ARTICLE IN BRIEF
Amphotericin B, an intravenous anti-fungal agent considered the most effective treatment for cryptococcal meningitis, becomes even more effective when administered with oral flucytosine, or 5-FC, an anti-fungal agent that inhibits fungal DNA, a new study found. But problems remain — in terms of access to the drug and high costs — in areas of the world where it is most needed, such as Africa.
Research published in the April 4 New England Journal of Medicine (NEJM) confirms what has long been assumed — that two drugs commonly used to treat cryptococcal meningitis, a frequently fatal fungal infection of the brain and CNS, work better in combination. Unfortunately, the drugs are expensive, difficult to use, and frequently unobtainable in Africa, where a majority of cases of the disease occur.
Cryptococcal meningitis is an opportunistic infection found primarily among HIV and AIDS patients. It affects about 1 million people a year, with a majority — about 600,000 — in sub-Saharan Africa, where the disease now rivals tuberculosis as a cause of death.
Amphotericin B, an intravenous anti-fungal agent developed in the 1950s and considered the most effective treatment for cryptococcal meningitis, becomes even more effective when administered with oral flucytosine, or 5-FC, an anti-fungal agent also developed in the 1950s that inhibits fungal DNA.
However, because it must be administered with an intravenous drip that may take two hours, amphotericin B is impractical in remote, underdeveloped regions. Also, flucytosine can depress the production of new blood cells in bone marrow and cause leukopenia, anemia, and other blood problems, and comes with a warning that the blood, kidney, and liver status of patients must be monitored.
Such dangers are manageable in developing countries that lack medical resources, and the drugs offer a “huge potential” for reducing deaths from cryptococcal meningitis, according to lead author Jeremy N. Day, MD, PhD, of the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam.
“Clinical trials have demonstrated that amphotericin can be used safely in resource poor areas such as Vietnam and Uganda, and there are ongoing trials in Malawi,” said Dr. Day. “Ten-week mortality with treatment [combined amphoterocin B and flucytosine] was 30 percent versus 45 percent in patients receiving amphotericin, compared with the estimated three-month mortality of 55 percent in Asia and 70 percent in Africa. But access to these drugs is currently difficult. We hope the results from this study will help drive improved access to amphotericin and flucytosine.”
In addition to the obstacles of cost and the need for monitoring, flucytosine is not even registered for use in Africa. “The problem with flucytosine is that it's not available in any country in Africa,” said David Boulware, MD, MPH, of the University of Minnesota, who was not involved with the study. “And it's incredibly expensive. In the United States a two-week course of treatment can cost $7,000 — that's for an off-patent generic drug discovered in the 1950s.”
Dr. Boulware, the King distinguished assistant professor in the Division of Infectious Diseases and International Medicine at the University's Medical School, said various advocacy groups such as Doctors Without Borders and the Clinton Health Access Initiative are trying to change the situation. “They're trying to raise awareness,” he said. “There should be a market for flucytosine because there are about 1 million infections per year. This paper is very useful because it potentially builds demand (for the drug) with stakeholders.”
The NEJM paper reported the results of a study involving 299 patients with cryptococcal meningitis who were divided into three groups. After two weeks, 15 who received amphotericin plus flucytosine had died, compared with 25 patients receiving only amphotericin B, the standard treatment (hazard ratio, 0.57; unadjusted p = 0.08). By day 70, 30 who received the combination therapy had died compared with 44 in the amphotericin B only group (hazard ratio, 0.61; unadjusted p = 0.04). Patients in the third group, who received amphotericin B plus fluconazole, another drug often given to cryptococcal meningitis patients, displayed no survival benefit over those receiving amphotericin B alone at either 14 days (hazard ratio, 0.78; p = 0.42) or 70 days (hazard ratio, 0.71; p = 0.13).
“Moreover, amphotericin B plus flucytosine was associated with a higher likelihood of survival without disability than was amphotericin B monotherapy,” the authors observed.
Despite the clear superiority of flucytosine, fluconazole continues to be widely used in Africa because it is less expensive. Dr. Boulware and colleagues recently published a paper in PLoS Medicine demonstrating that a seven-day course of amphotericin combined with high-dose fluconazole was the most cost-effective option for treating cryptococcal meningitis in resource-limited settings, according to World Health Organization criteria.
“Clearly amphotericin plus fluconazole is less effective than amphotericin plus flucytosine,” Dr. Boulware said. “However, the cost is dramatically less, and flucytosine is just not available in low and middle income countries.”
Apprehension about the toxicity of flucytosine limits its use even where it is available. “[T]he fear of toxic effects frequently drives the interruption of flucytosine therapy,” said John R. Perfect, MD, chief of the Division of Infectious Diseases at the Duke University Medical Center, in an editorial in the same issue of the NEJM. “At my own medical center, a review of the duration of flucytosine induction therapy in 101 patients with cryptococcal meningitis showed that only 37% of patients received at least a 14-day course of this drug.”
The results reported in the NEJM study were not surprising since amphotericin and flucytosine have long been used together to treat cryptococcal meningitis, according to Karen L. Roos, MD, the John and Nancy Nelson professor of neurology and a professor of neurological surgery at the Indiana University School of Medicine.
“The combination of amphotericin B and flucytosine has been the standard of care for greater than 10 years,” she said.
Dr. Boulware agreed, but said he was glad to see data confirming the use of the two drugs in combination. “It's a great trial,” he said. “It's the first trial that has shown that amphotericin B plus flucytosine has a mortality benefit over amphotericin alone. Amphotericin and flucytosine have been recommended as the best treatment for cryptococcal meningitis for 15 years, but the data supporting that recommendation have been based on improving CSF culture sterility. Now there are clinical trial data which support a survival benefit.”
TREATMENT RECOMMENDATIONS FOR CRYPTOCOCCAL MENINGITIS IN HIV
For the treatment of cryptococcal meningitis in HIV-infected people, the World Health Organization (WHO) recommends a 14-day regimen of intravenous amphotericin plus oral flucytosine or fluconazole. However, the combination of cost, toxicity, and unavailability of amphotericin and flucytosine — the most effective combination according to a recent study in the NEJM — leaves fluconazole as the most common treatment.
But efforts are under way to change that. Tihana Bicanic, MD, Wellcome Trust intermediate clinical fellow and consultant in infectious diseases at St. George's University of London, along with several colleagues, have formed an advocacy group they call Cryptococcal Meningitis Action Group (CryptoMAG) that is campaigning to shift amphotericin B and flucytosine from the WHO's list of complementary drugs to its list of core drugs, considered essential medicines. Since cryptococcal meningitis is the most common cause of meningitis among adults in Africa, the group believes endorsement of sub-standard treatment is unacceptable.
“Fluconazole, the least effective drug, is on the WHO Core Essential Medicines List, whereas the other two (amphotericin B and flucytosine) are on the Complementary List,” she said. “That means countries don't prioritize getting those drugs. We want them moved to the Core List. We're also making an effort to get cryptococcal meningitis declared a neglected disease. We've just prepared a document that gives reasons why it fulfills the criteria.”
WHO's Expert Committee on the Selection and Use of Essential Medicines is reviewing the reasons, and is expected to issue a decision soon. Even if moved to the Core List, getting flucytosine approved in Africa would take years, so Dr. Bicanic and her colleagues in CryptoMAG are seeking funding to support a sustainable drug supply from sources such as UNITAID, a global health organization based in Geneva, which works to improve access to treatments for HIV/AIDS, malaria, and tuberculosis in underdeveloped countries.