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Tipranavir Virally Effective in Patients with Extensive PI Resistance
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Reported by Jules Levin
"Impact of 3 or 4 Protease Mutations at Codons 33, 82, 84, and 90 on Two week Virologic Responses to Tipranavir, Lopinavir (Kaletra), Amprenavir, and Saquinavir, All Boosted by Ritonavir in Phase IIB Trial BI 1182.51"
Doug Mayers (Boehringer Ingelheim) reported preliminary results from this study at the XIII International HIV Drug Resistance Workshop (June 8-12, 2004, Tenerife, Canary Islands, Spain). I think two important highlights from this Workshop are the Tipranavir data presented in the study, as this ought to be an important drug for patients with extensive resistance to protease inhibitors, and secondly there were a lot of studies related to Tenofovir resistance in posters. This will be the subject of soon forthcoming NATAP reports.
Multiple protease mutations at codons 33, 82, 84, and 90 have been associated with significant resistance to amprenavir, indinavir, lopinavir, ritonavir, and saquinavir. These are generally considered major protease inhibitor mutations. Treatment experienced patients with 3 or more protease mutations at codons 33, 82, 84 and 90 entered a randomized trial of dual boosated protease inhibitor (PI) regimens including tipranavir/ritonavit (TPV/r) to assess pharmacokinetics and safety.
BRIEF SUMMARY: On average patients with 3 or 4 of the key PI mutations listed above had greater viral load reduction with tipranavir/r than the other boosted PI regimens (-1.2 log vs <0.5 log) after 2 weeks of study drugs. Half of patients taking TPV/r had a >1 log viral load reduction in the presence of 3 or 4 of these mutations. Antiviral response to TPV/r decreased 4 weeks later on treatment; the study authors felt this was due to lack of effective background drugs. Large scale Phase III studies for TPV/r are ongoing and we need to wait for the results but the data from this study appeared impressive and suggests that tipranavir/r will be effective in patients with extensive PI resistance when other boosted PI regimens may not be very effective. Phase III study data should be available in the Fall 2004, and the Tipranavir Expanded Access Program is also expected to begin in the Fall of 2004. Some patients in the study added T-20 as a new drug, but the data on their responses were not presented. A key to success with TPV/r will be combining it with additional active drugs. The responses to patients T-20 for the first time along with TPV/r will be important to see.
During the first two weeks of the study, 284 patients received twice daily doses of either:
--TPV/r 500 mg/100 mg (63 patients)
--LPV/r (Kaletra) 400mg/100mg (79 patients)
--APV/r 600mg/100mg (74 pts), or
--saquinavir /r 1000mg/100mg (75 pts)
along with an optimized background regimen. After two weeks, TPV/r 500mg/100mg was added to the non-TPV-containing regimens. Genotypic resistance was determined by population sequencing. So, after 14 days in study all patients received 500mg TPV/200mg RTV plus the other PI.
14% of the patients in this study received T-20 as a new drug. The response for these patients was not reported at this conference and are expected to be reported at the Retrovirus Conference in 2005. After Doug Mayers reported these study results, a researcher asked from the microphone whether these patients did better and Mayers suggested it appears they did have better responses based on a preliminary peak at the data.
At baseline patients with 3 key PI mutations were phenotypically sensitive to TPV (2.2 median fold change in IC50, while patients with 3 mutations were 17 to 100 fold phenotypically resistant to the other protease inhibitors.
BASELINE PHENOTYPIC SUSCEPTIBILITY -Virco Antivirogram
| N | Fold WT IC50 | Q25-Q75 | | Amprenavir | 71 | 41.0 | 21.5-63.3 | | Atazanavir | 71 | 99.9 | 62.3-115.0 | | Indinavir | 69 | 56.6 | 26.4-73.1 | | Lopinavir | 71 | 101.3 | 100.3-106.4 | | Nelfinavir | 71 | 41.7 | 41.3-51.3 | | Ritonavir | 71 | 361.0 | 272-382 | | Saquinavir | 71 | 46.2 | 22.8-50.1 | | Tipranavir | 70 | 4.7 | 2.3-12.8 |
93% of study patients were men. Average age was 44 yrs. Median CD4 count was 140 cells. Baseline viral load was on average 5.0 log (100,000 copies/ml). Prior antiviral use: NRTI (median) 6; NNRTI (median) 2; PI (median (6); T-20 19%.
HIV RNA MEDIAN CHANGE IN HIV VIRAL FROM BASELINE TO 2 WEEKS
After two weeks of treatment:
TPV (n=64): -1.15 log
LPV (n=71): -0.38 log
SQV (n=71): -0.29 log
APv (n=71): -0.21 log
IMPACT OF KEY MUTATIONS ON VIRAL LOAD RESPONSE
Percent with 1 log reduction at 2weeks
| Mutation | TPV/r | APV/r | SQV/r | LPV/r | | 33 | 52% | 26% | 22% | 32% | | 82 | 53% | 21% | 28% | 31% | | 84 | 58% | 26% | 14% | 31% | | 90 | 55% | 24% | 21% | 31% |
VIRAL LOAD RESPONSE BY KEY MUTATIONS
Percent with 1 log reduction at 2 weeks
| TPV/r | APV/r | SQV/r | LPV/r | | 3 mutations | 56% | 25% | 23% | 34% | | 33^& 82^& 84 | 1/3 | 1/4 | 2/8 | 3/5 | | 33^& 82^& 90 | 52% 20% | 31% | 32% | | 33^& 84^& 90 | 56% | 37% | 6% | 41% | | 82^& 84^& 90 | 80% | 13% | 0 | 13% | | 4 mutations | 6/12 | 1/8 | 2/10 | 3/14 |
Interestingly, patients with 9 PI mutations (IAS USA mutations) had --1.5 log viral load reduction to tipranavir (n=16) at 2 weeks; almost a 1 log reduction to Kaletra (n=18); no viral load reduction to amprenavir (n=11); -0.2 log reduction to saquinavir(n=12). When patients had 10 --12 mutations viral load reduction to Kaletra was --0.5 log; -0.2 to --0.5 to amprenavir; 0 to --0.2 to saquinavir. There appeared to be a better response to tipranavir when patients had 10-12 mutations; when patients had 10 mutations tipranavir resulted in --1.0 log viral load reduction, with 11 mutations reduction was --0.5 log, and with 12 mutations reduction was --1.0 log. When averaging the responses to all protease inhibitors except TPV and comparing response to TPV, viral load reduction was --0.2 log to protease inhibitors when 10,11, or 12 mutations were present; viral responseto TPV was --1.5 to 9 mutations, -1.0 to 10 mutations, and --0.5 log to 11 mutations.
MEDIAN 2 WEEK HIV RNA RESPONSE FOR DIFFERENT AMINO ACIDS AT PROTEASE CODON 82
For 82V and 82A, TPV/r had better viral responses than other PI regimens in this study (-1 to 1.4 log vs <-0.7 log). To mutation 82T responses to all PI regimens were similar (-0.7 to --0.4). For 82 CFILS, Kaletra had best response (-1.3 log), TPV --0.7 log), APV --0.3 log, SQV no response.
AUTHOR'S CONCLUSIONS
Patients whose virus had 3 or 4 mutations at codons 33, 82, 84 and 90 had a --1.2 log antiviral response at 2 weeks on TPV/r.
Significantly lower antiviral responses (<0.5 log) were seen with LPV/r, SQV/r, and APV/r at 2 weeks.
Addition of TPV/r to the other PI/r regimens led to >1 log antiviral response in all treatment regimens. Antiviral responses decreased at 8 weeks in all arms potentially due to lack of background drugs to support TPV/r or dual-boosted PI regimens.
24 week safety and efficacy of these regimens is currently being analyzed.
Resistance
Combinations of 3 or 4 protease mutations at codons 33, 82, 84, and 90 are associated with significant reductions in phenotypic susceptibility and reduced antiviral responses for ritonavir-boosted SQV, LPV, and APV.
Different combinations of 3 of these mutations resulted in loss of antiviral activity for each boosted PI:
--33, 82, 90 SQV
--82, 84, 90 APV, LPV
Combinations of 3 or 4 protease mutations at codons 33, 82, 84, and 90 are associated with modest reductions in phenotypic susceptibility and transient 1 log antiviral responses to TPV/r.
TPV/r responses are reduced when mutations at codons 33, 82, and 84 are present: this 3 codon combination had similar antiviral to the patients whose virus had all 4 mutations present.
The L90M mutation does not affect TPV susceptibility or antiviral responses but is necessary to predict reduced responses to the other boosted protease inhibitors.
Half of the patients had a >1 log response to TPV/r in the presence of 3 or 4 of these mutations.
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