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1st International Workshop on HIV Drug Resistance & Treatment Strategies25-28 June 1997, St. Petersburg, Florida, USA |
A STUDY OF REDUCED SENSITIVITY TO INHIBITORS OF HIV PROTEASE IN VIRUS ISOLATES FROM SELECTED PATIENTS AFTER THERAPY WITH SAQUINAVIR
Antiviral Therapy 1997;2 (Suppl 5):17 (abstract no. 27)
C Craig, E Race, J Sheldon, L Whittaker, J Rose, S Gilbert, IB Duncan and N Cammack
Roche Discovery Welwyn, Welwyn Garden City AL7 3AY, UK
HIV isolates from 27 patients, with high initial viral loads, treated with saquinavir monotherapy or in combination with reverse transcriptase (RT) inhibitor for 42 weeks (median) were selected in order to study the effect of the key resistance mutations (G48V and L90M) on sensitivity to protease inhibitor (PI). Virus sensitivity to several PI (including saquinavir, indinavir, ritonavir, nelfinavir and 141W94) was measured. Virus genotype was also determined.
Six patient groups could be identified. Group 1: wild-type virus from seven patients did not show significant (>fourfold) reduction of sensitivity to any of the PIs. Only one patient did not show a virological response (>10-fold drop in HIV RNA plasma levels). Group 2: isolates with 90M from four patients also showed no change in sensitivity to any of the PI relative to baseline values. Group 3: four virus isolates with 90M and one with a double mutation (48V, 90M) (five patients) showed resistance to saquinavir only. Group 4: isolates from two patients (one with wild-type virus and one with 90M) did not show resistance to saquinavir but did display significant resistance to 141W94 or ritonavir, respectively. Group 5: isolates from four patients showed limited cross-resistance to some but not all PIs. Three of these isolates were found to carry the 48V/ 90M double mutation. In addition, one virus isolate with double mutation showed 97-fold reduction of sensitivity to saquinavir. This virus retained sensitivity to 141W94 and showed a relatively modest reduction in sensitivity to the other PI. The patient retained a virological response to saquinavir/zalcitabine for some months. Group 6: Three patients showed a modest reduction of sensitivity to all PI tested. These isolates showed a tendency for greater deviation of the proteinase gene from a standard sequence.
Of isolates from six patients studied at two time points post-therapy, two retained sensitivity to all PI, one remained in group 5 with sensitivity to at least one PI, two changed genotype to 48V or 90M and showed broad cross-resistance. One reversion was found from group 6 at 24 weeks to group 1 at 60 weeks. These findings suggest that selection of cross-resistance during therapy with saquinavir is not inevitable, and is relatively infrequent. Our results combined with ‘incidence of reduced sensitivity’ data from NV14256 suggest >85% of patients retain sensitivity to all PIs, and approximately 95% retain activity to at least one PI after 1 year of saquinavir/zalcitabine therapy. The use of current standards of treatment with two nucleoside analogues and saquinavir might be expected to reduce this further.
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1997-06-25
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