October 29, 2001
Maximinus was an important leader of the Roman Empire, the second of the great ancient empires 2,000 years ago. His name was echoed in a noteworthy comparative study presented today in Greece, the heart of the first great ancient European civilization.
In this case, the name is a play on words. Two of the main pharmacokinetic parameters used to evaluate therapeutic agents are the Cmax (peak) and Cmin (minimum, or trough) values. This study was the first comparative study between boosted protease inhibitor regimens. The use of protease inhibitors with booster agents such as low (or "baby") doses of ritonavir or, much less commonly, co-dosing with the NNRTI delavirdine is increasingly used to improve the administration characteristics and possibly efficacy of protease inhibitors. This approach is rapidly becoming (or, I would say, firmly established as) the standard of care with protease inhibitor use. The rationale for using pharmacokinetic enhancers with protease inhibitors includes:
The study was run as a European collaborative effort by the Copenhagen HIV Program (CHIP) under the auspices of Dr. Jens Lungren. The study compared standard boosted dosing of indinavir (IDV) 800mg + ritonavir 100mg BID with saquinavir soft gel (fortovase, SQVs) 1,000mg + ritonavir 100mg BID together with two NRTIs of the physicians' (and patients') choosing. No viral load or CD4 entry criteria were used. Patients could be treatment- or protease inhibitor-naive, single protease inhibitor-experienced or intolerant to a current successful protease inhibitor regimen. Essentially, the whole range of use of boosted protease inhibitors except for multi-protease inhibitor-experienced was studied. The study evaluated whether, in this broad treatment population, the treatments were, statistically speaking, "equivalent."
Outcomes for "failure" included a composite of viral load >200 if <200 cps/ml at baseline, a rise of 0.5 log10 from baseline values or values above 50,000 at week four, 5,000 at week twelve and 200 cps/ml at week twenty-four. In total, 306 patients entered the study, with 158 on IDV and 148 on SQVs. Overall 22 and 28 patients were treatment-naive, and a further 37 and 41 patients in the IDV and SQV arms, respectively, were protease inhibitor-naive but NRTI-experienced. The viral load was a median 4.0 log10 (10,000) in each group with CD4 at 280 and 275 cells/mm3. Treatment-experienced patients had previously received a median of two NRTIs before entering the study. Patients could enter max Cmin PI experience with either suppressed viral load and current PI intolerance or viral rebound on a PI. Patients intolerant of current PI and who switched with viral load <200cps/ml made up 42% and 37% of patients in the two arms, respectively.
Seventy-three percent of IDV and 83% of SQVs patients remained on the study to week 24, with only 16 patients in each group experiencing viral failure. Adverse effects (grades 1-4) leading to treatment discontinuation were reported in 20% of IDV vs. 8% of SQVs patients, with grade 3-4 laboratory shifts in 15 and 16 patients, respectively. Regarding grade 3 or 4 clinical events (the more severe ones), kidney-related events such as kidney stone, loin pain and blood in the urine occurred in 10 of IDV and 0 of SQVs patients. For other events, the respective numbers of patients were: skin problems 10 vs. 6, gastrointestinal upsets 18 vs. 14 and nervous system problems 6 vs. 3. Overall, a total of 75 IDV and 45 SQV patients reported grade 3-4 adverse events of clinical or laboratory types.
Understanding efficacy was more challenging due to the array of definitions used. The FDA-preferred analysis includes a "failures" category -- all patients who meet the study viral failure criteria -- those who have switched to a different therapy, all withdrawals and anyone lost to follow (i.e., a patient who moved away to another place would be called a "failure" even if at <50 or 400 cps/ml at last attendance). By this criteria 60% of IDV and 76% of SQVs patients were considered treatment successes. If we count people who modified treatment without viral rebound (i.e., "switch included") the success rates rise to 72% for IDV and 79% for SQVs regimens. Statistical analysis did not indicate differences between regimens in any viral load or CD4 analysis.
So, what does this mean? The data at present cover a relatively short period of follow up, so it may be premature to apply these to clinical practice. However, the data indicate that a regimen of 1,000/100mg BID SQVs/RTV is at least as effective as 800/100mg BID IDV/RTV, but with trends to fewer adverse events. Even in the gut where saquinavir tends to cause most of its side effects -- nausea and diarrhea -- the event rates for severe events are similar. While the SQVs/RTV regimens involve more tablets (six BID) than the IDV/RTV regimen (three BID), many patients and physicians may now consider that taking a few extra pills in exchange for a lower risk of adverse effects with at least as good efficacy is the way to go.
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