Seattle Treatment Education Project: STEP Perspective - Volume 4, Number 3 - October 1992
Mari Kitahata, M.D.

Combining nucleoside analogues in simultaneous or alternating regimens may have advantages over treatment with only one substance. Combination therapy may do more to delay or prevent the development of resistant isolates of HIV, reduce drug toxicity by allowing lower doses to be used, and additive or synergistic inhibition of viral reverse transcriptase. Data were presented from a pilot study designed to evaluate the toxicity and efficacy of concurrent vs. alternating regimens of AZT and ddI in patients with AIDS or symptomatic HIV infection and CD4 cells below 350 (Yarchoan et al MoB0054). forty-one patients with less than three months of prior ddI therapy randomly received either: (1) simultaneous AZT 300 mg/day plus ddI 250 mg/day; or (2) AZT 600 mg/day for three weeks alternating with ddI 500 mg/day for three weeks. At 27 weeks, the CD4 response was better with concurrent therapy (mean increase 68 vs. 4). Both regimens were well tolerated and a decrease in detectable serum p24 antigen was seen in both groups. It should be noted that the results of this study are preliminary and need to be confirmed in a larger trial. The issue of whether antiretroviral drugs used in combination should be alternated will be addressed in ACTG 193, a study that will compare concurrent AZT and ddI, or AZT and ddC, with regimens in which AZT is alternated with ddI or ddC on a monthly basis.

The efficacy of combination therapy with AZT and ddI was examined in a randomized trial of 116 asymptomatic patients with CD4 counts between 200 and 500, assigned to four arms: (1) AZT 150 mg/day plus ddI 134 mg/day; (2) AZT 300 mg/day plus ddI 334 mg/day; (3) AZT 600 mg/day plus ddI 500 mg/day; (4) ddI 500 mg/day (Ragni et al MoB0055). At 24 weeks, there was no statistical difference in the increase in CD4 counts among the four arms, showing trends similar to treatment with ddI alone. The combination of AZT and ddI was well tolerated.

ACTG 116b/117, the largest and most conclusive study of monotherapy with AZT or ddI in patients who had tolerated more than 16 weeks of AZT, showed that ddI is superior to AZT in delaying the development of new opportunistic infections in patients with previous long-term AZT exposure, although it did not improve survival (MoB0079). This was a randomized, double-blind controlled trial that enrolled patients with AIDS or ARC whose CD4 counts were below 300, or asymptomatic patients with CD4 counts below 200, to receive AZT (600 mg/day) or ddI at two dose levels (500 and 750 mg/day). Patients randomized to ddI at 500 mg/day had a statistically significant delay in the time to a new AIDS-defining event compared with the AZT group: 28 percent vs. 40 percent at one year. The duration of prior AZT therapy did not affect the drugs' relative efficacy. There was no significant difference in disease progression between the group receiving ddI at 750 mg/day and that receiving AZT, but both ddI groups had a median increase in CD4 count of 10 compared with the AZT group. The benefit of switching to ddI was seen in patients who entered the trial with asymptomatic HIV infection of ARC, but not in those with AIDS. This finding suggests that the switch to ddI did not benefit patients with advanced disease who might be more likely to have AZT-resistant HIV.

Two studies that evaluated the efficacy of switching to ddI in patients who had tolerated at least six months of AZT therapy were presented. A double-blind study of ddI vs. continued use of AZT in 197 patients with CD4 counts between 200 and 500 was conducted by the Canadian HIV Trials Network (MoB0081). The patients were randomly allocated to receive AZT (600 mg/day) or ddI (334 mg/day or 500 mg/day for body weights below or above 60 kg, respectively). Clinical endpoints included mortality, progression to ARC or AIDS, frequency and severity of opportunistic infections, development of neoplasms and neurological disease, and significant decline in CD4 count from baseline. CD4 counts at 48 weeks were better for the ddI treated groups and were statistically significant, but no differences in clinical outcomes were observed. The investigators point out that U.S. government approval of ddI and ddC resulted in high drop-out rates and poor enrollment in the study by the spring of 1992, which led to early closure and an inability to accurately measure clinical outcomes. The benefit of switching to ddI was again seen in patients with early disease and persisted for 24 weeks. Preliminary results of a randomized multicenter study from Italy (ISS-901 MoB0082) of 140 patients assigned to continue AZT therapy or to switch to ddI (after at least six months of prior AZT) showed a trend toward better survival and lower incidence of AIDS-defining disease for patients who switched to ddI.

At the conclusion of this session, Dr. Margaret Fischl of the University of Miami discussed unanswered questions for further study in the use of nucleoside analogues. It is still unclear when to initiate therapy with the newer agents: CD4 below 200 or between 200 and 500 (advanced disease vs. earlier disease); in priortreated or untreated patients, or those intolerant to prior therapy. We know that AZT delays the onset of opportunistic infections in patients with CD4 counts below 500, and that early intervention has a greater and sustained benefit. In patients with prior AZT treatment, is the waning efficacy over time due to the limitation of AZT, resistance to AZT, or both? In patients with ARC who have CD4 counts below 200, it appears that switching to ddI after 12 months of AZT therapy results in better CD4 counts and decreased progression to clinical disease. There is a suggested benefit in ARC patients with CD4 counts of 200 to 500, but no clear conclusion that ddI is better than AZT. Is the switch important (AZT to ddI, or ddI to AZT), or is it the superiority of ddI that is being observed? As yet, there is no head-on comparison of AZT vs. ddI to assess which would be better initially. ACTG 116A is a randomized, double-blind trial comparing AZT and ddI in patients with less than 16 weeks of prior therapy with AZT. Results from this head-to-head comparison are expected within a year and should reveal which drug is superior as initial therapy.

AZT has been shown to be less toxic when used earlier in disease. A similar trend is observed with ddI. Peripheral neuropathy was an important side effect in Phase I trials of ddI, but was seen with less frequency in the newer abstracts. Lower doses of ddI were used in subsequent trials and may account for this difference. In addition, 500 mg of ddI appeared to have more benefit than 750 mg. This difference may have been due to the ability to give continuous antiretroviral therapy because fewer side effects were experienced with lower doses. Lastly, Dr. Fischl pointed out that the endpoints in clinical trials are changing. AIDS-defining events are more difficult to assess with increased prophylaxis. Quality of life assessments, as well as virologic markers, are needed to assess outcome because surrogate markers such as CD4 counts do not adequately reflect the clinical course of disease. In addition, the time to switch nucleoside analogues in these studies was based on the length of time of AZT treatment, and not on clinical progression. Phase III studies need to be designed to more adequately assess clinical events and, in particular, differences in survival.

Copyright (c) 1992 - Seattle Treatment Education Project. Non- commercial reproduction encouraged.
9210
STEP4302

Copyright © 1992 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102.    Email: step100@aol.com  STEP web page