1060423 慢性ｃ型肝炎治療新進展

Recent Advance of the Treatment of Chronic Hepatitis C 胡琮輝醫師 Tsung-Hui Hu, MD, PhD

內科部 胃腸肝膽科系

肝炎 肝硬化

肝癌 3

Anti-HCV prevalence varies regionally

An estimated 160 million people are chronically infected worldwide Central Asia, East Asia and North Africa / Middle East are regions with high anti-HCV prevalence Low: <1.5% Moderate: 1.5–3.5% High: >3.5% anti-HCV, antibody to HCV

© John Wiley & Sons 2013. Reproduced with permission from Mohd Hanafiah K et al. Hepatology 2013;57:1333–1342.

3

Geographic variation and distribution of HCV genotypes

HCV genotypes 1 and 3 are the most prevalent genotypes globally HCV genotype 1b (type2) is the major genotype in most countries in Asia Pacific

1b

Š John Wiley & Sons 2011. Reproduced with permission from Negro F, Alberti A. Liver Int 2011;31 Suppl 2:1â&#x20AC;&#x201C;3 4

C型肝炎在台灣 C型肝炎(HCV)病毒經由血液與體液傳染，導致肝臟發炎 Ｃ肝病毒盛行率：

1

2-4.4％

1a、1b

2

2a、2b

帶原者：約60萬人

3

依基因型分類， 共有6種主要基因型

4

• 台灣6成病患為第一型病毒 • 其中基因亞型1b的病毒較 容易引起肝癌，對干擾素 的治療反應也較差。

5 6 10 謝佩真et al.,C型肝炎病毒基因分型及其臨床重要性.內科學誌

2009；20：309-319

Prevalence of HCV infection peaked in 2001 A substantial cohort of currently asymptomatic patients will begin to develop HCV-related morbidity and mortality in coming years

Number (millions)

6 5

Acute hepatitis Ever infected Chronic HCV

4 3 2 1 0 1950

1960

1970

1980 Peak incidence

1990

2000

2010

2020

2030

Year

© Elsevier 2010. Reproduced with permission from Davis GL et al. Gastroenterology 2010;138:513–521.e1–6.

6

Hepatitis C: Who is at risk?

Risk of occupational HCV exposure Non-sterile piercing or tattoo recipients

Injection drug users

Children born to HCV-infected mothers

HIV patients

Recipients of blood products and organs

High risk sexual behaviour Haemodialysis patients

HIV, human immunodeficiency virus

Mauss S et al. Hepatology - A Clinical Textbook. Flying Publisher & Kamps; 2014 7

Up to 5% of all HCV-infected patients will die of cirrhosis or liver cancer Weeks to months

HCV infection (often asymptomatic)2

>20 years

Chronic HCV (75−85%)

Natural resolution of infection (15–25%)

*Includes patients who progress to moderate disease and eventually die from other causes.

Decompensated cirrhosis and liver failure (10−20%)

Liver inflammation and/or moderate fibrosis in first 20 years (60–80%)*

HCC (1−5%)

Cirrhosis develops and progresses slowly; patient dies from other causes (10–15%)

1. World Health Organization. Hepatitis C. 2002. Available at: http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/. Accessed 8 May 2014 8

What predicts disease progression?

The REVEAL-HCV Study Risk Evaluation of Viral Load Elevation and Associated Liver Disease / Cancer – HCV (REVEAL-HCV) Study: Community-based, natural history cohort to evaluate long-term predictors of HCC

23,820 participants aged between 30 and 65 years living in seven townships in Taiwan enrolled 1991–1992

HBsAg, hepatitis B surface antigen

1095 positive for anti-HCV and negative for HBsAg

Followed-up for ≥5 years (abdominal ultrasound and serologic tests

Lee M-H et al. J Clin Oncol 2010;28:4587–4593 9

Patients with elevated serum levels of HCV RNA are at increased risk of HCC

Cumulative risk of HCC (%)

REVEAL-HCV: Cumulative incidence of HCC by HCV RNA level in Taiwan High HCV RNA levels (n=318) Low HCV RNA levels (n=315)

14.7%

HCV RNA undetectable (n=292) Anti-HCV seronegatives (n=18,172) P for entire cohort: <0.001 P for anti-HCV seropositives: <0.001 P for HCV RNA seropositives: 0.02

6.4%

1.1% 0.4%

Follow-up time since after the fifth year post-enrollment (years) ALT, alanine aminotransferase; RNA, ribonucleic acid

Š American Society of Clinical Oncology 2010. All rights reserved.

Reproduced with permission from Lee M-H et al. J Clin Oncol 2010;28:4587â&#x20AC;&#x201C;4593 10

Patients with elevated serum levels of ALT are at increased risk of HCC

Cumulative risk of HCC (%)

REVEAL-HCV: Cumulative incidence of HCC by ALT level in Taiwan ALT ever ≥45 U/L (n=352) ALT ever ≥15 U/L but never > 45U/L (n=374)

13.8%

ALT persistently ≤15 U/L (n=199) Anti-HCV seronegatives (n=18,172) P for entire cohort: <0.001 P for anti-HCV seropositives: <0.001

4.2% 1.7% 0.4%

Follow-up time since after the fifth year post-enrolment (years) © American Society of Clinical Oncology 2010. All rights reserved.

Reproduced with permission from Lee M-H et al. J Clin Oncol 2010;28:4587–4593 11

Patients infected with HCV genotype 1 are at increased risk of HCC

Cumulative risk of HCC (%)

REVEAL-HCV: Cumulative incidence of HCC by HCV genotype in Taiwan HCV genotype 1 (n=331) HCV genotype non-1* (n=255) HCV RNA undetectable (n=292)

12.6%

Anti-HCV seronegatives (n=18,172) P for entire cohort: <0.001 P for anti-HCV seropositives: <0.001 P for HCV RNA seropositives: 0.01

4.5% 1.1% 0.4%

Follow-up time since after the fifth year post-enrolment (years) * HCV genotype 3 is not a major HCV genotype in Taiwan.

Š American Society of Clinical Oncology 2010. All rights reserved.

Reproduced with permission from Lee M-H et al. J Clin Oncol 2010;28:4587â&#x20AC;&#x201C;4593 12

C型肝炎患者較一般人肝病三部曲死亡風險增加

C型肝炎患者肝硬化死亡風險為一般人的5.38倍 C型肝炎患者肝癌死亡風險為一般人的21.63倍 Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based LongTerm Prospective Study Journal of Infectious Diseases Advance Access published July 17, 2012

12

Up to 76% of patients develop an extrahepatic manifestation during the course of the disease1 CNS

disorders2

Chronic fatigue*, subclinical cognitive impairment, psychomotoric deceleration, symptoms of depression*, neurocognitive disorders

Endocrine2 Autoimmune thyroidopathies, insulin resistance / diabetes mellitus*, growth hormone and vitamin D insufficiencies

Renal disorders2 Peripheral neuropathy*, glomerulonephritis*

Cardiovascular diseases2 Cardiomyopathy / myocarditis

Rheumatologic disorders2 Mixed cryoglobulinaemia*, cryoglobulinaemic vasculitis* rheumatoid arthralgias / oligopolyarthritis, rheumatoid factor positivity*, Sicca syndrome

Hematologic disorders2 Lymphoproliferative disorders / non-Hodgkin lymphomas*, ITP, monoclonal gammopathies*, autoimmune hemolytic anaemia

Dermatologic disorders2 Palpable purpura, PCT, lichen planus, pruritus

The presence of mixed cryoglobulinaemia, molecular mimicry and virus-induced autoimmune phenomenon may cause these manifestations3 *Based on strong epidemiological prevalence and/or clear pathogenetic mechanisms.

CNS, central nervous system; ITP, immune thrombocytopenic purpura ; PCT, porphyria cutanea tarda

1. Cacoub P et al. Medicine 2000;79:47â&#x20AC;&#x201C;56. 2. Mauss S et al.

Hepatology - A Clinical Textbook. Flying Publisher & Kamps; 2014. 3. Ferri C et al. Autoimmun Rev 2007;7:114â&#x20AC;&#x201C;120 14

Elevated HCV RNA levels is associated with increased mortality from extrahepatic diseases Circulatory diseases (n=523) HCV RNA seropositives

HCV RNA undetectable Anti-HCV seronegatives

HCV RNA seronegatives Anti-HCV seronegatives

P<0.001 for comparison among three groups

P=0.005 for comparison among three groups

P=0.02 for HCV RNA detectable vs. undetectable

P=0.36 for HCV RNA detectable vs. undetectable

12.2%

11.0%

Cumulative risk (%)

Cumulative mortality (%)

19.8%

HCV RNA detectable

Nephritis, nephrotic syndromes and nephrosis (n=81) HCV RNA seropositives HCV RNA seronegatives Anti-HCV seronegatives

5.0%

P=0.008 for comparison among three groups P=0.71 for HCV RNA detectable vs. undetectable

3.5% 2.9%

Cumulative risk (%)

All extrahepatic diseases* (n=2199)

1.48% 0.92% 0.47%

Follow-up years *Non-liver cancers, diabetes mellitus, circulatory diseases, respiratory diseases and, nephritis, nephrotic syndromes and nephrosis.

Follow-up years

Follow-up years

Š Oxford University Press 2012. Reproduced with permission from Lee M-H et al. J Infect Dis 2012;206:469â&#x20AC;&#x201C;477 15

SECTION II TREATMENT GUIDELINES â&#x20AC;&#x201C; RECOMMENDATIONS FOR WHEN AND IN WHOM TO INITIATE TREATMENT

HCV therapy aims to eradicate HCV infection to avoid future complications What is the goal of therapy?

To eradicate HCV infection (to prevent cirrhosis, decompensation, HCC and death), as evidenced by an SVR (undetectable HCV RNA, ie <15 IU/mL at 12 and 24 weeks after the end of treatment)1–3 A1 Who should be treated?

All patients with chronic HCV infection1–3 Priority should be given to those at high risk for complications (A1) and those with high transmission risk (C2a)1,2 What about patients with cirrhosis?

Treatment is strongly recommended. Viral eradication reduces the rate of decompensation and HCC. Surveillance should continue1 A1 SVR, sustained virological response

1. EASL Recommendations on Treatment of Hepatitis C. 2014. 2. AASLD and IDSA. Recommendations for Testing Managing and Treating Hepatitis C. 2014. 3. Omata M et al. Hepatol Int 2012;6:409–435 17

Patients with significant fibrosis should be treated with highest priority

F0â&#x20AC;&#x201C;F1

F2

F3

F4

Decompensated cirrhosis

Treatment should be prioritized for patients with significant fibrosis (METAVIR score F3â&#x20AC;&#x201C;F4)1,2

1. EASL Recommendations on Treatment of Hepatitis C. 2014.

2. AASLD and IDSA. Recommendations for Testing Managing and Treating Hepatitis C. 2014 18

Patients at risk of rapidly progressive disease should be prioritized for therapy

Organ transplant

HIV-1 or HBV coinfection

Treatment should be prioritized for patients with high risk for complications1,2

Other coexisting liver disease (eg NASH) HBV, hepatitis B virus; NASH, non-alcoholic steatohepatitis

Extrahepatic manifestations

Debilitating fatigue

1. EASL Recommendations on Treatment of Hepatitis C. 2014.

2. AASLD and IDSA. Recommendations for Testing Managing and Treating Hepatitis C. 2014 19

Treatment should be prioritized in patients who will impact further HCV transmission Active injection drug users

Persons on long-term haemodialysis

Treatment may be beneficial in persons with high HCV transmission risk1

Incarcerated persons

Men who have sex with men with high-risk sexual practices AASLD and IDSA. Recommendations for Testing Managing and Treating Hepatitis C. 2014 20

SECTION III EFFECTIVE HCV TREATMENT RESULTS IN A CURE â&#x20AC;&#x201C; THE SIGNIFICANCE OF ACHIEVING SVR

C型肝炎病毒迄今 仍無疫苗

傳統療法－2合1療法(P/R) P/R=Peginterferon Alfa(長效型幹擾素)+雷巴威林(Ribavirin)

• 每週注射一次 • 誘發酵素,防止病毒 複製

長效型干擾素

雷巴威林 (ribavirin)

• 每天口服兩次。 • 作用機轉未明

• 增加免疫細胞作用。

二合一療法治療時程約半年~一年，接受完整治療難度高，部份病人不堪長期治療的副作 用而中途放棄。 C型肝炎治療新知，張明鈴 C型肝炎病毒之臨床治療 陳薇安 藥師

17

病毒基因第1型之持續病毒學應答率在 五個大型的研究中非常一致 PegIFNα-2b加上RBV

持續病毒學應答率(%)

42

• 這五個大型研究收了

44 40

39

39*

10,291位元元病毒基因1 型之病患，其中7,862位 接受PegIFNα-2b加上RBV 的治療

• 在上述病患中的4,792位 348 Manns 2001

951 Witthoeft 2010

1019

1161

1313

McHutchison Cooper Jacobson 2009 2009 2007

接受48周1.5 μg/ kg/wk 之PegIFNα-2b標準劑量治 療 N = 4,792†

*Estimated SVR analysis: intended to account for patients with undetectable HCV RNA at the end of treatment who lacked follow-up data and were considered non-responders in the primary analysis.†Patients treated with standard dose and schedule of PegIFNα-2b combination therapy. SVR, sustained virologic response,i.e.negative HCV RNA 24 weeks after completion of therapy.

Manns MP,et al.Lancet. 2001;358:958-965.Witthoeft T,et al.J Viral Hepat. 2010;17:459-468; McHutchison JG,et al.N Engl J Med. 2009;361:580-593; Cooper C,et al. Poster presented at: 60th Annual AASLD; October 30-November 3, 2009; Boston, MA. No. 820.5. Jacobson IM,et al.Hepatology. 2007;46:971-981.

亞洲基因1型病患之持續病毒學應答率 PegIFN-α 加上RBV †

133

65

21

107

38

70

50

47

†病患皆達到早期病毒學應答並接受48周之治療

Chu CJ,et al. Aliment Pharmacol Ther2009;29:46-54; Chu CJ,et al. Hepatogastroenterology2007;54:866-870; Fung J,et al. J Infect Dis2008;198:808-812;Hung CH,et al. Liver Int2006;26:1079-1086;Lee SD,et al. J Viral Hepat2005;12:283-291; Tsang OT,et al. J Gastroenterol Hepatol2010;25:766-771; Kim MN,et al.

Korean J Hepatol2009;15:496-503, Lee S,et al. Intervirology2010;53:146-153.

Side effect of interferon based therapy

26

2014 FDA approval 27

Direct-acting antivirals for HCV infection

28

Evolution of HCV treatment landscape: increased cure rates in genotype 1 patients 1998

2001

2011

2013–2014

IFN1

IFN+RBV1,2

PegIFN + RBV3

PIs+ PegIFN + RBV4–5

New DAAs + PegIFN + RBV6

IFN-free regimens7,8

SVR (%)

1991

*In genotype 1b patients.

DAA, direct-acting antiviral; PegIFN, pegylated interferon; PI, protease inhibitor RBV, ribavirin

1. McHutchison JG et al. N Engl J Med 1998;339:1485–1492. 2. Poynard T et al. Lancet 1998;352:1426–1432.

3. Fried MW et al. N Engl J Med 2002;347:975–982. 4. Poordad F et al. N Engl J Med 2011;364:1195–1206.

5. Jacobson IM et al. N Engl J Med 2011;364:2405–2416. 6. Lawitz E et al. Lancet Infect Dis 2013;13:401–408.

7. Afdhal N et al. N Engl J Med. 2014;370:1889–1898. 8. Manns M et al. Lancet 2014;384:1597–1605 29

Approved in September 2015

Protease inhibitor

NS5A inhibitor

Polymerase inhibitor

â&#x20AC;&#x201C;

Ledipasvir

Sofosbuvir

1st generation NS5A inhibitor (L31/Y93 resistance)

The first nucleotide analog

30

ION-1 study: efficacy in HCV genotype 1 naive patients according to the absence/presence of cirrhosis

Approved in December 2015

Protease inhibitor

NS5A inhibitor

Paritaprevir

Ombitasvir

2nd generation (D168 resistance)

1st generation (L31/Y93 resistance)

Non-nucleoside NS5B inhibitor

Dasabuvir

32

SAPPHIRE-I: Results in HCV- 1 treatment-naive patients

Paritaprevir/r + Ombitasvir + Dasabuvir +/- RBV (Abbvie)

Approved in September 2014

Protease inhibitor

NS5A inhibitor

Polymerase inhibitor

Asunaprevir

Daclatasvir

â&#x20AC;&#x201C;

2nd generation (D168 resistance)

1st generation (L31/Y93 resistance)

34

Daclatasvir and Asunaprevir in Non-Japanese Asian Patients with Chronic HCV Genotype 1b Infection 91

94

87

60 64

(Indication: 1b) CI, confidence interval.

NS5A RAVs not exclusive 91

26 28

145 159

Wei et al., AASLD 2015; Poster LB-18.

Proportion with NS5A polymorphism (%)

Prevalence of baseline NS5A polymorphisms in GT-1b patients

1/127 1/80 1/127 1/80

•

2 277 77

16 16 449 451

9 12 72 10 9 127 10 80 12 77 72 449 127 80 77 451

10 10 12711 127 80

11 8014 77

14 7785 451

85 449

The prevalence of NS5A-L31F/I/M/V or NS5A-Y93H was lowest among patients from mainland China and highest in Taiwanese and Japanese patients •

NS5A-Y93H prevalence in mainland China was similar to that previously reported for patients from non-Asian countries (7.2%)1 GT, genotype.

1. McPhee F, et al. Adv Ther 2015;32:637–649.

McPhee F, et al. APASL 2016; Poster P-0102.

36

Impact of NS5A RAVs at Baseline on SVR12 With NS5A RAVs at baseline

Without NS5A RAVs at baseline

44 0 1 • • • •

145 157

99

98

92

8 18

42 137 140

8 19

137 139

NS5A (L31M or Y93H) and NS3 (D168E) RAVs were present at baseline in 19 (12%) and 1 (1%) patient, respectively SVR12 was achieved by 8/19 (42%) patients with NS5A RAVs at baseline The 1 patient with NS3 D168E at baseline achieved SVR12 SVR12 was achieved by 137/139 (99%) patients without NS5A RAVs at baseline ‒ 43/44 (98%) with cirrhosis, 94/95 (99%) without cirrhosis RAV, resistance associated variants; SVR, sustained virologic response.

Wei et al., AASLD 2015; Poster LB-18.

Once SVR is achieved, lifetime virological cure is expected in >99% of patients Achieved SVR†, n

Late relapse, %

Chemello et al. Ann Intern Med 1996;124:1058

80

0

Mean: 35 (18–48)

Marcellin P et al. Ann Intern Med 1997;127:875

80

4

Mean: 48 (12–90)

Toccaceli F et al. J Viral Hepat 2003;10:126

87

0

NR (36–76)

McHutchison JG et al.J Hepatol 2006;46:S275

492

1

Mean: 65 (NR)

Desmond CP et al. J Viral Hepat 2006;13:311

147

0.7

Formann E et al. Aliment Pharmacol Ther 2006;23:507

187

0

Median: 29 (12–172)

Chavalitdhamrong D et al. World J Gastroenterol 2006;12:5532

171

0

Mean: 35 (13–57)

Moreno M et al. J Viral Hepat 2006;13:28

132

0

Mean: 42 (12–156)

75

0

NR (36–108)

Martinot-Peignoux M et al. J Hepatol 2008;48:S302

278

0

Mean: 56 (6–132)

Manns M et al. J Hepatol 2008;48:S300

366

1

Mean: 57 (36–260)

0

Median: 39 (6–216)

150

0

Median: 61 (12–93)

Koh C et al. Hepatology 2010;52:S436

103

2.9

Median: 91 (6–264)

Giannini EG et al. Aliment Pharmacol Ther 2010;31:502

231

0.9

Median: 38 (32–42)

1343

0.9

Mean: 47(10–85)

Study reference*

Torres-Ibarra R et al. J Hepatol 2007;46:S247

Patients with SVR did not experience HCV Maylin S et al. Gastroenterology 2008;135:821 344 infection recurrence even after 18 years George SL et al. Hepatology 2009;49:729

Swain MG et al. Gastroenterology 2010;139:1593

Follow-up, months (range)

Mean: 28 (4–124)

*All patients received IFN-based therapies including standard interferon alpha; leukocyte interferon-α; lymphoblastoid interferon and PegIFN. sensitivities were between 5 and 50 IU/mL or 10 and 10,000 copies/mL. NR, not reported

†Assay

38

Achieving SVR is protective against HCC development Retrospective analysis of 1371 HCV-treated patients with a median follow-up of 10 years: all patients

HCC incidence (%)

30

Did not achieve SVR Achieved SVR

20 P<0.0001

10

0 0

5

10

15

20

25

Time (years) Purevsambuu T et al. J Hepatol 2014;60:S52 abstract 0125 39

HCC and Fibrosis according to SVR 100

100

Fibrosis 0-1

90

non-SVR SVR

70 60

P-value= 0.005

50 40 30

SVR

70 60 50 40

P-value= 0.0267

30 20

20

10

10

0

0 0

50

100

100 months

150

0

200

Cumulative risk (%)

70 60 50

P-value= 0.0018

40 30

150

200

non-SVR

80

SVR

100 months

Fibrosis 4

90

non-SVR

80

50

100

Fibrosis 3

90 Cumulative risk (%)

non-SVR

80 Cumulative risk (%)

Cumulative risk (%)

80

Fibrosis 2

90

SVR

70 60 50 40

P-value <0.0001

30 20

20

10

10

0

0 0

50

100 months

150

200

0

50

100 months

150

200

Chang KC and Hu TH* Br J Cancer 2013: 109:2481-248840

Patients who achieve SVR experience extrahepatic clinical benefits

Cumulative Incidence (%)

SVR reduces the risk of diabetes mellitus development by two-thirds2 Did not achieve SVR (n=1667) Achieved SVR (n=1175)

SVR protects against the development of malignant lymphoma3 Cumulative incidence (%)

SVR has a beneficial effect on cerebral metabolism and neurocognitive function1

Did not achieve SVR Achieved SVR 2.56% 1.49%

P=0.0159

0.36% 0%

0%

0%

Follow-up (years)

Follow-up (years)

1. Byrnes V et al. J Hepatol 2012;56:549–556.

2. © John Wiley & Sons 2009. Reproduced with permission from Arase Y et al. Hepatology 2009;49:739–744.

3. © Elsevier 2007. Reproduced with permission from Kawamura Y et al. Am J Med 2007;120:1034–1041.

41

SVR significantly reduces the onset of diabetes mellitus Incidence of new-onset diabetes mellitus in 2842 IFN-treated patients in Japan (mean follow-up: 6.4 years)

Development rate of diabetes mellitus(%)

Did not achieve SVR 60

Age ≥50 years

Achieved SVR Liver cirrhosis

Pre-diabetes

Non-SVR (n=139)

50 40 P<0.001

Non-SVR (n=975)

Non-SVR (n=151)

P=0.017

P<0.005

30 20

SVR (n=54)

SVR (n=535)

10

SVR (n=90)

0 0

10

20

0

10 Time (years)

20 0

10

20

© John Wiley & Sons 2009. Reproduced with permission from Arase Y et al. Hepatology 2009;49:739–744 42

HCV treatment improves renal and cardiovascular outcomes in HCV-infected patients with diabetes Population-based cohort study of individuals with diabetes mellitus and HCV infection from the Taiwan National Health Insurance Research Database (NHIRD) End-stage renal disease 10

HCV-infected, treated cohort (n=1411) HCV-infected, untreated cohort (n=1411) Uninfected cohort (n=5644)

8

9.3%

Modified log-rank P<0.001

6

4

3.3%

2

Cumulative incidence (%)

Cumulative incidence (%)

10

Acute coronary event HCV-infected, treated cohort (n=1411) HCV-infected, untreated cohort (n=1411) Uninfected cohort (n=5644)

8

6.1%

Modified log-rank P<0.001

6

4

5.3%

2

3.1%

1.1% 0

0 0

1

2

3 4 5 Time (years)

6

7

8

0

1

2

3 4 5 Time (years)

6

7

8

Š Elsevier 2014. Reproduced with permission from Hsu Y-C et al. Hepatology 2014;59:1293â&#x20AC;&#x201C;1302 43

Achieving an SVR is associated with multiple lifelong benefits Biochemical / virological • Negative HCV RNA for life in >99% of cases • Disappearance of HCV RNA in the liver and peripheral blood mononuclear cells • Negative detection of anti-HCV • Normalization of aminotransferases • Platelet increase in patients with thrombocytopenia Liver histology Ultrasound, elastography • Reversion to regular liver contours • Reduction in portal vein diameter in the case of portal hypertension • Disappearance of lymph nodes near the hepatic hilum and splenomegaly • Normalization of Fibroscan® values Clinical events • Reduced risk of progression to cirrhosis, decompensated liver disease and liver cancer, and recurrence after transplantation • Reversion of cirrhosis in some cases

Extrahepatic involvement • Improvement of extrahepatic manifestations Wellbeing, quality of life • Improved quality of life (disappearance of asthenia, fatigue, general wellbeing) • Reduced psychological impact (anxiety/depression) • Reduced personal, family and social stigma Survival • Reduced risk of mortality by any cause Transmission • Elimination of transmission risk (sexual, injection drug users and perinatal) • Public health benefits Economic • Cost-effectiveness of treatment • Decreased health insurance premiums, and immediate and long-term healthcare costs Marinho RT et al. J Gastrointestin Liver Dis 2014;23:85–90 44

From IFN to DAA

106年度健保給付 C型肝炎全口服新藥 必治妥 ASV/DCV

艾伯維 3D (PrOD)

1. 曾經參加「全民健康保險加強慢性B型及C型肝炎治療計畫」且使用干 擾素加ribavirin治療失敗者 2. 自費使用干擾素加ribavirin治療失敗者

Indication

Fibrosis

F3 or F4

NS5A RAS

Wild type

No need to check

24 wks

12 wks

1a without cirrhosis

No indication

+Ribavirin, 12 wks

1a with cirrhosis

No indication

+Ribavirin, 24 wks

Yes

Yes

Contraindication

Contraindication

Treatment duration 1b

Compensation Decompensation

等同METAVIR system纖維化大於或等於F3之定義為 1. 肝臟纖維化掃描 (Fibroscan)≧9.5Kpa或 ARFI≧1.81。 2. Fibrosis-4 (FIB-4)≧3.25，計算公式為[Age(years) × AST(U/L)] / [Platelet count(109/L) × √ALT(U/L)]。

超音波檢查結果為肝硬化加脾臟腫大或食道或胃靜脈曲張等同肝纖維化F4

(五) 個案接受治療後，醫事服務機構必須依時序登錄個案後續追蹤之病毒量 及相關檢驗結果（使用後第4週、療程結束時及療程結束後第12週），並 於療程結束後12週登錄完成病毒量檢查及相關檢驗結果時通報「結案」。 (六) 個案開始治療後之前8週，宜每次處方2週藥量，並觀察病患用藥反應。 (七) 接受治療之個案，應在同一位醫師照護下之完成療程。 (八) 每位個案僅能選用一種治療組合，並限給付一個療程。 (九) 接受治療之個案，有下列情形之一者，必須停止後續治療： 1. 中途放棄或中斷治療超過1週 2. 服藥後4週，經檢驗病毒量未降低100倍以上 3. 其他因素，經專業醫療評估必須停藥者

AASLD/IDSA Guideline The assessment of HCV viral load at week 4 of therapy is useful to determine initial response to therapy and adherence.

If HCV RNA is detectable at week 4 of treatment, repeat quantitative HCV RNA viral load testing is recommended after 2 additional weeks of treatment (treatment week 6). If quantitative HCV viral load has increased by greater than 10-fold (>1 log10 IU/mL) on repeat testing at week 6 (or thereafter), then discontinuation of HCV treatment is recommended.

EASL Guideline In patients treated with an IFN-free regimen, HCV RNA or HCV core antigen levels should be measured at baseline, between week 2 and 4 for assessment of adherence (optional)

Overview • Drug Adherence • Side effects • Drug-drug interactions (DDIs)

Drug Adherence

* Keep Record is a good choice

Drug Adherence

• 坦克干 Dalinza: Once Daily

夏奉寧 Harvoni: Once Daily

• 速威干 Sunverpra: Twice Daily

索華迪 Sovaldi: Once Daily

需隨餐

When Patients Forgot to Take?

夏奉寧 Harvoni: Once Daily

When Patients Forgot to Take?

• 坦克干 Dalinza: Once Daily • 速威干 Sunverpra: Twice Daily

When Patients Forgot to Take?

需隨餐

Safety and Monitoring during DAA treatment Liver enzyme monitoring (Safety)

DAA is safe

But a few patients have allergy, such as skin rash (around 1%)

Emergent Grade 3–4 Laboratory Abnormalities During 24 Weeks of DUAL Treatment Parameter ALT, n (%) AST, n (%) Total bilirubin, n (%) Hemoglobin, n (%) Platelets, n (%) Absolute lymphocyte count, n (%) Absolute neutrophil count, n (%) Lipase, n (%)

Immediate DUAL treatment N=155

Placebo-deferred DUAL treatment N=51

Overall

7 (5)a 5 (3)a 1 (1) 3 (2) 1 (1) 0 (0) 1 (1) 3 (2)

2 (4)b 1 (2)b 0 (0) 0 (0) 0 (0) 1 (2) 0 (0) 0 (0)

9 (4) 6 (3) 1 (<1) 3 (1) 1 (<1) 1 (<1) 1 (<1) 3 (1)

N=206

•

Emergent grade 3–4 laboratory abnormalities were infrequent (overall incidence ≤4%)

•

9 patients had emergent grade 3–4 ALT and/or AST abnormalities – All reversed rapidly (within 8–11 days)c either during or post-completion of DUAL treatment

a1

patient with concomitant but reversible treatment-related grade 3 ALT and AST laboratory abnormalities discontinued due to additional symptoms of jaundice and nausea (patient achieved SVR12); b1 patient who experienced vomiting, decreased appetite and myalgia (all resolved), plus grade 3 ALT and AST abnormalities (both reversible), interrupted DUAL treatment for 2 days (patient achieved SVR12); cMedian times to reversal: 11.0 days for ALT abnormalities; 8.5 days for AST abnormalities.

Safety During the 12-Week Double-Blind Phase Parameter AEs leading to discontinuation, n (%) Serious AEs, n (%) AEs (any grade), ≥5%, n (%) ALT elevation AST elevation Hypertension Upper respiratory tract infection Platelet count decrease Pyrexia On-treatment grade 3–4 laboratory abnormalities, n (%) ALT AST Total bilirubin Hemoglobin

• aHEV

Immediate DUAL treatment N=155 0 (0) 5 (3)b

Placebo-deferred DUAL treatment N=52 1 (2)a 3 (6)a,c

5 (3) 2 (1) 11 (7) 10 (6) 3 (2) 1 (1)

12 (23) 8 (15) 4 (8) 3 (6) 4 (8) 3 (6)

1 (1) 1 (1) 1 (1) 3 (2)

5 (10) 3 (6) 0 (0) 0 (0)

Safety was comparable between patients treated with DUAL and placebo, although aminotransferase elevations were more frequent in patients who received placebo

infection and liver injury (n=1); bTreatment-related: study drug overdose (n=2); Unrelated to treatment: ventricular extrasystoles (n=1), acute cholecystitis (n=1), intervertebral disc protrusion (n=1); cALT elevation (n=1), coronary artery disease (n=1).

ASV/DCV phase III studies: hepatic safety overview Safety Any SAE (%) Grade 3/4 ALT increase (%) Time to grade 3â&#x20AC;&#x201C;4 ALT increase (time to first ALT elevation) (weeks) Time from grade 3â&#x20AC;&#x201C;4 ALT elevation to reversal (weeks) Grade 3/4 bilirubin increase (%) Hepatic decompensation in patients with hepatic adverse events Study drug discontinuations Discontinuations due to any adverse event (%) Discontinuations due to increase in ALT/AST (%) SVR in discontinuations due to increase in ALT/AST (%)

AI447-0261

AI447-0282

AI447-0313

5.9

6.0

4.3

7

2

10.1

10

16

9

2.5

3.6

3.5

0.9

0.5

0

None

None

None

4.9

1.6

5.0

4.5

0.8

4.2

80

86

100

ALT, alanine aminotransferase; AST, aspartate aminotransferase; SAE, serious adverse event; SVR, sustained virologic response at post-treatment follow-up Week 12.

1. Kumada et al. Hepatology. 2014;59:2083. 2. Manns et al. Lancet. 2014;384:1597. 3. Kumada et al. J Gastrol Hepatol. 2015: DOI:10.1111/jgh.13073..

ONYX-I: PrOD in Noncirrhotic GT1b HCV-infected Asian Patients Post-Baseline Laboratory Abnormalities •

Post-baseline laboratory abnormalities with grade ≥3 were rare

•

Elevations in ALT and bilirubin levels did not associate with each other, or with clinical symptoms, and were all resolved without treatment interruption or discontinuation Arm A: 3-DAA N=325

Arm B: Placebo N=325

2 (0.6)

2 (0.6)

0

0

9 (2.8)*

49 (15.1)

2 (0.6)*

13 (4.0)

Grade ≥2

6 (1.8)*

22 (6.8)

Grade ≥3

4 (1.2)

8 (2.5)

Grade ≥2

33 (10.2)*

8 (2.5)

Grade ≥3

1 (0.3)

0

Hemoglobin Grade ≥2 Grade ≥3 Alanine aminotransferase (ALT) Grade ≥2 Grade ≥3 Aspartate aminotransferase (AST)

Total Bilirubin

*Difference from Arm B statistically significant (p ≤ 0.5).

ONYX-II: PrOD Cirrhotic GT1b HCV-infected Asian Patients • •

Post-baseline laboratory abnormalities with grade ≥3 were rare In general, cases of bilirubin increase were asymptomatic, transient and were not associated with other abnormal liver function

Post Baseline Laboratory Abnormalities

Total N=104

Hemoglobin Grade ≥2

10 (10)

Grade ≥3

0

Alanine aminotransferase Grade ≥2

4 (4)

Grade ≥3

3 (3)

Aspartate aminotransferase Grade ≥2

2 (2)

Grade ≥3

2 (2)

Total bilirubin Grade ≥2

52 (50)

Grade ≥3

7 (7)

Laboratory Abnormalities of PrOD Treatment SAPPHIRE I / II

PEARL II / III / IV

TURQOISE II

TURQOISE III

3D + RBV x 12 wks (n=770)

3D X 12 wks (n=509)

3D + RBV x 12-24 wks (n=380)

3D x 12 wks (n=60)

0.8% (6/770)

0.3% (2/509)

2.1% (8/380)

0%

Grade 2: 8-10 g/dl

5.4% (41/765)

0%

7.9% (30/380)

1.7% (1/60)

Grade 3: 6.5-8 g/dl

0.1% (1/765)

0%

0.8% (3/380)

0%

Grade 4: <6.5 g/dl

0%

0%

0.3% (1/380)

0%

Grade 3: 5-20x

0.8% (6/765)

0.2% (1/509)

1.1% (4/380)

1.7% (1/60)

Grade 4: >20x

0.4% (3/765)

0%

0.5% (2/380)

0%

Grade 3: 3-10x

2.5% (19/765)

0.4% (2/509)

9.7% (37/380)

0%

Grade 4: >10x

0.1% (1/765)

0%

0%

0%

Discontinuation for adverse event Hemoglobin

ALT

Total bilirubin

Fatal hepatic failure after 3D therapy in a patient with Child A liver cirrhosis

T.Bil mg/dl

• A 64-year-old male with HCV-LC, HCC post RFA and partial hepatectomy on Jun 2016 received Viekirax 2# QD and Dasabuvir 1 # bid since 26 Sep 2016 • 2016/6/20 pre OP, Alb 3.8 g/dL, GOT 82 U/L, GPT 95 U/L, T.bil 1.4 mg/dL, PT 10.9 sec, INR 1.07, PLT 98 • 2016/6/29 post OP 106-6-29 T.bil 2.2 mg/dL, alb 3.0 g/dL, PT 13.3 sec, INR 1.3

Alb 3.7 PT 11.9 GOT 126 GPT 94

28-Jul 4-Nov

26-Sep

GOT 112 GPT 73 PT 16.3 INR 1.6

HCV-RNA(-) GOT 53 GPT 39

13-Oct (W2)

20-Oct (W3)

27-Oct

GOT 121 PT 17.5 GPT 96 Cr 4.0 PT 17.5 NH3 214 Cr 2.4

Expire 2-Novd

Overview • Drug Adherence • Side effects • Drug-drug interactions (DDIs)

DAAs are involved 4 Major Metabolic Pathways

Dick TB, et al. Hepatology 2016; 63:634â&#x20AC;&#x201C;643.

DDI Risk in Different DAA

Expert Opin. Drug Metab. Toxicol. (2014) 11(3)

Source of DAA

EASL Guideline

Liverpool http://www.hep-druginteractions.org/printable_charts

1. Less drugs 2. Update annually

1. More drugs 2. Update monthly 3. APP support

DDI Risk in Different DAA

Conclusion Risk for Failure

• Drug Adherence – Take the DAA everyday (keep record) – Understand how to rescue when loss – Take the 3D with meal

• Side effects • Drug-drug interactions (DDIs) – – – – –

Metabolized through 4 enzymes Higher ratio in elderly patients Amiodarone/ Lipitor/ Crestor Don’t take herbal medicine at the same time.

2 resources: EASL and Liverpool

感謝聆聽