essential. NGS can detect the lower-frequency variants that may be missed by traditional Sanger sequencing (SS). This study evaluates the diagnostic accuracy of next-generation sequencing (NGS) compared to Sanger sequencing for detecting HIV-1 INSTI resistance mutations and estimates the prevalence and factors associated with drug resistance among adults with virologic failure on INSTI-based regimens in Uganda. Utilizing the Illumina MiSeq platform for NGS, data was analyzed using STATA V.18 and a logistic regression model at 5% level of significance. This study demonstrates that NGS achieved 100% sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy in detecting major mutations. NGS identified INSTI DRMs in 4% of adults at a ≥20% threshold and was able to detect both high- and low-abundance variants, which could have important implications for clinical outcomes. This study emphasizes the need for HIVDR testing before antiretroviral therapy (ART) initiation, given the increasing use of INSTIs. We recommend that healthcare providers adopt more sensitive diagnostics such as NGS and use detailed resistance profiles to tailor antiretroviral therapies. This approach is critical for effectively managing and preventing drug-resistant HIV strains. Full article

Implementation of universal antiretroviral treatment (ART) in pregnancy has improved maternal health and reduced vertical transmission. However, women living with HIV (WLHIV) still experience worse perinatal outcomes. This retrospective study compared demographic, virological factors, ART regimens and perinatal outcomes in pregnant WLHIV between 2000–2010 (n = 318) and 2011–2021 (n = 140) at a tertiary center in Barcelona. Significant demographic shifts included changes in ethnic distribution, substance use, educational attainment, and maternal BMI. Significant progress in infection control was observed, with increased ART coverage up to 97%, improved viral suppression (80% to 91.3%, p = 0.002), and enhanced immunological status. ART regimens shifted significantly, with an increase in integrase strand transfer inhibitors (INSTI)-based regimens (0.7% to 39.2%, p < 0.001). Obstetric management evolved, with a rise in vaginal deliveries (24.8% to 44.3%, p < 0.001) and a decline in intrapartum zidovudine (93.7% to 54.7%, p < 0.001). Notably, preterm birth rates sharply declined, yet small-for-gestational-age (SGA) infants (26.4% vs. 20%, p = 0.323) and preeclampsia rates remained unchanged and higher than in the general population. All statistical analyses were performed in IBM SPSS statistics 23. In conclusion, although maternal and perinatal outcomes in pregnant WLHIV have improved over the past two decades, a high rate of adverse perinatal outcomes related to placental dysfunction (SGA, preeclampsia) persist. Our findings highlight the need for optimized prenatal care and further research to develop targeted interventions for WLHIV. Full article

Background/Objectives: Excessive weight gain is a growing concern among people living with HIV (PWH) receiving integrase strand transfer inhibitor (INSTI)-based regimens as first-line antiretroviral therapy (ART), as it may contribute to multimorbidity. The mechanisms driving weight gain in INSTI users are not fully understood but are thought to be multifactorial. This study examines the plasma metabolome associated with weight gain in PWH on INSTI-based regimens. Methods: We conducted a nested case–control study within the randomized clinical trial MICTLAN (NCT06629480). Sixty-six participants were randomized to receive INSTI-based regimens, either bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), and followed for 18 months. Weight gain >10% relative to baseline was considered a primary endpoint and used as a criterium to categorize cases (n = 28) and controls (n = 38). Anthropometric and clinical measurements, plasma insulin, and metabolomic profiles were assessed at baseline and 18 months post-ART. Plasma untargeted metabolomics was performed using liquid chromatography–mass spectrometry (LC-MS/MS) to identify metabolomic changes linked to weight gain. Bioinformatic tools, including Partial Least Squares Discriminant Analysis (PLS-DA), volcano plots, and KEGG pathway enrichment analysis, were used to analyze plasma metabolomes and identify significant differential metabolites. Results: Weight gain at 18 months in PWH on INSTI-based ART was associated with insulin resistance, as measured by HOMA-IR (OR 3.23; 95% CI 1.14–9.10; p = 0.023), and visceral adipose tissue thickness > 4 cm (OR 4.50; 95% CI 1.60–13.03; 9.10; p = 0.004), and hypertriglyceridemia (OR 3.9; 95% CI 1.38–10.94; p = 0.008). Baseline HIV RNA viral load >50,000 copies/mL (OR 8.05; 95% CI 2.65–24.43; p = 0.0002) was identified as a baseline predictor of weight gain (aOR 6.58 (1.83–23.58); p = 0.004). In addition, accumulation of circulating medium-chain acylcarnitines, indicative of mitochondrial dysfunction, and insulin resistance were linked to weight gain in PWH on INSTI-based regimens after 18 months of therapy. Conclusions: This metabolomic study identified metabolites reflecting mitochondrial dysfunction, dysregulated lipid metabolism, and altered amino acid metabolism as key mechanisms underlying insulin resistance and weight gain in PWH on INSTI-based ART. Full article

The HIV-1 epidemic continues to challenge global public health, especially in sub-Saharan Africa. The rise in drug-resistant viruses, particularly pan-resistant strains, threatens treatment effectiveness, hindering progress toward UNAIDS viral suppression goals. This is critical in low-to-middle income countries (LMICs) like Zimbabwe, where treatment options and access to drug resistance testing are limited. This cross-sectional study analyzed 102 genotypes from patients with HIV-1 RNA ≥ 1000 copies/mL after at least 6 months on a dolutegravir (DTG)-based ART. HIV-1 genotyping and drug resistance interpretation were performed using the Stanford HIV Drug Resistance Database. Overall, 62% of genotypes harbored at least one drug resistance mutation, with 27% showing integrase strand transfer inhibitor (INSTI)-associated mutations. High-level resistance to DTG and cabotegravir was found in 14% and 23% of integrase sequences, respectively, primarily driven by G118R and E138K/T mutations. Pan-resistance was observed in 18% of complete genotypes, with one case of four class resistance. These results highlight the emergence of INSTI resistance in LMICs. The study underscores the urgent need for enhanced HIV drug resistance testing, continuous surveillance, and strategic optimization of ART regimens in resource-constrained settings to ensure effective HIV management. Full article

Background: Treatment failure continues to play a role in HIV-related morbidity in Mozambique. Antiretroviral therapy (ART) regimen switches are decided empirically, as HIV genotypic resistance testing (HIV-GT) is unavailable in Mozambique’s public health system. Since 2016, Médecins Sans Frontières (MSF) and I-TECH have provided access to HIV-GT at Alto Maé Health Center, Maputo. We describe the cohort of people with virologic failure (VF) that underwent HIV-GT and analyze dolutegravir (DTG) resistance (R) patterns. Methods: This cross-sectional assessment of routine programmatic data between July 2020 and February 2024 was conducted to guide future program enhancements. People living with HIV (PLWH) receiving ART beyond the first line with confirmed VF were included. Mutations were interpreted according to the Stanford HIVdb algorithm. We applied Bayesian bootstrapping for analysis, and the threshold for significance of effects was defined as a probability of 95%. Results: A total of 106 persons underwent HIV-GT following a structured adherence strategy, 62 (58.5%) of whom were on a DTG-based regimen. Fifty-seven of the 62 samples from persons on a DTG-based regimen were sequenced, and 51 (89.5% [95% CrI: 80.7, 96.2]) had confirmed resistance to DTG; the mean DTG-R score was 70.2 (95% CrI: 62.2, 78). Samples with DTG-R had a median of three INSTI mutations (IQR 1–4). Major DTG-associated mutations were found in 46 out of 57 samples: G118R (n = 28), R263K (n = 15), and Q148RK (n = 7). None of the people on the protease inhibitor regimen had an INSTI mutation. Conclusions: In contexts with limited access to resistance testing, the introduction of algorithms to identify PLWH at risk of developing drug resistance is strongly recommended. The proposed algorithm incorporates adherence reinforcement strategies, as recommended in national policies, followed by a short, supervised antiretroviral therapy (ART) support strategy. This approach has shown a high predictive value for identifying PLWH with resistance mutations to dolutegravir (DTG), thereby allowing the continuation of the effective DTG regimen without unnecessary regimen switches. Full article

Background: HIV drug resistance (DR) mutations can compromise antiretroviral therapy (ART) success among children living with HIV (CLHIV). We conducted a secondary analysis using data from a randomized control trial for ART monitoring among CLHIV in Kisumu County, Kenya from 2019 to 2023, to assess clinical, psychosocial, and structural factors associated with HIV DR. Methods: 704 CLHIV were followed for 12+ months, with characteristics captured at enrollment and follow-up visits in the “parent” randomized-controlled-trial (of point-of-care plasma viral load testing and for viremias ≥ 1000 copies/mL HIV genotyping for DR vs. standard-of-care) and an observational “extension” substudy (of participants on a dolutegravir-containing ART with genotyping performed on viremic specimens ≥ 200 copies/mL). A multivariate modified Poisson regression model was used to analyze factors associated with sequences yielding a Stanford HIVDR database DR penalty score (DR-PS) ≥ 30 to a nucleos(t)ides and/or non-nucleoside reverse transcriptase inhibitor, protease inhibitor (PI), and/or integrase inhibitor (INSTI). Results: Among 113 (16.1%) participants who underwent genotyping, 93 (82.3%) had a DR-PS ≥ 30. DR-PS ≥ 30 were associated with age 1–5 years (adjusted risk ratio (ARR) = 1.84; 95% confidence interval (CI): 1.07, 3.14), history of viremia ≥ 1000 copies/mL (ARR = 4.18; 95% CI: 2.77, 6.31), prescription of a PI- (ARR = 6.05; 95% CI: 3.43, 10.68) or INSTI-containing regimen (ARR = 1.83; 95% CI: 1.08, 3.11), poor adherence to ART (ARR = 1.91; 95% CI: 1.32, 2.76), lack of caregiver confidence in ART administration (ARR = 1.89; 95% CI: 1.11, 3.22), and mid-sized clinic populations (ARR = 0.55; 95% CI: 0.33, 0.92). Conclusion: Addressing social factors associated with DR-PS ≥ 30 may improve ART success among CLHIV. Full article

Human papillomavirus (HPV) significantly contributes to anogenital cancers, with elevated risks among people living with HIV (PWH), particularly men who have sex with men (MSM). This study assessed anal HPV prevalence and associated risk factors in PWH in Mexico, focusing on the role of antiretroviral therapy (ART). Methods: A cross-sectional study at an HIV clinic in Mexico City (October 2023–December 2024) enrolled 214 MSM with HIV. The participants completed a validated risk factor questionnaire and provided anal samples for real-time PCR testing of 28 HPV genotypes. Logistic regression analyzed associations between HPV infection, ART regimens, and clinical/behavioral factors. Results: HPV prevalence was 89.3%, with HPV-16 (20.1%) being the most common high-risk genotype. Integrase inhibitor (INSTI) use was inversely associated with HPV-16 infection (OR: 0.42; 95% CI: 0.21–0.83; p = 0.011), while protease inhibitor use increased HPV-16 (OR: 2.16; 95% CI: 1.09–4.29; p = 0.025) and HPV-6 risks. Higher CD4+ counts (≥500 cells/mm³) and undetectable HIV viral load (<40 copies/mL) were protective against multiple HPV genotypes. Lower education and smoking increased HPV risk. Conclusions: This first Mexican study in the ART and HPV vaccination era highlights high anal HPV prevalence in PWH and suggests that INSTI-based regimens may reduce HPV-16 risk, informing ART selection for HPV prevention. Full article

The emergence and spread of HIV drug resistance mutations (DRMs) pose a threat to current and future treatment options. To inform policy, this review aimed to determine the magnitude and patterns of DRMs in patients on ART in Tanzania. A systematic literature search was conducted in MEDLINE through PubMed, Embase, and CINAHL up to December 2024. A total of 9685 HIV patients from 23 eligible studies were analyzed. The prevalence of virological failure in studies that used a threshold of >1000 and >400 copies/mL was 24.83% (95% CI: 17.85–32.53%) and 36.94% (95% CI: 24.79–50.00%), respectively. Major DRMs were observed at 87.61% (95% CI: 76.25–95.91%). A decrease in prevalence was observed in studies conducted from 2019, with a pooled prevalence of 62.15% (95% CI: 31.57–88.33%). The most frequently observed HIV-1 subtypes were subtype C at 36.20% (95% CI: 30.71–41.85%), A1 at 33.13% (95% CI: 28.23–38.20%), and subtype D at 16.00% (95% CI: 11.41–21.12%), while recombinant forms of the virus were observed at 13.29% (95% CI: 9.79–17.17%). The prevalence of DRMs against NRTIs and NNRTIs was significantly high, while that against INSTIs and PIs was low, supporting the continued use of PI- and INSTI-based regimens in Tanzania and the need for continued surveillance of DRMs. Full article

Pregnancy introduces significant physiological changes that alter the pharmacokinetics (PK) of antiretroviral therapy (ART), impacting its safety and efficacy in HIV-positive women. Optimizing ART during pregnancy is critical to maintaining maternal virological suppression and preventing mother-to-child transmission (MTCT) of HIV. This review evaluates the impact of pregnancy-induced PK changes on ART and proposes strategies for tailored regimens to improve outcomes. A comprehensive review of published literature was conducted, focusing on PK adaptations during pregnancy and their implications for different ART classes, including protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). Key studies were analyzed to assess drug exposure, efficacy, and safety. Pregnancy significantly alters the PK of antiretrovirals, with increased hepatic metabolism, renal clearance, and changes in plasma protein binding leading to reduced drug exposure. For example, drugs like lopinavir and atazanavir require dose adjustments, while dolutegravir maintains efficacy despite reduced plasma levels. Integrase inhibitors demonstrate favorable virological suppression, although cobicistat-boosted regimens show subtherapeutic levels. Tailored approaches, such as therapeutic drug monitoring (TDM), optimize ART efficacy while minimizing toxicity. Pregnancy-specific PK changes necessitate evidence-based ART adjustments to ensure virological suppression and reduce MTCT risk. Incorporating TDM, leveraging pharmacogenomic insights, and prioritizing maternal and neonatal safety are critical for personalized ART management. Further research into long-acting formulations and global guideline harmonization is needed to address disparities in care and improve outcomes for HIV-positive pregnant women. Full article

Dolutegravir-based antiretroviral therapy (ART) simplification is increasingly common, although some patients cannot take this drug due to intolerance or drug resistance. Boosted-protease inhibitors (bPI) might be an option in this scenario. Nevertheless, long-term outcomes have not been studied yet. A controlled cohort study comparing 5-year outcomes of ART simplification bPI-based regimens (without integrase strand transfer inhibitor—INSTI) versus ART maintenance was conducted in a Brazilian referral center. Viral suppression rates and mortality after 5 years were the primary outcomes of the study. Eighty individuals were included in each group; 47.5% were women, and the mean age was 56 years. The five-year survival rate was 88.8% in the simplified group and 87.5% in the maintenance arm (log-rank = 0.41). Viral suppression rate was 78.8% and 70.0%, respectively (p = 0.28). Individuals presented less renal function decline (−5 vs. −10 mL/min/1.73 m²; p < 0.05) in the simplified arm. No difference was observed in metabolic parameters. Based on our findings, ART simplification without INSTI has shown efficacy and safety comparable to maintenance of triple therapy even in the long term, and could be an option in these situations, which might be even more important in settings with limited options. Full article

A treatment-experienced, highly adherent person living with HIV for over 25 years developed resistance mutations against all four major ART classes, including bictegravir (BIC). This led to viral failure on a quadruple regimen including BIC and doravirine (DOR). Resistance emergence was associated with M184V, thymidine analog mutations (TAMs), NNRTI mutations (108I, 234I, 318F), and INSTI mutations (T97A, G140S, Q148H, G149A), likely driven by suboptimal BIC levels due to divalent cation interactions. During a two-month ART interruption, the resistant virus was rapidly replaced by an ancient wild-type strain. Despite resistance to all four ART classes, a genotype-adapted salvage regimen, including fostemsavir, achieved viral suppression within seven months. Full article

Background: This study examined the impact of the COVID-19 lockdown on antiretroviral therapy (ART) prescriptions among persons living with HIV (PWH) in Italy. Methods: Data from the ICONA cohort included ART-naïve individuals who started ART between January 2019 and December 2022, and ART-experienced individuals who started new ART with HIV RNA ≤50 cps/mL from January 2016 to December 2022. The analysis focused on the proportion of PWH starting or switching to dual (2DR) versus triple (3DR) ART regimens. Comparisons were made using Chi-square and Kruskal-Wallis tests, with logistic regression (LR) to assess associations, adjusting for sex and age. Results: Among 2481 ART-naïve PWH, 17% were female, with a median age of 40. Using 2020 as the comparator (the lockdown year), the odds ratio (OR) from fitting a LR showed a reduced probability of prescribing 2DR both before and after 2020. The proportion of PWH starting 2DR was 9% in 2019, 18% in 2020, 13% in 2021, and 10% in 2022. Among 12,335 ART-experienced PWH, 20% were female, with a median age of 47. The proportion switching to 2DR rose from 24% in 2016 to 38% in 2020, 62% in 2021, and 65% in 2022, showing a >3-fold higher probability to be switched to 2DR instead of 3DR in recent years (2021-2022). Conclusions: For ART-naive PWH, 2DR initiation did not decrease during the 2020 lockdown but changed in the following years, possibly indicating shifts in clinical practice or resuming HIV services. For ART-experienced PWH, 2DR prescriptions increased significantly over time, especially for INSTI-based regimens. Full article

Body weight is impacted by several individual host and environmental factors. In a person living with HIV (PLWH), weight is also influenced by the disease stage. Wasting syndrome is derived from disease progression, and it can be reversed by the effective use of highly active antiretroviral therapy (HAART). Body weight alterations have been studied and compared in several clinical ART trials, and they differ according to antiviral regimens. The newer integrase strand transfer inhibitors (INSTIs), such as bictegravir and dolutegravir, especially when co-administered with tenofovir alafenamide fumarate (TAF), seem to lead to greater weight increases compared to regimens that include tenofovir disoproxil fumarate (TDF), which seem to have an attenuating effect on weight gain. Nevertheless, despite the established association between INSTI and TAF and the negative impact on weight, more recent data suggest a more cautious approach when HAART treatment decisions are taken. In this manuscript, we review weight changes among PLWH receiving HAART and the relevant underlying pathogenic mechanisms described in recent literature. We try to provide a more critical appraisal of the available data and to underline the challenges in assessing the role of HAART in weight changes in both ART initiation and setting switching. Full article