Revised Guidelines for HIV/AIDS Treatment: A Newsmaker Interview With John G. Bartlett, MD

Laurie Barclay, MD

July 15, 2003

July 15, 2003 — Editor's Note: The latest update of the U.S. Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents , released on July 14, should facilitate selection of an appropriate treatment regimen from the increasing options in antiretroviral treatment.

Earlier versions of the guidelines seemed almost like a Chinese restaurant menu, allowing clinicians to select drugs from different columns to create a combination regimen, but the new guidelines classify suggested regimens as either "preferred" or "alternative" based on results of clinical trials and expert opinions.

"With 22 FDA-approved formulations of antiretroviral agents, selecting the right multidrug combination can be a challenge for even experienced clinicians," Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, and co-chair of the Panel on Clinical Practices for the Treatment of HIV Infection, said in a news release. "These revised guidelines help simplify the process by which caregivers and patients chart a course of therapy, whether they are receiving antiretroviral treatment for the first time or are treatment-experienced and contemplating a change in drug regimen."

The updated guidelines include new tables listing the advantages and disadvantages of individual antiretroviral agents plus regimens or components that should not be used. Considerations for initial therapy include once-daily dosings, drugs that are contraindicated, drug-drug interactions, and suggestions for treatment of pregnant women or women who may become pregnant.

The guidelines acknowledge that the incidence of drug resistance continues to increase as more patients are being treated with antiretroviral therapy for longer periods of time, and they provide additional strategies for managing treatment failure.

To learn more about the basis for and practical applications of these guidelines, Medscape's Laurie Barclay interviewed panel co-chair John G. Bartlett, MD, chief of the Division of Infectious Diseases and a professor of medicine at Johns Hopkins University Medical Center in Baltimore, Maryland.

Dr. Bartlett is a member of Medscape HIV/AIDS editorial board. When he coauthored the guidelines, he was on the HIV advisory board for Abbott, and he has subsequently participated in a "think-tank" session for Bristol-Myers Squibb.

Medscape: What are the main differences between these guidelines and earlier guidelines?

Dr. Bartlett: The guidelines for when to start therapy haven't changed. The guidelines are now much more precise on what to start when you do decide to initiate treatment. Not only do the new guidelines define treatment failure, but what to choose when a patient fails is much more developed in these guidelines. One of the greatest strengths of this new document is the 28 tables, which contain a lot of useful, practical information based on a large number of resources.

Medscape: Compared with the old approach of selecting different drugs from different columns, how will selection of treatment regimens be facilitated by the new guidelines?

Dr. Bartlett: The new guidelines are much more specific in recommending specific combinations — it's no longer the doctor's choice of any two "nucs" and a protease inhibitor.

Medscape: How much are these regimens individualized based on unique clinical factors and treatment history for each patient?

Dr. Bartlett: The guidelines do address specific patient factors such as pregnancy and other medical conditions. It was quite a ritual that the panel went through to make these decisions, based on the availability and results of appropriate clinical trials. These trials had to compare a new test regimen to one that was already recommended; they had to continue for at least 24 weeks; and they had to look at side effects and reduction of viral load before the panel decided that a particular regimen was now acceptable.

Medscape: How were factors of potency and durability weighed against toxicity and adverse events?

Dr. Bartlett: Potency is based on the ability to achieve no detectable virus within a certain period, so we looked at the time it took to achieve less than 50 or less than 500 viral copies with each regimen. To evaluate durability, we looked at trials that went at least 24 weeks, and we preferred those that went 48 weeks. Some trials went as long as four to five years, but it would be unfair to use only those. We're pretty sure that if you have a durable response at one year, there's no reason for it to cave in after that. But on the other hand, 16 to 18 weeks is not really long enough to evaluate durability. The trials that were considered for these recommendations also had to document toxicity and adverse events.

Medscape: How important are additional factors, such as likelihood of compliance, pill burden, and potential for interactions with other drugs or with food?

Dr. Bartlett: We do consider factors of patient convenience and tolerance — 18 pills per day is probably not acceptable. Anything that affects quality of life is a judgment call, but to make it more objective, we looked at dropout rates. When comparing new drugs with standard drugs, if the trials showed that the new drugs had increased dropout, that indicates that tolerability is probably unacceptable.

Medscape: What was the basis for identifying certain regimens or individual treatments that should not be used?

Dr. Bartlett: There are two tables identifying regimens which are better not used. The Working Group consists of about 50 people who have been doing this for a long time, and who are involved in patient care as well as with the science. The panel was pretty much agreed on which drugs not to use, because they are too toxic, or because they don't work well, like hydroxyurea, or because they have been around a long time but have never been tested. Some may argue with the panel on the positioning of recommended drugs or regimens, but I doubt that very many would argue with drugs and regimens that the panel recommended against.

Medscape: Why do you think some might argue with positioning of individual drugs or regimens?

Dr. Bartlett: There really is no consensus about which drugs should be used for initial therapy. You have about 19 drugs used in combinations of three, which makes for a very high number of possible combinations. If you asked a room full of 10 people, you might get 10 different answers. But the panel reached a consensus based not only on their own clinical experience but also based on a critical review of the literature.

Medscape: How do these guidelines deal with increasing drug resistance and treatment failure?

Dr. Bartlett: These guidelines are much stronger now in terms of drug failure. If you had drug failure before, you got resistance testing and did the best you could. Now we have a lot more options, not all proven, but we list the evidence for each. If a patient has one treatment failure, there is a good chance of achieving success with another regimen if you start it soon enough, before viral load gets too high. After multiple failures, chances of success are less, and the goals shift to reducing the number of AIDS-related complications. In between one treatment failure and multiple failures, there are about 8 to 10 options to approach the failing patient. These options are in a constant state of evolution.

As an example, we used to stop therapy to try to get a sensitive strain to come back. That's still an option, but it doesn't seem to work very well. You could do it, but the available studies don't really support it. On the other hand, some methods to deal with the failing patient are cast in concrete, like resistance testing, then picking a drug on the basis of that test.

Medscape: What are your expectations for how widely these guidelines will be used and implemented?

Dr. Bartlett: AIDS care is like a lot of other things in medicine. Those who do a lot of it may say they don't need the guidelines, because they consider themselves experts and they will continue to practice on the basis of their experience. Others will say that the guidelines reinforce what they already do, which is evidence reinforcing the validity and consensus opinions expressed by the guidelines. Still others may change the way they practice based on these guidelines. Third-party payors may use these guidelines as a standard of care to justify reimbursement for certain regimens but not for others. How the guidelines make an impact may be diverse — they may create standards of care or performance standards, or they may dictate reimbursement.

Reviewed by Gary D. Vogin, MD

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