Search Results (189)

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

The advent of effective antiretroviral therapy in the mid-1990s, which successfully prevented the progression to AIDS in people living with HIV (PLWH), was associated with the appearance of the so-called HIV-associated lipodystrophy. This condition involved subcutaneous fat atrophy; abdominal fat hypertrophy; and, in some cases, lipomatosis. It was also associated with systemic metabolic disturbances, primarily insulin resistance and dyslipidemia. Following the replacement of certain antiretroviral drugs, particularly the thymidine-analog reverse transcriptase inhibitors stavudine and zidovudine, with less toxic alternatives, the incidences of lipoatrophy and lipomatosis significantly declined. However, lipodystrophy resulting from first-generation antiretroviral therapy does not always resolve after switching to newer agents. Although the widespread use of modern antiretroviral drugs—especially integrase strand transfer inhibitors and non-lipoatrophic reverse transcriptase inhibitors such as tenofovir alafenamide—has reduced the incidences of severe forms of lipodystrophy, these regimens are not entirely free of adipose tissue-related effects. Notably, they are associated with weight gain that resembles common obesity and can have adverse cardiometabolic consequences. Recent evidence also suggests the hypertrophy of specific fat depots, such as epicardial and perivascular adipose tissue, in PLWH on last-generation treatments, potentially contributing to increased cardiovascular risk. This evolving landscape underscores the persistent vulnerability of PLWH to adipose tissue alterations. While these morphological changes may not be as pronounced as those seen in classic HIV-associated lipodystrophy, they can still pose significant health risks. The continued optimization of treatment regimens and the vigilant monitoring of adipose tissue alterations and metabolic status remain essential strategies to improve the health of PLWH. Full article

(1) Background: Second-generation integrase strand transfer inhibitors (INSTIs) are now the preferred first-line therapies for human immunodeficiency virus (HIV). However, concerns regarding their side effects, such as weight gain and metabolic disturbances, have emerged. This scoping review aims to assess the effects of INSTIs on the gut microbiota, with a focus on differences between agents and their clinical implications. (2) Methods: A scoping review was conducted using PubMed, Web of Science, and Embase, with reports collected following PRISMA for Scoping Reviews (PRISMA-ScR). (3) Results: The majority of available evidence focused on dolutegravir, which demonstrated beneficial effects on microbiota diversity and composition. However, factors such as younger age, lower CD4+ counts, and extreme BMI were associated with proinflammatory changes. Limited data on bictegravir also suggested favorable alterations in the gut microbiota. Raltegravir, a first-generation INSTI, was associated with improvements in alpha diversity and microbial composition, although these changes were not consistently beneficial. Moreover, associated changes in inflammatory and microbial translocation markers suggested unfavorable alterations. (4) Conclusions: Based on the evidence mapped, second-generation INSTIs may generally induce favorable changes in the gut microbiota. However, further research is needed to explore the clinical implications of these microbiota alterations, particularly in specific patient groups. Full article

In this study, we investigated the proportion of transmitted drug resistance (TDR) mutations and human immunodeficiency virus (HIV)-1 subtypes among 487 antiretroviral therapy (ART)-naïve individuals in South Korea from 2021 to 2024 to inform more effective treatment strategies. Consistent with previous reports, subtype B was most prevalent among HIV-1 subtypes at 50.7%; however, its proportion decreased annually (p = 0.047). Various subtypes of circulating recombinant forms (CRFs) were analyzed in this study, resulting in high genetic diversity. The subtype distributions of Korean and non-Korean patients differed, with subtype B (53.7%) and CRF01_AE (34.4%) being dominant in the former and latter, respectively. TDR across antiretroviral drug classes was approximately 3.5% in South Korea. Non-nucleoside reverse transcriptase inhibitors elicited the greatest drug resistance, which increased from 2021 to 2023, with a slight decrease in 2024. The integrase strand transfer inhibitor drugs, elvitegravir and raltegravir, most frequently exhibited high resistance scores. We provide a comprehensive overview of the HIV-1 genetic distribution and TDR patterns in South Korea from 2021 to 2024. Within the broader context of HIV-1 epidemiology in Asia and the Pacific, the findings contribute to a comprehensive understanding of the global distribution of HIV-1 resistance and genotypes, enabling the development of effective interventions. 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/Objective: This study aimed to develop a predictive model to classify and rank highly active compounds that inhibit HIV-1 integrase (IN). Methods: A total of 2271 potential HIV-1 inhibitors were selected from the ChEMBL database. The most relevant molecular descriptors were identified using a hybrid GA-SVM-RFE approach. Predictive models were built using Random Forest (RF), eXtreme Gradient Boosting (XGBoost), Support Vector Machines (SVM), and Multi-Layer Perceptron (MLP). The models underwent a comprehensive evaluation employing calibration, Y-randomization, and Net Gain methodologies. Results: The four models demonstrated intense calibration, achieving an accuracy greater than 0.88 and an area under the curve (AUC) exceeding 0.90. Net Gain at a high probability threshold indicates that the models are both effective and highly selective, ensuring more reliable predictions with greater confidence. Additionally, we combine the predictions of multiple individual models by using majority voting to determine the final prediction for each compound. The Rank Score (weighted sum) serves as a confidence indicator for the consensus prediction, with the majority of highly active compounds identified through high scores in both the 2D descriptors and ECFP4-based models, highlighting the models’ effectiveness in predicting potent inhibitors. Furthermore, cluster analysis identified significant classes associated with vigorous biological activity. Conclusions: Some clusters were found to be enriched in highly potent compounds while maintaining moderate scaffold diversity, making them promising candidates for exploring unique chemical spaces and identifying novel lead compounds. Overall, this study provides valuable insights into predicting integrase binders, thereby enhancing the accuracy of predictive models. Full article

The scale-up of antiretroviral therapy (ART) has markedly increased pretreatment drug resistance (PDR) among newly diagnosed HIV-infected individuals. This study aims to assess the prevalence and characteristics of PDR, infer the genetic transmission network, and evaluate the effect of PDR on ART in Nanning City, Guangxi. Methods: This study was conducted in the Fourth People’s Hospital of Nanning from 2019 to 2023. PDR was estimated using the Stanford algorithm. Genetic transmission networks were inferred by HIV-TRACE and visualized with Cytoscape. Logistic regression identified PDR-related factors. The Cox proportional hazards model assessed the impact of drug resistance on virological and immunological failure. Among 234 participants, the prevalence of PDR was 8.97%. CRF07_BC (35.9%), CRF-01AE (27.35%), and CRF08_BC (23.9%) were the top three HIV-1 strains. Resistance to non-nucleoside reverse-transcriptase inhibitors, protease inhibitors, nucleoside reverse-transcriptase inhibitors, and integrase strand-transfer inhibitors was 4.27%, 2.56%, 1.28%, and 0.43%, respectively. Overall, 21.37% of the participants exhibited drug resistance mutations (DRMs). Homosexuals were less likely to have PDR compared to heterosexuals ([aOR] 0.09, 95% CI 0.01–0.86). In the genetic network, V179D/E was also the most frequent DRM. Additionally, the incidence of virological failure (19.23%) and immune failure (20.09%) after one year of treatment did not show significant differences in different drug resistance groups. Conclusions: The prevalence of PDR in Nanning City is moderate, driven largely by the V179D and K103N mutations. The cross-transmission networks emphasize the imperative of PDR testing and targeted interventions. Full article

Background/Objectives: We evaluated the effects of glucagon-like peptide-1 receptor agonists (GLP1-RAs) on body weight and metabolic parameters in people with HIV and diabetes (PWHD) receiving maintenance therapy with integrase inhibitor, using a real-world study design. Methods: PWHD on integrase inhibitors-based antiretroviral therapies for at least 6 months, and treated with GLP1-RAs for at least 3 months, were included in this retrospective study. The primary study outcome was the absolute and relative change in body weight, as assessed during routine outpatient visits. Secondary analyses included evaluating the impact of GLP1-RAs on additional metabolic parameters, such as serum glucose, glycated hemoglobin, and LDL-cholesterol. Results: A total of 25 PWHD (74% males, mean age 65 ± 7 years, with 16% having a body mass index > 30 Kg/m²) receiving GLP1-RAs-based antihyperglycemic therapy were identified from our hospital database. No significant effects of GLP1-RAs on body weight were observed (absolute reduction −1.9 ± 3.0 Kg; relative reduction −2.2 ± 3.7%). Treatment with GLP1-RAs was associated with a progressive and significant reduction in serum glucose and glycated hemoglobin, with no observed impact on LDL cholesterol. Conclusions: Long-term GLP1-RA treatment significantly reduced serum glucose and glycated hemoglobin in overweight PWHD with no effects on body weight. Full article

Acute HIV-1 infection (AHI) is a transient period where the virus causes evident damage to the immune system, including an extensive apoptosis of CD4+ T cells associated with a high level of activation and a major cytokine storm to fight the invading virus. HIV infection establishes persistence by integrating the viral genome into host cell DNA in both replicating and non-replicating forms, effectively hiding from immune surveillance within infected lymphocytes as cellular reservoirs. The measurement of total HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) is a reliable reflection of this reservoir. Initiating treatments during AHI with nucleoside reverse transcriptase inhibitors (NRTIs) and/or integrase strand transfer inhibitors (INSTIs) is essential to alter the dynamics of the global reservoir expansion, and to reduce the establishment of long-lived cellular and tissue reservoirs, while preserving and enhancing specific and non-specific immune responses. Furthermore, some of the patients treated at the AHI stage may become post-treatment controllers and should be informative regarding the mechanism of viral control, so patients treated during AHI are undoubtedly the best candidates to test innovative remission strategies toward a functional cure that could play a pivotal role in long-term HIV control. AHI is characterized by high levels of viral replication, with a significant increase in the risk of HIV transmission. Detecting AHI and initiating early treatment following diagnosis provides a window of opportunity to control the epidemic, particularly in high-risk populations. Full article

Contemporary ART as Dolutegravir (DTG) has significantly advanced antiretroviral therapy, but relatively few data are available on its impact on the emergence of HIV-1 drug resistance mutations (DRMs). Monitoring the emergence of INSTI-associated DRMs following the introduction of DTG in Suriname will provide general insight and guide national HIV treatment strategies. All people living with HIV (PLHIV) in Suriname, for whom an INSTI drug resistance test was requested between September 2019 and February 2024 (n = 20), were included. HIV-1 integrase gene sequences were determined using Sanger sequencing. INSTI-associated mutations were identified using the Stanford HIV Drug Resistance Database program. The majority of the participants (66.7%) harbored HIV-1 subtype B, and 33.3% were B-recombinant forms. In addition to the INSTI wildtype, a strain was revealed carrying E157EQ and one person harbored a highly INSTI-resistant strain (E138K, G140S, Q148H and N155H). The emergence of a highly INSTI-resistant HIV-1 strain in Suriname, with unusual mutations for ART-experienced PLHIV exposed to DTG as the only INSTI, accentuates the need for continuous monitoring of the emergence of INSTI drug resistance mutations, not only to enable timely interventions and optimized treatment outcomes for PLHIV, but also to steer the decision making for ART protocols, especially for second generation INSTIs. Full article

Background/Objectives: The development of HIV drug resistance to current antiretrovirals, and the antiretrovirals’ inability to cure HIV, provides the need of developing novel drugs that inhibit HIV-1 subtypes and drug-resistance strains. Fungal endophytes, including Alternaria alternata, stand out for their potentially antiviral secondary metabolites. Hence, this study investigates the anti-HIV activities and mechanism of action of the A. alternata crude extract against different HIV-1 subtypes and integrase-resistant mutant strains. Methods: Cytotoxicity of the A. alternata crude extract on TZM-bl cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was performed. The crude extract antiviral activity against subtypes A, B, C, and D and integrase drug-resistant strain T66K and S230R was determined using a luciferase-based antiviral assay. Luciferase and p24 ELISA-based time-of-addition assays were used to determine the mechanism of action of the crude extract. Docking scores and protein ligand interactions of integrase T66K and S230R strains against the identified bioactive compounds were determined. Results: The crude extract CC₅₀ was 300 μg/mL and not cytotoxic to the TZM-bl cell lines. In HIV-1 subtypes A, B, C, and D, the crude extract exhibited 100% inhibition and therapeutic potential. The A. alternata crude extract had strong anti-HIV-1 activity against integrase strand transfer drug-resistant strains T66K and S230R, with a 0.7265- and 0. 8751-fold increase in susceptibility. The crude extract had antiviral activity during attachment, reverse transcription, integration, and proteolysis. In silico calculations showed compounds 2,3-2H-Benzofuran-2-one, 3,3,4,6-tetramethyl-, 3-Methyl-1,4-diazabicyclo[4.3.0]nonan-2,5-dione, N-acetyl, Coumarin, 3,4-dihydro-4,5,7-trimethyl-, Cyclopropanecarboxamide, N-cycloheptyl, Pyrrolo[1,2-a]pyrazine-1,4-dione, and hexahydro-3-(2-methylpropyl)- crude extract bioactive compounds had strong docking scores and diverse binding mechanisms with integrase. Conclusions: The A. alternata crude extract demonstrates strong antiviral activity against different HIV-1 subtypes and integrase drug-resistance strains. The extract inhibited various stages of the HIV-1 life cycle. The bioactive compounds 2,3-2H-Benzofuran-2-one, 3,3,4,6-tetramethyl-, 3-Methyl-1,4-diazabicyclo[4.3.0]nonan-2,5-dione, N-acetyl, Coumarin, 3,4-dihydro-4,5,7-trimethyl-, Cyclopropanecarboxamide, N-cycloheptyl, Pyrrolo[1,2-a]pyrazine-1,4-dione, and hexahydro-3-(2-methylpropyl)- may be responsible for the antiviral activity of A. alternata. Full article

Second-generation integrase strand transfer inhibitors (INSTIs) are strongly recommended for people living with HIV-1 (PLWH). The emergence of resistance to second-generation INSTIs has been infrequent and has not yet been a major issue in high-income countries. However, the delayed rollouts of these INSTIs in low- to middle-income countries during the COVID-19 pandemic combined with increased transmission of drug-resistant mutants worldwide are leading to an increase in INSTI resistance. Herein, we evaluated the antiviral potencies of our lead developmental INSTI 4d and the second-generation INSTIs dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) against a panel of IN quadruple mutants. The mutations are centered around G140S/Q148H, including positions L74, E92, and T97 combined with E138A/K/G140S/Q148H. All of the tested INSTIs lose potency against these IN quadruple mutants compared with the wild-type IN. In single-round infection assays, compound 4d retained higher antiviral potencies (EC₅₀ values) than second-generation INSTIs against a subset of quadruple mutants. These findings may advance understanding of mechanisms that contribute to resistance and, in so doing, facilitate development of new INSTIs with improved antiviral profiles. Full article

Background: The global AIDS pandemic highlights the urgent need for novel antiretroviral therapies (ART). In our previous work, Zinc C295 was identified as a potent HIV-1 integrase strand transfer (ST) inhibitor. This study explores its potential to also inhibit 3′-processing (3′P), thereby establishing its dual-targeting capability. Methods: The inhibitory activity of Zinc C295 against 3′P was evaluated using a modified in vitro assay adapted from our earlier ST inhibition studies. Molecular docking and molecular dynamics simulations were employed to analyse Zinc C295’s interactions with the 3′P allosteric site of HIV-1 integrase. Results: Zinc C295 demonstrated significant inhibition of HIV-1 integrase 3′P activity in in vitro assays (IC50 = 4.709 ± 0.97 µM). Computational analyses revealed key interactions of Zinc C295 within the enzyme’s allosteric site, providing insights into its dual inhibitory mechanism. Conclusions: Zinc C295’s dual inhibition of HIV-1 integrase ST and 3′P establishes it as a promising candidate for next-generation ART. Its dual-action mechanism may offer potential advantages in enhancing treatment efficacy and addressing drug resistance. Further studies are warranted to evaluate its therapeutic potential in clinical settings. Full article

Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance of which has often not been determined during registration trials of the drugs involved. Therefore, it is important to identify potential clinically relevant DDIs in order to establish the most appropriate therapeutic approaches. This review aims to summarize and analyze data from studies published over the last two decades on DDI-related adverse clinical outcomes involving anti-HIV drugs and those used to treat comorbidities. Several studies have examined the pharmacokinetics and tolerability of different drug combinations. Protease inhibitors, followed by nonnucleoside reverse transcriptase inhibitors and integrase inhibitors have been recognized as the main players in DDIs with antivirals used to control co-infection, such as Hepatitis C virus, or with drugs commonly used to treat HIV comorbidities, such as lipid-lowering agents, proton pump inhibitors and anticancer drugs. However, the studies do not seem to be consistent with regard to sample size and follow-up, the drugs involved, or the results obtained. It should be noted that most of the available studies were conducted in healthy volunteers without being replicated in patients. This hampered the assessment of the clinical burden of DDIs and, consequently, the optimal pharmacological management of people living with HIV. Full article