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HIV Mutations Can both Reduce and Enhance Virological Response to Boosted Darunavir (Prezista)

Development of viral resistance to anti-HIV drugs is a potential barrier to long-term treatment success. In the current study, published ahead of print in the January 15, 2009 online edition of the Journal of Antimicrobial Chemotherapy, French researchers sought to identify a pattern of HIV protease gene mutations associated with virological response to regimens containing ritonavir-boosted darunavir (Prezista).

The investigators analyzed 153 treatment-experienced patients starting a new salvage regimen that included darunavir/ritonavir as the sole protease inhibitor (PI). At baseline, median HIV RNA level was 4.7 log10 copies/mL and the median CD4 cell count was 142 cells/mm3.

Virological response was defined as an HIV RNA load < 200 copies/mL at month 3. The impact of individual protease gene mutations on virological response to darunavir/ritonavir was evaluated, and the combination of mutations most strongly associated with response was identified.

Results

• At month 3, 55% of patients had a virological response and the median decrease in viral load from baseline was 1.7 log10 copies/mL.
• All patients had detectable plasma darunavir concentrations at month 3.
• Cochran-Armitage procedure identified 8 mutations with a negative impact on virological response, namely K14R, K20I, E34Q, I47V, I54M, K55R, T74P, and I84V.
• 2 mutations (E35D and V82A), by contrast, had a positive impact on virological response.
• In multivariate analyses, genotypic resistance scores were highly predictive of virological response at month 3.
• Other predictors were baseline plasma viral load and use of enfuvirtide (Fuzeon) in enfuvirtide-naive patients.

The study authors wrote, "Among the eight mutations with a negative impact on the virological response, I47V, I54M, T74P and I84V were previously described as darunavir resistance-associated mutations." The others were newly identified.

They also observed that some PI resistance mutations had a positive impact on virological response, indicating that they rendered HIV more susceptible to darunavir/ritonavir.

In conclusion, the researchers stated, "These findings might help to explain the potency of darunavir/ritonavir on PI-resistant HIV."

AP-HP, Groupe hospitalier Bichat-Claude Bernard and Université Denis Diderot-Paris 7, Laboratoire de Virologie, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpêtrière, Service de Virologie, Paris, France; SGS, Aster, S.A.S, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpêtrière, Service de Maladies Infectieuses et Tropicales, Paris, France; AP-HP, Groupe hospitalier Bichat-Claude Bernard and Université Denis Diderot-Paris 7, Service de Maladies Infectieuses et Tropicales, Paris, France.

1/30/09

Reference

D Descamps, S Lambert-Niclot, AG Marcelin, and others. Mutations associated with virological response to darunavir/ritonavir in HIV-1-infected protease inhibitor-experienced patients. Journal of Antimicrobial Chemotherapy. January 15, 2009 [Epub ahead of print]. (Abstract).