3TC Clinical Benefit: More Data Presented

In June a major international trial of 3TC was stopped early, after a preliminary analysis showed that adding this antiretroviral to certain other antiretroviral treatments (based mainly on AZT) cut disease progression and death in half (see "3TC: Combination Trial Stopped Early As Clinical Benefit Shown," AIDS TREATMENT NEWS #252). More information was released at the September 15-18 ICAAC conference in New Orleans, in the presentation by Julio Montaner, M.D., of the Canadian Clinical Trials Network.

This study is called CAESAR (an acronym for Canada, Australia, Europe, and South Africa, the regions where it has taken place); it is less well known in the U.S., since there were no sites here. 1800 patients with CD4 between 25 and 250 were enrolled in this trial, which was sponsored by Glaxo-Wellcome and also by Janssen. The trial participants (who were 90% male, average age 36) were all receiving either AZT or AZT+ddI or AZT+ddC, and were randomly assigned to add to that treatment either: placebo, 25% chance; 3TC alone, 50% chance; or 3TC+loviride, 25% chance. (Loviride is an experimental non-nucleoside reverse transcriptase inhibitor being developed in Europe. Its previous name was alpha-APA; AIDS TREATMENT NEWS reported on its early development in September 1992 and March 1993.) After the 52 weeks of the trial, participants were offered open-label 3TC+loviride. The study was stopped early because it was almost finished, and it was clear that nothing that happened subsequently could have changed the result.

The rate of disease progression (to new AIDS-defining condition, or death) was 17% in the group randomly assigned to placebo (in addition to the AZT-based treatment), 9% in the group which added 3TC alone, and 8% in the group which added 3TC+loviride; for all patients, diagnosis of AIDS-defining conditions was confirmed by a review of the medical records, by experts who did not know which drugs the patient was receiving. Death rates in the trial were 4.6% placebo, 2.4% 3TC alone, and 2.7% 3TC+loviride. Overall, adding 3TC to these AZT-based treatments led to a 54% reduction in the relative risk of disease progression or death, and a 53% reduction in the risk of death.

The use of loviride in this combination did not appear to add any additional benefit. (It should be noted, however, that this study was not designed to look for a clinical benefit of loviride, and that this drug might still be valuable in other combinations. In the early history of 3TC, that drug too appeared to be minimally useful, and we are lucky that it was not abandoned before its value in combination with AZT was discovered.)

The CAESAR study found no additional toxicity from adding 3TC to the other treatments. (But physicians need to be aware of side effects seen in other trials, especially pancreatitis in pediatric patients.)

Some of the trial participants were antiretroviral-naive, and started their AZT-based treatment when they entered CAESAR. Their data will be analyzed separately.