NIAID Backgrounder - June 1993
by National Institute of Allergy and Infectious Diseases

The National Institute of Allergy and Infectious Diseases (NIAID) leads the way in U.S. research concerning these life- threatening infections. As part of the NIAID effort, investigators focus on defining the optimal therapies, alone and in combination, to prevent and treat OIs. They seek ways to earlier identify infections and resistance to therapies and work to improve methods for comparing candidate treatments.

What are OIs?

Most people with HIV experience a gradual deterioration of their immune systems, leaving them vulnerable to numerous viral, fungal, bacterial and protozoal organisms. Held in check among individuals with healthy immune systems, these microbes become active and take advantage of the opportunity of the damaged immune system of people with HIV to cause disease.

Though several OIs occur in people with compromised immune systems caused by other diseases, their frequency and severity in people with AIDS are unsurpassed. Some OIs, however, are so rare in the general population that little research has been done on them and few treatments or ways to prevent them are available.

OIs: A Major Focus

NIAID uses a two-pronged approach to the treatment and prevention of OIs: clinical research to develop and evaluate promising drugs and basic laboratory research to learn how microbes cause disease.

As of May 1993, the NIAID Division of AIDS (DAIDS) and the Division of Intramural Research support 23 open, recruiting clinical trials aimed at preventing and treating OIs. Three additional studies are slated to open for this summer and four others are in development.

Prevention and treatment of the OI Pneumocystis carinii pneumonia or PCP has been extremely important to the NIAID OI effort. NIAID also investigates other OIs, particularly cytomegalovirus (CMV) infection, Mycobacterium avium intracellulare (MAI) infection and tuberculosis (TB). Although they occur so frequently among HIV-infected people, few drugs are available 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. PCP often is the first OI to appear in HIV-infected people and remains the most frequent AIDS-defining condition.

The PCP organism, a microscopic parasite, appears to infect most people during childhood. In persons with healthy immune systems, it 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.

If HIV-infected patients with PCP are not treated, close to 100 percent die. During the 1980s, the development of effective therapies led to more successful management of PCP. Two of the approved therapies for preventing and treating PCP, pentamidine and trimethoprim-sulfamethoxazole (TMP-SMX), are considered to be very effective, but both have serious side effects and patients may not be able to take them or have to stop treatment with them. In addition, atovaquone is approved for patients with mild to moderate PCP who cannot tolerate TMP/SMX.

The combination of TMP-SMX is recommended more often than pentamidine for treatment and prevention of PCP because it is effective, tolerated by about half of the patients who take it and works against other disease-causing organisms as well. Virtually all patients given pentamidine have adverse reactions related to administration of the drug. In 1992, an NIAID-supported trial proved that TMP/SMX is better than pentamidine at preventing a second episode of PCP in people with AIDS who can tolerate both drugs.

NIAID studies have played an important role in PCP research. One trial showed that the combination of primaquine, an antimalarial drug, and clindamycin could be an effective oral therapy for PCP.

The search for new, more effective, less toxic drugs for PCP continues. NIAID currently supports three studies of drugs to treat and three to prevent PCP.

CMV: A Herpes Virus

Infection with CMV, a virus in the herpes family, occurs throughout life. By age 50, about 50 percent 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 infection of the light-sensitive inner layer of the eye, is the most common CMV infection and leads to blindness if left untreated. Infections also occur in the gastrointestinal tract, lungs, brain, heart and other organs.

Both intravenous ganciclovir and foscarnet currently are approved for treatment of 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 foscarnet and ganciclovir are equally effective for CMV retinitis, although foscarnet further increased survival for patients.

MAI Infection: A Bacterial OI

Infection with the organism Mycobacterium avium-intracellulare (MAI) 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. MAI disease appears to significantly reduce the life span of people with AIDS.

MAI is found everywhere in the environment--in soil, water, animals, insects, dairy products and poultry and is thought to be acquired through the mouth or gastrointestinal tract. From there, it can spread to the lungs, liver, spleen, lymph nodes, bone marrow, intestines and blood. MAI causes a variety of symptoms such as persistent fever, night sweats, weight loss, chronic diarrhea, abdominal pain and severe anemia.

While there is no standard therapy for MAI, the U.S. Public Health Service Task Force suggests that all treatment include at least two drugs, including clarithromycin or azithromycin. Combinations of drugs sometimes have succeeded in alleviating symptoms such as fever and night sweats in HIV-infected people. Treatment of MAI infection is difficult because antibiotics may not be able to penetrate MAI-infected cells adequately and MAI strains often are resistant to antimycobacterial drugs.

In the past five years, several agents showing activity against MAI have become available for patients. However, only rifabutin is approved for the prevention of MAI disease.

NIAID currently has several studies under way looking at the role of drugs such as clarithromycin, rifabutin, azithromycin and sparfloxacin, alone and in combination, to prevent and treat this serious disease.

TB: An Airborne Disease

TB is a chronic bacterial infection primarily of the lungs that causes more deaths worldwide than any other infectious disease. One-third of the world's population is infected with the predominant TB organism, Mycobacterium tuberculosis.

The World Health Organization (WHO) estimates that 4.4 million people worldwide are coinfected with TB and HIV. The WHO predicts that by the year 2000, TB will take one million lives annually among the HIV-infected.

Because of their weakened immune systems, persons with HIV are particularly 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. In fact, TB may be the first indication that a person is HIV-infected. TB also causes disease outside the lungs of HIV-infected people, particularly in the later stages of AIDS.

Of particular concern for people with AIDS is multi-drug- resistant TB (MDR-TB). MDR-TB occurs when patients fail to take their TB medicine for the prolonged periods necessary to destroy all parts of the TB organism and it becomes resistant to the drugs. These resistant organisms can be spread to other people. Even with treatment, for individuals coinfected 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 with no 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 recently launched the first large U.S. study to assess TB treatment strategies for people coinfected with HIV and TB. The study is aimed at finding state-of-the-art treatment for these people. NIAID is the lead institute for TB research at the National Institutes of Health, supporting more than 50 research projects related to TB, including five other trials for HIV- infected persons.

Other OIs

NIAID-supported scientists are studying many other OIs including fungal infections, herpes simplex virus infections and toxoplasmosis.

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 June 1993