Grazoprevir/elbasvir treatment for the relapse of HCV genotype 1b infection after ledipasvir/sofosbuvir: A case report

  • Authors:
    • Tomoko Tadokoro
    • Asahiro Morishita
    • Kyoko Oura
    • Koji Fujita
    • Shima Mimura
    • Teppei Sakamoto
    • Takako Nomura
    • Joji Tani
    • Hirohito Yoneyama
    • Tsutomu Masaki
  • View Affiliations

  • Published online on: May 23, 2018     https://doi.org/10.3892/etm.2018.6207
  • Pages: 1026-1028
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The treatment of chronic hepatitis C has radically changed due to the development of direct‑acting antiviral agents (DAAs). Twelve‑week treatment with ledipasvir and sofosbuvir (LDV/SOF), a combination of DAAs, is highly effective in patients with hepatitis C virus (HCV) genotype 1 infection. However, the overall sustained virological response rate 12 weeks after the end of treatment (SVR12) is not 100%. Elbasvir (EBR) combined with grazoprevir (GZR) is the latest approved therapy for patients with genotype 1 or 4 chronic hepatitis C. However, to the best of our knowledge no case reports have described retreatment with GZR/EBR in patients with a history of failed LDV/SOF treatment. The present case report indicated a case in which GZR/EBR was effective for the retreatment of a patient with a history of failed LDV/SOF treatment and chronic hepatitis C. The present study indicated a 55‑year‑old Japanese male with a history of chronic hepatitis C and compensated liver cirrhosis. The patient exhibited the amino acid mutation Y93H in NS5A. Therefore, treatment with LDV/SOF was initiated, which was effective and suppressed the virus during oral administration. However, 4 weeks after treatment, the patient's viral load relapsed and returned to its original level. After the patient provided informed consent, treatment with GZR/EBR was initiated. No problems related to GZR/EBR were observed during treatment and the patient's SVR12 was evaluated at 12 weeks posttreatment. In conclusion, GZR/EBR treatment was useful for treating a relapse of HCV genotype 1b infection in the present case after LDV/SOF treatment, despite liver fibrosis, in the presence of the high‑frequency amino acid mutation Y93H in NS5A. Although it will be necessary to examine a large number of cases, the present findings suggest that GZR/EBR may be a potential treatment option for relapse of HCV genotype 1b infection after LDV/SOF treatment.

Introduction

Hepatitis C virus (HCV) remains the main cause of severe liver disease. Due to medical progress, the number of new HCV infections has been decreasing. However, HCV-related morbidity and mortality are expected to continue rising, and approximately 399,000 people die each year from hepatitis C, mostly due to cirrhosis and hepatocellular carcinoma (http://www.who.int/mediacentre/factsheets/fs164/en).

To date, several direct-acting antiviral agents (DAAs) have been designed and developed to target individual portions of the viral proteins, including NS3/4A, NS5B, and NS5A (1). A new treatment method using DAAs is highly active against HCV and has few side effects. In particular, twelve-week combination treatment with the DAAs ledipasvir (LDV), an NS5A inhibitor, and sofosbuvir (SOF), an NS5B polymerase inhibitor, is highly effective in patients with HCV genotype 1 infection (2). However, the treatment is not perfect, as the overall SVR at 12 weeks after the end of treatment is 98.8%, not 100% (3). In addition, the next treatment regimen for LDV/SOF failure cases has not been established.

Elbasvir (EBR), an NS5A inhibitor, combined with grazoprevir (GZR), an NS3/4A protease inhibitor, is the latest approved therapy for patients with genotype 1 or 4 chronic hepatitis C (4). Compared to LDV/SOF, EBR/GZR has few side effects and limited drug interactions and can be given to patients with illnesses such as heart failure. In the 2016 AASLD/IDSA guidelines, 12 weeks of EBR/GZR treatment was recommended as level A therapy for treatment-experienced patients (prior exposure to peginterferon/ribavirin) with genotype 1a or 1b infection. However, clinical experience and trial data on the retreatment of any patient that had previously received treatment with LDV/SOF are very limited (http://www.hcvguidelines.org.). Therefore, the present study reported a case in which GZR/EBR was effective for the retreatment of a patient with a history of failed LDV/SOF treatment for chronic hepatitis C.

Case report

A 55-year-old Japanese male had a history of chronic hepatitis C with compensated liver cirrhosis; his viral load was 6.0 log IU/ml, and his viral genotype was 1b. In addition, he exhibited the high-frequency amino acid mutation (>99%) Y93H in NS5A. Although his medical history included three instances of gastroesophageal varix rupture due to excessive drinking in addition to HCV infection, suggesting uncompensated liver cirrhosis, the patient later stopped drinking, and the liver function reflected compensated cirrhosis. Therefore, we started treatment for the patient's chronic hepatitis C infection using LDV/SOF.

Two weeks after commencing LDV/SOF treatment, his viral load decreased to below the detection sensitivity. However, 4 weeks after treatment, his viral load increased and returned to its original level. No change was observed in the amino acid mutation after LDV/SOF treatment; the high-frequency Y93H mutation (>99%) in NS5A remained stable (Fig 1; Table I).

Table I.

RAV alignment of NS3 and NS5A in patient before and after the treatment of LDV/SOF.

Table I.

RAV alignment of NS3 and NS5A in patient before and after the treatment of LDV/SOF.

RAVsBefore LDV/SOFAfter LDV/SOF
NS3/V36A
NS3/T54A
NS3/T54S
NS3/Q80L
NS3/Q80R
NS3/A156S
NS3/A156T
NS3/A156V
NS3/D168A
NS3/D168E
NS3/D168H
NS3/D168T
NS3/D168V
NS5A/L31F
NS5A/L31M
NS5A/L31V
NS5A/Y93HH>99%H>99%

[i] LDV, ledipasvir; SOF, sofosbuvir; RAV, resistance-associated variant; Y93H H>99%, substitution rate of tyrosine to histidine at amino acid 93 is >99%.

There was no evidence for subsequent treatments after failure on LDV/SOF. His liver function reflected the compensated cirrhoss as before treatment with LDV/SOF (Table II). Therefore, after the patient gave informed consent, we started treatment with GZR/EBR, including an NS3/4A protease inhibitor, which was not used in the previous treatment. No side effects of GZR/EBR, such as headache, nausea, fatigue, decreased appetite, anemia, pyrexia, or ALT elevations (4), were observed during the treatment, and the patient achieved an SVR at 12 weeks posttreatment.

Table II.

Laboratory patient data before treatment with grazoprevir/elbasvir.

Table II.

Laboratory patient data before treatment with grazoprevir/elbasvir.

VariablesValueUnitsReference range
Total protein8.3g/dl6.5–8.2
Albumin4g/dl3.5–5.5
Albumin/globulin ratio0.93 1–1.8
Blood urea nitrogen19.8mg/dl8.2–4.3
Creatinine0.97mg/dl0.5–1
Total bilirubin1.2mg/dl0.1–1.2
Direct bilirubin0.5mg/dl0.1–0.6
Aspartate transaminase32U/l10–35
Alanine transaminase29U/l5–40
Alkaline phosphatase;509U/l100–340
Lactate dehydrogenase113U/l110–220
γ-glutamyl transpeptidase18U/l0–30
Total cholesterol99mg/dl130–219
Triglyceride47mg/dl30–149
Na138mmol/l135–146
K4.2mmol/l3.5–4.6
Cl104mmol/l96–110
White blood cells1,410/µl4,700–8,700
Red blood cells 375×104/µl370–490
Hemoglobin10g/dl13–17
Hematocrit31.3%35–45
Platelets 2.9×104/µl15–35
Neutrophils78.5%38–71.9
Eosinophils1%0.2–6.8
Basophils0%0–1
Lymphocytes11.5%26–46.6
Monocytes9.5%2.3–7.7
Prothrombin time49%80–100

[i] Laboratory data revealed severe pancytopenia due to increased splenic function. The patient's FIB4 index was 11.27.

Discussion

This case report provides two important clinical suggestions regarding retreatment after failure of LDV/SOF therapy for patients with chronic hepatitis C. First, GZR/EBR treatment might be useful for treating relapsed HCV genotype 1b infection after LDV/SOF treatment. Second, GZR/EBR was effective in a patient with advanced cirrhosis who exhibited the high-frequency amino acid mutation Y93H in NS5A.

Some reports have related a poor response to LDV/SOF with resistance-associated variant (RAV)-positivity and high values of the FIB4 index (5). On the other hand, RAVs in the NS5B region, such as S282T, have not been confirmed in Japan (6). In particular, because a mutant form of NS5A (Y93H) shows diminished binding to LDV, HCVs expressing this mutant are resistant to LDV (7). However, RAV-positivity is also related to a poor response to GZR/EBR (8). To elucidate why GZR/EBR was effective in this case, it will be necessary to examine a large number of cases, and obtaining appropriate informed consent is necessary before initiating this treatment. Despite these facts, GZR/EBR was useful in this case and may provide an option for patients who undergo ineffective LDV/SOF treatment.

In the near future, it will be necessary to examine a large number of cases to determine whether the administration of GZR/EBR may serve as a potential treatment option for relapsed cases of HCV genotype 1b infection after LDV/SOF treatment.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

All data generated or analyzed during this study are included in this article.

Authors' contributions

TT, SM and TM designed the case report. AM, KF, TS, TN, JT, HY and TM acquired and interpreted the patient's data. TT and KO collected the patient clinical data and TT was a major contributor in writing the manuscript.

Ethics approval and consent to participate

In accordance with the Declaration of Helsinki, informed consent was obtained from the patient.

Consent for publication

Consent for publication was obtained from the patient.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

DAA

direct-acting antiviral agent

LDV

ledipasvir

SOF

sofosbuvir

HCV

hepatitis C virus

SVR

sustained virological response

EBR

elbasvir

GZR

grazoprevir

References

1 

Zopf S, Kremer AE, Neurath MF and Siebler J: Advances in hepatitis C therapy: What is the current state-what come's next? World J Hepatol. 8:139–147. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, et al: Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 370:1889–1898. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Ogawa E, Furusyo N, Nomura H, Dohmen K, Higashi N, Takahashi K, Kawano A, Azuma K, Satoh T, Nakamuta M, et al: NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b. J Gastroenterol. 52:845–854. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Bell AM, Wagner JL, Barber KE and Stover KR: Elbasvir/grazoprevir: A review of the latest agent in the fight against hepatitis C. Int J Hepatol. 2016:38521262016. View Article : Google Scholar : PubMed/NCBI

5 

Akuta N, Sezaki H, Suzuki F, Fujiyama S, Kawamura Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Suzuki Y, et al: Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan. J Med Virol. 89:284–290. 2017. View Article : Google Scholar : PubMed/NCBI

6 

Kanda T, Yasui S, Nakamura M, Suzuki E, Arai M, Ooka Y, Ogasawara S, Chiba T, Saito T, Haga Y, et al: Real-world experiences with the combination treatment of ledipasvir plus sofosbuvir for 12 weeks in hcv genotype 1-infected Japanese patients: Achievement of a sustained virological response in previous users of peginterferon plus ribavirin with HCV NS3/4A inhibitors. Int J Mol Sci. 18(pii): E9062017. View Article : Google Scholar : PubMed/NCBI

7 

Kwon HJ, Xing W, Chan K, Niedziela-Majka A, Brendza KM, Kirschberg T, Kato D, Link JO, Cheng G, Liu X and Sakowicz R: Direct binding of ledipasvir to HCV NS5A: Mechanism of resistance to an HCV antiviral agent. PLoS One. 10:e01228442015. View Article : Google Scholar : PubMed/NCBI

8 

Komatsu TE, Boyd S, Sherwat A, Tracy L, Naeger LK, O'Rear JJ and Harrington PR: Regulatory analysis of effects of hepatitis C virus NS5A polymorphisms on efficacy of elbasvir and grazoprevir. Gastroenterology. 152:586–597. 2017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

August-2018
Volume 16 Issue 2

Print ISSN: 1792-0981
Online ISSN:1792-1015

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Tadokoro T, Morishita A, Oura K, Fujita K, Mimura S, Sakamoto T, Nomura T, Tani J, Yoneyama H, Masaki T, Masaki T, et al: Grazoprevir/elbasvir treatment for the relapse of HCV genotype 1b infection after ledipasvir/sofosbuvir: A case report. Exp Ther Med 16: 1026-1028, 2018
APA
Tadokoro, T., Morishita, A., Oura, K., Fujita, K., Mimura, S., Sakamoto, T. ... Masaki, T. (2018). Grazoprevir/elbasvir treatment for the relapse of HCV genotype 1b infection after ledipasvir/sofosbuvir: A case report. Experimental and Therapeutic Medicine, 16, 1026-1028. https://doi.org/10.3892/etm.2018.6207
MLA
Tadokoro, T., Morishita, A., Oura, K., Fujita, K., Mimura, S., Sakamoto, T., Nomura, T., Tani, J., Yoneyama, H., Masaki, T."Grazoprevir/elbasvir treatment for the relapse of HCV genotype 1b infection after ledipasvir/sofosbuvir: A case report". Experimental and Therapeutic Medicine 16.2 (2018): 1026-1028.
Chicago
Tadokoro, T., Morishita, A., Oura, K., Fujita, K., Mimura, S., Sakamoto, T., Nomura, T., Tani, J., Yoneyama, H., Masaki, T."Grazoprevir/elbasvir treatment for the relapse of HCV genotype 1b infection after ledipasvir/sofosbuvir: A case report". Experimental and Therapeutic Medicine 16, no. 2 (2018): 1026-1028. https://doi.org/10.3892/etm.2018.6207