The Division of AIDS Services (DAIDS) has issued a pregnancy safety alert to its trial sites regarding efavirenz (also known as DMP 266 and Sustiva) based on information provided by the drug's manufacturer, DuPont Merck. A study conducted by the company has found that severe birth defects occurred in 3 of 13 monkeys (23%) born to efavirenz-treated mothers. The doses used in the monkeys were equivalent to those being studied in humans. The infant monkeys were born with gross abnormalities. One had both a missing eye and a missing brain, another had small eyes and a third had a cleft palate. Efavirenz was administered to the pregnant monkeys very early in gestation, in the period analogous to the first trimester in humans. According to representatives from DuPont Merck, the birth defects resulted from the drug's impact on initial fetal development rather than by drug-induced genetic damage. There were no adverse effects observed in the mother monkeys.

It is not known whether these types of birth defects could occur in humans, so women taking efavirenz should not become pregnant. All efavirenz protocols, as well as the expanded access program, exclude pregnant women. The drug has not had any effect on male sperm in rat and rabbit studies, but monkey studies have not been conducted. Nonetheless, males participating in any of the efavirenz programs will be required to use barrier contraception during the studies, if they are not already using it.

DuPont Merck is now contacting all its investigators and modifying the informed consent form to include a warning and require the use of additional methods of birth control for both men and women. The company plans to go forward with its filing of a New Drug Application (NDA) with the FDA in May or June. Despite the birth defects seen in the monkey study, DuPont Merck is still planning to request that its drug be designated pregnancy category C. Category C means that safety in human pregnancy has not been determined, but animal studies have found risk to the fetus. According to the FDA guidelines, a category C drug should not be used during pregnancy "unless the potential benefits outweigh the potential risk to the fetus." Rather than accepting this designation, the FDA could request further information or put efavirenz in category X, which carries a much more strongly worded warning.

DuPont Merck claims these findings do not rule out plans to conduct vertical transmission studies where dosing would occur late in the third trimester. Lynne Mofenson, M.D., of the NIH, stated, "I don't think that the FDA or the pediatric investigators would be too happy with evaluating this drug in pregnant women when we have other drugs that appear safer."

Meanwhile the expanded access program for efavirenz was enlarged this winter to allow enrollment for anyone who has had a CD4 count below 400 at any time and is unable to assemble an effective treatment combination from FDA-approved drugs. To date, the program has enrolled 2,362 participants in the U.S. (20% of them women) and 3,159 participants worldwide.