Hepatology Associates Course (*K) June 14 (Thu) 14 June Antiviral Therapy for Chronic and C

Hyun Phil Shin

Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, South Korea

Introduction (Fri) 15 June

Chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are global health burden and important risk factors of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC).1,2 Development of potent nucleos(t)ide analogues (NAs) with high resistance barrier represents the treatment of choice for chronic hepatitis B virus (HBV). With the emergence of direct acting antivirals (DAAs), the success rate of elimination of hepatitis C virus (HCV) has improved dramatically. The goal of this review is to suggest up to date recommendations for using antiviral therapy in chronic HBV and HCV in Korea.

Antiviral Therapy for Chronic hepatitis B (in Korea) June 16 (Sat) 16 June

1. Goals of Treatment The reason to treat patients with chronic HBV infection is to prevent disease progression, and occurrence of HCC. The goal of nucleos(t)ide analogue (NA) therapy is to suppress HBV replication. Proper timing of therapy, disease state of liver and the patients’ age when treatment are important to achieve this goal successfully.

2. When and in Whom? (in Korea) Table 1. Guidance statements on CHB treatment in Korea Patients with HBeAg-positive and HBV DNA ≥20,000 IU/ml & ALT≥80 U/L should start treatment regardless of the degree of fibrosis. Patients with HBeAg-negative and HBV DNA ≥2,000 IU/ml & ALT≥80 U/L should start treatment regardless of the degree of fibrosis. Patients with compensated cirrhosis, and HBV DNA ≥2,000 IU/ml should start treatment. Patients with decompensated cirrhosis (or hepatocellular carcinoma), and HBV DNA-positive should start treatment.

3. What Regimens We Can Choose There are several treatment options for CHB patients: treatment with a NA or with Peginterferon (Peg-IFN). The NAs that have been approved in Korea the treatment of patients with chronic hepatitis B include (LAM), (ADV), (ETV), , clevudine, fumarate (TDF) and (TAF), and recently besifovir. The preferred regimens were ETV, TDF, TAF, Peg-IFN and besifovir can be considered.

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4. Endpoints of Therapy The induction of complete HBV suppression is the main endpoint of all antiviral therapy and the level of HBV replication is the most important predictive marker of antiviral therapy. HBsAg loss, with or without anti-HBs se- roconversion is an optimal endpoint, but it is very hard to achieve. Indefinite antiviral therapy for CHB should be done in patients with HBeAg-negative, immune active CHB or cirrhosis unless there is a stone rationale for discontinuation. HBeAg-positive patients without cirrhosis but with CHB who seroconvert to anti-HBe during therapy can discontinue NAs after treatment consolidation.3

5. Summary ETV, TDF, TAF, Peg-IFN, besifovir can be first line therapy. Discontinuation of therapy should be carefully de- cided and can be done in limited condition.

Antiviral Therapy for Chronic hepatitis C 1. Goals of Treatment Recently, many DAAs have been developed and the pace of change has accelerated dramatically.4 Unlike chron- ic hepatitis B, the primary goal of HCV therapy is to eradicate HCV infection. HCV cure is needed in order to pre- vent HCV-related complications, onward transmission, and improve quality of life. The HCV infection is cured in more than 99% of patients with SVR.5 A sustained virological response (SVR) is defined as undetectable level of HCV RNA 12 weeks (SVR 12) or 24 (SVR 24) weeks after treatment completion.

2. When and in Whom? Evidence supports treatment for all patients with HCV infection, without contraindications for treatment. Treat- ment must be considered especially in patients with significant fibrosis or cirrhosis, although treatment is best -ad ministered before progression of liver fibrosis. Patients with short waiting time for liver transplantation will benefit from transplantation first before antiviral treatment.5 DAAs can be used except few contraindications, but certain cytochrome P450 inducing drugs can’t be used simultaneously with all DAAs due to decreased concentrations of DAA. Treatment is generally not recommended in patients with limited life expectancy because of non–liver-relat- ed comorbidities.

What Regimens We Can Choose (HCV DAA)?

1. Genotype 1a Grazoprevir/elbasvir+/-(RBV)- [NS5A RASs for elbasvir] Sofosbuvir+ledipasvir+/-RBV Paritaprevir/ombitasvir/ritonavir+Dasabuvir+RBV Sofosbuvir+daclatasvir+/-RBV

2. Genotype 1b Grazoprevir/elbasvir+/-RBV Sofosbuvir+ledipasvir+/-RBV Paritaprevir/ombitasvir/ritonavir+Dasabuvir Sofosbuvir+daclatasvir+/-RBV

352 June 14-16, 2018 ｜ Grand Hyatt Incheon, Korea Hepatology Associates Course (*K)

Daclatasvir+asunaprevir

3. Genotype 2 (Thu) 14 June Sofosbuvir+RBV

4. Pangenotype Glecaprevir/pibrentasvir Sofosbuvir/velpatasvir Sofosbuvir/velpatasvir/voxilaprevir

Table 2. HCV DAAs approved or not in Korea in 2018. Product Approved in Korea (Fri) 15 June Pangenotypic drugs or drug combinations Sofosbuvir o Sofosbuvir/velpatasvir x Sofosbuvir/velpatasvir/voxilaprevir x ◊ Glecaprevir/pibrentasvir x/o Genotype specific drugs or drug combinations Sofosbuvir/ledipasvir o Sofosbuvir/daclatasvir o Paritaprevir/ombitasvir/ritonavir o (Sat) 16 June Dasabuvir o Grazoprevir/elbasvir o Asunaprevir/Daclatasvir o

5. Endpoints of Therapy The endpoint of therapy is a SVR, defined by undetectable HCV RNA in blood 12 weeks (SVR12) or 24 weeks (SVR24) after the end of DAA therapy, confirmed by a sensitive molecular method. Both SVR12 and SVR24 have been accepted as endpoints of therapy because their concordance is more than 99%.6

6. Follow Up after Therapy Untreated patients or those who failed SVR should be regularly followed. A fibrosis evaluation using non-inva- sive methods is recommended. HCC surveillance must be done in patients with advanced fibrosis or cirrhosis.

Summary

CHC can be cured using DAAs, but in patients with advanced liver diseases and non-sustained virological re- sponders should be followed up after therapy.

References

1. European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167–185.

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2. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17:107–115. 3. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM et al. Update on prevention, diagnosis, and treat- ment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. 4. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62(3):932-54. 5. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol. 2017;66(1):153-194. 6. Martinot-Peignoux M, Stern C, Maylin S, Ripault MP, Boyer N, Leclere L et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated and ribavirin. Hepatology. 2010;51(4):1122-6.

354 June 14-16, 2018 ｜ Grand Hyatt Incheon, Korea