Gay Men's Health Crisis Treatment Issues, Vol. 5, No. 5 - June 20, 1991
Gabriel Torres, M. D.

ddC VS. AZT IN PATIENTS WITHOUT PRIOR AZT USE

Hoffmann-La Roche is analyzing data from an on-going major study, which compares ddC to AZT in patients with AIDS or advanced ARC. The study is sponsored by the federally-funded AIDS Clinical Trials Group (ACTG). Early data suggest that in patients who have never used AZT or have taken it for less than three months, ddC might not be as effective as AZT. In the study, 600 patients were treated with either AZT or ddC for an average of 19 weeks. There was no significant difference in survival between patients taking ddC and patients taking AZT. It is notable, however, that more opportunistic infections (OIs) and cancers occurred in patients taking AZT. Not surprisingly, more cancers and OIs were found in ddC patients who entered the study with T4 cell counts under 100. Additionally, patients on ddC with T4 cell counts under 100 had no increase in T cell counts. Those with counts over 100 had only a limited rise. Patients in both treatment groups, who had experienced rises in T4 cell counts, saw them decline back to original levels after 20 weeks of therapy. Similarly, neither drug had a more pronounced effect on p24 antigen levels (a measurement of the amount of HIV reproduction in the body).

Some patients needed to interrupt treatment due to toxicity. Treatment was stopped for 18 patients on ddC who experienced peripheral neuropathies. Eleven patients on AZT experienced anemia and neutropenia (low white and red blood cell counts) for which interruption of treatment was required. Other toxicities, which required the discontinuation of ddC, included oral ulcers, anemia, neutropenia and low platelet counts. Additionally, increased liver enzymes caused discontinuation in two patients on ddC and two patients on AZT.

ddC VS. AZT IN PATIENTS WITH PRIOR AZT USE

Another study compared ddC to AZT in patients with AIDS or ARC who had previously used AZT for one year. One-hundred-and- two patients who were treated for an average of 16 weeks were evaluated. Interestingly, an early analysis of this study has shown a trend for fewer OIs and cancers in patients taking ddC, than in patients taking AZT. This trend may suggest that ddC is more effective as a second-line therapy for people who have already taken AZT for more than a year.

These are very early evaluations from small trials. It should be noted that until all the data from these trials are available and analyzed, it is impossible to draw conclusions about who might benefit most from which drug.

EXPANDED ACCESS NEWS

By the end of March 1991, the ddC expanded access program had enrolled 1,921 patients. Data from the first 833 patients, who were followed for eight weeks, showed that 25 patients had to discontinue ddC due to toxicity. Thirteen of these patients had peripheral neuropathy, and three had pancreatitis (inflammation of the pancreas). Physicians continue to enroll people with AIDS or ARC who are ineligible, intolerant, or are failing AZT.

Unfortunately, the paperwork for such enrollment and follow-up is voluminous. Various activist groups (mostly ACT-UP) and physicians (including ACTG researchers and community doctors) have been writing letters in support of curtailing the paperwork. According to a Hoffmann-La Roche representative, the paperwork will be trimmed to two pages within the next few months.

OTHER DRUGS AND ddC TOGETHER

Physicians have received warnings about the combination of ddC and other commonly used drugs. It is recommended that patients needing radiation therapy, amphotericin B, pyrimethamine, sulfadiazine, and intravenous (IV) formulations of Bactrim (Septra), ganciclovir, pentamidine, and acyclovir (or oral acyclovir in doses over 1000 mg/day) stop taking ddC until they become stable on a maintenance dose of the above medications. Only then should ddC be restarted. Patients on combination therapy with ddC and one or more of these drugs should have frequent (weekly, if possible) laboratory assessments. Drugs that have potential for causing neuropathy (such as Dilantin, vincristine, and Dapsone) should be avoided by patients on ddC, if possible.

In all patients in ddC studies through May 31, 1991, there have been a total of 17 cases of pancreatitis. Nine of these cases were considered to be possibly or probably related to ddC. Patients on ddC should be advised to avoid excessive use of alcohol or other drugs that can cause serious damage to the pancreas. Eleven additional cases of esophagitis (inflammation of the esophagus) or esophogeal ulcers were reported to be possibly related to ddC use. In cases of esophagitis that does not respond to acyclovir or antifungal drugs, ddC should be stopped.

COMBINATION ANTIVIRAL THERAPY

Two treatment regimens that look promising are switching back and forth between ddC and AZT (alternate weeks or months) or taking the two drugs together. Early data indicate that ddC and AZT taken together sustain increases in T4 cell counts better than AZT alone. The doses which are shown to have the best effects are 2.25 mg of ddC (.75 mg/three times daily). Combination therapy with ddC and AZT may be less toxic, and may delay development of resistant strains of HIV.

One interesting report in the Journal of AIDS described a patient who developed severe neuropathy after 16 weeks of alternating therapy between ddC and AZT. Two weeks after stopping ddC, but continuing AZT alone, the patient's symptoms resolved. The patient then began a treatment regimen with ddI, and began to experience a worsening case of neuropathy, which manifested as a shooting pain from the balls of his feet. This is a common symptom of ddI neuropathy. Stopping ddI resolved the symptoms within a month. This case suggests that patients may be more susceptible to ddI toxicity if they have previous nerve damage due to ddC. It is possible that once neuropathy develops with one drug, other drugs with similar side effects should not be used. Self-experimentation with combinations of ddC, AZT, and ddI are not recommended and may prove to be harmful.

One final piece of news from Hoffmann-La Roche is worthy of note. The company will be submitting a New Drug Application (NDA) in the near future. If the application is approved by the FDA, ddC will become available by physician prescription. It is expected that the drug will be approved for use in patients who are ineligible, intolerant to, or failing on AZT. Rumor has it that new data on the combination of AZT and ddC will be published soon, showing an advantage of combination use over the use of AZT alone. If so, it is conceivable that Hoffman-La Roche would pursue licensing for the use of AZT and ddC together, as first- line therapy, or therapy for people who have no prior use of AZT.

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