Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 9 - October, 1993
Derek Link

In a two-day meeting full of ironic twists, the FDA Antiviral Advisory Committee voted on September 20 to fully approve ddC monotherapy and withdraw combination AZT/ddC's accelerated approval. Advisory Committee decisions carry no official authority, although FDA usually follows them. The monotherapy approval was based on CPCRA 002, an open-label, non- randomized comparison of ddC and ddI in advanced AIDS patients who were intolerant or failing AZT. Hoffmann LaRoche, the New Jersey-based affiliate of the Swiss drug company that manufactures ddC, also submitted data from earlier monotherapy studies, the ddC monotherapy control arm of ACTG 155, and the ddC expanded access program to support the approval. During the vote, Fred Gordin, MD, VA Medical Center in Washington DC, a committee member said, "we use ddC monotherapy as salvage therapy in advanced patients. This brings the indication in line with its clinical use."

In a separate decision, the committee voted to withdraw ddC combination therapy's accelerated approval. Accelerated approval is a new regulatory mechanism which allows marketing approval before a drug's clinical efficacy has been established. AZT/ddC combination therapy obtained the first accelerated approval in June 1992. Committee members cited several reasons for the withdrawal including insufficient data supporting efficacy of the combination, lack of ddC access problems, and doubts that accelerated approval could be implemented after ddC received a full monotherapy approval.

AZT liver Toxicity Syndrome More Common in obese Women

On the second day, the committee reviewed data on FIAU, the experimental hepatitis B virus treatment that killed five patients in phase II studies. Jay Hoofnagle, the principal investigator of the FIAU study, detailed the horrible chronology of this clinical research disaster. The patients died from severe drug-induced liver damage characterized as lactic acidosis and hepatic steatosis, leading to organ failure and death. A preliminary report from Yung-chi Cheng of Yale University suggests that the FIAU syndrome may be caused by damage to mitochondrial DNA. Mitochondrial DNA is responsible for energy production in cells. FIAU, a nucleoside analog, may become integrated into mitochondrial DNA so that it continues to block DNA function even if the drug is discontinued.

The FIAU tragedy ignited fears that other nucleoside analogs could produce a similar syndrome. The Committee reviewed data on six deaths due to lactic acidosis and hepatic steatosis, reported to the FDA's post-marketing surveillance system, that may have been caused by AZT. Five of the six deaths occurred in women, four of whom were obese. Obese women are, however, at higher risk for fatty liver and lactic acidosis in general. While these cases appear similar to the FIAU syndrome, no AZT-related mechanism has yet been found. AZT does not appear to have a FIAU-like effect on mitochondrial DNA, according to Cheng's preliminary report.

Dr. David Barry, Vice President of Burroughs Wellcome, AZT's manufacturer, presented an overview of lactic acidosis and hepatic steatosis reports from AZT clinical studies, post- marketing surveillance, and hospital records. This analysis includes cases that did not result in death. Forty-three cases have been identified thus far. Again the rate appears higher in women than in men. Although the data are incomplete, preliminary information suggests that the syndrome occurs at a rate of 6/100,000 for men, and 20/100,000 for women.

AZT's label has already been amended to reflect this new information and Burroughs Wellcome mailed out a "Dear Doctor Letter" to all physicians describing what is now known. However, the mechanism of these toxicities and their relationship to AZT remains unclear.

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