Indinavir/Ritonavir-based Regimens May Be Able to Overcome Resistance in Patients with Multiple Prior Protease Inhibitor Failures

Despite the success of anti-HIV therapy, a large number of patients still experience virologic failure. Although not all viruses recovered from patients who fail protease inhibitor (PI)-based regimens show decreased susceptibility to PIs , significant numbers do so, especially after the failure of multiple PI-based regimens.  

However, Norvir (ritonavir/RTV) is known to substantially increase plasma levels of other co-administered PI through inhibition of the cytochrome P450 system. Recent  studies suggest that Crixivan (indinavir/IDV) exposures achieved with co-administration of IDV 800 mg with RTV 200 mg twice daily may be high enough to suppress the replication of viruses resistant to IDV and to other PI.

In the current study, researchers at Merck Laboratories and at the University of Miami School of Medicine analyze the associations between response to IDV-RTV-based regimens, reported adherence to therapy, and baseline genotypic and phenotypic resistance among 28 individuals with prior virologic failures of multiple PI-containing regimens.

Twenty-eight patients initiating salvage regimens with IDV-RTV (800 mg and 200 mg twice daily, respectively) plus one or more reverse transcriptase inhibitor (RTI) were identified retrospectively. Genotypic and phenotypic susceptibilities to multiple antiretroviral agents were determined on viral samples collected at initiation of the salvage regimens, and adherence to therapy was determined through patient self-reporting. Response to therapy (viral RNA ≤ 400 copies/ml) was assessed at the end of and beyond 6 months of follow-up.

Results

Based on responses measured in the first 6 months of follow-up, 16 responders and 12 non-responders were identified without differences in baseline demographic factors, laboratory parameters, extent of prior antiretroviral therapy, or characteristics of the RTI components of the new IDV-RTV-based regimens.

Adequate adherence was associated with virologic responses (P = 0.005). There were trends for genotypic and phenotypic resistance to be associated with adequate adherence, and, surprisingly, phenotypic resistance to IDV was associated with virologic response rather than with therapeutic failure (P = 0.02). Beyond 6 months of follow-up (mean follow-up 69 weeks), adequate adherence was still associated with virologic response (P = 0.001), but genotypic or phenotypic resistance to IDV were not associated with therapeutic failure.

According to the authors, “These results suggest that IDV-RTV-based regimens may be able to overcome IDV resistance. This underscores the importance of drug adherence, potency, and exposure in determining virologic responses to antiretroviral therapy.”

08/27/03

Reference
RE Campo and others. Efficacy of indinavir-ritonavir-based regimens in HIV-1-infected patients with prior protease inhibitor failures. AIDS 17(13): 1933-1939. September 5, 2003.