Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

Joseph Phan, Mercer University College of Pharmacy

It is estimated that cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year, with the vast majority in sub-Saharan Africa and in South and Southeast Asia. [1] Current guidelines on the management of cryptococcal disease by the Infectious Disease Society of America suggest that the use of glucocorticoids may be beneficial in central nervous system infections in certain settings. [2] A study has been performed to determine whether adjunctive treatment with dexamethasone would improve survival among adults with HIV-associated cryptococcal meningitis. [3]

Title: Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis
Design Double-blind, randomized, placebo-controlled trial; N= 451
Objective To determine whether adjunctive treatment with dexamethasone would improve survival among adults with HIV-associated cryptococcal meningitis
Study Groups Randomized 1:1 with either dexamethasone (n= 224) or placebo (n= 227)
Methods Adult patients were randomized to receive either dexamethasone intravenously at 0.3 mg/kg/day during the first week, and 0.2 mg/kg/day during the second week, followed by oral administration of 0.1 mg/kg/day during the third week, 3 mg/day during the fourth week, 2 mg/day during the fifth week, and 1 mg/day during the sixth week or placebo. Patients received antifungal therapy according to international guidelines for regions in which flucytosine is unavailable.   Induction therapy consisted of amphotericin B deoxycholate at a dose of 1 mg/kg/day and fluconazole at a dose of 800 mg/day for two weeks, followed by consolidation therapy (800 mg of fluconazole/day for eight weeks) and then maintenance therapy (200 mg fluconazole/day). All patients received daily pneumocystis prophylaxis with trimethoprim-sulfamethoxazole.
Duration February 2013 to September 2014
Primary Outcome Measure Survival until 10 weeks after randomization
Baseline Characteristics   Dexamethasone; n (%) Placebo; n (%)
African residence 122 (54) 124 (55)
Asian residence 102 (46) 102 (45)
Male sex 147 (66) 132 (58)
Median age 35 (31 – 41) 35 (30 – 40)
History of intravenous drug use 17 (8) 18 (8)
Median illness duration (days) 14 (7 – 21) 14 (7 – 28)
Results By 6 months, 128 of 224 patients in the dexamethasone group, as compared with 109 of 226 patients in the placebo group, had died. Dexamethasone was associated with a higher risk of death or disability than was placebo at both 10 weeks and 6 months, with odds ratios for a good outcome of 0.42 (95% CI, 0.25 to 0.69; p < 0.001) at 10 weeks and 0.49 (95% CI, 0.31 to 0.77; p = 0.002) at 6 months.
Adverse Events Common Adverse Events: new neurologic event (27%), infection/infestation (21%), gastrointestinal disorder (13%), renal or urinary disorder (10%)
Serious Adverse Events: new AIDS-defining illness (39%), anemia (54%), leukocytopenia (16%), thrombocytopenia (15%), hypercreatinemia (35%), hyperkalemia (48%), hyponatremia (51%)
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions We found compelling evidence that at the dose and regimen used in the study such use was harmful, with significantly increased rates of disability and excess severe adverse events, including infectious episodes and renal, gastrointestinal, and cardiac disorders. The study was stopped early because of consistent evidence of harm across several outcomes. It is highly unlikely that dexamethasone benefits survival in such patients. The consistency of findings across Asian and African populations and all prespecified subgroups strengthens this conclusion.

The researchers hypothesized that the addition of dexamethasone would improve outcomes by reducing intracranial pressure and inflammatory complications. The cerebral spinal fluid opening pressure was seen to decrease more rapidly in patients receiving dexamethasone, but no survival benefit was seen. Because the study was stopped early, recruitment was not sufficient for adequate statistical power to show an effect of dexamethasone on the primary outcome of mortality at six weeks. A shorter duration of dexamethasone might have resulted in a different outcome; however, overall, the effects of dexamethasone seem to be negative. With no effective adjunctive therapy yet identified, improving access to the most effective antifungal treatments, including flucytosine, must remain a global priority.

References

  1. Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009;23:525-530
  1. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010;50:291-322
  1. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med. 2016;374(6):542-54.
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s