The Gay Men's Health Crisis Newsletter of Experimental Therapies - Volume 6, Number 2 - February 1992
Spencer Cox

Background

Acyclovir is a nucleoside analogue (one class of general antiviral drugs) which has activity against viruses in the herpes family, including herpes simplex I & II; herpes zoster (chicken pox or shingles), Epstein-Barr Virus (EBV), and cytomegalovirus (CMV).[2] The drug is approved for the treatment of herpes simplex and herpes zoster, and for prevention of herpes simplex. In addition, it has been suggested that very large doses of the drug may prevent reactivation of latent CMV infections in persons who have a compromised immune system.[3]

It has recently been hypothesized that since acyclovir acts against herpes viruses, the drug may work against the newly-discovered human herpesvirus-6 (HHV-6), a virus which may play an important role in the deterioration of the immune system. HHV-6 has been found in the saliva of HIV-infected individuals,[4] and has been found in high concentrations among individuals with primary CMV infection.[5]

CMV Infection, Disease, and Prophylaxis

CMV is a herpes virus that is generally benign in persons with healthy immune function. Many people in the general population (60-90%) have been exposed to the virus, but are able to build antibodies against it and stave off CMV illness. In other words, many people have "latent" or inactive CMV infection. However, in people with AIDS and other immune-compromising conditions, in newborns, and organ transplant patients, latent CMV can become reactivated and cause serious diseases including retinitis, colitis, pneumonia, ulcers in the stomach and esophagus, hepatitis, and other organ-system diseases.[6] Additionally, new infections of CMV in persons with weak immune systems can cause severe flu-like symptoms including swollen glands, fever, and a sore throat.

A British study indicated that high dose acyclovir may not prevent active CMV infections in persons with AIDS, but seems to extend their life.

Infection with CMV is fairly common in the U.S. CMV is transmitted through sexual contact, from CMV-infected mother to fetus, and by organ transplants. The virus has been found in about 5% of donated blood. The probability of infection seems to-rise with age: about 20% of 20-year-olds are infected with CMV, and about 70% of 60-year-olds.[7] Gay men may be at particular risk for CMV infection. One study of men attending an STD clinic in San Francisco found that 94% of gay men were infected with CMV as opposed to 54% of heterosexual men.[8] Similar findings have been reported from Houston, Germany and the Netherlands.[9]

Following infection with CMV, the virus usually enters a period of latency, which means it does not actively cause illness. However, the virus is susceptible to reactivation and when activated can be transmitted by what is called viral "shedding." When the patient is shedding virus, CMV can be detected in bodily fluids such as saliva, urine, and semen. Shedding seems to be correlated with immunosuppression: one study found CMV shedding in 100% of gay men with under 100 T4 cells; 83% of men with T4 cells from 100-199; and 75% of men with 200-300 T4 cells.[10] Several studies have found evidence of symptomatic CMV disease in about 50% of autopsies performed in persons with AIDS.[11] One study suggested that CMV was the immediate cause of death in 12% of persons with AIDS.[12]

Recent evidence points out that CMV infection is a significant co-factor for HIV disease progression. In a study of 108 HIV-positive hemophiliac patients, the risk of developing AIDS was 2.5 times higher in CMV-infected persons compared to people who did not have CMV infection.[13] There are many proposed reasons for this possible correlation. First, active CMV infection is thought to cause immune suppression.[14] CMV is also believed to stimulate the production of a growth-causing protein called tumor necrosis factor (TNF), which has been shown to increase HIV reproduction in infected cells. Furthermore, in cells infected with both CMV and HIV, reproduction of both viruses is thought to be enhanced.[15]

CMV-related Illness

CMV is the most frequent cause of blindness and retinal damage. Retinitis occurs in 5%-10% of AIDS patients. Gastrointestinal disease due to CMV is seen in about 10% of AIDS patients, and may be a significant cause of weight-loss, malabsorption, and diarrhea. Other CMV diseases seem to occur less frequently in AIDS.

Treatment for CMV

Ganciclovir (DHPG; brand name Cytovene) and foscarnet (brand name Focavir) are standard treatments for CMV disease. However, these drugs are inconvenient for preventing CMV in patients who have not been previously exposed, since the drugs require a catheter and have significant toxicities. Several studies of acyclovir, administered intravenously and orally, found that the drug caused significant reductions in the occurrence of CMV disease and improved survival in organ transplant patients.[16] It should be noted, though, that there is some conflicting evidence concerning the effectiveness of oral acyclovir in preventing CMV disease.[17] Some studies seem to indicate that acyclovir might be more effective at preventing CMV infection in persons who have not been exposed, than in preventing a reactivation in persons who have been exposed and have a latent, or asymptomatic infection.[18]

In a recent study by Dr. Craig Metroka, a New York physician, found no evidence of CMV disease in 51 patients with under 150 T4 cells who were taking high-dose oral acyclovir. Additionally, 15 patients of another group of 51 who did not take the treatment, developed CMV retinitis.[19] Acyclovir is relatively non-toxic, but occasionally produces headaches or nausea. At high doses, it can sometimes cause toxicity to the kidneys.

Controversial Recent Findings

The controversial British study followed 300 patients with T4 cell counts under 150. Half of the participants took 3200 mg per day of oral acyclovir and half took placebo. Results showed that the drug did not reduce the probability of CMV disease[20] After one year, it was clear that just as many people receiving acyclovir were developing CMV infection as those who were not receiving the drug. Burroughs Wellcome, stopped the trial for this reason. It was incidentally noted, upon preliminary analysis of the data, that participants receiving acyclovir had a better survival rate than those not receiving the drug. The survival benefit shown by high dose acyclovir did not depend on whether or not participants took AZT, ddI, ddC, or had no anti- HIV therapy.[21] It should be noted, that this study was not designed to compare survival rates, and full analysis of the data is needed.

In a phone interview, one British investigator stated clearly that the study was too small and the patients were too healthy to detect a significant effect of the drug on CMV disease. For the most part, CMV disease is found in patients with under 100 T4 cells. According to this investigator, the researchers involved believe that the difference in survival was due to the effect of acyclovir on latent CMV infection, and deserves further investigation.

Physicians' Views on Wide-Spread Use

Dr. Joseph Sonnabend, the Medical Director of the Community Research Initiative on AIDS (CRIA) is adamant about the value of high-dose acyclovir for the prevention of latent CMV infections. "There is an entire body of evidence that the herpes viruses are co-factors for HIV disease progression," says Dr. Sonnabend. "DHPG, foscarnet, and now acyclovir have been shown to extend survival." Sonnabend believes that the herpes viruses, through a variety of mechanisms, can speed up HIV disease. CMV and EBV have clear immune-suppressing effects, he says. "Acyclovir may not provide comprehensive protection against symptomatic CMV," he asserts, "but there are clear benefits to long-term, high-dose acyclovir therapy in people with AIDS."

Dr. Sonnabend prescribes acyclovir for patients with less than 300 T4 cells, or patients with less than 500 T4 cells if they are declining rapidly. The standard dose he prescribes is one 800 mg pill every four waking hours or four grams of acyclovir a day.

Dr. Howard Grossman, a prominent physician in private practice in New York City, is a bit more conservative about prescribing acyclovir. "I used to try to put whoever wanted [the treatment] on high-dose acyclovir," explains Dr. Grossman. "Then people started to talk about CMV retinitis that was resistant to DHPG, and there were indications that people were getting retinitis in spite of acyclovir prophylaxis." Now Dr. Grossman prescribes lower doses--400 mg of acyclovir a day in 200 mg pills. This dose is standard for the suppression of herpes. "If T4 cells go below 75, then I put patients on high-dose acyclovir. I give those patients 3200 mg a day, which is four 800 mg pills." Dr. Grossman states that there have been few side effects. "I've seen some abdominal upset and diarrhea, but we're not even sure it's drug related."

Dr. Donald Abrams of the Community Consortium in San Francisco claims that he has never seen any toxicities with acyclovir. "Almost all of our patients are taking it," he said. "Our observational data base found that 270 of 300 patients were on some dose of acyclovir, and the mean dose was about 1 gram per day." Dr. Abrams routinely prescribes acyclovir, "for no particular reason."

"It's a benign drug," he explains, "I tell my patients that obviously HIV will have a harder time attacking the immune system without the help of a herpes virus." Dr. Abrams routinely prescribes 3200 mg of acyclovir for patients at risk for CMV disease.

While high-dose acyclovir seems to be a common addition to treatment regimens, there is some evidence that using acyclovir may be of little benefit to persons with HIV/AIDS

The Jury's Still Out?

While high-dose acyclovir seems to be a common addition to HIV regimens, there is some evidence that using acyclovir may be of little benefit to persons with HIV/ AIDS. An early ACTG study found neither added benefit nor added toxicity by adding high dose acyclovir to AZT therapy.[22] It should be noted that this trial studied only 67 patients for a short 12-week period. However, the same no-benefit conclusion was drawn from a similar but larger European-Australian study of 200 ARC patients.[23] Some researchers and doctors are skeptical of the benefit, and are conservative about prescribing high-dose acyclovir until conclusive scientific evidence indicates a clear benefit to the drug in HIV treatment.

Toxic to the Pocketbook

The main toxicity to high-dose acyclovir is a pain in the wallet. One bottle of 100 pills (200 mg per pill) routinely costs $60 - $85 . The price is unlikely to be reduced. In fact, each time Burroughs Wellcome has reduced the price of AZT, it has also increased the price of acyclovir. Since high doses of acyclovir are not approved for the prevention of CMV, there may be difficulty with insurance reimbursement. The New York State AIDS Drug Assistance Program (ADAP) has refused to pay for high-dose acyclovir, and private insurers are notoriously conservative about reimbursing the use of unapproved drugs.

References:

1. "Skepticism on AIDS Report," New York Times, December 31,1991.

2. Physicians Desk Reference, Vol. 44,1990, p. 816.

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

4. Levy JA et al. Characterization of a new strain of HHV-6 recovered from the saliva of an HIV-infected individual. 178:113-21, 1990.

5. Irving WL et al. Dual antibody rises in CMV and HHV-6: frequency of occurrence in CMV infections and evidence for genuine reactivity to herpes viruses. The Journ of Infect Dis 161:910-916, 1990.

6. Drew et al. Herpes virus infections caused by CMV, HSV, and VZV: in The Medical Management of AIDS, ed Sande & Volberding (Philadelphia: W.B. Saunders Co., 1988), p.271.

7. Wentworth BB & Alexander ER. Seroepidemiology of infections due to members of the herpes virus group. Journ of Epidem 94:496-507, 1971.

8. Drew WL et al. Prevalence of CMV in homosexual men. Journ Infect Dis 143:188-192, 1981.

9. Greenberg SB et al. Lymphocyte subsets and urinary excretion of CMV among heterosexual men attending a clinic for STDs. Journ of Infect Dis 150:330-333, 1984; Coutinho RA et al. Infection with CMV in homosexual men. Brit Journ of Vener Dis 60:249-252, 1984; and Doldi K et al. Proliferative responses to human CMV in lymphocyte cultures of male homosexuals. Journ of Clin Lab Immun 17:111-114, 1985.

10. VIIth Int'l Conf on AIDS, Poster Presentation # W.B .2277, Florence, June 1991.

11. Klatt EL. Diagnostic findings in patients with AIDS. Journ of AIDS 1:459-465, 1988; and VII Int'l Conf on AIDS, Abstract # M.B. 81, Florence, June 1991.

12. Klatt EL. Diagnostic findings in patients with AIDS. Journ of AIDS 1:459-465, 1988.

13. Webster A. Cytomegalovirus a possible cofactor in HIV disease progression. Journ AIDS 4 [suppl]:S47-52, 1991.

14. Rinaldo CR Cytomegalovirus as a cofactor, in HIV infection and AIDS in Cofactors in HIV Infection and AIDS (Boca Raton: CRC Press, 1990) pp. 151-85.

15. Skolnik et al. Bidirectional interactions between HIV type-1 and CMV. Journ of Infect Dis 157:508-514, 1988.

16. Meyers et al. Acyclovir for prevention of CMV infection and disease after allogenic marrow transplantation. NEJM 318:70-75, 1988; Gluckman E et al. Prophylaxis of herpes infection after bone marrow transplantation by oral acyclovir. Lancet (ii):706-8, 1983; and Balfour et al. A randomized placebo-controlled trial of oral acyclovir for the prevention of CMV disease in recipients of renal allografts. NEJM 320:1381-7, 1989.

17. Wade JC et al. Oral acyclovir for prevention of herpes virus reactivation after marrow transplantation Ann of Intern Med 100:823, 1984; and Prentice HG et al. Use of prophylaxis of herpes infection in severely immunocompromised patients. Journ of Antimicrob Cherno 12 [suppl. B]:153-159, 1983.

18. Gluckman E et al. Prophylaxis of herpes infection after bone marrow transplantation by oral acyclovir. Lancet (ii):706-8, 1983; and Balfour et al. A randomized placebo-controlled trial of oral acyclovir for the prevention of CMV disease in recipients of renal allografts. NEJM 320:1381-7, 1989.

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

20. Youle, M. Personal Communication, January 3, 1992.

21. Ibid.

22. Collier AC et al. A pilot study of low dose zidovudine in HIV infection. NEJM 323:1015-21, 1990.

23. Cooper DA et al. The efficacy and safety of AZT with ot without acyclovir in the treatment of patients with ARC. AIDS 5(8):933-43, 1990.

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