TAG: The OI Report - forward & introduction

THE OI REPORT:
A Critical Review of the Treatment & Prophylaxis of
AIDS-Related Opportunistic Infections (OIs)

FOREWORD
by William G. Powderly, M.D.

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, OI research was in its infancy. Pneumocystis carinii pneumonia was by far the most common OI, with an associated mortality of 20-40%. Two drugs were available for therapy, trimethoprim-sulfamethoxazole Bactrim (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 and 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 OIs, 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 microsporidiosis 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 some 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 preservation of 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 are all 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 develop overt CMV disease. Several reports have suggested that CMV virologic measures might be predictive of invasive CMV disease, especially retinitis . If confirmed, 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 there should be a high priority for clinical and basic research in this arena.

The series of articles that you will read in this report provides a thorough review of the state of the art for these tremendously varied infections and provides a more detailed analysis of some of the questions that I have alluded to. It is to be hoped that all of you who read this will be provoked into recognizing that there are many more questions to be answered and will be stimulated into providing support and encouragement to help produce some of the answers. We should be unstinting in our thanks to Michael Marco and his colleagues from the Treatment Action Group for producing this document.

William Powderly is the principal investigator, Washington University Medical School AIDS Clinical Trials Unit (ACTU) in St. Louis, Missouri, and is the chair, Complications of HIV Disease Research Agenda Committee (RAC), AIDS Clinical Trials Group (ACTG).

INTRODUCTION
by Michael Marco

January 1997

Five years ago, at the Amsterdam AIDS Conference, after joining a group of activists to zap the Astra booth in protest at the obscene price of FoscavirTM brand foscarnet, I followed them to to a canal into which they scattered the ashes of Michael Wright, an AIDS treatment activist from San Francisco who died that January of hepatitis, and whose ashes they had brought to the Astra zap. Right then and there I realized that people with AIDS needed a lot more than zaps to save their lives, and that dedicated treatment activists were dying a lot faster than they were being replaced. So I decided to become a treatment activist. I had never even met Michael Wright, but I knew that he'd worked wonders in a brief, brilliant activist career which began after watching Peter Staley's inspirational opening address at the 1990 San Francisco AIDS Conference. Soon after, I started working with Andy Zysman, also of San Francisco, who educated me in the ins and outs of AIDS malignancy research, until he too died suddenly midway through 1993.

Treatment activists, and people with AIDS, are still dying faster than they're being replaced, and one of the great pleasures of creating this report has been working with a group of committed TAG volunteers to develop a new understanding of the challenges facing AIDS research as we approach the next millennium. AIDS-related opportunistic infections (OIs) will be with us for the foreseeable future, for -- contrary to the assertions of naively-optimistic commentators in The New York Times and The Wall Street Journal -- AIDS is not over. Indeed, on a global scale, the killing has just begun. HIV disease is still chronic, but it is not yet manageable, and what limited tools we have to extend health and life largely began with the explosion of AIDS OI research -- an explosion instigated by AIDS treatment activists -- in the late 1980s. "More OI Research!" was one of ACT UP's demands at "Storm the NIH" in 1990, and this report documents the major progress made in preventing and treating AIDS-related OIs in response to activist pressure. Special mention here should be made of the Countdown 18 Months Project of ACT UP/New York's Treatment + Data Committee, which included Garance Franke-Ruta, Derek Link, Rich Lynn, Kim Powers, Jerry Jontz and Scott Slutsky, the last two of whom did not live to see the fruit of their labors. Scott Slutsky in particularly continued to work on expediting development of MACtreatment and prophylaxis even as he contended with CNS lymphoma; the major advances in this field documented below are a testament to his work.

It has been exciting to work with the researchers (and some of the few remaining treatment activists) who cut their teeth in the early days of forcing the government to pay attention to the "S" in AIDS -- the syndrome of opportunistic complications, not just the underlying HIV infection. In the last ten years, it is safe to say, advances in OI research have saved more lives than antiretrovirals. While that may be changing, we have only short-term data on new antiretroviral regimens, and the likelihood is that all too many people will eventually progress, as before, only over a longer period of time. This report is dedicated to all the treatment activists who have struggled before, and to those who will follow.

It is seldom recognized how great the benefit is for people with other life-threatening diseases because of AIDS treatment activism. Every year hundreds of thousands of people without HIV will take drugs which were tested and approved faster because of AIDS activists. Eventually, everyone will develop a disease -- be it cancer, iatrogenic infection or autoimmune disorder -- whose treatment outlook may be better because of research done on people with HIV.

OIs in patients with HIV are the acquired immunodeficiency syndrome(s) caused by HIV-inflicted immune damage. As an HIV-positive person becomes increasingly immune deficient, he or she is open to a myriad of viral, bacterial, fungal and protozoal infections. Many OIs can be treated, yet a person remains at risk for relapse or a cascade of different OIs, which may cause suffering or death. No HIV-positive person is immune from any OIs, nor will he or she be able to tell which will strike first. Thus, the clinical spectrum of OI research -- manifestations, diagnosis, treatment, and prevention -- should be of concern to all HIV-positive individuals, their physicians and care partners.

Many of the common OIs, Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV) retinitis, Mycobacterium avium complex (MAC), and candidiasis, are not new to AIDS; they have often affected individuals with primary immunodeficiency syndromes, iatrogenically immunosuppressed patients, organ transplant patients and those immunosuppressed due to cytotoxic chemotherapy regimens used to treat cancer. Research on treatment for many of these OIs began in the 1960s and 1970s with the advent of many new antibiotics. For example, it was Walter Hughes who discovered that trimethoprim-sulfamethoxazole (Bactrim) could treat and prevent PCP in childhood leukemia. Likewise, fluconazole was originally developed and tested in cancer patients to treat their various fungal infections.

This OI report, however, is AIDS-specific, and attempts to detail what we know and what we don't know about the epidemiology, pathogenesis, diagnosis, treatment and prevention of approximately sixteen viral, bacterial, fungal and protozoal infections. This very large report -- which will grow still longer in Version 2.0 to include recent developments, missing OIs, policy recommendations, and future prospects, is the work of six dedicated members of TAG's OI Committee who have spent over a year researching, writing and editing articles on their respective pathogens. All of us were gifted to have prominent AIDS researchers -- many of whom conducted the major OI studies detailed in the report -- as our advisors and editors.

We have attempted to write this report for multiple audiences, including patients, primary care physicians, researchers, industry representatives, and government officials. Herein lies a detailed history of, and unanswered questions about, our most commonly used drugs (i.e, Bactrim, ganciclovir, clarithromycin, fluconazole), as well as practical information for people living with HIV, which may help them understand their infection and give them the tools they need to stay healthy and live longer by making informed treatment decisions. Broader use of PCP and MAC prophylaxis alone will save tens of thousands of lives.

It should be noted that almost all of the data discussed are from studies completed well before the advent of the protease inhibitors. With combination therapy antiretroviral therapy becoming the standard of care in 1997, we have no data on the current epidemiology or clinical course of our major OIs. Nonetheless, OIs are not simply "going away." For many, protease inhibitors will not rebuild a devastated immune system. We still need basic and clinical research on a majority of OIs so that we might better understand their pathogenesis and treat or prevent them successfully with less-toxic agents, as well as manage emerging drug-resistant organisms. This will take a concentrated effort on the part of industry, physicians, government and the HIV community alike if we are to challenge and ultimately overcome the syndrome of AIDS.

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