An experimental drug that fights the AIDS virus by attacking the enzymes that enable it to replicate has proved effective in a nationwide clinical study.
Named adefovir dipivoxil, the drug reduced viral load-the amount of HIV in the blood-by an average of about 60 percent in patients. Adefovir is an antiretroviral drug known as a nucleotide analog.
The drug was tested in a double-blind trial involving 442 HIV-positive patients at 33 U.S. HIV treatment centers. The study was designed to test the ability of adefovir to produce an effect and its safety.
Study findings are reported in the December 22 issue of the Journal of the American Medical Association. Lead authors are James Kahn, MD, associate professor of medicine at the University of California, San Francisco, and Stephen Lagakos, PhD, chair of the Department of Biostatistics at the Harvard School of Public Health.
Adefovir was developed by Gilead Sciences, Inc., of Foster City, Calif., which sponsored the study. Last month, an advisory panel of the Food and Drug Administration recommended against approval of Gilead's application for the drug. The company has since announced that it will terminate U.S. development of adefovir. An accompanying editorial in JAMA reviews the development of drugs that are effective against drug-resistant HIV and cites the FDA decision.
"We found adefovir to show promise as an HIV medication, particularly in patients whose virus showed resistance to other nucleotide analogs," said Kahn. "Its benefits must be balanced, however, with side effects that were manageable but did involve nausea and other gastro-intestinal problems as well as increasing kidney problems in about 60 percent of the patients over time." Kahn specializes in treating HIV/AIDS patients at the UCSF Positive Health Program based at San Francisco General Hospital Medical Center.
Among other positive results, the drug showed that it remained active when integrated with other antiretroviral drugs in a treatment regimen known as combination therapy. Combination therapy is designed to maximum the medication potency against HIV by striking at a variety of different biochemical mechanisms and at several vulnerable points in the viral lifecycle.
Over the past four years, antiretroviral therapy has led to improved survival for many HIV patients, however, because of the development of resistance, there is an ongoing effort to develop new anti-HIV medications that will add to the drug arsenal for combination therapy, Kahn said. "Every patient is different, so there is no universal combination drug therapy. The combination needs to be adjusted and individually tailored for each patient for optimum benefit. Although adefovir had significant kidney related toxicities, it is still a shame that another treatment option is not going to be available to our patients," said Kahn.
Like other nucleotide analogs, adefovir works by inhibiting a critical enzyme called reverse transcriptase (RT). Current experience in treating HIV patients shows that the best results occur when combination therapy involves drugs that are RT inhibitors-such as adefovir-- along with protease inhibitors or other classes of drugs. The goal of combination therapy is to keep HIV from replicating and then spreading into more cells and to give the body the chance to increase its supply of the infection-fighting CD4+ cells that are destroyed by the virus.
All study participants were treated for at least eight weeks with antiretroviral combination therapy immediately preceding the beginning of the trial. Half the patients received the drug and half received a placebo, an inert substance with no medical benefit. All were encouraged to continue with their antiretroviral regimens. The drug was administered as a pill, taken orally once a day for 24 weeks. At the conclusion of this period, followup screening evaluations continued for another 24 weeks and participants in the adefovir group and placebo group were given the option of continuing with adefovir in their treatment regimen if their health status was appropriate.
In comparison to the reduction in viral load in the adefovir group (about 60 percent or 0.4 log), the level in the placebo group remained constant throughout the study period. Viral load is measured in the number of copies of viral genetic material per milliliter of blood. In both groups, the change in the level of CD4+ cells was not significant.
Participants demonstrating HIV-resistance to other nucleotide analogs- lamivudine or lamivudine in combination with zidovudine-showed "significant benefit" from adefovir, according to study results. More than 75 percent of participants had this resistance at the beginning of the study, and viral load in this group decreased an average of about 70 percent (or 0.5 log) over the 24-weeks.
During the study period, adefovir was associated in some patients with side-effects of elevated liver enzyme levels, gastrointestinal problems, and weight loss. Early indications of kidney dysfunction occurred in about 60 percent of patients who took the drug beyond 24 weeks, but the condition was reversed by stopping adefovir treatment.
These complications were unanticipated, according to the researchers, and should be taken into account in any future use. Findings suggest overall that the drug is useful as an "additional medication for patients who need to build effective treatment combinations to reduce viral replications, but it should be used with close clinical and laboratory monitoring," they write in JAMA.
Co-authors of the JAMA article are Steven Deeks, MD, UCSF Positive Health Program at SFGHMC; Deborah Cherng, MS, and Edmund Ng, PhD, Harvard University; Michael Wulfsohn, MD, PhD, Michael Miller, PhD, Julie Cherrington, PhD, Dean Winslow, MD, John J. Toole, MD, PhD, and Dion Coakley, PharmD, all of Gilead Sciences, Inc.; Avid Hardy, MD, Pacific Oak Research, Beverly Hills; Gildon Beall, MD, Harbor/University of California-Los Angeles Medical Center, Torrance; Richard Cooper, MD, Kraus Medical Partners, Los Angeles; Nesli Basgoz, MD, Massachusetts General Hospital, Boston; and Robert Murphy, MD, Northwestern University Medical School, Chicago.
Journal
JAMA