Protease Inhibitor Update: Treatment Combination Strategies

Representatives of the companies developing the leading protease inhibitors agreed at the January 6 protease inhibitor forum (announced in AIDS TREATMENT NEWS December 22) that even the most potent of these drugs will work best in combination with the nucleoside analogs--AZT, ddI, ddC, d4T, and 3TC--and possibly with each other.

Sharon Chapman, Ph.D., said that Agouron's nelfinavir (Viracept, AG 1343) lowered viral load below the limit of detection in 5 of 5 people who took this protease inhibitor with d4T in a 4-week study. When given by itself three times a day for a total daily dose of 2250 mg, nelfinavir lowered viral load more than 1.5 log (32-fold) in 90% of people studied for 4 weeks, and to below the limit of detection in 60%. Six larger trials in people with HIV infection, which will begin in February at 40 sites across the country, will focus on nelfinavir in combination with (1) d4T, (2) AZT plus 3TC, and (3) whatever HIV drug therapy a person may be taking. Chapman said Agouron is trying to find trial sites where many women and minorities are cared for.

In a 75-person, 24-week trial of Merck's indinavir, AZT, and the two drugs combined, about 50% of those taking the combination had viral load reductions below the limit of detection, compared with 30% taking indinavir alone. Merck's Emilio Emini, Ph.D., said these proportions held true for an additional 24 weeks. In a study combining indinavir with both AZT and ddI, the proportion with undetectable circulating virus is greater than in the indinavir/AZT study, according to Emini. Results of that study will be presented at the Human Retroviruses meeting later this month. But a preliminary report last December noted that some people in this 6-month trial had a 3-log (1000-fold) drop in circulating virus. Then their viral loads began to go back up, but possibly because some stopped the indinavir/AZT/ddI treatment at that point.

Updating results from a 25-person French trial combining Abbott's ritonavir with AZT and ddC (see AIDS TREATMENT NEWS #231), Abbott investigator Dave Pizzuti, M.D., said that about 40% have now attained a 3-log (1000-fold) decrease in viral load at 5 months. As this trial proceeds, the proportion of people with several-log drops in viral load continues to increase. Pizzuti also said that laboratory tests show little cross-resistance between ritonavir and saquinavir, the Roche protease inhibitor now being studied in combination with ritonavir.

The Vertex/Glaxo Wellcome protease inhibitor (VX-478 or 141W94) has not yet been studied in combination with other antiretroviral drugs. But Glaxo Wellcome's Marty St. Clair, Ph.D., reported that VX-478 does not share resistance patterns with nelfinavir, indinavir, ritonavir, or saquinavir, so it could be a good candidate for combination with any of those drugs. Another potential advantage of VX-478 is that it appears to penetrate brain and lymph tissue better than the other protease inhibitors. But St. Clair stressed that these findings are from rat studies and must still be confirmed in humans.

Saquinavir is the only protease inhibitor already approved by the FDA; it is approved only in combination with one or more nucleoside analogs. At the New York symposium, organized by activist Jules Levin, Roche's Mickey Salgo, M.D., Ph.D., vowed that no one who wants to take saquinavir would be denied the drug because of financial need. Financial assistance specialists who can be reached at 1-800-282-7780 will help connect people with appropriate third-party payers, or, failing that, will make other arrangements for people who cannot afford the drug.

Note concerning limit of detection of viral load, referred to above: Agouron used a research bDNA assay with a 100-copy cutoff; Merck used the Roche PCR assay with a 200-copy cutoff.