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administration, and it appeared to be well-tolerated without major side effects. Marked reductions in serum HBV DNA levels were noted in the majority of patients in that trial, with clearance of HBeAg from two of the patients. In some this inhibition was sustained, but in others HBV DNA levels returned to the pretreatment baseline levels. Some of these patients had complex medical problems and were also receiving other antiviral drugs with potential side effects, complicating subsequent interpretation of possible FIAU-associated toxic effects. In addition, since HIV infected patients are immunocompromised and as such may be less likely to have a sustained response to therapy, treatment in nonimmunocompromised patients seemed the logical next step.

Given the lack of effective orally available antiviral agents for the treatment of HBV infection and the promising nature of these early studies, a 1-month study was conducted at NIH to look at the safety and efficacy of this drug in patients with HBV infection alone. In NIH trial 91-DK-AI-123 (Lilly Trial R91-010), FIAU was shown to inhibit HBV replication effectively. However, this inhibition was transient, with viral reactivation in most patients. The rationale behind the final NIH FIAU study was that retreatment of approximately 20 patients with chronic HBV infection for 24 weeks would result in short-term inhibition of viral replication, normalization of serum aminotransferase levels, and potentially long-term virologic remission. The protocol was written in September 1992, before completion of the R91 study. Submission of the retreatment protocol to FDA was delayed because of the lack of long-term animal toxicity data. Six-month toxicity data from studies in animals or humans were not yet available. Appendix F summarizes the preclinical toxicity data available when the PPPC trial was finally begun in March 1993. These included a 6-month study in mice, and similar studies in rats, dogs, and monkeys were under way.

AVAILABLE CLINICAL DATA REGARDING POTENTIAL TOXICITY

At the time of initiation of the PPPC trial in March 1993, there was knowledge of eight deaths of patients who had participated in previous FIAC/FIAU trials: patients 107 (hepatic failure), 105 (bacterial pneumonia), 103 (AIDS), and 110 (AIDS) from R89; patients 101 (Pneumocystis pneumonia), 401R (hepatic failure), and 406R (pancreatitis) from R90; and patient 4D in protocol R91 (hepatic failure). Patient 408R in trial R90 also died of liver failure, but his death occurred after the follow-up period and investigators did not learn of the death until July 1993. These deaths have been reviewed in previous sections. Concern about patient 4D and recognition of a similar spectrum of signs and symptoms when it arose in patient 2 in the PPPC trial led to prompt and appropriate termination of this study in late June 1993.

A variety of other potential toxic effects had been identified from earlier trials (R89 and R90) in HIV-positive patients. Nausea, vomiting, and abdominal discomfort were side effects of FIAC/FIAU and were dose limiting. Peripheral neuropathy was also considered to be a possible adverse event associated with FIAU therapy. One of the patients from trial R91 (patient 1A) had a clear-cut neuropathy. This 52-year-old man received 28 days of FIAU therapy in March and April 1992, but sensations of numbness and tingling were not noted until late September 1992 (5 months after receiving his last dose of FIAU). Because of progressive pain, he underwent nerve conduction studies at NIH in January 1993. These were consistent



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