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Gilles Peytavin

Publications and source records attributed to Gilles Peytavin.

At least 55 records · Page 3Linked to original sources
PubMed2004

Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients.

OBJECTIVE: To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy. METHODS: HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method. RESULTS: The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of < or = 2 predicted the absence of resistance to TDF and > or = 6 mutations predicted resistance to TDF with corresponding reductions in viral load of -1.3 +/- 1.1, and +0.1 +/- 0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3-5, the decrease in viral load was -0.8 +/- 1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score > or = 6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score. CONCLUSION: In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.

Adenine↗
PubMed2003

Plasma levels of indinavir and nelfinavir at time of virologic response may have a different impact on the risk of further virologic failure in HIV-infected patients.

Indinavir and nelfinavir plasma levels were studied in 407 patients having plasma HIV RNA <500 copies/mL after 4 months of treatment with these drugs. For each drug, an observed/predicted (O/P) ratio was calculated between individual and mean time-adjusted population plasma drug levels. The relationship between the O/P ratio and the risk of rebound of plasma HIV RNA >500 copies/mL beyond month 4 was studied using Cox proportional hazard models. Median follow-up was 20 months. There was no association between indinavir plasma levels and risk of virologic rebound, whereas low nelfinavir + M8 (active nelfinavir metabolite) plasma levels were associated with a higher risk of virologic rebound. In multivariate analysis, the adjusted relative hazard of virologic rebound for patients with an O/P ratio of nelfinavir + M8 metabolite <0.8 compared with others was 2.2 (P = 0.01). In some patients, plasma levels of nelfinavir sufficient to achieve early viral response may not be sufficient to maintain it in the long term. This may be related to insufficient compliance with dietary recommendations. Monitoring of nelfinavir plasma levels thus seems useful, even in patients having early virologic response.

Biotransformation↗
PubMed2003

Clinically relevant interpretation of genotype for resistance to abacavir.

OBJECTIVE: To develop a stepwise methodology for the development and validation of clinically relevant genotypic score for resistance to antiretroviral drugs and to apply this approach to the genotypic resistance to abacavir. METHODS: All patients having received abacavir during the Narval trial were included in this study. The impact of each nucleoside analogue resistance mutation on the virologic response to abacavir was studied in a univariate analysis. Mutations with a P value < 0.20 and those selected by abacavir were retained. According to the number of mutations three levels of resistance were defined. A multivariate analysis accounting for confonding variables assessed whether the genotypic score was an independent predictor of the response. The robustness of the score was analysed using the bootstrap resampling method. RESULTS: In the 175 patients exposed to abacavir, the strongest association between the decrease in viral load and the number of mutations was observed with a set of six mutations at codons 41, 67, 210, 215, 74 and 184 of the reverse transcriptase gene. In patients with fewer than four mutations (no evidence of resistance) the median decrease in viral load was -1.64 log(10) copies/ml while it was -0.69 log(10) and -0.19 log(10) in those with four (possible resistance) and five or six (resistance) mutations respectively. In the multivariate analysis this score was an independent predictor of the response. The bootstrap analysis showed the robustness of the score. CONCLUSIONS: We developed a new strategy for the analysis of correlation between genotype profile at baseline and virologic response.

Algorithms↗
PubMed2003

Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal.

OBJECTIVES: To study the effectiveness, adherence and tolerance of a once-a-day highly active antiretroviral therapy regimen in adults in Senegal. DESIGN AND METHODS: In a prospective, open-label one-arm study, 40 treatment-naive HIV-1-infected patients took the following three drugs once a day at bedtime: didanosine, lamivudine and efavirenz. The primary endpoint was the percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months. The analysis was done on an intent-to treat basis. RESULTS: Eighty-five per cent of patients were at Centers for Disease Control and Prevention stage B or C and the plasma HIV RNA level was 5.4 +/- 0.4 log(10) copies/ml at baseline. The percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months was 95% [95% confidence interval (CI), 83-99]. The proportions of patients with plasma HIV-1 RNA below 50 copies/ml at months 3, 6, 9, 12 and 15 were 26% (n = 39; 95% CI, 12-39), 78% (n = 40; 95% CI, 65-90), 70% (n = 40; 95% CI, 56-84), 77% (n = 39; 95% CI, 64-90) and 69% (n = 39; 95% CI, 55-84), respectively. The CD4 cell count was 164 +/- 75 x 106/l at baseline and increased by a mean of 199 +/- 101 x 106/l at month 15. Permanent treatment discontinuation was never necessary for serious adverse effects. Adherence was excellent, as shown by plasma drug concentrations and according to the results of the questionnaire. CONCLUSIONS: The once-daily regimen of didanosine, lamivudine and efavirenz was safe, easy-to-take and demonstrated strong antiretroviral and immunologic effects in African patients with advanced HIV infection.

Adult↗
PubMed2003

The detection of non-adherence by self-administered questionnaires can be optimized by protease inhibitor plasma concentration determination.

Self-reported adherence and plasma protease inhibitor concentration (PPIC) were assessed in 642 HIV-infected patients at month 4 of a single protease inhibitor-containing regimen. PPIC was below the limit of quantification (LOQ) in 32% of non-adherent patients and in 8% of adherent patients. The relationship between non-adherence and a detectable HIV viral load was enhanced when adherent patients with PPIC below LOQ were considered to be non-adherent. PPIC combined with self-report may more reliably detect non-adherence.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients.

OBJECTIVE: To evaluate the pharmacokinetics, efficacy and tolerability of a low-dose boosted indinavir (IDV)/ritonavir (RTV) regimen [100 mg RTV/400 mg IDV twice daily (bid)] in patients previously receiving a standard IDV regimen [800 mg three times a day (tid)]. METHODS: In a prospective, open-label, cross-over trial, patients with plasma HIV RNA < 200 copies/ml receiving an IDV-containing regimen (800 mg tid) were switched to an RTV/IDV (100/400 mg bid)-containing regimen. Minimal and maximal IDV plasma concentrations ( Cmin and Cmax ) were determined before the switch (day 0), at week 2 and week 4 after the switch. The CD4 cell count and plasma HIV RNA were determined at day 0, week 2 and week 4, then every 8 weeks. The primary end-point was the percentage of patients with plasma HIV RNA below 200 copies ml at week 48. RESULTS: Twenty patients were enrolled. At baseline, on IDV 800 mg tid, median IDV Cmin was 194 ng/ml and median IDV Cmax was 8449 ng/ml. On RTV/IDV (100/400 mg), median IDV Cmin increased to 536 ng/ml at week 2 and 475 ng/ml at week 4, while Cmax decreased to 2983 ng/ml at week 2 and 2997 ng/ml at week 4 ( P < 0.001). The median area under the IDV plasma concentration-time curve measured in seven patients was 25 126 ng.h/ml, and the IDV half-life (t1/2 ) was 4.4 h. All patients had plasma HIV RNA remaining < 200 copies/ml at week 48. Tolerability of RTV/IDV was excellent. CONCLUSION: RTV/IDV (100/400 mg bid) yields significantly higher IDV plasma Cmin and lower IDV Cmax values relative to the standard IDV regimen, thereby improving both tolerability and efficacy.

Adult↗
PubMed2003

Mitochondrial and metabolic effects of nucleoside reverse transcriptase inhibitors (NRTIs) in mice receiving one of five single- and three dual-NRTI treatments.

Although treatments with nucleoside reverse transcriptase inhibitors (NRTIs) can modify fat metabolism and fat distribution in humans, the mechanisms of these modifications and the roles of diverse NRTIs are unknown. We studied the mitochondrial and metabolic effects of stavudine (d4T), zidovudine (AZT), didanosine (ddI), lamivudine (3TC), zalcitabine (ddC), and three combinations (AZT-3TC, d4T-3TC, and d4T-ddI) in mice treated for 2 weeks with daily doses equivalent to the human dose per body area. Concentrations of AZT and d4T in plasma were lower when these drugs were administered with 3TC or ddI. Whatever the treatment, mitochondrial DNA was not significantly decreased in muscle, heart, brain, or white adipose tissue but was moderately decreased in liver tissue after the administration of AZT, 3TC, or d4T alone. Blood lactate was unchanged, even when NRTIs were administered at supratherapeutic doses. In contrast, the level of plasma ketone bodies increased with the administration of AZT or high doses of d4T but not with ddC, 3TC, or ddI, suggesting that the thymine moiety could be involved. Indeed, the levels of plasma ketone bodies increased in mice treated with beta-aminoisobutyric acid, a thymine catabolite. Treatment with AZT, d4T, or beta-aminoisobutyric acid increased hepatic carnitine palmitoyltransferase I (CPT-I) mRNA expression and the mitochondrial generation of ketone bodies from palmitate. In conclusion, therapeutic doses of NRTIs have no or moderate effects on mitochondrial DNA and no effects on plasma lactate in mice. However, AZT and high doses of d4T increase the levels of hepatic CPT-I, mitochondrial fatty acid beta-oxidation, and ketone bodies, and these catabolic effects are reproduced by beta-aminoisobutyric acid, a thymine metabolite.

Aminoisobutyric Acids↗
PubMed2003

Genotypic inhibitory quotient as predictor of virological response to ritonavir-amprenavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients.

Forty-nine protease inhibitor (PI)-experienced but amprenavir (APV)-naïve patients experiencing virological failure were treated with ritonavir (RTV) (100 mg twice a day [b.i.d.]) plus APV (600 mg b.i.d.). Patients responded to therapy with a median viral load decrease of -1.32 log(10) by week 12. The addition of low-dose RTV enhanced the minimal APV concentration in plasma (APV C(min)) up to 10-fold compared with that obtained with APV (1,200 mg b.i.d.) without RTV. Baseline PI resistance mutations (L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S, I84V) identified by univariate analysis and included in a genotypic score and APV C(min) at week 8 were predictive of the virological response at week 12. The response to APV plus RTV was significantly reduced in patients with six or more of the resistance mutations among the ones defined above. The genotypic inhibitory quotient, calculated as the ratio of the APV C(min) to the number of human immunodeficiency virus type 1 protease mutations, was a better predictor than the virological or pharmacological variables used alone. This genotypic inhibitory quotient could be used in therapeutic drug monitoring to define the concentrations in plasma needed to control replication of viruses with different levels of PI resistance, as measured by the number of PI resistance mutations.

Adult↗
PubMed2003

Interruption of nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy for 2 months has no effect on levels of human immunodeficiency virus type 1 in plasma of patients harboring viruses with mutations associated with resistance to NNRTIs.

A 2-month interruption of only nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients carrying mutations associated with resistance to NNRTIs was followed by no change in either viral load or CD4 cell counts. These data suggest that these compounds have lost all of their in vivo antiviral activity in such cases.

Alkynes↗
PubMed2003

Predictors of the virological response to a change in the antiretroviral treatment regimen in HIV-1-infected patients enrolled in a randomized trial comparing genotyping, phenotyping and standard of care (Narval trial, ANRS 088).

OBJECTIVE: To identify predictors of the virological response to antiretroviral therapy in patients in whom initial therapy has failed. METHODS: The Narval trial was designed to compare phenotyping, genotyping and standard of care for the choice of antiretroviral therapy in patients in whom a protease inhibitor (PI)-containing regimen had failed. Virological success was defined as viral load below 200 copies/ml at week 12. Baseline variables including demographic, clinical and biological characteristics, HIV reverse transcriptase and protease mutations, the randomization arm, the drugs prescribed, as well as adherence to treatment and plasma concentrations of PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) at week 12 were tested in the model. Variables that were significantly associated with virological success in univariate analysis were included in a logistic regression model. RESULTS: Five-hundred-and-forty-one patients were randomized. Virological success at week 12 was obtained in 200 patients. In multivariate analysis, the following factors were significantly associated with virological success: prescription of efavirenz to NNRTI-naive patients (OR=4.37; 95% CI: 2.76-6.90), randomization to the genotyping arm (OR=2.13, 1.20-3.79), prescription of lamivudine (OR=1.69, 1.01-2.83) and prescription of abacavir to abacavir-naive patients (OR=1.66, 1.02-2.72). Factors significantly associated with virological failure were prescription of nelfinavir (OR=0.30, 0.13-0.68), a high baseline viral load (OR=0.37, 0.28-0.50), the presence of at least five PI mutations (OR=0.42, 0.26-0.66), the presence of at least three thymidine analogue mutations (OR=0.61, 0.39-0.97) and at least 30 months of prior PI exposure (OR=0.64, 0.41-0.99). CONCLUSIONS: These results confirm that among heavily pretreated patients, prescription of efavirenz to NNRTI-naive patients is associated with a good virological response, while a high baseline viral load, a large number of PI mutations and nelfinavir prescription at baseline are associated with a poor virological response. Genotyping was found to be beneficial, while this was not the case for phenotyping. This work was presented at the XI International HIV Drug Resistance Workshop, Sevilla, Spain, July 3-6 2002 (Abstract N(o)133); and at the XIV International Conference on AIDS, Barcelona, Spain, July 7-11 2002 (Abstract N(o)ThOrB138).

Adult↗
PubMed2003

Once-daily administration of antiretrovirals: pharmacokinetics of emerging therapies.

Adherence to therapy is of critical importance for the long-term success of the treatment of HIV infection. Once-daily administration of antiretroviral agents is appealing, as it may increase patient's adherence. The pharmaceutical industry is making huge efforts to develop drugs or combinations of drugs with pharmacokinetic properties allowing once-daily administration. The major pharmacokinetic requirement for once-daily administration is that the intracellular concentration of the antiretroviral or its active metabolite remains above the minimal concentration that can inhibit viral replication during the entire 24-hour period. Soon, all three major classes of antiretroviral agents will be available as once-daily formulations. However, only a few clinical trials have yet assessed the efficacy and safety of truly once-daily antiretroviral combinations. Preliminary results from these small pilot studies suggest that once-daily administration of antiretrovirals is a feasible approach. Large comparative trials are needed before the real benefits of such a strategy can be fully assessed.

Anti-HIV Agents↗
PubMed2003

Efficacy and safety of ritonavir/indinavir 100/400 mg twice daily in combination with two nucleoside analogues in antiretroviral treatment-naive HIV-infected individuals.

OBJECTIVE: To evaluate the efficacy and tolerability of indinavir/ritonavir (IDV/RTV) 400/100 mg twice daily in combination with two nucleoside reverse transcriptase inhibitors in antiretroviral-naive patients. DESIGN AND METHODS: Antiviral therapy-naive patients with plasma HIV-1 RNA > 5000 copies/ml were enrolled in this pilot, single-arm study. CD4 cell count and viral load were evaluated at weeks (W) 4, 12, 24 and every 3 months until W48. The primary end-point was the percentage (%) of patients with viral load < 400 copies/ml at W48. Intent-to-treat (ITT) (missing values or change in treatment equalled failure) and on-treatment (OT) analyses were performed. RESULTS: Forty patients were enrolled. Baseline median viral load was 5.36 log10 copies/ml, median CD4 count was 84 cells/mm3. At W48 by ITT analysis, the % patients with viral load < 400 copies/ml was 65% (95% CI: 48-79) and 50% (95% CI: 35-65) with viral load < 50 copies/ml, and 96% (26/27) (95% CI: 89-100) and 74% (95% CI: 57-91], respectively, by OT analysis. The median decrease in viral load at W48 was -3.83 log10 copies/ml (-0.1; -5.19) and the median increase in CD4 was +167 cells/mm3 (6-474 cell/mm3). At W4 (34/40), the median IDV C(min) was 500 ng/ml (range 5-8100) with 91% of patients with an adequate IDV C(min) > 150 ng/ml. Ten patients discontinued the study treatment before W48: adverse events (eight), patient's will (one) and simplification of therapy (one). Three patients were lost to follow-up. Only one virological failure occurred and was associated with poor compliance and sub-optimal concentrations of IDV/RTV. CONCLUSIONS: IDV/RTV 400/100 mg twice daily is an effective and safe first-line antiretroviral therapy. The simplicity and the low cost of IDV/RTV is of major interest particularly in countries with limited resources.

Adult↗
PubMed2002

Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine or stavudine, each in combination with lamivudine and indinavir.

The authors studied the effect of zidovudine (ZDV) resistance mutation on virologic response to treatment with ZDV or stavudine (d4T) each in combination with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA at study entry and concerned 155 patients previously treated with ZDV, didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were investigated: early response (<50 copies/mL at week 24), late response (<500 copies/mL at week 80), and virologic failure (two HIV-1 RNA >5000 copies/mL). Patients were classified as resistant or susceptible to ZDV according to the ANRS algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV resistance mutations. The number of ZDV resistance mutations was positively correlated with the duration of prior antiviral therapy (p <.001). At week 24, 74% and 77% of patients with virus classified as resistant were responders in the d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic failure was reached in 7 of 24 patients with virus classified as susceptible and in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients classified as resistant had longer times to virologic failure than those classified as susceptible (p =.003). In conclusion, sustained virologic response despite presence of ZDV resistance mutations implies that these mutations do not preclude an early and durable response to treatment with a potent three-drug regimen in these patients. Patients susceptible to ZDV had lower median mean corpuscular volumes and lower random indinavir levels, suggesting that adherence was the main reason for failure.

Anti-HIV Agents↗
PubMed2002

HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy.

OBJECTIVE: To determine HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. METHODS: Twenty-three consecutive HIV-infected patients (median age, 43 years; male:female ratio, 18:5; median CD4 cell count, 419 x 10(6)/l) undergoing Coleman's lipostructure were enrolled prospectively in this study. HIV-1 RNA and plasma concentration of antiretroviral drugs were determined blindly in plasma and adipocyte lysate samples. HIV-1 proviral DNA was detected by nested PCR in fresh frozen adipocytes. RESULTS: Mean plasma HIV-1 RNA was significantly higher than that in adipocyte lysate samples (this was below the limit of detection in all patients tested). HIV-1 proviral DNA was positive in two out of 18 adipocyte samples with a level between 2 and 5 copies; the distribution seemed to be specific and comparable within each therapeutic class--protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). NNRTI concentrations in adipocyte lysates were approximately 100-fold higher than those of PI. Efavirenz may accumulate in fat tissue as a function of treatment duration. CONCLUSION: Our results suggest that HIV does not replicate and does not integrate its genome in fat tissue in patients with fat redistribution abnormalities. In patients with effective nadir plasma concentrations of PI and NNRTI, determination of concentration in adipocyte lysates suggests that PI may diffuse in fat tissue with the same pattern of distribution for all structurally related components tested. NNRTI present a high affinity for fat tissue and may accumulate in this compartment.

Adipocytes↗
PubMed2002

Mechanisms of early virologic failure in antiretroviral-naive patients starting protease inhibitor-containing regimens: the APROVIR Study.

The virologic and pharmacologic mechanisms of virologic failure (VF) were studied in 243 antiretroviral-naive patients starting first-line protease inhibitor (PI)-containing therapy (nelfinavir in 66% and indinavir in 19%). Among the 220 patients with follow-up data, VF occurred in 35 (16%) during the first year of follow-up. A higher baseline virus load and poorer adherence to therapy were associated with VF. At the time of VF, key PI-resistance mutations were detected in 11 (48%) of 23 patients who started on nelfinavir but were absent in 6 patients with indinavir treatment failure. PI plasma levels were more often below the range of active concentrations in VF with wild-type viruses (74%) than in VF with PI-resistant viruses (25%; P=.02). The mechanisms of early VF and of selection of PI-resistant viruses differed by type of PI and were dependent on PI plasma levels.

Adult↗
PubMed2002

Nevirapine or lamivudine plus stavudine and indinavir: examples of 2-class versus 3-class regimens for the treatment of human immunodeficiency virus type 1.

We compared use of a 3-class regimen (nevirapine [Nvp], stavudine [d4T], and indinavir [Idv; 1000 mg 3 times daily]) with use of a 2-class regimen (lamivudine [3TC], d4T, and Idv [800 mg 3 times daily]) for 145 patients infected with human immunodeficiency virus type 1 (HIV-1). At week 72, the plasma HIV-1 RNA level was undetectable in 52% of Nvp recipients versus 79% of 3TC recipients (P<.001). Idv trough levels were 81 ng/mL in the Nvp group and 99 ng/mL in the 3TC group (P=.012). In the Nvp group, 42.5% of patients discontinued the study regimen; in the 3TC group, 22.5% of patients discontinued therapy (P=.013). The rate of resistance to nonnucleoside analogue reverse-transcriptase inhibitors among patients in the Nvp group with virological failure was not different from the rate of resistance to 3TC among patients in the 3TC group with virological failure. These results do not support the use of a 3-class regimen that includes Nvp for patients with no or limited exposure to nucleoside analogues.

Adult↗