AIDS Commentary Research Articles

Guide to major clinical trials of antiretroviral therapy in human immunodeficiency virus-infected patients: protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors.

In this AIDS Commentary, Drs. Tavel, Miller, and Masur of the National Institutes of Health present this compilation of clinical trials of antiretroviral therapy in HIV-infected patients, which complements two similar reviews published as AIDS Commentaries in Clinical Infectious Diseases (1995;20:1145–51 and 1996;23:15–27). Whereas the previous compilations focused on trials of nucleoside analogues, this review is based on published articles and abstracts of clinical trials of protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors in HIV-infected patients. The intent is to present a thorough, but not necessarily exhaustive, review of studies that have shaped our principles of antiretroviral therapy. Preference is given to clinical endpoint trials, proof-of-concept trials that have influenced the standard of care for HIV treatment, double-blind, randomized trials, and large trials with long-term patient followup. Smaller trials that address important questions are also included.

Refractory mucosal candidiasis in patients with human immunodeficiency virus infection.

Difficult-to-manage mucosal candidal infection has been a hallmark of individuals with advanced infection due to human immunodeficiency virus type 1. In this AIDS Commentary, Drs. Fichtenbaum and Powderly comprehensively review the literature and their experience with refractory candidiasis in such patients. Of interest is their delineation of resistance, a lack of susceptibility to an antifungal agent in vitro among patients with refractory or clinically unresponsive disease. These authors believe that the establishment of resistance should be based upon standards established by the National Committee on Clinical Laboratory Standards, which they propose to define as a failure to respond to systematic therapy with specific doses of itraconazole, fluconazole, or parenterally or orally administered amphotericin B within 14 days. There have been many definitions of "refractory candidiasis," and the one proposed by these authors will be debated; however, this definition has the advantage of establishing a standard by which to judge the efficacy of their proposed algorithm for the treatment of persistent or refractory oropharyngeal candidal infections. Drs. Fichtenbaum and Powderly have performed a useful service in their attempt to bring coherence to the management of this common and often vexing problem.

Drug interactions in patients infected with human immunodeficiency virus.

Patients with AIDS who are receiving optimal medical care, including combination therapy with antiretroviral agents and more effective prophylaxis and therapy for opportunistic infections and neoplasms, are surviving longer. However, the potential for drug interactions in these patients is increased because many of the currently used antibiotics and antiviral agents have profound effects on the hepatic cytochrome P-450 enzyme system, on renal tubular function, and on bone marrow function. In this AIDS Commentary, Dr. Piscitelli and colleagues have succinctly reviewed the current state of our knowledge regarding the potential for additive or synergistic drug interactions that can result in enhanced toxicity or, alternatively, augmented therapeutic benefit. Information on these interactions will become more important as more intensive and effective therapy becomes available for persons with far-advanced infection due to human immunodeficiency virus type 1.

Prevention of perinatal transmission of human immunodeficiency virus: a progress report 2 years after completion of AIDS Clinical Trials Group trial 076.

In this AIDS commentary, Dr. Wilfert has reviewed the American experience with vertical transmission of human immunodeficiency virus type 1 (HIV-1) since the closing of the 076 trial performed by the AIDS Clinical Trials Group in February 1994. The news generally is good; the rate of transmission from mother to child in nonstudy situations has been reduced when counseling and therapy are offered to pregnant women. As Dr. Wilfert emphasizes, the mechanism of the beneficial effect remains to be elucidated. More important, the resources required to insure that women have access to counseling and care need to be secured. In addition to these issues discussed by Dr. Wilfert, questions that need to be addressed include the efficacy and safety of more-potent antiretroviral agents or combinations in further reducing the risk of transmission, the optimal intervention for women who become pregnant while receiving antiretroviral therapy, the optimal postpartum management for women, and the most-effective treatment strategy for children born to infected women. The newborn child who is infected in spite of treatment of the mother potentially could receive great benefit from aggressive therapy designed to reduce the rate of viral replication and the selection of drug-resistant HIV-1. Finally, inexpensive and user-friendly methods of reducing the rate of vertical transmission in developing countries are urgently needed. Progress in reducing the prevalence of pediatric HIV-1 infection transmitted by mothers, the most common source of this infection in children, has been made, but further research and effort to insure access to care and answers to unsolved problems are necessary.

Early initiation of antiretroviral therapy for infection with human immunodeficiency virus: considerations in 1996.

In this AIDS Commentary, Dr. Nadler provides a rationale for early initiation of antiretroviral therapy in patients infected with human immunodeficiency virus (HIV). Although no definitive clinical trials have been published that are relevant to the question of whether early treatment will produce long-term benefit, many experienced investigators believe that early reduction in the level of viral replication will effectively prolong clinical latency of the infection and immunologic stability. A second question is that of the best combination of antiretroviral agents to be used for early treatment of HIV infection. A third issue is whether initial therapy should be continued until there is evidence of virological, immunologic, or clinical progression of disease, or alternatively, whether a course of induction therapy with the most potent combination of agents should be followed by a treatment-free period or by less-aggressive maintenance therapy. These issue will continue to be debated over the next several months. Dr. Nadler's review is timely, and it is a useful statement of the questions to be answered regarding treatment of early HIV infection.

Antiretroviral Therapy: Reference Guide to Major Clinical Trials in Patients Infected with Human Immunodeficiency Virus

Physicians have difficulty keeping up with the rapidly evolving field of antiretroviral chemotherapy. Dr. Henry Masur's and Dr. Clifford Lane's group at the National Institutes of Health has maintained an up-to-date file, in tabular form, of the results of clinical trials. The tables are based on published articles and abstracts and contain each study's stated conclusions and subjective comments based upon the group's interpretation of the results of each trial. Clinical Infectious Diseases plans to publish an update of these summary tables annually as an AIDS Commentary. Our goal is to aid physicians in providing care to individuals infected with HIV type 1. -John P. Phair

Cytomegalovirus infections of the nervous system in patients with AIDS.

Retinitis due to cytomegalovirus (CMV) infection is a widely recognized complication of advanced disease due to human immunodeficiency virus type 1 (HIV-1). Less appreciated are other neurological manifestations of CMV infection in persons with AIDS. Dr. J. Allen McCutchan has comprehensively reviewed the various clinical presentations of CMV neurological disease as well as the methods of diagnosis, the neuropharmacology of available antiviral agents, the results of therapy, and the potential for prevention of these sequela of advanced immunosuppression. As the ability to prevent diseases such as Pneumocystis carinii pneumonia, bacteremia secondary to Mycobacterium avium, tuberculosis, serious fungal infections, and toxoplasma cerebritis is increasing, physicians must now treat more HIV-1-infected persons with CMV disease. This AIDS Commentary provides a timely update of the current state of our knowledge regarding this serious problem.

AIDS, tuberculosis, and the health care worker.

The combination of tuberculosis and infection with the human immunodeficiency virus type-1 (HIV-1) poses an increased hazard to health care workers. In this AIDS Commentary, Dr. Kent Sepkowitz of Memorial Sloan-Kettering Cancer Center and New York Hospital-Cornell Medical Center reviews the current state of our knowledge with regard to the risk to health care workers of infection and active disease due to Mycobacterium tuberculosis, in the setting of HIV-1 infection and in the absence of infection with this virus. The goal of achieving complete protection from tuberculosis for persons working in hospitals and clinic will remain elusive until the rapid diagnosis of pulmonary tuberculosis is possible. Standard infection control measures have been documented to decrease the hazard to nurses, physicians, and other health care personnel. As physicians, it is our responsibility to insure that these measures are used effectively. Evaluation of unproven interventions is badly needed, as premature implementation of these often-expensive measures can result in poorer patient care, a false sense of security among health care personnel, and further strain on the resources to be devoted to inpatient care in the future. Dr. Sepkowitz has raised a number of provocative issues that deserve wide and rigorous discussion.

Mandatory screening of pregnant women for the human immunodeficiency virus.

In this AIDS Commentary, Dr. Catherine Wilfert addresses the issue of vertical transmission of the human immunodeficiency virus type 1 (HIV-1). She reviews the results of the recently completed trial conducted by the AIDS Clinical Trials Group that evaluated the effectiveness of administering zidovudine to pregnant women in reducing the incidence of vertical transmission. In view of the success of this trial, Dr. Wilfert addresses the problem of the efficacy of voluntary counseling and testing of pregnant women. Identification and treatment of HIV-1 infected women could potentially reduce the incidence of pediatric HIV-1 infection and increase the number of women receiving appropriate therapy. She makes the point that legislative mandates have been necessary to produce rates of childhood immunization that are effective in reducing the occurrence of vaccine-preventable diseases. This suggests that such mandates are an option to consider in the effort to control vertical transmission of HIV-1 infection. Her cost-benefit analysis indicates that universal screening of pregnant women for HIV infection would result in enormous overall savings for the health care system. Obviously, making the testing of pregnant women mandatory raises a number of difficult issues and is controversial. Dr. Wilfert has provided a service by raising this issue; further discussion is needed.

Antiretroviral therapy for infection due to human immunodeficiency virus in children.

Infection with human immunodeficiency virus type 1 (HIV-1) in children presents problems that greatly differ from those seen in adults. The great majority of children are infected either during gestation or at the time of birth. As Drs. Pizzo and Wilfert note in their AIDS Commentary, this results in rapid development of immunosuppression and clinical manifestations in patients whose immune systems are in the process of maturing. Thus, a thorough understanding of the pharmacokinetics of antiretroviral agents in infants and small children is required. This AIDS Commentary provides a comprehensive review of the current state of our knowledge and possible future directions for the management of HIV-1 infection in this young population

Combination therapy for infection due to human immunodeficiency virus type 1.

The preliminary results of the Concorde trial demonstrated the transient clinical benefit of monotherapy with zidovudine (AZT) in asymptomatic persons infected with human immunodeficiency virus type 1 (HIV-1). This result, which has been widely disseminated and discussed, was predictable given the previous demonstration of the development of resistance to AZT in isolates from individuals receiving prolonged treatment with the drug and given the finding that didanosine (ddI) is more efficacious than continued therapy with AZT in individuals who have received > or = 6 months of AZT monotherapy. On the basis of these findings, interest in combinations of antiretroviral agents has continued to grow. Many in vitro studies of nucleoside and nonnucleoside inhibitors of reverse transcriptase combined with interferon-alpha or inhibitors of protease have been published. In addition, numerous clinical trials of various combinations have been completed or are under way. Dr. Martin Hirsch and his colleagues at the Massachusetts General Hospital have been among the leaders of this effort. He and Dr. Angela Caliendo review, in this AIDS Commentary, the current state of our knowledge regarding the potential utility of combination therapy for infection with HIV-1.

Cryptococcal meningitis and AIDS.

Dr. William G. Powderly provides a comprehensive review of the state of our knowledge regarding cryptococcal infection in persons with infection due to human immunodeficiency virus type 1. The introduction of fluconazole and itraconazole increased insight into prognostic factors affecting these patients. The need to suppress this fungal infection in individuals with impaired immunity has greatly altered the management of cryptococcal meningitis; therapy for this condition was established by the landmark study conducted by the Mycosis Study Group in 1979 (Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in treatment of cryptococcal meningitis. N Engl J Med 1979;301:126-31). In this AIDS commentary Dr. Powderly clearly outlines the progress made through clinical investigations and the problems that remain to be resolved.

Mycobacterium avium complex infection and AIDS: advances in theory and practice.

The role of disseminated infection with the Mycobacterium avium complex (MAC) in the natural history of AIDS has been controversial. It is now clear that this complication of immunosuppression induced by human immunodeficiency virus type 1 (HIV-1) has a major impact upon the quality of life and duration of survival of patients with advanced HIV-1 infection. Progress has been made in our understanding of the bacteriology, pathogenesis, prevention, and treatment of MAC infection. Drs. Constance Benson and Jerrold Ellner (of Rush Medical College in Chicago and Case Western Reserve University in Cleveland, respectively) have led the effort by the AIDS Clinical Trials Group to develop new methods of managing this serious complication of advanced HIV-1 infection. In this AIDS commentary they review our current knowledge of MAC organisms and the clinical problems resulting from infection with these mycobacteria.

Cryptosporidiosis in patients infected with the human immunodeficiency virus.

Infection caused by Cryptosporidium species has proved to be one of the most taxing and frustrating conditions faced by clinicians caring for patients with AIDS. Unfortunately, this unique organism, which was identified as a human pathogen only shortly before the AIDS epidemic began to manifest itself, has received only minimal attention during the past decade. Dr. Carolyn Petersen, an assistant professor of medicine at the University of California, San Francisco, and a member of the Division of Infectious Diseases at San Francisco General Hospital, is a molecular parasitologist whose investigative career is focused on elucidating the biology of Cryptosporidium species. In this AIDS Commentary Dr. Petersen provides an update on recent developments in this field.

AIDS Enteropathy

Chronic diarrhea is one of the hallmarks of advanced human immunodeficiency virus (HIV) disease. The symptoms of this complication are troublesome, have a significant impact on the patient's quality of life, and in severe cases can lead to extreme abnormalities in fluids and electrolytes and can even cause death. The workup for AIDS-associated diarrhea is often frustrating and frequently unrewarding. However, during the last 10 years, much has been learned about the causes of diarrhea; while treatment is still often ineffective, some advances have been made. Dr. John G. Bartlett and his colleagues in the Department of Medicine at Johns Hopkins University School of Medicine have been responsible for many of these advances. In this AIDS Commentary, these experts discuss recent advances that have enhanced our understanding of chronic diarrhea in HIV-infected persons and offer their recommendations for the most efficient and effective approach to managing these patients.

Diagnosis of infection with the human immunodeficiency virus.

The development and subsequent widespread use of accurate, sensitive, and relatively inexpensive diagnostic tests for infection with the human immunodeficiency virus (HIV) have been critically important in mapping the spread of the virus and managing HIV-infected individuals. Although the ELISA (for screening) and western blot (confirmatory test) techniques have, for the most part, fulfilled these criteria, interpretation of results of these tests is not always as straightforward as would be ideal. For example, what is the significance of an indeterminate western blot? How many times should the test be repeated? When can the patient be told he/she is truly HIV antibody negative? In this AIDS Commentary, Drs. John P. Phair and Steven Wolinsky of the Department of Medicine at Northwestern University Medical School address these questions and present their thoughts on these timely and extremely important issues.

Management of occupational exposures to bloodborne pathogens: hepatitis B virus, hepatitis C virus, and human immunodeficiency virus.

Being a health care worker in today's world is not without risks. Accidental exposure to blood carries with it a definite risk of transmission of infection by various bloodborne pathogens, especially the hepatitis B, hepatitis C, and human immunodeficiency viruses. While infectious disease specialists, hospital epidemiologists, and infection control clinicians can develop many important strategies to reduce this risk--aggressive training, utilization of safer needles, identification of high-risk activities, and efficient disposal systems--their overriding responsibility is to design and implement a comprehensive plan for expeditiously and effectively dealing with accidental exposures when they occur. Among other things, the plan must address a number of key issues, including testing, administering postexposure prophylaxis, providing short- and long-term follow-up care, and, particularly, counseling for helping the health care worker deal with the tremendous anxiety associated with the injury. Drs. Julie L. Gerberding of the University of California, San Francisco, and San Francisco General Hospital and David K. Henderson of the National Institutes of Health and the Warren G. Magnuson Clinical Center have both made significant contributions in this area; in this month's AIDS Commentary they discuss the essential elements of such a plan.

Prophylaxis for Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus.

Following the initial observation by Dr. Margaret Fischl that trimethoprim-sulfamethoxazole can prevent Pneumocystis carinii infection in patients with Kaposi's sarcoma, initiating prophylaxis for pneumocystic infection in all patients with less than 200 CD4+ cells/mm3 has become accepted practice. This prophylactic intervention has been found not only to reduce the development of pneumonia due to P. carinii but also to prolong life. Drs. Henry Masur and Joseph A. Kovacs first reviewed prophylaxis for P. carinii pneumonia in patients infected with the human immunodeficiency virus for the AIDS Commentary 3 years ago. They have updated that initial review for this AIDS Commentary, placing currently available information into concise clinical perspective and detailing a rational plan for the clinician to follow based on results of recent studies.

Interactions and toxicities of drugs used in patients with AIDS.

As clinicians have come to realize, patients who have AIDS are uniquely predisposed to drug-associated toxic effects and allergic reactions. In San Francisco General Hospital's first clinical trial involving patients with pneumonia due to Pneumocystis carinii, only one-third of all patients who were treated initially with either trimethoprim-sulfamethoxazole or pentamidine were able to complete the 3-week course. Because of drug-related toxic effects, most patients required an alteration in therapy. In addition, with the multi-drug approach to management of infection due to human immunodeficiency virus (HIV) and its complications, drug-drug interactions commonly complicate the pharmacokinetics and toxicities of the therapeutic agents used. Both factors make caring for HIV-infected patients a complicated and perplexing process for the clinician. We've invited Drs. Belle Lee and Sharon Safrin of the University of California, San Francisco School of Medicine to contribute the AIDS Commentary this month. Drs. Lee and Safrin are active investigators in the field of pharmacokinetics and conduct clinical trials of agents used in the treatment of patients who have AIDS. In this commentary, they review what is known about the complexities involved in treating patients with AIDS and offer some practical suggestions for management.

CD4+ lymphocyte cell enumeration for prediction of clinical course of human immunodeficiency virus disease: a review.

Over the last 10 years the appreciation of the full breadth of the spectrum of human immunodeficiency virus (HIV) infection has gradually increased; it is now known that AIDS represents merely the end stage of this progressive infectious process. The surrogate marker that most closely correlates with the stage of HIV infection is the CD4+, or T helper, cell count. Because this count is relied on in making important therapeutic decisions, it is of paramount importance that clinicians be cognizant of and fully understand the multiple factors that can influence this parameter: the variability of the count from day to day and from morning to night, the influence of intercurrent viral infections, the influence of drugs. In this AIDS Commentary, Sten H. Vermund and his colleagues at the National Institutes of Health discuss these issues and put the CD4+ cell count into a lucid and practical clinical perspective.