tipranavir and etravirine

This review focuses on the use of tipranavir/ritonavir, darunavir/ritonavir and etravirine for the treatment of HIV infection that has become resistant to protease inhibitors and/or nonnucleoside reverse transcriptase inhibitors.. Tipranavir/ritonavir and darunavir/ritonavir are boosted protease inhibitors highly active against HIV that has developed mutations that confer resistance to other protease inhibitors. For both drugs, there are scores to predict activity based on a combination of mutations. Best results are obtained when each drug is combined with one and preferably two other completely active antiretrovirals. The interaction profile and toxicity profile is better for darunavir/ritonavir, which in addition has shown positive outcomes in clinical trials of patients with early failure.Etravirine is a nonnucleoside reverse transcriptase inhibitor highly active against HIV that has developed mutations that confer resistance to nevirapine or efavirenz. Clinical trials results suggest that etravirine should be used with other active antiretrovirals. Best results for etravirine have been obtained in combination with darunavir/ritonavir in patients with extensive protease inhibitor and nonnucleoside reverse transcriptase inhibitor resistance. The role of etravirine for the treatment of early failure of efavirenz-based or nevirapine-based regimens remains to be elucidated. Resistance to etravirine requires the accumulation of multiple reverse transcriptase mutations different from K103N, which has no impact on activity.. Tipranavir/ritonavir, darunavir/ritonavir and etravirine are very important additions to the therapeutic armamentarium against HIV that has become resistant to protease inhibitors and nonnucleoside reverse transcriptase inhibitors.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Viral; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Nitriles; Pyridazines; Pyridines; Pyrimidines; Pyrones; Ritonavir; Sulfonamides

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

Topics: Clinical Trials as Topic; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Nitriles; Pyridazines; Pyridines; Pyrimidines; Pyrones; Sulfonamides; Treatment Outcome

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

Topics: Anti-HIV Agents; Benzophenones; Cytidine Triphosphate; Darunavir; Deoxycytidine; Emtricitabine; HIV; HIV Fusion Inhibitors; HIV Reverse Transcriptase; Humans; Imidazoles; Nitriles; Protease Inhibitors; Pyridazines; Pyridines; Pyrimidines; Pyrones; Reverse Transcriptase Inhibitors; Sulfonamides; Sulfur Compounds; Zalcitabine

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

In Brazil, where three distinct HIV-1 subtypes (B, F, and C) cocirculate, a significant portion of the HIV-infected population has been exposed to antiretroviral drugs. This study analyzes the antiretroviral resistance profiles of HIV-1-infected individuals failing antiretroviral therapy. Genotypic resistance profiles of 2474 patients presenting virologic failure to antiretroviral therapy in the city of São Paulo, Brazil, were generated and analyzed. Resistance mutations to protease inhibitors and nucleoside reverse transcriptase inhibitors were less common in subtype C viruses, whereas nonnucleoside reverse transcriptase inhibitor resistance mutations were less common in subtype F viruses. The thymidine analog mutation pathway known as pathway 1 was more prevalent in subtype B viruses than in subtype C viruses, whereas pathway 2 was more prevalent in subtype C viruses. Selected resistance mutations varied according to subtype for all three classes of antiretrovirals. We describe two distinct pathways of nonnucleoside reverse transcriptase inhibitor resistance (to nevirapine and efavirenz). Although cross-resistance to etravirine should occur more frequently among individuals failing nevirapine treatment, the prevalence of cross-resistance to etravirine, darunavir, and tipranavir was found to be low. We found that increases in the number of resistance mutations will be related to increases in the viral load. Special attention should be given to resistance profiles in non-B subtype viruses. The accumulation of knowledge regarding such profiles in the developing world is desirable.

Topics: Alkynes; Benzoxazines; Brazil; Cohort Studies; Cyclopropanes; Darunavir; Drug Resistance, Multiple, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Mutation; Nevirapine; Nitriles; Pyridazines; Pyridines; Pyrimidines; Pyrones; Reverse Transcriptase Inhibitors; Sulfonamides; Treatment Failure; Viral Load

The effect of enfuvirtide (ENF) in 11 HIV-1 heavily antiretroviral-experienced children and adolescents enrolled in the HIV-1 Paediatric Spanish cohort was further investigated. Patients who received ENF with novel drugs (etravirine, darunavir, and/or tipranavir) reached and maintained undetectable plasma HIV-1 RNA levels and showed immunological recovery within the first 3 months of therapy that was maintained during the follow-up. Viremia was not fully suppressed in patients who did not combine ENF with novel drugs but interestingly, immunological benefit was observed in half of these patients. Therefore, ENF showed a greater and more stable efficacy when administrated with novel drugs.

Topics: Adolescent; Child; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Nitriles; Peptide Fragments; Pyridazines; Pyridines; Pyrimidines; Pyrones; Sulfonamides; Time Factors; Treatment Outcome; Young Adult