Two studies on the use of ritonavir for HIV infection

HIV protease is an enzyme necessary for the formation of infectious viral particles. Inhibition of this enzyme is an attractive approach to anti-retroviral therapy. Saquinavir, a protease inhibitor, is just being approved by the FDA; ritonavir is another protease inhibitor being evaluated, which is the subject of these two papers. The first study is from multiple centers in Europe and one in Australia, the second from several institutions in the United States.

1. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease.

Authors: Danner S, Carr A, Leonard J, Lehman L, Gudiol F, et. al.
Source: New England Journal of Medicine. 333:1528-33. December 7, 1995.
Institution: multiple hospitals in Europe, one in Australia.
Financial support: Abbott Laboratories.



Measurements Results

84 patients enrolled (3 women), 39 in group 1, 45 in group 2.
Baseline CD4+, p24, viral RNA and prior use of antiretrovirals (60-85%) were not statistically different (except for CD4+ in placebo (lowest) vs. 1000 mg group).

2. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.

Authors: Markowitz M, Saag M, Powderly W, Hurley A, Hsu A, et. al.
Source: New England Journal of Medicine. 333:1534-39. December 7, 1995.
Institution: multiple institutions in the US.
Financial support: NYU, Washington University, Aaron Diamond Foundation and Abbott Laboratories.



Measurements Results

62 patients enrolled (2 women), 31 in group 1, 31 in group 2.
Baseline CD4+, viral RNA and prior use of antiretrovirals were not statistically different between groups.

Summary comparison of the methods of the two trials

                   European Study             U.S. Study

Eligibility        CD4+ > 50                  CD4+ 50-500
                   HIV p24 > 10 pg/ml         Viral load > 25 000

Pre-               2 week washout             2 week washout
randomization      from anti-retrovirals      from antiretrovirals

4-week study       Group 1: 600 mg,           Group 1: 600 mg,
                   800 mg or placebo          900 mg or placebo

                   Group 2: 1000 mg,          Group 2: 800 mg,
                   1200 mg or placebo         1200 mg or placebo

Continuation       32 weeks                   12 weeks 


The lessening of the drug effect on viral RNA appeared earlier in the American study. In that study, drug levels were lower during the second part of the study; could it be that the tid/qid dosing employed here induced more rapid metabolization of the drug?

In neither study do the authors state how they calculated a mean viral RNA titer when a patient's titers were below the limit of detection of the bDNA assay (10,000). Did they use 10000, 5000, zero or some other number to calculate the mean, and could a difference between the approach used in the two studies account for the apparent earlier loss of effectiveness in the US study?

Both of these studies demonstrate impressive anti-viral activity of ritonavir, a protease inhibitor, which decreases after several weeks of treatment, however, due to the emergence of resistant mutations. As the authors of both studies state, the place of ritonavir in the anti-viral armamentarium, particularly in combination therapy with the nucleoside analogues (such as AZT, ddI, ddC), remains to be determined. Its antiviral activity appears to be greater than that of the other drugs, at least initially, its pharmacokinetics are favorable, and it is fairly well tolerated. Clearly, there will be more trials with this drug, particularly in combination with other therapy.


Reader comments

Date: Thu, 29 Feb 1996
Subject: Danger of abreviated testing for protease drugs

Protease inhibitors cause a transient drop in viral levels. Levels increase in time because of appearance of drug resistant strains.

Since there is no evidence of clinical improvement in the patients, it is very unwise to promote mutant organisms that once transmitted result in a more difficult situation to treat.

The FDA has become nothing but the ever compliant wagging tail of nonphysician AIDS activists. This is a dangerous problem that must be stopped.

Mark I. Klein, MD

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