Combination therapy with zidovudine (AZT) and the experimental drug ddC is well-tolerated and appears to increase the number of certain crucial immune system cells in persons with advanced HIV disease, according to a pilot study of 56 patients supported by the National Institute of Allergy and Infectious Diseases.
However, Anthony S. Fauci, M.D., Director of NIAID, cautioned, "This is a pilot study that awaits confirmation in a larger group of patients. The data presented are too preliminary to make a final conclusion about the toxicities of the two drugs, or to recommend treatment using a combination regimen of ddC and AZT."
The research report and an accompanying editorial by Dr. Fauci appear in the January 1, 1992 edition of the Annals of Internal Medicine.
Based on the data from this study, a much larger NIAID-supported trial (ACTG 155) with more than 1000 patients is now under way to compare combination therapy (ddC and AZT) with monotherapy or with either drug alone.
Data from ACTG 155 should provide a clear answer to the question of whether and AZT/ddC combination is superior to single drug therapy," said Daniel F. Hoth, M.D., Director of the Division of AIDS at NIAID.
The current study, known as ACTG 106, was carried out at two sites of the AIDS Clinical Trials Group, a network of clinical research centers supported by NIAID. Volunteers enrolled in the study at the University of Miami and the University of California, San Diego, between July 1989 and May 1990.
The investigators report that combinations of AZT and ddC increased the count of CD4+ lymphocytes -- white blood cells crucial to the immune response -- to higher levels for a longer period of time than has previously been shown with either drug taken alone by persons with advanced HIV disease.
Combination therapy also decreased the levels of p24 antigen, an HIV protein, suggesting the suppression of HIV replication. In addition, side effects of the combinations were no more severe, in this small group of patients, that those of the two drugs taken alone.
Although ACTG 106 was not specifically designed to determine the optimal dose of AZT, the researchers found that a low daily dose of AZT -- 150 milligrams -- was less effective that the currently recommended dose of AZT, and was no less toxic.
"This observation suggests that doctors should not use the loser dose of AZT either alone or in combination with other agents, except in cases of AZT-related toxicity," Dr. Fauci said. "The currently recommended dose of AZT, 500 to 600 milligrams daily, remains the first-line antiretroviral therapy for patients with advanced HIV disease."
For HIV-infected patients who cannot tolerate or do not respond to AZT, the recently approved drug didanosine (ddI) is a reasonable course of therapy, Dr. Fauci writes in his editorial.
Upon enrollment, the study subjects in ACTG 106 all had AIDS or advanced AIDS-related complex and CD4+ lymphocyte counts of 200 cells/mm3 or less; none of them had previously been treated with an antiretroviral drug. All of the patients received inhaled pentamidine for the prevention of Pneumocystis carinii pneumonia (PCP).
The patients were divided into six groups. One group received the low (150 mg.) daily dose of AZT; the other five groups received various dosages of AZT (150-600 mg./day) in conjunction with one of two doses of ddC (0.015 mg. or 0.030 mg. per kilogram of body weight/day).
The mean number of CD4+ lymphocytes increased with all regimens and increases were sustained beyond one year with three of the combination regimens. The levels of p24 antigen decreased with five of the six regimens by week two and this decrease persisted throughout the study. With the lowest dose combination regimen, the suppression of p24 levels was not noted until week eight.
In test tube studies, AZT and ddC together have been shown to complement each other's antiviral activity. In the current study, "The apparent increased benefit with combination therapy may be related to the additive or synergistic activity of the two drugs that has been seen previously in vitro," said study collaborator Margaret A. Fischl, M.D., of the University of Miami School of Medicine. "Also, the emergence of drug-resistant strains of HIV may have been diminished by the use of AZT and ddC together."
ddC, like AZT, inhibits an HIV enzyme called reverse transcriptase, which allows the virus to transcribe RNA and DNA.
However, the two drugs have different side effects, which holds out hope the two might be effective together because their toxicities do not overlap. The most common side effect of ddC is sensory peripheral neuropathy, a nerve degeneration that results in pain in the feet and toes. AZT can cause severe anemia and a reduction in certain white blood cells in patients with advanced disease.
In the study, 14 patients had 16 episodes of serious adverse experiences that may have been attributable to study medication. No differences among the various regimens were noted in the frequency of adverse experiences.
Collaborators on ACTG 106 included Tze-Chiang Meng, M.D., Stephen A. Spector, M.D., Brian Wright, and Douglas D. Richman, M.D., University of California, San Diego; Margaret A. Fischl, M.D., Ahmad M. Boota, M.D., and Shenghan Lai, Ph.D., University of Miami School of Medicine; Donald Bennett, Ph.D. and Yiannis Bassiakios, Ph.D., Frontier Science and Technology Research Foundation.