Showing papers on "Dolutegravir published in 2020"

Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model

Abstract: The infection of a novel coronavirus found in Wuhan of China (SARS-CoV-2) is rapidly spreading, and the incidence rate is increasing worldwide. Due to the lack of effective treatment options for SARS-CoV-2, various strategies are being tested in China, including drug repurposing. In this study, we used our pre-trained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of SARS-CoV-2. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing an inhibitory potency with Kd of 94.94 nM against the SARS-CoV-2 3C-like proteinase, followed by remdesivir (113.13 nM), efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM). Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of SARS-CoV-2 with an inhibitory potency with Kd

Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy.

Abstract: BACKGROUND Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)-based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens. METHODS Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)-, and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals. RESULTS Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/μL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant. CONCLUSIONS Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.

Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Phase 3, Randomized, Noninferiority TANGO Study.

Abstract: Background The 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with human immunodeficiency virus type 1 (HIV-1). We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals.

Predicting commercially available antiviral drugs that may act on the novel coronavirus (2019-nCoV), Wuhan, China through a drug-target interaction deep learning model

Abstract: The infection of a novel coronavirus found in Wuhan of China (2019-nCoV) is rapidly spreading, and the incidence rate is increasing worldwide. Due to the lack of effective treatment options for 2019-nCoV, various strategies are being tested in China, including drug repurposing. In this study, we used our pretrained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of 2019-nCoV. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing a inhibitory potency with Kd of 94.94 nM against the 2019-nCoV 3C-like proteinase, followed by efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM). Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of 2019-nCoV with an inhibitory potency with Kd

Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment–Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials

Abstract: Two-drug regimens (2DRs) can potentially reduce long-term cumulative drug exposure and decrease treatment-associated costs for HIV-1–infected individuals, who require lifelong therapy.1 The core antiretroviral agent in a 2DR must have high potency and a high barrier to resistance.1 As such, early studies investigating 2DRs as initial or maintenance therapy for HIV infection evaluated the pairing of the potent, well-tolerated nucleoside reverse transcriptase inhibitor (NRTI) lamivudine with pharmacologically boosted protease inhibitors (PIs), which have a high barrier to resistance.2–6 Although noninferior efficacy was shown against 3-drug regimens (3DRs), PIs are associated with adverse metabolic effects, long-term toxicities, and drug–drug interactions, limiting their appeal as components of lifelong therapy.7,8 Thus, a need remains for well-tolerated, potent 2DRs with a high barrier to resistance. The integrase strand transfer inhibitor (INSTI) dolutegravir has a high barrier to resistance, making it a well-suited candidate for inclusion in a 2DR,9 particularly when paired with lamivudine,10 as previously observed.11,12 In primary week 48 analyses of the 2 phase III studies GEMINI-1 and GEMINI-2 in treatment-naive adults, dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL according to the US Food and Drug Administration (FDA) Snapshot algorithm.13 Importantly, resistance mutations associated with INSTIs or NRTIs did not emerge in the few participants who had virologic failure. These data led to the approval of the fixed-dose combination of dolutegravir/lamivudine as a once-daily, single-tablet 2DR by the FDA and the European Medicines Agency.14,15 In addition, the 2019 update to the US Department of Health and Human Services treatment guidelines for HIV-1 infection supports the use of dolutegravir + lamivudine as initial treatment in patients for whom abacavir, tenofovir disoproxil fumarate, or tenofovir alafenamide either cannot be used or are not optimal.16 European AIDS Clinical Society guidelines also indicate that when preferred regimens are not feasible or available,17 dolutegravir + lamivudine can be used. Both guidelines indicated the need for longer-term data to support the use of dolutegravir + lamivudine in a broader patient population. Here, we report longer-term results from the GEMINI-1 and GEMINI-2 planned secondary analyses at 96 weeks.

The Integrase Inhibitors Dolutegravir and Raltegravir Exert Proadipogenic and Profibrotic Effects and Induce Insulin Resistance in Human/Simian Adipose Tissue and Human Adipocytes

Abstract: Background Although some integrase strand transfer inhibitors (INSTIs) promote peripheral and central adipose tissue/weight gain in people with human immunodeficiency virus (PHIV), the underlying mechanism has not been identified. Here, we used human and simian models to assess the impact of INSTIs on adipose tissue phenotype and function. Methods Adipocyte size and fibrosis were determined in biopsies of subcutaneous and visceral adipose tissue (SCAT and VAT, respectively) from 14 noninfected macaques and 19 PHIV treated or not treated with an INSTI. Fibrosis, adipogenesis, oxidative stress, mitochondrial function, and insulin sensitivity were assessed in human proliferating or adipocyte-differentiated adipose stem cells after long-term exposure to dolutegravir or raltegravir. Results We observed elevated fibrosis, adipocyte size, and adipogenic marker expression in SCAT and VAT from INSTI-treated noninfected macaques. Adiponectin expression was low in SCAT. Accordingly, SCAT and VAT samples from INSTI-exposed patients displayed higher levels of fibrosis than those from nonexposed patients. In vitro, dolutegravir and, to a lesser extent, raltegravir were associated with greater extracellular matrix production and lipid accumulation in adipose stem cells and/or adipocytes as observed in vivo. Despite the INSTIs' proadipogenic and prolipogenic effects, these drugs promoted oxidative stress, mitochondrial dysfunction, and insulin resistance. Conclusions Dolutegravir and raltegravir can directly impact adipocytes and adipose tissue. These INSTIs induced adipogenesis, lipogenesis, oxidative stress, fibrosis, and insulin resistance. The present study is the first to shed light on the fat modifications observed in INSTI-treated PHIV.

The time is now: expedited HIV differentiated service delivery during the COVID-19 pandemic.

Abstract: At its core, differentiated service delivery (DSD) for HIV is centred around clients’ needs and expectations and relieving unnecessary burdens on the health system [1]. In the 2016 World Health Organization (WHO) antiretroviral therapy (ART) guidelines, it was acknowledged that adaptations to the delivery of HIV services were necessary to achieve the “treat all” recommendation [2]. This transition from a “onesize-fits-all approach” to DSD means modifying the location, frequency and package of services as well as the cadre providing services, considering the clinical needs, specific population and the context including urbanicity, stability of context (for example high migration, conflict or pandemic) and type of HIV epidemic [2-4]. Existing global and national policies around DSD for HIV can be leveraged during the COVID-19 pandemic to play a critical role in supporting uninterrupted ART and reducing avoidable contact with health facilities, thereby supporting health systems to focus on COVID-19. Recent statements from The Global Fund for HIV, Tuberculosis and Malaria (Global Fund), the Global Network of People Living with HIV (GNP+), UNAIDS, the United States President’s Emergency Plan for AIDS Relief (PEPFAR) and the WHO all endorse leveraging components of DSD for people living with HIV (PLHIV) during the COVID-19 pandemic [4-9]. The time is now to accelerate access to DSD for all PLHIV. We acknowledge that accelerating access requires capacity in addition to policy decisions. Scaling up the provision of longer ART refills is highly dependent on supply chains that may be currently under threat. There are concerns of constraints in ART production in the coming months as a result of the lockdown in India; with the Global Fund currently rating the operational risk assessment as “moderate” [10]. The global supply situation is being closely monitored and coordinated by partners with PEPFAR tempering language around the duration of multi-month dispensing to ensure continuity of care [11,12]. Countries are being encouraged to submit orders well in advance, adjust supply plans for longer leads times, distribute stock to clinics rather than holding it centrally and transparently communicate stock levels by regimen at the national and provincial level to support planning [11,13,14]. Concerns regarding ritonavir-boosted lopinavir availability pre-dated COVID-19, and plans to transition to other antiretrovirals are being accelerated in countries with large numbers of patients on this regimen [15]. With many sub-Saharan countries’ forecasts increasing numbers of PLHIV on a Dolutegravir (DTG)-based first-line regimen and a slower enrolment and transition to DTG regimens than predicted, this stock may be less threatened than the Efavirenz (EFV)-based regimens. This further strengthens the need for supporting patients to immediately transition to DTG regimens without requiring additional clinical monitoring visits to health facilities.

Computational Drug Discovery and Repurposing for the Treatment of COVID-19: A Systematic Review

Abstract: Background: Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the disease. Considering the matter of time, the computational methods of drug repurposing offer the best chance of selecting one drug from a list of approved drugs for the life-threatening condition of COVID-19. The present systematic review aims to provide an overview of studies that have used computational methods for drug repurposing in COVID-19. Methods: We undertook a systematic search in five databases and included original articles in English that applied computational methods for drug repurposing in COVID-19. Results: Twenty-one original articles utilizing computational drug methods for COVID-19 drug repurposing were included in the systematic review. Regarding the quality of eligible studies, high-quality items including the use of two or more approved drug databases, analysis of molecular dynamic simulation, multi-target assessment, the use of crystal structure for the generation of the target sequence, and the use of AutoDock Vina combined with other docking tools occurred in about 52%, 38%, 24%, 48%, and 19% of included studies. Studies included repurposed drugs mainly against non-structural proteins of SARS-CoV2: the main 3C-like protease (Lopinavir, Ritonavir, Indinavir, Atazanavir, Nelfinavir, and Clocortolone), RNA-dependent RNA polymerase (Remdesivir and Ribavirin), and the papain-like protease (Mycophenolic acid, Telaprevir, Boceprevir, Grazoprevir, Darunavir, Chloroquine, and Formoterol). The review revealed the best-documented multi-target drugs repurposed by computational methods for COVID-19 therapy as follows: antiviral drugs commonly used to treat AIDS/HIV (Atazanavir, Efavirenz, and Dolutegravir Ritonavir, Raltegravir, and Darunavir, Lopinavir, Saquinavir, Nelfinavir, and Indinavir), HCV (Grazoprevir, Lomibuvir, Asunaprevir, Ribavirin, and Simeprevir), HBV (Entecavir), HSV (Penciclovir), CMV (Ganciclovir), and Ebola (Remdesivir), anticoagulant drug (Dabigatran), and an antifungal drug (Itraconazole). Conclusions: The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression.

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials.

Abstract: HIV remains a major global health concern, with the Joint United Nations Programme on HIV/AIDS and the World Health Organization (WHO) estimating the number of people living with HIV (PLWH) to be ∼37.9 million in 2018.1,2 Improvements in HIV treatment efficacy are reflected in the increases in longevity of PLWH.3 Despite this progress, the effectiveness of current antiretroviral therapy (ART) is challenged by the need to maintain high levels of adherence to sustain virologic suppression.4 Factors related to regimen complexity, such as dosing frequency and pill burden, food considerations, stigma, and drug–drug interactions between oral antiretrovirals and commonly prescribed non-ART medications, are reported to contribute to this challenge.4–6 Furthermore, the emotional burden of living with HIV may be compounded by daily oral pill taking and additional complexities.7 Therefore, there is considerable interest in developing long-acting (LA) treatments that can address many of these issues while simplifying ART for PLWH.8 The recommended ART regimen for PLWH generally consists of daily doses of either an oral 2-drug or 3-drug combination.9,10 This combination typically involves an integrase strand transfer inhibitor (INSTI) (dolutegravir as the sole INSTI preferred for use in adults in the WHO guidelines9 and either dolutegravir, bictegravir, or raltegravir preferred in the US Department of Health and Human Services guidelines10), in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs); although, a single NRTI (lamivudine) in combination with dolutegravir has recently been recommended as a 2-drug regimen in HIV treatment guidelines.10 Cabotegravir (CAB) (GSK1265744) is an investigational INSTI and structural analog of dolutegravir.11 Rilpivirine (RPV) is a next-generation non-NRTI (NNRTI) currently approved as a once-daily oral tablet to be used in combination with other antiretrovirals for the treatment of HIV infection.12,13 Both compounds are formulated as LA agents to be administered intramuscularly (IM), with oral formulations of RPV and a new formulation of CAB in development.13 These oral formulations have been used during an oral lead-in phase in the ATLAS14 and FLAIR15 studies to assess safety and tolerability before study participants transitioning to LA therapy with CAB and RPV. This 2-drug oral combination therapy of CAB and RPV was assessed in the LATTE ({"type":"clinical-trial","attrs":{"text":"NCT01641809","term_id":"NCT01641809"}}NCT01641809) study and shown to provide similar antiviral activity compared with efavirenz plus dual NRTIs.16 A single IM injection of CAB LA 800 mg or RPV LA 1200 mg demonstrated sustained mean or geometric mean plasma concentrations above their respective in vitro protein-adjusted 90% inhibitory concentrations (PA-IC90) at 32 weeks postdose for CAB LA17 (PA-IC90 0.166 μg/mL), and 24 weeks postdose for RPV LA18 (PA-IC90 12 ng/mL), providing rationale to investigate the 2 drugs as an LA combination regimen. In the LATTE-2 ({"type":"clinical-trial","attrs":{"text":"NCT02120352","term_id":"NCT02120352"}}NCT02120352) randomized, open-label phase 2b clinical trial, the injectable LA combination of CAB and RPV (CAB + RPV LA) as a 2-drug HIV-1 maintenance therapy, administered every 4 or 8 weeks, was similar to daily 3-drug oral therapy of CAB plus abacavir/lamivudine in maintaining viral suppression (plasma HIV-1 RNA <50 copies per/mL; FDA Snapshot algorithm) through 96 weeks.19 Together, these results supported phase 3 investigation of CAB + RPV LA. ATLAS ({"type":"clinical-trial","attrs":{"text":"NCT02951052","term_id":"NCT02951052"}}NCT02951052)14 and FLAIR ({"type":"clinical-trial","attrs":{"text":"NCT02938520","term_id":"NCT02938520"}}NCT02938520)15 are ongoing randomized, open-label, multinational phase 3 studies. These studies demonstrated that monthly injections of CAB + RPV LA were noninferior based on the primary endpoint (participants with plasma HIV-1 RNA ≥50 copies/mL at week 48) compared with a control group who continued their oral current antiretroviral regimen (CAR). The individual results of these studies are published elsewhere.14,15 Here, we present the preplanned pooled analyses of the efficacy (noninferiority), viral resistance, pharmacokinetic analysis, safety and tolerability, and preference findings observed in participants enrolled in the ATLAS and FLAIR studies.

Structural basis of second-generation HIV integrase inhibitor action and viral resistance

Abstract: Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz.

Abstract: Background Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART). Methods We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm. Results There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

Polypharmacy and Drug-Drug Interactions in People Living With Human Immunodeficiency Virus in the Region of Madrid, Spain: A Population-Based Study.

Abstract: Drug-drug interactions (DDIs) involving antiretrovirals (ARVs) tend to cause harm if unrecognized, especially in the context of multiple co-morbidity and polypharmacy.; A database linkage was established between the regional drug dispensing registry of Madrid and the Liverpool HIV DDI database (January-June 2017). Polypharmacy was defined as the use of ≥5 non-HIV medications, and DDIs were classified by a traffic-light ranking for severity. HIV-uninfected controls were also included.; A total of 22,945 patients living with HIV (PLWH) and 6,613,506 uninfected individuals had received medications. Antiretroviral therapy regimens were predominantly based on integrase inhibitors (51.96%). Polypharmacy was significantly higher in PLWH (32.94%) than uninfected individuals (22.16%; P<0.001), and this difference was consistently observed across all age strata except for individuals aged ≥75 years. Polypharmacy was more common in women than men in both PLWH and uninfected individuals. The prevalence of contraindicated combinations involving ARVs was 3.18%. Comedications containing corticosteroids, quetiapine, or antithrombotic agents were associated with the highest risk for red-flag DDI, and the use of raltegravir or dolutegravir-based antiretroviral therapy was associated with an adjusted odds ratio of 0.72 (95% confidence interval: 0.60 - 0.88; P=0.001) for red-flag DDI.; Polypharmacy was more frequent among PLWH across all age groups except those aged ≥75 years and was more common in women. The persistent detection of contraindicated medications in patients receiving ARVs suggests a likely disconnect between hospital and community prescriptions. Switching to alternative unboosted integrase regimens should be considered for patients with high risk of harm from DDIs.

Factors Associated With Weight Gain in People Treated With Dolutegravir

Abstract: Background An unexpected excess in weight gain has recently been reported in the course of dolutegravir (DTG) treatment. The aim of the present study was to investigate whether weight gain differs among different DTG-containing regimens. Methods Adult naive and experienced people with HIV (PWH) initiating DTG-based antiretroviral therapy (ART) between July 2014 and December 2019 in the Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) prospective cohort were included. We used an adjusted general linear model to compare weight change among backbone groups and a Cox proportional hazard regression model to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for weight increases >10% from baseline. Results A total of 713 participants, 25.3% women and 91% Caucasian, were included. Of these, 195 (27.4%) started DTG as their first ART regimen, whereas 518 (72.6%) were ART-experienced. DTG was associated with abacavir/lamivudine in 326 participants, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 148, boosted protease inhibitors in 60, rilpivirine in 45, lamivudine in 75, and tenofovir alafenamide (TAF)/FTC in 59. At 6 and 12 months, weight gain was highest among PWH on TDF/FTC+DTG and TAF/FTC+DTG. Baseline CD4 10% from baseline. Higher weight (HR, 0.97 by 1 kg; 95% CI, 0.96 to 0.99) and female gender (HR, 0.54; 95% CI, 0.33 to 0.88) were protective against weight gain. Conclusions Naive PWH with lower CD4 counts and those on TAF/FTC or TDF/FTC backbones were at higher risk of weight increase in the course of DTG-based ART.

HIV-1 Integrase Inhibitors: A Comparative Review of Efficacy and Safety.

Abstract: The newest class of antiretrovirals for all persons living with HIV are the integrase strand transfer inhibitors (INSTIs). Since 2007, five INSTIs have been introduced: raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. The INSTIs have favorable pharmacokinetic and pharmacodynamic properties, which contribute to both their effectiveness and their ease of use. With the exception of cabotegravir, each INSTI is US Food and Drug Administration approved for treatment-naive individuals initiating antiretroviral therapy. All of the INSTIs, except raltegravir, are approved for antiretroviral treatment simplification for virologically suppressed patients without INSTI resistance. Data also support the use of dolutegravir and raltegravir in individuals with antiretroviral resistance as part of an optimized antiretroviral regimen. INSTIs are generally well tolerated by people living with HIV compared with older classes of antiretrovirals, but emerging data suggest that some INSTIs contribute to weight gain. Due to their efficacy, safety, and ease of use, HIV treatment guidelines recommend oral INSTIs as preferred components of antiretroviral therapy for individuals initiating therapy. The newest INSTI, cabotegravir, represents an alternative to oral administration of life-long antiretroviral therapy with the availability of a long-acting injectable formulation. This review summarizes the current use of INSTIs in adults living with HIV, highlighting the similarities and differences within the class related to pharmacodynamics, pharmacokinetics, safety, dosing, and administration that contribute to their role in modern antiretroviral therapy.

Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance

Abstract: Background Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission. Objectives We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance. Methods To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir. Results Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K. Conclusions A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.

No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV.

Abstract: Objective:Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy.D

In-silico drug repurposing for targeting SARS-CoV-2 main protease (Mpro).

Abstract: COVID-19, caused by novel coronavirus or SARS-CoV-2, is a viral disease which has infected millions worldwide. Considering the urgent need of the drug for fighting against this infectious disease, we have performed in-silico drug repurposing followed by molecular dynamics (MD) simulation and MM-GBSA calculation. The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses, therefore, this was screened for already known FDA approved drugs and some natural compounds. Comparison of docking and MD simulation results of complexes of drugs with that of inhibitor N3 (experimentally obtained) suggests EGCG, withaferin, dolutegravir, artesunate as potential inhibitors of the main protease (Mpro). Further, in silico docking and MD simulation suggest that EGCG analogues ZINC21992196 and ZINC 169337541 may act as a better inhibitor. Communicated by Ramaswamy H. Sarma.