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Kaletra + Amprenavir & Boosted Ritonavir in PI Experiened Patients
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A French research group reported at the key antiretroviral oral session at ICAAC the 26-week results from the PUZZLE-1 Study. This small study looks at giving patients with very limited treatment options an extra 100 mg of ritonavir taken twice daily in combination with Kaletra in combination with amprenavir. So patients received a total daily dose of 400 mg ritonavir instead of the usual 200 mg. The purpose of this additional dose is to see if it will lead to a more potent regimen, one that better suppresses HIV, because many patients have extensive resistance to available HIV drugs and in particular to available protease inhibitors. Kaletra is a coformulation in one capsule of 400 mg of lopinavir plus 100 mg of ritonavir. The low dose of ritonavir boosts the lopinavir levels in the blood to much higher levels and makes it a potent treatment for patients, particularly those with resistance to protease inhibitors. By adding an additional 100 mg of ritonavir it is hoped that the regimen would be more potent. Several small pilot studies combining Kaletra with amprenavir have seen varied drug interactions, but the clinical implications when using this combinatio in patients is uncertain. At the Pharmacology Workshop in the Spring of 2002, Rick Bertz from Abbott explored Kaletra and 750 mg of amprenavir in 8 healthy volunteers, and saw increased amprenavir levels (AUC and Cmin) but reduced lopinavir levels. You can read the NATAP Report from this meeting:
www.natap.org/2002/3pharm/day1.htm
This study looks at the viral load and CD4 response of 37 patients randomized to Kaletra standard dose plus amprenavir (APV) or Kaletra plus APV with an added 100 mg of ritonavir. Patients also received new nukes. Patients had no prior Kaletra or APV experience. The study patients were had extensive prior experience with HIV medications and had rather low Cd4 counts. They had previously received at least 2 protease inhibitors and 1 NNRTI. They had viral load over 10,000 copies. The CD4 count was 200 in both groups before study treatment and the viral load was also the same in both groups (50,000 copies). The two treatment groups were comparable in other baseline characteristics: number of prior antiretrovirals - 7.8; average duration of prior use of protease inhibitors - 53 months; average prior use of NNRTI - 28 months. They used an average of 7 protease inhibitors previously, and had on average 22 nuke resistance mutations. Again, a group of patients with extensive PI experience.
RESULTS
The patients (n=19) receiving the additional boost of ritonavir had a better response in viral load. At week 26 the viral load reduction was on average -2.5 log in the patients receiving the boosted ritonavir regimen vs -1.4 log in the patients without the boost (n=18). 61% of the patients receiving the boosted regimen had <50 copies/ml viral load vs 32% for the non-boosted regimen. These differences were statistically significant. Although it did not appear to be significant the CD4 increase appeared greater for patients receiving the boosted regimen.
Additionally, the difference between the two groups was evident after the first two weeks of therapy and increased. After 2 weeks the viral lad decline was -0.8 in the non-boosted regimen vs -1.3 in the boosted regimen. After 6 weeks, the boosted regimen saw a decline of -2.2 log vs -1.5 in the non-boosted regimen. At week 6 17% (n=3) receiving the boosted regimen had <50 copies vs 5% (n=1) in the non-boosted group.
SAFETY
There were 4 treatment discontinuations in each group (21%). There did not appear to be a difference in grade 4 adverse events between the 2 groups. AE related to study drug: 8/10 and 6/7. There were no deaths and AIDS defining events.
Using a multivariate analysis, the use of an additional ritonavir boost was significantly associated with successful virologic response (p=0.007). The number of protease mutations the patient had before starting study drugs was also significantly associated with a viral response (p=0.02). And baseline phenotypic resistance to APV and lopinavir were not correlated with viral response. The lopinavir inhibitory quotient (IQ) at week 6 was correlated with viral response. But the APV IQ at week 6 was not correlated with viral response at week 26.
The authors concluded this boosted regimen is potent, durable and well tolersated ( Ithink more than 26 weeks followup would be helpful). The drug-drug interactions between APV and lopinavir do not appear in this study to affect the virologic efficacy of this combination
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