Opportunistic Infections (OIs) cause most of the illnesses and deaths among people infected with HIV, the virus that causes AIDS. The National Institute of Allergy and Infectious Diseases (NIAID) leads the way in U.S. research on these life-threatening infections. As part of the NIAID effort, investigators are defining the optimal therapies, alone and in combination, to prevent and treat OIs. They seek ways to identify infections earlier and recognize resistance to therapies more quickly.
What are OIs?
The immune systems of most people with HIV gradually deteriorate, leaving them vulnerable to numerous viruses, fungi, bacteria and protozoa that are held in check in people with healthy immune systems. These microbes can become active in HIV-infected individuals, causing frequent and severe disease.
NIAID uses a two-pronged approach to the treatment and prevention of OIs: basic laboratory research to learn how these microbes cause disease and clinical research to develop and evaluate promising therapies.
Prevention and treatment of one such disease, Pneumocystis carinii pneumonia or PCP has been a major thrust of the NIAID program. Other NIAID investigations include cytomegalovirus (CMV) infection, Mycobacterium avium complex (MAC) and tuberculosis (TB). Institute research focuses on these infections because, although they occur repeatedly among HIV-infected people, they are rare in the general population and few drugs are available now to prevent and treat them.
PCP: The Most Common OI
PCP remains the most common, life-threatening opportunistic infection in people with HIV, occurring in up to 80 percent of individuals who do not take preventive therapy.
The PCP organism, a microscopic parasite, appears to infect most people during childhood. In people with healthy immune systems, the parasite normally remains dormant, but may cause disease in people with damaged immune systems.
PCP infection is characterized by a dry cough and shortness of breath. Individuals may experience other, less specific symptoms such as fever, fatigue and weight loss for weeks or even months before respiratory problems appear. As PCP infection progresses, the functioning lung tissue becomes clogged, which decreases the transport of oxygen from the inhaled air into the blood. At this point, the oxygen in the blood may be lowered to dangerous or even fatal levels.
Without treatment close to 100 percent of HIV- infected patients die. During the 1980s, the development of effective therapies led to more better management of PCP. Drugs for preventing and treating PCP include aerosolized pentamidine and trimethoprim-sulfamethoxazole (TMP-SMX),but both can result in serious side effects that prevent some patients from taking the drugs.
TMP-SMX is recommended more often than aerosolized pentamidine for treating and prevention of PCP because the combination is effective, tolerated by about half of the patients who take it and works against other disease-causing organisms as well. In 1992, an NIAID-supported trial proved that TMP/SMX is better than aerosolized pentamidine at preventing a second episode of PCP in people with AIDS who can tolerate either therapy.
Although definitive research data are lacking, other agents may be considered in situations in which neither TMP/SMX nor aerosolized pentamidine can be given. The drug atovaquone is approved for patients with mild to moderate PCP who cannot tolerate TMP/SMX. One NIAID study showed that primaquine, an antimalarial drug, with clindamycin is an effective oral therapy for PCP. TMP with Dapson is an alternative treatment.
The search for new, more effective, less toxic drugs and combinations of drugs to fight PCP continues. One trial compares three drug regimens--TMP/dapsone, primaquine/clindamycin and TMP/SMX--for oral treatment of mild to moderate PCP. Another protocol looks at an 8- aminoquinoline, an antimalaria drug, while a third trial considers two regimens of TMP/SMX to prevent PCP.
CMV: A Herpes Virus
Infection with CMV, a virus in the herpes family, may occur throughout life. By age 50, about half of the general population has been exposed to this virus, yet most people do not become ill. After the original infection, the virus may lie dormant and reactivate itself if the immune system becomes suppressed.
For people with HIV infection, CMV is one of the most frequent and serious OIs they face. CMV retinitis, an inflammation of the light-sensitive inner layer of the eye, is the most common CMV infection and leads to blindness if left untreated. Infections may occur in the gastrointestinal tract, lungs, brain, heart and other organs.
Both intravenous ganciclovir and foscarnet are approved to treat CMV retinitis. Life-long maintenance on either treatment is required because the drugs do not kill CMV, they merely slow down its ability to grow. Even with therapy, the rate of relapse is high.
NIAID studies of CMV and other herpes viruses have shown that intravenous foscarnet and ganciclovir are equally effective for CMV retinitis, although foscarnet was associated with increased survival for patients. An ongoing trial is testing an oral form of ganciclovir to prevent CMV disease. The oral form of the drug would be much easier and safer for patients to take.
MAC Infection: A Bacterial OI
Infection with (MAC) is diagnosed in up to 40 percent of people with AIDS in the United States, making it the most common bacterial OI. Usually, it affects people in advanced stages of HIV disease, when the immune system is severely suppressed.
The MAC organism is found widely in the environment and is thought to be acquired most commonly through the mouth or gastrointestinal tract. It can spread to the lungs, liver, spleen, lymph nodes, bone marrow, intestines and blood. MAC causes chronic debilitating symptoms--fever, night sweats, weight loss, fatigue, chronic diarrhea, abdominal pain, liver dysfunction and severe anemia.
Rifabutin is the first drug to be approved for preventing MAC disease in people with advanced HIV infection. The Food and Drug Administration based this approval on clinical studies showing that patients who received rifabutin were one- third to one-half as likely to develop MAC as were patients who received placebo.
To prevent MAC disease, a U.S. Public Health Service Health Service Task Force on Prophylaxis and Therapy for MAC suggests that patients with HIV infection and fewer than 100 CD4+ T cells receive oral rifabutin for the rest of their lives unless disease develops. In the latter case, multiple drug treatment is needed. CD4+ T cells are immune system cells targeted and killed by HIV. No other drug regimen is recommended currently to prevent MAC. Azithromycin and clarithromycin are promising agents for prophylaxis, but studies of these agents have not been completed.
Increasing evidence suggests that treatment can benefit patients with disseminated MAC, especially multiple-drug regimens including either clarithromycin or azithromycin. Therefore, the PHS task force suggests that all regimens, outside of a clinical trial, should consist of at least two drugs, including clarithromycin or azithromycin plus one other agent such as clofazimine, rifabutin, rifampin, ciprofloxacin and, in certain situations, amikacin. They recommend continued therapy for the patient's lifetime, as long as clinical benefit and reduction of mycobacteria are observed.
NIAID has several studies under way looking at the roles of clarithromycin, azithromycin, and other drugs such as sparfloxacin, alone and in combination, to prevent and treat this serious disease.
TB: An Airborne Disease
TB, a chronic bacterial infection causes, more deaths worldwide than any other infectious disease. About One-third of the world's population is harbors the predominant TB organism, Mycobacterium tuberculosis and is at risk for developing the disease.
The World Health Organization (WHO) estimates that 4.4 million people worldwide are co-infected with TB and HIV. WHO predicts that by the year 2000, TB will take one million lives annually among the HIV-infected.
Because of their weakened immune systems, people with HIV are vulnerable to reactivation of latent TB infections, as well as new TB infections. Transmission of this disease occurs most commonly in crowded environments such as hospitals, prisons and shelters--where HIV-infected individuals make up a growing proportion of the population.
Active TB often occurs early in the course of HIV infection, often months or years before other OIs. TB most often affects the lungs, but it also can cause disease in other parts of the body, particularly in people with advanced HIV disease.
Of particular concern for people with AIDS is multi-drug- resistant TB (MDR-TB). MDR-TB can occur when patients fail to take their TB medicine for the prolonged periods necessary to destroy all TB organism which then becomes resistant to the drugs. These resistant organisms can be spread to other people. Even with treatment, for individuals co-infected with HIV and MDR-TB, the death rate may be as high as 80 percent, as opposed to 40 to 60 percent for people with MDR-TB alone. The time from diagnosis to death for some patients with HIV and MDR-TB may be only months, as they are sometimes left without adequate treatment options.
The initial site of TB infection is in the balloon-like sacs at the ends of the small air passages in the lungs. In these sacs, white blood cells called macrophages ingest the inhaled TB organism. Some of the organisms are killed immediately, while others remain and multiply within the macrophages. If the organism breaks out of the sacs, TB can become active disease. This spreading sometimes results in life-threatening meningitis and other problems.
NIAID launched the first large U.S. study to assess TB treatment strategies for people co-infected with HIV and TB. The study is aimed at finding state-of-the-art treatment. NIAID is the lead institute for TB research at the National Institutes of Health, supporting more than 50 research projects related to TB.
NIAID-supported scientists are studying other OIs including fungal infections, herpes simplex virus infections toxoplasmosis and cryptosporidium infections.
NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis, allergies, immunology and infectious diseases. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
Prepared by: Office of Communications National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland 20892
Public Health Service U.S. Department of Health and Human Services