AIDS TREATMENT UPDATE, Issue 27 - March 1995
Edward King

Previous research

Acyclovir, often known by its tradename Zovirax, has been used for several years to treat infections with herpes simplex and herpes zoster (shingles). After a test-tube study suggested that the combination of AZT plus acyclovir had a greater anti-HIV effect than AZT alone _ a finding that hasn't been confirmed by other test-tube studies _ placebo-controlled trials to investigate the combination were begun. The results apparently showed that among people with ARC or AIDS, those taking acyclovir as well as AZT were less likely to die during the first year of treatment than those taking AZT alone. However, people taking acyclovir tended to have slighter higher CD4 counts at baseline, and when this was taken into account the difference in survival was no longer statistically significant i.e. it could have been due to chance.

Other researchers were investigating whether high doses of acyclovir could prevent disease caused by CMV, which also belongs to the herpes virus family. The trial found that it couldn't _ there was no difference in the occurrence of CMV disease between acyclovir recipients and placebo recipients. But people with CD4 counts below 150 who took acyclovir did live significantly longer than those in the placebo group.

More evidence came from a retrospective analysis of participants in the US Multicenter AIDS Cohort Study (MACS). Last year, researchers reported that participants who took acyclovir for treating or preventing herpes simplex infections seemed to have significantly longer survival than people who didn't take acyclovir. The longer the uninterrupted time during which people took acyclovir, the greater the improvement in survival seemed to be. However, retrospective studies like this are subject to various unpredictable biases and their results can never be considered definitive.

Scientists have tried to explain these findings by pointing to evidence that herpes virus infections may act as co-factors to HIV, speeding up the progression of the disease. Laboratory studies have shown that herpes simplex and CMV may increase HIV replication, and that infection with human herpes virus 6 (HHV-6) may make cells more vulnerable to infection with HIV too. HIV and herpes viruses may also infect the same cells, causing increased damage, or even merge to create viruses that can infect a wider range of cells than either virus alone. It's not known what implications, if any, these test-tube phenomena may have for disease progression in people. Research from the Royal Free Hospital in London has suggested that HIV-positive hæmophiliacs who are also infected with CMV may progress to AIDS faster than those who do not have CMV, although statistically this finding could simply be due to chance (see AIDS Treatment Update issue 21/22, page 14).

Latest research

The two new studies were presented at the Second National Conference on Human Retroviruses and Related Infections held in Washington at the end of January. The first was a placebo-controlled trial known as ACTG 063, which was designed specifically to compare the survival of people treated with the combination of high-dose acyclovir (4 g/day) plus AZT with that of people treated with AZT alone. It enrolled 334 people who had been diagnosed with PCP or who had a CD4 count below 200; their average CD4 count on entry to the study was 63. The researchers concluded that acyclovir did not prolong survival because they could detect no difference between the groups in terms of the number of deaths, the duration of survival or the causes of death. There were still no differences if they looked only at people with CD4 counts below 100 or only at those with counts below 50.

It is not the case that this trial was too small to be able to show a survival benefit; it was designed to be able to detect overall treatment effects similar to those seen in the earlier trials described above. However, although the trial followed participants for an average of over 2.5 years, participants received acyclovir or placebo for less than a year of this. For the rest of the follow-up time they were allowed to change treatment at will, but they were still analysed according to the original group to which they were assigned. This 'intention-to-treat' type of analysis could theoretically underestimate the effect of acyclovir if a significant proportion of the placebo group started taking acyclovir during the follow-up period. But nevertheless, this form of analysis is considered to give the most unbiased assessment of the likely effects of a treatment in the real world, in which people do stop and start various treatments.

The other study was a retrospective analysis of a cohort of over 1000 American HIV-positive gay men with CD4 counts below 250 who started taking AZT in 1987-1988. A third of the participants had taken acyclovir for at least 6 weeks during any 2-month period during which they were being followed. Unlike the MACS cohort described earlier, the researchers could find no evidence that acyclovir prolonged survival. Again, even looking at sub-groups such as those with CD4 counts below 100 or people with long durations of acyclovir use, no survival benefit could be seen.

Implications

These contradictory trial results leave people with HIV and their doctors in a dilemma. Some of the evidence suggests that acyclovir may prolong survival in people with low CD4 counts, while these recent studies suggests that it may be a waste of time and money. Even if acyclovir does affect survival, there is no clear information on what dose should be used _ the MACS study suggested that people taking the standard doses used for treating or preventing herpes simplex had improved survival, while the two controlled trials that suggested benefits (as well as the one that did not) used much higher doses.

An ongoing trial, ACTG 204, is studying the effects of acyclovir on CMV disease and survival. Participants in this study are randomly assigned to receive either:

- standard dose acyclovir (800 mg/day) - high dose acyclovir (3.2 g/day) - valaciclovir (8 g/day).

Valaciclovir is an acyclovir 'pro-drug' that breaks down into acyclovir in the bloodstream, giving the equivalent of very high doses of acyclovir. The results of the study are due later this year and researchers hope that it will help to establish whether high doses of acyclovir result in longer survival than the standard dose.

In the light of the confusion, AIDS Treatment Update contacted doctors at London's largest HIV centres to see how they are interpreting the data.

Current clinical practice

Professor Jonathan Weber of St Mary's Hospital said that they do not routinely use high-dose acyclovir "because the trial results have always been contradictory". He pointed out that the use of high dose acyclovir was based on the theory that it might inhibit a CMV co-factor, but that trials had shown that there was no reduction in the occurrence of CMV disease among people taking it.

Dr Ian Williams of the Mortimer Market Centre noted that only one study seems to show an unambiguous survival benefit from acyclovir. "My impression is that any effect of acyclovir on survival may be of only marginal benefit, perhaps three to four months. We would discuss the data with patients and if they wanted to take it, that's fine."

Dr Margaret Johnson of the Royal Free Hospital said that many people with advanced HIV disease want to reduce the number of tablets they are taking. "I advise anyone with recurrent herpes to take 800 mg/day acyclovir and discuss its possible survival effects with other patients, but it isn't something that's at the top of my list".

Professor Tony Pinching of St Bartholomew's Hospital told us "If there is a survival benefit then the MACS data suggest that high doses may not be necessary. A lot of our patients are on moderate doses of acyclovir as herpes prophylaxis so if there is an additional survival benefit they will be receiving it. For those patients who aren't taking acyclovir for herpes, it is one of the many issues we raise and some who want to take on other options do start to take acyclovir."

Dr Brian Gazzard of Kobler Centre, which was a major centre in the 1994 study that did show a survival benefit for acyclovir, said "We routinely recommend people with CD4 counts below 100 to take acyclovir. The MACS study suggests that you do get the survival benefit using the standard 800 mg/day dose of acyclovir that is protective against herpes, and that a high dose may not be necessary. But we will be reviewing our policy when we have examined the results of ACTG 063".

REFERENCES

The published studies suggesting that acyclovir does provide a survical benefit are:

Cooper DA et al. AIDS 5:933-943, 1991.

Youle MS et al. AIDS 8:641-649, 1994.

Stein DS et al. Ann Int Med 121:100-108, 1994.

STOP PRESS

As this issue of AIDS Treatment Update went to press we learned of an important new development in research into acyclovir and survival, writes Edward King. The researchers in charge of the ACTG 204 trial have stopped the study early on the advice of its Data and Safety Monitoring Committee. Doctors have told participants that there were significantly more deaths in the valaciclovir arm than in the two acyclovir arms. 25% of the valaciclovir recipients are reported to have died, compared with only 20% of acyclovir recipients. However, valaciclovir was effective in reducing the occurrence of CMV disease, although acyclovir was not.

If confirmed, this finding adds a new level of complexity to the debate over whether acyclovir really does prolong survival. The study effectively compares three doses of acyclovir - standard dose (given in the form of normal acyclovir tablets), high dose (also given as acyclovir tablets) and a very high dose (provided by the valaciclovir).

One fact seems clear from this result - that high dose acyclovir was not more effective than the standard dose. However, the implications about valaciclovir are less sure.

One possible interpretation would be that acyclovir had no effect on survival in the two arms taking standard acyclovir tablets, and that people taking valaciclovir actually had their survival shortened by the drug. There are reasons to doubt this interpretation. Many thousands of people have been treated with valaciclovir, which is a licensed drug for treating herpes zoster, without any substantial side-effects occurring. Moreover, a large proportion of people enrolled in ACTG 204 had withdrawn for various reasons by the time the trial was stopped, and most deaths among people originally assigned to take valaciclovir occurred after they had stopped taking the drug.

Another possibility is that acyclovir does prolong survival, but that for some reason valaciclovir recipients did not benefit (and were not harmed). There was reportedly a higher drop-out rate in the valaciclovir arm, probably due to an increased rate of minor side-effects, so that group may have received less treatment and so had less benefit. A final possibility is that in reality there was no significant difference between the three arms of the trial (i.e. they were all equally effective or equally ineffective in prolonging survival) and that the increased death rate in the valaciclovir arm was simply a statistical fluke rather than a real phenomenon.

The next issue of AIDS Treatment Update will report further on these developments.

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