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Brief Summary Highlights From the 11th Resistance Workshop
Reported by Jules Levin
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The conference ended today at 5pm July 5 at the just ok Hotel Alcora in Seville. Tonite is the final awards dinner in town in Seville at 8pm. Until then I'm filing this brief summary report to you and hopefully I'll have some time to catch a swim in the pool to refresh. It's hot & sunny here until it gets dark and even after dark it can be hot here. More detailed summary reports will follow by NATAP writers Andrew Zolopa, MD, from Stanford University and David Margolis, MD, from the University of Texas Southwestern Medical Center in Dallas. You've already received two NATAP reports from this meeting from me. And tomorrow I'm off to Barcelona for the Intl AIDS Conference which has some interesting information being presented.
The first report discussed the presentations here on promising new drugs in new classes of HIV drugs: entry inhibitor programs and integrase inhibitor programs. At this meeting there were a bunch of presentations about T-20 showing the work that has been done in identifying T-20 resistance mutations and in finding that T-1249, which may be dosed once or twice a day, is effective against T-20 resistance. At the highest dose used in a preliminary study T-1249 reduced HIV viral load by about 2 log. So, patients who fail T20 look like they will be sensitive to T-1249. But T-20 is about to be approved probably by the end of first QTR 2003 and T1249 is in earlier development stage, as 14 day monotherapy study was reported here. I think many people attending this meeting were impressed and excited with the new drug developments including the 2 new classes, entry & integrase.
Tipranavir, new protease inhibitor against PI resistance
Also reported here was promising new information on tipranavir, a new protease inhibitor expected to enter phase III large studies in 2000 patients in about the Fall of 2002. In a preliminary open-label phase II study presented here 41 patients with extensive PI experience & resistance received tipranavir plus efavirenz one new nuke. These patients were NNRTI naive. The average viral load reduction after 48 weeks of therapy was 1.67 to 2.56 log. Even patients who had 16-20 PI resistance mutations experienced a 1.77 log viral load reduction. The study author, Doug Mayers, said that although 16-20 mutations showed reduced response the patients still showed a nice response after 48 weeks. Over the course of the study 35/41 patients had virus blood samples (viral isolates) that remained fully sensitive to TPV; this was despite an average of 11 PI resistance mutations in 33 patients. Mayers reported the isolates from the 6 remaining patients that developed reduced sensitivity to TPV had an average of 19 PI mutations. While signature TPV mutations have yet to be identified V82T and L33I/F/V emerged frequently in isolates from patients with multi-PI resistant virus that developed reduced sensitivity to TPV. Mayers said L90M and 84V may also be relevant PI mutations. It appears as though TPV had a significant effect in reducing HIV viral load despite the use of efavirenz. If TPV did not have a significant effect patients would have likely developed EFV resistance soon and their viral load rebounded. But, the large phase III studies will look at TPV without EFV in patients with extensive PI resistance and we will see those results.
A high and low dose of tipranavir boosted by ritonavir was used in this study, but a dose has not yet been identified. Two potential doses appear to be under investigation (750 mg or 500 mg TPV plus 200 mg RTV) to be selected for the upcoming large studies. Tipranavir will be studied in these phase III studies in patients with PI resistance and in patients with extensive PI resistance, so-called deep salvage.
A number of studies reported today that the incidence of transmission of drug resistance appears to be leveling off rather than increasing. There still is transmission of drug resistance but a few years ago there was concern about increasing rates. Although several studies from various parts of the world reported here that rates do not appear to be increasing, researchers here struggled with trying to understand this. It was suggested that this apparent trend could be misleading. There may be many reasons why this may appear to be occuring but may not be accurate. This apparent trend could also be real but may be due to the way the data is being collected and the changes in the patient population being studied. One suggestion for this apparent trend could be because chronically infected patients receiving treatment are in general succeeding better with therapy, more patients are achieving and maintaining low or undetectable viral loads. So, when HIV is transmitted perhaps there is no drug resistance. Also reported here was a decrease in drug resistance in chronically infected patients, which might be due in part to the same reason.
Tenofovir: 70% of patients with nuke resistance reduced viral load by 0.77 log in this study
Michael Miller from Gilead Sciences reported today on the phenotypic cutoffs for this drug. This is important because these cutoffs will help the physician and patient to judge whether a patient will be responsive to Tenofovir and what kind of response can be expected. This drug is effective for patients with extensive NRTI experience and resistance. Studies show that most patients with extensive prior NRTI experience can respond well to this drug. Miller used patients from study 907 to identify these cutoffs. The purpose of this clinincal cutoff study is to determine the tenofovir phenotypic susceptibility value at which patients will show a reduced response to tenofovir. The other purpose is to identify a value at which patients are likely to see no benefit from tenofovir. Fortunately, the results here show most patients are capable of achieving some benefit from the drug, 70% of patients in this study reduced their viral load by 0.77 log. Overall in the study, the viral load reduction for all the patients was 0.63 log. In this study 112 patients were looked at by obtain a phenotypic resistance test before starting tenofovir therapy in the study. Miller reported that a 1.4-fold tenofovir susceptibility cutoff corresponds to the beginning of reduced response to tenofovir, but only 23% of patients in the study had between 1.4 and 4.0 reduced susceptibility.
--70% of patients (n=78) had 1.4 or less reduced sensitivity to tenofovir as measured by the Virologic Phenosense HIV Assay (resistance test). The average viral load reduction for these patients was -0.77 log and 79% (n=62) of these patients had 0.3 log or greater viral load reduction.
--23% of patients (n=28) had 1.4 to 4.0 baseline reduced tenofovir sensitivity. Their average viral load reduction was 0.37 log. And 58% of these patients (n=15) had a viral load reduction of at least 0.3 log.
--Only 7% of patients (n=8) had phenotypic resistance to tenofovir of 4.0-fold reduced susceptibility, the level at which no benefit is expected. However 2 of these 8 patients did reduce their viral load by 0.3 log or more.
--These cutoffs were generally well accepted by the researchers in the audience. And it appears they are not completely black and white. That is a 1.3 or 1.5 fold reduced susceptibility still should yield benefit to a patient. And perhaps a 4.0 to 4.7 fold reduced suseceptibility may yield some benefit.
T-1249, entry inhibitor cousin of T-20 from Trimeris/Roche
115 patients received at least one dose of T-1249 monotherapy in a study reported at this meeting. Average viral load was over 100,000 copies/ml of HIV. Average Cd4 count was 125. 114 patients had prior treatment experience with an average of 10 drugs used. Patients received various doses of T-1249 either once of twice daily. At the highest doses used, either 150 mg or 200 mg once per day, the viral load reduction was 1.96 log after 14 days. The authors reported that T-1249 was well tolerated. There were 3 treatment related serious adverse events. 57% of patients experienced injection site reactions. There were no discontinuations due to the injection site reactions. The 3 serious adverse reactions were neutropenia, allergic reaction, fever associated with injection site reaction.
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