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Combination use of Ritonavir and Saquinavir in HIV-infected patients--Preliminary Safety and Activity Data

Abstract # Th.B.934, authors- William Cameron, E Sun, M Markowitz, C Farthing, D McMahon, D Poretz, C Cohen, S Follansbee, D Ho, J Mellors, A Hsu, GF Granneman, R Maki, M Salgo, M Court, J Leonard

For months, many have been waiting data on this combination, particularly AIDS treating doctors and people with AIDS, who have been anxiously anticipating some useful data. The negotiations between Roche and Abbott to conduct these studies began a year ago. The first trial in healthy HIV- volunteers began in December 1995, and the trial, under discussion here, in HIV+ individuals began in March 1996, and explores different dosing combinations of ritonavir and saquinavir.

The results discussed below are positive and promising, but it's important to note the results are preliminary, as these results consist of only 6 weeks of efficacy and safety data. We still are uncertain of what the optimal dosing regimen could be, the durability of these results and the longer-term safety of the combination.

Some of the concerns are:

At the Vancouver AIDS Conference, the Dr. William Cameron, of Canada's Ottawa General Hospital, presented the study results.

--He said,

Cameron presented a slide displaying the:

It depicted the effect of different regimens and dosing on saquinavir AUC (ug. hr/ml):

Cameron presented a slide entitled:

It showed the median steady-state AUC (ug.hr/ml)--

Commentary--As you can see, ritonavir greatly increases blood levels of saquinavir. Again, we do not yet know the longer-term effects of raising saquinavir blood levels to such high levels--durability and safety.

THE STUDY:
The study objectives are to evaluate dose combinations, pharmacokinetics, virology and long-term safety, tolerance and activity.

120 HIV-infected individuals, with 100-500 CD4 cells/mm3, were randomized in a multi-center study with all subjects receiving open-label saquinavir and ritonavir. All participants discontinued use of RT inhibitors for the study. Drugs were initiated in escalating dose fashion through the first few days to optimize tolerability.

After a 2-week safety evaluation period, study subjects are randomized to four groups:


Baseline HIV RNA and CD4:
				ritonavir 400 mg bid	ritonavir 600 mg bid
				saquinavir 400 mg bid	saquinavir 400 mg bid
HIV RNA (log10 copies/ml)	(n=33)			(n=30)         
mean 				4.53 (33,884 copies/ml)	4.68 (47,863 copies/ml)
median				4.63 (42,658 copies/ml)	4.65 (44,668 copies/ml)

			RTV 400mg bid+		RTV 600mg bid+                                 
			SQV 400mg bid		SQV 400mg bid
CD4 T-lymphocytes/mm3	(n=33)			(n=30)       
mean			274			299
median			249			255

HIV RNA and CD4, CD8 changes--

(n=61 at baseline, 59 at 2 weeks, 58 at 4 weeks, and 42 at 6 weeks--this is the total number of individuals upon which the data is based inclusive of both dosing groups).

400mg RTV bid + 400 mg SQV bid--

600 mg RTV bid + 400 mg SQV bid--

Commentary:
The number of study participants for which this data applies is small, and the resulting differences in data between the two groups is small, so at most you may be able to say there is a suggestion of a trend that the 600mg RTV+400mg SQV 400 mg is superior to the 400mg RTV bid/400mg SQV bid group; but, you could just as easily say the differences in data between the 2 groups is too small to draw any conclusion. It is also important to remember that the 2 other dosing regimens, for which we don't yet have efficacy data, are being studied (600mg bid RTV/600 mg SQV bid and 400mg RTV tid/400mg SQV tid), and they could prove to be superior (in terms of safety and/or efficacy) to both of the groups discussed here. end of commentary

Reduction of viral load below 200 copies/ml at 6 weeks--47% had undetectable RNA in the 400mg RTN bid/400mg SQV bid group, 65% were undetectable (below 200 copies/ml) in the group receiving 600 RTN bid/400 SQV bid.

at 6 weeks----70% in the 400/400 bid group had either a 2 log decrease in RNA from baseline or were below 200 copies (undetectable).

--86% in the 600 RTV/400 SQV group had either a 2 log decrease in RNA from baseline or were below the level of detection for this test (200 copies/ml).

Commentary:
Again, this is a small data set, but the graph line depicting the % of individuals who were RNA undetectable appeared to be ascending.(end of commentary)

CD8 changes:


Tolerance and safety of Ritonavir + Saquinavir
			RTV 400mg bid	RTV 600mg bid
				+		+
			SQV 400mg bid	SQV 400mg bid
			(n=33)		(n=32)        
Adverse symptoms--
  --Circumoral paresthesia	25		27   
    (tingling around mouth)                       
  --Diarrhea			21		24                                        
  --Fatigue			14		14
  --Nausea			12		12
  --Flushing			7		17                 

Lab abnormalities 
(grade 3 or 4)--
  --ALT increase		1		2
    (liver function test)      
  --Triglyceride increase	2		5
  --Uric acid increase		1		0
  --Glucose increase		1		0
  --CPK increase		1		1 

Discontinuations		1		1

NOTE-- The rate of discontinuation in this study, as well as in other studies, may be lower than the rate of discontinuation with ritonavir as it is used in private practice. This could be due to the management of side effects by the treating physician. The nurse and doctor running this study are very adept with properly informing individuals, who are taking ritonavir, on what side effects to expect, how to deal with them, how to properly use the dose escalation method recommended by Abbott, and generally guiding individuals through the process of acclimating to taking ritonavir. But, in private practice the treating physician may not be as well informed informed about the proper use of rironavir; and/or, they may not take the time to acclimate their patients in the details of properly using the drug.

Future directions for studies as outlined by Abbott--
ritonavir+saquinavir in combination with:

RTV+SQV+RT inhibitor(s):

Last modified 8/20/96
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