Treatment interruption delivers no benefit for most heavily treated, despite resistance loss

Treatment interruption in heavily pretreated patients failed to deliver an improved response to treatment when it was resumed, and two-thirds of patients suffered HIV-related illness as a result of stopping treatment, French investigators report in the October 15^th edition of AIDS. The findings contradict the results of a previous French study, GIGHAART.

The study, called REVERSE, was designed by the same group that carried out the GIGHAART study, which randomised treatment-experienced patients with detectable viral load and evidence of drug resistance to interrupt treatment for eight weeks before starting a new regimen or to begin a new regimen immediately. GIGHAART showed that the eight week treatment interruption was beneficial in terms of virologic response to the new regimen, although follow-up only lasted 24 weeks.

The REVERSE study tested whether prolonging the treatment interruption until resistance mutations to at least two classes of drugs had disappeared had any benefit for patients with extensive treatment experience and drug resistance.

Resistance to a drug class was deemed to have disappeared according to the following criteria:

• Nucleoside analogues: disappearance of at least three thymidine analogue mutations.
• NNRTIs: disappearance of all NNRTI-associated mutations.
• Protease inhibitors: disappearance of at least three primary PI mutations.

The study recruited 23 patients with a median of 8.5 years of treatment experience and median baseline CD4 count of 43 cells/mm³, 57% of whom had experienced at least one AIDS-defining event. Patients were eligible to join the study if they had viral load above 30,000 copies/ml whilst on treatment, plus resistance to all three classes of antiretrovirals. Participants had an average of 17 drug mutations and remained sensitive to an average of 0.8 drugs (according to the results of a genotypic resistance test).

Treatment interruption lasted a median of 24 weeks, and by the end of this period 70% of patients were deemed to have met criteria for reversion of resistance, with a a shift to completely wild type virus in 22%. Seventy per cent were deemed to have HIV that was susceptible to at least three drugs by this time.

However only one patient experienced a viral load reduction of at least 1 log₁₀copies/ml when the salvage regime was introduced, and by week 4 of the new regimen, 13 patients had experienced reversion of all mutations lost during the treatment interruption. By week 24 all patients had experienced a reversion to their baseline resistance profile.

Participants were highly susceptible to illness because of their low CD4 cell counts. CD4 counts fell by a median of 30 cells/mm³ during treatment interruption, and by a further 27 cells/mm³ during the 24 week follow-up. Two-thirds developed at least one AIDS-defining illness, but these all occurred after treatment was resumed, and there was no significant difference in CD4 cell count between those who developed illnesses and those who did not. The authors are unable to explain why this should be so, noting that the increase in viral load during treatment interruption was relatively low (+0.56log₁₀ copies/ml).

Despite these findings the authors argue that short-term treatment interruption should still be tested if ther subsequent salvage regimen contains drugs assumed to be highly potent in salvage therapy, such as TMC114, tipranavir and T-20.