7-Day-On, 7-Day-Off Regimen Could Reduce Cost, Toxicities of HIV Therapy
A pilot study at the National Institute of Allergy and Infectious Diseases (NIAID) suggests that it may prove feasible for certain people with human immunodeficiency virus (HIV) disease to move from a continuous regimen of anti-HIV therapy to a strategy in which they discontinue and then resume anti-HIV therapy in a pre-planned, cyclic fashion.
This approach is known as "structured intermittent therapy." In the NIAID study, 10 patients received repeated "on-off" cycles of therapy: seven days of treatment with potent combinations of HIV medications, followed by seven days off the drugs. At the time of study enrollment, the patients were being successfully treated with continuous highly active antiretroviral therapy (HAART). For the study, they switched to the intermittent HAART regimen with no apparent deleterious effects on the course of their disease, and with a significant reduction in certain HAART-related side effects.
"Because it halves the total time during which patients receive anti-HIV medications, structured intermittent therapy could significantly reduce the costs and side effects of anti-HIV drugs, important issues in both resource-rich and poor countries," notes lead author Mark Dybul, M.D., NIAID assistant director for medical affairs. "It is important to stress, however, that the results of randomized, controlled clinical trials - currently under way - are needed to prove the benefits of this experimental approach before it can be recommended to patients outside the setting of a controlled clinical trial. Don't try this at home!"
The NIAID researchers, led by Dr. Dybul and NIAID Director Anthony S. Fauci, M.D., report their findings in the December 4 online early edition of the Proceedings of the National Academy of Sciences. The bulk of the research was conducted within the NIAID Laboratory of Immunoregulation, which Dr. Fauci directs and where Dr. Dybul is a staff clinician.
The authors note that HAART has provided extraordinary benefits to many people infected with HIV, substantially reducing HIV-related morbidity and mortality. Unfortunately, the utility of HAART is limited by significant short- and long-term toxicities, complicated dosing regimens and associated problems with adherence, and the development of drug resistance. In addition, high monetary costs have precluded the widespread use of HAART in resource-limited countries.
"With further research, we would hope that the approach of structured intermittent therapy for HIV disease will lead to decreased HAART-related toxicities, reduced costs, and, potentially, to improved adherence," says Dr. Fauci. "Ultimately, structured intermittent therapy might be adapted for use in developing nations, where more than 95 percent of the world's HIV-infected people live, but where very few have access to HAART because of the cost of antiretroviral agents."
Upon study entry, patients were receiving HAART daily, in regimens that included combinations of three or four anti-HIV drugs. This therapy had kept patients' HIV levels below 500 copies per milliliter (mL) of plasma for more than six months, and below 50 copies/mL at the time of enrollment. All patients entering the study had CD4+ T-cell counts of at least 300 cells per cubic millimeter (mm3) of blood. CD4+ T cells are crucial immune cells typically depleted during HIV disease.
After enrollment in the NIAID study, the patients received a four-drug regimen comprising stavudine, lamivudine, indinavir and ritonavir, administered twice per day in the intermittent schedule of seven days on therapy followed by seven days off therapy. This on-off cycle was repeated 16 to 34 times - that is, for 32 to 68 weeks.
While receiving seven-day-on, seven-day-off cycles of intermittent HAART, study participants had no significant increases in the amount of HIV in their bodies, as determined by tests that measured HIV in their plasma and lymph nodes, as well as within immune cells. In addition, patients' CD4+ T-cell counts were maintained at pre-study levels, and no evidence suggested the development of resistance to HAART medications.
Importantly, the investigators also noted significant decreases in serum cholesterol and triglyceride levels, which frequently are elevated in HIV-infected individuals receiving HAART and can contribute to heart disease and other problems. Mean serum cholesterol and triglyceride levels dropped 22 percent and 51 percent, respectively, after 24 weeks of intermittent therapy.
"These provocative findings have spurred larger, controlled clinical trials of structured intermittent therapy by our group and others," says Dr. Fauci. "Hopefully, data obtained from these larger studies will validate the potentially important findings in the pilot study."
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Copies of the article are now available to reporters from the PNAS news office, tel. (202) 334-2138, or e-mail email@example.com.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov. The Web Site of the NIAID Laboratory of Immunoregulation is http://www.niaid.nih.gov/dir/labs/lir.htm.
For information about a randomized, controlled trial at NIH of short cycle intermittent HAART versus continuous HAART for the treatment of chronic HIV infection, please call 1-800-772-5464, ext. 58003. For information about other AIDS clinical trials enrolling patients at the NIH, please call 1-800-AIDS-NIH or visit http://clinicalstudies.info.nih.gov/. For information about AIDS clinical trials nationwide, please call the AIDS Clinical Trials Information Service at 1-800-TRIALS-A or visit http://www.actis.org.
M Dybul et al. Short cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters. Proceedings of the National Academy of Sciences Early Edition online (December 4, 2001).