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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 529-534

Effect of sofosbuvir and ribavirin therapy on hearing


1 Department of Audiovestibular Medicine ENT, El-Zaharaa University Hospital, Egypt
2 Department of Audiovestibular Medicine ENT, Kobry El Kobba Military Hospital, Cairo, Egypt

Date of Submission19-Mar-2020
Date of Decision08-Apr-2020
Date of Acceptance14-Apr-2020
Date of Web Publication2-Oct-2020

Correspondence Address:
MD Iman Eladawy
Department of Audiovestibular Medicine, Al-Azhar Faculty of Medicine for Girls, Al-Azhar University, 6 Elkhabeer Street Elzaitoun, Cairo, 11766
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_37_20

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  Abstract 


Introduction An estimated 185 million people worldwide are currently infected with chronic hepatitis C virus and ∼3–4 million new infections occur each year. Sofosbuvir (SOF) administered in combination with ribavirin (RBV) resulted in high sustained virological response rates across genotype (GT) 1–6 patients. It is also the first available regimen for patients who are unsuitable for interferon. A combination of SOF and RBV was safe and well tolerated with no death or discontinuation of treatment due to adverse events. The most frequent adverse events were headache, anemia, fatigue, and nausea.
Objective This study was designed to detect the effect of dual treatment with SOF/RBV on hearing and on cochlear hair cells in 50 patients with chronic hepatitis C.
Subjects and methods Fifty adult male patients with chronic HCV infection and fulfilling the indications to start the medical treatment with Sovaldi, they were subjected to pre and post treatment hearing assessment by Pure Tone Audiometry (PTA) and Oto Acoustic Emission (OAEs).
Results According to pure-tone audiometry, no statistically significant difference was detected in hearing threshold among patients at different frequencies, pretreatment and post-treatment. According to distortion-product otoacoustic emission (S/N), there was a highly statistically significant difference in distortion-product otoacoustic emission (S/N), at the most of frequencies in pretreatment and post-treatment. This differences confirmed (outer hair cell) damage as an ototoxic effect for SOF/RBV therapy.
Recommendation Long-term follow-up to determine this effect on the outer hair cell either temporary or permanent.

Keywords: distortion-product otoacoustic emission, hearing loss, pure-tone audiometry, sofosuvir and ribavirin


How to cite this article:
Ismail N, El-Serafy G, Ewida A, Eladawy I, Abd-Elmo'men M. Effect of sofosbuvir and ribavirin therapy on hearing. Sci J Al-Azhar Med Fac Girls 2020;4:529-34

How to cite this URL:
Ismail N, El-Serafy G, Ewida A, Eladawy I, Abd-Elmo'men M. Effect of sofosbuvir and ribavirin therapy on hearing. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Oct 26];4:529-34. Available from: http://www.sjamf.eg.net/text.asp?2020/4/3/529/296941




  Introduction Top


Hepatitis C virus (HCV) is a major health problem worldwide. In 2015, the global prevalence of HCV infection was 1.0%, with the highest prevalence in the Eastern Mediterranean Region (2.3%) followed by the European one (1.5%). The annual mortality due to HCV-related complications is estimated to be ∼700 000 deaths [1].

The highest prevalence of HCV infection is present in Egypt, with 92.5% of patients infected with genotype 4, 3.6% patients with genotype 1, 3.2% patients with multiple genotypes, and less than 1% patients with other genotypes [2],[3]. In 2015, the economic burden of HCV in Egypt was estimated to be $3.81 billion, whereas direct health-care costs of HCV-associated diseases exceeded $700 million annually [4].

In response to the major problem of HCV in Egypt, the Egyptian Ministry of Health and Population launched the National Committee for Control of Viral Hepatitis in 2006 to be in charge of combating HCV epidemic in the country [5].

The mass HCV treatment program started administering pegylated interferon (IFN) and ribavirin (RBV) between 2007 and 2014 [5]. However, the response to pegylated IFN and RBV was not satisfactory and was associated with many adverse events [6].

In October 2014, the introduction of sofosbuvir (SOF) markedly changed therapeutic outcomes [7]. SOF is the first nucleotide analog NS5B polymerase inhibitor with pan-genotypic activity and administered in combination with RBV resulted in high sustained virological response rates across genotype (GT) 1–6 patients. It is also the first available regimen for patients that are unsuitable for IFN [8]. So far, there are no known available studies about the effect of Sovaldi on hearing. Therefore, this is a preliminary study undertaken in a trial to detect this effect by using pure-tone audiometry (PTA) and distortion-product otoacoustic emission (DPOAE). DPOAE potentially reflects subclinical cochlear damage because DPOAE amplitude reduction arises from outer hair cell damage, which occurs before inner-hair-cell damage [9].

The subclinical hearing changes (cochlear function changes detected before the hearing loss is reflected on an audiogram) highlighted the importance of DPOAEs in monitoring ototoxic medications [10].


  Objective Top


The aim was to evaluate the effect of dual treatment with SOF/RBV, on hearing and the cochlear function.


  Patients and methods Top


Patients

Fifty adult male patients with chronic HCV infection randomly selected from Tropical Clinic at Kobry El kobba Military Hospital from January 1, 2016 through April 1, 2017 in a short-term longitudinal study. All patients signed an informed consent form after detailed explanation of the study. All participants gave their written consent before participation in the study. An approval from the ethical review board of Al-Azhar Faculty of Medicine (Girls) for this work was obtained in 2016.

Inclusion criteria

  1. Age range from 20 to 50 years.
  2. Chronic compensated HCV patients (no clinical symptoms or signs of liver cell failure) with the following criteria:
    1. No previous treatment with IFN.
    2. Liver fibrosis of less than 19 detected by FibroScan parameters (FibroScan is a noninvasive technology quantifying fibrosis).
    3. Grade 1 or absence esophageal varices.
  3. Recruited for treatment with Sovaldi.


Exclusion criteria

Chronic HCV patients with:
  1. Hearing impairment, tinnitus, or dizziness
  2. History of taking IFN therapy.
  3. History of ototoxic drug intake.
  4. History of chronic middle ear disease.
  5. History of head trauma or noise exposure.


Protocol of sovaldi therapy

Sovaldi 400 mg once daily+RBV which weight-based dose (<75 kg=1000 mg, 75 or >75 kg=1200 mg) daily in three divided doses taken orally with food for 6 months.

Equipment

  1. Sound-treated room (locally made).
  2. Two-channel audiometer (Corporate Headquarters, Florida, USA) (GSI 61).
  3. Immittancemeter (GSI 39).
  4. Distortion-product (DP) otoacoustic emission (GSI Audera Grason-Stadler).


Methods

All patients (pretreatment) were subjected to the following:
  1. Full history taking.
  2. Lab: complete blood count, aspartate transaminase, alanine aminotransferase, albumin, prothrombin time, partial thromboplastin time, international normalized ratio, PCR, urea, creatinine, T3, T4, and thyroid stimulating hormone.
  3. Imaging: fibroscan, abdominal ultrasound, and esophageal endoscopy.


All patients (pretreatment and post-treatment) were subjected to the following:
  1. Otological examination.
  2. Basic audiological evaluation in the form of:
    1. Pure-tone audiometry: routine air-conduction PTA (250, 500, 1000, 2000, 4000, and 8000) delivered via supra-aural headphone model TDH50 and extended high-frequency 12 000 Hz delivered via supra-aural headphone model Audiocups were carried out under standardized audiometric conditions in a sound-attenuating room. Bone conduction (for octave frequencies 500–4000 Hz) delivered via bone vibrator model AUDIOEAR 71 was carried out using ascending and descending technique.
    2. Speech audiometry: including speech reception threshold using Arabic spondee word [11] and word discrimination score using Arabic phonetically balanced word [12].
    3. Immittancemetry: tympanometry was done at a variable pressure range from +200 to −400 mm H20. Acoustic reflex threshold measurements using pure tones of 500, 1000, 2000, and 4000 Hz elicited ipsilateral and contralateral.
  3. DP otoacoustic emission:


The test was performed in a quiet environment. The patient was instructed to relax and avoid jaw movements, swallowing, or voice that could generate noise in the external auditory canal [13]. The probe for recording DPOAE typically contains two loudspeakers for stimulation and one or more microphones for recording [14].

Data were extracted DPOAEs elicited with an f2/f1 ratio=1.2 and moderate primary levels (L1=65 dB SPL; L2=55 dB SPL; L1–L2=10 dB). Range of frequency (represented by F2) was 500, 1000, 1500, 2000, 3000, 4000, and 8000 Hz. Test time varies depending on test parameters, environment, and scoring points.

The DPOAE response at the frequency 2f1–f2 (f2>f1) was measured and acoustic DP-gram was established with 2f1–f2 as horizontal coordinate and amplitude at 2f1–f2 as the vertical coordinate. The difference between the DP value and the background noise is the signal-to-noise ratio. Signal-to-noise ratio greater than 3 dB was considered as positive DPOAE.

Statistical analysis

Data were collected, revised, coded, and entered to the Statistical Package for the Social Sciences (IBM SPSS), version 20. The qualitative data were presented as number and percentages, while quantitative data were presented as mean, SD, and ranges when their distribution was found to be parametric.

The comparison between two paired groups regarding quantitative data with parametric distribution was done by using the paired t-test.

The confidence interval was set to 95% and the margin of error accepted was set to 5%. So, the P value was considered significant:
  • P greater than 0.05: statistically nonsignificant.
  • P less than 0.05: statistically significant.
  • P less than 0.01: statistically highly significant.



  Results Top


This short-term longitudinal study was conducted on 50 adult male patients having chronic hepatitis C on Sovaldi and RBV therapy. The mean age was 42.86±4.94 and ranges from 33 to 50 years.

Tympanometry was done in all patients and showed bilateral type A with preserved acoustic reflexes.

No statistically significant difference was detected in comparison between PTA for the right and left ears (pretreatment) and PTA for the right and left ears (post-treatment); so the data was pooled to detect any statistically significant difference between pretreatment and post-treatment for PTA (right+left) (number of ears=100).

No statistically significant difference was detected.


  Discussion Top


In the last decades, several new drugs appeared on shelves of pharmacies and hearing loss have been among the side effects of many of them. However, awareness of the community about new ototoxic medications is still not sufficient [15].

Life-threatening medical conditions may require treatment with highly ototoxic agents and the risk of hearing loss may be unavoidable. In many situations, however, alternative drugs, reduced dosages, or altered treatment regimens are options if ototoxicity is detected early in the treatment period [16].

The current short-term longitudinal study was designed to detect the effect of dual treatment with SOF/RBV on hearing and on cochlear hair cells in 50 patients with chronic hepatitis C with the mean age 42.86±4.94 and age range from 33 to 50 years.

In this study, comparing between the average of pretreatment and post-treatment PTA, there was no statistically significant difference detected among patients at different frequencies ([Figure 1]).
Figure 1 Pretreatment and post-treatment average of the pure-tone audiometry.

Click here to view


To our knowledge, so far, there were no available studies about the effect of combination of SOF and RBV therapy on hearing, but there was a case report not in agreement with the present study published by Chin-Loy et al. [17]. They stated that a 59-year old Caucasian man with chronic HCV and well-controlled hypertension was started on a course of oral SOF and RBV. Four weeks after starting treatment, the patient reported ocular inflammation, anemia, and hearing loss. The RBV dose was reduced, while the SOF dose remained unchanged. At 2 weeks later, he noted worsening vision, hearing loss, gait instability with tremor, joint pain, nausea, and fatigue. His RBV and SOF were both discontinued. Audiological evaluation showed bilateral moderate to severe sensorineural hearing loss requiring hearing aids ([Figure 2]).There were no other available studies about the effect of RBV neither alone nor in combination with SOF on hearing, but there were available studies about the effect of combination of IFN/RBV therapy on hearing. Results of the present study are in agreement with the study conducted by Hagr et al. [16] who concluded that IFN/RBV therapy does not have any impact on the hearing threshold of patients with HCV. They found that differences between pre and mid, pre and post, as well as mid and post were not significantly different (P>0.05) in PTA.
Figure 2 Pretreatment and post-treatment (S/N) for each ear at all frequencies.

Click here to view


The results of the present study are not in agreement with the study conducted by Akl et al. [18], who concluded that IFN/RBV therapy causes hearing impairment that may be irreversible.

In this study, no statistically significant difference was detected in speech reception threshold and SDS among patients in comparison between the average of pretreatment and post-treatment speech reception threshold and SDS ([Table 1]).
Table 1 Comparison between the average of pretreatment and post-treatment speech reception threshold and speech discrimination

Click here to view


The results of this study are in agreement with the study conducted by Akl and colleagues, who detected that there was no statistically significant difference as regards speech discrimination score after 3–6 months of receiving INF/RBV.

As regards DPOAEs, there was highly statistically significant difference in DPOAE (S/N) at most of frequencies in comparison between pretreatment and post-treatment DPOAE (S/N) for each ear ([Table 2]).
Table 2 Comparison between pretreatment and post-treatment distortion-product otoacoustic emission (S/N) for each ear

Click here to view


The results of this study are in agreement with Akl and colleagues who found reduction in S/N ratio of TEOAE and this reduction confirmed outer hair cell damage due to the ototoxic effect of IFN/RBV therapy.

On the other hand, the results of DPOAE are in disagreement with Hagr and colleagues, who concluded that the differences of DPOAE in patients who received IFN/RBV therapy between pre and mid, pre and post, and mid and post-treatment DPOAE were not significantly different (P>0.05).


  Conclusion Top


This study showed that:
  1. Hearing acuity was not affected after 3 months of treatment.
  2. There was affection of outer hair cells reflected on DPOAE.


Recommendations

  1. Long-term study to detect any hearing threshold affection after treatment with s SOF (Sovaldi) therapy.
  2. Increase sample size of the patients to detect any effect of SOF (Sovaldi) on hearing.
  3. DEOAEs before, during, and after cessation of treatment for early detection of ototoxicity effect of therapy.
  4. Multicenter studies on multiple groups receiving multiple combinations of new direct-acting antivirals.
  5. Vestibular evaluation of patients with chronic hepatitis C and receiving SOF combination with any direct-acting antivirals.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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WHO. Hepatitis C Fact sheet. July 2016.  Back to cited text no. 1
    
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World Bank Health Expenditure, total (% of GDP). Available from: http://data.worldbank.org/indicator/SH.XPD.TOTL.ZS. [Accessed April 13, 2017].  Back to cited text no. 4
    
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El-Akel W, El-Sayed MH, El Kassas M, El-Serafy M, Khairy M, Elsaeed K et al. National treatment programme of hepatitis C in Egypt: hepatitis C virus model of care. J Viral Hepat 2017; 24:262–267.  Back to cited text no. 5
    
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Soliman S. Speech discrimination audiometry using Arabic phonetically balanced words. Ain Shams Med J 1976; 27:27–30.  Back to cited text no. 12
    
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Kemp DT. Otoacoustic emissions, their origin in cochlear function, and use. Br Med Bull 2002; 63:223–241.  Back to cited text no. 13
    
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Dimitrijevic A, Michalweski HJ, Zeng F, Pratt H, Starr A. Frequency changes in a continuous tone: auditory cortical potentials. Clin Neurophysiol 2008; 119:2111–2124.  Back to cited text no. 14
    
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17.
Chin-Loy K, Galaydh F, Shaikh S. Retinopathy and uveitis associated with sofosbuvir therapy for chronic hepatitis C infection. Cureus 2016; 8:597.  Back to cited text no. 17
    
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    Figures

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    Tables

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