Darunavir Research Articles

Effectiveness and Tolerability of DOR/3TC/TDF in Experienced People with HIV Switching from RPV/FTC/TDF: A Retrospective, Single Center Cohort Study

Background: With advances in antiretroviral therapy for HIV treatment, newer drug combinations provide improved efficacy, safety, and compliance. This study evaluates switching to a regimen of doravirine (DOR), tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) in a cohort of people living with HIV (PLWH). Methods: this Italian retrospective study included 426 PLWH who switched from rilpivirine (RPV)/TDF/emtricitabine (FTC) to DOR/3TC/TDF. The analysis focused on treatment effectiveness, safety, and metabolic and renal markers. Results: this study reports a treatment failure (defined as virological failure or discontinuation of the regimen) rate of 2.34% (95% confidence interval, 1.28–4.50%), with significant improvement in CD4 counts (+49.93 cells/µL, p < 0.001). Notably, the switch to DOR/3TC/TDF did not result in adverse metabolic effects or significant changes in renal function. Analysis of lipid profiles showed stabilization in the majority of PLWH. Conclusions: this study indicates that switching to a DOR/3TC/TDF from RPV/TDF/FTC is an effective and well-tolerated option for PLWH, with benefits in terms of maintaining viral suppression, CD4 count recovery, and metabolic health, without evidence of renal impairment. These results support the continued use of DOR/3TC/TDF as part of HIV treatment strategies and highlight the need for ongoing research to refine ART regimens for different populations.

Lipid Profile Improvement after Switching to Dolutegravir-Based Regimen in People Living with HIV: A Cohort Study

Background: Integrase inhibitor (INSTI) based antiretroviral therapy is the mainstay for people living with HIV (PLHIV). Due to its favorable efficacy and safety profile, dolutegravir (DTG) is widely used in combination with nucleoside reverse transcriptase inhibitors (NRTIs). TLD, a fixed-dose combination of tenofovir disoproxil fumarate (TDF), lamivudine (3TC), and DTG, is the first-line treatment for PLHIV in Thailand. However, data on metabolic complications from DTG-based regimens in the Thai population have not been thoroughly investigated. Materials and Methods: A cohort study non-randomized trial was conducted at Buddhachinaraj Hospital, Phitsanulok, Thailand. Data on demographics, baseline antiretroviral regimens, and metabolic profiles such as triglycerides, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), fasting blood sugar, and aminotransferases, were collected at baseline and six months after switching to a DTG-based regimen in virologically suppressed PLHIV between November 1, 2022 and August 31, 2023. Informed consents were obtained from all participants. Results: One hundred thirty-eight PLHIV were enrolled, with a majority being men, at 59%, and a median age of 47.5 years (IQR 36.2, 55.1). Median CD4 count was 608 cells/mm³ (IQR 452, 805) and median duration of antiretroviral treatment was 13 years (IQR 8, 18). Underlying conditions included dyslipidemia with 44.2%, hypertension for 29.7%, and type II diabetes for 14.5%. Of the participants, 107 out of 138 (77.5%) were on TDF, 3TC, or emtricitabine (FTC) combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz (EFV) or rilpivirine (RPV) as their baseline regimen. After six months, significant changes were observed in median triglycerides, from 138.5 to 97.5 mg/dL (p<0.001), total cholesterol from 201 to 173 mg/dL (p<0.001), and LDL cholesterol from 117 to 103 mg/dL (p<0.001). Median body weight increased from 63.2 to 63.35 kg (p<0.001). Conclusion: DTG, a second-generation INSTI, is widely used as a key antiretroviral therapy in Thailand. While it demonstrates favorable effects on lipid profiles, body weight gain, which is a crucial factor for cardiovascular outcomes, should be monitored closely. Keywords: Integrase inhibitor; People living with HIV (PLHIV); Dolutegravir (DTG); Triglyceride; Total cholesterol; LDL-cholesterol; HDL-cholesterol; Fasting blood sugar; Aminotransferase

Brief Report: Switching to Long-Acting CAB/RPV: Data From an Italian Monocentric Cohort

Background: Cabotegravir (CAB)/rilpivirine (RPV) is the first long-acting injectable (LAI) antiretroviral therapy approved for virologically suppressed adults with HIV-1. Setting: Italian single centre cohort. Methods: We conducted a retrospective observational study to assess the durability, adherence to the prescribed injection schedule, and reasons for discontinuation of CAB/RPV LAI administered every 8 weeks (Q8W). Results: One hundred thirty-eight patients were included with a median observation period of 43 weeks [interquartile range (IQR) 34–47 weeks]. Of these, 32 (23.2%) were female, and the median age was 51 years (IQR 40–58 years). Twelve patients (8.7%) discontinued CAB/RPV LAI treatment with a median time to discontinuation of 21 weeks (IQR 12–35 weeks), and 92.8% of the injections occurred within the CAB/RPV LAI schedule. The most common reason for discontinuation was injection-related pain (5/12). No confirmed virological failure occurred during the period of observation with 3 individuals who experienced virological blips. Conclusions: Our findings showed that CAB/RPV LAI Q8W is tolerated well in clinical practice, with high adherence to the injection schedule and few discontinuations mainly related to injection site–related pain.

The steady-state pharmacokinetics of fixed-dose combination dolutegravir+rilpivirine in hemodialysis

Objective: Fixed dose combination (FDC) dolutegravir (DTG) plus rilpivirine (RPV) is an approved antiretroviral treatment regimen for people with HIV. The steady-state pharmacokinetics (PK) of FDC DTG+RPV in hemodialysis (HD) has not been previously studied. Design: We performed a single-center, prospective evaluation of the steady-state PK of FDC DTG +RPV in 4 adults without HIV either requiring HD and in 4 matched participants with normal renal function. Methods: All participants received FDC DTG(50mg)+RPV(25mg) daily for 10-14 days with food before undergoing an intensive 24-hour PK evaluation (performed between dialysis days for those requiring HD). Plasma drug and metabolite concentrations were measured using a validated UHPLC/MS/MS. Descriptive PK parameters were calculated. Results: The HD and normal renal function participants (each group with 2 men and 2 women) were of similar ages (range, 50-60 years) and body mass index (range, 18.5-34.5 kg/m2). No participant experienced serious or grade 3-4 adverse events; there were no study discontinuations. The AUC0-τ mean (SD) ratios of HD to normal renal function for DTG and RPV were 1.1 (0.4) and 1.1 (0.9), respectively. The mean (SD) Cmin for DTG and RPV in the HD group were 1033 (252) ng/mL and 49 (18) ng/mL, respectively. Conclusions: HD did not lead to clinically appreciable differential exposures to DTG and RPV. Exposures throughout the dosing interval were greater than the reported protein-binding adjusted IC90 efficacy values for DTG (64 ng/mL) and RPV (12 ng/mL) in all participants. These data suggest no dosing modifications are needed for the FDC DTG+RPV regimen in HD.

CD4+/CD8+ improvement after switch from a second-generation integrase inhibitor regimen to long-acting cabotegravir and rilpivirine.

Our study assessed the CD4+/CD8+ ratio in people with HIV (PWH) switching from a second-generation integrase inhibitor regimen to long-acting cabotegravir (CAB) and rilpivirine (RPV). Over one year, we observed a significant improvement in the CD4+/CD8+ ratio; In addition, our data showed that time spent in CAB+RPV was significantly associated with an increased CD4+/CD8+ ratio. These findings suggest that long-acting therapy may enhance immune recovery, also in treatment-experienced PWH.

Simeprevir induces ferroptosis through β-TrCP/Nrf2/GPX4 axis in triple-negative breast cancer cells

The effective treatment regimens of triple-negative breast cancer (TNBC), a specific subtype of breast cancer (BC) with proneness to relapse and poor prognosis, are still lacking. Simeprevir (SIM), approved for hepatitis C infection treatment, has been proved to be a competitive drug for the treatment of various solid tumors recently. However, the anti-tumor mechanisms of SIM and therapeutic effects on TNBC are uncertain. In this study, we suggested that SIM effectively restrained the growth of MDA-MB-231 and BT-549 cells, two cell lines from TNBC. The RNA sequencing revealed that ferroptosis signaling was activated in SIM-treated TNBC cells. SIM induced ferroptosis in TNBC cells through reduced glutathione (GSH) levels, increased iron levels, ROS and lipid peroxidation. Mechanistically, SIM promoted the expression of β-TrCP to inhibit the Nrf2/GPX4 axis in TNBC cells, leading to ferroptosis. Moreover, SIM administration into the xenografts formed by MDA-MB-231 dramatically suppressed the tumor progression by inducing ferroptosis in vivo. Collectively, this finding reveals that SIM may serve as a competitive therapeutic strategy to inhibit TNBC.

Impurities profiling of method development and validation of Etravirine (ETR) in their dosage forms by chromatography method as per international conference on harmonisation guidelines

Impurities profiling of method development and validation of Etravirine (ETR) in their dosage forms by chromatography method as per international conference on harmonisation guidelines

Virological History Predicts Non-sustained Viral Suppression With Long-Acting Cabotegravir and Rilpivirine Therapy, Independent of Pharmacokinetic Parameters

Abstract Background This study aimed to investigate factors contributing to non-sustained viral suppression, including intermittent viremia and persistent low-level viremia, during cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) injectable therapy, with a focus on pharmacokinetics (PK). Methods A prospective cohort study was conducted on people with human immunodeficiency virus (HIV, PWH) transitioning from stable oral antiretroviral therapy (ART) to bimonthly CAB + RPV LA. Standardized follow-up included close monitoring through blood sampling for plasma human immunodeficiency virus type 1 (HIV-1) viral load (VL) and multiple plasma drug concentrations measurements to analyze the connection between PK parameters and virologic outcomes. Results Among 173 patients with a median (interquartile range [IQR]) follow-up of 11.1(7.1–13.2) months and 789 pre-dose measurements, 38.7% experienced VL ≥ 20 copies/mL, and 16.2% had levels ≥50 copies/mL. Intermittent viremia occurred in 34.7% of patients, and persistent low-level viremia in 4%. Virological failure developed in 2 cases. Predictors of non-sustained viral suppression included VL at HIV diagnosis (adjusted hazard ratio [AHR]: 1.49 per log10 VL, 95% confidence interval [CI]: 1.04–2.12, P = .027), detectable viremia on oral ART (AHR: 2.45, 95% CI: 1.29–4.65, P = .006), and the level of viral suppression at transition (AHR: 0.38, 95% CI: .19–.75, P = .004). We found a significant association between low trough concentrations of CAB and RPV and episodes of detectable viremia exceeding 50 copies/mL. However, none of the assessed PK covariates predicted non-sustained viral suppression in multivariable models. Conclusions Non-sustained viral suppression in PWH transitioning from stable oral ART to CAB + RPV LA was linked to preexisting factors before transition. Higher VL pre-ART and incomplete suppression on oral therapy increased the risk, independent of PK parameters.

Long-acting antiretroviral therapy effectiveness and patient satisfaction using patient questionnaires: data from a real-world setting

BackgroundAntiretroviral therapy (ART) for HIV infection has evolved substantially. The development of long-acting drugs, such as cabotegravir (CAB) and rilpivirine (RPV) might improve treatment satisfaction among people living with HIV (PLWH). The real-world effectiveness of long-acting ART and its effect on patient satisfaction needs to be assessed. This study investigated antiviral effectiveness and treatment satisfaction in PLWH who switched from conventional to long-acting ART (CAB + RPV).MethodsThis prospective cohort study included PLWH aged 18 years and older who switched to CAB + RPV and received the injections every 8 weeks between June 2022 and May 2023, after a 4-week oral lead-in phase. The eligibility criteria included viral suppression, absence of hepatitis B virus (HBV) DNA, and no prior RPV resistance mutations. Clinical data, including renal, lipid, and glucose biomarker levels, were monitored from the baseline to 44 weeks after switching. Treatment satisfaction was assessed using the HIV Treatment Satisfaction Questionnaire. A linear mixed-effects model was used to estimate changes in clinical data from baseline.ResultsThirty-eight male participants were enrolled. Some participants had detectable levels of viral replication; however, all participants maintained viral suppression (HIV-RNA < 50 copies/mL) at 44 weeks and no cases of virological failure were detected. The creatinine level decreased by − 0.04 mg/dL (95% confidence interval [CI]: − 0.07 to − 0.01), lipid and glucose profiles remained stable, and treatment satisfaction increased by 6.6 points (95% CI: 2.4 to 10.8) after switching to CAB + RPV.ConclusionsLong-acting ART provides effective viral suppression and enhances treatment satisfaction in PLWH switching from conventional ART. Long-acting ART can improve patient well-being; however, patient selection and monitoring to prevent HBV-related complications are important.

The 3D-QSAR Study, Molecular Docking, and ADMET Analysis of Darunavir Derivatives of HIV-1 Protease Inhibitors

Background: Acquired Immunodeficiency Syndrome (AIDS) is one of most prevalent infectious diseases in the world , and HIV-1 protease (PR) is a vital target of drug design. Nowadays, three-dimensional quantitative structure-activity relationships (3D-QSAR) are applied to help design new protease inhibitions (PIs). Objective: The primary objective of this study is to apply the 3D-QSAR study to a series of 42 derivatives of Darunavir (DRV) and to design new molecules possessing high antivirus activity. Methods: Partial Least Squares (PLS) were used to cross-validate the dataset of compounds, and the optimal number of principal components (ONC), cross-validate coefficient (q²), standard error of estimate (SEE), non-cross-validated correlation coefficient (R²) and fisher test value (F) were calculated to assess model robustness. In this study, the CoMSIA-DAH model (q²=0.754, r²= 0.988, rpred2=0.57) possessed the highest predicted activity. Newly designed molecules were analyzed by docking studies with compound 25 taken as a template. Results: Within eight newly designed drugs, compound N02 possessed the highest antivirus activity (IC50=0.00461 nM) predicted by the CoMSIA-DAH model. The Surflex-Dock module of SYBYL-X 2.0 was used to affirm the predicted anti-PR activity of the newly designed compounds and the results of docking complex structure could be visualized. All newly designed molecules were in agreement with CSore above four and the docking study revealed that Asp29, Asp30, Ile50, Asp124, Asp128, Asp129 and Ile149 were critical residues in the process of inhibiting PR. Conclusion: One of the main aspects of this study is the successful design of a series of molecules with excellent investigatory values, which elucidates explicit quantitative structure-activity relationships of DRV derivatives and will provide significant suggestions for future pharmaceutical research.

Comprehensive database of HIV mutations selected during antiretroviral in vitro passage experiments

BackgroundIn vitro passage experiments are crucial to the development of antiretroviral (ARV) drugs. MethodsWe created an online database containing data from 102 published studies in which HIV-1 or HIV-2 was cultured with increasing concentrations of the FDA-approved nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), capsid inhibitor (CAI) lenacapavir, and nucleoside RT translocation inhibitor (NRTTI) islatravir. We summarized the mutations selected in the subset of passage experiments with NRTIs lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), tenofovir (TFV), and zidovudine (AZT), NNRTIs doravirine (DOR), efavirenz (EFV), and rilpivirine (RPV), INSTIs bictegravir (BIC), cabotegravir (CAB), and dolutegravir (DTG), and PIs atazanavir (ATV), darunavir (DRV), and lopinavir (LPV). Mutations selected in vitro were compared with those selected in persons receiving the same ARV. ResultsTwenty-seven studies described 89 experiments of wildtype isolates passaged with 3TC, FTC, ABC, TFV, or AZT; sixteen studies described 89 experiments passaged with EFV, RPV, or DOR; eleven studies described 76 experiments passaged with the INSTIs BIC, CAB, or DTG; six studies described 33 experiments passaged with ATV, LPV, or DRV. With several exceptions, mutations selected in two or more experiments were among the most common mutations selected in persons receiving the same ARV. ConclusionsWe created a database of published ARV in vitro selection experiments. Mutations emerging from these experiments generally predict those observed in persons receiving the same ARV. However, there are notable differences in mutation frequencies between in vitro and in vivo settings.

Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation

Activated hepatic stellate cells (aHSCs), the main perpetrators of liver fibrosis, are a promising therapeutic target in the treatment of chronic liver disease. During liver injury, HSCs transcend from a quiescent to a fibrotic phenotype, a process which involves major metabolic reprogramming with altered mitochondrial function. The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective and specifically antifibrotic effect in several animal models of chronic liver injury, as well as in vitro. Herein, we use HSCs activated with the profibrogenic cytokine TGF-β to explore whether mitochondrial function is implicated in this effect. The mitochondrial bioenergetic profile, morphology and dynamics of TGF-β-treated cells (48 h) were altered and these effects were prevented by co-treatment with clinically relevant concentrations of RPV. A MitoStress Test (Seahorse Analyzer) revealed that TGF-β increased both oxygen consumption rate (basal respiration, maximal respiration and spare respiratory capacity) and extracellular acidification rate (indicative of increased glycolysis). Cells exposed to TGF-β also displayed diminished mitochondrial membrane potential and enhanced mitochondrial fission. All of these effects were rescued with RPV. RNA sequencing analysis of cells exposed to TGF-β revealed the presence of 338 differentially expressed genes that encode mitochondrial proteins (mito-DEGs), of which 139 and 199 were significantly up- and down-regulated (adjusted p<0.05). This alteration in 15 (10.79 %) and 31 (22.03 %) of the up-regulated and 16 (8.04 %) and 49 (24.62 %) of the down-regulated mitoDEGs was prevented with co-exposure to RPV 4μM or 8μM, respectively. In conclusion, alterations in mitochondrial function are implicated in the antifibrogenic action of RPV, pointing to potential novel antifibrotic targets.

Quality by Design‐Assisted RP‐HPLC Method for Determination of Ritonavir and Darunavir in Pharmaceutical Formulation Using Central Composite Design

ABSTRACTThe quality by design enabled the development of cost‐effective, simple, precise, and rapid Reversed phase‐ high‐performance liquid chromatography techniques for determining ritonavir (RIT) and darunavir (DAR) in the tablet dosage form. Systematic method optimization was performed through central composite design by altering the flow rate and composition of the organic phase in the mobile phase as the critical method parameters for evaluating the necessary analytical attributes, namely, the tailing factor, theoretical plate count, and resolution. The optimal separation was achieved on a column with C18 in nature and dimensions of (250 mm length × 4.6 mm id × 5 µm particle size) using a mobile phase consisting of acetonitrile and water (75:25 v/v) at a flow rate of 0.9 mL/min. Detection was carried out at 247 nm. The retention time of DAR and RIT was 2.939 and 3.537 min, respectively, as per International Council for Harmonization (ICH) guidelines. The developed method was useful for the determination of bulk drug and formulations.

Rilpivirine Activates STAT1 in Non-Parenchymal Cells to Regulate Liver Injury in People Living with HIV and MASLD.

Liver fibrosis is a key determinant of the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Its increasing prevalence and a lack of effective treatments make it a major health problem worldwide, particularly in people living with HIV, among whom the prevalence of advanced fibrosis is higher. We have published preclinical data showing that Rilpivirine (RPV), a widely used anti-HIV drug, selectively triggers hepatic stellate cell (HSC) inactivation and apoptosis through signal transducer and activator of transcription (STAT)1-mediated pathways, effects that clearly attenuate liver fibrosis and promote regeneration. We performed a retrospective, cross-sectional study of RPV-induced effects on steatosis, inflammation, and fibrosis in liver biopsies from well-controlled HIV-infected subjects diagnosed with MASLD. Patients on RPV exhibited similar levels of HIV-related parameters to those not receiving this drug, while showing a tendency toward improved liver function and lipid profile, as well as an enhanced activation of STAT1 in hepatic non-parenchymal cells in those with identified liver injury. This protective effect, promoting STAT1-dependent HSC inactivation, was observed at different stages of MASLD. Our results suggest that RPV-based therapy is especially indicated in HIV-infected patients with MASLD-derived liver injury and highlight the potential of RPV as a new therapeutic strategy for liver diseases.

Analytical Profile of Antiviral Drugs-Remdesivir, Simeprevir, and Sofosbuvir: A Review

Remdesivir (RDV) is an antiviral drug and a phosphonamidite prodrug designed to have activity against a broad spectrum of viruses, act as a nucleoside analogue, and inhibit the RNA-dependent RNA polymerase [RDRP] of coronaviruses, including SARS-CoV-2, whereas Simeprevir (SMV) and Sofosbuvir (SFS) are direct-acting antiviral drugs approved for the treatment of chronic Hepatitis C virus (HCV) infection. Reports show that the structure and replication mechanism of HCV and SARS-COV-2 are comparable. Hepatitis C virus protease inhibitors include Simeprevir. Because it is an NS3/4A protease inhibitor, it inhibits protein synthesis, which stops viruses from maturing. A nucleotide analogue inhibitor called sofosbuvir selectively blocks the RNA-dependent RNA polymerase of HCV NS5B (non-structural protein 5B). This review article gathers and discusses the range of analytical techniques—UV, HPLC, and hyphenated procedures like LC-MS—that are available in the literature for the determination of RDV, SMV, and SFS. This review article can be effectively explored to conduct future analytical investigation for the estimation of the selected drugs in pharmaceutical and biological samples.

D-α-tocopheryl polyethylene glycol succinate-decorated dual drug-loaded lipidic nanocarriers: A strategic approach for targeting lymphatic uptake and p-gp efflux modulation to enhance oral bioavailability in HIV-1 viral reservoirs

The toxicity potential and inadequate bioavailability of antiretroviral therapy restrict their effectiveness in completely eradicating HIV-1 from viral reservoirs, as the drugs encounter difficulties in accessing these reservoirs. This study presents a combinatorial d-α-tocopheryl polyethylene glycol succinate (TPGS)-decorated nano-structured lipid carrier of Etravirine (ETR) and Darunavir Ethanolate (DRVE) that was formulated, optimized, and characterized to achieve synergistic effects against HIV-1 infection. The effectiveness of the combinatorial approach was evaluated by in silico studies, and their docking score and free binding energy showed that both drugs demonstrate synergistic effects against their respective enzymes. The cellular research of ED (ETR and DRVE) in TMZ-b1 cell lines also showed that the best ratio of ETR and DRVE (1:6.5 μg/mL) produced a combined effect. The formulation, termed ED-TPGS-NLCs, underwent optimization using central composite rotational design (CCRD) through a modified emulsification process, followed by characterization based on globule size, polydispersity index (PDI), percentage entrapment efficiency, percentage drug loading, and transmission electron microscopy (TEM) analysis. In vitro release studies demonstrated a notable improvement of drug release from the optimized lipid nanosystem, conforming to the Korsmeyer-Peppas kinetics model. Besides, the in-vitro studies, the intestinal permeation enhancement study, the intestinal depth analysis, and the pharmacokinetic assessment of the optimized formulation in Wistar rats were performed to improve permeation and increase plasma drug concentration. ED-TPGS-NLCs also stopped HIV-1 infection in TMZ-b1 cell lines by 50 %, and the lowest concentration needed to do this was about 58 times lower than purified ED suspension. These studies ensure that ED-TPGS-NLCs were taken up due to the formation of chylomicrons and inhibit the p-gp efflux system by TPGS and solutol to inhibit the first-pass hepatic metabolism, which helps to improve the intestinal permeation and enhance plasma drug concentration, leading to enhanced oral bioavailability of ED. Hence, the improved bioavailability of ED in the nanoformulation also enhanced the anti-retroviral efficacy and improved the safety margins of ED-TPGS-NLCs. These findings can also reduce the side effects of high doses of antiretroviral drugs.

Chronic Liver Enzyme Elevation and Use of Contemporary ARVs Among People With HIV.

While use of some older antiretroviral drugs (ARVs) is associated with chronic liver enzyme elevation (cLEE), the impact of newer ARVs remains unknown. People with HIV enrolled in the RESPOND cohort who started an ARV after January 1, 2012 were included (baseline). The primary outcome was first cLEE individuals were censored at first of cLEE, last visit, death, or December 31, 2021. Incidence rates (IRs; events/1000 person-years) were calculated for each ARV overall and by ARV exposure (6-12 months, 1-2 years, and 2+ years). Poisson regression was used to estimate the incidence rate ratio (IRR) of cLEE and its association with individual ARVs and ARV class. Of 17 106 individuals included contributing 87 924 person-years of follow-up, 1932 (11.3%) experienced cLEE (incidence rate [IR], 22.0; 95% CI, 21.0-23.0). There was no evidence of a cumulative ARV effect on cLEE incidence, (6-12 months: IR, 45.8; 95% CI, 41.4-50.19; 1-2 years: IR, 34.3; 95% CI, 31.5-37.4; and 2+ years: IR, 18.5; 95% CI, 17.4-19.7). Any use (vs no prior use) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class and tenofovir disoproxil fumarate (TDF) was independently associated with an increased IRR of cLEE, and any use of darunavir (DRV) was associated with a decreased risk of cLEE. cLEE is common and more frequent during the first year after initiating new ARVs. With a >5-year median follow-up, we found no short-term liver safety concerns with the use of INSTIs. Use of NNRTIs and TDF was associated with an increased cLEE risk, while DRV was associated with lower risk.

Unveiling Novel HIV-1 Protease Inhibitors through an Integrated Analysis of 3D-QSAR, Molecular Docking, and Binding Free Energy

Introduction: HIV-1, the primary causative agent of AIDS, remains a formidable and lethal virus globally, claiming the lives of millions over the past four decades since its discovery. Recent research has underscored the potential of HIV-1 protease as a therapeutic target, offering a promising strategy for inhibiting viral replication within the body. Method: In light of this, we have curated an extensive database comprising 193 derivatives of Darunavir (DRV), an HIV-1 protease inhibitor. Simultaneously, we have developed a comprehensive set of 3D-QSAR models to elucidate the structure-activity relationships of these 193 derivative inhibitors. Employing various computational simulation techniques, including Comparative Molecular Field Analysis (CoMFA), Comparative Similarity Indices Analysis (CoMSIA), and molecular docking, we have unveiled the fundamental three-dimensional structural features influencing their biological activity. Result: Results indicate that the optimal CoMSIA model (Q2 = 0.500, R2 ncv = 0.882, R2 pred = 0.797) surpasses other models, demonstrating superior predictive capability. Furthermore, docking results suggest that DRV derivatives maintain stable conformations within the binding cavity due to synergistic interactions, such as hydrogen bonding and non-bonded interactions. Drawing insights from the best computational models, we have designed five DRV derivatives with significant HIV-1 protease inhibitory activity through local modification, with theoretical calculations indicating favorable pharmacokinetic properties and synthetic feasibility for the newly proposed molecules. Conclusion: It is hoped that the findings and conclusions obtained herein may furnish theoretical underpinning and directional guidance for the design, optimization, and experimental synthesis of DRV derivative compounds for pharmaceutical purposes. conclusion: In conclusion, this research identifies key residues, including Asp25, Gly27, Asp29, Asp30, Asp124, and Asp129, as significant for ligand binding. The information derived from the in silico models contributes to the design of five newly proposed DRV derivative compounds as promising HIV-1 protease inhibitors, surpassing the inhibitory activity of compound 171. The study holds potential for optimizing Darunavir derivatives in the development of anti-HIV-1 protease drugs.

CCR5 Decorated Rilpivirine Lipid Nanoparticles Build Myeloid Drug Depots Which Sustains Antiretroviral Activities.

Antiretroviral therapy (ART) improves the quality of life for those living with the human immunodeficiency virus type one (HIV-1). However, poor compliance reduces ART effectiveness and leads to immune compromise, viral mutations, and disease co-morbidities. A novel drug formulation is made whereby a lipid nanoparticle (LNP) carrying rilpivirine (RPV) is decorated with the C-C chemokine receptor type 5 (CCR5). This facilitates myeloid drug depot deposition. Particle delivery to viral reservoirs is tracked by positron emission tomography. The CCR5-mediated RPV LNP cell uptake and retention reduce HIV-1 replication in human monocyte-derived macrophages and infected humanized mice. Focused ultrasound allows the decorated LNP to penetrate the blood-brain barrier and reach brain myeloid cells. These findings offer a role for CCR5-targeted therapeutics in antiretroviral delivery to optimize HIV suppression.

Crystal structure of rilpivirine hydrochloride, N6H19C22Cl

A monoclinic C form of rilpivirine hydrochloride, (N6H19C22)Cl, has been obtained and characterized using solid-state 15N, 13C, and 35Cl NMR spectroscopy and multitemperature synchrotron X-ray powder diffraction. The title compound crystallizes in the monoclinic system (space group C2/c, #15) at both room (295.0(2) K) and low (100.0(2) K) temperatures. At room temperature, the following parameters are a = 19.43051(3), b = 13.09431(14), c = 17.10254(18) Å, β = 109.3937(7), V = 4104.48(9) Å3, and Z = 8. The folded molecular conformation of the cation is similar with that of free base rilpivirine with the exception of cyanovinyl group disposition. The anion links cations to infinite chains parallel to the crystallographic c axis using N–H⋯Cl bonds where both amino groups and the protonated pyrimidine ring take part in the H-bonding. The powder patterns have been submitted to the ICDD for inclusion in the Powder Diffraction File™ (PDF®).