The belief of researchers in the promise of a week on, week off treatment strategy was finally laid to rest on the last day of the International AIDS Society Conference on HIV Treatment and Pathogenesis yesterday in Paris, when Prof. Bernard Hirschel presented findings from the Staccato study.
Staccato is an international randomised study with three arms. Individuals either continue their existing HAART regimen, or interrupt treatment in a week on, week off manner (WOWO), or according to their CD4 cell count (resuming treatment when it falls below 350 cells/mm3). The study has recruited 433 patients, largely in Thailand, and is a collaboration between Swiss, Australian and Thai researchers.
Bernard Hirschel presented results of a planned interim analysis of 112 patients who have completed 8 weeks in the WOWO arm of the study.
The one week interval was chosen on the basis that previous studies of treatment interruption have shown that viral load does not rise above 500 copies until at least a week after discontinuing treatment.
However, after 8 weeks or four cycles of interruption, 53% of those in the WOWO arm have experienced virologic failure, defined as two viral load measurements above 500 copies/ml. Three of four patients taking triple nucleoside regimens have experienced treatment failure (with one developing extensive thymidine analogue resistance), whilst two thirds of those taking ddI/d4T/saquinavir/ritonavir and two of three patients taking an unboosted protease inhibitor have also experienced failure.
However, amongst those receiving efavirenz, only one patient has experienced failure – a patient with a body mass index of 34 (obese) – and this patient developed the K103N mutation associated with NNRTI cross-resistance. Bernard Hirschel said that drug level monitoring had revealed low plasma levels of efavirenz, likely due to the greater body weight of the patient.
The WOWO arm of the study has now been discontinued, and attention is likely to shift to the strategy of treatment interruption guided by CD4 count.
Several randomised studies are ongoing to test this strategy, and promising early results from these studies were presented in Paris.
French researchers reported on the Window study, which is a 96 week randomised study comparing the time taken to reach a CD4 count below 300 cells/mm3 in patients with a CD4 cell count which has remained above 450 cells/mm3 for at least six months prior to joining the study, in patients taking continuous HAART and those who have interrupted treatment.
The study has recruited 390 patients, of whom 80 have already been followed for 48 weeks. No patients in the interruption group have fallen below 300 cells/mm3 yet, although two patients have experienced an acute antiretroviral syndrome since stopping treatment (Marchou).
A smaller Argentinean randomised study is examining the time to reach a CD4 count below 350 cells/mm3 in patients with a pre-treatment CD4 count below 350 and viral load above 60,000 copies/ml. 36 patients have been randomised, 20 to discontinue and 16 to continue HAART. The median CD4 cell count was 644 cells/mm3 in the discontinuation group After 48 weeks follow-up, none of the discontinuers have fallen below 350. The median CD4 count in this group after 48 weeks is 484 cells/mm3 (Krolewiecki).
An Italian randomised study, recruiting 111 patients with mean CD4 counts just above 1000 at the time of treatment interruption found that 19% had needed to resume therapy because of a CD4 decline below 400 cells/mm3 after 68 weeks of follow-up (Maggiolo).
A Spanish randomised study has recruited 52 patients with median CD4 counts around 900 cells/mm3; after 48 weeks two of the 25 patients randomised to discontinue have resumed therapy, and the median CD4 cell count is 455 cells/mm3. Triglycerides and cholesterol have declined significantly in the discontinuation group (Moreno).
Hirschel B, et al. Failures of one week on, one week off antiretroviral therapies in a randomized trial. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract LB4, 2003.
Krolewiecki A et al. A prospective randomized trial of treatment discontinuation in asymptomatic patients who started antiretrovirals with preserved immune function - 48 week data. Antiviral Therapy 8 (Suppl 1): S349, 2003.
Maggiolo F et al. Pulse therapy for HIV infection: preliminary results. Antiviral Therapy 8 (Suppl 1): S348, 2003.
Marchou B et al. ANRS-106 - Window: a prospective randomized multicentre trial of intermittent therapy in HIV-infected patients with successful viral suppression under HAART. Antiviral Therapy 8 (Suppl 1): S352, 2003.
Moreno S et al. A prospective randomised trial of treatment discontinuation after immunologic response to HAART. Antiviral Therapy 8 (Suppl 1): S348, 2003.