The Max Cmin 1 trial: indinavir/ritonavir vs. saquinavir/ritonavir
Graeme Moyle, M.D. for The Body
Maximinus was an important leader of the Roman Empire, in the second of the great ancient empires 2,000 years ago. His name was echoed in a noteworthy comparative study presented in Greece, in 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 measured for therapeutic agents are the Cmax (peak) and Cmin (minimum, or trough) values. The study was the first comparison 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 exploitation of pharmacokinetic interactions to enable both reductions in dose (and therefore tablet number) and less-frequent dosing; to
- provide additive or synergistic antiretroviral effects; and possibly to
- exploit non-overlapping resistance profiles to create a higher genetic barrier to resistance (i.e., the need for greater numbers of mutations than would be required for resistance to a single agent), thus delaying the appearance of escape mutants; or to
- overcome established low-level reduced sensitivity to this drug class.
The study was run as a European collaborative effort run from 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 enter 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 id <200 cps/ml at baseline, a rise of 0.5 log-10 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 a median of two previous NRTIs and 42 and 37% in each group were switched on max Cmin due to intolerance while viral load was <200/ml at baseline.
Patients have remained in the study to week 24 in 73% and 83% of IDV and SQVs patients, respectively, 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 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 the 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 system where saquinavir tends to cause most of its side effects — the gut with nausea and diarrhoea — the event rates for severe events are similar. While the SQVs/RTV regimens involve more tablets (6 BID) than the IDV/RTV regimen (3 BID), many patients and physicians may now consider that taking a few extra pills in exchange for a lower risk of adverse effects and at least as good efficacy is the way to go.
Dragsted UB et al. A phase IV randomised, open-label, multicentre trial to evaluate safety and efficacy of indinavir/ritonavir (800/100 mg BID) vs. saquinavir/ritonavir (1000/100 mg BID) in adult HIV-1 infection: The MaxCmin 1 trial. 8th ECCATH, Athens 2001. Abstract O10.