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Resistance part II (ddI and tipranavir resistance news)
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12th CROI- Resistance Report #2
Written for NATAP by Nancy Shulman, Stanford University
Defining DDI phenotypic resistance in the Jaguar study
Clinical cutoffs, both genotypic and phenotypic are essential to interpreting HIV resistance tests. Cutoffs for clinical response have not been determined for many of the older drugs like DDI. Interpreting DDI phenotypic resistance is particularly tricky as the dynamic range of resistance is very narrow. Fold change (FC) in IC50 over wild type are rarely greater than 3 and are usually less than 2.
Researchers at ViroLogic used data from the Jaguar study which randomized patients with detectable viral load on combination therapy excluding DDI to receive DDI EC (n=110) or placebo (n=58). The primary outcomes of the parent study were magnitude of viral load change from baseline to week 4 and the proportion who achieved > 0.5 log reduction or <50 HIV RNA. DDI was superior to placebo in the parent study reported at last year's conference. For this analysis, phenotype in the DDI group was obtained retrospectively on baseline plasma samples. Regression methods were used to determine at what DDI FC, the drug lost activity. They found that using a lower cutoff of 1.3 and an upper cutoff of 2.2 was predictive of viral load change and obtaining >0.5 logs/or <50 copies.
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These new data will be incorporated into the interpretation of their assay which had previously set a single cutoff for DDI at 1.7.
Bates M, et al. Prediction of early HIV-1 RNA reduction in the Jaguar Study using phenotypic susceptibility to didanosine. Abstract 105
News in PI Resistance
Baseline genotype and response to Tipranavir/ritonavir (TPV/r) in RESIST I and II phase 3 trials
Tipranavir (TPV) is a new PI that has activity against HIV isolates resistant to most other PIs that is currently available through Expanded Access and is awaiting FDA approval. Resist I and II were identical phase III trials in treatment experienced trials in the US and Europe. The 24 week data was presented at the 44th which showed that at 24 weeks, 41.2% achieved at least a 1 log reduction from baseline in the TPV/r arm vs. 18.9% comparator boosted PI (CPI), p<0.0001. Jonathan Schapiro and David Cooper gave separate presentations on 24 week combined RESIST analysis that futher analyzed the 24 week results by baseline genotype and predicted drug activity.
Design of Resist I and II: Ongoing international, multicenter, randomized open-label studies.
Major Inclusion:
- HIV+, 18+ years of age
- 3+ consecutive months of therapy with all 3-classes of drugs (NRTI, NNRTI, PIs, Prior enfuvirtide use was okay.
- Been on 2 PI regimens for at least 3 months, including current regimen
- HIV RNA of 1000+
- Have at least one "primary" PI mutation at positions 30, 46, 48, 50, 82, or 84
- Not more than two of the following: 33, 82, 84, or 90 (PRAMs-protease inhibitor-associated mutations, formerly known as "UPAMs"-universal protease inhibitor-associated mutations)
Exclusion:
- Drug holidays >7 days in the last 3 months
- Abnormal screening labs of grade 1 or higher (including ALT)
- Other study drugs, immunosuppressant drugs
Patients were genotyped and optimized background regimen (OBR) was chosen with the help of expert advice including the comparator boosted PI (CPI) to be used if patients were randomized to that arm. CPI options included lopinavir, indinavir, saquinavir, and amprenavir, all boosted with ritonavir. 1483 patients were randomized 1:1 to receive TPV 500mg/RTV 200mg BID vs. CPI plus OBR including enfuvirtide if desired. Primary endpoint was proportion who achieved at least 1 log reduction of HIV RNA from baseline. Failures in the CPI arm could receive TPV/r after week 8.
Genotypic/24 week response data was presented on 1159 patients.
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Overall, a nearly identically matched group except slightly higher T-20 use in the TPV/r group.
In the subgroup that had lopinavir as the selected CPI (n=293 in TPV, n=290 in CPI), response rates at 24 weeks were as follows:
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The TPV/r group did significantly better in the group that was lopinavir resistant by genotype and in the group that was lopinavir experienced.
Impact of enfuvirtide use on 24 week response (>1 log reduction):
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TPV/r response rates were double that of the CPI/r arm with and without enfuvirtide, but enfurvirtide greatly improved rates of responses of both, particularly in the group of first time users.
Number of predicted "active" drugs in the optimized background regimen and associated 24 week response (>1 log reduction):
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Tipranavir did better than the CPI/r in most patients even with lower baseline resistance. Safety/tolerability data was not presented at this meeting. They did not include anyone with even slightly abnormal labs which would exclude many HCV/HBV coinfected patients and other sicker patients.
$44
Schapiro JM, et al. Effect of baseline genotype on response to tipranavir/ritonavir compared with standard of care comparator in treatment-experienced patients: the phase 3 RESIST-1 and -2 trials. Abstract 104.
Cooper D, et al. 24 week RESIST study analyses: the efficacy of tipranavir/ritonavir (TPV/r) is superior to lopinavir/ritonavir (LPV/r), and the TPV/r treatment response is enhanced by the inclusion of genotypically antiretrovirals in the optimized background regimen. Abstract 560.
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