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HIV acquisition has been found to be associated with increased risk of cardiometabolic syndrome in the past. In this study, we attempt to delineate the associated factors of metabolic syndrome among persons living with HIV in a single medical center in Taiwan using mostly integrase inhibitors-based regimen as HAART. A cross-sectional study involving all people living with HIV (PLWH) aged ≥ 18 years who visited MacKay Memorial Hospital, Taipei, Taiwan between September 7, 2022 to January 31, 2023 was performed. A modified National Cholesterol Education Program ATP III definition of metabolic syndrome was used to define metabolic syndrome and body mass index was used as surrogate for waist circumference. 809 PLWH participated in the study, in which 81.3% of patients were on integrase inhibitor-based HAART regimen. The prevalence of metabolic syndrome was 10.0%, which is markedly lower than those reported in the literature. Age was a significant risk factor for metabolic syndrome. HIV-related factors (CD4, viral load, HAART regimen) did not affect the presence of metabolic syndrome. Prevalence rate of metabolic syndrome appeared to have declined among PLWH compared to previous reports, possibly secondary to widespread use of integrase inhibitors. Age remains a strong risk factor for the development of metabolic syndrome among PLWH. [ABSTRACT FROM AUTHOR]

Background Virological failures of first-line second-generation (SG) INSTI-based regimens are rare, usually characterized by low viremia and absence of drug resistance mutations. Objectives To explore the efficacy of rescue regimens introduced after virological failure (VF) to a first-line SG-INSTI therapy. Patients and methods This was a retrospective study on people living with HIV (PWH) failing a first-line SG-INSTI regimen [DTG/3TC, BIC/FTC/TAF, DTG-based three-drug regimen (DTG-3DR)] between 24 March 2016 and 31 December 2021. Follow-up accrued from the second viral load (VL) ≥ 50 copies/mL under SG-INSTI regimen (baseline) until virological success (VS, achievement of at least one VL < 50 copies/mL after baseline) or last visit. Cumulative probabilities of VS were estimated by Kaplan–Meier curves and compared using a log-rank test. Results Overall, of 521 naïve PWH who started a first-line SG-INSTI regimen, 45 (8.6%) had VF after a median of 14.9 (IQR = 6.9–25.9) months: 33/395 (8.4%) individuals failed a DTG-3DR, 11/102 (10.8%) a BIC/FTC/TAF and 1/24 (4.2%) failed a DTG/3TC. At baseline, 12/45 (27%) PWH changed antiretroviral therapy [median baseline VL 134 (IQR = 81–233) copies/mL], while 33 (73%) maintained their failing regimen [median baseline VL 75 (IQR = 60–145) copies/mL]. During a median follow-up of 5.13 (IQR = 3.8–7.1) months, 34 (75.6%) PWH achieved VS: 25/33 (75.8%) maintaining their failing regimen, 9/12 (75%) switched regimen; the estimated 6- and 12-months probabilities of VS were 59% and 84%, respectively. There was no difference in VS curves between PWH who maintained their failing regimen and those who switched therapy. Conclusions Most individuals remained on their failing regimen, achieving spontaneous virological suppression in most cases. These data help to understand a real-life VF scenario in the context of the current SG-INSTI era. [ABSTRACT FROM AUTHOR]

The main burden in treating human immunodeficiency virus (HIV) infection currently, is the side effects of the antiretroviral therapy (ART) used, because each treatment is toxic to the liver. This study uses optimal control theory applied to a mathematical model that describes the dynamics of HIV infection in the liver. The optimal controls are presented as therapy efficacy of reverse transcriptase inhibitors (RTIs), integrase inhibitors (INs) and protease inhibitors (PIs). An objective function is defined with an aim to investigate the optimal control strategy that minimises toxicity, viral load and cost of first-line and second-line HIV regimen. Results indicate that, in the first-line regimen with INs, a patient has to take medication for at least 98% of the treatment time and the regimen should be close to 100% efficacious regardless of the intervention cost. For second-line regimen, the period of drug administration of PIs largely depends on the weight constants. Inclusion of INs in the first-line regimen yields better HIV DNA suppression, as they are more efficacious than NRTIs. Of all drugs studied, nevirapine is highly efficacious but most toxic. The study recommends routine transaminase tests because results indicate liver enzyme elevation even with very low viral load. Numerical results with pharmacokinetic parameters further indicate an increase in HIV load at initiation of therapy, due to viral redistribution in plasma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The rising prevalence of pretreatment drug resistance (PDR) to non-nucleoside reverse-transcriptase inhibitors threatens the effectiveness of ART. In response, the WHO recommends dolutegravir-based ART regimens due to their high genetic barrier to resistance and better treatment outcomes. This is expected to contribute to achieving the Joint United Nations Programme on HIV/AIDS (UNAIDS) target of 95% viral suppression in people on ART. Objectives To estimate the prevalence of PDR among adults initiating ART and assess viral suppression and acquired HIV drug resistance (ADR) among individuals receiving ART in Belize. Patients and methods Nationally representative cross-sectional PDR and ADR surveys were conducted between 2021 and 2022. Sixty-seven adults were included in the PDR survey, and 43 children and adolescents and 331 adults were included in the ADR survey. Demographic and clinic data and blood specimens were collected. HIV drug resistance (HIVDR) was predicted using the Stanford HIVdb tool. Results The prevalence of PDR to efavirenz or nevirapine in adults was 49.3% (95% CI 42.2%–56.4%) and was significantly higher in those with previous antiretroviral exposure (OR: 7.16; 95% CI 2.71–18.95; P  = 0.002). Among children and adolescents receiving ART, 50.0% had viral suppression, with better rates for those receiving dolutegravir-based ART (OR: 5.31; 95% CI 3.02–9.34; P  < 0.001). In adults, 79.6% achieved viral suppression. No resistance to integrase inhibitors was observed in those on dolutegravir-based ART. Conclusions Prioritizing dolutegravir-based ART is critical for achieving HIV epidemic control in Belize. Efforts should focus on retention in care and adherence support to prevent HIVDR. [ABSTRACT FROM AUTHOR]

Background Antiretroviral therapy (ART) is recommended for all individuals with HIV infection, including those with acute HIV-1 infection (AHI). While recommendations are similar to those for chronic infection, efficacy data regarding treatment of acute HIV is limited. Methods This was a single arm, 96-week study of a once-daily integrase inhibitor (INSTI)-based regimen using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) in AHI. Primary endpoint was proportion of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL by treatment weeks 24 and 48, respectively. We also examined time to viral suppression and weight gain after treatment initiation. Outcomes and characteristics were compared with a historical AHI cohort using a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). Results Thirty-three participants with AHI were enrolled with 31 available for analyses. Most were African American (61%) and men who have sex with men (73%). Median age was 26 (IQR 22–42). Demographics were similar between the two AHI cohorts. By Week 24, 100% in the INSTI and 99% in the NNRTI cohort were <200 copies/mL; by Week 48, 100% in both cohorts were <50 copies/mL. Time to viral suppression was shorter in the INSTI cohort (median 54 versus 99 days). Mean weight change was similar with a 3.6 kg increase in the INSTI cohort and 2.4 kg in the NNRTI cohort at 96 weeks. Conclusions INSTI-based ART during AHI resulted in rapid and sustained viral suppression. Over 96 weeks, weight increased in the INSTI-based cohort but was similar to weight increase in a historical NNRTI-based AHI cohort. [ABSTRACT FROM AUTHOR]

Background The role of integrase strand transfer inhibitors (INSTI) in the cardiovascular risk of people with HIV is controversial. Objectives To assess the association of INSTI to subclinical atherosclerosis progression measured with the carotid intima-media thickness (cIMT). Methods Prospective study in virologically suppressed people with HIV receiving INSTI- or NNRTI-based regimens. cIMT was measured at baseline, 48 and 96 weeks. cIMT progression was analysed both as a continuous and categorical variable, defined as cIMT increase ≥ 10% and/or new carotid plaque. Adjustments through Cox proportional hazard regression and linear mixed models, and propensity score matching were conducted. Results 190 participants were recruited and 173 completed the 96 week follow-up. 107 (56.3%) were receiving an INSTI-containing, 128 (67.4%) a NNRTI-containing and 45 (23.7%) a NNRTI plus an INSTI-containing regimen. The overall median (IQR) 2-year change of cIMT was 0.029 (−0.041 to 0.124) mm; 87 (45.8%) participants experienced a cIMT increase ≥ 10%, of whom 54 (28.4%) developed a new carotid plaque. Adjusted Cox regression showed no differences between INSTI and NNRTI groups in the categorical 2-year progression of cIMT, both including or excluding participants receiving INSTI + NNRTI. Similar results were observed for the continuous cIMT increase through adjusted linear mixed models. Propensity score matching showed no significant differences in the 2 year cIMT change between treatment groups [0.049 mm (−0.031–0.103) in the INSTI group versus 0.047 mm (−0.023–0.115) in the NNRTI group; P  = 0.647]. cIMT progression was associated with traditional cardiovascular risk factors. Conclusions INSTI-based regimens are not associated with increased progression of subclinical atherosclerosis when compared to NNRTI. [ABSTRACT FROM AUTHOR]

Background Second-generation integrase strand transfer inhibitors (InSTIs) have a high barrier to resistance and potent antiretroviral activity. They are recommended as first- or second-line (FL and SL) options in two- and three-drug regimens (2DR and 3DR) in international treatment guidelines. However, there are limited real-world data on emerging resistance at the time of virological failure (VF) with these regimens. Objectives The Virostar-1 study objective is to analyse the emergence of resistance-associated mutations (RAMs) over 3 years with DTG-based 2DRs and DTG- or bictegravir (BIC)-based 3DRs in people living with HIV (PLWH) experiencing a VF (FL or SL). Methods Retrospective analysis of genotypic resistance detected at the time of a FL or SL VF with BIC/FTC/TAF, DTG/ABC/3TC, DTG/3TC and DTG/RPV between 2019 and 2022 was conducted from a French multicentre database. VF was defined as two consecutive HIV-1 plasma viral loads > 50 c/mL. Sanger assays were performed at VF within standard clinical care. Resistance mutations were reported using the ANRS algorithm. Selection biases prevent group comparisons. Results During the period, N  = 5986 PLWH were followed either in FL or SL. The VF rate was overall low: BIC/FTC/TAF, 6.8%; DTG/ABC/3TC, 7.5%; DTG/3TC, 5.1%; and DTG/RPV, 2.1%. Some emergent InSTI or NRTI RAMs were detected with BIC/FTC/TAF 4%, DTG/ABC/3TC 8.5%, DTG/3TC 18% and 39% emergent NNRTI RAMs with DTG/RPV. However, a complete absence of dual resistance against NRTIs and InSTIs was observed. Conclusions We detected rare emergent InSTI RAMs and few emergent NRTI RAMs in PLWH failing DTG- or BIC-based regimens in FL or SL. The observed rates of emergent RAMs at VF were 4% with BIC/FTC/TAF, 8.5% with DTG/ABC/3TC, 18% with DTG/3TC and 39% with DTG/RPV. [ABSTRACT FROM AUTHOR]

Rationale Methods Results Conclusions Doravirine (DOR) is an attractive new option both for ART‐naïve people with HIV (PWH) and those with suppressed HIV‐RNA who seek treatment simplification. We used real‐world data to examine the pattern of use of DOR‐containing regimens in these settings.All PWH enrolled in the Icona cohort after January 2020 who initiated a three‐drug regimen (3‐DR) with DOR or an integrase inhibitor (INSTI)‐based regimen as first antiretroviral therapy (ART) or when switching ART, with HIV‐RNA ≤50 copies/mL, were included. We used univariate and multivariable logistic regression models to identify demographic factors, immuno‐virological and laboratory markers associated with the prescription of 3‐DR DOR instead of INSTI‐based regimens.A total of 5803 PWH were included; 1958 were in the first regimen (80 DOR, 1,878 INSTI) and 3854 (387 DOR, 3,458 INSTI) were ART‐experienced virologically suppressed. In the first line, 3‐DR DOR was more frequently started in people who inject drugs, and its use was also associated with higher body mass index, higher low‐density lipoprotein levels, and less advanced HIV disease compared with PWH initiating an INSTI‐based regimen. In the switch setting, older age, Italian origin, higher estimated glomerular filtration rate and aspartate aminotransferase levels were all strongly associated with 3‐DR DOR use, as well as higher a CD4/CD8 ratio (only vs. 3‐DR INSTI), while the association with lipid abnormalities was attenuated.Our analysis shows that among PWH in care in Italy, those with less advanced HIV disease but with other fragilities and potential risk factors for comorbidities are more likely to use DOR‐ than INSTI‐based regimens, regardless of prior treatment history. [ABSTRACT FROM AUTHOR]

Herein, our work deals with developing a rapid, accurate, and reliable high‐performance liquid chromatographic technique with the application of quality by design (QbD) experimental tool to quantify Elvitegravir drug (Integrase inhibitors of antiretroviral drug) and its novel related impurities at low levels. Further, this unique method has been validated to prove its consistency. Separation of N‐methyl Elvitegravir (Impurity‐I), 2‐fluoro Elvitegravir (Impurity‐II), and Elvitegravir isopropyl ester (Impurity‐III) in Elvitegravir drug substance was executed by using Kinetex C18 column (150 mm × 2.1 mm × 1.7 µm) with water, acetonitrile, formic acid, and triethylamine (690:300:6:2, v/v/v/v/), mobile phase (MB‐A) and acetonitrile, formic acid and triethylamine (990:6:2, v/v/v), MB‐B. This developed analytical technique gave a well‐separated peak at the retention times of 9.126 min (Elvitegravir), 7.713 min (Impurity‐I), 7.972 min (Impurity‐II), and 8.548 min (Impurity‐III) adequate with the peak properties as per the United States Pharmacopeia guideline. The method's sensitivity and linearity are established by its detection and quantification limits at low levels with a correlation coefficient of 0.998. The method's repeatability, specificity, and accuracy suggest that this developed technique is a reliable determination strategy for Elvitegravir drug substance and its related impurities (Impurity‐I, Impurity‐II, and Impurity‐III) in a simple, feasible, and affordable way. [ABSTRACT FROM AUTHOR]

Since arising in 2019, COVID 19 has been causing rapidly-increasing mortality and morbidity rates across the globe. Herein, novel 1,3-indanedione-thiazole hybrids were designed and synthesized as small-molecule SARS-COV-2 Main protease (Mpro) inhibitors with potential anti-covid activity. All target compounds were screened in vitro for their ability to inhibit SARS-COV-2 Mpro. Several compounds displayed potent SARS-COV-2 Mpro inhibition at one-digit IC50 values ranging from 4.3 to 9.9 µM, compared to ritonavir (IC50= 2.4 µM). Moreover, antiviral assay revealed the ability of compounds 12c, 12f, and 16a to significantly inhibit the replication of SARS-COV-2 in Vero cells at EC50 values of 7.79, 2.79 and 1.65 µM, respectively, relative to ritonavir (EC50 = 1.72 µM). Cytotoxicity assay was also conducted. None of the tested compounds exhibited significant cytotoxicity in Vero cells showing CC50 values from 171.77 to 299.96 µM and SI from 38.5 to 178.6 µM. In addition, a docking study revealed proper orientation and well-fitting of title compounds into the binding pocket of SARS-COV-2 Main protease. [ABSTRACT FROM AUTHOR]

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The study assessed replicative human immunodeficiency virus-(HIV-) infection and replicative co-infections as well as molecular determinants of reduced susceptibility towards anti-retroviral therapy in a Ghanaian population of known HIV patients and a control group. Real-time PCRs for HIV-1, HIV-2, hepatitis B virus (HBV) and hepatitis C virus (HCV) were run with serum samples from known Ghanaian HIV-patients (n = 975) and control individuals (n = 105). For 108 individuals, HIV-sequence analysis was performed. Prevalence of replicative HIV-1 infection was 59.8% (583/975) in the known HIV-positive population and 2.9% (3/105) in the controls. Prevalences of replicative HBV-infection were comparable with 3.4% (33/975) in the HIV-positive individuals and 3.8% (4/105) in the controls. HIV-2 and HCV sequences were not recorded. Almost perfect concordance between two compared HIV-1-PCR assays was indicated by Fleiss' Kappa >0.8. Sanger sequencing indicated CRF_02AG, G and A3 as the quantitatively dominating HIV-1 subtypes, a minority of 3.4% CXCR4 tropism and high detection rates of mutations mediating reduced susceptibility towards nucleoside reverse transcriptase inhibitors (71.9%, 64/89), non-nucleoside reverse transcriptase inhibitors (95.5%, 85/89), protease inhibitors (95.9%, 93/97) and integrase inhibitors (22.4%, 22/98). The assessment did not suggest HIV-triggered increased replication of HBV and HCV in the investigated Ghanaian population. [ABSTRACT FROM AUTHOR]

Integrase strand-transfer inhibitors (INSTIs) are associated with weight gain in women living with HIV (WLH). Relationships between drug exposure, baseline obesity, and INSTI-associated weight gain remain unclear. Data from 2006 to 2016 were analyzed from virally suppressed WLH enrolled in the Women's Interagency HIV Study, who switched/added an INSTI to antiretroviral therapy: [raltegravir (RAL), dolutegravir (DTG), or elvitegravir (EVG)]. Percent body weight change was calculated from weights obtained a median 6 months pre-INSTI and 14 months post-INSTI initiation. Hair concentrations were measured with validated liquid chromatography-mass spectrometry (MS)/MS assays. Baseline (preswitch) weight status evaluated obese (body mass index, BMI, ≥30 kg/m2) versus nonobese (BMI 500 cells/mm3, >75% with undetectable HIV-1 RNA. Over ∼1 year, women experienced median increases in body weight: 1.71% (-1.78, 5.00) with RAL; 2.40% (-2.82, 6.50) with EVG; and 2.48% (-3.60, 7.88) with DTG. Baseline obesity status modified the relationship between hair concentrations and percent weight change for DTG and RAL (p's

An efficient oxidation of stilbenes to α‐diketones co‐catalyzed by bismuth nitrate and iodine is reported. The utilization of molecular oxygen as a terminal oxidant and water as the reaction solvent provides a low‐cost and environmentally friendly approach to preparing the α‐diketone derivatives from readily available stilbenes. Isotope labeling experiments suggest that the two oxygen atoms of the α‐ diketone products mainly originate from water. The method displays high functional group tolerance and we have demonstrated a concise route for preparing trifenagrel and HIV‐1 integrase inhibitors from 1,2‐diphenylethene. [ABSTRACT FROM AUTHOR]

Background: Heightened levels of inflammatory markers are linked to increased morbidity/mortality in people with HIV (PWH) and often remain elevated after virologic suppression by antiretroviral therapy (ART). As new combinations of ART become available, an evaluation of their effects on immune activation and inflammation is warranted. Additionally, it remains unknown whether transient increases in viral load ("blips") during ART are associated with increases in inflammation. Methods: We utilized cryopreserved samples from treatment-naïve PWH enrolled in two Phase 3 clinical trials investigating the efficacy and safety of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) or dolutegravir, abacavir, and lamivudine (DTG/ABC/3TC) or DTG + F/TAF over a 5-year window (GS-US-380-1489/1490). At week 144, participants were offered the option to switch to open label B/F/TAF for an additional 96 weeks. We measured levels of interleukin-6 (IL-6), C-reactive protein (hsCRP), D-dimer, soluble CD14 (sCD14), and tumor necrosis factor-α receptor 1 (TNFR1) from available baseline, week 24, 48, 144, and 240 samples (B/F/TAF, N=123; DTG/ABC/3TC, N=62; DTG+F/TAF, N=58). Additional samples from PWH who experienced a viral blip (n=44, defined as a single HIV-1 RNA >50c/mL) were also analyzed and paired with the most recent available suppressed sample before the blip. Longitudinal biomarker changes were assessed using a constrained mixed effects linear regression model adjusting for covariates. Results: Baseline demographics and selected laboratory characteristics were similar across groups. Levels of D-dimer, sCD14, and TNFR1 decreased significantly from baseline in all treatment arms, with no significant differences between arms at any timepoint. Biomarker levels also remained stable following ART-switch at week 144. No significant changes in hsCRP or IL-6 were observed versus baseline in any arm at any timepoint. A significant association was observed between sCD14 and increasing viral load (p=0.022) in viral blips; D-dimer also increased with blips in the B/F/TAF arm. Conclusions: Viral suppression was associated with reductions in most inflammatory markers in PWH, with no significant differences among the three ART regimens during the 144-week randomized period. These decreases were sustained after the open label switch to B/F/TAF. Viral blips were associated with increases in monocyte activation (sCD14). Further analysis is needed to confirm these findings and determine the potential impact on clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion People with HIV currently face a tenfold higher risk of developing cardiovascular disease (CVD) than those without HIV. Studies have shown various off‐target effects of antiretroviral treatment (ART) on the cardiovascular system, but little is known about the effects of currently used integrase strand transfer inhibitors (INSTIs) on platelets. Platelet activation is associated with increased CVD, thrombus formation, and release of proinflammatory mediators, so exploring platelet effects from currently prescribed ART may contribute to the understanding of CVD etiopathogenesis in people with HIV.We aimed to identify potential effects of INSTIs on platelet aggregation and activation markers from individuals without HIV after in vitro treatment with clinically relevant drug concentrations. We used bictegravir (BIC) and dolutegravir (DTG) individually or in the therapeutic drug combinations BIC/emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) or DTG/lamivudine (3TC). Additionally, we conducted a pilot study to compare platelet activity profiles from people with HIV on BIC/FTC/TAF and DTG/3TC.Changes to in vitro platelet aggregation responses upon exposure to different INSTIs were observed both upon individual drug application and when using therapeutic combinations. However, these effects were not reflected in flow‐cytometric evaluation of platelet degranulation. A pilot study in eight people with HIV and eight without HIV revealed no significant effects but established protocols for future patient studies.There is currently no consistent evidence of an effect of INSTIs on platelet activation. Further study is warranted, focusing on models with more pathophysiological relevance, including extensive studies in people with HIV. [ABSTRACT FROM AUTHOR]

Background: AIDS is a highly prevalent and life‐threatening global epidemic that severely compromises the host's immune system, increasing vulnerability to opportunistic diseases. The absence of definitive curative drugs emphasizes the importance and necessity of discovering novel anti‐HIV agents. Objective: This study aims to discover a natural molecular entity that acts as an Integrase strand transfer inhibitor (INSTI) with enhanced potency against HIV. Methods: A ligand‐based pharmacophore model was developed for 4 FDA‐approved INSTIs, with the potential for treating HIV‐1. AutoDock facilitated molecular docking and free energy calculation to discern IN activity. Subsequently, MD simulations assessed interaction stability. ADMET analysis preceded an in vitro anti‐HIV strand transfer assay. Results: The generated model revealed a specific interaction involving Mg2+ ion chelation. Crucial residues of HIV‐1 IN and their respective free‐binding energies were identified. The lead compound exhibited superior in silico characteristics which were substantiated by 100 ns MD simulations and MM‐PBSA analysis. Additionally, the in vitro assay demonstrated potent inhibition with the lowest IC50, forming strong molecular interactions with IN. Conclusion: These findings showed valuable insights for the strategic development of new antiretroviral treatments (ART), paving the path for the development of natural therapeutic agents for HIV treatment. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) for HIV drug resistance (DR) testing has an increasing number of applications for the detection of low-abundance drug-resistant variants (LA-DRVs) in regard to its features as a quasi-species. However, there is less information on its detection performance in DR detection with NGS. To determine the feasibility of using NGS technology in LA-DRV detection for HIV-1 pretreatment drug resistance, 80 HIV-infected individuals who had never undergone antiretroviral therapy were subjected to both NGS and Sanger sequencing (SS) in HIV-1 drug resistance testing. The results reported in this study show that NGS exhibits higher sensitivity for drug resistance identification than SS at a 5% detection threshold. NGS showed a better consistency compared with that of SS for both protease inhibitors (PIs) and integrase inhibitors (INSTIs), with a figure amounting to more than 90%, but worse consistency in nucleotide reverse transcriptase inhibitors (NRTIs), with a consistency ranging from only 61.25% to 87.50%. The consistency of non-nucleotide reverse transcriptase inhibitors (NNRTIs) between NGS and SS was around 85%. NGS showed the highest sensitivity of 87.0% at a 5% threshold. The application of NGS technology in HIV-1 genotype resistance detection in different populations infected with HIV requires further documentation and validation. [ABSTRACT FROM AUTHOR]

Background Drug–drug interactions between antiretroviral treatment (ART) and cytostatics may have a negative impact in the prognosis of people with HIV (PWH) and cancer. Objective The objective of this study is to evaluate the impact of the implementation of interdisciplinary management and the type of ART in PWH diagnosed with lymphoid neoplasms. Methods This is a multicentric, retrospective observational cohort study including PWH diagnosed with lymphoid neoplasm who started first-line chemotherapy between 2008 and 2020. Demographic, clinical and therapeutic variables were obtained from the electronic medical records and associated with 5-year progression-free survival (PFS) and overall survival (OS) using Cox proportional hazard models. Results A total of 118 individuals were included. Boosted ART was being used in 55 (46.6%) cases at the time of neoplasm diagnosis. The Infectious Diseases or the Pharmacy Department was consulted before starting chemotherapy in 79/118 (66.9%) cases. Interdisciplinary management resulted in fewer subjects taking boosted ART (17.7% versus 71.8%, P  < 0.001) and more subjects using unboosted integrase strand transfer inhibitor–based ART (74.7% versus 7.7%, P  < 0.001). The use of boosted ART with chemotherapy was associated with worse 5-year PFS (P  = 0.003) and 5-year OS (P  = 0.016). There was a trend towards better 5-year PFS and OS when interdisciplinary management was implemented, with significant differences for individuals receiving boosted ART at neoplasm diagnosis (P  = 0.0246 and P  = 0.0329, respectively). Conclusions Our findings underscore the significant impact of the type of ART on the prognosis of PWH undergoing chemotherapy. Encouraging collaborative management between oncologists, pharmacists and HIV teams for these patients enhances PFS and OS rates. [ABSTRACT FROM AUTHOR]

Transgender persons face a greater burden of HIV compared to cisgender counterparts. Concerns around drug–drug interactions (DDIs) have been cited as reasons for lower engagement in HIV care and lower pre‐exposure prophylaxis (PrEP) uptake among transgender populations. It is therefore imperative for hormone therapy, PrEP and antiretroviral therapy providers to understand the DDI potential between these therapies. Studies of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) PrEP with feminizing hormone therapies (FHTs) show reduced plasma tenofovir concentrations, but intracellular concentrations of tenofovir‐diphosphate are not reduced. Efficacy of PrEP is expected to be maintained despite this interaction. Masculinizing hormone therapies have no effect on tenofovir concentrations but may increase FTC to a nonclinically relevant extent. No interactions between FHT and cabotegravir or tenofovir alafenamide have been demonstrated. Administration of TDF/FTC PrEP has no effect on hormone levels in transmen or transwomen. PrEP is expected to be effective and safe in transpersons and should be provided to high‐risk individuals regardless of gender affirming hormone use. Enzyme inducing/inhibiting antiretroviral therapy may decrease or increase, respectively, the concentrations of FHT and masculinizing hormone therapy. Unboosted integrase inhibitors or enzyme neutral non‐nucleoside reverse transcriptase inhibitors are not expected to affect and are not affected by gender affirming hormones and can be considered in transmen and transwomen. Overlapping toxicities including weight gain, dyslipidaemia, cardiovascular disease and bone density effects should be considered, and antiretroviral modifications can be made to minimize toxicities. Interactions between supportive care medications should be assessed to avoid chelation interactions and hyperkalaemia. [ABSTRACT FROM AUTHOR]

With the widespread use of integrase inhibitors and the expanding use of long-acting cabotegravir in both pre-exposure prophylaxis and antiretroviral treatment, molecular surveillance on the transmission of integrase resistance has regained clinical significance. This study aimed to determine the frequency of INSTI-transmitted drug resistance mutations (DRMs) among treatment-naïve individuals in Poland from 2016 to 2023. INSTI resistance was analyzed in 882 antiretroviral treatment-naïve individuals using Sanger sequencing. Integrase DRMs were defined based on the Stanford HIV drug resistance database scores. Phylogeny was used to investigate subtyping and clustering. For the analysis of time-trends, logistic regression was used. Major (E138K and R263K) integrase mutations were detected in 0.45% of cases with minor resistance observed in 14.85%, most commonly (13.95%) E157Q. Overall, no major clusters of transmitted drug resistance were identified, and the transmission of E157Q showed a decreasing trend (p < 0.001). While the frequency of sub-subtype A6 increased, it was predominantly found among migrants and associated with L74 mutations. The frequency of major integrase-transmitted DRMs remains low, despite the changes in subtype variability. Surveillance of changing HIV molecular variation patterns is vital from the perspective of the optimal use of integrase inhibitors, especially due to expanding long-acting cabotegravir implementation. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) type 2 is known to be less pathogenic than HIV-1, possibly due to more effective immune control mechanisms. The mechanism of innate sensing of HIV-2 by T cells is at present unclear. In this study, we show that several primary isolates of HIV-2 (CBL20 and CI85) and HIV-1 (A8 and D2), similar to the molecular clone HIV-1 NL4.3-GFP-I, induce a significant type I interferon response in its main target, activated CD4+ T cells. However, they are unable to do so after shRNA-mediated knock-down of cGAS. In addition, both HIV-1- and HIV-2-induced type I interferon response in CD4+ T cells was dependent on productive infection and integration, as the presence of RT or integrase inhibitor dramatically suppressed the sensing. Our findings collectively showed that the cGAS-dependent type I interferon response of CD4+ T cells to HIV infection is conserved over HIV types and critically depends on productive infection. [ABSTRACT FROM AUTHOR]

Surveillance studies of Transmitted Drug Resistance (TDR) are crucial in tracking the evolution of HIV epidemiology. Our aim was to investigate TDR to nucleoside reverse transcriptase inhibitors (NRTIs), non‐nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), as well as to new drugs: lenacapavir, fostemsavir. Predictive sensitivity was evaluated for maraviroc and broadly neutralizing antibodies (bNAbs) (zinlirvimab and teropavimab). Between 2020 and 2023, 85 people with HIV (PWH) were diagnosed with primary HIV‐1 infection (PHI). Pol and env sequences were analyzed and TDR was characterized according to the French ANRS algorithm. The genotypic‐based prediction of bNAbs sensitivity was based on HIV env amino acid signatures I108, I201, F353 for teropavimab and N325, N332, H330 for zinlirvimab. TDR to NRTIs, NNRTIs, PIs and INIs was evidenced in 8.2%, 12.9%, 4.7%, and 5.9% strains, respectively. Ten viruses were CXCR4/dual mix. All viruses were susceptible to lenacapavir (100%) and 52% harbored resistance to fostemsavir. The genotypic profile was associated with a predictive positive value (PPV) > 83% of susceptibility to both teropavimab and zinlirvimab for 23 viruses (31%), while 22 (29%) had a PPV between 62% and 75%, suggesting reduced susceptibility to both bNAbs as soon as primary infection. The surveillance of TDR evidenced at the time of PHI is important with regard to new strategies for HIV patients with virological failure and global implementation of PrEP using NRTI, INI such as recently approved injectable cabotegravir, and future long‐acting drugs such as lenacapavir and bNAbs. [ABSTRACT FROM AUTHOR]

Background/Objectives: Out of 39.9 million adults living with HIV in 2022, 20 million were women. Despite bearing a significant burden, women remain underrepresented in clinical trials, including those for antiretroviral treatments (ART). This study evaluates the safety and efficacy of the bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) regimen in a real-life cohort of 99 women with HIV (females with HIV, FWH) over 48 and 96 weeks. Methods: A retrospective cohort study utilized data from the Sardinian HIV Network and Sicilian HIV Cohort (SHiNe-SHiC) research group. The study included FWH, who started B/F/TAF as a treatment switch. The primary objectives were achieving and maintaining an HIV RNA level of <50 copies/mL at 48 and 96 weeks. Secondary objectives included treatment safety, durability, and reasons for discontinuation. Data on demographics, viro-immunological markers, lipid profiles, and treatment interruptions were extracted for analysis. Results: Among the 99 FWH, the median age was 51.9 years, and the median duration of HIV was 15.1 years. At baseline, 80.8% had undetectable HIV-RNA, which increased to 93.8% at 96 weeks. There was a statistically significant increase in CD4 cells/mL (48w p < 0.001, 96w p < 0.001) and CD4/CD8 ratio (48w p < 0.009, 96w p < 0.048), and reductions in total cholesterol (48w p < 0.003, 96w p < 0.006) and LDL (48w p < 0.004, 96w p < 0.009) levels at 48 and 96 weeks. Nine treatment interruptions were noted, with one due to adverse events. The regimen was well-tolerated overall. Conclusions: B/F/TAF demonstrated high efficacy and safety in this real-world cohort of FWH, highlighting the critical need for gender-focused research in HIV treatment. Ensuring equitable access to effective treatment options for women is imperative for the global health community's efforts to eliminate HIV. [ABSTRACT FROM AUTHOR]

Background The aim of this meta-analysis was to synthesize the available evidence from the literature on the efficacy and safety of integrase inhibitor-based two drug regimens compared to triple drug regimens in virosuppressed people living with HIV (PLWH) in a long-term follow-up (at 96 weeks). Materials and Methods A systematic review and meta-analysis were conducted to evaluate the efficacy, safety, and adverse drug reactions leading to discontinuation of two drug regimens compared to triple drug regimens in virosuppressed PLWH patients at 96 weeks of follow-up. We searched MEDLINE, Google Scholar, and the Cochrane Library up to March 15, 2024, and studies were selected for eligibility based on predefined criteria. Data were extracted independently by two reviewers, and risk ratios (RRs) were calculated as the measure of association between therapy and incidence of events. Results Six studies were included in the analysis, both clinical trials and observational studies. The two drug regimens included cabotegravir/rilpivirine, dolutegravir/lamivudine, and dolutegravir/rilpivirine. No significant differences were observed in treatment failure (RR, 0.77; 95% confidence interval [CI], 0.53–1.13; P=0.182), virological failure (RR, 0.79; 95% CI, 0.48–1.29; P=0.341), adverse drug reactions leading to discontinuation (RR, 1.74; 95% CI, 0.73–4.17; P=0.215), or appearance of mutation (RR, 2.48; 95% CI, 0.33–18.68; P=0.379) between two drug regimen and triple drug regimen groups at 96 weeks of follow up. Conclusion The meta-analysis provide an overview of the available evidence and supports the use of two drug regimens as an option for simplifying treatment and improving clinical outcomes in virosuppressed PLWH. [ABSTRACT FROM AUTHOR]

Background Several antiretroviral therapy (ART) medications have been associated with increased cardiovascular risk, but less is known about the safety of modern ART. We sought to compare the risk of major adverse cardiac events (MACEs) among different ART regimens. Methods Using insurance claims databases from 2008 to 2020, we identified adults aged <65 years who newly initiated ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to protease inhibitors (PI)- and integrase inhibitors (INSTI)-based regimens. We used propensity score-weighted Kaplan-Meier functions to estimate the 6, 12, 18, 24, 36, and 48 months' risk and risk differences (RD) of MACE. Results Among 37 935 ART initiators (median age, 40 years; 23% female; 26% Medicaid-insured), 45% started INSTI-, 16% PI-, and 39% NNRTI-based regimens. MACE occurred in 418 individuals (1.1%) within 48 months after ART initiation. Compared to NNRTI initiators, the risk of MACE was higher at 12 months (RD, 0.50; 95% CI, 0.14–0.99), 18 months (RD, 0.53; 95% CI, 0.11–1.06), and 24 months (RD, 0.62; 95% CI, 0.04–1.29) for PI initiators, and at 12 (RD, 0.20; 95% CI, 0.03–0.37) and 18 months (RD, 0.31; 95% CI, 0.06–0.54) for INSTI initiators; the precision of estimates was limited for longer duration of follow-up. Conclusions Among ART initiators, PI-based and INSTI-based regimens were associated with higher short-term risk of MACE compared to NNRTI-based regimens. The pattern of association between INSTIs and PIs with excess risk of MACE was similar. [ABSTRACT FROM AUTHOR]

Background: Dolutegravir (DTG), an integrase strand inhibitor, is currently used as the first-line treatment for HIV. Despite relatively poor tissue penetration, the risk of adverse effects in metabolic and excretory systems should be considered. The trace aminergic system and trace amines are emerging as relevant role players in many chronic diseases that are commonly diagnosed but poorly understood. Trace amines are biogenic amines that are endogenously produced and can also be ingested by the intake of trace amine-rich food. Trace amines are known to differentially regulate inflammatory and neurological outcome. Objective: This study investigated the effects of DTG on the trace amine profile in a wistar rat model. Methods: A total of 24 healthy wistar rats were randomly divided into four experimental groups: male and female controls and male and female DTG-treated. Blood and tissue samples were collected following a 12-week DTG administration study. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was used to determine trace amine concentrations in urine, plasma, brain, and gastrointestinal tissue. Results: Current data illustrate that polyamines differ significantly (p < 0.05) between males and females in various matrices. DTG significantly (p < 0.05) reduced jejunal tyramine and urinary synephrine levels. Conclusion: Data do not raise major concerns about DTG in the context of the trace amine profile. However, given the importance of the dysregulated trace amine profile in various diseased states, including HIV, current data warrant clinical investigation to further evaluate the significance of DTG-associated effects on the trace amine profile. [ABSTRACT FROM AUTHOR]

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease. [ABSTRACT FROM AUTHOR]

HIV-1 virion maturation is an essential step in the viral replication cycle to produce infectious virus particles. Gag and Gag-Pol polyproteins are assembled at the plasma membrane of the virus-producer cells and bud from it to the extracellular compartment. The newly released progeny virions are initially immature and noninfectious. However, once the Gag polyprotein is cleaved by the viral protease in progeny virions, the mature capsid proteins assemble to form the fullerene core. This core, harboring two copies of viral genomic RNA, transforms the virion morphology into infectious virus particles. This morphological transformation is referred to as maturation. Virion maturation influences the distribution of the Env glycoprotein on the virion surface and induces conformational changes necessary for the subsequent interaction with the CD4 receptor. Several host factors, including proteins like cyclophilin A, metabolites such as IP6, and lipid rafts containing sphingomyelins, have been demonstrated to have an influence on virion maturation. This review article delves into the processes of virus maturation and Env glycoprotein recruitment, with an emphasis on the role of host cell factors and environmental conditions. Additionally, we discuss microscopic technologies for assessing virion maturation and the development of current antivirals specifically targeting this critical step in viral replication, offering long-acting therapeutic options. [ABSTRACT FROM AUTHOR]

This study investigates the prevalence and patterns of transmitted drug resistance mutations (TDRMs) and HIV-1 subtypes among antiretroviral therapy (ART) naïve individuals in Veneto, Italy, from 2017 to 2024. This research aims to understand the dynamic landscape of TDRMs and HIV-1 genetic diversity to inform treatment strategies effectively. We included all adult ART-naïve people with HIV (PWH) from seven infectious disease units in Veneto, Italy. We collected the genotypic resistance testing conducted to predict drug susceptibility and subtype distribution using the Stanford HIVdb algorithm. We included 762 PWH, showing a slight but statistically significant decline in the B subtype among Italian PWH (p = 0.045) and an increase in non-B subtypes among foreigners, though it was not statistically significant (p = 0.333). The most frequent mutations were in Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), especially in non-B subtypes, with a notable rise from 10.7% in 2017–2019 to 15.5% in 2020–2024. Notably, TDRMs were consistently detected, highlighting an ongoing challenge despite the stable prevalence observed over the years. In addition, the data revealed a concerning rise in mutations against newer drug classes, such as integrase inhibitors. Conclusively, the study underscores the necessity of continuous surveillance of HIV subtypes and resistance patterns to adapt ART regimens optimally. Despite the stable levels of drug resistance, the emergence of resistance against newer drugs necessitates ongoing vigilance and possible adjustment in treatment protocols to enhance clinical outcomes and manage HIV drug resistance effectively. [ABSTRACT FROM AUTHOR]

Abstract Background The Uganda ministry of Health recommends frequent blood glucose monitoring for the first six months on dolutegravir, in people with HIV (PWH) having pre-diabetes mellitus (pre-DM). We sought to determine if indeed PWH with pre-diabetes started on dolutegravir had worse blood glucose outcomes at 48 weeks compared to those with normal blood glucose. Methods In this matched cohort study, we compared 44 PWH with pre-DM and 88 PWH with normal blood glucose at baseline. The primary outcome was change in mean fasting blood glucose (FBG) from baseline to week 48 and 2-hour blood glucose (2hBG) from baseline to week 36 compared between the two groups. Results There was significant increase in FBG in PWH with normal blood glucose (mean change in FBG(FBG): 3.9 mg/dl, 95% confidence interval (95% CI): (2.2, 5.7), p value (p) =

Introduction Methods Results Conclusions Prevention of cardiovascular disease is a major issue in the current management of people living with HIV. Concern is growing about the metabolic impact of integrase strand transfer inhibitors (INSTIs), which could lead to an increased risk of diabetes, but the data are conflicting. This is an updated version of our previous analysis, with longer follow‐up and new molecules.We retrospectively evaluated the incidence of new‐onset diabetes in people living with HIV starting combined antiretroviral therapy with an INSTI compared with non‐nucleoside reverse transcriptase inhibitors and protease inhibitors. Data were collected from the Dat'AIDS cohort study, a collaboration of 30 HIV treatment centres in France. We used a propensity score‐based inverse probability of treatment weighting approach to adjust for baseline characteristics between the two groups (INSTI and non‐INSTI).Between 2009 and 2021, a total of 12 150 people living with HIV were included. The incidence of diabetes was higher in the INSTI group than in the non‐INSTI group (hazard ratio 1.38; 95% confidence interval 1.07–1.77; p = 0.012). Regardless of the third drug, but to a greater extent for INSTIs, we observed a peak of new‐onset diabetes in the year following initiation of combined antiretroviral therapy.The incidence of diabetes was higher in people treated with integrase inhibitors than in those receiving other third agents. This increased risk occurred both during the first year of treatment and in the longer term. [ABSTRACT FROM AUTHOR]

The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to a decreased quality of life, some of the most significant of which are neuropathic pain and the development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured the development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptase inhibitors (NRTIs), not other types of antiretrovirals such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote the development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate the design of less toxic forms of these drugs and/or potential mitigation strategies. [ABSTRACT FROM AUTHOR]

Introduction: To assess the effectiveness of novel HIV curative strategies, "cure" trials require periods of closely monitored antiretroviral therapy (ART) analytical treatment interruptions (ATIs). We performed a systematic review and meta‐analysis to identify the impact of ATI with or without novel therapeutics in cure‐related studies on the time to viral re‐suppression following ART restart. Methods: Medline, Embase and Web of Science databases were searched for human studies involving ATIs from 1 January 2015 till 22 April 2024. The primary outcome was time to first viral re‐suppression (plasma HIV viral load [VL] <50 copies/ml) stratified by receipt of interventional drug with ATI (IA) or ATI‐only groups. Random‐effects proportional meta‐analysis and multivariable Cox proportional hazards analysis were performed using R. Results: Of 1073 studies screened, 13 were included that met the inclusion criteria with VL data available after restarting ART (n = 213 participants). There was no difference between time to viral suppression in IA or ATI‐only cohorts (p = 0.22). For 87% of participants, viral suppression within 12 weeks of ART restart was achieved, and all eventually had at least one VL <50 copies/ml during follow‐up. After adjusting for covariables, while participants in the IA cohort were associated with less rapid suppression (adjusted hazard ratio [aHR] 0.61, 95% CI 0.40–0.94, p = 0.026), other factors include greater log VL at ART restart (aHR 0.56, 95% CI 0.46–0.68, p<0.001), duration since HIV diagnosis (aHR 0.93, 95% CI 0.89–0.96) and longer intervals between HIV VL monitoring (aHR 0.66, 95% CI 0.59–0.74, p<0.001). However, the use of integrase inhibitors was associated with more rapid viral suppression (aHR 1.74, 95% CI 1.16–2.59). Discussion: When designing studies involving ATIs, information on time to viral re‐suppression after restarting ART is important to share with participants, and should be regularly monitored and reported, to assess the impact and safety of specific trial interventions in ATI studies. Conclusions: The majority of participants achieved viral suppression after restarting ART in ATI studies. ART regimens containing integrase inhibitors and frequent VL monitoring should be offered for people restarting ART after ATI studies to ensure rapid re‐suppression. [ABSTRACT FROM AUTHOR]

In 2018, a significant neural tube defects (NTD) signal was reported after pre‐conceptional exposure to dolutegravir, but was not confirmed in further analysis. Since 2019, dolutegravir‐based regimen, an integrase inhibitor (INI), is recommended by WHO as the most‐effective first‐line therapy in all patients living with HIV. To explore the potential INI‐related teratogenic effect, we searched disproportionate signals between exposure to INI‐class drugs and congenital anomalies, compared to non‐INI drugs, using the international pharmacovigilance database, VigiBase®. We selected all the reports registered in VigiBase® between 01/01/2007 and 30/03/2021 on any antiretroviral drug‐related fetal or neonatal adverse drug reactions, declared either in children (<2 years) exposed in utero or in pregnant women (12–50 years). A case/non‐case study was conducted to detected signals between congenital anomalies and prenatal exposure to any INI‐class drug, compared to non‐INI drugs, by estimating adjusted reporting odds ratios (aROR) with 95% confidence intervals (95%CI). We identified 2521 unique reports, among which 664 (26.3%) were related to INI‐class use. Overall, 520 congenital anomalies were cited from 327 unique reports, of whom 31.0% were INI‐related. Compared to non‐INI drugs, no significant disproportionate reporting signal between prenatal exposure to INI‐class drugs and congenital anomalies was found (aROR 1.13; 95% CI:0.85–1.51). However, specific significant signals were reported for raltegravir/elvitegravir/dolutegravir drug exposure and urinary malformations (aROR 2.43; 95%CI:1.08–5.43), digestive malformations (aROR 3.09; 95%CI:1.22–7.84), and NTDs (aROR 3.02; 95%CI:1.09–8.37). Although specific congenital anomalies signals associated with raltegravir/elvitegravir/dolutegravir exposure were notified, causal relationship needs to be further investigated in prospective studies. [ABSTRACT FROM AUTHOR]

Background: The Uganda ministry of Health recommends frequent blood glucose monitoring for the first six months on dolutegravir, in people with HIV (PWH) having pre-diabetes mellitus (pre-DM). We sought to determine if indeed PWH with pre-diabetes started on dolutegravir had worse blood glucose outcomes at 48 weeks compared to those with normal blood glucose. Methods: In this matched cohort study, we compared 44 PWH with pre-DM and 88 PWH with normal blood glucose at baseline. The primary outcome was change in mean fasting blood glucose (FBG) from baseline to week 48 and 2-hour blood glucose (2hBG) from baseline to week 36 compared between the two groups. Results: There was significant increase in FBG in PWH with normal blood glucose (mean change in FBG(FBG): 3.9 mg/dl, 95% confidence interval (95% CI): (2.2, 5.7), p value (p) = < 0.0001) and decrease in those with pre-DM (FBG: -6.1 mg/dl, 95%CI (-9.1, -3.2), p = < 0.0001) at 48 weeks. 2hBG was significantly lower than at baseline in both groups with the magnitude of reduction larger in those with pre-DM at 12 weeks (adjusted differences in mean drop in 2hBG (a2hBG): -19.69 mg/dl, 95%CI (-30.19, -9.19), p = < 0.0001) and 36 weeks (a2hBG: -19.97 mg/dl, 95%CI (-30.56, -9.39), p = < 0.0001). Conclusion: We demonstrated that Ugandan ART naïve PWH with pre-diabetes at enrollment have consistent improvement in both fasting blood glucose and glucose tolerance over 48 weeks on dolutegravir. Intensified blood glucose monitoring of these patients in the first six months of dolutegravir may be unnecessary. [ABSTRACT FROM AUTHOR]

Objective: To compare the long-term effects on immune parameters, inflammation, and HIV-1 reservoir after switching to a two-drug (2DR) versus maintaining an integrase inhibitor (InSTI)-based three-drug regimen (3DR). Methods: Cross-sectional study in which HIV-1 treatment-naïve people started and maintained an InSTI-based 3DR or, at different times, switched to 2DR (dolutegravir or darunavir/cobicistat + lamivudine). CD4+ and CD8+ T-cell activation and exhaustion, plasma concentrations of hs-CRP, D-dimer, P-selectin, IL-1β, IL-6, TNF-α, IFN-γ, IP-10, sTNFR-I/II, MIP-1α/β, I-FABP, LBP, sCD14, sCD163, MCP-1, and cellular-associated HIV-1-DNA and -RNA were quantified by flow cytometry, different immunoassays, and droplet digital PCR, respectively. The U de Mann-Whitney test evaluated differences between 3DR and 2DR. Immune recovery was evaluated using a general linear model for repeated measures adjusted for different co-variables. Results: Fifty participants per group were included. The median time on 3DR was 82 months for the 3DR group and 30 months for the 2DR group, after which it switched to 2DR for a median of 57 months. We did not find differences between both groups in any of the parameters analyzed. Specifically, some values in 3DR and 2DR were hs-CRP, 0.92 mg/L (0.45–2.23) vs. 1.23 (0.61–2.38); D-dimer, 190.0 µg/L (150.0–370.0) vs. 190.0 (150.0–397.5); IL-6, 2.8 pg/mL (1.3–5.3) vs. 3.2 (2.1–4.7); sCD14, 4.5 ng/mL (3.3–6.2) vs. 5.0 (3.6–6.1), respectively, all p ≥ 0.399. Conclusion: In the long term, switching to 2DR does not negatively affect immunologic parameters, inflammatory markers, or HIV-1 reservoir. [ABSTRACT FROM AUTHOR]

Objective: Routine viral load and drug resistance testing are well supported in most resource-rich settings and provide valuable benefits in the clinical care of PLWH in these communities. Undoubtedly, there exist financial and political constraints for the scale-up of viral load and drug resistance testing in Sub-Saharan Africa. To achieve the global UNAIDS 95/95/95 targets, there is the need to bridge this inequity in patient care and allow for a universal approach that leaves no community behind. Methods: Venous blood from 96 PLWH on second-line ART from Korle-Bu Teaching Hospital were collected and processed into plasma for CD4+ T- cell and viral load assessments. Ribonucleic acid (RNA) was extracted from stored plasma and the protease gene amplified, sequenced and analyzed for subtype and drug resistance mutations using the Stanford HIV drug resistance database. Results: Out of the 96 PLWH, 37 experienced virological failure with 8 patients' samples successfully sequenced. The predominant HIV-1 subtype identified was CRF02_AG (6/8, 75.0%) with 12.5% (1/8) each of CFR06_cpx infection and one case unable to subtype. The major PI resistance mutations identified were; M46I, I54V, V82A, I47V, I84V and L90M. Conclusions: Persons living with HIV who had experienced virologic failure in this study harboured drug resistance mutations to PI, thus compromise the effectiveness of the drugs in the second line. Resistance testing is strongly recommended prior to switching to a new regimen. This will help to inform the choice of drug and to achieve optimum therapeutic outcome among PLWH in Ghana. Highlights: Protease inhibitors (PI) are prescribed for patients failing on reverse transcriptase-based regimen without adequate monitoring for viral load and drug resistance testing. The study provides evidence of PI resistance mutations and their implications for the relatively fewer individuals on PI-based regimen in the era of dolutegravir (DTG) use. Close monitoring on all HIV infected patients on PI is needed. [ABSTRACT FROM AUTHOR]

HIV drug resistance compromises the ability of anti-retroviral therapy (ART) to suppress viral replication, resulting in treatment failure. This study investigates the prevalence of pre-treatment drug resistance (PDR) in newly diagnosed individuals in a prosperous city (Wenzhou) in Southeastern China. A cross-sectional investigation was carried out among 473 newly diagnosed ART-naive HIV-1-infected individuals between January and December 2022. The protease–reverse transcriptase (PR-RT) region and integrase (IN) region of HIV-1 were amplified by two separately nested PCRs, followed by sequencing. Drug resistance mutations (DRMs) and drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs) were analyzed. The PDR prevalence was 6.5% [95% CI: 4.4–9.1] for any anti-retroviral drug, 0.9% [95% CI: 0.3–2.3] for NRTIs, 4.1% [95% CI: 2.5–6.5] for NNRTIs, 1.8% [95% CI: 0.8–3.6] for PIs and 0.5% [95% CI: 0.1–1.8] for INSTIs. According to the subtyping results of the PR-RT region, 11 different subtypes and 31 unique recombinant forms (URFs) were found. CRF07_BC was the dominant subtype (53.7%, 233/434), followed by CRF01_AE (25.3%, 110/434). V179D (1.6%) and K103N (1.4%) were the most predominant types of NNRTI DRMs. Q58E (1.2%) and M184V (0.7%) were the most frequent PI DRMs and NRTI DRMs, respectively. The INSTI-related DRMs Y143S (causes high-level resistance to RAL) and G163K (causes low-level resistance to EVG and RAL) were found in one patient each. Given the relatively high PDR prevalence of NNRTI (4.1%), non-NNRTI-based ART may be preferred in the future. It is recommended to include genotypic resistance testing before starting ART in regions where feasible. [ABSTRACT FROM AUTHOR]

Gag-Pol protein is one of the important structural proteins of human immunodeficiency virus (HIV), comprising the basic scaffold proteins and functional enzymes required during the lifecycle of HIV. Currently, the inhibitors targeting different functional domains on Gag-Pol include capsid (CA) inhibitors, protease inhibitors, reverse transcriptase inhibitors, and integrase inhibitors. The CA inhibitors inhibit the maturation of CA or disrupt the assembly of CA, so as to affect the replication of HIV. The primary mechanism of protease inhibitors is to inhibit the protease from cleaving at the cleavage site CA-spacer peptide 1 (SP1). The reverse transcriptase inhibitors block the reverse transcription process of HIV by mimicking the reverse transcription substrates. The integrase inhibitors impact the activity of integrase by targeting the zinc-finger structure at the active center of integrase. This article summarizes the inhibitors targeting HIV Gag-Pol protein and their mechanisms, and reviews the approved dosages and usages of approved patent drugs, so as to provide the references for the future clinical combination therapies and the development of new inhibitors targeting HIV Gag-Pol protein. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) can be personalized through simple formulations with high resistance barriers, favorable safety profiles, and novel administration routes. Switching treatments has become a key clinical strategy for addressing drug toxicity and interactions and enhancing adherence and convenience. This strategy aims to improve the quality of life and long-term efficacy, even in challenging cases like people living with HIV (PLWH) with multiple comorbidities, prior virological failure, and drug resistance. The authors reviewed clinical trials and cohort studies providing evidence of benefits and risks of current antiretroviral (ARV) drugs as switching options for PLWH in various scenarios. The literature search included clinical trials, meta-analyses, observational studies, and review articles in English published after 2000, and current HIV treatment guidelines in English and Spanish as of February 2024. New ARV drugs offer advantages in efficacy and safety over previous options but may also have adverse effects. Second-generation integrase inhibitors and tenofovir alafenamide show benefits as switching options in various scenarios, though more research is needed on potential weight gain and metabolic issues. Injectable long-acting ART is promising for switching strategies, but finding the optimal combination of new drugs remains challenging. [ABSTRACT FROM AUTHOR]

Introduction: The naturally occurring dipeptide Tryptophylglycine (WG) is enhanced in human immunodeficiency virus (HIV-1) infected Elite Controllers (EC). We have shown that this dipeptide has an anti-HIV-1 effect and evaluated now its synergistic antiretroviral activity, in combination with current antiretrovirals against multi-drug resistant HIV-1 isolates. Methods: Drug selectivity assay with WG-am and ARVs agains HIV-1 resistant isolates were carried out. Subsequently, two methods, Chou-Talalay's Combination Index (CI) and ZIP synergy score (SS), were used to quantify the synergism. Results: WG-am had a moderate/strong synergism with the four tested antiretrovirals: raltegravir, tenofovir, efavirenz, darunavir. WG-am:TDF had strong synergism at ED50, ED75, ED90 (CI: <0.2) in isolates resistant to protease inhibitors or integrase strand inhibitors (INSTI), and a slightly less synergism in isolates resistant to non-nucleoside or nucleotide reverse transcriptase inhibitors. WG-am combined with each of the four drugs inhibited all drug-resistant isolates with over 95% reduction at maximum concentration tested. The highest selectivity indexes (CC50/ED50) were in INSTI-resistant isolates. Conclusion: Our data suggest that WG, identified as occurring and enhanced in Elite Controllers has a potential to become a future treatment option in patients with HIV-1 strains resistant to any of the four major categories of anti-HIV- 1 compounds. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus type 2 (HIV-2) is a particular subtype of HIV, which is endemic in West Africa and is characterized by a more indolent course than HIV-1. As people living with HIV-2 (PWH-2) are at risk for the development of acquired immunodeficiency syndrome and can transmit the virus, antiretroviral therapy is usually indicated. However, the optimal treatment of HIV-2 is unknown and historically the protease inhibitors (PIs) were a regular part of therapy. Nowadays, the use of integrase strand transfer inhibitors (INSTIs) in HIV-2 is increasing but the evidence supporting this approach is limited. In this narrative review, we outline the clinical data on the use of INSTI-containing antiretroviral therapy in HIV-2. We found that in the setting of treatment-naïve PWH-2, the use of INSTIs is successful, but also noted large heterogeneity in reported outcomes and that most cohorts are small with limited follow-up time. There is a lack of studies comparing the efficacy of INSTIs to other first-line options. For treatment-experienced PWH-2, the efficacy of INSTI is highly variable. [ABSTRACT FROM AUTHOR]