Changing daily treatment from zidovudine (AZT), to didanosine (ddI appears to safely slow the progression of disease in certain HIV-infected patients who had tolerated AZT for at least 16 weeks, according in a report in the August 27 New England Journal of Medicine by investigators supported by National Institute of Allergy and Infectious Diseases.
The results of the trial suggest that ddI should not be limited to persons who cannot tolerate AZT or in whom AZT failed," says James O. Kahn, M.D., principal investigator of the study. "Rather, the findings support expanded use of ddI in patients similar to those studied."
For the Study, the investigators randomly assigned 913 patients to receive daily either 600 milligrams (mg) AZT, 750 mg ddI or 500 mg ddI. Neither the researches nor the patients knew which a drug a patient received. Investigators followed the patients for an average of 55 Weeks.
The study showed that patients who switched treatments from AZT to 500 mg of ddI had significant delays in the rate of AIDS-defining illness or death," says Dr. Kahn, assistant professor of medicine at the University of California, San Francisco. "For the subset of Patients with AIDS-Related Complex (ARC) or with no clinical symptoms (70 percent of the entire study group), switching to either dose of ddI significantly delayed AIDS or death. However, we found among patients who entered the study with AIDS, there were no differences according to treatment group. The three treatment groups had the same survival rates."
Study patients had AIDS or ARC with counts of CD4+ T white blood cells less than 300 cells per cubic milliliter or were HIV-infected but did not have clinical symptoms and had fewer than 200 CD4+ T cells/ml. Because HIV targets and kills CD4+ T cells, physicians count the number of cells to gauge the stage of infection. A healthy person has between 800 and 1,200 CD4 + T cells/ml.
We need further studies to clarify the best schedule for giving such drugs, the effectiveness of alternating drug regiments and clinical usefulness of using combination treatments," says Anthony S. Fauci, M.D., director of NIAID. AZT and ddI are the only two drugs approved by the Food and Drug Administration for use alone to slow the progression of HIV disease.
Compared with AZT, treatment with 500 mg ddI significantly reduced the rate of new, nonrecurrent AIDS-defining illnesses or death. Such rates were highest, 41 percent, among those who took the AZT, compared to 37 Percent for those on 750 mg of ddI and to 32 percent for those on 500 mg of ddI. The effectiveness of ddI did not relate to how long the patients previously took AZT.
Why there is no difference in clinical effectiveness for AIDS patients among the treatment groups is unclear, Dr. Kahn says. "It could be that the AIDS patients in our study were more likely to discontinue treatment, which could decrease our ability to detect a difference between the drugs."
All patients receiving ddI, in comparison with those taking AZT, had smaller declines in the number of CD4 + T cells and larger decreases in the levels of the p24 protein, part of the HIV inner structure.
Patients on AZT had higher rates of severe anemia and leukopenia, the depletion of certain red and white blood cells, than those taking AZT, had smaller declines in the number of CD4 + T cells and larger decreases in the levels of the p24 protein, part of the HIV inner structure.
For the study, investigators used a powdered buffer or sachet from of ddI, which is a different formula than the tablet from of ddI presently available commercially. "The amount of ddI processed by the body from the tablet form is grater than the powdered form," Dr. Kahn explains. "Therefore, a 400 mg tablet dose corresponds to the 500 mg sachet dose used in the study."
The study, AIDS Clinical Trials Group 116B/117 began in October 1989 and follow-up ended in November 1991. Reprints of the NEJM article and information about other trials are available from the AIDS Clinical Trials Information Service. 1-800-TRIALS-A.
Dr, Kahn's co-authors include Stephen W. Lagakos, Ph.D., and Song-Heng Liou, M.A., Harvard School of Public Health; Douglas D. Richman, M.D., University of California and the Veterans Affairs Medical Center, San Diego, Calif.; Anne Cross, Ph.D, Michael Brown, Mohan Beltangady and Laurie Smaldone, M.D., Bristol-Myers Squibb; Carla Pettinelli, M.D., Ph.D., NIAID; Paul A. Volberding, M.D., University of California, Los Angeles; Henry S. Sacks, Ph.D., Mount Siani School of Medicine, N.Y.; Thomas C. Merigan, Stanford University, Calf.; and Raphael Dolin,. M.D., University of Rochester, N.Y. For the study, Bristol-Myers Squibb supplied the ddI and Burroughs Welcome provided the AZT.
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National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) Wednesday, August 26, 1992
Questions and Answers, ACTG Protocol 116-B/117
What Was The Purpose of Study ACTG 116-B/117?
ACTG 116-B/117 was a randomized, double-blind clinical trial to evaluate the efficacy and toxicity of switching to one of two different doses of didanosine (also called dideoxyinosine, or ddI) compared to continuing treatment with zidovudine (formerly called azidothymidine or AZT. The study population consisted of HIV-infected patients with AIDS, ARC or asymptomatic infection who had previously been on and tolerated zidovudine therapy for more than 16 weeks.
The main purpose of ACTG 116-B/117 was to learn whether switching to didanosine would be better than staying on zidovudine in terms of slowing the progression of HIV infection. Progression of HIV infection was evaluated in terms of new AIDS-defining events or deaths which occurred during the study period (excluding Stage 1 AIDS Dementia and Kaposi's Sarcoma).
The study also evaluated the toxicities of didanosine and zidovudine in terms of frequency and degree of severity.
When and Where Was This Study Conducted?
Enrollment to this study began in October 1989 and ended in early April 1989. Follow-up of study participants was discontinued in November 1991. The Study lasted just over two years. A total of 44 sites participated in this trial, including sites located at AIDS Clinical Trials Group (ACTG) units, sites supported by the National Hemophilia Foundation and four sites supported by Bristol-Myers Squibb Company.
How Does Didanosine Differ From AZT?
Like zidovudine, didanosine us a nucleoside analogue which inhibits HIV reverse transcriptase. Didanosine is also similar to zidovudine in that it is metabolized to a triphosphate from which acts as a DNA chain terminator during HIV replication. Early cell culture studies suggested that didanosine would have a different therapeutic profile than zidovudine because it appeared to lack zidovudine's toxicity against bone marrow. Another difference was the longer intracellular half-life of didanosine as compared to zidovudine, which suggested didanosine could be administered less frequently than zidovudine but still reach affective levels inside HIV-infected cells. Lastly, it was seen in laboratory tests that HIV that was resistant to zidovudine could be inhibited by didanosine.
What Was The Patient Population For This Study?
The study was open to persons with HIV infection who were diagnosed with AIDS or ARC and CD4 cell counts less than 300 per milliliter, or who were asymptomatic with CD4 cell counts less than 200 per milliliter. All Study participants had been on and tolerated zidovudine for more than 16 weeks before entering the study.
How Was The Study Designed To Show Which Medication Was More Effective?
Eligible patients were assigned through randomization to continue on zidovudine, or to switch to one of two doses of didanosine. Everyone entering the study had a one in three chance of getting assigned to a given study treatment. Assignments were double-blinded, meaning that neither the participants nor study investigators following the participants knew which treatments were assigned to whom. By following the clinical course of these patients, the study was able to compare the efficacy and safety of these treatment strategies.
What Are The Results Regarding The Benefit of Didanosine Compared to Zidovudine?
Participants randomized to didanosine 500 mg/day (sachet formulation) had a statistically significant delay in time to first new AIDS-defining event or death, compared to those randomized to zidovudine. Patients randomized to didanosine 750 mg/day (sachet formulation) did not have a statistically significant difference in time to first new AIDS-defining event or death, compared to the zidovudine arm; however, the trend was in favor of the didanosine in delaying time to first new AIDS-defining event or death was primarily observed among the subgroup of participants with ARC or asymptomatic disease.
Was There A Survival Difference Between Patients Taking Didanosine And Those Taking Zidovudine?
No statistically significant differences in survival were observed between the study treatment arms.
What Were The Most Frequent Toxicities Observed With Didanosine And Zidovudine In This Study?
The incidence of pancreatitis, although rare in this study, was greater in patients taking didanosine 750 mg/day than in those assigned to zidovudine. Similarly, the incidence of increased amylase (an enzyme produced in the pancreas) in the blood was greater in participants taking either didanosine dose, as compared to zidovudine. In contrast, hematological toxicities (lowered blood cell counts) were more frequent in participants taking zidovudine than in those assigned to didanosine. No statistically significant difference in the incidence of peripheral neuropathy (i.e, pain, numbness or loss of sensation in the soles of the feet, legs, or hands and arms) was observed between didanosine at either dose and zidovudine.
What Happened To The CD4 Cell Counts of Patients In Study 116-B/117?
CD4 cell counts of patients assigned to didanosine increased during the first 8 to 12 weeks of therapy, and then started to decrease. Patients assigned to zidovudine had a decrease in CD4 cell count during the same time frame. On average, patients assigned to zidovudine had 10 to 15 fewer CD4 cells (per cubic milliliter) than those assigned to didanosine during their initial 24 weeks on study.
What Is The Recommended Treatment Now For HIV-Infected Persons Who Have Previously Been On Zidovudine?
Further analysis of this study along with the results of other studies of didanosine will need to be completed before any final recommendations can be made. However, this study clearly showed that didanosine was a valuable treatment option for patients with HIV infection who had been on zidovudine for more than 16 weeks. Completion of other, ongoing studies of didanosine (ACTG 116-A and ACTG 118) will help in determining the full impact of these results on patient management, for example, whether didanosine should be initiated in patients with less than 16 weeks of zidovudine therapy.
Does Didanosine Work In People Who Can't Take Zidovudine?
No clinical data are yet available on the role of didanosine therapy in persons who cannot tolerate zidovudine. This question should be addressed in part by protocol ACTG 118, the results of which should be available by early 1993.
Are There Any Clinical Trial Results Comparing Didanosine With Zalcitabine (dideoxycytidine, or ddC)?
To date, no data are available from studies comparing didanosine to zalcitabine. An ongoing study being conducted by NIAID's Community Programs for Clinical Research on AIDS (CPCRA 002) is comparing didanosine to zalcitabine in persons who cannot tolerate zidovudine or who had clinical failure on zidovudine therapy. This study should yield important on the relative benefits and toxicities of each drug. These results should be available during the fall of 1992.
Are There Any Recommendations Regarding Combination Therapy Using Didanosine and Zidovudine?
The role of combination therapy with drugs such as zidovudine and didanosine is still under study. No recommendations can be made at this time. The following ACTG protocols will help to answer the question of whether combination therapy offers superior benefits to persons with HIV infection:
o ACTG 143 is a pilot study of zidovudine-plus-didanosine to establish the safety of this combination. Data should be available for final analysis by early 1993. So far, the study has shown that combinations of zidovudine and didanosine are generally well tolerated.
o ACTG 155 is an ongoing Phase II/III study of combination therapy that is comparing zidovudine-plus-zalcitabine to zidovudine alone and zalcitabine alone in an advanced patient population. The analysis of this study is currently anticipated for late 1992 to early 1993.
o ACTG 175 is a phase II/III trial to study the relative benefits and toxicities of combination antiretroviral therapy versus single agent therapy in patients with early HIV infection. One of the four arms of this study is zidovudine-plus-didanosine. It is expected that this study will play a critical role in discerning the benefits of combination therapy for patients with early disease.
What Is The Role of Didanosine in the Treatment of HIV-Infected Children?
Data that compare zidovudine and didanosine are not yet available in children. There is no reason to believe that the relative efficacy of zidovudine and didanosine in children should be any different than in adults. An ongoing pediatric clinical trial, ACTG 152, compares zidovudine versus didanosine versus combination therapy with these two agents in
patients who have not received other antiretroviral agents. This trial should provide important information in order to answer this question. However, data are not yet available.
Is Didanosine Useful In Early HIV Infection?
The relative clinical efficacy and toxicity of didanosine in early HIV infection is being studied in ACTG 175, a large comparative study which enrolled patients with CD4 counts between 200 to 500 per cubic millimeter. The four treatment regimens being tested in ACTG 175 include zidovudine alone, didanosine alone, zidovudine-plus-didanosine, and zidovudine-plus zalcitabine. It is expected that ACTG 175 will reach final analysis in approximately two years.
Has Resistance to Didanosine Been Found, As It Has With Zidovudine?
The work from this study on resistance is now ongoing. A limited amount of data on resistance to didanosine from other studies has been reported, to date, in a small number of patients who were previously treated with zidovudine and subsequently switched to didanosine. Reduced sensitivity to didanosine was seen after 12 months or more of didanosine therapy. The clinical significance of resistance to zidovudine or didanosine is not yet known.
Are Other ACTG and CPCRA Studies of Didanosine Continuing, Now That Didanosine Has Been Licensed?
Yes, ACTG and CPCRA studies involving didanosine will continue as planned in order to answer critical questions concerning the clinical usefulness of didanosine and guidelines for didanosine therapy. Protocols ACTG 116-A and ACTG 118 are projected to reach final analysis during the last quarter of 1992. ACTG 116-A compares zidovudine and didanosine in persons with less than or equal to 16 weeks prior zidovudine. ACTG 118 evaluates different doses of didanosine in persons who experienced intolerable zidovudine-related toxicity. Further information from carefully controlled randomized trials is needed in order to elucidate the role of didanosine in the treatment of HIV infection relative to standard zidovudine therapy.
Reference: Kahn JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992;327:581-587.
Prepared by: Office of Communications National Institute of Allergy and Infectious Diseases NIH Bethesda, MD 20892
Public Health Service U.S. Department of Health and Human Services August 1992