The National Institute of Allergy and Infectious Diseases (NIAID) has launched two studies looking at the safety and effectiveness of drugs to prevent serious opportunistic infections (OI) in HIV-infected people with severely damaged immune systems.
One study looks at the ability of an oral form of the drug ganciclovir to prevent cytomegalovirus (CMV) infections of the retina and gastrointestinal tract. The second trial compares clarithromycin and rifabutin as therapies to prevent Mycobacterium avium complex (MAC) disease.
In people with normally functioning immune systems, the body can ward off most opportunistic infections," says Anthony S. Fauci, M.D., director of NIAID. "However, in people infected with HIV whose immune systems are severely damaged, these infections can become active and life-threatening. Safe, effective and easily administered therapies are needed urgently to prevent disease and treat people with these HIV-associated conditions."
The drugs ganciclovir and foscarnet are available to treat patients with active CMV disease. However, both medications require intravenous administration. No drug has been shown to prevent the disease. "If ganciclovir proves effective in preventing CMV disease, the oral form would be a much easier and safer way for patients to take the drug," says Lawrence R. Deyton, M.S.P.H., M.D., chief of the community clinical research branch of the Division of AIDS (DAIDS), NIAID. The branch coordinates the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), which is conducting the CMV trial.
Infection with CMV occurs throughout life. By age 50, about half of the general population has been exposed to CMV, yet most people do not get sick unless their immune systems are damaged severely. For people with HIV infection, CMV causes one of the most common and serious OIs they face. Patients undergoing organ transplants also may experience severe CMV infection.
Retinitis, an infection of the light-sensitive inner layer of the eye, is the most common CMV disease and without treatment leads to blindness. The disease occurs in 10 to 20 percent of AIDS patients and approximately 80 percent respond to therapy with intravenous ganciclovir or foscarnet.
The second most common manifestation of CMV infection is an acute inflammation of the esophagus, stomach and colon. This gastroenteritis affects 5 to 10 percent of people with AIDS.
Less frequently, CMV disease occurs in the lungs, brain, heart and other organs. Study investigators have chosen to target retinitis and gastroenteritis because they are the most frequently observed CMV conditions.
In the CMV prophylaxis protocol, participants will be randomly assigned to receive 3 grams of oral ganciclovir per day or a placebo. Neither patients nor study personnel will know whether the drug or placebo has been assigned. The placebo is necessary in this trial to ascertain the true effectiveness of oral ganciclovir and to accurately define the side effects. Then the results of the trial will enable patients to make an informed decision on whether to use this preventive therapy. All patients will be monitored for a minimum of 12 months to a common closing date, with follow-up ranging from 12 to 24 months. Researchers plan to enroll 850 people. Ganciclovir and matching placebo for the trial will be supplied by Syntex Research of Palo Alto, Calif.
The other new NIAID study considers rifabutin, recently approved by FDA for the prevention of MAC disease, and clarithromycin alone and in combination to prevent MAC infection. Clarithromycin has been recommended for approval by an FDA advisory committee for the treatment of active MAC disease in combination with other antimycobacterial agents. In preliminary clinical trials, this drug has reduced the amount of MAC bacteria and produced an apparent clinical improvement in patients. Some adverse side effects have been reported with clarithromycin, including nausea, vomiting and abdominal pain.
"Preventive therapy for mycobacterial infections like tuberculosis traditionally has been a single agent given for a prolonged period to people known to have been previously infected," says Steven M. Schnittman, M.D., chief of the medical branch of DAIDS, NIAID. "However, since mycobacteria such as MAC can develop resistance to a single agent, giving a two-drug combination for prophylaxis may be more beneficial."
Following the Public Health Service recommendations, the NIAID study includes rifabutin as the standard preventative therapeutic arm. Recent studies of rifabutin for MAC prevention suggest that the drug may have contributed to declines in MAC bacteria in the blood and a decrease in clinical symptoms. Possible side effects from rifabutin include reduction in platelets and white blood cells, rashes and gastrointestinal disturbances.
MAC causes disseminated or spreading infection in up to 40 percent of HIV-infected people in the United States, making it the most common bacterial OI. The infection usually affects people with advanced HIV disease whose immune systems are severely suppressed and appears to greatly reduce their life spans.
The MAC organism is found almost everywhere in the environment -- in water, soil, animals, insects, dairy products and poultry -- and is thought to be acquired through the mouth or gastrointestinal tract. From there, the disease can spread to the lungs, liver, lymph nodes, spleen, bone marrow, intestines and blood, causing a range of symptoms including persistent fever, night sweats, weight loss, chronic diarrhea, abdominal pain and severe anemia.
Researchers will compare the three treatment arms among 1,000 patients in the MAC study, ACTG 196/CPCRA 009. Participants will be randomly assigned to receive 500 milligrams of oral clarithromycin twice a day with a placebo, or 450 mg. of rifabutin once daily with a placebo, or the combination of clarithromycin and rifabutin at the same daily intervals. Patients will be seen every four weeks for the first eight weeks of the trial and every eight weeks thereafter. Study investigators plan to enroll all participants during a 12-month period and then follow them for 18 months.
Clarithromycin tablets and placebo will be supplied by Abbott Laboratories, Abbott Park, Ill. Rifabutin capsules and placebo will be provided by Adria Laboratories, Dublin, Ohio.
CMV and MAC study investigators will enroll people with CD4+ T cell counts of less than or equal to 100 per cubic millimeter of blood (mm3). HIV targets and kills CD4+ T cells, which are crucial to the immune system, making one susceptible to other infections like CMV and MAC. A healthy adult has 800 to 1,200/mm3 such cells. The studies are part of an ongoing NIAID effort to combat OIs, which includes 24 open clinical trials.
For enrollment information, site location and eligibility requirements for these studies, please call 1-800-TRIALS-A, Monday through Friday, 9 a.m. to 7 p.m., eastern time.
NIAID, part of the National Institutes of Health (NIH), supports research on AIDS, tuberculosis, allergies, immunology and infectious diseases. NIH is an agency of the U.S. Public Health Service, part of the Department of Health and Human Services.