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High-Dose Amphotericin B With Flucytosine for Treatment of Cryptococcal Meningitis in HIV: Presented at ECCMID-ICC

By Chris Berrie

MUNICH, GERMANY -- April 3, 2007 -- The combination of high-dose amphotericin B (AmB) 1 mg/kg/day with flucytosine 25 mg/kg as 4 doses PO for 2 weeks provides more rapid clearance of infection and clinically manageable renal impairment and anaemia for patients with HIV-associated cryptococcal meningitis (CM), according to a randomised study presented here.

Investigator Tihana Bicanic, MD, specialist and registrar in infectious diseases and microbiology, department of infectious diseases, St. George's Hospital, University of London, London, United Kingdom, presented the findings at the joint 17^th European Congress of Clinical Microbiology and Infectious Diseases and 25^th International Congress on Chemotherapy (ECCMID-ICC).

"Cryptococcal meningitis is an extremely common invasive fungal infection and, in the era prior to the availability of antiviral therapy, it had an incidence of up to 10% in AIDS patients," Dr. Bicanic said in a presentation on April 1^st.

"In sub-Saharan Africa where in many regions antenatal HIV seroprevalency is in the region of 20% to 30%, Cryptococcus neoformans is one of the commonest causes of community-acquired meningitis," she said.

Although the Infectious Diseases Society of America recommendation for CM is for AmB/flucytosine combinatory treatment, there is no comparative data on the efficacy and safety of the 2 doses of AmB recommended -- 0.7 to 1.0 mg/kg/day. Dr. Bicanic and colleagues therefore conducted their study to compare low-dose (0.7 mg/kg/day) and high-dose (1.0 mg/kg/day) AmB should be used.

In a previous unpublished study of combined data from studies in Thailand, South Africa and Uganda, Dr. Bicanic and colleagues demonstrated an association between rate of clearance of infection in individual patients (grouped as quartiles) and death within 2 weeks (P = .01).

This study took place in Cape Town, South Africa, at a secondary level peri-urban township hospital with a HIV prevalence of 11%, and with 2 to 3 cases of CM per week.

The researchers recruited 64 HIV-positive patients with a mean age of 21 years who were naïve to highly-active antiretroviral therapy (HAART). Patients had positive cultures to C. neoformans in cerebrospinal fluid and had their first episode of CM.

The treatment arms were AmB 0.7 mg/kg/day (n = 30) or 1.0 mg/kg/day (n = 34); both were combined with flucytosine 25 mg/kg as 4 doses PO for 14 days. All patients received electrolyte supplementation as required and normal saline loading prior to the AmB infusion. The maintenance dose in both arms was fluconazole 400 mg/day to 10 weeks, with HAART commenced 1 month after diagnosis.

The primary outcome was infection clearance as defined by an early fungicidal activity, as defined by a mean rate of decrease in cerebrospinal fluid of log CFU counts per day. Secondary outcomes were safety (renal impairment and anaemia) and mortality at 2 and 10 weeks.

There were no significant differences between treatment arms at baseline in terms of creatinine and haemoglobin levels, as well as baseline demographic characteristics. Also, mortality rates were similar in the 2 groups.

However, the researchers saw a significant difference in mean early fungicidal activity between arms (-0.45 and -0.56 logCFU/day; P = .02) that showed a benefit for high-dose compared with low-dose AmB.

At follow-up, however, there was a near significant greater mean increase in creatinine level in the high AmB dose (52% vs 88%, respectively; P = .07). This adverse effect was associated with early discontinuations in 1 low-dose patient and 2 high-dose patient, but it was reversible at day 14 and showed no long-term effects, with no patients requiring dialysis.

Haemoglobin levels saw significantly different mean percentage decreases of 16% and 26%, respectively (P = .01), which led to 2 early discontinuations and 1 transfusion. However, these effects were again reversible at the end of treatment, and showed no long-term effects.

On this basis of the more rapid clearance of infection seen in this study, accompanied by clinically manageable renal impairment and anaemia, Dr. Bicanic concluded that high-dose AmB in combination with flucytosine for 2 weeks is a good treatment for patients with HIV-associated CM.

However, she noted, it may be necessary for this treatment to be carried out where careful laboratory monitoring of patients and blood transfusion are available.


[Presentation title: High Dose Amphotericin B With Flucytosine for the Treatment of Cryptococcal Meningitis in HIV: A Randomised Study. Abstract O169]

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