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.
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.
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.
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).