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Opportunistic Infections Continue to Vex the Lives of PWAs as Long As Immunodeficiency Remains

‘Postponing the inevitable’

Michael Marco and his TAG colleagues working within TAG’s Opportunistic Infections Committee (Theo Smart, Laura Morrison, Tim Horn, Paul Dietz, Mark Harrington) released their 134-page OI Report at the national retroviral meeting in Washington, D.C. last month. The handsome volume includes summaries and analyses of the prevention and treatment of viral, bacterial, fungal and protozoal infections which threaten the lives and well-being of HIV-infected persons. A final section contains research policy recommendations. Washington University Medical School’s Dr. Bill Powderly, who also heads the ACTG’s OI committee, prepared this forward to the research report.

Opportunistic infections (OIs) remain the most important complications of HIV infection, resulting in profound morbidity and mortality. They clearly will remain a major issue as long as immunodeficiency is the inevitable result of long-standing HIV infection. As data from natural history studies show, while PCP prophylaxis has increased survival and delayed the onset of AIDS-defining illnesses, the inevitable is merely postponed. The advent of newer, more effective antiretroviral therapeutic regimens has clearly altered the equation in favor of the patient, but for many the question will be, “For how long?” Furthermore, it is clear that even for patients who experience effective antiviral responses to therapy, important questions regarding their immunocompetence and vulnerability to OIs remain.

The last ten years have elevated many once obscure pathogens to new prominence, and significant advances have been made. Just ten years ago, in 1987, opportunistic infection research was in its infancy. Pneumocystis carinii pneumonia (PCP) was by far the most common OI, with an associated mortality of 20-40%. Two drugs were available for therapy, trimethoprim-sulfamethoxazole (TMP/SMX), and pentamidine, and they were associated with dose-limiting toxicity in up to half of patients. Prophylaxis was used sparingly, only in certain parts of the country, and was not widely accepted. For the fungal infections, amphotericin B was the only available therapy, although phase I studies of the triazole antifungal agents fluconazole, itraconazole had been completed. For Toxoplasma encephalitis, pyrimethamine/sulfadiazine was effective, but it shared the same tolerability problems as TMP/SMX. Effective therapies for cytomegalovirus (CMV) retinitis, Mycobacterium avium complex (MAC) or acyclovir-resistant herpes simplex were not available or were not standardized and treatment was based on anecdotal information at best. The co-epidemic of tuberculosis was yet to be recognized.

We now have very effective therapies for many of the common opportunistic infections, such as PCP, tuberculosis, cryptococcosis and histoplasmosis; effective, but toxic therapies for toxoplasmosis and moderately effective treatment regimens for disseminated MAC and CMV infections. Only the enteric parasitic diseases such as cryptosporidiosis and micro-sporidiosis and the viral brain disease PML elude us in terms of at least modestly active treatment.

Yet these advances give us no reason for complacency. In some cases, we are just one short step, whether by drug toxicity or microbial mutation, away from a much less satisfactory situation. Clinicians well recognize the problems posed by sulfa-drug allergies in the management of PCP and toxoplasmosis, and by fluconazole-resistant fungal organisms such as Candida. Microbial resistance is increasingly an issue for mycobacterial and CMV infections as well. In too many cases, our successes are dependent on just one therapeutic agent, the loss of which may be catastrophic in terms of care.

The last ten years have also seen an increasing recognition that many OIs can be prevented. The use of prophylaxis for PCP has increased survival and delayed the onset of an AIDS-defining illness. The counterpart of this increased survival, however, is that patients using effective PCP prophylaxis have an increased risk of developing disseminated Mycobacterium avium complex (MAC), CMV disease, wasting syndrome and esophageal candidiasis — as well as the opportunistic neoplasms such as Kaposi’s sarcoma and lymphoma. Prevention of MAC has also proved to extend survival, and data also demonstrate that fungal and viral infections are preventable. However, this knowledge is tempered by the fact that multiple drug therapy for prevention of OIs is complicated by issues of toxicity, resistance, drug interactions, and cost. Thus, no consensus on how to best use multiple agents has yet been reached.

More effective antiretroviral therapy has provided new hope for many, and may be changing the course of OIs. Indeed, it could be argued that the most effective preventive therapy for all of the opportunistic infections will be more complete control of retroviral replication and with it better immunocompetence. It is clear that there are fewer OIs with the protease inhibitors — both in clinical trials and in clinical practice. What is not clear is the extent or durability of the immunologic protection. Thus, the answer to a critical question for patients and doctors alike — “Can I stop the prophylaxis?” — is unknown. Clearly this question needs to be addressed by clinical researchers.

We all are glad to be in an era of optimism about the prospects for treating AIDS and HIV disease, and hope it will continue. Nonetheless, we must recognize that our current foundations are shallow, and must strive to improve our chances of overcoming these opportunistic pathogens. In many cases, while we have improved diagnosis, treatment and prophylaxis, our understanding of the microbial pathogenesis of these opportunistic organisms has not kept pace with our clinical advances. Yet only by developing a fuller understanding of the complex stages of the life cycles of these parasites, and their interactions with the human host immune defenses will we be able to keep up with their alarming ability to mutate away from antimicrobial control. Only increased research on the pathogenesis of the OI organisms will provide us with success. An important goal, therefore, is to define better predictors of certain OIs and thus identify subsets among patients with advanced HIV disease who are at increased risk for these infections. One approach is to attempt to use clinical parameters. Patients who have experienced one OI are at greater risk of developing a second, at any given CD4 count — this is particularly true for MAC and CMV. Unfortunately, thus far these indicators merely identify relative rather than absolute risks and are not discriminatory enough to suggest strategies for prevention.

A more promising avenue is the use of microbiologic and immunologic markers, especially for CMV infection and MAC. As an example, the pathogenesis of CMV in patients with AIDS is far from clear. A majority of HIV-positive individuals have been exposed to CMV, yet only a minority develop overt CMV disease. A high proportion of individuals with advanced HIV disease are CMV viremic and/or viruric, yet many of these never have overt CMV disease. Several reports have suggested that CMV virologic measures might be predictive of invasive CMV disease, especially retinitis. If confirmed then it might be possible to identify patients at high risk of developing CMV disease. In that case, regular screening for early evidence of viral replication by polymerase chain reaction (PCR) might be useful in targeting early intervention, rather than true prophylaxis. Additionally, certain OI-specific immune response (or perhaps loss of specific OI responses) may be critical in the development of certain infections. These too could be used to better target prevention or early treatment. What is clear is that this should be a high priority for clinical and basic research in this arena.

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