Workshop tatalaksana hepatitis C 2017

1. Curriculum Vitae
Name:
A Muhammad Luthfi Parewangi
Place - Date of Birth: Wajo, Dec 2th 1970
Institution:
Division of Gastroenterohepatology, Departemen
of Internal Medicine, Hasanuddin University
Centre of Gastroenterology-Hepatology “HAM Akil”
Wahidin Sudirohusodo Hospital Makassar
Education:
1999: Medical Doctor, Hasanuddin university, Makassar
2007: Internal Medicine, Hasanuddin university, Makassar
2014: Consultan of Gatroentero-Hepatology, Hasanuddin university, Mks.
2015: Doctoral Program, Pascasarjana, Hasanuddin university, Makassar
Adv Training:
2015: Advanced therapeutic endoscopy, Cho Ray Hosp, Saigon
2016: The Training Program on the Advanced Technique of Endoscopy, Kobe, Japan
2017: Advanced ERCP-EUS course, Rajavithy Hosp, Bangkok, Thailand
2018: Advance Therapeutic Endoscopy Hands-On workshop in ESD, TTS Hosp, Singapore
Interest:
Hepatology, Cholangio-Pancreatology, Gastroenterology
Diagnostic and Advanced Therapeutic Endoscopy

2. Tatalaksana HCV
Konsensus HCV Indonesia 2017
AM Luthfi Parewangi
Centre of Gastroenterohepatology “HAM Akil”, Wahidin Sudirohusudo Hospital
Division of Gastroenterohepatology, Departement of Internal Medicine, Hasanuddin University, Makassar, Indonesia
https://luthfiparewangi.participoll.com/

4. Seberapa sering Anda menemukan kasus
Hepatitis C di tempat Anda berpraktek
A. Tidak pernah
B. 1 kasus / minggu
C. 1 kasus / bulan
D. 1 kasus / tahun
E. 1 kasus / 1 dekade
0
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A B C D

5. Global incidence of hepatitis C
1.. Ghany MG et al. Hepatology. 2009;49:1335-13741; 2. Sy T et al. Int J Med Sci. 2006;3:41-46;
31.9
13.1
21.3
8.9
32.3
62.2
0
10
20
30
40
50
60
70
Africa Americas Eastern
Mediterranean
Europe Southeast
Asia
Western
Pacific
Patients(Millions)
• World Health Organization (WHO) estimates that
~170 million people are infected with hepatitis C worldwide1
• Estimated hepatitis C infections, by region2

9. Apa manifestasi Hepatitis yang paling sering
Anda dapatkan
A. Asymptomatis
B. Sympromatis ringan
C. Fibrosis
D. Sirosis
E. hepatoma
0
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A B C D E

10. Infeksi KronisHepatitis Kronis

11. Perjalanan Klinis Hepatitis B & C
30–50 Tahun
Infeksi
Akut
Resolution
HBK Karier
Hepatitis
Kronis
KematianSirosis
Stabil
Progresif
Sirosis
Kompensata
Kanker Hati
Sirosis
Dekompensata
(Kematian)
10-30%

12. Source: WHO 2016. Guidelines for the screening, care and treatment
of persons with hepatitis C infection (Updated)
Manifestation of HCV infection

13. Hadziyannis SJ. J Eur Acad Dermatol Venereol. 1998;10:12-21
HCV Infection: Extrahepatic Manifestations
Hematologic
• Mixed cryoglobulinemia
• Aplastic anemia
• -cell lymphoma
Dermatologic
• Porphyria cutanea tarda
• Lichen planus
• Cutaneous necrotizing
vasculitis
Renal
• Glomerulonephritis
• Nephrotic syndrome
Endocrine
• Anti-thyroid antibodies
• Diabetes mellitus
Salivary
• Sialadenitis
Ocular
• Corneal ulcer
• Uveitis
Vascular
• Necrotizing vasculitis
• Polyarteritis nodosa
Neuromuscular
• Weakness/myalgia
• Peripheral neuropathy
• Arthritis/arthralgia
Autoimmune Phenomena
•CREST syndrome
Patients my come with these diseases

14. Bagaimana Anda mendiagnosis Hepatis C
A. Gejala klinis
B. Pemeriksaan Fisis
C. Pemeriksaan SGPT
D. Pemeriksaan anti-HCV
E. Pemeriksaan HCV-RNA
0
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A B C D E

15. PEMERIKSAAN
LABORATORIUM
PEMERIKSAAN
BIOKIMIA
PEMERIKSAAN
SEROLOGI
PEMERIKSAAN
MOLEKULAR

16. Pasien dating dengan anti-HCV reaktif kepada
Anda, Apa rencana Anda?
A. Periksa SGPT
B. Periksa ultrasonografi
C. Periksa derajat fibrosis
D. Periksa viral load: HCVRNA
0
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A B C D

20. Apakah semua pengidap virus Hepatitis C
mesti diobati?
A. Ya
B. Tidak
0
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A B

22. TUJUAN TERAPI
• Tujuan terapi antiviral adalah eradikasi virus
hepatitis C untuk mencegah komplikasi
penyakit hati, fibrosis, sirosis, karsinoma
hepatoselular, dan kematian.
EASL Recommendations on Treatment of Hepatitis C 2016, Article in Press.

23. Apa pilihan terapi pada Hepatitis C
A. Hepatoprotektor
B. Imunomodulator
C. Ribafirin (ROB)
D. Interferon (IFN)
E. Direct Antigen Antiviral (DAA)
0
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A B C D E

24. 0
10
20
30
40
50
60
70
80
6%
16%
34%
42% 39%
54-56%
67-75%
SVR(%)
Treatment regimen and duration
Strader &Seeff, Clinical Liver Disease 2012; 1:6-11
2001
1998
2011
Standard IFN
RBV
PegIFN
1991
DAAs
IFN Monotherapy
Evolution of Hepatitis C Therapies:
SVR rates for HCV infections (genotypes 1–3)

25. 0
10
20
30
40
50
60
70
80
6%
16%
34%
42% 39%
54-56%
67-75%
SVR(%)
Evolution of Hepatitis C Therapies:
SVR rates for HCV infections (genotypes 1–3)
according to the treatment regimen and duration
Treatment regimen and duration
Strader &Seeff, Clinical Liver Disease 2012; 1:6-11
2001
1998
2011
Standard IFN
RBV
PegIFN
1991
First generation
DAAs
IFN Monotherapy
Severe
adverse
reactions

28. • Nucleoside/nucleotide
• Non-nucleoside
…
previr
… buvir
… asvir

29. NS3/NS4
Inhibitor
NS5A Inhibitor
WHO Registration: 25 March 2015NS5B Inhibitor
Cyclophilin
Inhibitor
NucleosideN
S5B inhibitor
Non-
Nucleoside
NS5B inhibitor

31. HCV Therapy with Interferon Regimens
Four Patterns of Non-Response
“Breakthrough”
Relapse
“Non-response”
Response
to Continued
Treatment
Adapted from Pawlotsky JM, Hepatology vol. 32, #5, 2000
HCVRNA
Initial
IFN-Based
Treatment
“Nonresponse”
Based on EVR
LLD
Post-Treatment
Observation

32. Approved Direct-Acting Antiviral Agents (DAAs)
Bertino G et al. World J Hepatol. 2016;8:92; REBETOL®
Prescribing Information 2016;
ZEPATIER™ Prescribing Information 2016.
Ribavirin
NS5B
Non-NUC
Inhibitors
(NNI)
NS5B
NUC
Inhibitors
NS3
Protease
Inhibitors
NS5A
Replication
complex
Inhibitors
3’UTR5’UTR Core E1 E2 NS2
p7
NS4B
4A
NS3 NS5A NS5B
Boceprevir (BOC)
Telaprevir (TVR)
Simeprevir (SMV)
Paritaprevir (PTV)
Grazoprevir (GRZ)
Daclatasvir (DCV)
Ledipasvir (LDV)
Ombitasvir (OMV)
Elbasvir (EBR)
Velpatasvir
Dasabuvir (DSV)Sofosbuvir (SOF)

33. Availability of DAAs in Indonesia*
Name of DAA Registration status Remark
Sofosbuvir Original (Sovaldi)
Generic (Myhep)
Approved
Daclatavir Generic (Mydekla) Waiting for approval Can be obtained
through Special
Access Service
Simeprevir Original (Olysio) Approved
Grazoprevir &
Ebasvir
Zepatier Waiting for approval
Veltaspavir Epclusa (original) or
Generic
To be registered (end
of 2017)
*as per 30July 2017

34. April 2016

35. April 2016

36. April 2016

37. April 2016

45.  Clinical manifestation: HIV and HCV
 Treatment
 Evolution of Treatment
 Direct Acting antiviral (DAA)
 Three Important Issues
 Genotype preference
 HCV Resistance
 Drug-drug interaction
 A glance at Simeprevir
 Summary

46. The HCV Lifecycle is prone to Resistance
Echeverría N et al. World J Hepatol. 2015;7:831; Rong L et al.
Science Trans Med. 2010;2:30ra32;
Soriano V et al. J Antimicrob Chemother. 2008;62:1; Expert
Opinion: R Gish, 2016.
46
• High viral turnover rate
1012 virions/day
• Error-prone RNA polymerase
~1 error per 10,000 bases
Involved twice in replication
• No overlapping reading frames

47. Mechanisms of Resistance
Resistant
Sensitive
(wild-type)
Mechanisms of Resistance
Stop
Or Change
Drug
Low
Viral Fitness
of Resistant
Population
High
Viral Fitness
of Resistant
Population
Sensitive
Persistence of
Resistant Virus
Sensitive
Resistant
Add
Drug
Resistant
Outgrowth of
Sensitive Virus
Resistant variants
pre-exist in all
patients

48. Combined with Fixed dose
(Brand name)
Sofobuvir-based + Ribavirin
+ Ledispavir Harvoni
+ Simeprevir
+ Daclastavir
+ Veltaspavir Eclupsa
Non-sofosbuvir +Ombitasvir/paritaprevir/ritonavir Technivie
+Ombitasvir/paritaprevir/ritonavir and
Dasabuvir
Viekira Pak
Elbasvir/grazoprevir Zepatier
To prevent resistance:
Always combine DAAs with different targets

49.  Clinical manifestation: HIV and HCV
 Treatment
 Evolution of Treatment
 Direct Acting antiviral (DAA)
 Three Important Issues
 Genotype preference
 HCV Resistance
 Drug-drug interaction (DDI)
 A glance at Simeprevir
 Summary
Outline

50. Slide credit: clinicaloptions.com
HCV/HIV DDIs With Components of Selected
ART Regimens
SOF + SIM SOF/LDV SOF + DCV
PTV/RTV/OBV
+ DSV
GZR/EBV
Atazanavir + RTV     
Darunavir + RTV     
Raltegravir     
Dolutegravir     
Elvitegravir + COBI     
Elvitegravir/COBI/
TAF/emtricitabine
 *  * 
Efavirenz     
Rilpivirine     
Abacavir/lamivudine   †  
Tenofovir DF/
emtricitabine


nephrotoxicity
  
Adapted from AASLD/IDSA Guidelines. February 2016.
No clinically significant
interaction expected
Potential interaction may require adjustment to
dosage, timing of administration, or monitoring
Do not coadminister
*EVG/COBI/TAF/FTC [package insert]. †Liverpool Drug Interactions Group.

51. Selected Potential Drug–Drug Interactions
AASLD/IDSA Guidelines. February 2016.
Concomitant Medication SOF SIM LDV PTV/RTV/OBV
+ DSV
DCV GZR/EBV
Acid-reducing agents* X X
Amiodarone X X X X X X
Anticonvulsants X X X X X X
Digoxin X X X X
Ethinyl estradiol–containing products X
Glucocorticoids X X† X X
PDE5 inhibitors X X X
Rifamycin antimicrobials X X X X X X
Sedatives X X X
St John’s wort X X X X X X
Statins X X X X X
*eg, proton pump inhibitors such as omeprazole. †Inhaled, intranasal.
Slide credit: clinicaloptions.com

52. In persons who have not received treatment for either
HCV or HIV
Patients with no/mild fibrosis, first initiate treatment for HIV
and achieve HIV suppression before starting HCV
treatment
• This is particularly in patients with lower CD4 counts (eg,
<200 cells/mm3
In patients with moderate-to-severe fibrosis and at risk of
rapid disease progression. HCV infection should be
treated first and then initiate therapy for HIV

53. In persons already in HIV treatment
1. Precaution should be taken:
• They are at higher risk of developing side-effects of HCV
therapy.
• The risk of DDIs may increase the risk of ART-related
hepatotoxicity in the presence of HCV infection.
2. ARV drug substitutions could be made before starting
HCV therapy, based on the following consideration:
• Where DDIs are likely,.
• In view of the short duration of HCV treatment.
3. It is particularly imperative to collaborate with the HIV-
treating doctors in HCV therapy

54. Recommendation for Drug–Drug Interactions
in HIV/HCV co-infection
Review all prescription and supplements
 Require careful selection of HCV regimen
 Is a ART change needed?
• Permanent switch vs only while on HCV treatment?
• DCV + SOF ± RBV is recommended when ART regimen changes
cannot be made to accommodate other DAAs
Some interactions may be minor, but don’t neglect it
• Monitor labs, Report symptoms, Adjust timing of medication
AASLD/IDSA Guidelines. February 2016.

55.  Clinical manifestation: HIV and HCV
 Treatment
 Evolution of Treatment
 Direct Acting antiviral (DAA)
 Three Important Issues
 Genotype preference
 HCV Resistance
 Drug-drug interaction
 A glance at Simeprevir
 Summary
Outline

56. Simeprevir
• Effective in HCV genotypes 1 and 4 infection in
combination with Sofosbuvir,
• Can be used in combination with the drugs
peginterferon and ribavirin
• Can be used in patients with ART medications and/or
kidney disorder.
• Can be used for rescue treatment

57. • No patient discontinued because of adverse
events.
• 10 of 16 had a rapid response (week 4).
• SVR12 was achieved by 14 of 16 patients;
Simeprevir as a rescue treatment
When Daclatasvir + Sofosbuvir fail..

58. Simeprevir for Kidney Disease

60.  Epidemiology
 Clinical manifestation: HIV and HCV
 Treatment
 Evolution of Treatment
 Direct Acting antiviral (DAA)
 Three Important Issues
 Genotype preference
 HCV Resistance
 Drug-drug interaction
 A glance at Simeprevir
 Summary
Outline

61. Summary
HIV/HCV coinfection:
• Priority population for treatment
• Higher morbidity and mortality than HCV monoinfection
HCV screening at HIV diagnosis and at least annually.
In HCV/HIV coinfection, treat HCV as though HCV
monoinfected, but consider drug–drug interactions[1]
• Drug–drug interactions may require careful selection of
HCV regimen or changes in HIV ART regimens
• DCV + SOF ± RBV is recommended when ART regimen
changes cannot be made to accommodate other DAAs
Need collaboration between Non-HIV providers and
the HIV provider

62. When Should Treatment Be Discontinued for
Lack of Efficacy?
 HCV RNA measurement recommended after treatment Wk 4 and at
12 wks posttreatment
• If HCV RNA detectable at Wk 4, repeat at Wk 6
• If HCV RNA increase is > 10 fold (or > 1 log10 IU/mL), stop treatment
• Do not stop treatment if HCV RNA levels are not available during therapy
 ALT measurement recommended after treatment Wk 4
• If 10-fold increase, stop treatment
• If ALT increase is < 10-fold but pt experiences weakness, nausea,
vomiting, jaundice, or elevated bilirubin, alkaline phosphatase, or INR,
stop treatment
• If increase < 10-fold and asymptomatic, repeat at Wk 6, Wk 8 and
consider stopping treatment if persistently elevated
AASLD/IDSA Guidelines. February 2016.

67. Nucleos(t)ide analogue
HBV Treatment can reduce risk of cirrhotic
complications and HCC
Peg-IFN
Sustained remission by immune modulation
Maintained remission by continuous viral suppression
HBeAg seroconversion
HBV DNA <2000 IU/ml
Normal ALT
Undetectable HBV DNA
Normal ALT
years
HBsAg loss
? HBeAg seroconversion
? HBsAg loss

68. OBAT
 Potensi
 Barier genetik
terhadap
resistensi
Faktor Resistensi Virus terhadap NA
PEJAMU
 Terapi
sebelumnya
 Kepatuhan
 BMI tinggi
VIRUS
 Kadar HBV DNA
 Mutasi yang
sudah ada (pre-
existing)

69. Kesimpulan
Identifikasi penderita hepatitis B Kronik dengan
pemeriksaan biokimiawi, serologi, dan Molekuler
Tatalaksana HBK sesuai dengan Konsensus
Pemilihan regimen terapi sangat penting dalam
mengoptimalkan hasil jangka pendek maupun
jangka panjang
Pemantauan selama terapi sangat penting
Mendokumentasikan pencapaian target demi target

71. KASUS 1

72. Identitas Pasien
Nama : Tn. IH
Tanggal lahir : 17 Maret 1981
Jenis kelamin : Male
Alamat : Makassar
MR : 854690
Status : Menikah
Rumah Sakit : Wahidin Sudirohusodo

73. ANAMNESIS
Keluhan Utama :
Mudah Lelah dialami sejak 3 bulan ini, lelah bertambah jika
pasien beraktivitas.
Melakukan medical check up dan didapatkan hasil Anti HCV
Reaktif.

74. Pemeriksan fisis
Tidak ada kelainan

75. LABORATORY FINDING
PARAMETER 29/11/2018 RESULT NORMAL RANGE
SGOT 59 < 38 U/L
SGPT 80 < 41 U/L

76. LABORATORY FINDING
PARAMETER 29/11/2018 RESULT NORMAL RANGE
AFP - 0-7,02 IU
PT/ INR 10,3/0,96
APTT 24,8
PARAMETER 29/11/2018 RESULT NORMAL RANGE
HbsAg Non reactive Negative
Anti HCV Reactive Negative

77. LABORATORY FINDING
PARAMETER 29/11/2018 RESULT NORMAL RANGE
HCV RNA 2,19 x 106 (log 6,34) Tidak Terdeteksi

78. USG Abdomen ( 29/11/2018)

79. Fibroscan 6/9/2018
16,3 kpa (F4 pada HCV)

80. Diagnosis

81. Terapi

82. KASUS 2

83. Identitas Pasien
Nama : Tn. NW
Tanggal Lahir : 21 Juli 1980
Jenis kelamin : Laki-laki
MR : 862168
Status : Menikah
Rumah Sakit : Wahidin Sudirohusodo

84. ANAMNESIS
Keluhan Utama :
Perut Membesar dialami sejak 1 bulan ini, perut terasa penuh
dan mudah kenyang, nyeri perut hilang timbul, mual dan
muntah tidak ada.
Kuning seluruh badan ada dirasakan sejak 1 tahun ini akan
tetapi pasien tidak pernah berobat, gatal pada badan tidak ada
Buang air kecil lancar, warna kuning teh.

85. Pemeriksan fisis
Tekanan Darah : 120/80, Nadi : 82 kali/menit, pernapasan
: 20 kali/menit, suhu : 36
Anemis tidak , ikterik ada
Abdomen : cembung, peristaltik ada, kesan normal, hepar
teraba 1 jari dibawah arcus costa, lien teraba schuffner: 2,
ascites ada shiffting dullnes (+)
Edema tidak ada, eritema palmaris ada

86. LABORATORY FINDING
PARAMETER 29/11/2018 RESULT NORMAL RANGE
WBC 4.330 4000-10.000 /uL
HB 13,9 12-16 gr/dL
PLT 76.000 150.000-400.000 /uL
NEUT 51,9 52-75 %
RBG 132 140 mg/dL
Ureum 7 10-50 mg/dL
Creatinin 0.50 < 1.1 mg/dL
SGOT 346 < 38 U/L
SGPT 155 < 41 U/L

87. LABORATORY FINDING
PARAMETER 29/11/2018 RESULT NORMAL RANGE
AFP 8,65 0-7,02 IU
PT/ INR 13,5/1,13
APTT 30,8
Bilirubin Total 3,63 < 1.1 mg/dL
Bilirubin Direk 2,61 < 0.3 mg/dL
PARAMETER 29/11/2018 RESULT NORMAL RANGE
Alkali Fosfatase 408 < 240 U/L
Gamma GT 824 7-32 U/L
HbsAg Non reactive Negative
Anti HCV Reactive Negative
4 Tidak Terdeteksi

88. USG Abdomen 29/11/2018

89. Diagnosis

90. Diagnosis
Sirosis Hepatis Decompensata CTP B ec Hepatitis C
kronik
Ikterus Intrahepatik

91. Terapi

92. Terapi
Sofosbuvir 400 mg/ 24 jam/oral
Daclatasvir 60 mg/ 24 jam/ oral
Ursodeoxyholic Acid 250 mg/ 12 jam/ oral

93. Follow Up

94. THANK YOU

95. THANK YOU