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Resistance to Atazanavir
Reported by Jules Levin
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Since atazanavir is a new drug approaching FDA approval a number of basic studies were reported on at ICAAC addressing interactions with nukes and with ritonavir, the effect on liver enzymes for patients with hepatitis C and B, and the concentration of atazanavir in semen and cerobrospinal fluid. A report on these study findings will follow. Before getting to the resistance data here is a brief introduction. Atazanavir is a new once per day PI in the final phase III study stage. FDA approval is expected around June 2003. Studies presented at the recent Lipodystrophy and ICAAC conferences showed that atazanavir did not raise glucose in an initial 24 week study, and cholesterol and triglycerides did not increase or increased just a little in a 48 week study, which further confirms previous findings regarding cholesterol and triglycerides in smaller preliminary studies. Longer term followup of these findings are important. Early access to atazanavir is available for patients meeting certain criteria including patients with severe HAART associated elevated cholesterol and triglycerides despite using a lipid lowering drug (>750 mg/dL triglycerides or high cholesterol). For information physicians should call 1-877-726-7327.
As well, at ICAAC 48-week results were reported from a study comparing efavirenz to atazanavir where all patients also received AZT and 3TC. The study found the two treatment regimens to be comparable when looking at percent below 400 copies and 50 copies, but the antiviral results for efavirenz were less than had been seen in prior efavirenz studies.
There were several reasons suggested for the less than expected performance including that a viral load test used was more sensitive and might show higher viral load. Roche Amplicor version 1.0 and version 1.5 were used. The 1.0 was developed for patients in the US and Europe, most of whom are have HIV-1 subtype B. Since this test This assay is much less effective at amplifying the non-subtype B strains which are more prevalent in developing countries, version 1.5 was developed to amplify a broader diversity of virus strains. Apparently this test has become more widely used worldwide. In a substudy of the trial undertaken in hundreds of patients, use of the version 1.5 assay resulted in detection of HIV-1 RNA in 12% of patients whose viremia had been below the level of detection of the version 1.0 assay. Any switch of a drug in a regimen in this study was defined as a treatment failure. This appears to be the new FDA criteria for approval studies. In the past patients could switch from one 1 nuke to another due to intolerability without being considered a failure. Thirdly, if a patient had 2 consecutive viral load test results >50 copies they were considered a failure. So if a patient had 52 copies on 2 consecutive tests that was a failure.
Here are links to reports:
Effect of Atazanavir on Glucose After 24 Weeks
www.natap.org/2002/lipoWorkshop/day2.htm
Atazanavir vs Efavirenz: lipids and antiviral effect after 48 weeks
www.natap.org/2002/ICAAC/day5.htm
RESISTANCE
In a study reported at this Summer's Resistance Workshop, Rich Colonno from Bristol Myers Squibb looked at resistance testing (Virologic phenosense test and GeneSeq genotypic test) performed on 76 patients before and after treatment with atazanavir (ATV) who were treatment failures in 3 studies. They looked at patients who were treatment naive and PI resistant before starting ATV.
A total of 17 of 76 isolates (patient blood samples) obtained from atazanavir-treated patients showed evidence of atazanavir resistance. PI experienced patients showed different resistance patterns than treatment-naive patients.
Of 9 isolates from previously treatment-naive patients, 8 carried a I50L new mutation in protease which conferred resistance to atazanavir, and 5 of the 8 isolates had an I50L/A71V mutation. So the presence of I50L in treatment-naive patients with no other major PI mutations did not show resistance to other protease inhibitors, and increased HIV susceptibility to other PIs, including to amprenavir.
Interestingly, the presence of the I50V can lead to amprenavir resistance Amprenavir, but appears to leave virus sensitive to atazanavir and other Pis, suggesting that ATV and amprenavir may not be cross-resistant. By contrast, 8 isolates from PI-experienced patients who received combination therapy with atazanavir plus saquinavir who failed therapy did not have the I50L and all the patient isolates lost sensitivity to other protease inhibitors and to ATV.
These are preliminary results and larger followup clinical trials in treatment-naive patients will have to be conducted to confirm if patients in real life situations who fail ATV and have the I50L can be successfully treated with other protease inhibitors.
Atazanavir Resistance in Protease Inhibitor Experienced Patients
At the ICAAC meeting Rich Colonno (abstract H-2049), from Bristol Myers Squibb, reported on a study looking at resistance that develops to atazanavir after taking other protease inhibitors first. In other words, will ATV work after failing other protease inhibitors-- can a patient take ATV after failing other protease inhibitors and still have ATV suppress virus replication. For this study Colonno used a 3-fold increase in resistance as an indication of resistance to a drug, which the abstract called an arbitrary cutoff. So the data does not reflect if a patient had greater than 3-fold PI resistance.
This is a study of taking patient blood samples after failing protease inhibitors and looking to see in the test tube if the patient sample is resistant or not to ATV. This is preliminary research which should be confirmed with clinical studies in patients who have failed protease inhibitors.
Colonno looked at patients with resistance to 1, 2, 3, 5, or 5 protease inhibitors. Overall he found 88% of patients with resistance to 1 PI (amprenavir, nelfinavir, saquinavir, ritonavir) were sensitive to ATV: 2 of 2 amprenavir resistant viruses were still sensitive to ATV; 103 of 121 nelfinavir resistant viruses weresensitive to ATV; 7 of 7 saquinavir resistant viruses were sensitive to ATV.
81% of patients with resistance to 2 protease inhibitors (46/57 patients) were sensitive to ATV: 25 of 30 patients resistant (>3-fold) to nelfinavir and ritonavir were sensitive to ATV; 5 of 5 patients resistant to amprenavir and ritonavir were sensitive to ATV; 8 of 8 patients with resistance to ritonavir/saquinavir were sensitive to ATV; 2 of 5 patients resistant to nelfinavir and saquinavir were sensitive to ATV; 1 of 1 patient resistant to amprenavir & kaletra were sensitive to ATV; 1 of 3 patients resistant to nelfinavir and indinavir were sensitive to ATV; 2 of 3 patients resistant to indinavir and ritonavir were sensitive to ATV.
34% (34/99) of patients resistant to 3 protease inhibitors were sensitive to ATV. But, 5 of 5 patients resistant to APV, NFV, and RTV were still sensitive to ATV. Only 1 of 9 patients still were sensitive to ATV if they had resistance to APV, RTV, & SQV or Kaletra, NEV, and SQV.
16% (15/96) of patients with resistance to 4 protease inhibitors were still sensitive to ATV. And 5% (7/142) of patients with resistance to 5 protease inhibitors (APV, NFV, Kaletra, RTV, SQV or APV, IDV, NFV, RTV, SQV) were sensitive to ATV.
In sum, using a 3 fold cutoff for resistance to protease inhibitors, Bristol Myers Squibb reported that over 80% of patients were still sensitive to ATV. But these results may not apply if patients remain on failing PI therapy and develop greater than 3-fold PI resistance.
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