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NRTI Sparing Regimens
Reported by Jules Levin
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At ICCAC two nuke-sparing studies were reported.
Nuke Sparing in Treatment-Naïve Patients
In this study mostly, treatment-naïve patients were able to achieve significant viral load reduction at week 24 of the 48-week study using Kaletra and efavirenz. Although patients experienced the expected drug-related side effects for efavirenz (CNS side effects) and for Kaletra (digestive side effects), the regimen was potent in reducing viral load at week 24 by 2.75 log on average with 90% <400 copies/ml.
French researchers (abstract H-169) reported preliminary results from a 48 week study of individuals who received Kaletra plus efavirenz without nukes. Patients were either antiretroviral naïve or experienced, NNRTI naïve, and no more than one failure with a PI-containing regimen and less than 5 major protease inhibitor mutations. This is an open-label controlled study at 16 centers where 73 patients receive lopinavir/ritonavir (533mg/133mg) twice daily, also called Kaletra, plus efavirenz 600 mg once daily. 74% of patients were treatment-naïve and 19% were treatment-experienced (n=19). Of these 19 experienced patients 10 were PI-naïve and 9 PI-experienced, only 2 of these 9 patients had 2 or 3 PI mutations; 7 patients had 1 or no mutations. Average CD4 count was 323 and viral load was 52,000 copies. 40% of patients had >100,000 copies/ml viral load.
12 patients discontinued the study including: CNS side effects (2), grade 4 dyslipidemia-serious event, skin rash (3), serious in 2/3, poor adherence (2), virologic failure at week 24 (1).
Grade 3/4 nervous system adverse events: 16% related to efavirenz related nervous system; Kaletra-related digestive system: 12%, but no one discontinued due to digestive system problems; 5.5% skin rash. Grade 2 or greater: 44% nervous system; 45% digestive system.
After 24 weeks the average CD4 count increased by 160, and HIV viral load was reduced by 2.75 log on average (n=35). By on-treatment analysis 90% had <400 copies/ml viral load. Of the 4 virologic failures only 1 was a confirmed virologic failure.The study authors said the tolerability was acceptable; lipid levels increased until week 8. Then triglycerides slowly decreased from week 8 to week 24, and total cholesterol remained unchanged after week 8, although it increased in first 8 weeks.
Kaletra + Saquinavir Without Nukes In Treatment-Experienced Patients With No Nuke Options
Results from this study showed that after 24 weeks patients with extensive treatment-experience, and with no nuke options, achieved good viral reduction using only 2 protease inhibitors Kaletra and 1000mg saquinavir boosted by 100mg ritonavir.
Schlomo Staszewski reported an update at ICAAC on his study where patients with very limited or no nuke options and extensive treatment experience received a nuke-sparing regimen of Kaletra and saquinavir. The authors reported finding a growing number of patients who have lost their nuke options in their Frankfurt clinic due to resistance or toxicity, but may still have PI options.
64 patients who experienced failure of their current regimen due to resistance or toxicity and had limited nuke options were switched to saquinavir 1000mg twice daily plus Kaletra 400mg/100mg twice daily without nukes. 42 of the 64 patients were reported on who reached at least 24 weeks on therapy or have discontinued. 27/42 patients had a therapy interruption before starting Kaletra. To exclude unfavorable drug interactions, PK testing was performed after a minimum of 14 days on this therapy. Non-response in this study is defined as failing to decrease viral load by at least 1 log by week 24, or a sustained viral load rebound above 5000 copies.
The average CD4 count at the end of the failing regimen was 156 and 3000 copies. Average CD4 count at the start of Kaletra/SQV was 131 and 165,000. 62% switched to PI regimen for resistance & 38% for toxicity. The patients were heavily pre-treated: 78 months average ART treatment; 9 previous regimens; had taken 3 protease inhibitors; 26% had prior Kaletra experience; 21% prior amprenavir experience; 48% prior SQV experience; 79% prior indinavir experience; 9% of patients were PI-naïve; 64% had an STI before starting Kaletra/SQV.
PK
AUCss of SQV 1000mg bid with either LPV 100mg/RTV 100 mg bid or RTV 100mg bid were compared. In summary the authors said that in the boosted double PI regimen of LPV/r/SQV, ritonavir plasma levels were lower than in the RTV/SQV regimen, but low RTV plasma levels were effective in boosting both LPV and SQV. Comparison between LPV/r/SQV and RTV/SQV did not show disadvantageous PK interaction on SQV indicating that both protease inhibitors, LPV and SQV, may be combined without dose adjustments.
At the third Pharmacology Workshop April 11, 2002 preliminary interaction and pk data were presented on combining saquinavir 1000mg with ritonavir 100mg, where Rockstroh found in small study (abstract 7.14) that saquinavir Cmin was comparable but saquinavir AUC and Cmax were lower in this combination. Lopinavir Cmax, Cmin, and AUC were found to be comparable with product information:
www.natap.org/2002/3pharm/ndxPharm.htm
RESULTS
Average time on study therapy was 38 weeks. 81% (33/42) were still on therapy. There 9/42 discontinuations (21%). 5 discontinued for virologic failure. 3 for non-virologic reasons; 1 for virologic failure and toxicicity.Through week 24 CD4s were on average about 270, and viral load was below 100 copies.
PREDICTIVE OF FAILURE: low CD4 count. There were 8 non-responders and they had 75 CD4at the end of the failing regimen, 48 at the start of STI, and 18 at the start of LPR/r/SQV. Also predictive of failure: heavy pre-treatment, particularly with protease inhibitors. Non-responders had on average been exposed to 5-6 protease inhibitors.
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