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Recombinant Interferon-1b as Adjunctive Therapy for AIDS-Related Acute Cryptococcal Meningitis
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Journal of Infectious Diseases 2004;189:2185-2191
Peter G. Pappas,1 Beatriz Bustamante,8 Eduardo Ticona,9 Richard J. Hamill,2 Philip C. Johnson,3 Annette Reboli,4 Judith Aberg,5 Rodrigo Hasbun,6 and Henry H. Hsu7
1University of Alabama School of Medicine, Birmingham; 2Baylor University School of Medicine and Houston VA Medical Center, and 3University of Texas at Houston Medical Center, Houston; 4University of Medicine and Dentistry of New Jersey, Cooper Hospital, Camden; 5Washington University School of Medicine, St. Louis, Missouri; 6Tulane University School of Medicine, New Orleans, Louisiana; 7InterMune Pharmaceuticals, Brisbane, California; 8Universidad Peruana Cayetano Heredia, and 9Hospital dos de Mayo, Lima, Peru
ABSTRACT
We conducted a phase 2, double-blind, placebo-controlled study to evaluate the safety and antifungal activity of adjuvant recombinant interferon (rIFN)-g1b (recombinant interferon-gamma 1B) in patients with acquired immunodeficiency syndrome and acute cryptococcal meningitis.
Patients received 100 or 200 ug of rIFN-1b or placebo, thrice weekly for 10 weeks, plus standard therapy with intravenous amphotericin B, with or without flucytosine, followed by therapy with fluconazole. End points included conversion of cerebrospinal fluid fungal cultures from positive to negative at 2 weeks, resolution of symptoms, and survival.
Among 75 patients, 2-week culture conversion occurred in 13% of placebo recipients, 36% of rIFN-1b (100 g) recipients, and 32% of rIFN-g1b (200 g) recipients. There was a trend toward improved combined mycologic and clinical success in rIFN-g1b recipients (26% vs. 8%; P = .078). Therapy with rIFN-1b was well tolerated, and there was no apparent influence on serial CD4 cell counts and human immunodeficiency virus load measurements. Adjunctive therapy with rIFN-g1b holds promise for patients with acute cryptococcal meningitis and warrants further study.
INTRODUCTION
Cryptococcus neoformans is one of the most common causes of central nervous system (CNS) infection among patients with HIV and is the most common cause of fungal meningitis worldwide. Although the incidence of cryptococcal meningitis has declined among patients with AIDS in the developed world, because of ready access to highly active antiretroviral therapy (HAART), acute cryptococcal disease as a presenting manifestation of HIV infection still occurs and can lead to significant morbidity, even with therapy. In the developing world, cryptococcosis continues to cause significant morbidity and mortality and ranks among the 3 most common opportunistic pathogens in HIV-positive patients. Despite advances in antifungal therapy, at least one-third of patients with cryptococcal meningitis who receive appropriate antifungal therapy will have mycologic and/or clinical failure, defined as persistently positive cerebrospinal fluid (CSF) cultures, persistent clinical symptoms and signs, or death due to the infection. New therapeutic approaches could significantly reduce the morbidity and mortality of this potentially devastating infection.
Interferon (IFN) is an endogenous cytokine with diverse biologically beneficial properties, including immunomodulatory activities and enhancement of Th1 responsiveness by stimulating several host effector cells, such as macrophages, monocytes, NK cells, and neutrophils. IFN-g plays a key role in host defense against fungal, viral, parasitic, mycobacterial, and certain intracellular bacterial microorganisms. IFN- has been effective as adjunctive therapy for patients with refractory mycobacterial infections, including Hansen disease and leishmaniasis.
In 1990, recombinant IFN-1b (rIFN-g1b; Actimmune; InterMune) was approved in the United States for use in patients with chronic granulomatous disease, to reduce the frequency and severity of serious infections. More recently, rIFN-1b has been studied in vitro and in animal models of cryptococcosis, as adjunctive therapy to conventional antifungal agents, and has yielded promising results. In addition, there have been anecdotal reports of efficacy in patients with invasive fungal infection. On the basis of these encouraging results, we conducted a phase 2 clinical trial to determine the safety and clinical and mycologic activity of subcutaneously (sc) administered rIFN-1b, in conjunction with standard antifungal therapy, for treatment of acute cryptococcal meningitis in patients with AIDS.
AUTHOR'S DISCUSSION
To our knowledge, the present study is the first randomized, controlled clinical trial to examine the use of rIFN-1b as adjunctive therapy for a serious invasive fungal infection. Although the number of patients in this pilot study was too small to demonstrate a statistically significant difference in the primary efficacy end point (i.e., clearance of C. neoformans from CSF at 2 weeks), the results did show a trend toward more-rapid sterilization of CSF in the rIFN-g1b recipients, compared with placebo recipients. Furthermore, at the end of the study, CSF CrAg titers had decreased by 69-fold and 54-fold in the rIFN-g1b (100 ug) and rIFN-g1b (200 ug) recipients, respectively, versus 24-fold in the placebo recipients.
There was no dose response of lower-dose versus higher-dose rIFN-g1b, with respect to CSF fungal culture conversion (36% in the 100 ug group and 32% in the 200 ug group). At week 10, the culture conversion rate and survival were similar across the 3 therapy groups. However, there was a trend toward a greater proportion of patients showing improved combined mycologic-clinical outcome at both weeks 2 and 10 in the rIFN-g1b therapy arms, compared with the placebo arm.
The clinical significance of early culture conversion among patients with cryptococcosis and AIDS is not fully delineated, but some investigators have observed that persistently positive CSF fungal cultures at 2 weeks predict culture positivity at 10 weeks and poorer clinical outcome. Among HIV-negative patients with CNS cryptococcosis, persistently positive CSF fungal cultures are associated with a significantly worse clinical outcome. Thus, in both HIV-positive and -negative patients, early aggressive therapy leading to more-rapid CSF fungal culture conversion is prudent and could have a beneficial effect on the long-term clinical course of CNS cryptococcosis.
It is unclear why overall rates of culture negativity at 2 weeks in the present study (13% for placebo, 36% for rIFN-g1b [100 ug], and 32% for rIFN-g1b [200 ug] recipients) were lower, compared with results from other published clinical trials. Culture negativity rates of 51%60% after 2 weeks of induction therapy with amphotericin B, with or without flucytosine, were noted among US patients participating in a randomized trial of therapy for AIDS-associated acute cryptococcal meningitis. In the present study, only 26% of Peruvian patients were culture negative at 2 weeks, and all of these patients were treated with amphotericin B alone. This low conversion rate could reflect differences in therapeutic approach (i.e., no exposure to 5-flucytosine). However, in the present study, only 33% of a small number of US patients were culture negative at 2 weeks. A more likely explanation is that Peruvian patients had more-advanced cryptococcosis, as suggested by significantly higher CSF CrAg titers, twice the rate of cryptococcemia, higher initial CSF opening pressures, and more-frequent headaches. Each of these characteristics suggests more-advanced disease at the time of presentation. Access to HAART in the 2 populations probably had no effect on overall mycologic and clinical outcome in the present study, because patients began receiving HAART only several weeks after initiation of study therapy, and there were no observed differences in outcome between patients who did and those who did not receive HAART during the study period. Moreover, when assessed at 10 weeks, the Peruvian patients showed responses to therapy that were comparable to those expected for a US population.
rIFN-g1b was well tolerated and led to few dose-limiting adverse events, consistent with the results of previous studies. Only 11 patients were withdrawn from the study because of significant adverse events, and those prematurely withdrawn were distributed evenly among the 3 study arms. The most commonly reported adverse events were fever, malaise, myalgias, and a flulike illness, each of which appeared to increase in frequency with the higher dose of rIFN-1b. Hematologic disorders, especially anemia, were also more common in the rIFN-g1b (200 ug) group. Concerns about the potential negative influence of rIFN-g1b on the clinical course of HIV disease were not supported by evidence from the present study; indeed, quantitative HIV loads were generally lower in the rIFN-g recipients at 10 weeks, compared with baseline, and total CD4 cell counts and CD4 : CD8 ratios did not vary between therapy groups. Efficacy measures were similar between the 2 rIFN-1b arms, but, because of the trend toward more adverse events with the higher dose, 100 ug of rIFN-1b appears to be the most reasonable dose for further study.
Data from the present trial suggest that rIFN-g1b may induce more-rapid early sterilization of CSF among patients with HIV-associated cryptococcal meningitis and may result in better combined mycologic and clinical outcome. rIFN-1b is well tolerated and usually not associated with dose-limiting toxicity in this setting. No adverse events of therapy on key parameters of HIV infection were seen. These data support the concept that, in patients with invasive fungal infection, augmentation of the host immune response through the administration of adjunctive immunotherapy may have therapeutic potential. This approach may be especially important as the population of individuals at risk for invasive fungal infection expands to include not only patients with AIDS but also patients with hematologic malignancies, long-term glucocorticosteroid recipients, and others with underlying disorders associated with significant immune dysfunction.
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