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PI Perspective #17December 1995 View PDF En español Benefits of Combination Therapy ConfirmedLong awaited results from two large studies comparing single drug antiviral treatment to combination therapy have been released. Both studies confirm that combination therapy is superior to AZT alone. Beginning in 1992, the AIDS Clinical Trials Group (ACTG) study 175 enrolled 2467 people with CD4+ cell counts between 200 and 500, who had no major opportunistic infections (1067 of whom had never taken antivirals previously). People received either AZT alone, ddI alone, AZT + ddI or AZT + ddC. The doses used were 600mg/day of AZT, 400mg/day of ddI and 2.25mg/day of ddC. During the trial, anyone experiencing a 50% or greater drop in CD4+ counts or developing an opportunistic infection was reassigned to a different therapy. Those receiving monotherapy were switched to a combination, while those already on a combination were assigned to the alternate combination. This innovative approach was the first step toward a true “management strategy trial” as described in PI Perspective #16. It protected volunteers from the possible harm caused by staying on a therapy after it had begun to fail. Researchers evaluated the impact of treatment on three possible outcomes:
The treatment failure analysis showed that ddI alone, AZT + ddI and AZT + ddC were all superior to AZT alone. This was true for all study participants, regardless of whether or not they had previously taken antiviral therapy. The clinical progression analysis showed that overall, people receiving ddI alone or AZT + ddI were significantly less likely to progress to AIDS. People who had never taken antivirals previously received greater benefit from the AZT + ddC combination while those who had previously taken AZT benefited most from either AZT + ddI or ddI alone. In the survival analysis, overall there were significantly fewer deaths among people receiving either AZT + ddI or ddI alone. While there was no difference in survival between the four treatments for people who had never previously taken antivirals prior to the study, trends favored people who were on AZT + ddC. For people who were AZT-experienced, there were significantly fewer deaths among people receiving ddI alone or the AZT + ddI combination. These results are summarized in Tables 1 through 3.
Preliminary virologic data were collected on 348 participants using the PCR test. Initial analysis indicate that viral levels concur with the clinical results, further supporting the use of the PCR test as a tool for measuring the effectiveness of drugs. More PCR data will be available in the near future. Other virologic data will report on the levels and effects of AZT-associated resistance and the syncitium-inducing (SI) type of HIV (a viral type which may lead to more rapid disease progression). There were no significant differences in toxicity between the groups, although for people who had never taken antivirals previously, there appeared to be more toxicity among those on AZT alone. Overall there was no difference in clinical progression and death rates between those who immediately began combination therapy and those who failed on single agent therapy and were reassigned to one of the combination arms of the study. There was a trend, however, (32% reduction in risk of disease progression or death) toward improved outcomes for those who received immediate combination therapy who had never previously taken antivirals. Part of this result may be due to the fact that ddI was significantly superior to AZT and comparable with the combination therapies in most analyses, and therefore reduced the power in detecting a difference between immediate and delayed combination therapy. A week after the results of ACTG 175 were announced, a similar European/Australian study known as the Delta trial reported its results. Delta enrolled 3214 people with CD4+ cell counts between 50 and 350 (2131 of whom had never taken antivirals previously). People received either AZT alone, AZT + ddI or AZT + ddC, using the same doses as in ACTG 175. The major difference between Delta and ACTG 175 is that Delta allowed people with a previous opportunistic infection to participate. The trial consisted of two parts: Delta 1 included only people who had never taken antivirals previously and Delta 2 included only people who had used AZT for at least 3 months. The combined results of Delta 1 and Delta 2 show a 25% reduction in death rates for those on combination therapy. Delta was stopped when people on combination therapy showed a significant survival advantage. Of those on AZT alone, 17% died compared to 10% on AZT + ddI and 12% on AZT + ddC. Similarly, 28% on AZT alone had disease progression compared to 18% on AZT + ddI and 23% on AZT + ddC. Preliminary analysis of Delta 2 (people previously treated with AZT) shows no difference between monotherapy and combination therapy in delaying disease progression or death. Of those on AZT alone, 26% died compared to 23% on AZT + ddI and 26% on AZT + ddC. Thirty-nine percent on AZT alone had disease progression compared to 38% on both AZT + ddI and AZT + ddC. There were no significant differences in side effects between the treatment regimens, although people on AZT + ddI had more gastrointestinal problems. Results from these studies will likely change the standard of care for people with asymptomatic HIV infection and a recommendation has already been made in Europe to this effect. These are the first large studies to show that combination therapy can delay disease progression and prolong survival. People who have never taken antivirals previously may want to consider starting with combination therapy or ddI alone instead of AZT alone. The superiority of ddI alone compared to AZT alone contradicts an earlier study, ACTG 116A, which involved people with more advanced disease, but is consistent with the interim results of a pediatrics study, ACTG 152 (see May 1995 issue of the PI Perspective). Because of this contradiction, some may see the superiority of ddI over AZT monotherapy to be less conclusive. The debate may be moot since most researchers seem convinced that combination therapy, of one form or another, is ultimately superior. For AZT-experienced individuals, switching to or adding ddI is superior to remaining on AZT alone. Further analyses of these studies will provide more information on how to best use these therapies and possible explanations on why therapies lose their effectiveness. These results cannot be directly compared to other combination therapies such as AZT + 3TC or those involving the protease inhibitors. However, as confidence builds in the predictive value of PCR tests, it may be possible to compare these data to other combinations on the basis of their effect on viral levels. Using this parameter, existing data would suggest that the AZT + 3TC combination, as well as some of the combinations using protease inhibitors, may be superior to the AZT + ddI or AZT + ddC combinations tested here. For now, the most important finding of ACTG 175 and Delta is that there is now hard evidence that combination therapies are superior to AZT monotherapy, and that the reign of AZT monotherapy as the conservative “standard of practice” should quickly come to an end. This is little news to readers of PI Perspective, as Project Inform has been recommending the use of combination therapy over monotherapy since the late 1980s.
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CONTENTSFour New Concepts for Combating HIV Benefits of Combination Therapy Confirmed Medicaid Cuts Threaten People with HIV HIV Infection & “Managed Care” |
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