Apparent benefit from treatment interruption before multi-drug salvage therapy

Patients with heavy antiretroviral experience who begin a multi-drug salvage regimen comprising recycled agents, derive a stronger virological response if the regimen change is preceded by a drug-free period. That was the finding of the French ANRS 097 GIGHAART study presented by Professor Christine Katlama and colleagues from the Pitie-Salpetriere and Bichat Hospitals, Paris, today at the Fourteenth International AIDS Conference in Barcelona.

Seventy people with viral load above 50,000 copies, CD4 below 200, and prior experience of at least two protease inhibitors, two nucleoside analogues and one NNRTI were randomised to immediate or deferred “GIGHAART” therapy. The deferred group completed an eight week wash-out (off therapy) prior to the multi-drug regimen. The regimen consisted of three of four nucleoside analogues (either d4T, ddI, AZT, 3TC or abacavir), hydroxyurea (optional after April 2000), one NNRTI, and three protease inhibitors (ritonavir, amprenavir or lopinavir plus either indinavir, saquinavir or nelfinavir).

At baseline, median viral load was approximately 5.3 log, median CD4 was 27 cells, and median duration of prior therapy was approximately 6.5 years. Typical of such an advanced patients group, participants has been exposed to an average of eleven antiretrovirals (five nucleoside analogues, one NNRTI and four protease inhibitors).

Twelve week efficacy data were presented at a European AIDS conference in Athens last year. These early results appeared to support the hypothesis that a period off treatment would allow the patients’ HIV population to revert from one that is largely drug resistant to one that is drug sensitive.

Responses after twenty-four weeks continue to show a benefit in the deferred treatment group. A significantly greater proportion of those undergoing a treatment interruption had at least a one log drop in viral load after 24 weeks (50% versus 24% by intent to treat analysis). The fall in viral load after twenty-four weeks was –1.08 log in the deferred group compared with –0.29 in the immediate group (p=0.013).

Treatment interruptions are associated with a fall in CD4 count, which is of obvious concern in patients who begin with such low CD4 counts. The GIGHAART study, however, found no difference in HIV-related adverse events between the two arms (three in the immediate group versus five in the deferred group).

Evaluation of plasma drug concentrations suggest the results were not explained by differences in drug exposure – the proportion of patients with adequate or low drug concentrations was similar in the two groups.

Whether this approach constitutes the best treatment strategy in this hard-to-treat population is unclear. In a separate presentation in Barcelona today, Dr Anton Pozniak of London’s Chelsea and Westminster Hospital, reported final 48 week results from Gilead’s 407 study which added tenofovir to the stable background antiretroviral therapy of patients with heavy drug experience and virological failure. After 48 weeks, the time-weighted changes in viral load was –0.57 log in the tenofovir group, and 41% had viral load below 400 copies.

GIGHAART was completed prior to the availability of tenofovir which, despite ongoing wrangles over its price (reported elsewhere today on aidsmap.com), seems set to have a key role in salvage strategies. Speaking to aidsmap.com Professor Katlama said: “We provided proof of principle on treatment interruptions. Imagine what you could do with tenofovir as well”.