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Herpes Virus Infections, HIV, and Disease Progression

Recent reports have indicated that patients with HIV who take acyclovir in combination with antiretroviral agents experience prolonged survival, even though possible mechanisms for this effect are unclear and prophylactic acyclovir does not seem to affect progression to AIDS or development of CMV disease. We asked Daniel Stein, who has been involved in one of the acyclovir-antiretroviral investigations, to review the available data, and three other investigators to respond with their views. -- The Editors

Evidence of infection with one or more of the human herpes viruses, such as herpes simplex types 1 and 2, cytomegalovirus, and varicella, is common in individuals who are HIV infected. The interaction of the herpes viruses with HIV and their role in HIV-related morbidity and mortality have been the subject of extensive research. This brief review will focus on recent information related to whether prophylactic acyclovir can affect the progression of HIV infection.

Background

An acyclic nucleoside, acyclovir is highly effective and well tolerated in the treatment of varicella infections and in the treatment and prophylaxis of herpes simplex infections. Although acyclovir has no clinical role in the treatment of cytomegalovirus (CMV) infection, high oral doses (>3.2 g per day) decrease the development of symptomatic CMV disease in renal and bone marrow transplant recipients who are CMV antibody positive. Acyclovir alone has no activity against HIV-1. Broder and colleagues have reported in vitro synergistic activity when acyclovir is combined with AZT at concentrations between 2 and 200 µM, although this could not be confirmed by other investigators. No pharmacologic interactions between serum concentrations of acyclovir and AZT or apparent increase in toxicity have been demonstrated.

There are, however, mechanisms by which acyclovir could potentially affect HIV disease without a direct antiviral effect on HIV-1 or potentiation of AZT's action. Several investigators have reported an in vitro interaction between herpes viruses such as herpes simplex or CMV and HIV-1 replication. The early regulatory proteins of HSV (e.g., ICP0, ICP4) and CMV (e.g., IE gene) appear to lead to an activation of the HIV-1 long terminal repeat and increased transcription, resulting in increased production of HIV RNA. One could also speculate that the immune response to HSV or CMV replication would lead to increased cytokine release, which could potentially increase HIV replication.

In addition, pseudotyping, the phenomenon in which the core of one virus has the surface glycoproteins of another virus, has been observed with HIV when grown with HSV or CMV. Since the surface glycoproteins mediate the specific attachment whereby the host cell is infected, this could extend the potential infectable range of HIV.

It is unclear whether such interactions are clinically relevant, but two case reports of acute HIV-1/CMV coinfection suggested additional morbidity over what would be expected from either infection separately. In addition, a comparison of skin biopsies from patients with HIV-1/HSV coinfection as compared with specimens from patients with only HIV-1 or HSV as a single infection suggested a significant increase in the viral load of both viruses in the coinfected patients' keratinocytes and dermal macrophages. Other data suggest an increase in circulating HIV RNA at the time of a clinically recognized HSV infection.

Clinical Trials

In early clinical trials acyclovir doses of 3.2 g per day or more were used in an attempt to achieve serum concentrations that were predicted to be potentially synergistic with AZT. Despite these measures, no evidence of increased antiviral, immunologic, or clinical benefit was found for the combination of acyclovir and AZT over AZT alone. However, the power of these trials to find a difference in the comparison of combination with the AZT alone was limited by their small size and short follow-up. Larger comparative trials have subsequently been reported (see Table 1). In 12-month follow-up data from their earlier randomized, double blind, 6-month trial, Cooper et al. reported that acyclovir (3.2 g per day) significantly interacted with AZT to prolong survival in both the AIDS¹ and the AIDS-related complex groups² of their trial. They found no effect on progression to AIDS or development of clinical CMV disease. However, in a Cox model that adjusted for imbalances in baseline CD4 lymphocyte counts and disease symptoms, the observed difference in survival between the AZT and combination arms became nonsignificant. Most of the participants received acyclovir after the first year with follow-up to 192 weeks still showing a survival difference.

Similar findings were reported from the Wellcome-United Kingdom trial (Youle, et al.), which was stopped in December, 1991, for lack of effect of high-dose acyclovir on development of CMV disease. However, they reported a one-year estimated mortality probability in the acyclovir arm of 0.23 as compared with the control arm's 0.39 (P = 0.018).

In contrast to earlier trials, the AZT/Acyclovir Collaborative Group study (Michael Saag, personal communication), using 4.8 g of acyclovir/day with 600 mg of AZT over a 96-week follow-up, reported a trend toward greater CD4 lymphocyte cell count response in the acyclovir plus AZT arm over AZT alone during the first year. As might be expected in a study with patients with CD4 counts above 200, the death rate was very low (three on AZT alone and one on the combination) and not significantly different in the two groups.

To determine whether acyclovir plus AZT vs. AZT alone is associated with a beneficial effect on progression to AIDS, development of CMV disease, or survival, we analyzed data from the Multicenter AIDS Cohort Study (MACS), a large prospective epidemiologic study of homosexual men. Along with other information, clinical outcome and laboratory data on participants who used AZT with and without acyclovir have been gathered at regular six-month intervals. Since treatment group assignment is not randomized in such an observational study, care was taken to control for potential biases introduced by differential disease stage, use of other therapies, and temporal trends in survival between treatment groups.

Of 786 men who started AZT prior to a clinical AIDS diagnosis, 515 subsequently took acyclovir during the follow-up period. Acyclovir use by patient report was classified on the MACS data forms by response to two questions. Participants were asked if they had used any medication for health reasons not related to AIDS or if they had taken any medication to help fight AIDS or HIV. Acyclovir was one of the medications in the list under each question. The "any use of acyclovir" group (N=488) consisted of those who indicated use of acyclovir under either or both questions, while the "AIDS or HIV" group (N=242) indicated use only under the latter question. It was hypothesized that acyclovir for any use represented a population with a broad range of doses, administration, and chronicity of use similar to what might be expected in overall clinical practice. The "AIDS or HIV" indication group was hypothesized to represent a population that might better test acyclovir's effects because of the use of possibly higher and less intermittent doses than among men who used acyclovir for any indication. We also formally tested these assumptions on dose, administration, and chronicity.

The main findings of our analysis were a clinically significant prolongation of survival by the concurrent use of acyclovir and AZT and no effect on progression to AIDS or development of CMV disease. Acyclovir use with AZT was associated with a 26% and 36% decreased probability of death as compared to AZT alone for either any acyclovir use³ or acyclovir for an HIV indication.⁴ In the same model, as has been found in other studies, CD4 cell count, presence of HIV symptoms, and baseline hemoglobin were all predictive of survival. Trends were noted for the use of Pneumocystis carinii prophylaxis and use of other antiretroviral therapy being predictive of survival. Interestingly, reported symptomatic herpes episodes were associated with a trend towards shortened survival⁵ in the two models.

A relative hazard gives a ratio of the risk of development of an outcome to a reference group (in this case AZT and acyclovir vs. AZT alone). Therefore a relative hazard cannot give an absolute time difference between the two groups. In order to estimate what the absolute time difference might be, two landmark analyses of estimated survival were done, adjusting for baseline prognostic variables at the time of the landmarks.

The landmarks, or reference points in time, chosen were a) 1 year after starting AZT, an early time point, and b) reaching a CD4 count of 50 cells/mm³ or development of AIDS, a late time point. The use of acyclovir by the groups was compared relative to the landmarks. The categories used were: using acylovir at or prior to the landmark; either never using acyclovir or using it after the landmark; or never using acyclovir. Comparing the group using acyclovir at or prior to the landmark with the mean of the two comparison curves in each of the landmark analyses, the estimated length of the additional time to 90% survival is in the range of 154 and 210 days depending on the landmark used. Median survival was reached only for the late landmark (CD4 <50 cells/mm³ or clinical AIDS) and, utilizing the same assumptions, the increase in survival associated with acyclovir use would be approximately 374 days. Our analyses of drug administration indicate that the prolongation of survival by acyclovir in combination with other HIV therapy was associated with more uninterrupted use but was not associated with a discernible dose effect. (The median dose of acyclovir reported for the HIV indication group was 600 to 800 mg/day.)

The benefit appeared to be largest if concomitant acyclovir was given after a diagnosis of AIDS had been made. However, an important caveat is that this could also be secondary to the higher mortality in more advanced disease, which allows a difference to be more easily detected. The landmark analyses, although subject to a greater possibility of survival bias than the time-dependent models, demonstrated an estimated survival that was greater for the groups that started acyclovir at or prior to the landmark, or either never or after the landmark, as compared to those who never initiated acyclovir.

Potential biases which could have confounded our analysis include a systematic difference between participants taking acyclovir for different indications and its possible linkage to other care, which could potentially influence their survival. The presence of HIV-associated symptoms and symptomatic episodes of herpes were, however, both more common at baseline in the participants who reported taking acyclovir. Although adjustment for these prognostic factors were done in the time-dependent Cox models, any potential bias in these factors would tend to predict an increased mortality for the acyclovir groups, as we found that both of these covariates were associated with a tendency to shorten survival.

In the two groupings of acyclovir use there were similar effects on survival, indicating that the patient's reported reason for taking acyclovir did not appear to bias the outcome. The results of the dosage analysis, in which the participants taking acyclovir for an HIV indication, who were predicted to be both taking a higher dose and using the drug more chronically, demonstrated a median dose of 600 to 800 mg at the visits for which information was available and no discernible dose effect in the Cox modeling. It did not indicate a systematic difference between the groups. Consistent with the dosage analysis, the analysis of constancy of dosing done on all participants reporting acyclovir use indicated that greater uninterrupted use of acyclovir was associated with the greatest effect on survival.

The clinically significant difference in survival without an effect on progression to AIDS is an apparent incongruity. Potential explanations for this difference include:

• prophylaxis for various opportunistic infections and other changes in care that have resulted in a progressive prolongation of time to development of an AIDS-defining illness;
  
• changes over time in the types of events occurring;
  
• trends over time to progressively lower CD4 lymphocyte counts at the time of first AIDS event; and
  
• a trend towards an increasing proportion of patients who die without experiencing a 1987 CDC case-definition AIDS illness.
  

These trends would tend to increase the difficulty of distinguishing a difference between groups. The specific explanation however, remains unknown.

Conclusions

In our analysis and previous clinical trials no apparent effect on development of CMV disease or progression to AIDS was found. In the three studies with sufficient follow-up and number of deaths for analysis, all found a significant reduction in the risk of death in the concomitant acyclovir-AZT group.

One could argue on statistical grounds whether these trials were definitive. The groups in the Cooper et al. trial are not statistically different after correction for baseline imbalances; the Youle et al. trial was prematurely terminated; and the MACS analysis is of observational data.

If, however, we assume the results of these studies are correct and there is a survival advantage in the use of concomitant acyclovir, then what are the implications for care? What populations should be targeted for intervention? What dosage should be used? When should therapy be initiated?

Antibody testing showed the population examined in all of the large comparative studies had prior exposure to CMV. In the MACS it is likely that >90% also had prior exposure to HSV 1 or 2. Specific information from the other studies isn't available but prior exposure to HSV 1 or 2 is very common in homosexuals and intravenous drug users. Whether someone without prior CMV or HSV exposure would benefit from acyclovir use is unknown, but I would think it would be very unlikely. Whether it is the prior CMV or the prior HSV exposure that is more important for selecting the population that might benefit from concomitant acyclovir is unclear.

The dosage analysis from the MACS and the lack of effect on clinical CMV disease suggest HSV exposure to be the more important. A constant suppressing concentration of acyclovir could result in less reactivation of subclinical herpes replication and therefore less HIV replication. If this theory is correct, higher concentrations would not have additional benefit, which was, in fact, indicated in our analysis.

The optimal dose needed for an effect has not been determined. The randomized trials selected their use of high dose acyclovir (3.2 to 4.8 g/day) as part of their design. The only data on lower doses (those used for herpetic suppression, or 600 to 800 mg/day) is from the MACS analysis. The lack of an effect on CMV would suggest that high doses are unnecessary, but there is no comparative information. A multicenter international trial comparing low and high dose acyclovir with valacyclovir (a newer dosage form of acyclovir that has better absorption and therefore higher blood concentrations) will likely give needed information on dosage.

In all the large comparative studies the effect of concomitant acyclovir on survival was shown in those with low CD4 counts or after a clinical AIDS diagnosis. There isn't evidence at present that earlier use is beneficial. Since, as noted in the study by Saag et al. and in several early intervention antiretroviral trials, the death rate is very low in a group with a CD4 count of >200 cells, a trial to demonstrate an effect in this population is probably not feasible. Waiting until an individual's CD4 count is <150 or until after a clinical AIDS diagnosis would probably be the most cost-effective method of acyclovir use in the absence of other reasons to start earlier. Preliminary information from a large trial of 1 g three times daily of oral ganciclovir as compared to placebo in over 700 subjects with prior CMV exposure and CD4 counts <50 cells/mm³ may affect this conclusion. Ganciclovir, unlike acyclovir or famciclovir, has significant activity against CMV along with activity against HSV or varicella.

The manufacturer reports that the ganciclovir prophylaxis trial was terminated at its first Data Safety Monitoring Board review because of a highly significant effect on CMV disease with a borderline significant trend towards better survival. Further review of the data may support using oral ganciclovir in subjects with CD4 counts less than 50 cells and prior CMV exposure, with acyclovir or famciclovir being used in those with prior herpes simplex exposure alone. The finding of a survival difference in an additional trial using ganciclovir rather than acyclovir for prophylaxis of herpes viruses adds to the data in support of the role of herpes virus in increasing HIV disease progression.

Footnotes

1. One year estimated survival probability 0.54 versus 0.73 for the AZT and AZT plus acyclovir arms, respectively, P = 0.014

2. One year estimated survival probability 0.81 versus 0.97 for the AZT and AZT plus acyclovir arms, respectively, P = 0.045

3. Relative hazard = 0.74, 95% CI 0.53 to 1.03, P = 0.07

4. Relative hazard = 0.64, 95% CI 0.45 to 0.91, P = 0.01.

5. Relative hazard = 1.46, 95% CI 1.04 to 2.05, and relative hazard = 1.35, 95% CI 0.98 to 1.88, P = 0.03 and 0.07, respectively.

— Daniel S. Stein, MD

Dr. Stein is Associate Professor of Medicine and Director of the Clinical Pharmacology Studies Unit in the Divisions of Clinical Pharmacology and Infectious Diseases, Albany Medical College, Albany, New York.

Published in Journal Watch HIV/AIDS Clinical Care February 1, 1995

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Stein DS et al. The effect of the interaction of acyclovir with zidovudine on progression to AIDS and survival. Analysis of data in the Multicenter AIDS Cohort Study. Ann Intern Med 1994 121 100-108.

• Original article (Subscription may be required)
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