High-dose amphotericin B speeds clearance of cryptococcus from the brain

A combination of high-dose amphotericin B and flucytosine leads to faster declines in the presence of the fungus Cryptococcus in the brains of HIV-positive patients with meningitis, compared to standard treatment, say South African investigators in the July 1^st issue of Clinical Infectious Diseases. Dose-related toxicities are reversible and manageable, they say and suggest the combination may be of benefit in improving long-term prognosis.

The fungus Cryptococcus remains a common opportunistic infection in HIV-positive people in the developing world. Infection often leads to meningitis, the dangerous swelling of the membrane surrounding the brain and spinal cord. Death due to cryptococcal meningitis is a serious problem in many African countries; a recent Ugandan study reported high death rates (20 to 42%), even with access to effective antiretroviral therapy. (HIV & AIDS Treatment in Practice published a detailed clinical review of the management of meningitis, including the cryptococcal variety, in December 2007.)

There is an urgent need to improve treatment options, especially in resource-limited settings. Current standard medical treatment in North America combines amphotericin B dosed at 0.7 mg/kg per day along with flucytosine. Flucytosine is not widely available in Africa and so fluconazole is commonly used as the second drug.

Since the 1980s, clinical trials have used increasing doses of amphotericin B, and have shown the drug to be safe and effective at increasing levels. A few recent studies have shown positive preliminary results of a high dose of 1 mg/kg per day, but comparative data remains lacking.To address this void, investigators from South Africa and the Netherlands undertook a prospective study of the effects of standard-dose versus high-dose amphotericin B given with flucytosine.

The prospective study at a Cape Town hospital enrolled a total of 64 participants who had never received antiretroviral therapy and who were hospitalized with a confirmed first case of cryptococcal meningitis. Less severely affected patients were randomly assigned to either arm and more severely affected participants were assigned to try to ensure equal proportion in each arm. Treatment was not blinded.

The standard-dose arm received 0.7 mg/kg per day amphotericin B and 25 mg/kg four times per day flucytosine for two weeks. The high-dose arm received 1 mg/kg per day amphotericin B plus flucytosine for two weeks. At treatment end, patients were switched to maintenance therapy with fluconazole and were also started on antiretroviral therapy.

Cerebrospinal fluid samples were collected by lumbar puncture at diagnosis and during and after treatment. Investigators gauged treatment effect by measuring the mean rate of decrease in Cryptococcus in patients in each arm. They also recorded renal function, red blood cell counts and survival over the short and long term.

When investigators compared the rate of decrease between treatment groups, they saw a significantly faster decrease in the high-dose arm (p = 0.02). There were no differences in short-term and long-term survival between the two groups. The death rate was 6% at 2 weeks and 24% at 10 weeks. Survival was 68% at six months and 60% at one year. The investigators point out that the 10-week survival is the highest seen in an African study of fluconazole. And once the participants recovered from the acute infection and started therapy, their prognosis was good, as in the developed world, they write.

Anaemia, a side effect of amphotericin B, was common in both groups, affecting 50% of patients in the standard-dose arm and 71% in the high-dose arm. The difference was not statistically significant (p = 0.2). Haemoglobin levels rose two weeks after the end of treatment, suggesting the effect of amphotericin B was reversible.

Renal impairment was also observed in several patients, though the effects were reversible, with creatinine levels rising at week 2, the end of therapy, and falling at week 4, two weeks after the end of therapy. The rates of renal impairment were comparable with other studies, the investigators state.

A total of six patients left the study: 1 from the standard-dose group and 5 from the high-dose group. All were due to either complications involving the kidneys or levels of blood cells. The investigators acknowledge that differences in toxicity between the two groups may have been missed due to the small number of participants in the study. Nonetheless, they argue the higher dose of amphotericin B is safe, if properly monitored.

“On the basis of its more-rapid clearance of infection and manageable toxicity,” they conclude, “we favor the use of [amphotericin B] at a dosage of 1 mg/kg per day plus flucytosine for 2 weeks, provided that laboratory data are monitored carefully and that transfusion is possible if it is occasionally needed.”

What’s more, improved access to flucytosine in African and Asia may be warranted, they urge, if an ongoing Vietnamese study of high-dose amphotericin plus flucytosine demonstrates the value of the second drug.