TreatmentUpdate 66, Volume 8, No 2; February 1996
Sean Hosein

Researchers in the EU and Australia enrolled 84 HIV-infected subjects (3 females, 81 males) for this study. At least half of the subjects had CD4+ cell counts ranging from 86 to 170 cells. None of the subjects were supposed to have used a protease inhibitor before entering this study. Between 60% and 80% of subjects used other anti-HIV drugs before entering this study. Researchers randomly divided subjects into several groups giving them different doses of ritonavir. For the first 4 weeks of the study, neither subjects nor doctors knew which subjects received ritonavir or fake drugs (placebo). During this study subjects took their drugs twice daily.

Group 1

Researchers enrolled 39 subjects who were divided into 3 subgroups each having 13 subjects and receiving:

* placebo

* ritonavir 600 mg/day

* ritonavir 800 mg/day

Group 2

Researchers enrolled 45 other subjects (similar profile as group 1) and randomly assigned them to three sub-groups of 15 subjects receiving:

* placebo

* ritonavir 1,000 mg/day

* ritonavir 1,200 mg/day

After the first 4 weeks all subjects received ritonavir and were monitored.

Results - CD4+ cells

After the second week all subjects receiving ritonavir had increased cell counts compared to their pre-study level. For most subjects, the increase in CD4+ cell counts reached their greatest level at the 12th week. At this time, the average increase was about 170 CD4+ cells for subjects in the 800 mg/day, 1,000 mg/day and 1200 mg/day groups. Subjects in the 600 mg/day group had an increase of 100 CD4+ cells. After the 12th week nearly all of the various groups CD4+ cell counts began to decline. The exception was the group receiving 1,200 mg/day. However, by the end of the study there were only 7 subjects (out of 16) left in that group.

Results - production of HIV

All subjects receiving ritonavir had a huge reduction in the amount of HIV in their blood. By the fourth week of the study, the amount of virus in the blood of subjects receiving ritonavir 1,000 mg/day and 1,200 mg/day fell to 1/10 of their pre-ritonavir levels. In some subjects the level of viral production fell to 1/100 of its pre-study level. After the fourth week, however, the amount of HIV in blood samples began to increase suggesting that HIV-infected cells were developing resistance to ritonavir. By the eighth month of the study, subjects who were taking less than 1,200 mg/day of ritonavir had the amount of virus in their blood return to pre-study levels. In subjects receiving ritonavir 1200 mg/day, the amount of HIV in the blood was increasing, but remained relatively lower than their pre-study levels. Readers should note that by the eight month of the study only half of the subjects in the 1,200 mg group remained. As well, despite use of ritonavir, production of HIV continued.

Toxicity

According to the researchers, between 85% and 100% of subjects who received ritonavir during the four week, placebo-controlled phase reported at least one side effect including:

* nausea

* abnormal sensation in and around the mouth

* increased levels of liver enzymes (suggesting liver damage)

Eight subjects receiving ritonavir left during the first 4 weeks because of side effects including nausea and high levels of liver enzymes in the blood (the enzymes were aspartate aminotransferase and alanine aminotransferase).

After the 4th week, 75 subjects remained and chose to receive ritonavir (if they weren t already doing so). About 33% of these subjects left the study before the 8th month. Six of them left because of nausea and higher than normal levels of liver enzymes. During the first week of the study subjects receiving ritonavir 1,000 mg/day or 1,200 mg/day had significantly higher levels of:

* liver enzymes

* cholesterol

* triglycerides

These results suggest some liver damage had occurred (not life-threatening). By the 8th month, the increased levels of triglycerides and cholesterol persisted. It also appeared that as subjects received higher doses of ritonavir, they were more likely to experience side effects.

What next?

Results from this study clearly show that ritonavir can reduce the amount of HIV in the blood and increase CD4+ cell counts over the short term. The reduction in production of virus is greater than that seen with AZT and related drugs. After the first three months of use, it appeared that HIV-infected cells became increasingly resistant to ritonavir. Higher doses of ritonavir may delay the development of drug resistance. These researchers did not investigate the possibility that the drug may also interact with the immune system. The use of combinations of ritonavir and other drugs is reviewed in section E.

REFERENCES:

1. Danner SA, Carr A, Leonard JM, et al. A short term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. New England Journal of Medicine 1995;333(23):1528-15

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Copyright © 1996 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca