- Failures of One Week On, One Week Off Antiretroviral Therapies in a Randomized Trial (Oral LB4)
Authored by J. Ananworanich, R. Nuesch, M. Le Braz, P. Chetchotisakd, N. Khanna, C. Ebnöther, A. Vibhagool, S. Wicharuk, S. Ubolyam, K. Ruxrungtham, H. Furrer, M. Cavassini, E. Bernasconi, P. Vernazza, S. Yerly, D. Genné, L. Perrin, P. Phanupak, D. Cooper, B. Hirschel, and the Swiss HIV Cohort Study
Interruption of antiretroviral therapy (ART) for HIV is an interesting and important area of study. Although many studies have been performed, the study that has received the most attention was performed several years ago by Dr. Marc Dybul and published in the Proceedings of the National Association of Science in 2001. In that study, 10 patients were treated with d4T (stavudine, Zerit), 3TC (lamivudine, Epivir), ritonavir (RTV, Norvir) and indinavir (IDV, Crixivan) in a seven-day on, seven-day off format. No treatment failures were noted within six months. As expected, lipid levels improved in this group of patients.
Dr. Dybul presented another pilot study of this week-on, week-off strategy at this meeting (abstract 597). In that study, eight patients on efavirenz (EFV, Sustiva, Stocrin)-based ART, with viral loads less than 50 copies/mL were changed to once-daily efavirenz, 3TC and didanosine (ddI, Videx) on a schedule of week-on, week-off therapy. One patient withdrew at week 24 with a viral load less than 50 copies/mL; the other seven patients were successfully treated for more than 52 weeks. There were no increases in viral load and no development of viral resistance. Mean plasma concentrations of efavirenz after seven days off therapy were 275 mg/ml (73-718).
However, in a previous study, the Spanish Swiss Intermittent Therapy Trial (SSITT), viral rebound occurred about four to seven days after the last dose of medication in many patients. SSITT and other smaller studies have raised red flags about a week-on, week-off strategy because their findings suggest that allowing viral replication may lead to resistance.
This late-breaking oral presentation provided details of a larger study that looked at this week-on, week-off strategy for the treatment of HIV infection. This study, called "Staccato," was designed and performed within an international collaborative framework, although the majority of patients were treated by the HIVNAT group in Thailand.
In this study, patients were eligible for participation if their CD4 count was greater than 350 and their viral load was less than 50 copies/mL. They were randomized to one of three treatment arms:
Continue standard ART.
Discontinue ART, restart guided by declines in CD4 count.
Change to week-on therapy alternating with week-off therapy (Wowo).
This study began at the end of 2001. Four hundred and thirty-four patients have been enrolled -- a total of 600 patients are planned. The patients enrolled in this study were on a heterogeneous group of ART regimens. The week-on, week-off arm of this study was discontinued prematurely because of frequent virologic failures. Nineteen out of 36 patients (19/36) had virologic failure in the week-on, week-off arm at a median of 12 weeks. In contrast, there were two virologic failures in the continuous treatment arm and no virologic failures in the CD4-guided treatment arm.
Of the patients failing the week-on, week-off strategy, 12/18 patients taking ritonavir-boosted saquinavir (SQV, Fortovase, Invirase) regimens failed. There were 73 patients in Thailand treated with d4T, ddI, 100-mg ritonavir and 1,600-mg daily saquinavir. Of these patients, 72 had viral loads of less than 400 copies/mL at 24 weeks on continuous therapy and there was no viral resistance.
Eight patients on an efavirenz-containing regimen were randomized to the week-on, week-off strategy. One of these eight patients failed and developed a K103 mutation. However, this patient had a large body mass and had low levels of efavirenz noted before he changed to week-on, week-off therapy.
The results of this study will probably curb the enthusiasm for this investigational week-on, week-off HIV-management strategy. However, as newer, more potent agents with better pharmacokinetics and longer half-lives become available, this situation may change. There is a lot of interest in intermittent therapy strategies, especially for use in the less developed parts of the world with limited financial resources. Beyond cost savings, however, there is also potential reduction of toxicity as a consideration for patients in the developed world, so the story in this research arena is far from over.
For previous reports on this subject, click here.