icon_folder.gif   Conference Reports for NATAP  
  8th European Conference on Clinical Aspects and treatment of HIV-Infection (ECCATHI)
Athens, Greece - October 2001
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Indinavir + Ritonavir (800/100) vs Saquinavir + Ritonavir (1000/100), both twice daily
  This is a preliminary report at week 24 from an ongoing 48-week study comparing two ritonavir boosted PI regimens. This study is a randomized, open-label, multi-center trial comparing the safety, tolerability, and efficacy of indinavir+ritonavor (800/100 mg twice daily) to saquinavir+ritonavir (1000/100 mg twice daily) in adults. Patients also used 2 additional drugs in the regimen which I think could include NRTIs and an NNRTI. The pill count is 6 twice a day for the SQV/RTV regimen and 3 twice a day for the IDV/RTV regimen, not including the NRTIs. The study is being conducted at several international sites (not in the USA) including Argentina, Denmark, Italy, UK . The sponsor of the study is Jens Lundgren, MD, and the Copenhagen HIV Programme (CHIP). The interim results suggest that the SQV regimen is easier to tolerate and adhere to due to less adverse events. Although the interim analysis shows apparent equivalence in terms of antiviral effectiveness, this analysis does not analyze response by other factors such as baseline viral load and how much or the type of PI resistance patients had. Hopefully, the full 48-week analysis will address these questions.
The stated primary objective for the study is whether there is a difference in the incidence of virologic failure between the two arms. The study results report interimly the differences in adverse events and discontinuations between the study arms. The study design is complicated but is explained below.
Enrolled in this study were a full spectrum of patient experience. Patients were PI naive, PI failures, and PI intolerant. Patients were randomized equally to either arm and stratified according to their viral load at baseline (under or above 400 copies/ml).
The study results are analyzed and reported by the Intent-to-treat approach, but were further broken down by ITT (all patients randomized), ITT/e (patients who took at least 1 dose; this includes patients who took 1 dose and withdrew from study), ITT/d (patients who discontinued from the study) and ITTe/d (patients who started study drug and then discontinued).
Definition of Viral Failure
Viral load at baseline was <200 or >200. If viral load was >200 at baseline, failure was a rise in viral load of 0.5 log or more, >50,000 copies/ml at week 4, >5,000 copies/ml at week 12, and/or >200 copies/ml at week 24. Death, withdrawn consent, and loss to follow-up were included as viral failure, which is typical in an ITT analysis.
Baseline Characteristics of Patients
158 patients were randomized to the IDV/RTV arm and 148 to the SQV/RTV arm. Only 1 patient never started treatment in the IDV/RTV arm while 7 never started treatment in the SQV/RTV arm. There were 22 ART naive patients in the IDV arm and 28 in the SQV arm. 37 in the IDV arm were PI-naive and 41 were PI-naive in the SQV arm. There were 25 who were PI-experienced with VL>400 copies/ml in the IDV arm and 22 in the SQV arm. There were 38 who were PI-experienced with <400 in the IDV arm and 37 in the SQV arm.
There were 42 patients in the IDV arm and 37 in the SQV arm with <400 copies/ml at baseline suggesting they were intolerant or displeased for some other reason with the regimen they were taking prior to this study. Average CD4 count was 280 in the IDV arm and 275 in the SQV arm. The average nadir CD4 count was 88 in the IDV arm and 58 in the SQV arm.
Week 24 Interim Results
    IDV/r   SQV/r
Initiated but disct study   27%(42)   17%(25)
Viral failure   1%(2)   1%(2)
Non-fatal adverse event   20%(31)   8%(12)
  There were 20% discontinuations for adverse events in the IDV arm vs 8% in the SQV arm. Still on randomized treatment were 73% (116) in the IDV arm and 83% (123) in the SQV arm.
The adverse events leading to study discontinuation (ITT/e) for the IDV group were: nervous system (1%), cardio-vascular (1%), renal (6%), GI (8%), skin (2%), and other 2%. Adverse events leading to discontinuation (ITT/e) for the SQV arm were reported as 7% for GI and 1% for skin.
Total Number of Grade 3/4 Adverse Events
    IDV/r   SQV/r
Nervous System   6   3
Pulmonary   4   1
Cardio-vascular   2   0
Renal   10   0
GI, stomach   18   14
Skin and Hair   10   6
Fatigue and/or fever   3   3
Lab Results   15   16
Other   7   2
Total   75*   45*
  *some subjects experienced more than 1 grade 3/4 adverse event.
Interim Viral Load Response
At week 24 using the ITT/e analysis about 72% in the IDV arm and 79% in the SQV arm had <400 copies/ml. This analysis presumably included patients who were exposed to at least one dose in the study and those who switched regimens. When looking at the ITT/e/d analysis which presumably includes patients who received at least 1 study treatment dose and patients who discontinued from the study for any reason (labs, adverse events, lost to follow-up, withdrew consent), about 77% in the SQV arm and 61% in the IDV arm had <400 copies/ml.
The data from the study is interim and it's too early to make conclusions. But the interim results suggest that the SQV/r regimen results in fewer overall adverse events than the IDV/r regimen. The viral failure rate was low in both arms, but as you know studies do not represent what is seen in the real world of clinical practice. Patients in studies tend to be adherent and perhaps more able and willing to tolerate side effects and adverse events. Since the pill count is greater for the SQV arm (6 vs 3 twice a day, not including NRTIs), this may be a factor in adherence for some patients in clinical practice in the real world. For some patients, 6 pills plus 2 for NRTIs (making a total of 8 twice per day) vs 3 + 2 (making 5 twice per day) is a consideration. For initial or second-line therapy 8 pills may be difficult for patients to adhere to. But for patients with extensive treatment-experience and resistance they may be more willing to tolerate and adhere to a higher pill count. It may be helpful towards adherence to use NRTIs that are easier to take, have less side effects, and are more tolerable. For some patients perhaps 8 pills may be more tolerable if the side effect profile is easier. Oftentimes, some patients are able or willing to accept some side effects but not others. But these data are from a 24-week interim analysis, and the final 48 week results from this study should be more revealing. Perhaps, a more interesting comparison would be Kaletra vs SQV/r (1000/100 mg twice daily).
This interim analysis did not report differences in viral response between the 2 regimens when looking only at PI-viral failures or for patients who were ART naive. It also did not analyze response by whether patients had high or low baseline viral load. In addition, changes in lipids, sugar, and body changes do not appear included in the analysis. As well, differences in toxicities and hepatoxicity based on HCV status would be interesting.