October 8th, 1997 to October 14th, 1997

Protease inhibitors show weakness

53% failure in one study

by Lori Weiner

A research team at the University of California at San Francisco reported Sept. 29 that in a retrospective study of 136 HIV-infected patients taking protease-inhibitor drug therapy, 53% developed evidence of drug failure, according to a published report by BW Healthwire in Toronto.

Participants in the study were clients of the University's affiliate hospital, San Francisco General, and were not part of a clinical trial. The study results were presented in Toronto at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy

According to the BW Healthwire report, Dr. Steven Deeks, an assistant professor of medicine at UCSF in the UCSF AIDS program at San Francisco General Hospital, stated that "this is a real world study. We were looking at patients who were not the idealized research patient typically found in a clinical trial, but the average patient seen by our physicians in the hospital. We are concerned that the long-term efficacy of these drugs may be limited, particularly for patients who begin treatment with advanced HIV disease and for people who have been on multiple drugs in the past."

The success rate for the clinic patients in the study was much lower than that of patients in clinical trials, according to the BW Healthwire report.

Fifty-three percent of patients reported evidence of drug failure after at least six months of therapy. Failure rates in controlled clinical trials are usually in the 10 to 20 percent range. According to the BW Healthwire report, Deeks' research team learned that patients who failed in their protease inhibitor treatment were usually those who were at an advanced stage of the disease, were drug resistant, or were not adhering to the rigid treatment schedule required with protease inhibitors: as many as 20 pills per day need to be taken at very specific intervals, such as 1 or 2 hours before or after a meal.

According to Deeks, quoted in the BW Healthwire report: "Clinical trials tend to enroll patients who are healthy, who haven't been on much therapy in the past and are highly motivated; they are not the typical patient."

Bob Lederer, senior editor of POZ Magazine, told Outlines that "this (protease inhibitor failure) is not new. POZ has been reporting (on the phenomenon) for months, and doctors and PWA's also know many people have had bad experiences (with protease inhibitors). There are many reasons for (the failures), not just patient non-adherence." Lederer cites mis-prescribing of drug cocktail combinations-replacing just one drug from a triple drug combination, for example-and piling drugs on top of one another as "recipes for failure" and potential formulae for introducing viral mutations that are resistant to therapy. Lederer also points out that many PWA's suffer from gastrointestinal problems, particularly related to drug absorption, that contribute to the development of resistant virus.

Lederer believes that potential problems with protease inhibitors may not have arisen in clinical trials because the environments "are very controlled.

"There are a lot of complicated dynamics at work with other medications the patient may be taking, with drug interactions. Also, PWA's with anti-retroviral experience don't do as well on protease inhibitors as PWA's who have never taken antiretrovirals before."

"It will also be interesting to look at the gender breakdown (of protease inhibitor failure)," adds Lederer. "Are there a disproportionate number of women failing protease inhibitor therapy? Anecdotal evidence already suggests that women have more side effects (from protease inhibitor treatment) than men do." According to the Sept. 19 edition of The New York Times, new HIV/AIDS cases among women and heterosexuals who do not use drugs, particularly minorities, are rising.

Pablo Colon, executive director of Treatment, Education and Advocacy at the Gay Men's Health Crisis in New York City, agrees with Lederer's assessments.

Colon believes that new and better treatments will potentially provide those patients who do not do well on protease inhibitor therapy with better results. One possibility could be Sustiva, marketed by DuPont-Merck and billed as the first "one-a-day" pill for use in HIV/AIDS therapy. Sustiva, a nonnucleoside reverse transcriptase inhibitors, also is reported to cross the blood/brain barrier, a key to fighting HIV since the brain tends to harbor the virus. According to Reuters news service, preliminary data indicates the experimental compound in Sustiva, when combined with only one other drug, is as effective against HIV after 42 weeks as the current standard three-drug cocktail approach. DuPont Merck plans to market Sustiva in April 1998, pending approval (more information below).

Perry Halkitis, Ph.D., director of evaluation and research at the Gay Men's Health Crisis, says that approximately 60-75% of the agency's clients take protease inhibitors regularly. According to Halkitis, approximately 40% of PWAs receiving protease inhibitor therapy do not respond to the drugs, for a variety of reasons: a patient's body may be unable to tolerate the medications, issues of adherence to the treatment regimen, and resumption of risky sexual behavior. "Even in couples where both partners are positive, if one partner is taking a specific three-drug cocktail and the other partner's cocktail is different and they have unprotected sex, there is a chance that the partners can reinfect each other and create a strain of virus that is highly resistant-in effect, a "mega virus."

"Miracle drugs," says Halkitis, "aren't always miracles for everyone."

FDA approves 'Combivir'-reduces pill regimens
The Food and Drug Administration announced Sept. 19 that it had approved the combination AIDS medication Combivir, produced by Glaxo Wellcome. Combivir incorporates two common AIDS medicines, AZT and 3TC, in a single tablet. Thus, Combivir permits people using "cocktail" drug regimes to reduce their daily pill intake by as many as six pills--a substantial reduction for people who may be required to swallow 20 tablets a day on a rigid schedule. In addition, "studies have shown that the more pills someone takes [on a complex daily schedule], the less likely the patient is to take all the doses." HIV mutation may result from improper use of AIDS medications, so the simplifying of cocktail drug regimens has important medical benefits. The new single-tablet form of Combivir still may cause side effects associated with use of AZT and 3TC taken separately-nausea, diarrhea and anemia. Combivir will cost about the same as the two separate medications in total-over $6,000/year-and will be available in drug stores by mid-October.

AIDS' cocktails' may work without AZT
Multi-drug AIDS' cocktails" may not need to include AZT to fend off HIV, according to researchers. One new study described at a late September infectious diseases meeting of the American Society for Microbiology "compares three triple-therapy regimes [and] found all treatments equally effective-although there were fewer side effects without AZT," UPI reported. The regimens studied were AZT, 3TC and indinavir; d4t, 3TC and indinavir; and d4t, ddl and indinavir. Indinavir is a protease inhibitor, and all the other drugs used are nucleoside analogues. Dr. Joseph Eron of the University of North Carolina found that each regime "reduced virus in the blood more than 95 percent."

In another study, Dr. Frank Duff of Roche Laboratories found that "the new soft-gel form of Hoffman LaRoche's protease inhibitor saquinavir was well-tolerated and reduced HIV levels better than the original drug." The new saquinavir formulation is awaiting approval from the Food and Drug Administration.

More AIDS drug news ...
Two landmark AIDS drug studies were published in the New England Journal of Medicine in September. Dr. Roy Gulick, et al. wrote that "Protocol 035" revealed the protease inhibitor Crixivan (indinavir sulfate) taken with AZT and 3TCb reduced HIV to "below the level of detection" for most patients for up to a year. The benefits also accrued to patients who had taken AZT and whose immune systems were already damaged by HIV. The National Institutes of Health's AIDS Clinical Trial Group conducted "Study 320" (chaired by Dr. Scott Hammer), which for the first time compared triple therapy with Crixivan, AZT and 3TC to the dual combo of AZT and 3TC. Triple-drug users exhibited fewer AIDS-defining illnesses (6% vs. 11%) and had a lower death rate (1.4% vs. 3.1%). Collectively, the studies showed Merck's Crixivan was generally well-tolerated; it has been approved for use in 50 countries. The Journal also editorialized in favor of "prescribing ... effective [drug] combinations" including a protease inhibitor. Currently less than a third of all HIV+ individuals in the U.S. are taking protease inhibitors.

DuPont-Merck has released information from a 42-week study of their "non-nucleoside reverse transcriptase inhibitor" trademarked Sustiva (DMP 266) used in conjunction with Crixivan (indinavir) "achieved HIV-RNA below level of quantification and CD4 cell count elevation averaging 140 cells/mm3; the study also found a 99.99% average reduction in HIV-RNA among study participants. Another DuPont-Merck study showed that 26-week treatment with indinavir alone followed by combination therapy with indinavir, Zerit (staduvine) and DMP 266 reduced plasma levels of HIV-RNA below 400 copies/mL in 83% of patients studied. Company spokesman Mike Beyer says that "the results may point to once-a-day dosage" of Sustiva, which is currently in Phase III clinical trials.

Yet another AIDS-related drug study presented in September at the Interscience Conference on Antimicrobial Agents and Chemotherapy has demonstrated that intravenously administered Penciclovir (the active agent in Famvir, by SmithKline Beecham) "is a safe and effective treatment for herpes simplex virus infections in immunocompromised patients." Lead investigator Dr. Hillard Lazarus called the results "an important development in the treatment of herpes infections in people with severely weakened immune systems," many of whom cannot tolerate oral medications and for whom only a single drug treatment option is available. Attacking a weakened immune system, herpes can spread to the lungs and other sites, with life-threatening consequences. -P.J. Engelbrecht
POZLife Expo Oct. 24-25
POZ magazine's travelling POZLife Expo, a consumer fair for people with HIV/AIDS and their families/friends, is set for Chicago's Navy Pier Oct. 24-25. Call (212) 242-2163.

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