TREATMENT ISSUES, Volume 6, Number 5; The Gay Men's Health Crisis Newsletter of Experimental Therapies - May/June 1992
Gabriel Torres, M.D.

ddI

Dr. Claude Carbon of the Bichat School of Medicine in Paris presented data from the large multicenter European study called the ALPHA trial.[1] This study compares the efficacy and safety of two doses of ddI in patients with AIDS and ARC who are intolerant of AZT. The randomized double-blind trial compares low-dose ddI (100 mg twice daily) to the standard dose (375 mg twice daily). Patient enrollment concluded in November 1991 and totalled 1,995 participants. Of those patients enrolled, 45% had ARC and 55% had AIDS. The study population received AZT therapy for a little over a year. Participants have been followed for about eight months. Of all the participants, 659 died and 146 patients with ARC progressed to AIDS. Seventy-nine patients developed HIV-related neuro-cognitive disorder (formerly referred to in Treatment Issues as AIDS dementia complex, or ADC). The most significant adverse effects of ddI included the following: 28 cases of pancreatitis (8 of which led to death); 196 cases of elevated serum amylase levels, indicating pancreatic damage; 282 cases of peripheral neuropathy; 256 cases of diarrhea; and 81 cases of neutropenia (low white blood cell count). The final results from this study should be available at the VIIIth International Conference on AIDS in Amsterdam during July 1992.

A smaller ddI study from Belgium also compared a very low dose (67 mg twice daily) od ddI to a higher dose (250 mg twice daily) in patients who had failed or were intolerant of AZT.[2] Participants were followed for an average of five months. No significant differences in side-effects were caused by the different doses, except for a trend toward less pancreatitis in the lower dose group. T4 cell count elevations were seen in both groups. The range in T-cell increase was 19-36 cells after three months of treatment.

-------------------------------------------------- A German study found more opportunistic infections and more cases of pancreatitis among patients taking the high dose (of ddI) rather than the low dose. --------------------------------------------------

A German study which was presented as an abstract in the conference also compared two doses of ddI and found more opportunistic infections and more cases of pancreatitis among patients taking the high dose rather than the low dose.[3] In a poster presentation, the same German researchers reported that serum lipase levels were the best marker for early detection of ddI-related pancreatitis and that serum amylase levels and abdominal sonography were not as useful in detecting early pancreatitis.[4] Active CMV infection was found in three of four patients who developed ddI-related pancreatitis, suggesting that CMV may play a role in the development of this side-effect.

ddI resistance has also been documented in a few European patients who had switched from AZT to ddI and had taken ddI for 6 months or more.[5] Notably, four of thirteen HIV strains in patients who switched from AZT to ddI were still AZT resistant after no AZT for about eight months. These results conflict with studies in the U.S. that most viral strains regain sensitivity to AZT after a period off AZT.

European ddI studies have confirmed those in the United States, though the drug is still awaiting approval for general use in Europe. Unlike Americans, Europeans have decided to gather more definitive data on efficacy before making the drug widely available. Approval will probably not be final until the results of the ALPHA trial are available. In the meantime, an expanded access program makes ddI available to patients who are failing or are intolerant of AZT in European countries.

ddI In Children

A ddI trial from France studied the effects of the two tested doses of ddI in 34 children with symptomatic HIV infection who had failed or developed intolerance to AZT.[6] The mean duration of treatment was eight months. No significant side effects have been observed at these doses, except for three children who have developed elevated liver levels enzymes.

Comparing ddI to AZT

Results from a multicenter Italian trial comparing AZT and ddI in patients with ARC who had never received AZT (a state referred to as "AZT naive") and who had T4 cell counts under 500 were presented by Dr. Stefano Vella from the Instituto di Sanita in Rome.[7] The trial was designed to enroll 300 patients in each arm by April 1992. In a early analysis, 126 patients are taking AZT and 137 are taking ddI. The average length of follow-up was approximately five months. About the same percent of the total of each group have had to discontinue taking the drug due to side-effects. Early data about T4 cell counts suggest that patients who entered the trial with more than 50 cells had a more significant increase in T4 cell counts with ddI than similar patients had with AZT. However, those who entered the trial with less than 50 T4 cells had a better response with AZT.

Another Italian study is comparing AZT and ddI in patients with AIDS who have received AZT for at least six months. This study plans to enroll 200 patients in each arm. Over 50% of the patients enrolled in the Italian studies are intravenous drug users (IVDUs) and over 30% - 40% are women. This difference in populations may account for results that differ from U.S. trials that generally exclude large numbers of women.

Combining ddI and AZT

Dr. Margaret Ragni from the Hemophilia Center of Western Pennsylvania presented preliminary data from a Phase I-II trial which compared three dose combination regimens of AZT and ddI to ddI alone. The trial recruited asymptomatic HIV-positive patients with T4 cells between 200 to 500.[8] After a followup of 18 weeks, it was observed that the combination of AZT and ddI was well tolerated in participants. Of 126 patients enrolled, nine developed side effects (seven liver reactions, one gastrointestinal reaction, and one peripheral neuropathy). So far, no cases of pancreatitis has been reported. The T4 cell counts in all participants have increased, including an increase of 64 cells in patients taking ddI alone. After 24 weeks of observation there have been no significant efficacy differences among the four treatment areas.

New AZT Data

Several studies presented at the Conference focused on the use of AZT alone or in combination with interferon in different populations of patients. Interferon is a manufactured form of protein that fights off virus in infected cells. One observational study from the University of Bordeaux in France showed that AZT improved survival for persons with HIV and T4 cells under 350 for the first 12 months but not for the subsequent 24 months.[9] In the U.S., AZT has been shown to improve survival only for those with T4 cell counts under 200. The recently published Veterans Administration (VA) study of AZT failed to show a survival benefit for use of AZT in patients with T4 cells under 500.[10]

A Danish study compared AZT to placebo in 335 asymptomatic participants with T4 cell counts under 400.[11] The study was terminated in December 1990 when the federally-funded trial (ACTG study #019) showed that AZT (500 mg/ day) reduced progression of disease to ARC or AIDS after 60 weeks. Only 2% of the AZT recipients developed anemia (low red blood cell counts) and 3% developed neutropenia (count of low white blood cell, called neutrophils). T4 cell counts remained increased for a longer period in those participants taking AZT than in those taking placebo. No difference in survival was noted between the treatment groups.

---------------------------------------------- European trials with antiretrovirals have been limited to AZT and ddI. Most other similar drugs (ddC, 3TC, and FLT) are not available in Europe. ----------------------------------------------

Finally, a multicenter European and Australian study (H56-20) funded by Burroughs Wellcome, the manufacturer of AZT, showed that the drug reduced disease progression to AIDS in asymptomatic HIV-positive participants.[12] The study compared AZT (dose 500 mg twice per day) to placebo in nearly 1000 patients from 10 countries with entry T4 cell counts greater than 400. The overall progression rate for those on AZT was 14% after two years compared to 28% for those participants taking placebo. The benefits of the drug were seen in those with entry T4 cell counts of between 400-750. There were no significant differences in severe blood toxicities between participants taking AZT and those on placebo, though more patients on AZT required dose reduction. This study must be evaluated very cautiously, for the following reasons 1) AZT was taken in a dose twice that of the recommended dose in the U.S.; 2) participants were not followed for very long to assess efficacy and toxicity; and 3) the trial was sponsored by the drug's manufacturer.

AZT and Alpha Interferon

An Italian study compared the use of AZT and alpha interferon to AZT alone in 202 patients with asymptomatic HIV infection and T4 cell counts between 200-500.[13] The dose of AZT was 250 mg twice daily and the dose of alpha interferon 3 million units three times per week. Over 90% of the patients in both arms were IDVUs. Of those who were initially p24-antigen positive, a greater number in the combination arm became p24-negative. Four patients on the combination regimen have progressed to AIDS compared to none in the AZT-alone arm. However, more patients (six vs. four) in the AZT-alone arm have developed minor opportunistic infections indicative of early symptoms. The group receiving combination therapy had more neutropenia and the group on AZT alone had more anemia. More follow-up studies and data are needed before conclusions can be drawn as to the possible benefits of AZT and interferon in HIV disease.

AZT and GP160

A Swedish study reported on the use of gp 160 vaccine in combination with AZT in 40 asymptomatic patients with T4 cell counts over 400.[14] Subjects received six intramuscular injections of 160 micrograms of gp 160 (Vaxsyn HIV-1, MicroGenSys) in a set schedule lasting up to 26 weeks. They were also randomly assigned to receive either AZT or placebo. Though the study is still blinded, there has been a 14% increase in T4 cell counts in the entire group. T4 cell immune responses to the vaccine and an increase in the level of antibodies directed at the V3 loop (a section of the envelope protein of HIV) have been noticed. Three patients have also had a decrease in the amount of HIV detected in the blood. The only side-effects have been headaches and nausea.

AZT and Pregnancy

An Italian group presented a poster on the use of AZT during pregnancy.[15] Seven pregnant women were treated with AZT from 17-30 weeks of gestation until delivery. All had deliveries of infants with normal APGAR scores and neurodevelopmental measurements. After a year of follow-up none of the infants has become HIV-positive nor has evidence of HIV infection by PCR tests and viral cultures appeared. Except for mild anemia in the first week of life in two infants, no baby has developed side-effects.

AZT and Low Platelet Counts

Several Italian studies evaluated the effect of AZT treatment on low platelet counts (thrombocytopenia). This blood condition is defined as a platelet count of less than 150,000 and may affect women, children, and IVDUs disproportionately. Some studies have shown that relatively high doses of AZT are effective in increasing platelet counts in persons with HIV infection. One study presented compared the use of low dose AZT (500 mg per day) versus high dose (1000 mg) for thrombocytopenia.[16] After six months of treatment with AZT, 41% of the group receiving the high dose had maintained a platelet count above 100,000, compared to 12% of the group receiving the low dose. This study encourages the use of high dose AZT in conditions such as thrombocytopenia.

Conclusion

The European clinical trials with antiretroviral agents have been limited to the study of AZT and ddI. Most other similar drugs (ddC, d4T, 3TC, and FLT) are not available in Europe. Interpretation of these studies needs to be made in connection with results from major U.S. studies for a competent translation into actual clinical practice. (Editor's Note: A follow-up report on data from the European Conference relating to the management and prophylaxis of opportunistic infections is forthcoming in Treatment Issues.)

---------- References

1. Carbon C, Update on the ALPHA Trial (oral presentation). Third European Conference on AIDS, Paris, March, 1992.

2. Third European Conference on AIDS. Abstract #065, Paris, March, 1992.

3. Third European Conference on AIDS. Abstract #013, Paris, March, 1992.

4. Third European Conference on AIDS. Abstract #P149, Paris, March, 1992.

5. Third European Conference on AIDS. Abstract #P278, Paris, March, 1992.

6. Third European Conference on AIDS. Abstract #043, Paris, March, 1992.

7. Third European Conference on AIDS. Abstract #066, Paris, March, 1992.

8. Ragni MV. Phase I/II Study of Combination Zidovudine and Didanosine in the Positive Asymptomatic Patients (Oral presentation) Third European Conf. on AIDS, Paris, Mar.,1992.

9. Third European Conference on AIDS. Abstract #063, Paris, March, 1992.

10. Hamilton J, Simberkoff M. get title of Veteran's study (NEJM)

11. Third European Conference on AIDS. Abstract #064, Paris, March, 1992.

12. Burroughs-Wellcome. Wellcome trial H56-020 of zidovudine in "low risk" asymptomatic HlV-positive individuals (CD4.400)

13. Third European Conference on AIDS. Abstract #021, Paris, March, 1992.

14. Third European Conference on AIDS. Abstract #068, Paris, March, 1992.

15. Third European Conference on AIDS. Abstract #P132, Paris, March, 1992.

16. Third European Conference on AIDS. Abstract #P2&9, Paris, March, 1992.

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