Gay Men's Health Crisis "Treatment Issues"; Vol. 8, No. 7 - August 1994
Dave Gilden

One physician, Marcus Conant, M.D., of San Francisco, has long been a proponent of administering a succession of nucleoside analogs (AZT, ddI and ddC) once a patient's CD4 count starts falling below 500. Now, he says, "The anti-HIV drugs only work for eighteen to 24 months. People should only go on them when signs of immune deterioration arise."

Dr. Conant recommends that his patients start acyclovir as soon as they know that they are HIV-positive, a regimen he says he first tried in 1987. He thinks that acyclovir helps slow disease progression by suppressing herpes viruses, which perhaps act as a co-factor in producing AIDS. The dose he recommends is 400 mg twice a day, the standard one used to prevent recurrent herpes attacks.

Dr. Conant's recommendation is really based on his intuitive feeling; he has little data to back him up. Other community physicians may have different ideas. In New York, for example, Craig Metroka, M.D., prescribes high dose acyclovir in an effort to prevent infections with CMV (cytomegalovirus), which is a member of the herpes family that can cause blindness and death. However, studies, as of yet, have failed to confirm that acyclovir prevents CMV.

Dr. Metroka says, "Generally I start people with less than 100 T- cells on 800 mg five times a day. Before I started acyclovir there was much more CMV in my patients."

Previous Acyclovir Studies

Two recently published trial reports do give some guidance about using acyclovir but these two studies raise many questions. The first paper[1] described a ten-year-old study in people with ARC or AIDS. The 265 trial participants received high doses of both AZT (250 mg four times daily) and acyclovir (4,800 mg per day). During the one year of follow-up, the death rate among the participants with AIDS was 41 percent in the AZT only arm and 21 percent in the AZT plus acyclovir arm. In the group with ARC, the death rate in the combination arm was a quarter of those in the monotherapy arm, but because of the small number of deaths, this reduction was only barely statistically significant. Adding acyclovir seemed to have no influence on CD4 counts or blood levels of HIV p24 antigen, although there was a profound decrease in herpes episodes.

Unfortunately, this trial was marred by the fact that nearly half the participants dropped out of the study before its termination, indicating a high level of dissatisfaction with the conditions of the trial. One of the problems was that participants were not allowed to receive prophylaxis for pneumocystis carinii pneumonia (PCP), which since then has become standard practice. The survival benefits of PCP prophylaxis are now well established and might overwhelm any benefit acyclovir confers when the two are used together.

The second paper described a trial in people with ARC or AIDS who were using acyclovir to prevent infections with cytomegalovirus (CMV).[2] Acyclovir failed to reduce the incidence of CMV despite the use of very high doses (800 mg four times a day). Herpes outbreaks were significantly reduced, though, and death rates decreased by more than 40 percent over the course of a year.

These two studies are highly suggestive, but neither is definitive about how and when to gain the most advantage from acyclovir. One important issue is the proper dosage to take. Another is the duration of acyclovir's benefit.

The MACS Study

Now, statisticians have analyzed data obtained from the Multicenter AIDS Cohort Study (MACS), which follows the experiences of over 2,600 HIV-positive men in four U.S. cities.[3] The new analysis looked back at what happened to 786 men who began AZT prior to an AIDS diagnosis, including 515 who subsequently also received acyclovir for any reason. The authors found that the use of acyclovir was not associated with a lower rate of progression to AIDS. But once one had AIDS, it reduced the risk of death in any given time period, again, by more than 40 percent. The median dose of acyclovir used by MAC participants was in the 600 to 800 mg per day range. Survival benefits conferred by the drug did not seem related to the dose, although they did correlate with greater duration of use. Neil Graham, M.D., of Johns Hopkins University and one of the report's authors, says, "Given the limited nucleoside analogs available, taking acyclovir now makes sense. It's well tolerated. There's now enough data to indicate that people with both AIDS and herpes virus should take it. This is the first evidence that combination therapy works."

Lead author Daniel Stein, M.D., of the Albany [New York] Medical Center, is more circumspect, however. He commented, "Before we can say whether people should take acyclovir, we have to look at the unanswered questions. There were certain things we couldn't answer: Exactly who do you treat? At what dose? When do you start?"

More Clinical Data

An observational data base like the MACS can indicate the unsuspected value of available therapies since it studies the outcome of using various medications in real clinical practice. Yet many of the details remain obscured because of the large differences in the way medicines are used and the range of individual differences between patients. There is also the problem of "confounding variables." Use of acyclovir may be associated with other factors, such as higher quality overall health care, higher income levels, and greater access to current treatment information and experimental therapies, which may be responsible for the decrease in death rate.

Data on the way from several clinical trials should help clarify the issues surrounding acyclovir's significance in prolonging survival. ZDV/ACV Collaborative Study: Two years ago, researchers released preliminary results from a three-year, 677-person study comparing AZT (also known as ZDV) to AZT plus high dose acyclovir (4,800 mg per day) in early symptomatic HIV infection were released.[4] Investigators reported at the time that "preliminary analysis suggests the combination of [AZT and high dose acyclovir] is safe and may enhance CD4+ cell response." The final analysis is now being prepared for publication, and, according to a Treatment Issues source, will not indicate any survival advantage to using high dose of acyclovir with AZT in this HIV-positive group. The slightly greater CD4 count in the group taking AZT plus acyclovir was not considered statistically significant.

ACTG 204: After two years, enrollment in another acyclovir study, the government-funded ACTG 204, has just filled up. This 1,000 person, one-year study compares high-dose acyclovir (800 mg four times a day) versus low-dose acyclovir (400 mg twice a day) versus high-dose valaciclovir (2,000 mg four times a day). (Valaciclovir is a new acyclovir "prodrug" that breaks down into acyclovir in the body and, reportedly, is much better absorbed. Like both acyclovir and AZT, it is manufactured by Burroughs Wellcome.)

Unfortunately, the main purpose of ACTG 204 is to test the two drugs as CMV preventives in people with AIDS. The previous trials mentioned above do not hold out any hope that they will delay CMV in people with HIV, although the massive quantities of drug delivered by the valaciclovir prodrug form have not been tried before.

The survival data collected in ACTG 204 will provide some further evidence as to whether people with AIDS live longer on high or low dose acyclovir. But since everyone in ACTG 204 will be on some regimen of acyclovir or valaciclovir, the trial cannot say whether some acyclovir is better than no acyclovir in prolonging survival.

ACTG 063: One study that could definitively answer many of the questions surrounding acyclovir's role in treating AIDS is ACTG 063, which has been languishing in the hands of the statisticians for over a year. ACTG 063 is a two-year trial comparing AZT to AZT plus acyclovir (400 mg twice daily) in 400 persons with CD4 counts of less than 200. Data collected included survival rates, the incidence of opportunistic infections, and the effect of treatment on human herpes virus-6 (HHV-6) and Epstein-Barr virus (EBV). Both of these viruses are herpes viruses related to the herpes simplex (HSV) and varicella zoster (VZV) viruses that cause cutaneous herpes outbreaks and shingles, respectively.

Results from ACTG 063 Languish

One of ACTG 063's principle investigators, Anne Collier, M.D., of the University of Washington, said, "I am extremely frustrated. I more than anyone want to know what the data say and fought to keep the trial going." Dr. Collier at this point would not hazard a guess as to when the analysis of 063 will be finished.

Dr. Collier lists in-fighting within the government's ACTG network and manufacturer Burroughs Wellcome's wavering financial support as two of the major obstacles to ACTG 063's completion.

AIDS-related acyclovir trials have not been accorded priority by either private or public researchers. According to noted AIDS researcher Michael Saag, M.D., of the University of Alabama, "People don't stand up and endorse acyclovir because no one understands why it should work." (Dr. Saag was one of the investigators in the acyclovir plus AZT for early HIV infection trial mentioned above. He now says that he is beginning to suggest that advanced patients take acyclovir, but "not with the same enthusiasm as I recommend prophylaxis for pneumocystis.")

Unknown Mode of Action

Acyclovir, although it is a nucleoside analog like AZT, has no established effect on HIV levels. Its proponents therefore wonder whether it works by preventing the effects of one or more herpes viruses.

The value of preventing a devastating, life-threatening opportunistic infection like PCP is obvious and the life-extension benefits have been documented in clinical practice.[5]

But herpes virus infections most often do not have extreme, debilitating effects (except for CMV, which acyclovir apparently does not prevent). It may be that the long-term immune stimulation provoked by a chronic unsuppressed herpes infection promotes an increase in HIV replication. Another possibility is that the specific type of immune response elicited by herpes viruses creates conditions favorable to HIV or that reinforces the disease process leading to AIDS. Altered levels of some specific cytokine (intercellular messenger molecule), say, could increase cell death, reinforcing the effect of HIV.

Finally, herpes viruses may force the cells they infect to produce some substance that is helpful to HIV. A report published last winter described an enormous increase in both HSV and HIV replication in cell cultures in co-infected individuals.[6] The report's chief author, Madalene Heng, M.D., of the University of California Los Angeles, told Treatment Issues, "We think that herpes simplex virus makes the difference between ARC and advanced disease. HIV and herpes simplex activate each other's promoter sequence and exchange DNA. Normally HIV infects only CD4 cells, but there are HSV-HIV hybrids that can enter most other cells."

Burroughs Wellcome's Role

Unless acyclovir's anti-AIDS mechanism is definitively elucidated, Burroughs Wellcome is unlikely to incur the substantial cost of a full-scale human testing program when the drug does not work well against HIV in the laboratory. But perhaps the major reason such a trial is unlikely is the fact that acyclovir's U.S. patent will expire in three years. One financial analyst noted, "The market for end-stage HIV is small compared to herpes. Wellcome's strategy seems to be to make acyclovir an over-the-counter drug (OTC) while shifting the prescription market to the new prodrug, valaciclovir." For HIV and AIDS therapy, Burroughs' new drugs include the nucleoside analog 3TC and a protease inhibitor - both bought from other companies and likely to be tested in combination with AZT.

There will be a small revolution in the cost of treatment should a major AIDS drug become available over-the-counter, without prescription. (As a prescription drug, acyclovir at present costs about $2.00 per 400 mg tablet.) But at the Food and Drug Administration, deliberations on changing acyclovir's status have been postponed until the end of the year.

The major issue holding up the change concerns the development of resistant viruses. Inappropriate or intermittent use of acyclovir creates environmental pressures favoring herpes viruses containing mutations that render the drug ineffectual. Resistant viruses are particularly likely to evolve in people with immune deficiencies, and these are just the people most in need of the active drug. (Infection with acyclovir-resistant herpes usually requires intravenous foscarnet therapy, which has serious toxicities.)

Assistance Programs for Acyclovir

One of the questions about making acyclovir an OTC medication is whether insurance companies and state programs will continue to reimburse patients who take it.

Right now both Medicaid and the AIDS drug assistance programs in some states, including New York, cover acyclovir. In response to pressure from activists who pointed out that acyclovir was originally priced for intermittent, and not continual use, Burroughs Wellcome has instituted a very limited price cap for unreimbursed HIV-infected individuals. Under the program, patients who use in excess of 730 grams of acyclovir per year are entitled to an additional 730 grams of acyclovir free for the remainder of the year. For more information on Patient Assistance Programs at Burroughs Wellcome, call 800/722-9294.

For Those Considering Acyclovir

At this point, most of those who recommend acyclovir as a therapy for HIV-infection suggest it only in advanced disease. There is no hard data, as of yet, which supports using the drug before an AIDS diagnosis. In addition, no studies support using more than 600 to 800 mg per day, the standard herpes simplex suppressive dose. Whatever dose and point in time is best, though, acyclovir should be continued without a pause after it is started to reduce the chance of resistant virus.

It remains to be seen whether acyclovir is useful in HIV-infected people without any evidence of herpes simplex infection, but this question may not be as important as it might seem. In the MACS study, nearly everyone who tested HIV-positive also was positive for herpes simplex. (The MACS group includes only gay men, though. Trials in other populations are needed to find out how universally helpful acyclovir could be.)

One Final Question

One last question is whether acyclovir increases survival in people who are not taking AZT. As one observer wryly noted, though, "One thing you'll never find out from Burroughs Wellcome is whether acyclovir is useful without AZT."

1 Cooper DA, et al. AIDS. Feb 1993; 7(2):197-207.

2 Youle MS, et al. AIDS. May 1994; 8(5):641-9.

3 Stein DS, et al. Annals of Internal Medicine. Jul 15 1994; 121(2):100-8.

4 Lavelle J, et al. Eighth International Conference on AIDS. Jul 19-24 1992; abstract PoB 3585.

5 Osmond D et al., Journal of the American Medical Association. Apr 13 1994; 271(14):1083-7.

6 Heng MC, et al. The Lancet. Jan 29 1994; 343():255-8.

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