Acyclovir: Maybe Good News -- but Press Confusion

Confusing and contradictory press reports, starting in
London in late December and later picked up by the world press,
suggested that adding acyclovir to standard AIDS treatment with
AZT could reduce the AIDS death rate by half. We called a number
of parties involved, including Burroughs-Wellcome (the owner of
both acyclovir and AZT) and Michael Youle, M. D., one of the
designers of and investigators in the study, for clarification.

Little hard information is yet available -- for example,
although the trial has been stopped, the physicians running the
trial had not been unblinded (told which patients were receiving
the placebo) as of the time we went to press. The available
information is also hard to interpret because a significant
number of patients dropped out of the study. Researchers are
working rapidly to analyze the trial, so more should be known
before too long.

Dr. Youle designed an acyclovir study after he saw a report
at the 1989 International Conference on AIDS, in Montreal,
suggesting that high-dose acyclovir might be useful as
prophylaxis for CMV (Metroka and Josefberg, 1989). He approached
Burroughs-Wellcome and found that they were already planning a
larger acyclovir study. The trial which took place, in Europe
and Australia, enrolled a total of 280 patients; they had to have
T-helper counts under 150 to enter, and most had counts under
100. Patients received either 800 mg of acyclovir four times a
day, or placebo.

The original endpoint of the trial was development of CMV;
later, mortality was added as another endpoint (for purposes of
looking for a statistically significant difference between
treatment and placebo groups). The trial was stopped in December
1991 because, in view of the data gathered to that point, it
would have been impossible for the trial to show a statistically
significant difference in CMV incidence between treatment and
placebo groups. (This does not mean that there was no
difference, but rather that this particular trial could not
determine whether there was a difference or not, which this trial
had been designed to do.)

This trial administered only acyclovir or placebo, not AZT.
The patients were receiving antiretroviral treatment anyway,
however, with most taking AZT, and a few taking ddI. No serious
toxicity of acyclovir has been seen.

This study was designed to look closely at viral culture
data, including viral resistance (to AZT and perhaps to other
drugs). This data, along with the survival results when they are
more fully analyzed, should be the most useful results of this
study.

History

The idea of using acyclovir in HIV treatment, other than for
its labeled use as an anti-herpes drug, is not new; AIDS
TREATMENT NEWS reported on this use in issue #83, July 14, 1989.
Many papers have been published on this use of acyclovir alone,
or in combination with AZT, and many physicians have used
acyclovir in this way. A number of them have suggested that
acyclovir might be beneficial, perhaps by suppressing viruses
which are harmful in themselves and which might act as cofactors
which could speed the progression of HIV disease. Physicians are
divided on this use of acyclovir.

The references below show some of the published studies on
use of acyclovir in HIV treatment (other than its standard use
against certain herpes viruses). This list is not complete, and
we have not had time to analyze these papers before writing this
article. We include the references to show how much work has
been done, and to provide a starting point to others who may want
to look deeper into the use of acyclovir in HIV treatment.

What should be done now? One possibility is to use a
relatively new statistical method called meta-analysis to combine
the information from the existing studies of long- term acyclovir
use in HIV treatment. The advantage of this approach is that no
new study has to be done; therefore the meta-analysis can be
completed much more rapidly and less expensively than the large-
scale, multicenter trial which would be necessary to obtain
similarly definitive results from a single study.

A meta-analysis could be particularly important if (as we
suspect may be the case) acyclovir is indeed beneficial in HIV
treatment, and has not been given due credit simply because each
separate study, seen by itself, is not definitive.

Technical Articles

Brockmeyer NH, Kreuzfelder E, Mertins L, Daecke C, and Goos M.
Zidovudine therapy of asymptomatic HIV1-infected patients and
combined zidovudine-acyclovir therapy of HIV1-infected patients
with oral hairy leukoplakia [letter]. J. Invest. Dermatol.
April 1989; volume 92, number 4, page 647.

Chavanet P, Aho S, Mallet J, and others. Randomized trial of
placebo versus high dosage acyclovir in HIV patients (English
translation of title). V International Conference on AIDS
[abstract # T. B. P. 304], Montreal, June 4-9, 1989.

Chavanet P, Mallet J, Waldner A, and others. A double-blind
randomized placebo trial on very high doses of acyclovir in
weakly symptomatic HIV patients. Cancer Detect. Prev. 1990;
volume 14, number 6, pages 669-673.

Collier A, Coombs R, Bozette S, and others. Virologic and
clinical response to combination zidovudine (AZT) and acyclovir
(ACV) in AIDS-related complex (ARC). Twenty-Ninth Interscience
Conference on Antimicrobial Agents and Chemotherapy [abstract #
30], Houston, September 17-20, 1989.

Coombs RW, Collier AC, Chaloupka K, and Corey L. Decreased HIV
plasma titer in response to combined low-dose zidovudine and
acyclovir therapy in CDC class IVA patients. VI International
Conference on AIDS [abstract Th.B. 24], San Francisco, June 20-
23, 1990.

Fiddian AP. Preliminary report of a multicentre study of
zidovudine plus or minus acyclovir in patients with acquired
immune deficiency syndrome or acquired immune deficiency
syndrome-related complex. J. Infect. January 1989; 18
Supplement 1, pages 79-80.

Hollander H, Lifson AR, Maha MA and others. A phase I study
evaluating combination zidovudine and acyclovir in asymptomatic
HIV-infected men: Virologic and immunologic effects. IV
International Conference on AIDS [abstract # 3135], Stockholm,
June 12-16, 1988.

Hollander H, Lifson AR, Maha M, Blum R, Rutherford GW, and
Nusinoff-Lehrmann S. Phase I study of low-dose zidovudine and
acyclovir in asymptomatic human immunodeficiency virus
seropositive individuals. American Journal of Medicine. December
1989; volume 87, number 6, pages 628-632.

Hollander H, Moore M, Nusinoff-Lehrmann S, Barnhart J, and Lifson
A. One year follow-up of zidovudine plus acyclovir in
asymptomatic HIV-seropositives. V International Conference on
AIDS [abstract # M. B. O. 50], Montreal, June 4-9, 1989.

Holmberg SD, Gerber AR, Stewart JA, Lee FK, O'Malley PM, and
Nahmias AJ. Herpesviruses as co-facators in AIDS [letter].
Lancet. September 24, 1988; pages 746-747.

Lifson AR, Hollander H, Maha MA and others. A phase I study of
combination zidovudine and acyclovir in asymptomatic HIV-
infected men: Safety and toxicity. IV International Conference
on AIDS [abstract # 3134], Stockholm, June 12-16, 1988.

Metroka CE and Josefberg H. Possible usefulness of high dose
acyclovir as prophylaxis for CMV. V International Conference on
AIDS [abstract # M. B. P. 126], Montreal, June 4-9, 1989.

Mulder J, De Wolf P, Coutinho RA, Goudsmit J, and Lange JMA. Long
term treatment with zidovudine (+/- acyclovir) of asymptomatic
HIV-I infected subjects. VI International Conference on AIDS
[abstract # S. B. 449], San Francisco, June 20-23, 1990.

Surbone A, Yarchoan R, McAtee N, and others. Treatment of the
acquired immunodeficiency syndrome (AIDS) and AIDS-related
complex with a regimen of 3'-azido-2',3'-dideoxythymidine
(azidothymidine or zidovudine) and acyclovir. A pilot study.
Annals of Internal Medicine. April 1988; volume 108, number 4,
pages 534-540.

Walger PP, Baumgart G, Wilke G, Kupfer U, Schwaaf A, and Dorst
KG. Effectiveness of low-dose-combination therapy with
azidothymidine (zidovudine) and acyclovir in AIDS- and ARC-
patients. V International Conference on AIDS [abstract # W. B.
P. 318], Montreal, June 4-9, 1989.

Weber R, Bonetti A, Luthy R, Putzi R, Spacey B, and Siegenthaler
W. Effect of combination of zidovudine and interferon-alpha
compared with zidovudine and acyclovir on HIV-antigenaemia in
asymptomatic patients. V International Conference on AIDS
[abstract # W. B. P. 321], Montreal, June 4- 9, 1989.

Webster A, Lee CA, Cook DG, and others. Cytomegalovirus
infection and progression towards AIDS in haemophiliacs with
human immunodeficiency virus infection. Lancet. July 8, 1989;
pages 63-66.