OI Prophylaxis and Treatment in the Era of HAART
There are a number of infections, cancers and neurologic problems that affect people with HIV infection. Collectively, these opportunistic illnesses (often called OIs) are the hallmark of the progressive immodeficiency associated with HIV infection. These illnesses often result in hospitalization, disabillity, and time off from work, and are responsible for most of the deaths in persons with AIDS. The most common OIs are recurrent bacterial pneumonia, oral and esophageal candidiasis (thrush), Pneumocystis carinii pneumonia (PCP), cytomegalovirus infection (CMV), Mycobacterium-avium complex infection (MAC); HIV-associated dementia, lymphoma, Kaposi's sarcoma and HIV wasting syndrome. Fortunately, many of these infections can be prevented.
The introduction of highly active antiretroviral therapy (HAART) and protease inhibitors has resulted in improved survival and decreased hospitalizations in persons with advanced HIV infection. This has been accompanied by an overall decline in the number of most OI events, and has led to the coining of a new phrase, "immune reconstitution," which leads to a number of important questions:
What is immune reconstitution?
How does a person know when s/he is "reconstituted"?
Can individuals still get OIs if they have immune reconstitution?
Can OI prophylaxis be stopped if immune reconstitution has occurred?
What should patients and physicians do right now?
What is being done to determine if it is safe to stop OI prophylaxis? For example, should a person with a CD4 count of 50 cells/mm3 that rises to 350 cells/mm3 after using HAART stop taking prophylaxis for PCP, MAC, toxoplasmosis, candidiasis or other infections?
What is Immune Reconstitution?
Immune reconstitution is the process of regeneration of the normal body defenses against specific infections and illnesses. Immune reconstitution, or bringing the body's immune defenses back to a level where they can defend themselves against these OIs, is one of the critical benefits of HAART. This process probably involves several parts:
First, reduction in the amount and effects of HIV within the body
Second, repopulation of both memory and naive T-cells back to levels sufficient to prevent disease
Third, functional return of many of the components of the immune system that have been lost with HIV infection
How Does One Tell When Immune Reconstitution Has Occurred?
A number of research groups are investigating how the human immune system regenerates in response to HAART. It would be rather simplistic to believe that immune reconstitution is a numbers game of lowering viral load and raising CD4 counts. There are a number of crude measures of immune function: reaction to skin tests (a test where some material is injected under the skin to see if the body reacts normally); return of the normal numbers of lymphocytes in the appropriate proportions; and the return of functional reactivity of lymphocytes to specific challenges with different stimuli. All of these tests are research tools that are not available (or interpretable) in clinical practice. None of the tests available are completely reliable or are able to fully explain what is actually happening with the use of HAART. Thus, the best measure of immune reconstitution is the lack of any OI occurring in a person who is taking HAART who was previously susceptible to OIs.
Do Individuals with Immune Reconstitution Still Get OIs?
Several recent studies have demonstrated conflicting data on the recovery of specific T-cell lymphocyte phenotypes (naive and memory cells) in response to HAART. This has led researchers to speculate that full recovery may not occur in everyone, particularly those with very advanced HIV infection (CD4 count of less than 50 cells/mm3). Thus, some patients may have very high levels of T-cells but still develop an OI because somehow they've permanently lost the ability to fight off that disease. In addition, several recent studies of HAART demonstrate that even though the virus level may drop below detection, OIs still occur (usually within the first three months after starting HAART). It may be that these infections were brewing even before the new antiretroviral therapy was started. Finally, there are reports of OIs occurring in individuals with higher T-cell levels and very low HIV viral load levels. At Washington University, we have observed this to occur in several of our patients with progressive multifocal leukoencephalopathy, a uniformly fatal infection of the brain.
Can OI Prophylaxis Be Stopped?
The quick answer is probably "Yes, but DON'T DO IT YET." This is the subject of intense study. Until there is sufficient safety data available, physicians and patients should be very cautious about stopping medications that have been proven to save lives. A number of small studies which have yet to be published demonstrate that OI prophylaxis can be stopped in some patients. Dr. Francesca Torriani and her colleagues at the University of San Diego have stopped anti-CMV therapy in patients who had CMV retinitis, and only one of 11 has recurred to date. Dr. Judy Aberg at the University of California at San Francisco stopped MAC therapy in four patients treated for at least one year without recurrence of their disease. Recently, researchers in the Swiss Cohort trial presented interim data at the 12th World AIDS Conference on the safety of stopping PCP prophylaxis. The results were quite encouraging. Collectively, these and other studies suggest that it may be safe to stop prophylaxis but more evidence is needed.
What is Being Done to Determine the Safety of Stopping OI Prophylaxis?
The AIDS Clinical Trials Group (ACTG) and a number of other research groups have designed several studies to test whether it is safe to stop these medications in persons who respond to HAART. One trial will determine whether it is safe to stop MAC prophylaxis. In ACTG 362, individuals whose T-cells have risen from less than 50 to above 100 cells/mm3 will be randomized to continue MAC prophylaxis with weekly azithromycin or receive a placebo. If their CD4 count declines again below 50, then MAC prophylaxis will be resumed. This study is almost fully enrolled, and results should be available within the next 18 months.
To study the removal of PCP prophylaxis, Dr. Susan Koletar and her colleagues in the ACTG have designed a trial for individuals whose CD4 count rises from below 100 to above 200. Propylaxis for PCP will be discontinued in all patients. About half the patients will have had PCP previously. Prophylaxis will be resumed if the CD4 count drops back below 200. In a third trial, individuals who have been treated for MAC disease for at least 12 months without symptoms and who are on HAART will be allowed to discontinue their MAC treatment (ACTG 393). If their CD4 count falls below 50, then they will start standard MAC prophylaxis. Frequent monitoring and MAC blood cultures will be done to detect any failures early.
Another study will discontinue CMV retinitis treatment in persons whose disease has responded to therapy and are now on HAART (ACTG 379). In this trial, the primary objective is to estimate the time-
The introduction of HAART has resulted in the longer survival of persons with AIDS. The lowering of HIV levels and increases in T-cells have led to the speculation that OI prophylaxis may not be necessary in patients responding to HAART. This is the subject of intense investigation. If true, this could result in the simplification of treatment for persons with HIV infection. The table [below] lists specific pathogens/diseases for which there is or is not evidence that the use of HAART decreases the chance of reoccurance. Patients should discuss stopping prophylaxis with their medical provider before taking any action. Withdrawal of OI prophylaxis is not advisable until there is more evidence that it is safe.
Carl J. Fichtenbaum, M.D. is an Assistant Professor of Medicine at Washington University in St. Louis. He is an active member of the Complications of HIV Disease Research Agenda Committee of the NIAID AIDS Clinical Trials Group.
Which OIs Can HAART Alone Prevent?
If HAART alone is effective, you may not need specific prevention or treatment for:
These OIs may occur even if HAART is effective:
It is not yet known whether HAART is effective for:
Visit CRIA on the Internet