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

The short-term results from ritonavir with its suppression of HIV production and increased CD4+ and CD8+ cell counts are encouraging. There are, however, several issues to consider when making decisions about the use of ritonavir and related drugs.

Which dose is best?

Results from two studies suggest that ritonavir taken by mouth was well absorbed. The amount of drug that reached the blood was high enough to suppress production of HIV by 90%. The greatest suppression of virus production happened at doses of 1,000 mg/day or 1,200 mg/day. At this time we do not have safety data on doses greater than 1,200 mg/day. Higher doses of ritonavir may delay the appearance of drug-resistant virus.

How often?

How often will ritonavir need to be taken? In the two studies reported earlier, subjects took ritonavir in different schedules every 6, 8 and 12 hours. The concentration of ritonavir in the blood seemed to depend on the total daily dose rather than the schedule. It is possible that taking the drug two or three times daily may be sufficient.

In combination with what?

Experiments using combinations of anti-HIV drugs are underway. Results from experiments on cells and HIV suggest that the anti-HIV activity of ritonavir is increased when used with AZT, ddI or saquinavir.

In one study, researchers gave subjects saquinavir 600 mg/day together with AZT 600 mg/day and ddC 2 mg/day. This combination caused production of HIV to fall to 1/100th of its pre-combination levels (see TreatmentUpdate 52 for details).

Experiments on rats suggest that ritonavir and saquinavir interact when taken together. Ritonavir appears to greatly increase and maintain high levels (290 times more) of saquinavir than when saquinavir is used alone. At this time no one knows if [levels of saquinavir] will [increase 290 times] when combined with ritonavir in humans. Nor do researchers know if this combination is safe.

Laboratory experiments suggest that ritonavir increases the time that other protease inhibitors remain in the blood viracept and VX-478.

Benefits?

Although use of ritonavir can increase CD4+ cell counts and decrease the amount of virus in the blood of subjects enrolled in the two studies, researchers do not know if these changes will increase resistance to life-threatening infections.

They already know that some of the CD4+ cells that appear when ritonavir is used are not competent. One immunology team has admitted that some of the increased numbers of CD4+ cells are not new. These cells have simply been moved from lymph nodes/tissues to the blood. The protease inhibitors are supposed to damage HIV. In laboratory experiments, when cells release protease-treated HIV, the viruses are not able to infect other cells. It would be interesting to see if ritonavir damages HIV when taken orally by HIV-infected humans.

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):1528-1533.

2. Markowitz M, Saag M, Powderly WG, et al. HIV-1 protrease, to treat HIV infection. New England Journal of Medicine 1995; 333(23): 1534-1539.

3. Mascolini M. Closing the circle on HIV or not. Journal of the International Association of Physicians in AIDS Care. October 1995, pages 10-29.

4. Schoofs M. A new AIDS trial tries to stop HIV by attacking it early. Village Voice 15 August, 1995.

5. Havlir D, McLaughlin MM and Richman DD. A pilot study to evaluate the development of resistence to nevirapine in asymptomatic Human Immodeficiency Virus-infected patients with CD4+ cell counts >500/mm3: AIDS Clinical Trials Group Protocol 208. Journal of Infectious Diseases 1995;172:1379-1383.

6. Kelleher AD, Carr A, Zaunders J and Cooper DA. Alterations in the immune response of Human Immodeficiency Virus (HIV) - infected subjects treated with an HIV-specific protease inhibitor, ritonavir. Journal of Infectious Diseases 1996; 173: 321-329.

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