The success of antiretroviral therapy has caused major decreases in most of the significant opportunistic infections and has led to new questions being posed by clinical investigators interested in this area.

The Changing Natural History of HIV/AIDS in the Era of "HAART": Clinical Implications

On the second day of the 8th Annual Clinical Care Options for HIV conference held in Scottsdale, Arizona, Dr. Richard Chaisson of the Johns Hopkins University reviewed the changing epidemiology of opportunistic infections in the era of more potent antiretroviral therapy.

Using data from the Johns Hopkins clinic he compared the incidence of new opportunistic diseases in the years 1993-5 and 1996-7. For all illnesses there has been a dramatic reduction in new cases. This was particularly striking for CMV infections, toxoplasmosis, disseminated MAC and cryptosporidiosis. When the Hopkins investigators examined risk factors for new opportunistic events, they found that patients in their clinic with CD4 counts less than 200 were more likely to develop an opportunistic event if they were not on a protease inhibitor and if they had higher baseline viral loads. The use of protease inhibitors decreased the risk by 60% and having an undetectable viral load reduced the risk by 80%. Thus as Dr. Chaisson stated the key to prevention of opportunistic infections was to maximize antiretroviral therapy and try and keep the viral load as low as possible.

If this is done and patients' viral loads are undetectable, then can one stop prophylaxis for opportunistic infections such as PCP or MAC? Dr. Chaisson reviewed the biphasic nature of the CD4 cell response to potent antiretroviral therapy -- an initial phase in the first 3 months that seems to represent expansion of existing cells, and a second phase after that which appears to represent new immune cells. He suggested that all the available clinical evidence indicates that patients do have restored immunity in this phase, since new infections are extraordinarily rare. As a result he suggested that, in patients whose viral load is undetectable and whose CD4 count has risen, that the calculated risk of stopping prophylaxis was a reasonable one and might be considered in an informed patient. Indeed, as he showed, there have been instances where stopping maintenance treatment for established infections such as CMV has been accomplished with apparent success in patients whose CD4 count has risen with antiretroviral therapy.

One interesting phenomenon that is increasingly recognized is that of a changed presentation of opportunistic infection that occurs in patients if they get an infection shortly after initiation of antiretroviral therapy. It has been most commonly described with mycobacterial infections, which are more localized often to lymph nodes causing significant enlargement and pain. This appears to be an inflammatory reaction associated with a recovering cell-mediated immunity and has been likened to the reversal reaction seen in lepromatous leprosy. The importance of recognizing this is that it probably does not represent failure of antiretroviral treatment which should therefore be continued.

Other speakers continued the theme of changing issues with opportunistic events.

HIV-RELATED CLINICAL UPDATES (1998):
Oncologic Disorders and Cytokines

Dr. Alexandra Levine of the University of Southern California discussed malignancies associated with HIV. Although there is some controversy associated with the use of antiretroviral therapy for the treatment of Kaposi's sarcoma, she suggested that about 50% of patients will respond to potent therapy of HIV, and that this should be tried first. There have been several advances in chemotherapy, of which the use of Taxol with response rates of 50-70% was the most promising.

Unlike Kaposi's sarcoma whose incidence has clearly decreased in the current era, there is much more uncertainty about non-Hodgkin's lymphoma, with some investigators reporting decreased incidences and other increased. As Dr. Levine pointed out, either could theoretically occur -- more potent treatment could lead to decreased B cell stimulation and less oncogenesis, or it could lead to longer survival with more time for continued B cell stimulation to lead to lymphoma development. Only time will tell.

HIV-RELATED CLINICAL UPDATES (1998):
Wasting/Endocrine Disorders

The interesting metabolic events associated with more potent therapy were reviewed by Dr. Donald Kotler of St. Lukes/Roosevelt in New York. High blood triglycerides and high blood hypercholesterol, hyperglycemia (raised blood sugar and diabetes mellitus), and a lipodystrophy (disorder of body fat) have all been described and attributed to the use of protease inhibitors. However as Dr. Kotler pointed out a causative relationship with the new drugs has not been established and he postulated that these events may not be related to the drugs per se but rather to altered metabolism in the setting of undetectable viral load. He reviewed in particular the changes in body fat distribution with increased visceral (intra-abdominal fat) and less peripheral fat and compared this to a rare and little known syndrome -- Syndrome X -- that has been described in individuals without HIV. The importance of this syndrome, he stated, was that such patients had higher rates of cardiovascular death and therefore this needed to be watched closely in treated HIV-positive patients.

HIV-RELATED CLINICAL UPDATES (1998):
CMV/Cytomegalovirus Disease

Dr. Bruce Polsky of Memorial-Sloan Kettering reviewed the data that has been gathered over the last few years showing the relationship between CMV viral load (measured by PCR or antigen detection) in the blood and the risk of CMV disease. Several groups have now shown that patients with detectable CMV in the blood are at significantly greater risk of developing end-organ disease such as retinitis and that the risk increases as the CMV viral load increases. Indeed, an increased CMV viral load also increases the risk of death, independent of the HIV viral load. Although the incidence of CMV infection is dramatically reduced, Dr. Polsky proposed that at risk patients (such as those with CD4 counts less than 50) have regular blood screening for CMV and that pre-emptive therapy be considered for viremic patients to try and prevent end-organ disease. This has yet to be widely tested (since these assays are not yet widely available) but seems to be a reasonable way of considering how to use them when they become more available.