**3. Antiviral medications**

#### **3.1. Interferons**

Interferons (IFN) are a group of naturally occurring proteins that are released by several cell types in response to infection or tumors. There are three classes of interferons: type I, type II and type III. Type I interferons include IFN-alpha and IFN-beta. Synthetic and recombinant interferons, alpha and beta, have been used for therapy of viral infections with hepatitis C or B virus. In addition, IFN-beta can be used to treat multiple sclerosis.

One of the first reports associating interferon treatment with hearing loss was published in 1994 [30]. In that report, a group of 49 patients (32 men and 17 women, mean age 48.6, age range 23–67) receiving various brands of interferons for chronic hepatitis B or C were assessed with pure tone audiometry before the onset of treatment and then in consecutive 1-week interval. In case of IFN-alpha, the drug was administered i.m. each day for 2 weeks and then three times a week for 14–22 weeks. In case of IFN-beta, the drug was administered i.v. daily for 6 weeks. The study demonstrated that 45% (22 patients) developed auditory dysfunction: 14 patients (29%) reported having tinnitus and 18 patients (35%) were diagnosed with sudden sensorineural hearing loss. More than half (56%) of the patients treated with interferonbeta (total of 27 subjects) developed auditory disability with unilateral or bilateral hearing loss affecting various frequencies diagnosed in 11 patients (41%). In the group treated with IFN-alpha (total of 22 subjects), seven developed unilateral hearing loss affecting 8000 Hz. Progressive hearing loss leads in two cases to withdrawal from therapy. There was no association between the clinical parameters such as proteinuria, leucopenia, liver functions and the hearing loss. Interestingly, all patients recovered within 2 weeks after finishing the interferon treatment.

Published 1 year later, prospective audiological study of 73 patients treated with IFN-alpha or IFN-beta for hepatitis confirmed the above observations, including the hearing loss exclusively affecting 8000 Hz in patients receiving IFN-alpha [31]. There was, however, one difference: in the larger sample studied, the hearing abilities of one patient have not recovered after discontinuation of therapy. Later, studies confirmed majority of these observations [32] and most importantly the general reversibility of ototoxic effects of IFN-alpha [33].

Interesting mechanistic insights of IFN-alpha-induced ototoxicity were delivered from studies using mouse model [34]. There was an elevated ABR threshold in mice treated with IFN-alpha as compared to untreated control group. Moreover, histological findings of cochleae dissected from experimental animals indicated abnormalities in the number (lower) and appearance (cytoplasmic vacuolization) of the spiral limbus fibroblasts in the IFN-alpha-treated mice. These findings point to direct negative effect of IFN-alpha on cochlear biology, which may result in the hearing loss.

#### **3.2. Pegylated interferons and ribavirin**

The epidemiological and case report data indicate that PDE5 inhibitors may have general negative impact on hearing. Moreover, PDE5 inhibitors may induce sudden sensorineural hearing loss that in some cases can be successfully treated with corticosteroids; in some other cases, the patients recover without any treatment; and lastly, it can also leave patients with

Interferons (IFN) are a group of naturally occurring proteins that are released by several cell types in response to infection or tumors. There are three classes of interferons: type I, type II and type III. Type I interferons include IFN-alpha and IFN-beta. Synthetic and recombinant interferons, alpha and beta, have been used for therapy of viral infections with hepatitis C or

One of the first reports associating interferon treatment with hearing loss was published in 1994 [30]. In that report, a group of 49 patients (32 men and 17 women, mean age 48.6, age range 23–67) receiving various brands of interferons for chronic hepatitis B or C were assessed with pure tone audiometry before the onset of treatment and then in consecutive 1-week interval. In case of IFN-alpha, the drug was administered i.m. each day for 2 weeks and then three times a week for 14–22 weeks. In case of IFN-beta, the drug was administered i.v. daily for 6 weeks. The study demonstrated that 45% (22 patients) developed auditory dysfunction: 14 patients (29%) reported having tinnitus and 18 patients (35%) were diagnosed with sudden sensorineural hearing loss. More than half (56%) of the patients treated with interferonbeta (total of 27 subjects) developed auditory disability with unilateral or bilateral hearing loss affecting various frequencies diagnosed in 11 patients (41%). In the group treated with IFN-alpha (total of 22 subjects), seven developed unilateral hearing loss affecting 8000 Hz. Progressive hearing loss leads in two cases to withdrawal from therapy. There was no association between the clinical parameters such as proteinuria, leucopenia, liver functions and the hearing loss. Interestingly, all patients recovered within 2 weeks after finishing the interferon

Published 1 year later, prospective audiological study of 73 patients treated with IFN-alpha or IFN-beta for hepatitis confirmed the above observations, including the hearing loss exclusively affecting 8000 Hz in patients receiving IFN-alpha [31]. There was, however, one difference: in the larger sample studied, the hearing abilities of one patient have not recovered after discontinuation of therapy. Later, studies confirmed majority of these observations [32] and

Interesting mechanistic insights of IFN-alpha-induced ototoxicity were delivered from studies using mouse model [34]. There was an elevated ABR threshold in mice treated with IFN-alpha as compared to untreated control group. Moreover, histological findings of cochleae dissected from experimental animals indicated abnormalities in the number (lower) and appearance (cytoplasmic vacuolization) of the spiral limbus fibroblasts in the IFN-alpha-treated mice.

most importantly the general reversibility of ototoxic effects of IFN-alpha [33].

B virus. In addition, IFN-beta can be used to treat multiple sclerosis.

permanent hearing impairment.

**3. Antiviral medications**

**3.1. Interferons**

238 Advances in Clinical Audiology

treatment.

Pegylated interferons are chemically "improved" interferons bound to polyethylene glycol (PEG). Pegylation assures longer half-time of interferons in the body. There are three groups of pegylated interferons available in the market–pegylated interferon-alpha-2a (PEG-IFNa2a), pegylated interferon-alpha-2b (PEG-IFNa2b) and pegylated interferon-beta-1a.

Ribavirin is a guanosine analog (nucleoside inhibitor) that stops viral RNA synthesis. It is used to treat various viral hemorrhagic fevers, and it is the only known drug against rabies. Although new therapeutic approaches are being introduced on the healthcare market for the treatment of hepatitis C (e.g., protease inhibitor telaprevir or boceprevir), ribavirin in combination with PEG-IFN-alpha is still a part of the current standard of care (SOC) therapy in some countries and it is also included in the new therapeutic regime.

Therapeutic use of PEG-IFN and ribavirin in hepatitis C infections induces similar otological effects as the therapy with non-pegylated interferons only. However, there is one major difference: the hearing abilities do not recover in the majority of cases. Although some reports describe no hearing disabilities [35] or sudden unilateral sensorineural hearing loss resolving spontaneously within 2 weeks after the end of treatment [36], some other demonstrate that patients may develop irreversible unilateral hearing loss [37] or irreversible unilateral pantonal hearing loss (measured by pure tone audiometry) and tinnitus [38].

#### **3.3. Inhibitors of viral reverse transcriptase**

According to the United Nations AIDS organization, approximately 36.7 million people worldwide are infected with the HIV virus. The patients with HIV are treated with drugs that inhibit the virus proliferation. Since HIV virus uses very unique enzyme to copy its genome, this enzyme–reverse transcriptase–is a pharmacological target of anti-HIV therapy. The unique thing about the HIV therapy is that it should never be stopped, even if the viral load is undetectable.

The discovery and the beginning of clinical application of reverse transcriptase inhibitors date back to the eighties last century. The first reports about their negative effect on hearing appeared some 10 years later and ever since conflicting conclusions are being drawn from several studies. In some studies, authors found the hearing loss among 30% of HIV patients taking the reverse transcription inhibitors [39–41], whereas in other studies, no association between audiological impairment and antiviral medication was found [42, 43]. Various inclusion criteria, diverse outcome measure methods, sample size and many other factors could contribute to these dissimilar results.

In the controlled environment of experimental laboratory, the results look much more uniform and point at universal ototoxicity of all types of reverse transcriptase inhibitors that are on the market, as measured by the viability of auditory epithelial cell line exposed to various concentrations of 14 types of pharmacological reverse transcription inhibitors as single agents and in combination, as used in the clinics [44].
