Early vs. Delayed Initiation of HAART in Patients with Cryptococcal Meningitis

Abstract & Commentary

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.

Dr. Winslow serves as a consultant for Siemens Diagnostics and is on the speaker's bureau for GSK and Cubist.

Synopsis: Fifty-four antiretroviral-naïve HIV-infected patients with first-episode cryptococcal meningitis (CM) were randomized to early (within 72 hours) vs. delayed (10 weeks) antiretroviral therapy (ART) following diagnosis and initiation of treatment for cryptococcosis. Three-year mortality was 88% in the early ART vs. 54% in the delayed ART groups.

Source: Makadzange AT, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-Saharan Africa. Clin Infect Dis. 2010; 50:1532-1538.

This prospective, open-label, randomized clinical trial was conducted at a large tertiary teaching hospital in Harare, Zimbabwe, in adult ART-naïve HIV-infected patients who received a first CM diagnosis. Patients were randomized to early ART (within 72 hours of CM diagnosis and initiation of antifungal therapy) vs. delayed ART (after 10 weeks of antifungal treatment). Antifungal therapy was fluconazole dosed at 800 mg daily, and the ART regimen was d4T, 3TC, and nevirapine (NVP). Patients were followed for three years. Twenty-eight patients were enrolled in the early ART arm and 26 in the delayed ART arm. The overall mortality at three years was 88% in the early vs. 54% in the delayed ART arms (p < .006). Median duration of survival was 28 days in the early vs. 637 days in the delayed treatment arms (adjusted hazard ratio 2.85). The study was terminated early by the data safety monitoring committee.

Commentary

This is an interesting study. While it suggests that caution be exercised in early initiation of ART in the setting of CM, the conclusions of the study may not be directly applicable to the management of CM in the developed world. Some of the limitations of this study include: 1) small sample size; 2) extremely early initiation of ART (72 hours vs. the more usual 1-2 weeks considered "early" in the United States); 3) use of fluconazole monotherapy rather than combination amphotericin B + 5-FC (as used for the initial two weeks of treatment in the United States); and 4) likely poor control of increased intracranial pressure in most of the patients.

It is of note that patients in this study were generally discharged from the hospital within seven days, and median follow-up time was only 27 days. Mortality typically occurred early, with most deaths occurring in both the early and delayed ART groups less than two weeks after enrollment. Causes of deaths were generally not known with certainty; autopsies were seldom performed. However, the authors speculate that immune reconstitution inflammatory syndrome (IRIS) may have been the most common cause of death in the early ART group.

I believe that the jury is still out on whether early institution of ART in the setting of CM is a bad idea in the developed world where increased intracranial pressure can be adequately managed. A similar prospective, randomized trial of early vs. delayed ART in patients with CM should be conducted in the developed world. My own anecdotal experience in managing about a dozen patients over the last seven years with CM in the setting of AIDS, in all of whom I started ARVs within 2-3 weeks of initiating antifungal therapy, has been positive. However, I treated all of these patients with two weeks of initial amphotericin B + 5-FC. In the two patients who did develop increased intracranial pressure (likely related to IRIS), I was able to manage this complication fairly easily with frequent LPs and short courses of glucocorticoids.