pyrimidinones and tipranavir

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 effect of HIV type-1 (HIV-1) subtype on in vitro susceptibility and virological response to darunavir (DRV) and lopinavir (LPV) was studied using a broad panel of primary isolates, and in recombinant clinical isolates from treatment-naive, HIV-1-infected patients in the Phase III trial, AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS).. Patients received DRV/ritonavir (DRV/r) 800/100 mg once daily (n=343) or LPV/ritonavir (LPV/r) 800/200 mg total daily dose (n=346), plus a fixed daily dose of emtricitabine and tenofovir disoproxil fumarate.. DRV demonstrated high antiviral activity against a broad panel of HIV-1 major group (M) and outlier group (O) primary isolates in peripheral blood mononuclear cells, with a median 50% effective concentration (EC(50)) of 0.52 nM. Most (61%) patients in ARTEMIS harboured HIV-1 subtype B; other prevalent subtypes were C (13%) and CRF01_AE (17%); 9% harboured other subtypes. Median EC(50) values (interquartile range) for DRV were 1.79 nM (1.3-2.6) for subtype B, 1.12 nM (0.8-1.4) for C and 1.27 nM (1.0-1.7) for CRF01_AE. Virological response to DRV/r (HIV-1 RNA<50 copies/ml [intent-to-treat, time-to-loss of virological response algorithm]) was 81%, 87% and 85% for patients with subtype B, C and CRF01_AE infections, respectively. Similar results were observed in the LPV/r treatment group.. In vitro susceptibility to DRV was comparable across HIV-1 subtypes in a broad panel of primary isolates and in recombinant clinical isolates. Once daily DRV/r 800/100 mg and LPV/r 800/200 mg were highly effective in ARTEMIS irrespective of the HIV-1 subtype studied, confirming their broad anti-HIV-1 activity.

Topics: Adamantane; Adult; Analysis of Variance; Atazanavir Sulfate; Carbamates; Darunavir; Drug Resistance, Viral; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Microbial Sensitivity Tests; Molecular Typing; Nelfinavir; Neuraminidase; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Saquinavir; Sulfonamides; Viral Load

Thymidine-based nucleoside analogue reverse transcriptase inhibitors and some protease inhibitors of HIV are associated with lipoatrophy, relative central fat accumulation and insulin resistance. The latter associations have not been well evaluated prospectively in adults commencing antiretroviral therapy. We studied the effects of protease inhibitor-based antiretroviral regimens on body composition, insulin sensitivity and adipocytokine levels.. 48-week substudy of a randomized, open-label, three-arm trial.. Hospital and community HIV clinics.. 140 HIV-infected adults naive to antiretroviral therapy.. Tipranavir/ritonavir [500/200 mg twice a day (TPV/r200)] or [500/100 mg twice a day (TPV/r100)] or lopinavir/ritonavir [400/100 mg twice a day (LPV/r)], each with tenofovir + lamivudine.. Body composition [dual-energy x-ray absorptiometry for limb fat; L4, abdominal computed tomography for visceral adipose tissue (VAT)]; and fasting metabolic parameters. The primary analysis was change in limb fat mass in each TPV/r group vs. LPV/r.. Limb fat increased in all three groups: LPV/r (1.17 kg) versus TPV/r200 (0.83 kg; P = 0.16) and TPV/r100 (0.41 kg; P = 0.07). VAT decreased in all groups: LPV/r (-3 cm) vs. TPV/r200 (-9 cm; P = 0.04) and TPV/r100 (-6 cm; P = 0.40). No significant change in insulin sensitivity was observed, including by oral glucose tolerance testing. The increase in leptin levels was significantly correlated with the increase in limb fat mass (r = 0.67; P < 0.0001). Despite increased limb fat, adiponectin levels increased, but significantly more with TPV/r200 (+6010 ng/ml; P < 0.0001) or TPV/r100 (+4497 ng/ml; P = 0.002) when compared with LPV/r (+1360 ng/ml).. Unlike many other antiretroviral regimens, TPV/r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks.

Topics: Adiponectin; Adult; Body Composition; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Lopinavir; Male; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

HIV infected patients often take at least three anti-HIV drugs together in Highly Active Antiretroviral Therapy (HAART) and/or Ritonavir-Boosted Protease Inhibitor Therapy (PI/r) to suppress the viral replications. The potential drug-drug interactions affect efficacy of anti-HIV treatment and major source of such interaction is competition for the drug metabolizing enzyme, cytochrome P450 (CYP). CYP3A4 isoform is the enzyme responsible for metabolism of currently available HIV-1 protease drugs. Hence administration of these drugs in HARRT or PI/r leads to increased toxicity and reduced efficacy in HIV treatment. We used computational molecular docking method to predict such interactions by which to compare experimentally measured metabolism of each HIV-1 protease drug. AutoDock 4.0 was used to carry out molecular docking of 10 HIV-protease drugs into CYP3A4 to explore sites of reaction and interaction energies (i.e., binding affinity) of the complexes. Arg105, Arg106, Ser119, Arg212, Ala370, Arg372, and Glu374 are identified as major drug binding residues, and consistent with previous data of site-directed mutagenesis, crystallography structure, modeling, and docking studies. In addition, our docking results suggested that phenylalanine clusters and heme are also participated in the binding to mediate drug oxidative metabolism. We have shown that HIV-1 protease drugs such as tipranavir, nelfinavir, lopinavir, and atazanavir differ in their binding modes on each other for metabolic clearance in CYP3A4, whereas ritonavir, amprenavir, indinavir, saquinavir, fosamprenavir, and darunavir share the same binding mode.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Computational Biology; Cytochrome P-450 CYP3A; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Pyridines; Pyrimidinones; Pyrones; Ritonavir; 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

The importance of the active site region aspartyl residues 25 and 29 of the mature HIV-1 protease (PR) for the binding of five clinical and three experimental protease inhibitors [symmetric cyclic urea inhibitor DMP323, nonhydrolyzable substrate analog (RPB) and the generic aspartic protease inhibitor acetyl-pepstatin (Ac-PEP)] was assessed by differential scanning calorimetry. DeltaT(m) values, defined as the difference in T(m) for a given protein in the presence and absence of inhibitor, for PR with DRV, ATV, SQV, RTV, APV, DMP323, RPB, and Ac-PEP are 22.4, 20.8, 19.3, 15.6, 14.3, 14.7, 8.7, and 6.5 degrees C, respectively. Binding of APV and Ac-PEP is most sensitive to the D25N mutation, as shown by DeltaT(m) ratios [DeltaT(m)(PR)/DeltaT(m)(PR(D25N))] of 35.8 and 16.3, respectively, whereas binding of DMP323 and RPB (DeltaT(m) ratios of 1-2) is least affected. Binding of the substrate-like inhibitors RPB and Ac-PEP is nearly abolished (DeltaT(m)(PR)/DeltaT(m)(PR(D29N)) > or = 44) by the D29N mutation, whereas this mutation only moderately affects binding of the smaller inhibitors (DeltaT(m) ratios of 1.4-2.2). Of the nine FDA-approved clinical HIV-1 protease inhibitors screened, APV, RTV, and DRV competitively inhibit porcine pepsin with K(i) values of 0.3, 0.6, and 2.14 microM, respectively. DSC results were consistent with this relatively weak binding of APV (DeltaT(m) 2.7 degrees C) compared with the tight binding of Ac-PEP (DeltaT(m) > or = 17 degrees C). Comparison of superimposed structures of the PR/APV complex with those of PR/Ac-PEP and pepsin/pepstatin A complexes suggests a role for Asp215, Asp32, and Ser219 in pepsin, equivalent to Asp25, Asp25', and Asp29 in PR in the binding and stabilization of the pepsin/APV complex.

Topics: Atazanavir Sulfate; Binding Sites; Binding, Competitive; Calorimetry, Differential Scanning; Carbamates; Crystallography, X-Ray; Darunavir; Furans; HIV Protease; HIV Protease Inhibitors; Humans; Indinavir; Kinetics; Lopinavir; Models, Molecular; Molecular Structure; Mutation; Nelfinavir; Oligopeptides; Pepsin A; Protein Binding; Protein Structure, Tertiary; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Saquinavir; Sulfonamides

Most HPLC-UV methods for therapeutic drug monitoring of anti-HIV drugs have long run times, which reduce their applicability for high-throughput analysis. We developed an ultra-performance liquid chromatography (UPLC)-diode array detection method for the simultaneous quantification of the HIV-protease inhibitors (PIs) amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir (TPV), and the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine.. Solid-phase extraction of 1 mL plasma was performed with Waters HLB cartridges. After 3 wash steps, we eluted the drugs with methanol, evaporated the alcohol, and reconstituted the residue with 50 microL methanol. We injected a 4-microL volume into the UPLC system (Waters ACQUITY UPLC BEH C8 column maintained at 60 degrees C) and used a linear gradient of 50 mmol/L ammonium acetate and 50 mmol/L formic acid in water versus acetonitrile to achieve chromatographic separation of the drugs and internal standard (A-86093). Three wavelengths (215, 240, and 260 nm) were monitored.. All drugs were eluted within 15 min. Calibration curves with concentrations of 0.025-10 mg/L (1.875-75 mg/L for TPV) showed coefficients of determination (r(2)) between 0.993 and 0.999. The lower limits of quantification were well below the trough concentrations reported in the literature. Inter- and intraassay CVs and the deviations between the nominal and measured concentrations were <15%. The method was validated by successful participation in an international interlaboratory QC program.. This method allows fast and simultaneous quantification of all commercially available PIs and NNRTIs for therapeutic drug monitoring.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sensitivity and Specificity; Solid Phase Extraction; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyridines; Pyrimidinones; Pyrones; Sulfonamides

Tipranavir (TPV) is a recently approved nonpeptidic protease inhibitor (PI) of HIV-1 and has been indicated for those infected with PIs-resistant HIV-1. However, in clinical practice, whether the HIV-1 from the patients with virological failure to the regimens containing first-line PIs remains susceptible to TPV/r may be questionable.. To assess the resistance levels to TPV of HIV-1 from patients with treatment failure to first-line PIs, patients who experienced virological failure were tested for genotypic resistance of HIV-1 since August 2006 in National Taiwan University Hospital. Patients were enrolled for this analysis if their failed regimens contained > 12 weeks of atazanavir or lopinavir/ritonavir (defined as ATV group and LPV/r group, respectively), but were excluded if they experienced both or other PIs. The levels of genotypic resistance to TPV/r were determined by TPV mutation score.. Till May 2008, 21 subjects in ATV group and 20 subjects in LPV/r group were enrolled. The TPV mutation scores in subjects in LPV/r group were significantly higher than these in ATV group (median, 3 vs 1, P = 0.007). 95.2% subjects in ATV group and only 45% subjects in LPV/r group had an estimated maximal virological response to TPV/r (P < 0.001). The resistance levels to TPV/r correlated with the duration of exposure to first-line PIs, whether in ATV or LPV/r group.. Cross-resistance from first-line PIs may impede the effectiveness of TPV/r-containing salvage therapy. TPV/r should be used cautiously for patients with virological failure to LPV/r especially long duration of exposure.

Topics: Adult; Atazanavir Sulfate; DNA Mutational Analysis; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Ritonavir; RNA, Viral; Sulfonamides; Treatment Failure; Young Adult

We reported that several HIV protease inhibitors (HIV-PIs) interfere with the endoproteolytic processing of two farnesylated proteins, yeast a-factor and mammalian prelamin A. We proposed that these drugs interfere with prelamin A processing by blocking ZMPSTE24, an integral membrane zinc metalloproteinase known to play a critical role in its processing. However, because all of the drug inhibition studies were performed with cultured fibroblasts or crude membrane fractions rather than on purified enzyme preparations, no definitive conclusions could be drawn. Here, we purified Ste24p, the yeast ortholog of ZMPSTE24, and showed that its enzymatic activity was blocked by three HIV-PIs (lopinavir, ritonavir, and tipranavir). A newer HIV-PI, darunavir, had little effect on Ste24p activity. None of the HIV-PIs had dramatic effects on the enzymatic activity of purified Ste14p, the prenylprotein methyltransferase. These studies strongly support our hypothesis that HIV-PIs block prelamin A processing by directly affecting the enzymatic activity of ZMPSTE24, and in this way they may contribute to lipodystrophy in individuals undergoing HIV-PI treatment.

Topics: Catalysis; HIV Protease Inhibitors; Humans; Lamin Type A; Lopinavir; Membrane Proteins; Metalloendopeptidases; Nuclear Proteins; Protein Methyltransferases; Protein Precursors; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Saccharomyces cerevisiae Proteins; Sulfonamides

Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Drug Approval; Drug Interactions; Drug Labeling; HIV Protease Inhibitors; Humans; Infant; Infant, Newborn; Lopinavir; Midazolam; Pediatrics; Pyridines; Pyrimidinones; Pyrones; Sulfonamides; United States; United States Food and Drug Administration

Over the past 10 years, protease inhibitors have been a key component in antiretroviral therapies for HIV/AIDS. While the vast majority of HIV/AIDS cases in the world are due to HIV-1, HIV-2 infection must also be addressed. HIV-2 is endemic to Western Africa, and has also appeared in European countries such as Portugal, Spain, and Estonia. Current protease inhibitors have not been optimized for treatment of HIV-2 infection; therefore, it is important to assess the effectiveness of currently FDA-approved protease inhibitors against the HIV-2 protease, which shares only 50% sequence identity with the HIV-1 protease. Kinetic inhibition assays were performed to measure the inhibition constants (K(i)) of the HIV-1 protease inhibitors indinavir, nelfinavir, saquinavir, ritonavir, amprenavir, lopinavir, atazanavir, tipranavir, and darunavir against the HIV-2 protease. Lopinavir, saquinavir, tipranavir, and darunavir exhibit the highest potency with K(i) values of 0.7, 0.6, 0.45, and 0.17 nm, respectively. These K(i) values are 84, 2, 24, and 17 times weaker than the corresponding values against the HIV-1 protease. In general, inhibitors show K(i) ratios ranging between 2 and 80 for the HIV-2 and HIV-1 proteases. The relative drop in potency is proportional to the affinity of the inhibitor against the HIV-1 protease and is related to specific structural characteristics of the inhibitors. In particular, the potency drop is high when the maximum cap size of the inhibitors consists of very few atoms. Caps are groups located at the periphery of the molecule that are added to core structures to increase the specificity of the inhibitor to its target. The caps positioned on the HIV-1 protease inhibitors affect selectivity through interactions with distinct regions of the binding pocket. The flexibility and adaptability imparted by the higher number of rotatable bonds in large caps enables an inhibitor to accommodate changes in binding pocket geometry between HIV-1 and HIV-2 protease.

Topics: Darunavir; HIV Protease; HIV Protease Inhibitors; Hydrogen Bonding; Kinetics; Lopinavir; Pyridines; Pyrimidinones; Pyrones; Saquinavir; Structure-Activity Relationship; Substrate Specificity; Sulfonamides

An accurate, sensitive and simple reverse-phase (RP) high-performance liquid chromatography (HPLC) assay has been developed and validated for the simultaneous quantitative determination of tipranavir with nine other antiretroviral drugs in plasma. A liquid-liquid extraction of the drugs in tert-butylmethylether (TBME) from 200 microL of plasma is followed by a reversed phase gradient HPLC assay with UV detection at 210 nm. The standard curve for the drug was linear in the range of 80-80,000 ng/mL for tipranavir; 10-10,000 ng/mL for nevirapine, indinavir, efavirenz, and saquinavir; and 25-10,000 ng/mL for amprenavir, atazanavir, ritonavir, lopinavir, and nelfinavir. The regression coefficient (r(2)) was greater than 0.998 for all analytes. This method has been fully validated and shown to be specific, accurate and precise. Due to an excellent extraction procedure giving good recovery and a clean baseline, this method is simple, rapid, accurate and provides excellent resolution and peak shape for all analytes. Thus this method is very suitable for therapeutic drug monitoring.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Stability; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Molecular Structure; Nelfinavir; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Pyrones; Reproducibility of Results; Ritonavir; Saquinavir; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Sulfonamides; Time Factors

Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

Topics: Alkynes; Amodiaquine; Antimalarials; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Burkina Faso; Chromatography, High Pressure Liquid; Cyclopropanes; Cytochrome P-450 CYP2C8; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Genotype; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Models, Biological; Polymorphism, Genetic; Pyridines; Pyrimidinones; Pyrones; Reverse Transcriptase Inhibitors; Saquinavir; Spectrophotometry, Ultraviolet; Sulfonamides; Treatment Outcome; Trimethoprim

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Topics: Alanine Transaminase; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Peptide Fragments; Pyridines; Pyrimidinones; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome; Viral Load

Week 48 HIV-RNA treatment response to the protease inhibitor tipranavir co-administered with ritonavir was compared with that of lopinavir co-administered with ritonavir in patients whose baseline isolates had varying lopinavir genotypic mutation scores. With increasing lopinavir mutation scores, the proportion of patients achieving a week 48 treatment response was increased in the tipranavir/ritonavir compared with the lopinavir/ritonavir arm. Tipranavir/ritonavir therapy improves treatment response rates compared with lopinavir/ritonavir in patients whose viruses have reduced susceptibility to lopinavir/ritonavir.

Topics: Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyridines; Pyrimidinones; Pyrones; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

Despite the increasing number of antiretroviral compounds, the number of useful drug regimens is limited owing to the high frequency of cross-resistance.. We studied in vitro two-drug combinations using three protease inhibitors (PIs), tipranavir, amprenavir and lopinavir, on isolates (003 and 004) derived from patients with resistance to multiple PIs compared with the drug-susceptible isolate 14aPre in peripheral blood mononuclear cells. Drug interactions were determined by median dose-effect analysis, with the combination index calculated at several inhibitory concentrations (IC).. In 14aPre experiments, the combination tipranavir + lopinavir demonstrated synergy at low concentrations (IC(50)), an additive effect at IC(75) and antagonism at IC(90)-IC(95); tipranavir + amprenavir were antagonistic at all concentrations except IC(95), where they were synergic; and the lopinavir + amprenavir combination was always antagonistic. In 003 and 004 infections, tipranavir + lopinavir and tipranavir + amprenavir combinations were antagonistic, and lopinavir + amprenavir were synergic, at all concentrations, with the exception of being additive at IC(95).. Our in vitro experiments did not show any advantage in combining second generation PIs as a therapeutic strategy in naive or multi-treatment failure subjects, with the exception of tipranavir + amprenavir at IC(95) in infections by a wild-type isolate.

Topics: Carbamates; Drug Resistance, Viral; Enzyme-Linked Immunosorbent Assay; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyridines; Pyrimidinones; Pyrones; RNA, Viral; Sulfonamides

Topics: Anti-HIV Agents; Antiviral Agents; Atazanavir Sulfate; Dioxolanes; Drugs, Investigational; Humans; Imidazoles; Lopinavir; Oligopeptides; Purine Nucleosides; Pyridines; Pyrimidinones; Pyrones; Sulfonamides; Sulfur Compounds