AIDS TREATMENT UPDATE, October 1995
Edward King

The two trials are the European-Australian Delta trial, and an American study known as ACTG 175. Both studies were designed to test the effects of combination therapy with AZT plus either ddI or ddC on clinical endpoints such as symptoms and survival. Nearly all previous trials of combinations have looked only at the drugs' effects on laboratory markers such as CD4 cell count and viral load.

DELTA RESULTS

The results of Delta are by the far the most impressive. Strictly speaking, it was two separate trials - Delta 1 for people who had never taken AZT before, and Delta 2 for those who had already taken AZT monotherapy for at least 3 months. The trial was open both to asymptomatic people and those already diagnosed with AIDS. All participants had to have a CD4 count between 50 and 350. Everyone in the trial received a standard dose of AZT (600 mg/day). They were then randomly assigned also to take:

- ddI (400 mg/day) plus a placebo designed to look like ddC -ddC (2.25 mg/day) plus a placebo designed to look like ddI - no additional treatment (i.e. a ddC placebo and a ddI placebo)

Delta started in 1992, and participants had been followed for an average of just over two years at the time this analysis was performed. Delta 1 recruited 2131 eligible people, and a further 1083 joined Delta 2. 88% of people in Delta 1 and 83% of those in Delta 2 had not been diagnosed with AIDS when they joined, and their average CD4 cell counts on entry were 212 and 189 respectively.

The results of the Delta 1 part of the trial were highly significant. People who began their anti-HIV treatment with either combination had a substantially reduced risk of clinical progression or death compared to people receiving AZT monotherapy.

During the two years of follow-up, 16.5% of people assigned to take AZT alone died. But among combination therapy recipients the death rate over the two years was reduced by 38%, to 9.6% in the AZT plus ddI group, and 11.6% in the AZT plus ddC group. The difference in death rate between the combinations was not statistically significant i.e. it could simply have been due to chance.

The combinations were also more effective than AZT monotherapy at preventing disease progression in every measure used. People with no symptoms were less likely to become symptomatic, people with mild symptoms were less likely to develop more serious symptoms, and people with AIDS were less likely to develop a more severe AIDS illness. Overall, 28.4% of the AZT monotherapy recipients developed AIDS or died, compared with 17.6% of the AZT plus ddI group, and 23.3% of the AZT plus ddC group.

Dr Brian Gazzard, the trial's UK Principal Investigator, said that the message from this part of the trial is absolutely clear. "If you're thinking of starting treatment - and these results should encourage people to get tested and begin treatment - you should start with combination therapy, not AZT alone."

AZT-EXPERIENCED

The results of Delta 2, the arm of the trial for people who had already taken AZT before, were less encouraging. In effect Delta 2 compared the effects of switching to combination therapy, or continuing to take AZT monotherapy. Participants tended to have quite substantial prior use of AZT - 63% had been on AZT for at least one year.

In this arm, there was no significant difference between the treatments. Combination therapy recipients did not have a significantly lower risk of disease progression or death compared with those continuing on AZT. However, the fact that Delta 2 did not detect a significant difference between the treatments does not necessarily mean there is no difference - only that the trial was unable to detect one.

Combining the results of Delta 1 and Delta 2, people taking combination therapy had a 25% reduced risk of death compared with those taking AZT monotherapy.

SIDE-EFFECTS

Combination therapy was no more likely to cause serious side-effects than AZT alone. Predictably, people taking ddI or ddC were at increased risk from the side-effects associated with those drugs. The most common ddC-related side-effects which led participants to stop taking the trial treatments were oral ulcers (12 discontinuations) and peripheral neuropathy (37 discontinuations). Eight cases of pancreatitis occurred, six among AZT plus ddI recipients and two among people on AZT plus ddC. ddI or the ddI placebo (which contained the same antacid buffer as real ddI, but no active drug) caused about 10% of recipients to withdraw from the trial due to side-effects of nausea and vomiting, making this the least well-tolerated treatment.

The risk of side-effects may deter some asymptomatic people from beginning treatment. But Dr Gazzard argues that "To reduce their mortality by nearly 40%, I'd have thought most people would accept some discomfort."

ACTG 175

The release of this interim analysis of the first two years' data from Delta came hot on the heels of the results of the similar American study known as ACTG 175, which were released on 14th September. This trial also found that starting treatment with the combination of AZT plus ddC was more effective at delaying AIDS and prolonging survival than AZT alone.

ACTG 175 started to recruit participants in December 1991. Volunteers had to have a CD4 count between 200 and 500, and not have been diagnosed with AIDS. 82% had had no symptoms at all, and the average CD4 count on entry was 352. They were randomly assigned to receive either:

- AZT monotherapy (600 mg/day) - ddI monotherapy (400 mg/day) - AZT plus ddI combination therapy - AZT plus ddC (2.25 mg/day) combination therapy

As in Delta, the effects of treatment were analysed separately for people who had never taken AZT before and for those who had prior experience of AZT. In the latter group, two-thirds had already taken AZT for over one year.

Among the 1067 who had never taken AZT before, the trial showed only relatively small differences between the arms. Nevertheless, AZT monotherapy was significantly less effective than the other three regimes in preventing a CD4 count decline of 50%, or the development of AIDS, or death. When analysed like Delta - looking only at clinical endpoints, not CD4 count changes - people receiving AZT plus ddC combination therapy were just significantly less likely to experience disease progression or death than those receiving AZT monotherapy.

Among the 1400 people who had taken AZT before, people who switched treatment to ddI monotherapy or a combination regime were less likely to have a 50% fall in CD4 count, develop AIDS or die. Looking only at clinical endpoints, not CD4 count changes, only regimes containing ddI seemed to be effective. Compared with people who remained on AZT monotherapy, those who switched to ddI monotherapy or to the AZT plus ddI combination were significantly less likely to die. Switching to AZT plus ddC was no more effective at delaying clinical endpoints than remaining on AZT alone.

As in Delta, there was no significant difference in the risk of developing serious side-effects between the arms. Overall, 19% of participants developed signs or symptoms described as 'severe or worse'. The proportion of people who stopped taking trial treatments because of side-effects was 13% in the AZT monotherapy arm, 8% in the ddI monotherapy arm, 14% in the AZT plus ddI combination arm, and 16% in the AZT plus ddC combination arm.

DOUBTS

Researchers told AIDS Treatment Update that the quality of the data from Delta is much better than that of ACTG 175. A fifth of people who joined ACTG 175 were lost to follow-up, and over half of those who remained stopped taking the trial treatments before they reached one of the set endpoints of CD4 decline, development of AIDS or death. This meant that relatively few people reached trial endpoints.

Professor Tony Pinching of St Bartholomew's Hospital in London told AIDS Treatment Update that the difference between combination therapy and monotherapy in ACTG 175 was "a very small effect, involving only small numbers of people out of a very large study". These factors make the findings of ACTG 175 more vulnerable to error, and so less convincing.

In Delta, participants were less likely to stop taking trial treatments before reaching an endpoint. Delta also recruited twice as many AZT-naive participants as ACTG 175, and it was in this group that most of the benefits of combination therapy were seen. These factors make the results of Delta much more secure.

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