AIDS TREATMENT UPDATE, October 1995
Edward King

For people who have not yet begun anti-HIV treatment, the results unequivocally indicate that they should start with combination therapy, not AZT monotherapy.

It's less clear which combination therapy people should use. In Delta, there was a trend for people taking the AZT plus ddI combination to do slightly better than people taking the AZT plus ddC combination. However, people taking the ddI combination were more likely to choose to stop treatment because of side-effects than those taking the ddC combination. In ACTG 175, only the AZT plus ddC combination was significantly better than AZT alone at delaying clinical progression or death.

On the basis of Delta, licensing authorities are likely to approve both ddI and ddC for use in combination with AZT as initial ('first-line') therapy. Glaxo-Wellcome also hope that 3TC will soon be licensed for use in first-line combination therapy, on the basis of trials showing that it boosts CD4 counts and reduces viral load. But to date there is no evidence from which to judge the effects of AZT plus 3TC on clinical progression and survival.

WHEN TO START?

Neither Delta nor ACTG 175 can answer the important question of when it is best to begin combination therapy - and no other ongoing trials are addressing this question.

In both trials the great majority of participants were asymptomatic on entry, so the studies do confirm that combination therapy is effective at delaying disease progression and prolonging life during asymptomatic HIV infection. However, Delta also enrolled people who had already been diagnosed with AIDS, and they too benefited from combination therapy with a reduced risk of disease progression and death. Based on the present anaylsis, Delta cannot judge whether the effects of combination therapy were greater or smaller in people who started treatment while asymptomatic as opposed to when they developed symptoms.

AZT-EXPERIENCED

It is less clear what people who have already taken AZT should do in the light of Delta and ACTG 175. No less than three trials have now shown that there is no clinical benefit in switching to AZT plus ddC combination therapy - Delta, ACTG 175 and the earlier trial ACTG 155 (reported in AIDS Treatment Update issue 8/9).

On the other hand, ACTG 175 - but not Delta - found that switching to AZT plus ddI or to ddI monotherapy reduced the risk of death. The trial ACTG 116B/117, whose results were reported in August 1992, found that people who switched to ddI monotherapy after they had taken AZT monotherapy for at least four months developed fewer new AIDS-defining illnesses than those who continued to take AZT. In that trial, switching to ddI did not prolong survival, although it was not designed to be able to detect an effect on survival.

Dr Gazzard says that "Sadly, there isn't clear evidence what AZT-experienced people should do. The best available evidence is that switching to combination therapy with AZT plus ddI is probably better than continued AZT, although switching to ddI monotherapy may be just as good."

Again, trials have provided no clear indication of precisely when it is best to switch from AZT monotherapy. In ACTG 116B/117, ACTG 175 and Delta, participants switched from AZT monotherapy even though they could still tolerate AZT, and before they suffered disease progression. However, some switched after only a few months of AZT, while others had taken AZT for years. And again, no other ongoing trials are expected to shed further light on when to switch.

However, further analysis of the data may reveal reasons why people who had taken AZT before did not respond well. One theory, supported by the ACTG 116B/117 trial, is that people who have developed a high level of resistance to AZT from prolonged use are less likely to benefit from AZT and also less likely to benefit from switching to ddI.

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