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Biomedical subjects

Gilles Peytavin

Publications and source records attributed to Gilles Peytavin.

66 records · Page 4Linked to original sources
PubMed2002

Relationship between levels of indinavir in hair and virologic response to highly active antiretroviral therapy.

BACKGROUND: Suboptimal levels of antiretroviral drugs result in virologic failure in HIV-infected patients treated with highly active antiretroviral therapy (HAART). OBJECTIVE: To assess the relationship between levels of indinavir in hair and virologic outcome. DESIGN: Cross-sectional study. SETTING: 7 AIDS clinics in France. PATIENTS: 89 HIV-infected patients who received HAART that included indinavir. MEASUREMENTS: Patients were classified as responders or nonresponders on the basis of viremia at the time of hair collection. In nonresponders, levels of indinavir in hair and resistance mutations in the protease gene were assessed at baseline and at the time of indinavir measurement. RESULTS: Mean indinavir levels (+/-SD) were significantly higher in the 65 responders than in the 24 nonresponders (24.4 +/- 16 microg/g vs. 12.9 +/- 8.6 microg/g) (P < 0.001). Nonresponders with intermediate levels of indinavir in hair had more mutations in the protease gene than did nonresponders with low levels of indinavir in hair. CONCLUSION: Indinavir levels in hair are associated with virologic outcome in patients receiving HAART.

Absorption↗
PubMed2002

Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial.

OBJECTIVE: To assess the respective value of phenotype versus genotype versus standard of care for choosing antiretroviral therapy in patients failing protease inhibitor-containing regimens. METHODS: Patients with plasma HIV-1 RNA exceeding 1000 copies/ml were randomly allocated to phenotyping, genotyping, or standard of care. RESULTS: Five-hundred and forty-one patients were randomized, 190 to phenotyping, 192 to genotyping and 159 to standard of care. The baseline median CD4 cell count (280 x 106 cells/l), the plasma HIV-1 RNA level (4.3 log10 copies/ml), and the number of drugs previously received (n = 6) were similar in the three arms. More patients in the standard-of-care arm received at least three new drugs (55% versus 20% in the other arms; P < 0.001) and a regimen containing drugs from the three different classes. Plasma HIV-1 RNA was < 200 copies/ml at week 12 in 35% of patients in the phenotyping arm, 44% in the genotyping arm and 36% in the standard-of-care arm (phenotyping versus standard of care, P = 0.918; genotyping versus standard of care, P = 0.120). In a secondary analysis of 179 patients experiencing a first protease inhibitor failure, the percentage of patients achieving HIV-1 RNA < 200 copies/ml was significantly higher in the genotyping arm (65%) than in the phenotyping (45%) and the standard-of-care arms (45%) (genotyping versus standard of care, P = 0.022). CONCLUSIONS: Overall, resistance assays did not demonstrate benefit over standard of care. In patients with the most limited protease inhibitor experience, a significant benefit was observed in the genotyping arm.

Anti-HIV Agents↗
PubMed2002

Final analysis of the Trilège induction-maintenance trial: results at 18 months.

BACKGROUND: First results of Trilège demonstrated that the strategy of less intensive antiviral therapy is less effective than continuation of triple-drug therapy. OBJECTIVE: To compare the final number of failures at month 18 and to study viral dynamics in patients experiencing a virological failure. DESIGN: Longitudinal follow-up from a randomized controlled trial. SETTING: Forty-three AIDS clinical-trial units. PATIENTS: A total of 279 HIV-1 infected adults randomized in Trilège. MEASUREMENTS: Analysis of recurrent values of HIV RNA > 500 copies/ml beyond time to virologic failure. RESULTS: A total of 83 patients experienced virological failure by month 18; 10 in the zidovudine (ZDV) + lamivudine (3TC) + indinavir (IDV) arm, 46 in the ZDV + 3TC arm, and 27 in the ZDV + IDV arm, confirming previous results. Whatever the treatment ultimately received, 87% of patients had an HIV RNA < 500 copies/ml at month 18 with no statistical difference between randomized arms. Patients experiencing a failure in the triple-drug regimen had a greater tendency to maintain HIV RNA > 500 copies/ml beyond the time of virological failure than patients in both less intensive treatment groups who experienced failure. Lower levels of HIV RNA at failure and reinitiating of either the original triple-drug regimen or a new combination of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors were associated with lower hazard ratios for developing recurrent HIV RNA > 500 copies/ml. CONCLUSION: Results confirmed the failure of a less intensive regimen to maintain patients with a viral suppression (HIV RNA < 500 copies/ml). Although there is a lower incidence of failure in the triple-drug regimen, randomization to a less intensive regimen of ZDV + 3TC or ZDV + IDV was not detrimental, as treatment modification, either to the original triple regimen, or a different regimen was successful.

Adult↗
PubMed2002

Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine.

BACKGROUND: Halofantrine, an antimalarial drug that prolongs the QT interval, is metabolized into N-debutyl-halofantrine by cytochrome P450 (CYP) 3A4. Grapefruit juice increases the bioavailability of several orally administered CYP3A4 substrates by inhibiting CYP3A4 at the enterocyte level and could therefore increase the risk of halofantrine-induced QT interval prolongation. We studied the effect of grapefruit juice on halofantrine bioavailability and on QT interval prolongation associated with its oral administration. METHODS: Twelve healthy male and female volunteers received 500 mg of halofantrine with 250 mL of water, orange juice, or grapefruit juice (250 mL once a day of regular strength for 3 days and once at 12 hours before halofantrine administration), in a random order, during a crossover study. Plasma pharmacokinetics of halofantrine and N-debutyl-halofantrine and QTc interval duration were studied during the following 168 hours. RESULTS: Compared with water, grapefruit juice increased halofantrine area under the plasma concentration versus time curve (AUC) and peak plasma concentration by 2.8-fold +/- 1.5-fold (P <.0001) and 3.2-fold +/- 1.3-fold (P <.0001), respectively. There was a concomitant 2.4-fold +/- 1.6-fold decrease in N-debutyl-halofantrine AUC (P <.01) but no significant change in halofantrine elimination half-life. Maximum QTc interval prolongation increased from 17 +/- 6 ms when halofantrine was administered with water to 31 +/- 12 ms when it was administered with grapefruit juice (P <.0005). Multiple regression analysis showed that QTc interval prolongation was better correlated with halofantrine (partial r = 0.432; P <.0001) than with N-debutyl-halofantrine (partial r = 0.117; P <.01) concentrations. There was no significant difference between the water and orange juice study periods. CONCLUSIONS: Grapefruit juice increases halofantrine bioavailability and halofantrine-induced QT interval prolongation. Grapefruit juice should be contraindicated during administration of halofantrine.

Adult↗
PubMed2002

Amprenavir inhibitory quotient and virological response in human immunodeficiency virus-infected patients on an amprenavir-containing salvage regimen without or with ritonavir.

The efficacy of an amprenavir (APV)-containing therapy without (group A) or with (group B) ritonavir was assessed in patients with failure of previous protease inhibitor therapy for human immunodeficiency virus (HIV) infection. The mean minimal plasma APV concentrations in groups A and B were 58 and 1,320 ng/ml, respectively, corresponding to APV inhibitory quotients of 0.2 (range, 0.03 to 0.70) and 7.0 (range, 1.4 to 145), respectively. At week 24, 2 of 8 and 13 of 14 patients in groups A and B, respectively, had <200 HIV RNA copies/ml of plasma, including 4 of 5 patients infected with APV-resistant viruses.

Anti-HIV Agents↗
PubMed2002

Human immunodeficiency virus (HIV) Type 1 reverse transcriptase resistance mutations in hepatitis B virus (HBV)-HIV-coinfected patients treated for HBV chronic infection once daily with 10 milligrams of adefovir dipivoxil combined with lamivudine.

Adefovir dipivoxil (ADV) at a suboptimal concentration for human immunodeficiency virus type 1 (HIV-1) (10 mg once daily) can be used to treat hepatitis B virus (HBV) infection in HIV-1-HBV-coinfected patients and does not, even in the case of uncontrolled HIV-1 replication, select for either ADV mutations at codons 65 and 70 or any other particular HIV-1 reverse transcriptase resistance profile.

Adenine↗
PubMed2002

Adherence to antiretroviral therapy and outcomes in HIV-infected patients enrolled in an induction/maintenance randomized trial.

OBJECTIVE: To examine the effect of adherence to therapy on early virological response, later virological failure, and occurrence of adverse events in HIV-infected patients. DESIGN: A randomized trial of 3-month induction period of zidovudine/lamivudine/indinavir followed by a maintenance phase of zidovudine/lamivudine/indinavir, zidovudine/lamivudine or zidovudine/indinavir. MAIN OUTCOMES: Adherence was assessed by pill count. In the induction phase, early virological response was defined as plasma HIV-RNA<500 copies/ml at month 2 and in the maintenance phase, virological failure was defined as plasma HIV-RNA >500 copies/ml in two consecutive specimens. RESULTS: The median adherence rate was 97% in both induction (n=366) and maintenance phase (n=237). In the maintenance phase, pairwise comparisons showed a lower adherence rate in zidovudine/lamivudine/indinavir versus zidovudine/lamivudine (P=0.03), or versus zidovudine/indinavir (P=0.05). Only 13% of patients had an adherence over the maintenance phase of 80% or lower, while 40% of patients occasionally had an adherence rate of 80% or lower during this phase. Among the 362 patients with documented HIV-RNA at month 2, 86% had an early virological response. Adherence of 80% or greater was the only variable statistically predictive to early virological response (P<0.001), while baseline CD4, baseline HIV-RNA, and adherence of 95% or greater were not associated to virological response. In the maintenance phase, adherence, baseline HIV-RNA, HIV-RNA at month 3 and treatment groups were independently predictive to time to virological failure. Analysis by randomized groups indicated that difficulty in adherence (<80%) was predictive to time to failure (P<0.001) only in both indinavir-containing regimens. Occurrence of two or more severe adverse events (grade 3 and 4) was higher in patients with poor adherence although not statistically associated (P=0.12), while no association was found with minor adverse events. CONCLUSION: Adherence rate was globally lower in patients maintaining the original triple-drug therapy compared with those receiving less intensive regimens. Adherence rate was a time-dependent variable. Adherence to antiviral regimen of 80% or greater was predictive to early virological response, and adherence rate lower than 80% or 95% was predictive to virological failure, especially in indinavir-containing regimens. Occurrence of adverse events was not clearly associated to adherence.

Adult↗
PubMedDate not supplied

Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial.

BACKGROUND: Generic fixed-dose combinations have been prequalified by WHO to treat HIV-infected patients in resource-limited countries. Despite their widespread use they are, however, not yet recommended by some of the major donor agencies owing to scarcity of clinical data on effectiveness, safety, and quality. We aimed to assess these issues for one of the most frequently prescribed treatments in Africa, a generic fixed-dose combination of nevirapine, stavudine, and lamivudine. METHODS: 60 patients were followed in an open-label, 24-week multicentre trial in Cameroon. All patients received one tablet of the fixed-dose combination drug twice daily. The primary outcome measure was the proportion of patients with viral load less than 400 copies per mL at the end of the study period, in an intention-to-treat analysis. FINDINGS: At baseline, 92% of patients (n=55) had AIDS; median CD4 count was 118 cells per microL (IQR 78-167) and median plasma HIV-1 RNA was 104?736 copies per mL (40804-243787). The proportion of patients with undetectable viral load (<400 copies per mL) after 24 weeks of treatment was 80% (95% CI 68-89). Median (IQR) change in viral load was -3.1 log10 copies per mL (-2.5 to -3.6) and in CD4 count 83 cells per microL (40-178). The probability of remaining alive or free of new AIDS-defining events was 0.85 (95% CI 0.73-0.92). Frequency of disease progression was 32.0 (95% CI 16.6-61.5), severe adverse effects 17.8 (7.4-42.7), and genotypic resistance mutations 7.1 (1.8-28.4) per 100 person-years. Mean reported adherence rate was 99%. Median drug concentrations in tablets were 96% of expected values for nevirapine, 89% for stavudine, and 99% for lamivudine. INTERPRETATION: Our findings lend support to use and funding of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine as first-line antiretroviral treatment in developing countries.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Usefulness of therapeutic drug monitoring of antiretrovirals in routine clinical practice.

BACKGROUND: Clinical trials have shown that therapeutic drug monitoring (TDM) of antiretrovirals (ARV) improves patient care. However, little is known about the usefulness of TDM in routine practice. METHOD: We reviewed all the trough concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors that were performed for therapeutic failure, suspected drug toxicity, or routine purposes. RESULTS: Between 1998 and 2001, 146 TDMs were done in 109 HIV patients. Of the 48 patients with therapeutic failure, 62% had resistance to ARV with adequate ARV concentrations, 16% had insufficient drug exposure without any ARV resistance mutations, and 16% combined both resistance and suboptimal drug concentrations. Subsequent therapeutic interventions (increasing adherence and/or changing HAART) resulted in an undetectable viral load in 37.5% of the patients (14/48). Five (24%) of 21 patients with suspected drug toxicity had high drug concentrations associated with side effects. In all the cases, adverse events regressed after reduction of drug dosage. Of the 77 TDMs done for routine purposes, 26% were outside the therapeutic range. CONCLUSION: The data show that TDM of ARVs in the clinical setting provides important information that can be used to improve the management of HIV patients receiving antiretroviral therapy.

Diagnostic Tests, Routine↗
PubMedDate not supplied

Predictors of virologic response to ritonavir-boosted protease inhibitors.

The primary mechanism of resistance to protease inhibitors involves the stepwise accumulation of mutations that alter and block the substrate binding site of HIV protease. The large degree of cross-resistance among the different protease inhibitors is a source of considerable concern for the management of patients after treatment failure. Although the output of HIV-resistance tests has been based on therapeutically arbitrary criteria, there is now an ongoing move towards correlating test interpretation with virologic outcomes on treatment. This approach is undeniably superior, in principle, for tests intended to guide drug choices. However, the predictive accuracy of a given stratagem that links genotype or phenotype to drug response is strongly influenced by the study design, data capture and the analytical methodology used to derive it. There is no definitively superior methodology for generating a genotype-response association for use in interpreting a resistance test, and the various approaches used to date all have their strengths and weaknesses. Combining the information of therapeutic drug monitoring and resistance tests is likely to be of greatest clinical utility in antiretroviral-experienced patients harboring HIV strains with reduced susceptibility. The combination of pharmacologic and virologic parameters as a predictor of the virologic response has been merged into the parameter known as "inhibitory quotient". This article discusses the potential interest of the use of inhibitory quotients as an approach for enhancing the potency and durability of boosted protease inhibitors against protease inhibitor-resistant viruses.

Anti-HIV Agents↗