icon-folder.gif   Conference Reports for NATAP  
  12th Conference on Retroviruses and Opportunistic Infections (CROI)
Feb 22-25, 2005
Boston, MA
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  Report by Jules Levin
At CROI today Johnathan Schapiro reported in an oral presentation the impact of baseline genotypic resistance on the response to tipranavir (TPV/r) in treatment-experienced patients in the phase III RESIST-1 & RESIST -2 trials.
--For the combined RESIST studies at week 24, 41% TPV/r patients achieved a treatment response (1 log or more viral load reduction) compared with 18.9% of patients receiving comparator PI boosted (CPI/r) regimen.
--TPV/r-based therapy was consistently superior to CPI/r for this patient population regardless of total baseline protease mutations, number of primary mutations, and number of UPAMs
--TPV/r provides effective therapy in triple-class, 2 PI-experienced patients
To enter these studies patients must've had at least 2 PI regimens, and 1 or more primary PI mutations at codons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M, and 2 or less of these mutations—33, 82, 84, or 90. However, the results of this analysis show these 4 latter mutations are not as relevant to tipranavir resistance as previously thought.
Treatment response is defined as confirmed 1 log or more reduction in viral load from baseline by week 24 without viral rebound, treatment change, or study discontinuation.
Patients in this study received resistance testing & then selected their optimized background regimen (OBR). Then they were randomized to TPV/r or CPI/r (comparator PI regimen: LPV/r, IDV/r, or APV/r). Failures in CPI arm after week 8 could receive TPV in rollover study.
In the 2 RESIST studies 582 patients received TPV/r & 577 received CPI/r. 87% were men. The median baseline HIV RNA was 67,000 copies/ml (4.83 log copies/ml). Median baseline CD4 count was low: 155 cells.
The study patients were very treatment-experienced with extensive PI resistance. Patients had an average of 12 antiretroviral drugs before this study. Patients had on average 3 protease inhibitors and ritonavir for boosting prior to this study. 45% of patients had 5 or more PIs before this study; 25% had 4 PIs before the study, 18% had 3 PIs before this study. Study patients had an average of 6 NRTIs before this study, and 12% had previous T-20 treatment.
60% of study patients had 3-4 primary PI mutations; 37% had 1-2 primary PI mutations; o.5% had 0 primary mutations. 50% of patients had at least 16 PI mutations. 20% of patients had 12 or less PI mutations.
Median resistance (fold-change) to
TPV/r: 1.7
LPV/r: 87.4
IDV: 41.0
SQV: 20.1
APV: 12.2
NFV: 40.7
RTV: 194.7
ATZ: 55.3
Patients had 12-fold resistance or greater to every PI except to TPV before starting the study.
Proportion With Treatment Response (>=1 log Viral load Reduction)

TPV/r: 41.2% had treatment Response vs
CPI/r: 18.9% had Treatment Response
TREATMENT RESPONSE at week 24 According to Baseline Protease Mutations
Change in Viral Load at Week 24 According to Baseline Protease Mutations
Treatment response at week 24 According to Number of Baseline Primary Mutations
Change in Viral Load at Week 24 According to Number of Baseline Primary Mutations
Treatment response at week 24 According to Number of Baseline UPAMs (mutations at codons 33, 82, 84, & 90)
These data show that UPAMs did not predict resistance. Prior to this study it was thought that having 2 or more of these mutations would predict resistance to TPV/r but as you can see having 2 or 3 UPAMs did not result in worse response by TPV/r. In fact 33-40% of patients with 2-3 UPAMs had treatment response.
Change in Viral load at Week 24 According to Number of Baseline UPAMs