HIV viral burden decreased by 99.9 percent in patients receiving a three-drug combination in a Phase II clinical trial.
The combination includes indinavir (Merck trade name Crixivan, code-named MK-639 and formerly called L-735,524 or L-524). Indinavir is one of the new class of anti-HIV drugs known as protease inhibitors now reaching advanced clinical trials. One protease inhibitor, saquinavir (Roche trade name Invirase), recently received U.S. approval as an AIDS therapy.
The other two drugs tested in combination with indinavir were zidovudine (AZT) and didanosine (ddI), both of which are currently approved nucleoside analog inhibitors of the HIV reverse transcriptase enzyme.
Merck researcher Ferdinand Massari reported the preliminary trial results to a plenary session of the National Institute of Allergy and Infectious Diseases Twentieth AIDS Clinical Trials Group (ACTG) Meeting, held December 2-6, 1995, in Washington, D.C.
"Combination therapy at 24 weeks was associated with 40 to 50 percent of patients having viral RNA levels below the detection limits of the assay," Massari said.
There was a 3-log mean peak decline in plasma levels of HIV RNA in the 21 trial participants who received indinavir plus AZT plus ddI. This is the most intense anti-HIV effect ever reported for any drug or drug combination.
"In the infectious disease field a log-three decrease is considered bactericidal," commented researcher Charles van der Horst of the University of North Carolina School of Medicine.
Nevertheless, none of the trial participants are expected to have cleared their HIV infections. While the patients maintained a decreased viral burden during the study period, most had a rebound from the peak decreases seen soon after initiation of therapy.
The 3-log decrease in viral burden was associated with an approximately 100-cell increase in CD4 cell counts.
The trial, which compared indinavir plus AZT plus ddI to indinavir alone and to AZT plus ddI alone, showed that the addition of the protease inhibitor to the nucleoside-analog combination had a "much greater effect" than the "nucleoside-analog combination alone."
"We can't yet prove that combination therapy is better than indinavir monotherapy," Massari said. "There is a preliminary indication that indinavir and ddI may have increased gastrointestinal effects."
Massari noted that early clinical trials of indinavir showed that HIV rapidly developed resistance to the drug. These trials suggested that the dose of indinavir was associated with antiviral response, but further study has shown this response to be due to the development of resistance at lower-than-optimal doses.
The optimal dose of indinavir - 800 mg every 8 hours - is so effective that recovery of virus from clinical samples for resistance studies has been difficult.
Massari reported that more than 1,000 participants are currently enrolled in a Phase III clinical trial of indinavir. The study includes patients with advanced HIV disease who are receiving many concomitant medications.
Thus far, he said, the drug has been well tolerated, although the drug is associated with indirect hyperbilirubinemia without hepatotoxicity.
Phase II studies showed that 5 to 6 percent of patients receiving indinavir developed kidney stones (nephrolithiasis). Enrollees in the current study undergo rigorous hydration - they must drink one to two liters of water per day.
Massari said that preliminary results indicate that there is a possible interaction between rifabutin and indinavir: in patients receiving both drugs rifabutin levels increased and indinavir levels decreased. He said that study investigators will likely decrease rifabutin doses by half in patients receiving both drugs.
A Phase III U.S. clinical trial exploring the combination of indinavir and stavudine (d4T) is currently under development. The trial is expected to enroll 1,750 adult participants; its official title is "ACTG 320. A Randomized, Double-Blind, Phase III Study of Indinavir Sulfate (IDV) with Open-Label Stavudine (d4T) in Subjects with HIV Infection with CD4 counts [of at least] 200 Cells/mm3 and [at least] 6 Months of Prior Zidovudine (ZDV) Experience."
Indinavir may be useful in another context: as an adjunct to immunotherapy.
Recent studies have shown that intermittent infusions of interleukin 2 (IL-2) greatly increase CD4 cell counts in patients with HIV disease. However, this treatment is accompanied by a troubling increase in plasma HIV levels.
A study reported at the 1995 ICAAC meeting by NIH researcher J. Falloon showed that when patients receiving IL-2 were taking indinavir, increases in viral load did not occur (see AIDS Weekly, October 30, 1995).
Moreover, some patients who initially did not respond to IL-2 did so after receiving MK-639.
"Indinavir can change IL-2 non-responders into responders," said NIAID researcher H. Clifford Lane.
Also at the 1995 ICAAC conference, Merck's Massari reported that AZT apparently prolonged the anti-HIV effects of indinavir (see AIDS Weekly, October 16, 1995).
"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 said. "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."
In an interesting poster presentation to the 1995 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 Indinavir 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."