TreatmentUpdate 67, Volume 8, No 3; April 1996
Sean Hosein

The drug of choice for treating some of the life-threatening fungal infections seen in AIDS is iv AmB (intravenous amphotericin B). Although effective, use of AmB may result in temporary kidney damage causing doctors to reduce or stop use of AmB. Several companies have been mixing AmB with lipids or packing the drug into tiny balls of fat called liposomes. Results from experiments on cells suggest one form of AmB called ABLC (amphotericin B lipid complex) is less toxic than regular AmB. In experiments on mice with weakened immune system, ABLC was effective for the treatment of serious fungal infections also seen in humans with AIDS. Details on treatments for life-threatening fungal infections in people with HIV/AIDS have appeared in TreatmentUpdate 38, 50, 54 and 61.

Study details

Researchers recruited 55 subjects with AIDS (51 males, 2 females) who were having their first attack of the life-threatening brain infection crypto (cryptococcal meningitis caused by the fungus C. neoformans). The researchers then randomly assigned subjects to receive one of 4 dose/schedules of iv ABLC or iv AmB. For the first two weeks subjects in their respective groups received one of two drugs in the following dose/schedules:

* Group 1: ABLC 1.2 mg/kg of body weight/day

* Group 2: ABLC 2.5 mg/kg/day

* Group 3: ABLC 5.0 mg/kg/day

* Group 4: AmB 0.7 mg/kg/day

Starting on the 3rd week, subjects in the following groups received their drugs three days weekly;

* Group 1: ABLC 2.5 mg/kg/day

* Group 2: ABLC 5.0 mg/kg/day

* Group 3: ABLC 5.0 mg/kg/day

* Group 4: AmB 1.2 mg/kg/day

At least half of the subjects assigned to receive ABLC had a CD4+ cell count of less than 50 cells. For those subjects who received AmB the equivalent figure was 66 cells.

Results - effectiveness

* Headache; at the start of the study "most" subjects had headaches and needed drugs to bring relief. At the end of the study "most" did not report headaches.

* Thinking/memory; At the start of the study all subjects had problems with memory and/or concentration. At the end of the study, all subjects who were not in group 1 and who survived the infection/treatment had their memory problems clear.

* Fungus; Overall, 86% of subjects receiving high-dose ABLC (5mg/day) and 65% of subjects on AmB had their signs/symptoms of crypto clear. However, lab technicians could still detect fungus in 42% of samples of blood, CSF and urine from subjects on high dose ABLC. Only 14% of subjects (two subjects) treated with AmB had detectable fungus in their fluid samples.

The researchers noted that despite randomization, more subjects likely to die or not recover from crypto were assigned to receive ABLC than AmB. This difference was statistically significant. Subjects assigned to ABLC were less likely to experience side effects than those assigned to AmB.

Two subjects died because of complications due to crypto, one, ten weeks after receiving ABLC 2.5 mg/kg/day and later 5 mg/kg/day three days weekly. This subject's condition did not improve. The other subject received 11 weeks of "anti-fungal therapy" .5 mg/kg/day. Doctors removed him from the study and gave him AmB but he did not recover from crypto.

Toxicity - symptoms

According to researchers, "overall, [94% of subjects in the AmB group and 97% of those in the ABLC groups] experienced at least one side effect. While subjects were being infused with their drugs, between 33% and 50% reported:

* chills

* headache

* nausea

* vomiting

The number of side effects reported were the same in subjects in the ABLC or AmB group. Giving subjects Gravol(R) and Tylenol(R) 60 minutes before an infusion helped reduced the severity of side effects. If these drugs did not help, subjects could also use meperidine or hydrocortisone. The researchers noted that subjects complained about bone and muscle pain. As well, the researchers reported that subjects had "pain, [sleeping problems], diarrhea, and swelling/redness/itching on the skin around the infusion tube."

Toxicity - lab tests

Use of high-dose ABLC (5 mg/kg/day) caused less kidney damage (monitored by measuring levels of creatinine in the blood) than AmB. This difference was statistically significant; that is, not likely due to chance alone.

Transfusions

Similarly, subjects receiving AmB were more likely to have reduced numbers of red blood cells than others receiving ABLC. This difference was also statistically significant. Indeed, 60% of subjects on AmB needed transfusions while only 18% of subjects on ABLC did. This difference was statistically significant.

Deaths

Although 12 people died "between 2 hours and 30 weeks after receiving [their] last dose of study medication, only 2 [subjects deaths were considered possibly related to the drugs used in the study]. One of the two received nifedipine because his blood pressure rose when he was given AmB. He blood pressure then fell below normal and his heart stopped beating and he died. The other subject had blood pressure that changed sharply while receiving ABLC. During his second infusion his blood pressure fell and his heart stopped beating and he died.

References:

1. Sharkey PK, Graybill JR, Johnson ES, et al. Amphotericin B Lipid Complex compared with Amphotericin B in the Treatment of Cryptococcal Meningitis in patients with AIDS. Clinical Infectious Diseases 1996; 22:315-321.

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