Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097)
Katlama, Christinea; Dominguez, Stéphaniea; Gourlain, Karineb; Duvivier, Claudinea; Delaugerre, Constanceb; Legrand, Mayeulea; Tubiana, Rolanda; Reynes, Jacquesc; Molina, Jean-Micheld; Peytavin, Gillese; Calvez, Vincentb; Costagliola, Dominiquea
From the aDépartement des Maladies Infectieuses et Tropicales/INSERM E 0214, and bLaboratoire de Virologie, Hôpital Pitié-Salpêtrière, 47–83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France; cService des Maladies Infectieuses, Hôpital Guy de Chauliac, 80 Avenue Augustin Fliche, 34295 Montpellier cedex 5, France; dService des Maladies Infectieuses, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris cedex 10, France; and eLaboratoire de Pharmacologie, Hopital Bichat-Claude Bernard, 47 rue Henri Huchard, 75877 Paris Cedex 18, France.
Correspondence to: Christine Katlama, Departement des Maladies Infectieuses, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France.
Tel: +33 1 42 16 01 30/42; fax: +33 1 42 16 01 26; e-mail: firstname.lastname@example.org
Received: 19 February 2003; revised: 24 June 2003; accepted: 7 July 2003.
Background: Both highly potent antiretroviral drug rescue therapy and treatment interruption have been suggested to be effective in patients with multiple treatment failure.
Objective: To assess both the benefits and risks of an 8-week treatment interruption associated with a six to nine-drug rescue regimen in patients with multiple treatment failures.
Design: A randomized comparative controlled trial in 19 university hospitals in France.
Patients: Sixty-eight HIV-infected patients with multiple previous treatment failures and CD4 cell counts less than 200 × 106 cells/l and plasma HIV-1-RNA levels of 50 000 copies/ml or greater.
Measurements: The primary efficacy outcome was the proportion of patients with at least a 1 log10 decrease (copies/ml) in the plasma HIV-1-RNA level after 12 weeks of therapy.
Results: Treatment interruption followed by multidrug salvage therapy led to a greater proportion of patients achieving virological success (i.e. 1 log10 decrease) at 12 weeks compared with patients receiving multidrug therapy alone (62 versus 26%, intent-to-treat analysis; P = 0.007). The median decrease in the HIV-1-RNA level was −1.91 and −0.37 log10 copies/ml (P = 0.008), respectively. Treatment interruption led to an increase in the number of sensitive drugs of the multidrug regimen (71 versus 35% of regimen with at least two sensitive drugs; P = 0.004). Factors associated with virological success were treatment interruption, the reversion of at least one mutation to wild type, adequate plasma drug concentration, and the use of lopinavir.
Conclusion: Treatment interruption was beneficial for treatment-experienced HIV-infected patients with advanced HIV disease and multidrug-resistant virus.
The goal of antiretroviral therapy in patients with HIV/AIDS is to achieve a complete and durable suppression of plasma viral replication in order both to restore or maintain immune function and minimize the development of viral drug resistance. However, in observational databases, failure to achieve optimal viral suppression occurs in 40–60% of treated HIV-infected patients [1,2]. Severe treatment failure defined as a CD4 cell count less than 200 × 106 cells/l and an HIV-RNA level greater than 50 000 copies/ml occurs in 5% of all patients receiving antiretroviral therapy . Most of these patients had been exposed to suboptimal suppressive antiviral therapy over long periods of time. Furthermore, the progression of HIV disease despite highly active antiretroviral therapy (HAART) remains associated with low CD4 T cell counts (< 200 × 106 cells/l) and high plasma HIV-RNA levels .
Depending on the drug class, incomplete viral suppression leading to resistance to antiretroviral therapy occurs progressively over time, particularly for the nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI) drug classes, and is characterized by a marked decrease in drug susceptibility. At present, there are few recommended therapeutic options for the management of patients with highly resistant viral strains and severe therapeutic failure. The use of an antiretroviral regimen containing five to six active drugs, so-called mega-HAART, has been reported to be at least partly effective in these patients [5–7]. On the other hand, interrupting therapy has been reported to be associated with changes in resistance profiles from mutant to wild-type viruses in the plasma of patients on failing regimens [8–10]. However, even though an improved virological response on the re-initiation of treatment may follow these viral shifts from resistant to wild type, resistance mutations may be rapidly re-selected . Furthermore, a concern with this approach is that it allows the re-emergence of a drug-susceptible wild-type virus that is likely to have an increased ability to replicate and deplete peripheral blood CD4 cells .
We designed the GigHAART study to assess both the benefits and risks of treatment interruption in association with an intense salvage therapy regimen (GigHAART) in HIV-infected patients experiencing severe virological failure with evidence of multidrug-resistant virus.
We conducted an open-label, randomized, multicentre study to evaluate the benefit of an 8-week treatment interruption in HIV-infected patients with severe immune suppression who had experienced multiple therapeutic failures on the virological efficacy of a subsequent multidrug salvage regimen (GigHAART). Patients were randomly assigned to receive the GigHAART salvage regimen for 24 weeks either immediately (immediate treatment group) or after 8 weeks after the discontinuation of all previous antiretroviral treatment (deferred treatment group). Randomization was centralized, performed on a one-to-one basis with a block of size 6; the list of randomization was obtained using the SAS procedure plan.
Patients aged 18 years or older with HIV infection were eligible for enrolment if they had a plasma HIV-1-RNA level above 50 000 copies/ml at two consecutive visits in the past 6 months and a CD4 cell count below 200 × 106 cells/l while receiving an antiretroviral treatment regimen with three or more drugs from at least two different drug classes. Also, patients had to have a previous history of antiretroviral therapy with at least two PI, one non-nucleoside reverse transcriptase inhibitor (NNRTI), and two NRTI. At study entry, patients were required to have an absolute neutrophil count greater than 750 × 106 cells/l, a haemoglobin level greater than 10 g/dl, a platelet count greater than 50.0 × 109/l, a serum creatinine concentration less than 150 μmol/l, and liver enzyme levels no more than five times the upper limit of normal.
Patients were excluded if they had an active opportunistic infection or a history of poor adherence to therapy, severe drug intolerance to any one class of drug, or treatment interruption of more than 15 days before the start of the study. Also excluded were pregnant women and patients receiving cytostatic chemotherapy. The study protocol was approved by the Institutional Review Board of the Pitie-Salpetriere Hospital, and all patients provided written informed consent.
The salvage regimens used in this study contained seven to eight antiretroviral drugs, three to four NRTI, one NNRTI, and three PI, with or without hydroxyurea. The NRTI used were stavudine (30 or 40 mg twice a day based on body weight), zidovudine (300 mg twice a day), didanosine (250 or 400 mg a day based on body weight), abacavir (300 mg twice a day), lamivudine (150 mg twice a day), or zalcitabine (0.75 mg three times a day). Any one of the NNRTI, nevirapine, efavirenz, or delavirdine, could be used at the standard dosage. The PI component included a backbone of ritonavir (400 mg twice a day) and amprenavir (600 mg twice a day) plus a third PI, either indinavir (400 mg twice a day), nelfinavir (1250 mg twice a day), or saquinavir (600 mg twice a day). After September 2000, patients were allowed to receive ritonavir/lopinavir (Kaletra 400 mg twice a day) with ritonavir (300 mg twice a day) instead of amprenavir. Adding hydroxyurea (500 mg twice a day) to the regimen became optional after April 2001. Each clinical investigator selected the treatment regimens based on individual treatment history and drug tolerance. Resistance testing was not used to predetermine the salvage regimen. The management of side-effects was left to clinical investigators, including both symptomatic treatments and modifications of salvage therapy.
Clinical and laboratory evaluations
Patient evaluations occurred at screening (within 4 weeks of enrolment) and at the start of the study (day 0) at weeks 1, 2, and 4 and every 4 weeks thereafter until week 24 in the immediate treatment group, and at weeks 4, 8, 9, 10, 12, and every 4 weeks thereafter until week 32 in the deferred treatment group. At each visit, clinical examination and safety assessments were performed, including plasma HIV-1-RNA level, CD4 cell count, and plasma drug concentrations. The quantification of plasma HIV-1 RNA was performed using the Amplicor Monitor assay 1.5 (Roche Diagnostics, Basel, Switzerland) with a detection limit of 400 copies/ml. Genotypic resistance testing was performed retrospectively at day 0 in the immediate group and day 0 and week 8 in the deferred group. Reverse transcription polymerase chain reaction of HIV-1 reverse transcriptase (RT) and protease genes was performed on plasma viral HIV-1 RNA as previously described . The codons assessed for genotypic changes were those as previously described for the protease and RT genes . In the case of the simultaneous presence of different quasispecies (wild-type codon and codon associated with resistance), the result at that position was expressed as ‘resistant'. Resistance reversion was defined as the loss of at least one resistance mutation in the RT gene, or one primary mutation in the protease gene. The sensitivity of the drug regimen was assessed using the ANRS AC11 algorithm (http://www.HIVfrenchresistance.org/).
Determination of plasma antiretroviral concentrations
Steady-state drug concentrations were obtained after 2 weeks of treatment. Plasma samples were collected at each visit in heparinized tubes at trough plasma concentrations (Cmin) approximately 12 h after drug administration. The time between the last dose given and blood sampling was recorded. PI and NNRTI plasma concentrations were determined by specific and validated high-performance liquid chromatography assays coupled with either ultraviolet photodiode array detection or spectrofluorometric detection . The coefficients of variation within-day and between-day were below 10% in plasma quality controls.
We defined the cut-off values for trough plasma concentrations as follows: 1000 ng/ml for amprenavir, 150 ng/ml for indinavir [16–19], 1000 ng/ml for nelfinavir [19,20] and its active metabolite M8, 2100 ng/ml for ritonavir , 3000 ng/ml for lopinavir, 250 ng/ml for saquinavir, 3400 ng/l for nevirapine , and 1100 ng/ml for efavirenz [23,24]. Plasma drug concentrations were considered to be adequate at each timepoint if all (but one) trough concentrations were above the cut-off values. A patient was considered to be evaluable with plasma concentrations available for at least two visits after 2 weeks of study regimen. A patient was considered as having an adequate plasma concentration if concentrations from all available visits were judged to be adequate.
Criteria for efficacy
The primary efficacy endpoint was a decrease from the baseline in viral load of at least 1 log10 HIV-1-RNA copies/ml after 12 weeks of treatment at week 12 in the immediate group and at week 20 in the deferred group. This relatively short-term endpoint was chosen as a result of concerns of participant survival in the setting of salvage therapy in this patient population and the potential toxicity of the HAART regimens used. Secondary endpoints included the proportion of patients with a decrease in viral load of at least 1 log10 HIV-1-RNA copies/ml at week 24 of treatment, the percentage of patients with a viral load of less than 400 HIV-1-RNA copies/ml at weeks 12 and 24 of treatment, a change from baseline in CD4 cell count at week 24, changes in the viral load and CD4 cell count during treatment interruption, and the safety and tolerability of the treatment strategies.
The sample size was chosen to permit the detection of a difference of 30% in the success rate (with success defined as a decrease in the viral load of at least 1 log10 HIV-1-RNA copies/ml at week 12 of treatment) between the deferred treatment group (70%) and the immediate treatment group (40%), with a power of 80%, a type I error of 0.05, and a two-tailed test. Therefore, 42 patients per arm should be included, with 45 patients per arm to account for the dilution effect in case some patients were unevaluable.
Continuous variables were expressed as the median and range, and comparisons on as-observed values were made using non-parametric Mann–Whitney tests. Categorical variables were compared using chi-square tests, first on an intent-to-treat (ITT) missing equal failure basis and second on an as-observed basis. A multivariate analysis of factors associated with virological success was conducted using a backward logistic regression. Variables included in the analyses were a history of antiretroviral treatment (duration of exposure and number of drugs in each drug class), the baseline HIV-1-RNA level and CD4 cell count taken as continuous variables after log10 and log2 transformations, respectively, an adequate or low plasma drug concentration, a change in resistance profile defined as reversion or no reversion, and the use of amprenavir versus lopinavir, the use of efavirenz versus nevirapine, and the use of hydroxyurea. Only variables for which the univariate P value was lower than 0.20 were considered for multivariate analysis.
An interim analysis suggested by the data analysis centre was performed on the first 52 patients enrolled, of whom 45 were evaluable for the primary endpoint. It was decided to use the Fleming–Harrington–O'Brien rule with a P value of 0.015 for the interim analysis and of 0.0418 for the final analysis. In the ITT missing equals failure analysis, a significant difference in the primary endpoint was found with a P value of 0.005. Following these results, the scientific committee decided to suspend trial enrolment and continue follow-up of the 70 patient already enrolled.
All reported P values are two-tailed, with a significance level of 0.0418 to account for the interim analysis. Analyses were performed using the SPSS software package (SPSS Inc., Chicago, Illinois, USA).
Patient disposition and baseline characteristics
A total of 70 patients were enrolled in the study from November 1999 to June 2001; two patients never took study drugs, leaving 68 patients for evaluation. Overall, 63 patients, 32 in the immediate group and 31 in the deferred group, were evaluated at weeks 12/20 (one death at week 4, one lost to follow-up, three missed visits) and weeks 24/32 (one death at week 4, three lost to follow-up, one missed visit). The baseline characteristics of each group were comparable with marked elevations in viral load and declines in CD4 cell counts (Table 1). The median number of resistance mutations within the three drugs classes was 13 (range 6–18), with no imbalance between the two arms.
On-study salvage therapy comprised eight antiretroviral drugs for 31% of patients, seven drugs for 68%, and six for one patient. Fifty-four patients received at least one new drug: 43 patients received one new drug; 10 received two new drugs; and one received three new drugs. The distribution of drugs is shown in Fig. 1. There was no imbalance between the study arms except for NNRTI.
The treatment regimen was reduced to fewer than six drugs in six patients within the first 12 weeks of therapy and in 17 patients between 12 and 24 weeks, with no difference between treatment groups. Hydroxyurea was discontinued in 19 patients (seven in the immediate group; 12 in the deferred group).
Change in plasma HIV-RNA level and CD4 cell count
After 12 weeks of salvage therapy, a greater proportion of patients in the deferred treatment group achieved a 1 log10 reduction in the plasma HIV-1-RNA level compared with those who did have treatment interrupted before salvage therapy, with the results significant for both the as-observed analysis (68 versus 28%; P = 0.002) and the ITT missing equal failure analysis (62 versus 26%; P = 0.007) (Table 2, Fig. 2). The results at 24 weeks showed a similar trend. The median increase in CD4 cell count after 24 weeks of treatment was +51 × 106 cells/l in the deferred group and +7 × 106 cells/l in the immediate group (P = 0.047).
Impact of discontinuation of therapy
After 8 weeks of treatment interruption, the deferred treatment group experienced little change in virological and immunological status (Table 2). In the 31 evaluable patients of the deferred arm, a reversion of mutations occurred in 16 patients (52%): six patients had mutation reversion in one drug class, eight in two drug classes, and two in all three drug classes. These shifts in drug sensitivity involved PI mutations in six patients, NRTI mutations in 13 patients, and NNRTI mutations in nine patients. Return to a wild-type viral genotype was observed in only one patient.
At baseline, the number of antiviral drugs that retained viral sensitivity was similar between the immediate and the deferred groups (zero to one drug: 65 versus 56%; two to three drugs: 29 versus 41%; four or more drugs: 6 versus 3%). After treatment interruption the percentages of regimens with sensitive drugs were 32.5% for zero to one drug, 35% for two to three drugs, and 32.5% for four or more drugs. The difference in the sensitivity of the GigHAART regimen measured at baseline for the immediate group and week 8 for the deferred group became statistically significant (P = 0.006)
Antiretroviral plasma concentrations
Overall, up to 12 weeks of therapy, 65% of patients in the immediate treatment group and 74% in the deferred treatment group had adequate drug plasma concentrations.
Factors associated with virological response
In the multivariate analysis performed in 61 patients with complete data, three factors were associated with virological success: treatment interruption, particularly when treatment interruption led to mutation reversion [relative hazard (RH) = 12.4]; adequate drug concentration (RH = 5.6); and use of lopinavir (RH = 6.0) (Table 3, Fig. 3).
Over the study period, 15 out of 68 patients (22%), seven in the immediate arm and eight in the deferred arm, experienced an infectious or cancerous event: oesophageal candidiasis (n = 3), death related to lymphoma (n = 1), Pneumocystis carinii pneumonia (n = 2), bacterial pneumonia (n = 2), Kaposi's sarcoma (n = 1), tuberculosis (n = 1), disseminated Mycobacterium avium intracellulare infection (n = 1), systemic salmonella (n = 1), pulmonary nocardiosis (n = 1), recurrent herpes zoster (n = 1), and dual cryptosporidiosis and microsporidiosis-related colitis (n = 1). There was no excess of clinical events during the treatment interruption: three in the deferred treatment arm compared with three in the immediate arm during the first 8 weeks of the study.
Overall, 41 patients (60%) experienced at least grade III/IV–a serious adverse drug-related effect (Table 4). Increased triglyceride levels were found in 18 patients (26%). Clinical adverse events were relatively uncommon. The most serious effects were lactic acidosis, which occurred in two patients receiving didanosine and hydroxyurea, and one pancreatitis.
Evolution over one-year follow-up
Although the trial has been designed with a follow-up period of 24 weeks of treatment, we also collected data at 48 weeks. At week 48, four patients were dead, two in each arm. Among the remaining 64 patients, 47% in the deferred arm and 22% in the immediate arm were still on a GigHAART regimen (i.e. a treatment regimen with more than six drugs). The median changes from baseline in the plasma HIV-1-RNA level and the CD4 cell count were −0.79 log10 copies/ml and +69 × 106 cells/l in the deferred group compared with −0.37 log10 copies/ml and +7 × 106 cells/l in the immediate group.
Salvage therapy for extensively pre-treated patients is a challenging area, and there is little information available to guide clinicians. The purpose of the GigHAART study was to evaluate whether a structured treatment interruption followed by a salvage regimen would improve the antiviral response in patients with multiple treatment failure. Our study showed a striking difference between the deferred and the immediate treatment arms, with significant virological and immunological benefit associated with treatment interruption before salvage therapy. The reason for the magnitude of the difference in the efficacy of the two strategies in this study appears to be almost entirely caused by the use of a treatment interruption in these patients. There was no imbalance at baseline with regard to previous antiretroviral therapy, the resistance profile, or the type of salvage therapy. Furthermore, despite the heavy pill burden and the potential for multiple drug–drug interactions associated with a regimen of seven or more drugs, there was no difference in the compliance of patients with their salvage regimens, as suggested by a similar and relatively high percentage of patients in the two groups with adequate plasma drug concentrations. There were no between-group differences in the rates of treatment discontinuation or modification in the first 12 weeks of treatment.
Importantly, 50% of these patients who had treatment interrupted experienced a median increase of at least 50 × 106 CD4 cells/l (compared with 25% who did not have treatment interrupted), with even higher rates (82%) for patients who experienced a 1 log10 drop in viral load after 12 weeks of treatment. Several reports have pointed out the clinical benefits of an increase of 50 × 106 CD4 cells/l after 6 months of HAART [25,26], and our results are therefore particularly important for patients with low CD4 cell counts. In this study, only two of the clinical events during the study (tuberculosis, herpes zoster infection) were observed in patients who achieved virological success. Our results compare favourably with those reported for other studies performed in highly treatment-experienced patients [27–31], in which the median decrease in viral load ranged from 0.38 to 1.23 log10 HIV-1-RNA copies/ml. The median increases in CD4 cell counts in the studies did not exceed 40 × 106 CD4 cells/l [27–31]. Interestingly, in our study, the immunological and virological benefits were sustained over one year of follow-up.
Two-thirds of patients (66%) exhibited a high degree of resistance to all three classes of antiretroviral drugs at study entry. After the 8-week treatment interruption, the reappearance of the wild-type amino acid in at least one position was observed in half of the patients. This is in accordance with previous reports in which a reversion of mutations was observed after treatment discontinuation [8,32]. A reasonable hypothesis is that the better antiviral efficacy observed was caused by the presence of more sensitive viruses. Interestingly, in our patients in whom plasma genotyping assays did not apparently show any reversion of mutations after 8 weeks of treatment interruption, a median 2 log10 reduction in viral load was still observed. This finding appears to challenge the hypothesis that improved antiviral efficacy is related to the loss of viral mutations in this setting. However, the preliminary data of retrospective molecular cloning of circulating quasi-species suggest that reversions in the different clones were indeed present but were not detected on RT and protease sequences in the polymerase chain reaction products routinely used for genotypic resistance testing (data not shown). The reason why a seven to nine drug intervention with mostly recycled drugs was so highly effective may be that not every clone harbours all viral mutations found in a genotypic assay.
In this study, in which the median baseline CD4 cell count was already very low and the median viral load very high, treatment interruption alone had little impact on these markers. This is in contrast to other studies that reported clinically important CD4 cell decreases and viral load rebounds after treatment interruption in patients with comparably higher baseline CD4 cell counts [9,12].
In this study, lopinavir was associated with a higher virological success rate compared with amprenavir. The proportion of patients who were naive for each of these drugs at study entry was similar; however, the median trough concentrations reached with lopinavir boosted with 400 mg ritonavir were 3.5-fold the therapeutic cut-off level, whereas those of amprenavir boosted with 400 mg ritonavir were only 1.8-fold its cut-off level. Therefore, both a slightly better virological resistance profile, together with a high median concentration may account for the better efficacy of the lopinavir-containing regimens.
The overall tolerance of such a multidrug therapy in our patients was acceptable. The rate of treatment discontinuations was unexpectedly low, suggesting that this salvage therapy was reasonably tolerable in the context of highly motivated patients. Interestingly, non-toxic plasma drug concentrations were obtained in this study, in which patients received six or more drugs in combination. This is also probably related not only to the correct drug dosages being used, but also reciprocal drug interactions between ritonavir and the other PI and NNRTI used in the regimens.
In conclusion, this study is the first to demonstrate the benefit of treatment interruption for patients who had lost all of their therapeutic options among the currently available antiretroviral drug classes. The optimal situation would be, of course, to provide these very advanced patients with several potent drugs to which they had not yet been exposed, including new classes of drugs with no or limited cross-resistance to their previous failing treatments. However, the strategy reported here for this severely compromised patient population can minimize the clinical consequences of virological failure and may allow these patients to survive until newer drugs are available.
This work has been presented, in part, at the 8th European Conference on Clinical Aspects and Treatment of HIV Infection in Athens, October 2001, and at the British HIV Association meeting, April 2002, and the XIVth International AIDS Conference, Barcelona, 7–12 July 2002.
This study has been granted by ANRS (France) Ageue Nationale de recherche sur le SIDA.
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Appendix: others members of the GIGHAART Trial Group
D. Ponscarme, J.M Molina, Hôpital Saint-Louis, Paris; C. François, F.Raffi, Hopital Hôtel Dieu, Nantes; V. Baillat, C. Merle, J. Reynes, M. Vidal, Hôpital Gui de Chauliac, Montpellier; I. Beguinot, C. Rouger, P. Remy, Hôpital Robert Debré, Reims; M. Bonarek, P. Morlat, Hôpital Saint André, Bordeaux; T. Nguyen, L. Nait Ighil, W. Rozenbaum, Hôpital Rothschild, Paris; D. Sissoko, Y. Mouton, CHU de Tourcoing, Tourcoing; C. Burty, L. Boyer, T. May, Hôpital Brabois, Nancy; H. Gil, B. Hoen, G. Achard, Hôpital Besançon, Besançon; C.R. Verdon, C. Bazin, P. Goubin, CHU Caen, Caen; M. Bendenoun, M. Parinello, P. Caulin, Hôpital Lariboisière, Paris; M. Kazatchkine, C. Piketty, P. Le Houssine, Hôpital Européen Georges Pompidou, Paris; M. Bonmarchand, A. Simon, S. Herson, Hôpital Pitié Salpêtrière, Paris; C. Ceppi, J.P. Cassuto, Hôpital de l'Archet, Nice; D. Dihn, V. Marin, J.A Gastaut, Hôpital Sainte Marguerite, Marseille; F. Boue, Hôpital Béclère, Clamart; C. Chandemerle, Hôpital Louis Mourier, Colombes; C. Rousseau, J.F. Delfraissy, Hôpital Bicêtre, Kremlin Bicêtre.
Members of the Scientific Committee
C. Katlama, R. Tubiana, C. Duvivier, S. Dominguez, V. Calvez, G. Peytavin, B. Diquet, M. Legrand, F. Clavel, S. Matheron, F. Brun-Vezinet, P.M. Girard, J.M Molina, P. Morlat, D. Costagliola, A. Metro (ANRS), M.J. Commoy (ANRS).
Participating pharmaceutical companies
V. Pajadon (Merck Sharp and Dohme, Chibret); B. Baumelou (Boerhinger Ingelheim); E. Dohin (Roche); B. Anduze-Faris (Bristol-Myers Squibb); V. Gregoire (Dupont Pharma); I. Cohen-Coddar (Abbott); D. Lapierre (GlaxoSmithKline).
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