Cocktails of anti-AIDS drugs have dramatically increased survival of individuals infected with HIV. But the virus often develops resistance to the drugs in people who previously have taken multiple combinations of the medications.
Now a multi-center, randomized, and placebo-controlled trial of 481 people infected with HIV, co-chaired by Dr. Scott Hammer of Columbia University and Dr. John Mellors of the University of Pittsburgh, shows that giving patients a new combination of drugs, which includes two protease inhibitors rather than one, can reduce the virus load in a substantial proportion of patients who already had taken several anti-HIV drugs.
"Control of virus load levels in the blood leads to an improved immune system and a greater period of health, delaying the opportunistic infections and death associated with HIV infection," says Dr. Hammer. Dr. Hammer is professor of medicine and Harold C. Neu Professor of Infectious Diseases at P&S and professor of epidemiology at the Mailman School of Public Health. He is also chief of the Division of Infectious Diseases at Columbia Presbyterian Medical Center of NewYork-Presbyterian Hospital. Dr. Mellors is professor of medicine, chief of the Division of Infectious Diseases, and director of the HIV/AIDS program at the University of Pittsburgh School of Medicine.
The study results were published online July 6 by the Journal of the American Medical Association (JAMA) to coincide with the International AIDS Conference in Barcelona, Spain.
In the federally sponsored Adult AIDS Clinical Trial Group 398 study, which took place between October 1998 and April 2000 at 31 participating medical centers in the United States, patients were split into four groups, each taking the protease inhibitor, amprenavir, and either a placebo or a second protease inhibitor (saquinavir, indinavir, or nelfinavir). A protease inhibitor interferes with an enzyme HIV uses to reproduce itself.
All participants also received drugs that act on the HIV reverse transcriptase enzyme: abacavir, a nucleoside reverse transcriptase inhibitor; efavirenz, a non-nucleoside reverse transcriptase inhibitor; and adefovir dipivoxil, a nucleotide reverse transcriptase inhibitor. Reverse transcriptase is another essential enzyme the virus uses to reproduce itself in human cells. These drugs had not been taken before by the patients.
After 24 weeks, the investigators found that 31 percent of these antiretroviral-experienced patients with moderately advanced immunodeficiency could significantly lower their virus counts to below "detectable levels" with regimens containing four or five new drugs.
"The overall response rate in the study was modest but resistance in this experienced population is a difficult problem to overcome and we set a high standard of virus suppression (i.e., a viral load less than 200 HIV/RNA copies/milliliter) to show success," Dr. Hammer says.
On average, though, the patients showed more than a 90 percent reduction in their blood viral loadalthough they may not have achieved a 200 RNA copies/milliliter level. "The decrease should be associated with improved health," Dr. Hammer says.
Certain subgroups of patients, however, did better than others: patients who took two protease inhibitors and those who had never taken a non-nucleoside-type drug before the study. Patients who had a higher-than-usual level of sensitivity to the non-nucleoside inhibitor, efavirenz, had a better response than those with the usual level of sensitivity to the drug.
"The study results have clear implications for HIV-infected individuals who are planning their long-term treatment approach," Dr. Hammer says. "Reserving potent classes of drugs, if possible, rather than using all of them in a cocktail during first-and second-line treatments should improve the long-term response rates of patients to anti-HIV drugs."
The study also points to the continuing need for new types of drugs that have activity against HIV strains resistant to older drugs. "There are promising drugs on the horizon that should move the field closer to the goal of long-term viral suppression and clinical well being over many years, if not decades," Dr. Hammer says.
Dr. Hammer also was vice chair of a panel, called the International AIDS Society-USA, that at the Barcelona conference issued updated AIDS treatment guidelines, which also were published in JAMA. The recommendations address new antiretroviral drugs and treatment regimens and support using CD4 cell count as the primary indicator for when to start therapy. First convened in 1995, the panel develops treatment guidelines for healthcare practitioners.
The clinical trial research was supported by the Adult AIDS Clinical Trials Group within the National Institute of Allergy and Infectious Diseases.