TREATMENT ISSUES, Volume 6, Number 5; The Gay Men's Health Crisis Newsletter of Experimental Therapies - May/June 1992
Mark Harrington

HIGH DOSE ACYCLOVIR

Reports have suggested that high-dose oral acyclovir (Zovirax, made by Burroughs-Wellcome) may have some anti-CMV activity. Oral acyclovir, however, does not remain in the body at high enough doses to stop CMV growth.[3] A report of oral acyclovir's anti-CMV activity, conducted by Craig Metroka, a New York City physician, was not randomized. Thus, one cannot know whether the difference in CMV outcomes in participants taking the drug compared to those taking placebo was due to the use of high-dose acyclovir (4000 mg/day, or 800 mg taken every 4 waking hours), or to other uncontrolled factors.

More recently, British tabloid reports about a Burroughs Wellcome study of AZT with or without high-dose acyclovir claimed that those on combination AZT and acyclovir lived longer than those on AZT alone (See Treatment Issues, February 1992, "High Dose Acyclovir Controversy"). The study found no difference in CMV-disease progression. Sixteen of the study participants taking acyclovir and nine taking placebo developed CMV and organ disease. However, it was later noted that 12 patients on the placebo died, as compared to only six on high-dose acyclovir. Whether these results are statistically significant is not known. Regardless of whether or not high-dose oral acyclovir may extend survival, it appears to lack efficacy in preventing CMV disease.

Dr. Brian Gazzard, the principal investigator of this much-hyped study, spoke at a conference called "The AIDS Crossroads" presented by ABEL Health Management Services in New York City on April 16. Dr. Gazzard emphasized that despite the articles in the London Times and New York Times articles reporting his findings, data from the trial had only become available a week previous to the conference. Nonetheless, his findings markedly resembled information printed in media sources, including Treatment Issues, Vol. 6, No. 2, though Dr. Gazzard revealed new tidbits about his research.

300 patients with fewer than 150 T4 cells were randomly assigned to take either acyclovir (3200 mg/day) or placebo. Of the 151 participants evaluated for taking acyclovir, 25 developed CMV disease, compared to only 17 participants of 149 taking placebo. Therefore, it is assumed that high-dose acyclovir failed to prevent CMV disease. However, significantly fewer patients assigned to high-dose acyclovir died in the study. Twenty-seven participants taking acyclovir died, compared to 43 participants in the placebo arm. According to Dr. Gazzard of St. Stephen's Hospital in London, this difference in survival times was statistically significant. Some have speculated that the apparent survival benefit seen with high-dose acyclovir may be related to inhibition of other herpes viruses that cause immune suppression like Epstein-Barr virus (EBV).

Most of the participants in this study were white men under 40 years old, many of whom had a T4 count lower than 50. Slightly more participants were taking AZT or ddI in the placebo arm than those on acyclovir. Reasons for withdrawal from the trial included episodes of herpes (participants knew then they were taking placebo and so dropped out) and deterioration of health. The probability of getting CMV in patients taking the drug was equivalent to those who were taking placebo (no drug), thus indicating that acyclovir may not prevent CMV disease. However, participants taking acyclovir had only a 23% probability of death after one year of treatment, as compared to participants taking placebo who had a 39% probability of dying. Such a finding is not completely unexpected, since AZT and acyclovir research has reported some improved survival all along.

Dr. Gazzard concluded with the following notes. The data is incomplete and he and his staff will conduct at least fifty more analyses of it. He maintains that quality of life is important; that low doses of acyclovir for anti-herpes must be considered; and that the difference in mortality must be assessed for its clinical significance. Treatment Issues will report further as details become available.

New Oral Drugs

Two new oral anti-CMV drugs have completed preliminary phase I trails to test their safety, activity against the virus and ability to spread throughout the body. Both of these drugs are now ready for phase II clinical trials. Syntex Corporation makes the first drug, oral ganciclovir (DHPG), and Burroughs-Wellcome makes a drug called BW256. The drugs will enter phase II trials later in 1992. An intravenous form of ganciclovir was approved by the FDA in 1989 after a long struggle led by ACT UP/New York. The new oral formulation needs to be taken at high doses (3 grams daily) because it is not easily absorbed from the gut into the blood.

Burroughs-Wellcome's drug is an acyclovir prodrug, BW256, that once inside the body is broken down into acyclovir. This enables the drug to be absorbed into the blood at levels three-to-four times greater than that of oral acyclovir. These higher levels seem able to prevent CMV disease in bone-marrow transplant patients. While such findings in transplant patients offer significant promise, similar findings need to be exposed in people with HIV. BW256 will be administered at doses of between 3-4 grams daily.

A Study for Science or Money?

The Cytomegalovirus Pathogen Study Group (CMV PSG), involved in federally-funded trial designs, has been trying for a year to persuade the sponsors of oral DHPG and BW256 to collaborate in a three-arm study. The study would enroll participants with under 100 T4 cells and would assign them randomly to receive either oral DHPG, BW256, or placebo (no drug at all). This would minimize the number of people with CMV in clinical trials who are receiving no drug. In this trial design, two-thirds of the participants would get active drug. However, if the ACTG and the companies conduct two separate studies each comparing each drug to placebo, 50% of participants would get placebo.

The three-arm trials design answers three questions simultaneously:

1) Is oral DHPG better than placebo in preventing CMV?

2) Is BW256 better than placebo?

3) Which oral CMV drug is safest and most effective? Syntex has been difficult to persuade. Syntex claims that drug-manufacturing problems and limited supplies make a collaborative study impossible. Dr. Ellen Cooper, who was director of FDA's Division of Anti-Viral Drugs Products when the agency approved intravenous ganciclovir in 1989, is now the director of clinical research at Syntex - an ironic turnabout. On the other hand, Burroughs-Welcome has been cooperative.

Conclusion

Community activists are now working to persuade Syntex to participate in the three-arm ACTG trials and to consider opening an expanded access program for oral ganciclovir. If Syntex will be done outside the ACTG, comparing oral ganciclovir to placebo. This would force the ACTG to compare BW256 to placebo alone.

The picture will become somewhat clearer later this year. In the meantime, some even newer anti-CMV drugs are slated to begin phase I trials this year, including HPMPC by Gilead Pharmaceutical Products and Cyclobut-G by Bristol-Myers Squibb.

---------- References

1. A Webster et al. Cytomegalovirus infection and progression towards AIDS in hemophiliacs with HIV infection. Lancet i:63-66, 1989; J Laurence. Molecular interactions among herpesviruses and human immunodeficiency viruses. J. Infect. Dis. 162:338-346,1990; A Webster. Cytomegalovirus as a possible cofactor in HIV disease progression. J AIDS 4 (Suppl): 47-52,1991; and E Levy et al. Cytomegalovirus IgG and IgA Serum Antibodies in a Study of HIV Infection and HIV Related Diseases in Homosexual Men. J Med Virol 35(3):174-179,1991.

2. V Int'l Conf AIDS. Abstract #M.B.P.126, Montreal, June, 1989.

3. Burroughs Wellcome Foundation. Unpublished letter. Zovirax Clinical Review,51-52, 1988.

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