tipranavir and fosamprenavir

Protease inhibitors (PIs) are potent competitive inhibitors of the human immunodeficiency virus (HIV) widely used in the treatment of the acquired immune deficiency syndrome (AIDS) and prescribed in combination with other antiretroviral drugs. So far ten PIs were approved by the United States Food and Drug Administration (FDA) for the treatment of HIV infection. In this mini review, quality control methods of each PI are discussed on the basis of analytical techniques published in the literature. Special attention is given to summarize the LC methods described for the analysis of the selected PIs in both drug substances and products with the available literature till date.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Chromatography, Liquid; Darunavir; Drug Contamination; Furans; HIV Protease Inhibitors; Indinavir; Lopinavir; Nelfinavir; Oligopeptides; Organophosphates; Pyridines; Pyrimidinones; Pyrones; Quality Control; Ritonavir; Saquinavir; Sulfonamides

The human immunodeficiency virus (HIV) was discovered in 1982, but treatment strategies were not introduced until 5 years later. Early regimens consisted of one or two drugs and often led to treatment failure. Since the advent in 1995 of highly active antiretroviral therapy (HAART), which consists of at least three agents, a dramatic improvement has been seen in the number of patients attaining undetectable viral loads, improved CD4 counts, and improved survival. However, early HAART often consisted of drugs with complex dosing schedules, strict food requirements, treatment-limiting adverse effects, and the need to take 16-20 pills/day. These treatment barriers often led to patient nonadherence, with subsequent treatment failure and development of resistant strains. The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated. Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome-defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm(3) or below. In patients with CD4 counts above 350 cells/mm(3) and viral loads above 100,000 copies/ml, some clinicians prefer to defer treatment, whereas others will consider starting therapy; treatment is deferred in patients with CD4 counts above 350 cells/mm(3) and viral load s below 100,000 copies/ml. If therapy is started, the selection of appropriate agents is based on comorbidities (liver disease, depression, cardiovascular disease), pregnancy status, adherence potential (dosage regimen, pill burden, dosing frequency), food restrictions (dosing with regard to meals), adverse drug effects, and potential drug-drug interactions. Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir. This review focuses on the concepts of antiretroviral therapy, barrier

Topics: Adenine; Animals; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Deoxycytidine; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Drugs, Investigational; Emtricitabine; Enfuvirtide; Furans; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Oligopeptides; Organophosphates; Organophosphonates; Patient Compliance; Peptide Fragments; Pyridines; Pyrones; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Furans; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Oligopeptides; Organophosphates; Pyridines; Pyrones; Sulfonamides

The effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzed in vitro susceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.

Topics: Atazanavir Sulfate; Carbamates; Darunavir; Furans; HIV Protease; HIV Protease Inhibitors; HIV-1; Indinavir; Least-Squares Analysis; Lopinavir; Mutation; Nelfinavir; Oligopeptides; Organophosphates; Polymorphism, Genetic; Pyridines; Pyrimidinones; Pyrones; Saquinavir; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Carbamates; Deoxycytidine; Dioxolanes; Drugs, Investigational; Emtricitabine; Furans; Guanosine; HIV Fusion Inhibitors; Humans; Imidazoles; Oligopeptides; Organophosphates; Organophosphonates; Organophosphorus Compounds; Prodrugs; Protease Inhibitors; Pyridines; Pyrones; Quinazolines; Reverse Transcriptase Inhibitors; Sulfonamides; Sulfur Compounds; Tenofovir