Being Alive; February 1994
Walt Senterfitt

Fortunately, uveitis is a much less severe problem. It may go away on its own and almost always clears up, leaving no damage to eyesight, with a few days or weeks treatment with eye drops or ointment containing a topical corticosteroid. If one gets a severe case and leaves it untreated for weeks or months, it may lead to some permanent sight loss, but this is very rare.

Canadian Study Results

Uveitis is believed to be an immunologic reaction, and thus may occur spontaneously in the course of HIV infection. However, it can also occur as a side effect of medications. Recently, there were reports of an unusually high incidence of uveitis in a Canadian clinical trial of treatment for MAC infection. Specifically, uveitis was reported in 23 of the 60 study participants who were taking a three-drug combination of high dose rifabutin (600 mg/day or four 150mg capsules), clarithromycin 1000 mg twice a day and ethambutol 15 mg/kg/day (dose dependent on body weight).

Twenty of the 23 participants had complete resolution of their symptoms following topical corticosteroids and were able to continue taking the above doses of the study medications. The other three also had resolution of their eye symptoms but had to stop the MAC medications. The trial subsequently reduced the rifabutin dose in half, to 300 mg/day.

More than 25,000 people across the US (most of whom are HIV+) have taken rifabutin 300 mg/day as a single agent for the prophylaxis of MAC. Among this large group, only three cases of uveitis have been reported, though the number may have been larger if every treating physician had been aware of this possible side effect.

The much higher incidence in the Canadian study is probably a function both of the higher dose of rifabutin used for treatment as compared to prophylaxis and of the interaction of rifabutin with both clarithromycin and fluconazole. Most (75%) of the Canadian participants experiencing uveitis were also taking fluconazole. Data from two other studies show that clarithromycin may increase the level of rifabutin in the blood by 50% and fluconazole may increase it 50-80%. In other words, the rifabutin blood level of those experiencing uveitis was probably much higher than had been recognized.

ACTG 196/CPCRA 009 MAC Prophylaxis Trial

The Canadian report raised concern among the investigators and participants in a large (1162 participants) ongoing trial of MAC prophylaxis, comparing rifabutin to clarithromycin to a combination of both. The leadership and staff of the ACTG 196/CPCRA 009 trial asked every site to closely check for incidence of uveitis and conducted an extensive evaluation of all reported adverse events. As of January 24, a total of 12 cases of uveitis had been reported, affecting about 1% of study participants. Two of these cases were rated as "severe" and the rest "mild to moderate." All cases have resolved with topical corticosteroid treatment and three of them stayed on study medications.

As a precaution, the study team has decided to reduce the rifabutin dose from the 450 mg/day (three capsules) originally used to 300 mg/day which is the currently-recommended prophylactic dose, based on the trials used for FDA approval.

The ACTG and CPCRA will also be shortly distributing a letter of explanation and an amended "Informed Consent" form to all study participants. If any symptoms of uveitis occur, participants will be instructed to hold their study medications, seek consultation with an ophthalmologist (through their study site) for appropriate evaluation and treatment, and if symptoms resolve, they may resume study medications.

After study and consultation with several physicians, I believe that these precautions are well-founded and sufficient and that people who had chosen to enroll in this important trial should not drop out over concern about uveitis.

Other Implications

The manufacturer of rifabutin, Pharmacia Adria, recently mailed a "Dear Doctor" notification letter to all physicians who have prescribed rifabutin. The letter advises physicians to discontinue rifabutin promptly if signs and symptoms of uveitis develop while taking the drug and to refer the patient to an ophthalmologist. They note the very low incidence of uveitis reported among patients taking the prophylactic dose, and state "In summary, patients who are currently receiving Mycobutin<CONTROL 168> 300 mg daily for MAC prophylaxis should continue to do so with reassurance. Patients who are receiving higher doses may be at increased risk for the development of uveitis; physicians should take this increased risk into account in prescribing these doses."

That seems reasonable to me. I think it wise to discuss your rifabutin dose with your physician at your next appointment, especially if you are also taking clarithromycin and/or fluconazole.

In the meantime, call your doctor or nurse right away if you experience any of these symptoms: eye pain, eye redness, sensitivity to light or blurred vision. Temporarily stop taking rifabutin or any blinded study medication which may be rifabutin.

This little episode also points how much we still have to learn about the interactions among the various medications many of us take.

(Thanks to Dr. Constance Benson of Rush University in Chicago, Chair of the ACTG 196 Protocol Team, for providing useful documentation for this report.)

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