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Valacyclovir Study Stopped -- Worse Survival


AIDS TREATMENT NEWS Issue #217, February 17, 1995

In an unexpected setback for Burroughs-Wellcome -- but one which might turn into good news for people with AIDS -- a study of valacyclovir was stopped early because patients assigned to that drug had worse survival than those in either the low dose or high dose acyclovir arms, which were intended as control groups for the valacyclovir treatment.

Valacyclovir is a prodrug of acyclovir -- meaning a drug which turns into acyclovir inside the body. Its advantage is that higher doses can be absorbed orally than when acyclovir itself is given. Therefore, doses which would otherwise require intravenous acyclovir can be given orally with valacyclovir. Burroughs-Wellcome has focused recent development work on valacyclovir rather than acyclovir, because the patent on acyclovir will soon run out, and that drug will become generic -- meaning that it will be inexpensive for the purchaser, but not very profitable for the company.

The study which was stopped, called ACTG 204, had been run by the AIDS Clinical Trials Group (ACTG) with support from Burroughs-Wellcome. The purpose was to see whether valacyclovir could help to prevent CMV disease in persons with advanced HIV infection (CD4 count under 100).

Due to ethical problems with using a placebo in such a study, low dose and high dose acyclovir regimens were used for control (comparison) groups. High-dose acyclovir has been shown to prevent CMV disease in organ-transplant patients (who have immune deficiencies due to immune-suppressive drugs taken to prevent rejection of the new organ); but prior attempts to use it to prevent CMV disease in AIDS have not been promising. The theory behind ACTG 204 was that the higher dose possible with valacyclovir might provide a practical treatment to prevent CMV disease.

But this study was stopped on February 13 because there were more deaths in the valacyclovir arm than in either acyclovir arm. No one knows why this happened. But we have learned that volunteers assigned to the valacyclovir arm were on the drug for less time than those assigned to the acyclovir arms. And the main cause of death -- progression of HIV disease -- seemed to be similar in all the arms.

Comment This study may stimulate research in use of acyclovir to increase survival by persons with late-stage AIDS. Since those assigned to acyclovir lived longer than those assigned to valacyclovir, either the acyclovir was helping, or the valacyclovir was hastening death, which seems unlikely.

One possibility is that the valacyclovir dose was too high for this patient population, leading to side effects and interruption of treatment, resulting in more time off drug in the valacyclovir arm. The acyclovir arms may then have shown a greater survival effect because of greater time on treatment, or greater consistency of treatment. A recent epidemiological study using the MACS (Multicenter AIDS Cohort Study) database suggested that "consistent use of acyclovir at a dose sufficient to suppress herpetic recurrences (that is, 600 to 800 mg/day) has a clinically significant effect on prolonging survival in a well-characterized cohort with extensive previous exposure to herpesvirus infections" (D.S. Stein and others, "The Effect of the Interaction of Acyclovir with Zidovudine on Progression to AIDS and Survival," ANNALS OF INTERNAL MEDICINE, July 15, 1994, pages 100-108) --finding that consistent use, not high dose, seemed to matter. The same study also found the effect in late-stage disease -- another finding consistent with ACTG 204.

There have also been negative results. For example, two studies presented at the recent Human Retroviruses conference in Washington, D.C., failed to find a survival benefit of acyclovir. But it also appears that neither of them can rule out a benefit, due to certain limitations of those studies.

We hope to learn more about what happened in ACTG 204 at the semi-annual ACTG meeting next week. We especially want to know how the two acyclovir arms compared, and any details in the differences in outcome among the valacyclovir, high-dose acyclovir, and low-dose acyclovir arms. And we want to see how researchers and physicians interpret this very unexpected result.

ACTG 204 might accidentally have been the controlled study needed to focus research interest in acyclovir and survival -- with the valacyclovir arm unintentionally providing the control. This interpretation will be supported or contradicted as more information becomes available.

Copyright 1995 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.


Copyright © 1995 -AIDS Treatment News, Publisher. All rights reserved to AIDS Treatment News (ATN), Email AIDS Treatment News .

Information in this article was accurate in February 17, 1995. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.