Next HIV guidelines likely to include salvage therapy

Latest version touts abacavir as alternative

The federal HIV treatment guidelines, which give clinicians a national seal of approval for various drug regimen choices, soon will include recommendations about choosing salvage therapy, providing guidance in deciphering the increasingly complex science of cross-resistance and HIV mutations. Salvage therapy occurs after the failure of a protease inhibitor-based regimen.

"The [guidelines] panel is taking on salvage therapy, and hopefully when we have our next update to the guidelines, we’ll have something useful to say," says Oren Cohen, MD, executive secretary for the Panel on Clinical Practices for Treatment of HIV Infection convened by the Washington, DC-based Department of Health and Human Services (HHS) and the Henry J. Kaiser Family Foundation of Menlo Park, CA. Cohen also is the assistant director for science policy at the National Institute of Allergy and Infectious Diseases in Bethesda, MD.

"As increasing numbers of HIV drugs are licensed, salvage therapy becomes more and more of an issue, making choices harder," Cohen says. "It’s good news that there are more options, but there’s little data available to help you make the right decision."

The recently released update to the "Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents" is the fifth revision to appear on the AIDS Treatment Information Services Web site at www.hivatis.org. The guidelines have been printed twice.

The latest version upgrades the nucleoside analog reverse transcriptase inhibitor abacavir (Ziagen). Previously, abacavir was listed as an experimental drug available through treatment investigations. Now the guidelines recommend it as an alternative to the preferred list of regimens.

Hypersensitivity remains problematic

The guidelines caution clinicians to watch for signs of hypersensitivity in patients on an abacavir regimen. In fact, it was partly because of this problem, which occurs in 3% to 5% of cases, that the panel was leery of making the drug a preferred recommendation, according to Eric P. Goosby, MD, director of the office of HIV/AIDS Policy at HHS.

Goosby, along with Paul Volberding, MD, professor of medicine and director of the Positive Health Program at the University of California School of Medicine in San Francisco, spoke at a recent teleconference about the revised guidelines. Goosby and Volberding are members of the guidelines panel.

"The key feature of abacavir sensitivity is that it tends to happen early on in treatment, often in the first few days," Volberding said. "It includes a fever, rash, malaise, and other things, but typically it’s quite noticeable, and it gets worse with each dose."

Clinicians who have patients experiencing these side effects should immediately stop the drug and not restart it. If the drug is restarted, the side effects could worsen and even progress to death. One patient involved in an abacavir study died from what appeared to be a circulatory collapse, Volberding said. "Patients could potentially go into shock."

The guidelines as they appear on the Internet include a hypertext link to background material on hydroxyurea, and the tables on drug interactions are more user-friendly, Cohen says.

"We were unhappy with how the tables were growing and becoming difficult to use, so the panel put a lot of hard work into updating them," Cohen says. "So now it’s a very nice reference for clinicians."

The updated guidelines also address the issue of whether women’s HIV disease progresses at the same rate as men’s disease. The panel’s conclusion is that there is too little evidence of any difference for the guidelines to recommend clinicians start treatment sooner with women.

"One study suggested women progress at the same rate as men with only half the viral load," Cohen says. "So while it’s an argument that could be made in favor of treating women sooner than men, the differences are not that great, and the study was in a cohort of injection drug users, so it’s not clear the results can be applied generally."

Plus, other studies have found no difference between men and women in the rate of HIV progression, he adds. "So the panel reviewed this data and found no compelling reason to recommend a different threshold for women than men."

When the guideline’s panel members finally address salvage therapy or second-line regimens, they could best do so with principles and illustrations rather than recommendations about specific drugs, says Daniel Kuritzkes, MD, associate professor of medicine and microbiology at the University of Colorado Health Sciences Center in Denver.

"Every patient has a unique history, and precisely what you use in salvage therapy depends on what kind of patient you have seen before, the patient’s mutation resistance, and any susceptibility that may be present," Kuritzkes says.

"Also, much of what you do in salvage therapy depends on the drugs that are approved and the drugs that may be available through expanded access, and that’s hard to codify because the guidelines by nature tend to be somewhat conservative," Kuritzkes adds. "Drugs currently under study are going to be hard to put in the guidelines because there’s not an adequate data base."

Salvage therapy will be a difficult topic to distill into a format suitable for the guidelines, Volberding says. "Most of us grapple with this every day, and we know it’s a big issue."

Plus, the guidelines never were intended to be a clinical cookbook, Goosby says. "We felt it really was an organic, viable, living document that needed to be updated."

Panel members know HIV is evolving, as are standard treatments for it, so the guidelines are updated at irregular intervals to reflect these changes.

"There’s now a doubling and tripling of protease inhibitors occurring regularly that have not been studied adequately enough for us to put them in the document with confidence — but they’re out there," Goosby adds.

By the time the guidelines are updated, many clinicians already have been using the newest drugs on the list, says Aaron E. Glatt, MD, chief of the division of infectious diseases at the Catholic Medical Center of Brooklyn, NY.

For example, the next version of the guidelines will include recommendations for one of the newest protease inhibitors, amprenavir (Agenerase), Cohen says. Amprenavir, which received accelerated approval in April from the Rockville, MD-based Food and Drug Admini stra tion has been available since September 1998 to several thousand patients through three early access protocols.(See story on FDA’s approval of amprenavir, p. 77.)

"It’s an exciting time, but everything is in a flux," Glatt says. "Everyone is doing all different sorts of regimens now, with some people using five drugs. I’m using four drugs for patients with very high viral loads, and we experiment depending on what their response is and based on their viral load and previous drug history."

[Editor’s note: For a printed version of the "Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents," call (800) 448-0440. For more information about salvage therapy, check the Medscape Web site at www.medscape.com and click on the link to "Salvage Therapy for the Treatment of HIV Infection."]