The Gay Men's Health Crisis Newsletter of Experimental Therapies - Volume 6, Number 2 - February 1992
Gabriel Torres, M.D.

So seems the case with AZT and HIV. In fact, after six months of treatment, AZT generally seems to lose its activity against HIV (usually reflected by a decline in T4 cell counts). Such a decline may translate into a deterioration in the health of the patient. Combining AZT with other drugs is one promising strategy to prevent resistance from developing, and to prolong the period of the drug's ability to sustain T4 cell counts. Combination strategies may also allow for the use of smaller doses of each drug, which may lower toxic side effects.

Recent test tube studies confirm that AZT and ddC work well together against HIV without additive toxic side effects.[1] This article will focus on the use of AZT and ddC together as a first choice anti-HIV therapy and as a secondline anti-HIV therapy for patients with AZT resistance.

New Data Released From Combination Study

The first promising study of AZT and ddC combination therapy was reported early this new year in the Annals of Internal Medicine.[2] The study conducted at the University of Miami and the University of California at San Diego, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Fifty-six patients with AIDS or ARC, and with T4 cells under 200, were studied from July 1989 to May 1990. None of them had ever taken anti-retroviral drugs, such as AZT, ddI, or ddC. All patients received aerosolized pentamidine to prevent PCP. The participants were assigned to one of several dose combinations of AZT and ddC. The doses of AZT included: 150 mg, 300 mg, and 600 mg/ day. The doses of ddC were 0.03 mg and 0.015 mg/kilogram/day. One additional group of participants received AZT alone at a dose of 150 mg/day.

T4 cell counts increased in participants in each of the groups. However, patients receiving 600 mg of AZT and either 0.015 or 0.03 mg/kg of ddC were better able to sustain T4 increases than what would be expected from either drug alone. A decline in p24 antigen levels, indicating a decrease in HIV activity, was noted in all groups, except in the group of participants receiving AZT alone at 150 mg/day. Not surprisingly, the group on low-dose AZT alone had the fastest drop in T4 cell counts and a shorter suppression p24 antigen production. In the group receiving ddC and lowdose AZT declines in T4 cell counts were slower. This implies that the addition of ddC to AZT therapy may have had a synergistic effect in humans. Synergism is when two drugs have a stronger effect together than is expected when combining the drugs (i.e. 2+2 = 5). This synergistic effect of AZT and ddC occurred originally in test tube studies.[3]

Toxicity

In the study reported above, 17.9% of the patients had declines in white or red blood cell counts. However, there seemed to be no difference in toxicity among the different groups. Only two patients developed peripheral neuropathy, a common side effect of ddC. These peripheral neuropathies manifested as pain and numbness in the legs and feet. Several patients did develop opportunistic infections and lymphoma during the study. One patient died. Unfortunately very little information regarding the clinical outcomes of the patients after prolonged follow-up (40.6 weeks of observation after the trial) on the combination therapy was reported.

Notable strategies to reduce toxicity include using alternating or intermittent combinations of the two drugs. In alternating AZT/ddC therapy, patients switch from one drug to another every week or month. The theory is that time off of AZT should allow AZT-related bone marrow toxicity to recover and the time off ddC should allow ddC-related nerve toxicity to recover. Schedules of alternating AZT and ddC have been studied in patients with AIDS or ARC who have toxic side effects from AZT. The drugs were given either every other week or every other month to 109 patients in a federally funded human study.[4] A preliminary report showed that alternating the drugs on a weekly basis caused less blood toxicity than alternating them on a monthly basis.[5] However peripheral neuropathy occurred more commonly in patients alternating the drugs on a weekly basis.[2] A second toxicity-reducing strategy is intermittent regimens, which means taking the drugs together followed by a period of no drug at all. However, it should be noted that intermittent regimens run the risk of virus reproduction during the time off of antiretroviral agents.

CONCLUSION

The authors of the study conclude that combination therapy using higher doses of AZT (300 mg or 600 mg) along with ddC produces higher rises in T4 cell counts than had previously been observed in studies of either AZT or ddC alone. One of the study collaborators, Dr. Margaret Fischl, stated that "the emergence of drug-resistant strains of HIV may have been diminished by the use of AZT and ddC together." Despite such optimistic conclusions, an accompanying editorial by Anthony Fauci, Director of NIAID, expressed caution in early interpretation of these results. Fauci also warned against using this combination until larger-scale trial data are available.[6]

A federally-funded human trial of combination therapy,[7] hopes to enroll more than 1000 participants. Trial #155 is designed to compare the combination use of AZT and ddC to AZT alone or ddC alone. The doses chosen for that trial are 600 mg of AZT and 0.03 mg/kg of ddC, and were based on the results of the trial reported above from the Annals.

Practicing physicians and persons with HIV are not likely to wait for the results of ACTG trial #155 before trying the combination. It is expected that if ddC is approved, many physicians will begin prescribing the combination of AZT and ddC as initial therapy (for people who haven't had previous AZT therapy), and may reserve ddI for persons who are intolerant or failing AZT.

In the meantime, ddC is available for patients who are intolerant, ineligible, or failing AZT though an expanded access program from Hoffman-LaRoche. Doctors can call 1-800-DDC-21-HIV.

References:

1. VIIth Int'l Conf on AIDS. Abstract #W.B. 2110, Florence, June 1991.

2. Meng TC et al. Combination therapy with AZT and ddC on patients with advanced HIV infection. Ann Intern Med 116:13-20, 1992

3. Ibid.

4. AIDS Clinical Trials Group (ACTG) Trial #050.

5. VIth Int'l Conf on AIDS, Abstract # S.B. 425, San Francisco, June 1990.

6. Fauci AS. Combination therapy for HIV infection: Getting closer. Ann Intern Med 116:85-86, 1992

Copyright (c) 1992 - Gay Men's Health Crisis. Non-commercial reproduction encouraged.

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