"We've been fortunate to have a variety of choices for antiretroviral therapy," says Gregory Robbins, MD, MPH, of the Massachusetts General Hospital. "But many had previously believed that how the drugs were combined did not make much difference. This study shows that some combinations are more powerful than others and that how they are sequenced makes a difference." Preliminary results of this study were presented at the 2002 International AIDS Conference in Barcelona and have been incorporated into current HIV/AIDS treatment guidelines issued by the U.S. Department of Health and Human Services.
Combination drug therapy – also called highly active antiretroviral therapy (HAART) – made a huge difference in the treatment of HIV infection during the 1990s, changing HIV/AIDS into an illness that people could live with for many years. Combinations of three antiviral drugs could keep the virus in check for a while, and when one treatment regimen failed to suppress the virus or became too toxic, switching to a different combination often renewed effective viral control. The current studies are the largest and most complex examination of the outcomes of different treatment strategies.
When triple combination therapy was first introduced, physicians combined two drugs called nucleoside reverse transcriptase (RT) inhibitors with another drug called a protease inhibitor. In recent years, a class of drugs called non-nucleoside RT inhibitors became available and is often used to replace the protease inhibitor in combination therapy.
One portion of the study, led by Robbins, compared four three-drug regimens to determine whether the order in which they were used affected how long they were successful. At 79 sites in the U.S. and Italy, 620 patients who had not previously been treated were enrolled and followed for more than two years. For nucleoside RT inhibitors, study participants received either ZVD and 3TC or they received stavudine (d4T) and didanosine (ddI). The alternatives for the third drug were either the non-nucleoside RT inhibitor EFV or the protease inhibitor nelfinavir (NFV).
Results of the three-drug comparison showed that the ZDV/3TC/EFV regimen appeared to be the best initial combination. Participants starting with that combination were most successful in postponing failure of the first and in some instances the second drug regimen. Even those who had higher viral levels when they entered the study showed similarly positive results from the ZDV/3TC/EFV combination.
The second part of the study – led by Robert Shafer, MD, assistant professor of medicine at Stanford – asked whether using four drugs in combination would be better than two consecutive three-drug regimens. Although four drugs could potentially increase effectiveness, the combination might also increase toxicity and be more expensive and more difficult to follow than a three-drug regimen. The team evaluated a regimen using ddI, d4T, EFV and NFV and one using ZDV, 3TC, EFV and NFV in 360 previously untreated patients and compared results with the sequential three-drug regimens previously mentioned. Since an initial four-drug regimen exposed participants to all three drug classes, there was no second regimen for those who failed the first.
After an average of 28 months, the four-drug regimens proved to be no more effective than any of the sequential three-drug regimens. However, an intriguing finding came to light. "When we looked at the time it took for the first regimen to fail, using four drugs delayed failure longer, except when compared with ZDV, 3TC and EFV, which worked as well as the four-drug combinations" said Shafer. "And that particular triple-drug regimen also led to faster viral load suppression than did using four drugs."
In both studies, participants who began treatment with ddI and d4T had more drug toxicity problems, such as nerve damage and pancreatic inflammation. Shafer said that this is the first time the toxic effects of these drugs have been followed in a large study of previously untreated patients, and the result led the researchers to recommend that treatment of HIV infection should not begin with these two drugs, a recommendation that has been incorporated into federal treatment guidelines.
The researchers also note that their results can only be applied to the specific drug regimens studied and that several other combinations may be in use today. However, they hope to investigate the biological mechanism behind their current findings in order to improve current treatment plans and develop new options that will be even more successful.
"We are exploring possibilities that may explain the apparent greater potency of one combination," says Robbins, "and we hope to find new ways to minimize toxicity and side effects. As patients are living longer, we need longer-term trials that can help us determine which regimens are more effective and better tolerated." Robbins is an instructor in Medicine at Harvard Medical School (HMS) and on the staff of the Partners AIDS Research Center.
The overall study was carried out through the AIDS Clinical Trial Group, funded by the Division of Acquired Immune Deficiency Syndrome of the National Institute of Allergy and Infectious Disease (NIAID). Robbins and Shafer were co-chairs of the study; the co-senior authors were Martin Hirsch, MD, of the MGH and HMS, and Thomas Merigan, MD, of Stanford; and the lead statisticians were Victor De Gruttola, ScD, and Laura Smeaton, MS, of Harvard School of Public Health.
Additional co-authors of the three-drug comparison are Sally Snyder, of Social & Scientific Systems; Carla Pettinelli, MD, PhD, NIAID; Michael Dubé, MD, Indiana University; Margaret Fischl, MD, University of Miami; Richard Pollard, MD, University of California at Davis; Robert Delapenha, MD, Howard University; Linda Gedeon, Frontier Science & Technology Research Foundation; Charles van der Horst, MD, University of North Carolina; Robert Murphy, MD, Northwestern University; Mark Becker, PharmD, Agouron Pharmaceuticals, a division of Pfizer; Richard D'Aquila, MD, Vanderbilt University; and Stefano Vella, MD, Istituto Superiore di Sanita, Rome.
Additional authors of the four-drug study were Victoria Johnson, MD, University of Alabama at Birmingham; Gene Morse, PharmD, State University of New York at Buffalo; Mostafa Nokta, MD, University of Texas Medical Branch, Galveston; Ana Martinez, RPh, NIAID; Barbara M. Gripshover, MD, Case Western Reserve University, Cleveland; Pamposh Kaul, MD, University of Cincinnati; Richard Haubrich, MD, University of California-San Diego; Mary Swingle, RN, Bristol-Myers Squibb; and Debra McCarty, BS, GlaxoSmithKline.
For additional information on the lead investigators' institutions, please visit these websites:
Massachusetts General Hospital – www.massgeneral.org
Stanford University Medical Center - http://mednews.stanford.edu
Harvard School of Public Health - http://www.hsph.harvard.edu
Journal
New England Journal of Medicine