The powerful anti-HIV effects of the Merck protease inhibitor indinavir sulfate are sustained when it is administered in combination with zidovudine (AZT).
Indinavir sulfate (MK-639, formerly L-735,524 or L-524, trade name Crixivan), is one of several members of this new class of anti-HIV agents in the advanced stages of clinical development. Unlike currently approved anti-HIV drugs, which target the reverse transcriptase enzyme required in the early stages of viral replication, the HIV protease inhibitors target an enzyme needed for the processing of viral proteins.
Early clinical trials showed that the drug had an appreciable antiviral effect and resulted in weight gain and increased CD4 counts.
In a report to the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 17-20 in San Francisco, California, Merck researcher F. Massari reported results from a trial comparing indinavir or AZT alone to indinavir plus AZT.
"Indinavir produced a profound decline in viral RNA sustained to 24 weeks," he said. "Co-administration of AZT may have increased the proportion of patients with a 2-log drop in viral load at 24 weeks."
The 73 study participants, enrolled at eight sites in the U.S. and at one site in Germany, at baseline had a median CD4 count of 221 cells/(micro)L and a median 4.92 log copies of HIV RNA per milliliter of plasma.
Maximum declines in HIV RNA were 0.6 log for the group receiving AZT alone, 2.3 log for the group receiving indinavir alone, and 2.6 log for the group receiving the indinavir/AZT combination.
But after 24 weeks of treatment, RNA titers remained 0.3 log below baseline for the AZT group, 1.5 log below baseline for the indinavir group, and 2.5 log below baseline for the indinavir/AZT group.
Massari reported that about 60 percent of the participants receiving the indinavir/AZT combination had a 2-log decline in HIV RNA sustained at 24 weeks. Some three-fourths of these patients had a 50 percent or greater increase in CD4 counts over this time.
"Indinavir sulfate, alone or in combination with zidovudine, mediated a profound decline in serum viral RNA levels and an increase in CD4 cell counts which were markedly superior to those seen with zidovudine alone in therapy-naive patients," he concluded. "Addition of zidovudine to indinavir sulfate had no effect on the initial viral decline, but may have had an effect on the duration of the response."
Four of the indinavir recipients developed urolithiasis but were able to resume treatment without recurrence.
Massari noted that trial participants received indinavir at a dose of 600 mg every six hours. Phase III trials of the drug are using a dose of 800 mg every eight hours.
In another report to the ICAAC meeting, University of Pittsburgh researcher John Mellors reported results from the extension phase of a clinical trial comparing two doses of indinavir (200 mg q6h or 400 mg q6h) to continued AZT therapy. After 24 weeks of treatment, participants in the AZT arm crossed over to indinavir.
The indinavir doses were modified to 600 mg q6h when Phase I trial results showed that the higher dose delayed the rebound of serum viremia.
Subjects had a median baseline CD4 count of 110 cells/(micro)L. After 52 weeks of indinavir monotherapy, serum levels of HIV RNA returned to baseline, but a 50-cell/(micro)L increase in median CD4 count was sustained over this period.
About half of the participants who switched from AZT to indinavir had a 1-log reduction in serum HIV RNA after 24 weeks and about a third of these subjects had a 2-log decrease. Nearly all of these individuals had at least a 25-cell/(micro)L increase in CD4 count; half had an increase of 100 cells/(micro)L.
Mellors addressed the interesting finding that CD4 increases were more prolonged than HIV RNA responses after 52 weeks of indinavir therapy.
"By simply counting [HIV] RNA molecules I don't think we can predict all the immunologic changes," he said. "Perhaps with MK-639 we are selecting a less virulent virus."
In an interesting poster presentation to the ICAAC meeting, Merck researcher Ali Shafiee reported that Merck screened microorganisms for their ability to modify indinavir into new analogs of the drug.
Two such microorganisms were found, and six MK-639 metabolites were isolated and investigated for anti-HIV activity.
"One of these compounds was more potent than the parent MK-639," Shafiee et al. reported. "The remaining metabolites were, in general, less active, although some showed significant HIV protease inhibitory properties."