GMHC Treatment Issues, 9(10) - October 1995
Gabriel Torres, M.D.

ACTG 175 compared monotherapy with AZT or ddI to combination therapy with AZT/ddC and AZT/ddI, as well as benefits of immediate vs. delayed combination therapy. The study population included both antiretroviral-naive and -experienced people with HIV and CD4 cell counts between 200 and 500. The trial involved a higher proportion of women, African-Americans, Hispanics and injecting drug users than in previous ACTG studies. The study's primary endpoints were the times to a 50 percent decline in CD4 cell count or a clinical condition, namely an AIDS-defining condition or death.

Participants who reached either the CD4 or clinical endpoint were switched in a blinded manner to receive combination therapy with AZT/ddI or AZT/ddC if they had previously received AZT or ddI monotherapy or to receive the alternate combination if previously on combination therapy. This allowed for a comparison of immediate versus delayed combination therapy.

At the conclusion of the study, 69 percent of the endpoints occurred in the antiretroviral experienced group, and 31 percent in the naive group. Over two-thirds of the endpoints were declines in CD4 cell counts. The rate of side effects in this study was 19 percent and did not vary significantly among the treatment arms (although in the naive group there were more adverse events in the AZT monotherapy arm). More patients discontinued AZT/ddC than other regimens due to adverse effects, mostly peripheral neuropathy. The study found no significant difference between immediate versus delayed combination therapy. Other findings are summarized in the table on page 2.

Delta compared AZT to AZT/ddI and AZT/ddC in AZT-naive (Delta I) or -experienced (Delta II) individuals with CD4 cell counts between 50 and 350 (see table). The average CD4 cell count for participants in Delta I was around 200, much lower than in the naive population of ACTG 175. Delta I was also larger than the naive subset in ACTG 175, and more convincing because of the greater number of clinical endpoints counted. Delta II was comparable in size to the experienced cohort in ACTG 175, but participants in this study again had much lower CD4 cell counts than the AZT-experienced cohort in ACTG 175 (189 versus 338). More patients stopped AZT/ddI than AZT/ddC due to side effects, mostly nausea and vomiting. Delta's findings are also summarized on page 2.

The recommendations potentially resulting from these trials include: 1) for antiretroviral naive patients, initiate therapy with either AZT/ddC or AZT/ddI or (according to ACTG 175) ddI monotherapy. This latter finding contradicts the results of a previous ACTG trial (116A) which found AZT monotherapy superior to ddI monotherapy in naive patients. It is consistent with the results of ACTG 152 which showed superior survival for ddI or AZT/ddI over AZT in children. 2) Again, based on ACTG 175, for AZT experienced patients: switch to or add ddI rather than staying on AZT monotherapy. Adding ddC to AZT in the experienced group did not provide additional benefits. This is consistent with ACTG 155, a trial that found no clinical benefit (in terms of progression of disease or survival) to AZT/ddC therapy in people with previous long AZT experience.

Final guidelines utilizing the results from both studies are expected to be forthcoming from a state-of-the-art panel which will review the data in the near future. This must await the results of the NuCombo trial. This study is being conducted by the Community Programs for Clinical Research on AIDS (CPCRA) in the U.S. and compares AZT to either AZT/ddC or AZT/ddI in advanced patients with CD4 counts below 200. Results from this trial should be available by the end of the year.

Summary of Data from ACTG 175 and Delta Trials

These trials compared AZT to AZT plus ddI or ddC and also (in ACTG 175) to ddI alone. Trial participants either had prior experience with AZT or were AZT-naive.

The following conclusions from the trial are based on the effect of each treatment on progression to AIDS or death. ACTG 175 AZT-naive: AZT/ddC was superior to AZT monotherapy. AZT-experienced: AZT/ddI was superior to AZT monotherapy.

(Overall: AZT/ddI and ddI monotherapy were superior to AZT monotherapy.)

Delta AZT-naive: either AZT/ddI or AZT/ddC was superior to AZT monotherapy.

AZT-experienced: all drug regimens were equal. (Overall: AZT/ddI and AZT/ddC were superior to AZT monotherapy.)

For more details and the implications of these trial's findings, see pages 3 and 4.

[ACTG Table omitted from electronic addition]

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