Gay Men's Health Crisis Treatment Issues, Vol. 5, No. 9, December 1991
Gabriel Torres, M. D.

EARLY STUDY RESULTS

Four phase I trials have been conducted, enrolling a total of 170 patients, 75% of whom had previously been treated with AZT. Most of the patients in these trials were white, homosexual, or bisexual men. The mean T4 cell count was 62 at study entry. ddI was administered in different doses and by different routes (orally or intravenously) for a median duration of 38 weeks. The average daily dose was 10.3 mg/kg.

The historical control groups consisted of patients from placebo groups of three randomized, blinded studies which compared AZT to placebo and patients from a dextran sulfate study. Response definitions included a 50 T4 cell rise or 50% rise from baseline in T4 cells (50:50 response), maintained for 4 weeks or longer, or a 10 T4 cell rise or 10% rise over baseline (10:10 response). Results were as follows:

- 22% of patients receiving ddI had a 50:50 response compared to 28 -- 12% of the patients in the historical control groups.

- 50% of patients receiving ddI had a 10:10 response in T4 cell counts compared to 17%-31% of the historical control group.

Pancreatitis occurred in 9% of patients who received ddI at a dose less than 12.5 mg/kg, and in 27% of patients who received a dose greater than 12.5 mg/kg. Peripheral neuropathy occurred in 34% of patients treated with less than 12.5 mg/kg of ddI and in 51% of those treated with greater 12.5 mg/kg. It occurred more frequently in patients with a history of previous neuropathy or those taking other drugs which can cause neuropathy.

DATA FROM LARGE HUMAN TRIALS

ACTG study #116 compares ddI to AZT in patients previously treated with AZT. Data available from the first 12 weeks of the study included information on 412 patients who had received an average of 13 months of AZT therapy and had an average T4 cell counts of 83 at study entry. The group who received ddI had an 11% increase in T4 cells from baseline compared to a decrease of 3.2% in patients who remained on AZT. No data on clinical outcomes in this study are currently available.

EXPANDED ACCESS

While the package insert for ddI reports an overall low incidence of toxic side effects for the first 7,806 patients in expanded access programs, various smaller studies presented at the VIIth International Conference on AIDS in Florence, and at the 31st Interscience Conference on Antimicrobials Agents and Chemotherapy (ICAAC), report a considerably higher rate of toxicities.

A study of 166 patients with AIDS or ARC was presented at ICAAC by Dr. James Steinberg from Emory University in Atlanta, Georgia.[3] After an average of 31 weeks of follow-up, fewer than 30% were still receiving ddI. Thirty-one patients became too sick to continue the drug or died. In 76 patients the drug had to be stopped because of pancreatitis, peripheral neuropathy, diarrhea or abdominal pain. The incidence of pancreatitis was 13.8% (including two deaths), which is higher than the 5% reported by Bristol-Meyers in the package insert. Because there was no control group it cannot be determined whether patients in this study benefited from ddI.

Another study presented at Florence compared patients in the expanded access protocols who received ddI to a matched control group who received AZT or no anti-HIV therapy.[4] No difference in survival was seen for the ddI group, yet patients _maintained_on_one_ [italics] of the anti-HIV drugs developed opportunistic infections less frequently. However, ddI had a beneficial effect on the majority of patients in this study with dementia.

A London study showed that patients who are intolerant of AZT and who switched to ddI are more likely to have T4 cell rises if their baseline T4 cell count is greater than 100.[5] The authors of this study also reported several new side effects of ddI, including diabetes (elevated blood sugar) and Raynaud's phenomenon (pain and cold feeling in the fingertips resulting from constriction of the blood vessels in the fingers).[6]

Though the expanded access protocols were not designed to produce data on efficacy, the experience from these patients is very valuable since the final results of comparative trials are still not available, and physicians and patients must make treatment decisions in the interim. Since the drug is approved for patients who have experienced AZT intolerance or failure, it behooves us all to become aware of the toxicities, drug interactions, and clinical outcomes of patients in the expanded access protocols, since they may predict the similar outcomes in patients who will now receive the drug by prescription.

DOSE AND ADMINISTRATION

ddI (Videx) is available as a mint-flavored, buffered, cheweable tablet of 25, 50, 100 or 150 mgs. It is also available to children or adults as a buffered powder to be added to water for easy drinking. Two tablets at each dose every 12 hours is recommended. The exact dose depends on body weight, but should approximate 10 mg/kg. Some professionals recommend lower doses for patients with underlying opportunistic diseases such as CMV or MAC, which may predispose patients to pancreatitis or neuropathy.

DRUG INTERACTIONS

Drugs whose absorption can be affected by the amount of acidity in the stomach (such as ketoconazole and dapsone) should be taken at least two hours prior to ddI. Since ddI tablets contain a buffer (magnesium hydroxide, sodium carbonate and sodium citrate), they should not be taken with the antibiotic tetracycline or any of its derivatives. Since the absorption of quinolone antibiotics (Cipro, Noroxin, and Floxin) are decreased by antacids, ddI should be administered at least 2 hours after these antibiotics are given. No drug interactions have been noted between ddI and ganciclovir, although this combination has been in widespread use.

RESISTANCE

HIV strains taken from five AIDS patients were shown to have developed ddI resistance by researchers from Burroughs Wellcome.[7] These particular patients received AZT for longer than 12 months and were switched to ddI after appearing to deteriorate clinically. The viral strains seemed to have recovered their sensitivity to AZT in test tube experiments. The mechanism for ddI resistance was traced to a mutation in the gene, called reverse transcriptase (RT). RT is the enzyme which copies the HIV blueprint inside newly infected cells. The ddI mutation apparently eliminates one of the mutations responsible for AZT resistance, allowing the virus to once again be inhibited by AZT. The mutation responsible for ddI resistance also causes ddC resistance.

This test tube work suggests that patients who receive ddI after receiving AZT may be able to derive benefit from AZT once again. How well clinical deterioration correlates with test tube resistance is yet to be determined. Combinations of ddI and AZT may prevent the development of resistance since the mutation sites are different.

CONCLUSION

Videx is now approved for use in HIV-infected patients who are intolerant or failing AZT. Unfortunately, relatively little data is available on patients who have never taken AZT, or on long-term effects and toxicities. Definitively, use of the drug among asymptomatic patients cannot be recommended until more information on long-term effects is available. Toxicities in advanced or late-stage disease are significant, and dose modifications may be appropriate. Combinations of AZT and ddI are just now receiving adequate attention and may become widely used before formal studies are available.

REFERENCES

1. Bristol Laboratories, VIDEX package insert.

2. AIDS Clinical Trial Group ACTG Trial #116.

3. Steinberg JP et al. Outcome and Toxicities on DDI in the Expanded Access Program (abstract), 31st ICAAC, 1991, Chicago, Illinois.

4. VII Int'l Conf on AIDS. Abstract #W. B. 2113, Florence, June, 1991.

5. VII Int'l Conf on AIDS. Abstract #W. B. 2090, Florence, June, 1991.

6. VII Int'l Conf on AIDS. Abstract #W. B. 2111, Florence, June, 1991.

7. St. Clair MH. et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 253:1557-1559, 1991.

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