Cryptococcal Meningitis Study Halted after Early HIV Treatment Linked to Higher Mortality

A study looking at timing of antiretroviral therapy (ART) in people with cryptococcal meningitis was stopped early because patients who started HIV treatment immediately had a higher risk of death than those who waited until a few weeks after starting meningitis treatment.

Research has shown that people with some AIDS-related opportunistic infections -- notably tuberculosis -- and various non-AIDS conditions have better outcomes if they start ART sooner. But data from a Phase 4 study known as COAT found that this is not the case with cryptococcal meningitis, a fungal infection of the membranes surrounding the brain and spinal cord.

Below is an edited excerpt from a National Institute of Allergy and Infectious Diseases bulletin issued May 30, 2012.

HIV Treatment Study in Patients with Cryptococcal Meningitis Ends Enrollment Early

Higher Mortality Rate Found with Early Antiretroviral Therapy

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is ending enrollment in its "Cryptococcal Optimal ART Timing" (COAT) study because of higher mortality rates among participants in one of the two HIV treatment arms.

The Phase IV study began in November 2010. It was evaluating whether HIV-infected participants hospitalized with cryptococcal meningitis (CM) but not yet taking antiretroviral therapy (ART) would improve their chances of survival if they began ART while receiving CM treatment as inpatients compared with the standard practice of beginning ART as outpatients, approximately five weeks after receiving CM treatment.

Two reviews of the COAT trial’s safety and effectiveness data last month by an independent data and safety monitoring board (DSMB) found substantially higher mortality rates among the 87 participants who received early ART compared with the 87 participants who received delayed HIV treatment. For this reason, the DSMB recommended that study enrollment end immediately. As the study’s sponsor, NIAID agreed with the DSMB’s recommendation.

Cryptococcal meningitis is a fungal infection of the brain and spinal cord that annually occurs in an estimated 1 million people worldwide, killing roughly 600,000. It primarily affects people with weakened immune systems, including individuals infected with HIV. In Sub-Saharan Africa, cryptococcal meningitis is a leading cause of death among individuals with HIV/AIDS.

The COAT study, which was being conducted at two sites in Uganda and one in South Africa, was intended to enroll 500 volunteers ages 14 years and older diagnosed with CM and HIV but not yet taking ART to treat HIV. Cryptococcal meningitis treatment consisted of 14 days of the anti-fungal drug amphotericin B followed by fluconazole. Antiretroviral therapy included an efavirenz-based regimen in accordance with national treatment guidelines, The study was slated to end in June 2015.

Participants are being notified of the study’s developments and will continue to be followed by study staff. Treating clinicians are being advised to continue or modify ART for current study participants based on standard of care and medical judgment.

The COAT trial was initiated and is being coordinated by the University of Minnesota’s Clinical and Translational Science Institute in collaboration with NIAID; Mbarara University of Science and Technology-Uganda; the Infectious Diseases Institute/Makerere University-Uganda; and the University of Cape Town-South Africa. The ClinicalTrials.gov identifier for the COAT Trial is NCT01075152.

6/5/12

Source

National Institute of Allergy and Infectious Diseases. HIV Treatment Study in Patients with Cryptococcal Meningitis Ends Enrollment Early. NIAID/NIH Bulletin. May 30, 2012.