AIDSWEEKLY Plus, Monday, 27 October 1997
Daniel J. DeNoon, Senior Editor

Patients who simply add a protease inhibitor to existing anti-HIV drug regimens risk treatment failure, new studies suggest.

A report that more than half of real-world patients fail highly active antiretroviral therapy (HAART) was the most widely reported story from the American Society for Microbiology's 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 28 to October 1, 1997, in Toronto, Ontario, Canada.

But most media ignored data on why these failures occurred, and failed to report another ICAAC presentation showing that failure rates can be greatly reduced by switching other components of patients' treatment regimens at the same time protease inhibitors are added.

"Adding two potent drugs is important - not just adding two drugs," said New York University researcher Roy Gulick, who presented data from the latter study. "It's only recently been appreciated that you have to start the two new drugs at the same time."

The Gulick et al. data came from a clinical trial in which 97 patients with a median 2.5 years of prior zidovudine (AZT) treatment received either concurrent or sequential triple therapy with indinavir (the Merck protease inhibitor, trade name Crixivan), AZT, and lamivudine (3TC).

The first group of patients received the three-drug regimen from the outset, while the second group of patients switched to the triple combination after 24 to 52 weeks of treatment with AZT/3TC or indinavir alone.

Patients who began treatment with the two nucleoside analogs or with indinavir monotherapy had a high failure rate. About 60 percent of patients in these groups failed to achieve a viral load of less than 500 copies/mL after a switch to indinavir/AZT/3TC.

In contrast, 80 to 85 percent of patients originally receiving the three-drug regimen achieved a viral load of <500 copies/mL, and this success was sustained to the end of the two-year study period.

"There is a striking difference between concurrent and sequential triple-drug therapy," Gulick said. "Delayed, sequential triple-drug therapy achieves more modest antiretroviral effects."

Patients who originally received indinavir/AZT/3TC had continually increasing CD4 cell counts that after 100 weeks of treatment reached a median increase from baseline of 230 cells/mL. Patients with delayed triple-drug therapy had a smaller increase over baseline CD4 counts - about 100 cells/mL - that reached a plateau and did not continue to rise.

Gulick concluded that for patients who have received prior therapy with nucleoside-based reverse-transcriptase inhibitors, it is not enough simply to add a protease inhibitor to existing regimens. At the time a protease inhibitor is added, he said, at least one potent new reverse- transcriptase inhibitor should be added as well.

Confirmation of this data came from the more widely reported ICAAC presentation by Steven Deeks of the University of California, San Francisco, AIDS Program.

"Virologic failure to indinavir and ritonavir [the Abbott protease inhibitor, trade name Norvir] is more common in the primary care setting than that reported in controlled clinical trials," said Steven Deeks of the AIDS Program at the University of California, San Francisco.

Deeks spoke to a standing-room-only crowd during a late- breaker ICAAC abstract session.

"The efficacy of these drugs has not been studied in the real world," he said.

Deeks and colleagues therefore performed a retrospective chart review of all patients who received ritonavir or indinavir from March 1996 to March 1997 under the regular care of an experienced AIDS clinician. They defined treatment success as a viral load of less than 500 HIV copies/mL on the two most recent viral-load measurements using a branched DNA (bDNA) assay.

Of the 137 patients who completed at least 24 weeks of treatment, more than half (53 percent) had evidence of failure. The success rate of 47 percent dropped to only 33 percent in a more rigorous intent-to-treat analysis.

"Predictors of failure were low baseline CD4 count, high baseline viral load, prior nucleoside-analog therapy, failure to change nucleoside-analog therapy when indinavir or ritonavir was initiated, prior saquinavir therapy, and evidence of non-compliance or dose reduction noted in the medical records," Deeks reported.

Prior nucleoside-analog therapy increased the risk of failure by a factor of 10.1 (P= 0.007). A baseline CD4 count of less than 200 cells/mL increased failure risk by a factor of 7.4 (P= 0.009).

"A dramatic finding is that patients on at least eight weeks of suboptimal therapy were more likely to fail," Deeks said. "Patients with a clinical suspicion of non-compliance fared poorly."

The UCSF clinician predicted that earlier use of aggressive treatment strategies would increase their success rate, and said that his findings "essentially confirm" the Gulick et al. data.

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