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  AIDS 2002 Barcelona
Barcelona, Spain July 7-12 2002
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New PI Boosted Regimen: Saquinavir/ritonavir
  Graeme Moyle reported a 48-week update on the MaxCmin1 study at Barcelona. This pilot study compares two twice daily PI boosted regimens: indinavir/ritonavir (800mg/100mg) vs saquinavir/ritonavir (1000mg/100mg). This study is a forerunner to future studies looking at SQV/r 1000/100 twice daily.
93% of study patients have completed study followup. In this study the SQV/r regimen appeared equal in terms of antiviral effectiveness (%<400), but more tolerable as reflected by less discontinuations from drug and less adverse events. More patients taking IDV/r permanently switched off IDV/r (41% vs 28%). This was mostly due to clinical non-fatal adverse events, which patients taking IDV/R experienced more often (28% vs 15%). Discontinuation due to virologic failure was about the same in each group. More patients were still on the treatment they were randomized to in the SQV/r group after week 48 (72% vs 59%). More patients experienced at least 1 grade 3/4 adverse events in the IDV/r arm (39% vs 20%). See below for the list of events. About 78% had <400 copies/ml in both treatment groups (ITT/e) after 48 weeks. But when counting patients as failures if they switched off the original regimen 53% IDV/r had <400 vs 68% SQV/r had <400.
Roche is planning to develop the 1000mg saquinavir/100mg ritonavir bid boosted PI regimen with additional studies since the regimen compared favorably to indinavir/ritonavir in this study. Fortovase is the formulation of saquinavir used in this study but Invirase appears to be as successful and more tolerable. In PK studies the blood levels appear to be as good for Invirase when boosted by ritonavir as the blood levels for Fortovase when boosted by ritonavir. Several studies show that the stomach & GI side effects are more tolerable for Invirase than Fortovase. Fortovase studies using 1200mg three times daily report nausea (18%), diarrhea (15%), abdominal discomfort (13%), and dyspepsia (9%). Roche is expected to develop a 500 mg Invirase capsule which will reduce the pill count for saquinavir. As well, itıs expected that Fortovase may be discontinued in favor of Invirase.
The purpose of this study is to look at the discontinuation rate & tolerability (adverse events) of the two regimens and the effectiveness. This is an open-label randomized phase 4 trial taking place from September 2000 to March 2001. 317 patients were enrolled and physicians selected NRTI and NNRTIs for combination in the regimens.
Patients were PI experienced (60%), ART naive (20-28%), or PI naive 38-41%). The patient baseline characteristics were comparable between the 2 regimens (IDV/r vs SQV/r). 30% of patients had more advanced HIV (CDC category C). HIV viral load was 3.9 log (6300 copies/ml). 37% in both treatment groups already had <100 copies/ml viral load and 38-41% in both groups already had <400 copies/ml. CD4 counts were on average 275. The lowest CD4 counts patients had ever had (nadir) were 119 in the IDV/r group and 107 in the SQV/r group showing that a number of patients had advanced HIV at one point.
The IDV/r regimen (800/100) was 3 capsules twice daily, non-food dependent, and extra fluid was needed to prevent risk of indinavir-related kidney problems. The SQV/r (1000/100)was also non-food dependent, 6 capsules twice daily, and patients did not take extra fuid.
158 patients initiated IDV/r therapy & 148 initiated SQV/r therapy
More patients taking IDV/r permanently switched their regimen (41% vs 28%). This was due mostly due to clinical non-fatal adverse events (25% IDV/r vs 15% SQV/r).
REASONS for discontinuation:
The difference in the permanent discontinuation between the IDV vs SQV treatment groups was due to clinical non-fatal adverse events: 28% DV/r vs 15% SQV/r. Permanent discontinuation due to virologic failure was the same in both groups(2 in IDV vs 1 in SQV), and discontinuation due to lab abnormality was also about the same: 3 in IDV/r group & 1 in SQv/r group.
Most treatment discontinuations for patients in clinical practice are due to grade I and II less severe adverse events. In this study, patients discontinued from the IDV/r arm at a rate of 6% due to kidney problems. Discontinuations due to GI side effects were about 13% in the IDV arm vs 10% in the SQV arm. There were more discontinuations in the IDV arm for dermatologic reasons (6% vs 1%).
Grade 3 and/or 4 Adverse Events
Patients receiving IDV/r more often had at least 1 grade 3/4 event: 39% IDV/r vs 20% (SQV/r); treatment related toxicity: 26% IDV/r vs 11% SQV/r. IDV/r vs SQV/r grade 3/4 events by organ system: renal (13 vs 1); GI (19 vs 17); dermatologic (18 vs 4); pulmonary (5 vs 1); nervous system (8 vs 4); laboratory (21 vs 21).
The patients receiving SQV/r had as good or better viral response at week 48. When looking at patients who received at least one dose of study drug but were considered a failure if they had to switch their regimen (ITT/e/switch=failure), 53% in IDV group (n=158) vs 68% in SQV group (n=148) had <400 copies/ml. When looking at the ITT/e analysis (patients switching regimens were not counted as failures) the response was the same for both groups 77% IDV/r vs 79% SQV/r.
MaxCmin2 is planned to compare Kaletra vs SQV/r for antiviral efficacy and lipids.