By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: A retrospective cohort study found that patients treated with voriconazole had increased mortality during the first 42 days after the start of treatment compared to patients who received itraconazole.

SOURCE: Hendrix MJ, Larson L, Rauseo AM, et al. Voriconazole versus itraconazole for the initial and step-down treatment of histoplasmosis: A retrospective cohort. Clin Infect Dis 2020; Oct 18:ciaa1555. doi: 10.1093/cid/ciaa1555. [Online ahead of print].

Currently, the Infectious Diseases Society of America (IDSA) guidelines for the management of histoplasmosis recommend itraconazole for mild disease or as step-down therapy following amphotericin B. Voriconazole has emerged as an attractive alternative agent given its in vitro activity against Histoplasma capsulatum and better tolerability than itraconazole. Because no comparative data had been published, Hendrix and colleagues sought to determine whether there was any difference in mortality between voriconazole and itraconazole in the treatment of histoplasmosis.

The study was a single-center retrospective cohort of adults 18 years of age or older diagnosed with histoplasmosis at Barnes-Jewish Hospital in St. Louis between Jan. 1, 2002, and Dec. 31, 2017. Patients were included in the study if they had either a positive Histoplasma antigen, microbiological isolation of H. capsulatum from any source, coding for International Classification of Diseases (ICD) codes for Histoplasma infection, or a positive Histoplasma antibody. Patients were classified in two groups based on the azole initially prescribed for treatment, either voriconazole or itraconazole. Those who received amphotericin B before starting an azole were classified based on the first azole that was given as step-down therapy.

There were 194 patients included in the study. Of these, 175 (90.2%) received itraconazole and 19 (9.8%) received voriconazole. The median age was 48 years, the majority were white (74.7%), and most (60%) were immunocompromised. Also, 106 (54.6%) patients had disseminated disease, 133 (68.6%) had constitutional symptoms, 13 (70.6%) had respiratory symptoms, 81 (41.8%) had gastrointestinal symptoms, and 26 (13.4%) had skin manifestations. Immunocompromised patients were distributed equally between the two groups. There was no difference in mortality for patients started on amphotericin B before they switched to either voriconazole or itraconazole (27.3% vs. 24.4%, respectively; odds ratio [OR] 1.16; 95% confidence interval [CI], 0.28-4.83; P = 0.83). Furthermore, there was no statistical difference in the need for amphotericin B re-initiation within three to 90 days of beginning voriconazole or itraconazole (15.8% vs. 6.8%, respectively; OR 1.46 [95% CI, 0.38-5.69]; P = 0.58).

Forty-seven (24.2%) patients died within 180 days after the start of azole therapy, with 41 (23.4%) in the itraconazole group and six (31.6%) in the voriconazole group. After controlling for disseminated disease, the survival analysis found a significant association between voriconazole and an increase in mortality early in the treatment course (0 to 42 days) (hazard ratio [HR] 4.3 [95% CI, 1.3-13.9]; P = 0.015) that was not found later in the course of therapy (43 to 180 days) (HR 0.0 [95% CI, 0.0-99.0]; P = 0.89). Disseminated disease was an independent predictor of mortality (HR 3.1 [95% CI, 1.1-8.4]; P = 0.026). Finally, the year of diagnosis had no impact on any of the primary outcomes.

COMMENTARY

This is the first published study to compare itraconazole and voriconazole for the treatment of histoplasmosis. Itraconazole has been the standard therapy for most cases of histoplasmosis for many years. However, voriconazole has been gaining interest recently because of its better absorption and tolerability, especially with long-term use, compared to itraconazole. But the study by Hendrix and colleagues should raise concern about using voriconazole to treat histoplasmosis. Notably, the mortality rate for the patients who received voriconazole as the initial azole treatment was 4.3 times higher during the first 42 days. This suggests that voriconazole might be inferior to itraconazole for histoplasmosis. The mortality rate was similar between the two groups after 42 days. However, there were very few events between days 42 and 180, such that the cohort was not powered to be able to detect a large difference.

These findings should be viewed as preliminary and, ideally, should be replicated in a randomized controlled trial that compares the two drugs head-to-head. Until such data are available, itraconazole should remain the preferred azole. Similar data would be useful for the newer azoles (e.g., posaconazole and isavuconazole) as well. The authors hypothesized that the poorer outcome with voriconazole was due to the induction of the Y136F mutation, which leads to a four-fold increase in voriconazole minimum inhibitory concentrations (MICs).

The study had a few limitations. Most importantly, the size of the voriconazole group was small, thus lowering the overall power of the study. It was conducted at a single academic medical center in the midwestern United States, so the results might not be generalizable to other settings and populations. Finally, the findings may have been influenced by unmeasured confounding factors as a result of the retrospective design.

Hendrix and colleagues have provided some useful information for clinicians deciding about oral therapy for histoplasmosis. Other questions, such as whether voriconazole is a safe option after 42 days and whether the newer azoles, which are better tolerated than itraconazole, are just as effective, remain to be answered.