Gay Men's Health Crisis Treatment Issues, Vol. 5, No. 6 - August 30, 1991
Kevin Armington

AZT With ddC

The most promising antiviral data from Florence in the opinion of this observer, emerged from studies of AZT and ddC. Oddly enough, these data were not prominently presented as part of the regular conference program. Dr. Margaret Fischl, a researcher at the University of Miami, is the principal investigator of the study on ddC that was recently completed. This trial compares five different combinations of AZT and ddC. Rumor has it that the results will soon be published in a prestigious medial journal. In any event, the data are quite impressive.

Fifty-six patients with AIDS or ARC, with average T4 counts between 60 and 70, received different doses of this combination and were observed for 40 weeks. Patients on lower doses (150 mg AZT and .015 mg/kg ddC daily) experienced only small, transient rises in T4 counts. However, at higher does of drug (300 or 600 mg AZT with 0.03 mg/ kg ddC daily), patients saw increases in T4 counts of up to 120 cells. At this dose the T4 counts remained above baseline values for as long as a year. No other treatment option has produced and maintained similar increases in T4 counts for so long in persons with such low T4 counts. There was also some evidence that 600 mg AZT daily wa more effective than 300 mg AZT daily.

In general the combination was well-tolerated. Two patients experienced peripheral neuropathies, which resolved when ddC was discontinued. Two other patients had to withdraw from the study because of low white cell counts. At least one case of drug- related liver toxicity was observed. A larger efficacy trial is now under way to gather more data on this promising combination. AIDS Clinical Trials Group (ACTG) trial #155 is employing 600 mg AZT with 0.03 mg/kg ddC. The study is open to persons whose T4 counts are below 300 and who have taken at least 500 mg of AZT daily for six months. Many sites nationwide are recruiting. For a complete list offering more information on clinical trials call 1-800-TRIALS-A.

AZT with Alpha Interferon

Theoretically, it makes good sense to target HIV with AZT and alpha interferon, since each drug interferes at a different point in the virus' "life cycle." However, results in people so far have not shown the same positive effects as test tube studies. Three small studies, presented in Florence, examined the effects of this combination in mildly symptomatic patients with evidence of increased HIV reproduction in their blood (i.e., p24 antigen positive). The most optimistic results were reported by Dr. Donna Mildvan, who is conducting a study (trial #068) supported by the ACTG at Beth Israel Medical Center. This ongoing trial is also offered at a number of centers around the country: for a complete list, call 1-800-TRIALS-A. Twenty three patients with T4 counts over 200 and p24 antigen levels over 70 received AZT alone or AZT with alpha interferon for at least six months.

The bottom line result of this subtle and complicated trial was that the combination had a greater suppressive effect on viral replication than AZT therapy alone. Dr. Mildvan went so far as to claim that AZT plus alpha interferon had a synergistic effect on p24 antigen levels. This means that the two drugs together had a greater effect than the combined effects of each drug taken alone (i.e., 2+2=5). One the negative side, 12 out of 28 participants needed to cut their doses by 50% due to toxicity. Dr. Mildvan also noted that the combination was better tolerated when d at the same time, rather than adding one drug after a period of monotherapy. Due to strict eligibility criteria, it is extraordinary difficult to recruit patients for this rial. Therefore, it may be some time before these very preliminary and encouraging results are verified.

A somewhat larger study conducted int he Netherlands yielded conflicting results. This study compared 1000 mg AZT daily to 600 mg AZT daily augmented with three million units (MU) of alpha interferon three times a week. This dose of interferon is less than the amount administered in ACTG trial #068 (described above) which calls for a range of 7 to 42 MU/week. Forty patients with T4 counts above 150 were treated for a t least six months. Patients on the combination had a greater drop in HIV reproduction and higher T4 increases after three months. However, there were no longer any significant differences in these parameters between the two groups after six months of treatment. Also, the incidence of opportunistic infections (OIs), Kaposi's Sarcoma, and neuropathy was the same for both groups. In addition, the author is reported that the combination resulted in more toxicity, more need for dose reduction, and more fatigue than with single therapy. On the other hand, the authors also concluded that the combination is worth further investigation because the use of AZT and alpha interferon may delay the development of resistance to AZT.

Researchers at the Center for Special Immunology in Ft. Lauderdale tried adding alpha interferon to AZT in fifteen patients who had high p24 levels despite six months of AZT alone (600-1200 mg/day). Trial participants received huge amounts of alpha interferon: three MU/day for the first week, five MU/day for the second week, and 10 MU/day thereafter. The dose of AZT was 600-800 mg/day. Four patients withdrew: three due to toxicity. Five of the remaining eleven "responded," and had reduced HIV reproduction. Those who responded had higher T4 cell count percentages and fewer clinical events. In other words, people who were healthier had more benefit from the combination therapy. The authorities also reported that responding patients could be identified in the first month of treatment. The implication may be that combination AZT and alpha interferon is worth trying for one month to see if results are desirable.

Asymptomatic persons with T4 counts between 300-600 were the focus of a six month trail of AZT plus alpha interferon at Laennee Hospital in Paris. Seventeen participants received 500 mg AZT/day and eleven participants received 500 mg AZT/day plus 3 MU alpha interferon three times a week. During the trial only one patient, who was taking AZT alone, progressed to AIDS. Researchers noted a more pronounced drop in p24 antigen levels for patients receiving the combination. While p24 antigen levels were on the rise again at six months, those on the combination showed a more gradual rise. No information on toxicity was reported

Traditionally, alpha interferon has produced better results in treating Kaposi's sarcoma in people with T4 counts above 200. So there is perhaps a greater hope for the drug's antiviral effect in people with counts in that range. It does not necessarily follow, however, that alpha interferon will not be useful to people with counts below 200. In fact, one study showed that alpha interferon and AZT produced improvements in some KS patients with T4 counts below 200.

AZT with ddI

Two small studies in adults and children of combination AZT/ddI are still ongoing. Very early data from both trials were presented in Florence. Dr. Ann Collier presented data from a small study of 37 adults who have received varying doses of AZT with ddI or AZT alone. The group consisted of asymptomatic persons with T4 counts below 400 and positive p24 antigen levels. None had received AZT for more than three months before the trial began. Dr. Collier found that T4 counts rose more impressively in people taking the combination therapy versus people taking AZT alone. However, after six months of treatment, T4 counts declined in both groups. There was some evidence that T4 counts stayed elevated longer in people on higher doses of AZT (600 mg/day as opposed to 300 mg or 150 mg combined with ddI).

The two drugs were not antagonistic and caused little serious toxicity. While nine participants needed to reduce their doses, only one person withdrew altogether from the trial due to toxicity. combination AZT and ddI is also being given to children in a small trial at L.A. Children's Hospital. Many different dose levels are being tried. Nine children had been accrued by the time the abstract was published and the drugs had been well- tolerated for an average of six weeks. No efficacy data is yet available.

CONCLUSION

Current evidence strongly suggests that combination therapy may very well be the way of the future for antiviral therapy. larger human trials are needed to compare the many combination possibilities and to determine which options and dosings are the most effective. Trial designs will inevitably become more complicated. Such research raises the stakes for efficiency and smooth functioning of clinical trials. Treatment Issues looks forward to creative and effective designs from researchers with input from AIDS activists.

Copyright (c) 1991 - Gay Men's Health Crisis Treatment Issues. Non-commercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. Direct Dial: v.34+: 714.248.2836; v.120/ISDN: 714.248.0433 Internet: telnet:aegis.com www: www.aegis.com

910830
GM050601

Copyright © 1991 - Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011  fredg@gmhc.org  http://www.gmhc.org

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Elton John AIDS Foundation, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2003. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2003. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .