raltegravir-potassium and tipranavir

Since 1996, the prognosis of those living with HIV and AIDS has improved significantly due to highly active antiretroviral therapy (HAART). Treatment failure can occur clinically, immunologically or virologically. Until recently, treatment options for those individuals harboring resistance to the three initial licensed classes of drug have been limited. These three classes are the nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). New drugs are now available in these classes (second generation NNRTIs and novel PIs) as well as new classes of drugs, integrase inhibitors, CCR5 antagonists and fusion inhibitors. If these new drugs are used appropriately with other active antiretroviral agents, it is probable that antiretroviral therapy can achieve the optimum outcome of HIV therapy - durable suppression of HIV viraemia. This article is a review of currently available antiretroviral agents including the new classes and second generation drugs, resistance pathways and treatment options for salvage therapy.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Darunavir; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Maraviroc; Nitriles; Pyridazines; Pyridines; Pyrimidines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Salvage Therapy; Sulfonamides; Treatment Outcome; Triazoles

Antiretroviral rescue therapy has been revolutionized by the development of new drugs in the last few years: enfuvirtide (a fusion inhibitor), tipranavir/ritonavir (a high genetic barrier protease inhibitor), darunavir/ritonavir (a high genetic barrier protease inhibitor), etravirine (a non-nucleoside reverse transcriptase inhibitor active against nevirapine- and efavirenz- resistant HIV), maraviroc (a CCR5 coreceptor inhibitor) and raltegravir (an integrase inhibitor). The use of these drugs in rescue regimens has allowed the goal of antiretroviral rescue therapy to be the same as that in treatment naive-patients: to achieve a viral load lower than 50 copies of RNA of HIV/ml. Raltegravir is the first integrase inhibitor available for clinical use in Spain. This drug is primarily metabolized through UGT1A1-mediated glucuronidation and consequently has a low potential for interactions with drugs metabolized by the cytochrome P450 pathway. Raltegravir has been demonstrated to have high efficacy in two large clinical trials of rescue therapy, especially when combined with darunavir/ritonavir and enfuvirtide. Preliminary data suggest that raltegravir could also be an effective drug in treatment-naive patients and as substitution therapy in patients with toxicity due to boosted protease inhibitor therapy. The drug's unusual mechanism of action has reopened the possibility of a positive effect on latent HIV reservoirs.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Forecasting; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Maraviroc; Nitriles; Peptide Fragments; Pyridazines; Pyridines; Pyrimidines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Sulfonamides; Triazoles

Once patients have a triple class virological failure, their treatment options are limited and there is an increased risk of death. In order to construct active treatment regimens, new potent antiretroviral agents are available for these patients. The virological target in patients with treatment failure is now plasma HIV RNA level below 50 copies/ml when 2 or more potent drugs are identified. If at least two active drugs cannot be identified, the current regimen should be maintained until new drugs become available, assuming that there is an immunological and clinical stability, in order to avoid the use of a single-active drug that usually leads to rapid development of resistance, further limiting the future treatment options. In this article, the current state of knowledge about these new agents available and the guidelines of main societies are reviewed.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Organic Chemicals; Peptide Fragments; Practice Guidelines as Topic; Pyridines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; RNA, Viral; Sulfonamides

Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (C(12)) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66; P = 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19; P = 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46; P = 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL C(12) was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.

Topics: Adolescent; Adult; Female; HIV Protease Inhibitors; Humans; Male; Middle Aged; Pyridines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Young Adult

The rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded α-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 M. For the study, we have targeted the SARS-CoV-2 M. The phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir-Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 M. In the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir-Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation.

Topics: Antiviral Agents; Betacoronavirus; Coronavirus 3C Proteases; Coronavirus Infections; COVID-19; Cysteine Endopeptidases; Drug Combinations; Drug Repositioning; Humans; Lopinavir; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Phylogeny; Pneumonia, Viral; Protease Inhibitors; Pyridines; Pyrones; Raltegravir Potassium; Ritonavir; SARS-CoV-2; Sulfonamides; Viral Nonstructural Proteins

Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for the treatment of COVID-19 till date. Drug repurposing strategy helps to find out the drugs for COVID-19 treatment from existing FDA approved antiviral drugs. In this study, FDA approved small molecule antiviral drugs were repurposed against the major viral proteins of SARS-CoV-2.. The 3D structures of FDA approved small molecule antiviral drugs were retrieved from PubChem. Virtual screening was performed to find out the lead antiviral drug molecules against main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) using COVID-19 Docking Server. Furthermore, lead molecules were individually docked against protein targets using AutoDock 4.0.1 software and their drug-likeness and ADMET properties were evaluated.. Out of 65 FDA approved small molecule antiviral drugs screened, Raltegravir showed highest interaction energy value of -9 kcal/mol against Mpro of SARS-CoV-2 and Indinavir, Tipranavir, and Pibrentasvir exhibited a binding energy value of ≥-8 kcal/mol. Similarly Indinavir showed the highest binding energy of -11.5 kcal/mol against the target protein RdRp and Dolutegravir, Elbasvir, Tipranavir, Taltegravir, Grazoprevir, Daclatasvir, Glecaprevir, Ledipasvir, Pibrentasvir and Velpatasvir showed a binding energy value in range from -8 to -11.2 kcal/mol. The antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine also exhibited good bioavailability and drug-likeness properties.. This study suggests that the screened small molecule antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine could serve as potential drugs for the treatment of COVID-19 with further validation studies.

Topics: Antiviral Agents; Coronavirus Protease Inhibitors; COVID-19 Drug Treatment; Drug Repositioning; Heterocyclic Compounds, 3-Ring; Humans; Indinavir; Molecular Docking Simulation; Nitriles; Oxazines; Piperazines; Pyridines; Pyridones; Pyrimidines; Pyrones; Raltegravir Potassium; RNA-Dependent RNA Polymerase; SARS-CoV-2; Sulfonamides

To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects.. In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%.. 7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir.. In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Female; Genotype; High-Throughput Nucleotide Sequencing; HIV Infections; HIV-1; Humans; Male; Mutation; Pyridines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sulfonamides; Treatment Failure