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1st International Workshop on HIV Drug Resistance & Treatment Strategies25-28 June 1997, St. Petersburg, Florida, USA |
ACQUISITION OF GENOTYPIC MUTATIONS ASSOCIATED WITH REDUCED SUSCEPTIBILITY TO PROTEASE INHIBITORS DURING SAQUINAVIR MONOTHERAPY
Antiviral Therapy 1997;2 (Suppl 5):19 (abstract no. 30)
P Scott Eastman1, Ian B Duncan2, Chris Gee1 and Esther Race2
1Chiron Corporation, Emeryville, USA; and 2Roche Discovery Welwyn, Welwyn Garden City, UK
OBJECTIVE: To identify genotypic changes in the HIV-1 protease associated with changes in viral load during saquinavir monotherapy.
METHODOLOGY: Changes in the amounts of genotypic resistance mutant populations in plasma virus RNA were monitored by RT-PCR followed by differential hybridization. CD4+ cell counts were determined by flow cytometry and viral loads were determined by RT-PCR.
RESULTS: Seven subjects from the saquinavir monotherapy arm of the phase III clinical trial NV14256 (600mg three times daily) who experienced significant decreases in plasma virus RNA levels and subsequent rebounds in viral load were selected for further analysis. The mean decrease in plasma virus RNA levels was 2.00 log10 (range 1.27 to 3.54) and the mean CD4+ cell increase was 74 cells/mm3 (range -2 to 226). Rebounds in viral load were associated temporally and quantitatively with the development of an L90M mutation alone in four subjects. Two subjects developed a G48V as the primary mutation associated with the rebound in viral load, and one subject experienced viral load rebound with a G48V/L90M double mutant. All three subjects with the G48V mutation developed subsequent additional mutations including a V82A mutation. Two of these subjects acquired an L90M mutation which was subsequently lost in the presence of the V82A mutation. One subject gained an I54V mutation prior to the acquisition of a V82A and I84V, but then lost the I54V mutation.
CONCLUSIONS: Loss of in vivo suppression of viral replication during saquinavir monotherapy is associated primarily with the development of an L90M mutation. A V82A mutation was observed only in the presence of a G48V mutation. The L90M mutation was lost in the presence of both the G48V and the V82A mutation. These results indicate the potential for switching from saquinavir to other protease inhibitors following viral load rebounds in the presence of an L90M mutation and the absence of a G48V mutation. The phenotypic and therapeutic consequences of V82A in the context of G48V remain to be established. Additionally, these results suggest a potential added benefit to saquinavir/ritonavir combination therapy beyond inhibition of cytochrome P450 metabolism of protease inhibitors.
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1997-06-25
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