Can peginterferon alfa-2a or ribavirin cause hearing loss?/nThe question concerns a 70-year-old wom

Fråga: Can peginterferon alfa-2a or ribavirin cause hearing loss? The question concerns a 70-year-old woman with hepatitis C, diabetes mellitus type II, essential hypertension and hypothyreosis. Treatment with peginterferon alfa-2a (Pegasys) 180 ug/week and ribavirin (Copegus) was started and thereafter she developed appetite loss, depressiveness, vertigo and hearing loss. Two months after initiation of therapy she was totally deaf on her right ear. Treatment was withdrawn. Outcome of the patient is not known.

Sammanfattning: Hearing loss has been reported for interferons, including peginterferon alfa-2b. In some of the reports the patients have also been treated with ribavirin. The hearing loss has been reversible within a month after discontinuation of therapy in most cases. However, recently a few reports of irreversible hearing loss have been published. The mechanism has not been established, but direct ototoxicity, autoimmune mechanisms and hearing loss secondary to thrombocytopenia have been discussed. No reports of hearing disorders during monotherapy with ribavirin have been found.

Svar: A similar question has been answered in Drugline (1). Sudden hearing loss has occasionally been described during interferon treatment. In two prospective studies with interferon alfa and beta, hearing disabilities (hearing loss and tinnitus) occurred in approximately 40% of the patients. The incidence tended to increase at doses above 100 MU (million units) and the symptoms usually resolved within 7-14 days after discontinuation of therapy. No information concerning ribavirin and hearing loss had been found.

Since then, some more studies and case reports concerning interferon alfa and peginterferonalfa and hearing loss has been published. Observe that the doses of these two drugs have different units (MU and ng) and can therefore not be compared.

In one study with 27 patients treated with interferon alfa (10 MU three times per week) due to chronic hepatitis B hearing loss was detected in 33% of the patients after seven days and the degree had increased when measured after 21 days of treatment. The hearing loss did not exceed 20 dB for any frequency with continued interferon therapy, and the patients were fully recovered one month after cessation of therapy (2). In another study with 26 patients treated with interferon alfa-2b (10 MU three times per week), due to chronic active hepatitis B, no statistically significant difference between hearing threshold levels were seen before and after six months of therapy. However, two patients developed tinnitus which disappeared 10-14 days after discontinuation of therapy (3). In one case report sudden hearing loss developed after 15 days of treatment with interferon alfa (5 MU daily) and disappeared five days after withdrawal. Immunological examination showed presence of antiendothelial cell antibodies (4). In another report a patient developed sensineural hearing loss in the left ear and polyneuropathy after five months of treatment with interferon alfa-2a. The treatment was withdrawn and her polyneuropathy improved, but at follow-up after five months her hearing had not improved (5).

In the summary of products characteristics, hearing disorders are mentioned as adverse effects of combined therapy of peginterferon alfa-2a and ribavirin (6,7). Up to date, there are nine cases of sudden hearing loss during treatment with peginterferon alfa and ribavirin published (8,9,10,11). In the first case the patient developed otalgia and sudden onset of left-sided hearing loss after 22 weeks of treatment with peginterferon alfa-2a (180 ug/week) and ribavirin (800 mg/day). The symptoms resolved two weeks after discontinuation of therapy (8). In the second case, the patient was treated with peginterferon alfa-2b (120 ug/day) and ribavirin (1000 mg/day) for ten weeks before he developed bilateral hearing impairment. Three months after cessation of therapy, further impairment of his hearing was observed and after 18 months of follow-up he still reported deterioration of his hearing. This case is complicated by the fact that the patient has Turner syndrome, which can cause hearing loss. However, peginterferon/ribavirin may have acted as a triggering factor (9). In the third case sudden right-sided hearing loss (described as deafness) is reported in a patient two months after initiation therapy with peginterferon alfa-2b (100 ug/week) and ribavirin (1000 mg/day). Despite discontinuation of therapy her hearing impairment did not improve. She restarted therapy four months after the initial discontinuation, and her unilateral hearing loss persisted but did not worsen (10). The last report is a case series of six patients. Sudden hearing loss and tinnitus developed on day 1 and after 4, 23, 25,36 and 40 weeks of therapy with peginterferon alfa-2a (180 ug/week) or -2b (1.5 ug/kg/week) and ribavirin (1000-1200 mg/day). In these cases the hearing loss did not fully resolve after discontinuation of therapy, nor did they worsen on continued treatment (11).

Three mechanisms have been discussed concerning interferon induced hearing loss (3,8,9,11). Firstly, interferon may be directly ototoxic. Interferon enhances the excitability of cultured neurons which may lead to direct ototoxicity to the auditory nerve. However, interferon did not cause loss of hair cells (a major histopathologic feature of ototoxic drugs) when administered on the mouse cochlea. It has therefore been suggested that interferon causes reversible biochemical and metabolic changes in the cochlea, rather than morphologic abnormalities. Secondly, autoimmune mechanisms induced by interferon have been suggested. Interferons can induce or enhance autoimmune diseases, and autoimmunity is believed to be one of the major ethologies of idiopathic sudden hearing loss. In one of the cases immunological examination showed presence of antiendothelial cell antibodies (4), which may support an autoimmune mechanism. Thirdly, the sudden hearing loss can be related to the hematologic side effects of antiviral therapy. Thrombocytopenia (which is a common side effect of interferon) may lead to intracochlear hemorrhage, resulting in sensorineural hearing loss (3,8,9,11).

In the Swedish adverse drug reactions register there are six cases of impaired hearing and one on tinnitus for the whole group of interferons (of a total of 420 reports). In five of these cases the patients were also treated with ribavirin (12).

No reports of hearing disorders during monotherapy with ribavirin have been found. However, ribavirin is not authorised for monotherapy (7).