Reported in the special AIDS theme issue (July 10) of the Journal of the American Medical Association, the recommendations represent the consensus of a 17- member expert panel. The international panel of AIDS specialists was first convened in 1995 with the mission of developing treatment guidelines for health care practitioners, based on all information available. The panel has continued to develop recommendations around the four central issues in antiretroviral drug therapy: when to start therapy; what to start with; when to change therapy in the face of regimen failure; and what to change to. The last version was issued in January 2000.
Notable updates in the new recommendations include:
·More data have emerged to support using the CD4 cell count as the primary indicator for when to start therapy. Previous guidelines used the plasma HIV RNA level (i.e., viral load) as a key laboratory indicator, but it now has less of a role in deciding when to start. Viral load remains an important marker of response to antiretroviral therapy.
·Newer formulations of drugs and the availability/approval of new drugs have resulted in effective and more convenient regimens (e.g., once daily dosing regimens, smaller pill size, protease inhibitor "boosting" strategies, etc).
·Designing a new regimen after treatment failure remains an important clinical issue. Viruses resistant to an increasing number of drugs raise challenges, both for the clinicians who need to design alternative regimens active on such viruses using their expertise as well as results from virus resistance testing, and for new drug discovery. Several new recently released drugs are active against such viruses.
"Because modern antiretroviral therapy has shifted HIV disease from a rapidly fatal disease to a chronic disease, much recent attention of researchers and clinicians has focused in finding ways to improve quality of life and minimize drug side effects in patients treated with antiretroviral drugs," says Patrick Yeni, M.D., chair of the IAS-USA volunteer panel and professor of medicine at Hospital Bichat-Claude Bernard in Paris, France.
"New drug development is aimed at identifying simplified, non-toxic regimens that will maximize benefit and minimize side effects. Antiretroviral guidelines will need to adapt to this ever changing therapeutic landscape," said Scott M. Hammer, M.D., vice chair of the panel and professor of medicine, Harold C. Neu Professor of Infectious Disease, chief of the Division of Infectious Diseases at Columbia Presbyterian Medical Center, and professor of epidemiology at the Mailman School of Public Health.
The new guidelines are intended to assist practitioners in the developed world, where patients have access to antiretroviral drugs and laboratory assays; the recommendations are limited to therapies approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products and available in 2002, according to Dr. Yeni.
Highlights of the treatment recommendations are:
·When to initiate antiretroviral therapy
Physicians and patients must weigh the risk and benefits of starting therapy and make individual informed decisions. When to initiate therapy and what regimen to choose are crucial decisions. It is known that therapy should not be delayed until the CD4+ count declines to 200 cells/ microliter, because of the increased risk of death if therapy is started this late. The point above this level at which it is most beneficial to start therapy is not known. At the higher CD4 cell counts, several other factors are considered, including specific CD4 + cell count or decline rate, the viral load level, the patient's commitment to adhere to therapy, and the risk of side effects.
·Initial Regimens
Recommendations for specific starting combinations of specific drugs cannot be made. There are three general types of regimens that the panel notes are recommended: (1) a protease inhibitor (with or without low-dose ritonavir to "boost" the concentration of the first protease inhibitor) in a combination with two nucleoside drugs; (2) a non-nucleoside drug with two nucleoside drugs; and (3) a combination of three nucleoside drugs. The precise role of therapeutic drug monitoring is not yet elucidated.
·Monitoring therapy
Assessing and reinforcing patient adherence is key to the success of therapy. Both CD4 counts and HIV RNA levels are important for measuring treatment response. The HIV RNA levels should decrease rapidly after therapy is initiated. Failure to achieve a 90 percent reduction in viral load after four weeks of therapy suggests poor adherence, inadequate drug absorption, or drug resistance. Once virologic suppression is achieved, viral load and CD4 cell counts are usually checked every 8 to 12 weeks.
·Changing therapy/regimens
The decision that the regimen is failing and should be changed should be individualized. In the case of regimen failure, virus resistance testing provides valuable information for designing a new regimen. "Antiretroviral therapy is a dynamic and rapidly changing field. Guidelines and recommendations need to be responsive and continue to evolve over time as new information accumulates," Dr. Hammer says. Even this week, at the World AIDS Conference in Barcelona, the panel expects new data to be presented that will result in refinements in care, but it is not expected that the new information will change the basic structure of the recommendations.
"It has to be remembered that the progress highlighted in this paper needs to be made available to patients living in resource limited settings, if we want to successfully fight this pandemic," Dr. Yeni says.
IAS-USA is a national not-for-profit organization based in San Francisco that provides information and education for physicians involved in HIV/AIDS care (IAS-USA is not affiliated with the worldwide IAS, based in Sweden). The authors for the newly released guidelines, in addition to Yeni and Hammer, are: Charles CJ Carpenter, M.D., Brown University School of Medicine; Margaret A. Fischl, M.D., University of Miami; Jose M. Gatell, M.D. Ph.D., University of Barcelona; Brian G. Gazzard, MA, M.D., Chelsea and Westminster Hospital, London; Martin S. Hirsch, M.D., Harvard Medical School; Donna M. Jacobsen, BS, IAS-USA; and David A. Katzenstein, M.D., Stanford University. Also, Julio S.G. Montaner, M.D., St. Paul's Hospital. Vancouver; Douglas D. Richman, M.D., University of California San Diego; Michael S. Saag, M.D., University of Alabama at Birmingham; Mauro Schecter, M.D., Ph.D., University Federal do Rio de Janeiro; Robert T. Schooley, M.D., University of Colorado; Melanie A. Thompson, M.D., AIDS Research Consortium of Atlanta; Stefano Vella, M.D., Istituto Superiore de Sanita, Rome; and Paul A. Volberding M.D., vice chair of medicine at University of California San Francisco, chief of the medical service at San Francisco Veterans Affairs Medical Center, and chair of the board of the IAS-USA.
Journal
JAMA