Bulletin of Experimental Treatments for AIDS, No. 4, November 1989
Etienne Hafs

ddI (dideoxyinosine) is one of a group of promising anti-HIV drugs called nucleoside analogues. Like AZT and other analogues, it works by inhibiting replication of HIV and reducing the rate atx which cells become infected with the virus. It has no effect on cells already infected with HIV, however, and is not a cure for HIV infection. NIAID* is now recruiting for 3 Phase II and III trials of ddI, alone and in combination with AZT, through its AIDS Clinical Trials Groups (ACTG). These trials, which are expected to enroll approximately 2600 people, will be conducted at medical centers across the US. The inclusion and exclusion criteria are too numerous to be fully reported in this article. If you are interested in participating in one of the protocols, talk to your physician or call 1-800-874-2572 for further information about these criteria.

Phase I Trial Results

A Phase I* study conducted at the National Cancer Institute (NCI) and reported in Science July 28, 1989, tested ddI for 42 weeks in 26 people (10 PWA* and 16 PWARC*). All of the participants had fewer than 300 T-helper cells, and ten were unable to tolerate AZT. Participants were given ddI intravenously at 1 of 8 dosage levels for 14 days, and then received the drug orally at twice the intravenous level. Oral doses were administered on an empty stomach, and participants took antacids before receiving the drug because its effectiveness is substantially lessened by stomach acid.

The oral bioavailability* of ddI in fasting patients who had taken antacids 2 minutes before receiving it was 35%, and the drug crossed the blood-cerebrospinal fluid barrier*. Those who received one of the 4 lower intravenous doses (between 0.2 mg/kg* and 0.8 mg/kg every 12 hours, and 0.8 mg/kg every 8 hours) had relatively little change in their condition. However, those who received one of the 4 higher doses (1.6 mg/kg every 12 hours, 1.6 mg/kg every 8 hours, 3.2 mg/kg every 12 hours, and 3.2 mg/kg every 8 hours) showed substantial improvement.

The number of T-helper cells in these people increased by more than 50% during the first 6 weeks of the study, remained essentially unchanged during weeks 6 to 10, and at week 28 was still substantially higher than at entry into the study. The level of p24 antigen* decreased in all of the high-dose participants who were antigen-positive at the beginning of the study, and in 5 of these people, p24 antigen became undetectable. In addition, participants showed other signs of an improvement in their immune function. Those who had previously been anergic*, had increased responses to skin allergy tests. Only 1 person at a higher dose developed an opportunistic infection during the study.

After receiving ddI, 14 of the study participants had increased energy and less fatigue or need for sleep. Five reported enhanced appetite, and the majority gained weight (average of 1.6 kg) by week 10. Another study of ddI has shown improvement in people with HIV-related dementia.

The NCI researchers reported several side effects of ddI. An increase in blood uric acid* was observed at the 2 highest dose levels. Thirteen participants developed mild headaches, restlessness, or insomnia, but these symptoms ended by week 5. Other infrequent adverse effects may have been caused either by ddI or by the underlying HIV infection. These included seizures (2 patients), neutropenia* (2 patients), recurrence of preexisting hepatitis (1 patient), and a temporary skin rash (1 patient). The researchers did not see a dose-related pattern to any of these side effects, and they believe that they have not yet reached the highest dose level that can be tolerated.

However, peripheral neuropathy* was observed in 21% of participants in two ddI studies conducted by the NCI and the ACTG* medical centers, according to reports from the County Community Consortium in San Francisco. In addition, 5 of 42 people in the ACTG study developed acute pancreatitis*, a potentially life-threatening condition. Because of this, people with a history of moderate to severe peripheral neuropathy or pre-existing pancreatitis have been excluded from ddI protocols.

In the test tube, ddI is effective against strains of HIV that have developed resistance to AZT, and the two drugs may have a synergistic effect. In addition, the anemia* that is one of the most common side effects of AZT was not observed in the NCI study. These findings suggest that people who cannot tolerate AZT may be able to take ddI instead, and that the two drugs given in combination or alternating therapies may suppress HIV infection better than either drug alone. However, this has not been proven, and confirmation awaits Phase II* and III* clinical trials.

Phase II Trials

ACTG 117 study will evaluate the difference between ddI and AZT in people who have been using AZT for more than 12 months. People will be randomized to either AZT 200 mg every 4 hours or ddI 375 mg twice daily. The study is for PWARC (at least one symptom) with fewer than 300 T-helper cells or PWA who have been on AZT for more than 12 months. Your physician must document your AZT history, and you must be able to tolerate at least 600 mg AZT a day. This is an 18-month study.

ACTG 118 will evaluate the effectiveness of two different doses of ddI in people who cannot tolerate AZT because of anemia or a drop in white blood cell count. You must have used AZT for longer than 3 months but less than 12. Your physician will need to document your AZT history. This is also an 18-month study.

Phase III Trial

ACTG 116 will evaluate the difference between ddI and AZT. People will take either AZT 200 mg every 4 hours or ddI 375 mg twice a day. The study is for PWARC (at least one symptom) with fewer than 300 T-helper cells or PWA who have been taking AZT for longer than 2 months but less than 12 months. Your physician must document your AZT history. The study will continue for 2 years.

ACCESS TO ddI OUTSIDE CLINICAL TRIALS

NIAID and the FDA* have approved 2 ddI protocols for people who need the drug but do not qualify for the clinical trials. In FDA 39A, an "open label study regimen," and FDA 40A, a Treatment IND* protocol, participants will take ddI twice daily at dosage levels determined by body weight. A total of approximately 5000 people will have access to the drug through these protocols. As with the clinical trials, Bristol-Myers -- the manufacturer of the drug -- will provide the drug free of charge during these protocols.

Open Label Study Regimen

Protocol 39A will make ddI available to PWA who are "clinically deteriorating" on AZT. Participants must have a diagnosis of AIDS that conforms to the current CDC* definition. Their health status must show indication of serious decline as evidenced by at least one of the following symptoms: (1) involuntary weight loss of 2 to 2.5 pounds a week for 4 weeks, (2) marked neurologic deterioration, (3) opportunistic infections at least 3 times in the last 6 months, (4) 2 T-helper cell counts of less than 50 per mm3* taken at least 1 month apart, or (5) a Karnofsky score* of 40% or less for at least 1 month.

Treatment IND Protocol

Protocol 40A will make ddI available to PWA & PWARC who have developed intolerance to AZT. Participants must have a diagnosis of AIDS as defined by the CDC or be HIV-positive and symptomatic with a T-helper cell count of less than 200. AZT intolerance is defined by any one of several adverse reactions, including the following: (1) a drop in hemoglobin* of at least 2 grams a month, (2) a drop in neutrophil* count to less than 750 cells per mm3, (3) severe nausea and/or vomiting, (4) severe headaches that do not respond to analgesics, and (5) declining muscle strength, such as inability to climb stairs. The participant's private physician must be able to document that these side effects occurred while the person was taking AZT, disappeared when AZT therapy was interrupted, and reappeared when AZT therapy was resumed.

Bristol-Myers, the manufacturer of ddI, is requiring physicians to provide considerable data on participants in these protocols. This will include laboratory evaluations every 7 to 10 days during the first 2 months of ddI therapy. Adverse effects of any severity noted during this period must be reported by phone to Bristol-Myers. If the participant decides to continue on the drug after the first 2 months, follow-up laboratory evaluations and adverse experience report forms must be submitted every 10 days.

As with the ACTG trials, both of these protocols have extensive exclusion criteria not reported in this article. People who want information about the open label study regimen or the Treatment IND protocol should call the NIAID Clinical Trials Information Service at 1-800-874-2572. Those interested in participating in either protocol should contact their physicians, who must register with Bristol-Myers by calling 1-800-662-7999.

Free Public Forum on ddI

A free public forum on ddI will be held on Wednesday, November 15, 1989 at 8:00 p.m. in the auditorium of the San Francisco Medical Society at 250 Masonic Street (near Turk). Topics to be discussed include dosage, toxicity, clinical trials, and the Treatment IND protocol and open label safety regimen. Several expert researchers and clinicians will make presentations and answer questions. Guest speakers will include Dr. Robert Yarchoan of the National Cancer Institute, Dr. Paul Worrall of Bristol-Myers and Dr. Paul Volberding, director of the AIDS program at San Francisco General Hospital. The forum is cosponsored by BETA, the County Community Consortium in San Francisco, and the San Francisco Medical Society. For more information, call the AIDS Foundation Hotline at (415) 863-AIDS or (800) FOR-AIDS in Northern California.
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Copyright © 1989 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182.  beta@sfaf.org  http://www.sfaf.org/beta.html