The Body PRO Covers: The 6th International Congress on Drug Therapy in HIV Infection

Shift in HIV-1 Resistance After Treatment Interruption in Patients With Virological Failure

November 19, 2002

  • Shift in HIV-1 Resistance After Treatment Interruption in Patients With Virological Failure and Antiviral Effect Following Trizivir Plus Efavirenz (AZLF3003 Study)
    Authored by Izopet J., Massip P., Force G., Delmas B., Gallais H., Aquilina C.H., and David F., on behalf of the AZLF3003 study group
    Poster P207

The authors of the study attempt to address three issues: 1) the reversion of mutant virus to wild type following strategic treatment interruption (STI), 2) reduction in CD4 counts during STI, and 3) the short-term virological and immunological benefit of Trizivir (AZT+3TC+ABV) + efavirenz (EFV, Sustiva) following STI.

Drug-experienced patients with a CD4 of more than 300 and more than 1,000 HIV RNA had treatment interrupted for 14 weeks after which Trizivir and efavirenz were started. Standard genotypic resistance testing from plasma was performed before, during and after the STI and phenotypic testing was performed before and after as well. Mutations in PBMCs were also studied before and after the STI. CD4 and HIV RNA were followed for 24 weeks on the new regimen.

Fifty-one patients were screened for the study, 30 were enrolled but 24-week results are only reported for 17 patients. During the 14-week STI, 20 out of 30 patients showed reversion or partial reversion to wild type. No information is provided regarding the genotyping or its ability to detect minor mutant populations as they are diluted by the emerging wild type. The 10 patients who did not show reversion were removed from the study and did not receive the new regimen.

CD4 decreased more than 100 cells on average (range -5 to 387) during the STI. After starting therapy, 53 percent of patients were less than 400 copies at week 24 and CD4 cells had increased above pre-interruption levels. Seventy-five percent of patients reported at least one adverse event judged to be treatment related, 81 percent were mild or moderate. Two out of 20 patients had treatment discontinued due to possible hypersensitivity reactions to abacavir (ABV, Ziagen).

This is a very small study attempting to address a number of big questions. The study indeed supports our current knowledge that over the weeks and months following drug interruption, mutated virus can no longer be detected by resistance testing. As seen here, the rate at which this occurs differs between patients and probably depends on many factors. Although the authors show that mutations also were lost from PBMCs in some patients, this is by no means convincing evidence that the patient has truly "lost" all mutant viruses. Considering the many cell populations and tissues in which mutant virus can "hide out," much more comprehensive work would be required. Also the rapid loss of CD4 cells seen in other STI studies is once again confirmed.

Since the study not only lacks any control arm, but reports results of so very few patients and is of relatively short follow-up for an STI trial, we cannot make any conclusions regarding the benefit of this strategy. The authors also fail to provide insight regarding the baseline susceptibility of these patients to the specific regimen, such as a genotypic susceptibility score (GSS) for each patient and how that correlated with response.

We have a relatively good understanding of the resistance patterns that predict response to the four drugs in this regimen -- AZT, 3TC (lamivudine, Epivir), abacavir and efavirenz. Performing resistance testing on a drug experienced population such as the one that was studied and choosing drugs based on the results and other clinical considerations (drug history, patient preferences, dosing schedules, adverse events, etc.) has been shown to be beneficial and is becoming the standard of care. To date, this study and others have not shown convincing evidence that an STI will improve our long-term results while it may in fact jeopardize the patient if CD4 loss is severe. Additional studies continue to investigate the clinical utility of STIs.

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