The Washington Blade - August 27, 1999
Lisa Keen

Reports at international AIDS conferences in Geneva last year and in Chicago this past February warned that only about half of patients taking protease inhibitors are getting their viral loads under control and keeping them there for more than two years. Some suggested that statistic might be optimistic, given that it was based largely on patients in clinical trials who are motivated to stick with their drug regimens and given support to do so.

The report this month, from researchers at Case Western Reserve University and two other medical research facilities in Cleveland, confirmed that suspicion. It found that less than half are able to "achieve durable suppression of viral replication" outside the clinical trial atmosphere.

In the Aug. 9/23 issue of the Archives, the study's authors noted that only 47 percent of patients overall (145 out of a group of 310) kept their viral loads significantly controlled for more than two years. The success rate was worse for certain subgroups.

While 42 percent of the male patients succeeded in keeping their viral loads down for more than two years, only 17 percent of the women did so. While 49 percent of the white patients kept their viral loads down, only 31 percent of blacks did, and only 27 percent of other people of color did.

A smaller study at Johns Hopkins University, reported in the July 20 Annals of Internal Medicine, found that only 37 percent of patients had success outside a controlled trial. It also found less success among women and racial minorities.

Research reports began indicating last year that only about half of patients were finding success on protease inhibitor regimens. (Notably, each study has its own definition of success. Some say it means keeping the viral load below 50 particles per milliliter; the Cleveland report said success was keeping it below 400.)

While early studies suggested the problem might be the virus's ability to mutate enough to "resist" the antiviral drugs, later studies suggested the failure rates are more likely due to the difficulty many patients have in adhering to the cumbersome and complex pill-taking regimens required by protease inhibitor combinations. Still others blamed the failures on giving patients too few drugs.

The Cleveland study, titled "Human Immunodeficiency Virus 1 Protease Inhibitors in Clinical Practice," found indirect evidence to suggest that patient adherence is a big factor in determining success.

"Sixty-three percent of patients judged by their physicians as adherent experienced virological success," noted the authors, while "only 13 percent of patients judged by their physicians as nonadherents experienced virological success." The doctors judged adherence on how many times patients missed follow up visits.

The study also found that patients who started taking protease inhibitors in the months soon after the drugs became available did more poorly than patients who started the drugs at a later date. They speculated this disparity might be due to improved knowledge over time about how to use the drugs.

And the Cleveland study found that patients whose lowest CD4 count was among the highest compared to other patients had more success than patients whose lowest CD4 count was among the lowest. And patients whose highest viral load was among the lowest compared to other patients also had more success.

Salvage therapy recommendation

But in more optimistic news, a separate study, published in the July 30 journal AIDS, doctors in France reported that a five-drug combination -- consisting of two protease inhibitors, one non-nucleoside analog, and two nucleoside analogs -- helped more than 70 percent of patients who had failed a standard three-drug regimen of one protease inhibitor and two nucleosides.

The French researchers took 32 patients who had been on a triple-drug therapy (involving either indinavir or ritonavir) and whose viral loads had gone down but shot back up. They were given the combination of ritonavir-saquinavir-efavirenz and two "recycled" nucleosides. ("Recycled" drugs are ones that the patient has taken in the past but has gone off -- due to failure -- for a period of time.) All approved nucleosides except abacavir were used.

The researchers found the five-drug combination to be beneficial in both reducing the amount of virus in the blood and boosting the immune system of those patients who had failed on conventional triple-drug combinations. They said 71 percent of the 32 patients were able to get their viral loads below 500 within six months and that the five-drug combination was "well tolerated."

Other problems continue

Meanwhile, a letter in the Aug. 19 issue of the New England Journal of Medicine reminded doctors that side effects continue to emerge with patients taking protease inhibitors. Three doctors in Paris reported 10 patients who experienced significant body hair loss associated with their taking the protease inhibitor indinavir. The hair loss began during the first six months the men were on indinavir and, initially, involved only the hair on the men's legs; eventually, however, some men had almost complete hair loss in the pubic area, the chest, and two men lost hair from the scalp. Eight men experienced dry skin, six suffered inflammation of their lips, and four had inflammation in the skin around their nails. The doctors noted that the hair regrew within four months of the patients' stopping indinavir and starting a replacement drug, but the other symptoms did not improve. The doctors suggested that the symptoms resembled ones associated with deficiencies in vitamin A and thus, may be caused by some effect indinavir has on vitamin A in the body. They noted that these symptoms have not been occurring with other protease inhibitors.
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