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The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.

Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.

Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance to the approved integrase inhibitors raltegravir (RAL) and elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient-derived RNA extracts for resistance phenotype for a panel of viruses containing G140S/Q148H with additional accessory substitutions. The accumulation of multiple integrase substitutions confers high-level resistance to all 5 integrase inhibitors. There is extensive cross-resistance between DTG, BIC, and CAB (r = 0.96-0.97).

Integrase strand transfer inhibitors (INSTIs) are crucial for the treatment of human immunodeficiency virus (HIV) type 2 infection, due to limited available therapeutic options. Recently, bictegravir has been approved for HIV-1, but no data are currently available for HIV-2. We assessed the phenotypic susceptibility of 12 HIV-2 clinical isolates, obtained from 2 antiretroviral-naive and 10 antiretroviral-experienced patients, to 5 INSTIs (bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir) at the virological failure of an INSTI-based regimen. The 50% inhibitory concentrations (IC50s) were determined. Phenotypic inhibitory quotients were determined using trough INSTI plasma concentrations. Wild-type viruses were susceptible to the 5 INSTIs, with IC50s in the nanomolar range. Bictegravir had a lower IC50 than the other INSTIs on those HIV-2 isolates bearing major, resistance-associated mutations (codons 143, 148, and 155). We identified a new resistance profile-a 5-amino-acid insertion at codon 231 of the HIV-2 integrase (231INS)-in 6 patients at the virological failure of a raltegravir-based regimen. Those patients had adequate raltegravir concentrations, but harbored multiresistant viruses with low genotypic susceptibility scores (median = 1.5). This insertion rendered isolates highly resistant to raltegravir and elvitegravir, and moderately resistant to dolutegravir and cabotegravir. Regarding bictegravir, 2 isolates remained susceptible and 2 had a slight increase in IC50 (3- to 5-fold change). Our results confirm the potency of INSTI on HIV-2 clinical isolates with wild-type integrase. In addition, we identified a new resistance pathway, 231INS, selected in antiretroviral-experienced patients with multiresistant HIV-2 viruses. This highlights the need of close follow-up of those patients initiating an INSTI-based regimen.

Background Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates. Two new INSTIs, Cabotegravir (CAB) and Bictegravir (BIC), are currently in late-stage clinical trials. Results Both CAB and BIC had much broader antiviral profiles than RAL and EVG against the INSTI-resistant single, double, and triple HIV-1 mutants used in this study. BIC was more effective than DTG against several INSTI-resistant mutants. Overall, in terms of their ability to inhibit a broad range of INSTI-resistant IN mutants, BIC was superior to DTG, and DTG was superior to CAB. Modeling the binding of CAB, BIC, and DTG within the active site of IN suggested that the “left side” of the INSTI pharmacophore (the side away from the viral DNA) was important in determining the ability of the compound to inhibit the IN mutants we tested. Conclusions Of the two INSTIs in late stage clinical trials, BIC appears to be better able to inhibit the replication of a broad range of IN mutants. BIC retained potency against several of the INSTI-resistant mutants that caused a decrease in susceptibility to DTG.

Background. Adherence to antiretroviral therapy (ART) is a major challenge in pediatric human immunodeficiency virus (HIV) management, especially in young children due to medication formulation, administration difficulties, and psychosocial barriers. Single-tablet regimens (STRs) have been shown to improve adherence and viral suppression in adults and adolescents, yet their use in younger children remains limited. Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is an STR with a high genetic barrier to resistance, making it a promising option for pediatric patients with adherence difficulties. Case Presentation. We report a case of a 2-year-old girl with perinatally acquired HIV who experienced persistent viremia despite multiple ART regimens. The mother received zidovudine prophylaxis during delivery, and the infant was started on zidovudine (AZT) prophylaxis on the first day of life. The patient’s ART history included AZT monotherapy at birth, followed by combination therapy with lamivudine (3TC), lopinavir/ritonavir (LPV/r), and later tenofovir/emtricitabine (TDF/FTC) with dolutegravir (DTG). Despite these regimens, poor adherence related to medication administration difficulties and caregiver challenges contributed to persistent viremia. A multidisciplinary team approach was implemented to address adherence barriers. Given the patient’s ongoing virological failure and resistance mutations (L76V and V179E), off-label use of BIC/FTC/TAF (50mg/200mg/25mg) was approved. The dosage was adjusted based on weight, and medication administration was closely monitored. Within one month of treatment, HIV RNA levels significantly declined from 1,800,000 to 207 copies/mL. Viral suppression was maintained over subsequent three-month intervals, with HIV RNA levels of 35, 40, and 43 copies/mL, alongside immune recovery as indicated by increased CD4 counts. Conclusion. The successful off-label use of BIC/FTC/TAF in a treatment-refractory pediatric HIV case highlights its potential efficacy in young patients facing adherence challenges. Its high genetic barrier to resistance and favorable tolerability make it a promising option when standard therapies fail. Further research is needed to optimize pediatric ART strategies and expand access to STRs globally.

Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet antiretroviral therapy regimen. B/F/TAF has become a popular treatment choice because of its small tablet size, high barrier to resistance, favorable tolerability, and limited drug-drug interaction profile. Continued research on B/F/TAF has revealed additional potential for this regimen. This review presents recent literature supporting the use of B/F/TAF as an option for consolidating therapy and maintaining virologic suppression in individuals despite M184V/I mutations. Additionally, children are a unique patient population with limited antiviral options. Standard dose B/F/TAF has demonstrated similar drug exposure in children and adolescents as adults, and low-dose B/F/TAF is approved for children living with HIV greater than two years of age and weighing at least 14 kg. Data supporting this recommendation is described in this review. Finally, despite a lack of prospective data, B/F/TAF may have a role in the future of pre- and post-exposure prophylaxis. This review discusses these discoveries and the continued exploration of the hidden potential of B/F/TAF.Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet antiretroviral therapy regimen. B/F/TAF has become a popular treatment choice because of its small tablet size, high barrier to resistance, favorable tolerability, and limited drug-drug interaction profile. Continued research on B/F/TAF has revealed additional potential for this regimen. This review presents recent literature supporting the use of B/F/TAF as an option for consolidating therapy and maintaining virologic suppression in individuals despite M184V/I mutations. Additionally, children are a unique patient population with limited antiviral options. Standard dose B/F/TAF has demonstrated similar drug exposure in children and adolescents as adults, and low-dose B/F/TAF is approved for children living with HIV greater than two years of age and weighing at least 14 kg. Data supporting this recommendation is described in this review. Finally, despite a lack of prospective data, B/F/TAF may have a role in the future of pre- and post-exposure prophylaxis. This review discusses these discoveries and the continued exploration of the hidden potential of B/F/TAF.

Background The recent global pandemic has placed a high priority on identifying drugs to prevent or lessen clinical infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused by Coronavirus disease-2019 (COVID-19). Methods We applied two computational approaches to identify potential therapeutics. First, we sought to identify existing FDA approved drugs that could block coronaviruses from entering cells by binding to ACE2 or TMPRSS2 using a high-throughput AI-based binding affinity prediction platform. Second, we sought to identify FDA approved drugs that could attenuate the gene expression patterns induced by coronaviruses, using our Disease Cancelling Technology (DCT) platform. Results Top results for ACE2 binding iincluded several ACE inhibitors, a beta-lactam antibiotic, two antiviral agents (Fosamprenavir and Emricasan) and glutathione. The platform also assessed specificity for ACE2 over ACE1, important for avoiding counterregulatory effects. Further studies are needed to weigh the benefit of blocking virus entry against potential counterregulatory effects and possible protective effects of ACE2. However, the data herein suggest readily available drugs that warrant experimental evaluation to assess potential benefit. DCT was run on an animal model of SARS-CoV, and ranked compounds by their ability to induce gene expression signals that counteract disease-associated signals. Top hits included Vitamin E, ruxolitinib, and glutamine. Glutathione and its precursor glutamine were highly ranked by two independent methods, suggesting both warrant further investigation for potential benefit against SARS-CoV-2. Conclusions While these findings are not yet ready for clinical translation, this report highlights the potential use of two bioinformatics technologies to rapidly discover existing therapeutic agents that warrant further investigation for established and emerging disease processes.

The Emtricitabine, Bictegravir and Tenofovir are used to treat Cystic fibrosis treatment. For estimation of this drug in bulk and pharmaceutical dosage form the standard, simple, accurate RP-HPLC method was devoloped, to run the sample column used was Kromasil C18 150×4.6mm,5µ and mobile phase of 0.1%OPA and acetonitrile of 55:45 v/v at a flow rate of 1ml/min, 30°C temperature was maintained, 272.0 nm wavelength was used. The retention times for tenofovir, bictegravir, and emtricitabine were 2.140,2.432, and 2.992 minutes, respectively. Emtricitabine, Bictegravir, and Tenofovir were found to have 1.1, 1.0, and 0.9 percent RSD of method precision respectively. Emtricitabine, Bictegravir, and Tenofovir all recovered 100.24 percent, 100.19 percent, and 100.06 percent of their doses, respectively and LOQ values are 0.93 ppm, 0.34 ppm and 0.23ppm respectively, and LOQ values are 2.80ppm, 1.04, 0.70ppm, respectively, for Emtricitabine, Bictegravir, and Tenofovir.