AEGiS-CATIE: ANTI-HIV AGENTS: Protease inhibitors - indinavir, ritonavir, saquinavir and viracept

ANTI-HIV AGENTS: Protease inhibitors - indinavir, ritonavir, saquinavir and viracept

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

A virus gets in Much like using a key to get into a locked room, HIV attaches itself to a receptor (the lock ) called CD4. This activity allows the virus to get inside the cell. Once inside, the virus hijacks the control centre of the cell. At some point, HIV turns the cell into a virus factory producing many HIVs. This process is complex and there are many steps involved.

A viral assembly line

Several enzymes play important roles at different stages in the viral assembly line that is the hijacked cell. One such enzyme is RT (reverse transcriptase). Drugs such as AZT, ddC, ddI, 3TC and nevirapine are supposed to block the creation of this enzyme. Without this enzyme it is impossible for the virus to take over a cell.

HIV proteinase

Other vital enzymes include integrase, RNAse and proteinase. HIV proteinase works in the final stages of the assembly line. Without the help of this enzyme, the viruses produced are not supposed to be able to infect cells. Drugs that affect HIV proteinase are called protease inhibitors and include:

indinavir (MCK-639 or Crixivan ) ritonavir (ABT-538, Norvir ) saquinavir (Invirase ) viracept (AG 1343)

Saquinavir plus

In TreatmentUpdate 51 we reported results from an American study (ACTG 229), using a combination of AZT, ddC and saquinavir on HIV-infected subjects. Subjects receiving all three drugs showed a prolonged increase in CD4+ cell counts compared to others who did not receive the triple combination. Researchers do not know if the use of saquinavir (alone or in combination) can delay or prevent life-threatening infections/cancers or extend survival compared to people who do not use them.

Saquinavir alone

Saquinavir alone in doses of 1800 mg/day has been able to cause temporary increases in CD4+ cell counts in one study. In that same study, however, after weeks of use, technicians could still detect HIV that was capable of infecting cells. These suggests that saquinavir has not had a major impact on HIV-infected cells. Please read TreatmentUpdate 62 for details on that study.

Combinations and some problems

As more anti-HIV agents become available, physicians and their HIV-infected patients will begin experimenting with various combinations of AZT and related drugs and protease inhibitors. It is not clear which combinations of AZT (and related drugs) and protease inhibitors are useful. Results from some laboratory experiments suggest that some combinations may not have increased antiviral activity compared to one drug alone. Here are some results from laboratory experiments:

indinavir may reduce the anti-HIV activity of the combination of 3TC/AZT; combinations of indinavir and ritonavir may not be useful; when either indinavir or nevirapine are added to a combination of AZT and 3TC, the anti-HIV effects of 3TC/AZT are reduced; Combinations of 3TC/ddC and d4T/AZT may not be useful; VX-478 has increased anti-HIV activity when used with AZT or ddI; viracept shows increased anti-HIV effects when used together with AZT, ddI or ddC.

After deciding which combination to use, some people also consider injections of the T cell stimulant IL-2 (interleukin-2). In experiments on a very small number of HIV-infected subjects, intermittent doses of IL-2 appeared to raise CD4+ cell counts in the blood. Please read TreatmentUpdate 58 for details.

Researchers do not know if these increases in CD4+ cell counts in the blood can protect subjects from life-threatening infections/cancers. Next we bring you reports from short-term studies using ritonavir.

REFERENCES:

1. Lipsky JJ. The glimmer of HIV proteinase inhibitors. Lancet 1995;345:936-937.

2. Kitchen VS, Skinner C, Arioshi K, et al. Safety and activity of saquinavir in HIV infection. Lancet 1995;345:952-955.

3. Mascolini M. A Lisbon Traviata. Journal of the International Association of Physicians in AIDS care. 1995;1(8):10-22.

4. Mascolini M. Closing the circle on HIV or not. Journal of the International Association of Physicians in AIDS care. 1995;1(9):10-25.

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Always watch for outdated information. This article first appeard in 1996. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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

This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1996. AEGIS.