The document discusses updates to treatment of chronic hepatitis C virus (HCV) infection in 2017. It notes that approximately 200 million people worldwide are infected with HCV, with genotype 1 being the most common globally. New direct-acting antiviral (DAA) drugs have greatly improved treatment success rates for HCV compared to previous interferon-based regimens. Treatment is now recommended for all patients with chronic HCV infection except those with very short life expectancies. Various DAA combinations can achieve sustained virologic response rates of over 90% for genotypes 1-6, including for patients with advanced fibrosis or cirrhosis. Ongoing challenges include optimizing treatment for all genotypes, managing side effects, monitoring after treatment, and ensuring
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CẬP NHẬT ĐIỀU TRỊ VIÊM GAN VIRUT MAN NĂM 2017
1. CẬP NHẬT ĐIỀU TRỊ
VIÊM GAN VIRUS C MẠN
NĂM 2017
PGS.TS.TRẦN VĂN HUY
HỘI NGHỊ NỘI KHOA TOÀN QUỐC LẦN THỨ X
HUẾ - THÁNG 4/2017
2. ĐẶT VẤN ĐỀ
• Khoảng 200 triệu người trên thế giới nhiễm HCV
(Lavanchy D, 2009)
• HCV genotype 1 lại chiếm ưu thế trên toàn cầu,
ước tính chiếm từ 55-95%.
• Chưa có vắc xin phòng bệnh chủ động
• Một gánh nặng của y tế toàn cầu
6. • Các nghiên cứu về ĐT đã có các bước
tiến lớn, nhất là sự ra đời của các thuốc
kháng HCV trực tiếp (DAA)
7. Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD.
SVR(%)
IFN
6 mos
PegIFN/ RBV
12 mos
IFN
12 mos
IFN/RBV
12 mos
PegIFN
12 mos
2001
1998
2011
Standard
IFN
RBV
PegIFN
1991
DAAs
PegIFN/
RBV/
DAA
IFN/RBV
6 mos
6
16
34
42
39
55
70+
0
20
40
60
80
100
ĐIỀU TRỊ HCV QUA CÁC GIAI ĐOẠN
2014/5
90-98
PegIFN/
RBV/
DAA
Or DAA+RBV
8. THÁCH THỨC !
– Phác đồ tiếp cận cho toàn bộ genotype
– Điều trị cho bn xơ gan, bệnh thận mạn
– Quản lý, theo dõi sau điều trị
– Điều trị lại sau thất bại với DAA
– Dự phòng tái hoạt hóa HBV sau DAA
– Dự phòng kháng thuốc
– Khả năng tiếp cận điều trị
– Hiệu quả thực sự của các thuốc generic!!!
→ đòi hỏi tiếp tục nghiên cứu & cập nhật thường
xuyên về điều trị VGC!
9. CÁC NỘI DUNG CHÍNH
1. Mục tiêu điều trị
2. Chỉ định điều trị
3. Đánh giá trước, trong và sau điều trị
4. Phương tiện điều trị
5. Tóm tắt hướng dẫn của WHO-2016
6. Một số điều trị mới
10. 1. Mục tiêu và điểm kết của
điều trị
• Mục tiêu điều trị : tiệt trừ nhiễm HCV, hạn chế nguy
cơ xơ gan, ung thư gan
• Điểm kết của điều trị : đáp ứng virus bền vững (SVR).
• Khi đạt được SVR, khả năng tiệt trừ HCV lên đến 99%
12. SVR12 # SVR24 ?
• January 2015 Hepatology,
• Eric Yoshida et al
• So sánh SVR12 & SVR24 bn dùng sofosbuvir.ở
• 779 bn có SVR 12: 777 bn có SVR- 24 (99.7%)
• 2 bn ko có SVR-24: đ u là genotype 3ề
• Ko tính 2 bn genotype 3: 100% bn có SVR -12
đ u có SVR24.ề
13. Gastroenterology 2010 139, 1593-1601DOI: (10.1053/j.gastro.2010.07.009)
A Sustained Virologic Response Is Durable in Patients With Chronic Hepatitis C Treated
With Peginterferon Alfa-2a and Ribavirin
Mark G. Swain, Gastroenterology , 2010
14. Gastroenterology 2010 139, 1593-1601DOI: (10.1053/j.gastro.2010.07.009)
A Sustained Virologic Response Is Durable in Patients With Chronic Hepatitis C Treated
With Peginterferon Alfa-2a and Ribavirin
Mark G. Swain, Gastroenterology , 2010
SVR # CURE !!!
15. Ý NGHĨA LÂM SÀNG C A SVR?Ủ
• Cải thiện chức năng gan & men gan (*)
• 39% to 73%: cải thiện xơ hóa gan (*)
• Xơ gan thoái triển trên 50% bn (**)
• Tăng áp cửa, cường lách: cải thiện (***)
• Giảm >70% HCC nguy cơ ung thư gan (***)
(*)Poynard 2002, (**)Veldt 2007, (***)Van der
Meer, 2012; (****): Morgan 2013.
16. BENEFITS OF ACHIEVING SVR
↓ Cirrhosis
↓ Decompensation
↓ HCC
↓ Transplantation
↓ All-cause mortality
Improved QoL
Malignancy
Diabetes
CVD
Renal
Neurocognitive
Cure
Improved clinical
outcomes[1,2]
1. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19.
2. Negro F, et al. Gastroenterology. 2015;149:1345-1360.
3. George SL, et al. Hepatology. 2009;49:729-738.
Hepatic Extrahepatic
Decreased
transmission[1]
18. WHO 2016
• bệnh gan tiến triển (F3–F4)
• Có các yt nguy cơ thúc đẩy xơ hóa gan nhanh:
- đồng nhiễm HIV hoặc HBV
- nghiện rượu nặng
– Hội chứng chuyển hóa
– biểu hiện ngoài gan…
19. AASLD- IDSA 2016
• Treatment is recommended for all patients
with chronic HCV infection, except those with
short life expectancies that cannot be
remediated by treating HCV, by transplantation,
or by other directed therapy.
• Patients with short life expectancies owing to liver disease should be
managed in consultation with an expert.
20. HCV CURE ASSOCIATED WITH IMPROVED 15-YR
SURVIVAL IN PTS WITH F0/F1 DISEASE
• Single-center cohort of consecutive pts since 1992 (N = 1381)
• Progression to F3/F4 was observed in 15.3% of F0/F1 pts with available liver
biopsy (n = 157)
Jézéquel C, et al. EASL 2015. Abstract P0709.
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 20
Yrs From Biopsy to Death
F0/F1 Fibrosis
P = .003
Treated pts without SVR
Untreated pts
Treated pts with SVR
Survival
21. 3. ĐÁNH GIÁ TRƯỚC ĐIỀU TRỊ
• Định lượng HCV RNA , ngưỡng phát hiện ≤ 15
IU/ml; lý tưởng là Real-time PCR
• Đánh giá bệnh lý gan trước khi điều trị
- SGOT, SGPT
- SA bụng
- Tiểu cầu
- Child- Pugh
22. 3. Đánh giá trước điều trị (tt)
- Đánh giá xơ hóa gan:
- FibroScan, ARFI
- Các chỉ điểm huyết thanh (fibrotest, APRI…) (F2-
F4)
• Xác định các kiểu gen
• IL28B: phác đồ có PEG ?
23. • Nghiện rượu
• Thuốc lá
• NASH
• Tiểu đường
• Chức năng thận, Ferritin
• Đồng nhiễm: HBsAg, anti HIV
3. Đánh giá trước điều trị (tt)
24. Tiên đoán đáp ứng điều trị
Các yếu tố quan trọng nhất :
• Kiểu gen HCV
• Giai đoạn xơ hóa gan
• Tiền sử điều trị hay chưa ĐT
• Bệnh thận đi kèm…
• IL 28 B (?)
29. KHÔNG QUÊN THEO DÕI SAU
ĐIỀU TRỊ/SAU SVR !
• HCV RNA, chức năng gan
• AFP
• SIÊU ÂM BỤNG
• 6 tháng
30. 4. HIỆU QUẢ CỦA MỘT SỐ
PHÁC ĐỒ ĐIỀU TRỊ HIỆN NAY
• INTERFERON- FREE REGIMENS
• DAA:
# Direct Acting Antiviral
31. HCV LIFECYCLE & DAA TARGETS
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Receptor binding
and endocytosis
Fusion
and
uncoating
Transport
and release
(+) RNA
Translation and
polyprotein
processing
RNA replication
Virion
assembly
Membranous
web
ER lumen
LD
LD
ER lumen
LD
NS3/4
protease
inhibitors
NS5B polymerase
inhibitors
*Role in HCV lifecycle not well defined
NS5A* inhibitors
34. 0
20
40
60
80
100
SVR(%)
SOF/ LDV +/-
RBV x 8-12 wks
97-100% 93-100%
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
Poordad F, et al. EASL 2014. Abstract O163
2015 /2016 : Genotype 1 : điều trị lần đầu:
nhóm không xơ gan và nhóm xơ gan
ABT 450/rtv + ombitasvir
+ dasabuvir+RBV
X 12 wks
35. 0
20
40
60
80
100
SVR(%)
SOF/ LDV +/-
RBV 12-24 wks
82-100% 93-100%
2015 /2016: G1, ĐÃ TỪNG ĐIỀU TRỊ:
ABT 450/rtv + ombitasvir
+ dasabuvir+RBV
X 12 -24 wks
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.
36. 0
20
40
60
80
100
SVR(%)
PegIFN/RBV
X 24 wks
70-80%
97%
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
GENOTYPE 2 VÀ 3, ĐIỀU TRỊ LẦN ĐẦU
Geno 2
SOF+RBV
X 12 wks
92-94%
Geno 3
SOF+RBV
X 24 wks
Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
37. LDV/SOF+ RBV Ở BN HCV CÓ XƠ GAN
MẤT BÙ
SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis
CTP B CTP C
SVR12(%)
26/30 19/22 18/2024/27
Error bars represent 90% confidence intervals.
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
T l SVR t ng t tu n 12 ho c 24 c a LDV/SOF + RBVỷ ệ ươ ự ở ầ ặ ủ
Flamm, AASLD, 2014, Oral #239
38. Ascites Hepatic Encephalopathy
Patients, n
SOF + RBV
n=25
Observation
n=25
SOF + RBV
n=25
Observation
n=25
Baseline 6 9 5 2
Week 12 5 8 3 3
Week 24 0 7 0 4
Platelets (103
/µL) Albumin (g/dL)
SOF+RBV Observation 24 weeks
ALT (U/L)
CTP A CTP B
Afdhal N, EASL, 2014, O68
p=0.003
p=NS
p=0.001 p=0.001
‡
XƠ GAN MẤT BÙ DO HCV
39. CÁC TRỊ LIỆU CÓ SẴN NĂM 2016-2017
Regimen Approved
Genotypes
Grazoprevir/elbasvir 1, 4
Ombitasvir/paritaprevir/rit
onavir
4
Ombitasvir/paritaprevir/rit
onavir + dasabuvir
1
Sofosbuvir + daclatasvir 1, 3
Sofosbuvir/ledipasvir 1, 4, 5, 6
Simeprevir + sofosbuvir 1, 4
Sofosbuvir/velpatasvir 1, 2, 3, 4, 5, 6
Hữu hiệu cho các
kiểu gen
Dạng uống chứa 2
hoạt chất
hiệu quả cho tất cả
genotype !
40. SVR12 – GRAZOPREVIR/ELBASVIR- CHƯA
ĐIỀU TRỊPatients,%
All Patients
144/157 129/131299/316
92% 99%95%
GT1a GT1b GT4
100
%
18/18
0%
25%
50%
75%
100%
GT6
80%
8/10
40
Zeuzem S, et al. published on-line at Ann Intern Med
www.annals.org on 24-April-2015
Hiệu quả cao trên bệnh nhân xơ gan (SVR12 = 97.1%)
41. HCV KI U GEN 1 & 6 / BN ĐÃ ĐI U TR PEG-INF+ RBVỂ Ề Ị
35
35
37
37
35
38
39
39
61
67
58
64
62
66
62
62
* Per-protocol population excluded 12 patients [Lost to follow up (2 patients), Withdrew consent (2 patients), No
documentation for prior treatment failure classification (2 patients), Prohibited prior medical condition - ascites (1
patient), Non-medication-related non-compliance with study drug (1 patient), Illegal drug user (1 patient),
Prohibited medication (1 patient), Non-compliance due to adverse event (1 patient), Death (1 patient]
95% Confidence Intervals by the Clopper-Pearson (exact) method
42. SVR12- SVR12 – GRAZOPREVIR/ELBASVIR- X GANƠ
12 weeks 12 weeks 16/18 weeks
Chưa từng điều trị Thất bại với điều trị
LTFU/Early Discon. 1*
0 2†
1‡
0 0
SVR12 (mFAS)
98.5%
(135/137)
90.3%
(28/31)
92.3%
(48/52)
92.5%
(74/80)
93.9%
(46/49)
100.0%
(49/49)
Bùng phát 1 1 0 0 0 0
H i ngồ ứ 0 0 0 0 2 0
Tái phát 1 2 4 6 1 0
28
/31
48
/54
74
/81
46
/49
49
/49
*Death (coronary artery disease)
†Death (lymphoma) n=1;discontinued due to noncompliance, n=1 ‡Death (motor vehicle accident)
Patients,%
135
/138
43. SVR12: NHÓM CKD
0
50
25
75
100
Patients,(%)
94%
GZR/EBR 12 weeks
MFAS = primary efficacy analysis; FAS was a secondary analysis
*Noncirrhotic, interferon-intolerant patient with HCV GT1b infection relapsed at FW12
†lost to follow-up (n=2), n=1 each for death, non-compliance, withdrawal by subject, and withdrawal by
physician (due to violent behavior)
99%
115/116
Full Analysis
Set
Modified
Full Analysis
Set
Relapse 1* 1
Discontinued unrelated to Tx 0 6†
115/122
Elbasvir
(50 mg)
Grazoprevir
(50 mg)
45. HCV-TARGET: TÁC ĐỘNG CỦA BIẾN
CHỦNG RAV LÊN LDV/SOF & SMV + SOF
• Multicenter, prospective, observational cohort study
• GT1 HCV, LDV/SOF or SMV + SOF, each ± RBV
– Sequencing for RAVs with NGS using 10% threshold
– N = 492 in RAV prevalence analysis; n = 472 in efficacy analysis
• Overall prevalence of BL RAVs: NS3: 45%; NS5A: 13%;
NS5B: 8%; ≥ 2 classes: 10%
– NS3 RAVs more frequent in GT1a vs GT1b
– NS5A and NS5B RAVs more frequent in GT1b vs GT1a
Wang GP, et al. EASL 2016. Abstract PS102.
46. HCV-TARGET: LDV/SOF
Efficacy Analysis by Baseline RAVs
LDV/SOF:
- LDV RAVs (aa28, 30, 31, 58, 93) associated with
nonsignificant 1% to 7% SVR12 rate differences across
pt subgroups
- Y93 LDV RAV infrequent (4%) but associated
with significant decrease in SVR12 rate to
LDV/SOF: 96% vs 75% (P = .046)
Wang GP, et al. EASL 2016. Abstract PS102.
48. 6. TÓM TẮT CÁC KHUYẾN CÁO-2016
Bn HCV genotype 1 không ho c có x gan:ặ ơ
– ledipasvir/ sofosbuvir ± ribavirin
– daclatasvir/sofosbuvir ± ribavirin.
– Grazoprevir + Elbasvir
PD Thay th :ế
– simeprevir/sofosbuvir ± ribavirin
– ombitasvir/paritaprevir/ritonavir/ dasabuvir ±
ribavirin.
49. HCV- G2
• Bn HCV genotype 2 có ho c không x gan:ặ ơ
1+ Sofosbuvir/ ribavirin.
• PD Thay th :ế
2+ Daclatasvir/sofosbuvir.
50. HCV- G3
Bn HCV genotype 3 có ho c không x gan :ặ ơ
1.Daclatasvir/sofosbuvir
ho c 2.ặ sofosbuvir/ribavirin.
Bn HCV genotype 3 có x gan:ơ
3. Daclatasvir/sofosbuvir/ ribavirin.
PD Thay th G3 có x gan:ế ơ
4. Sofosbuvir + pegylated interferon/ribavirin.
51. HCV- G6
• Bn HCV genotype 6 có ho c không x gan:ặ ơ
1. Ledipasvir/sofosbuvir.
• PD Thay th :ế
2. Sofosbuvir/pegylated interferon/ribavirin.
52. AASLD & EASL 2015
• Đi u tr có th rút ng n 8 tu n:ề ị ể ắ ầ
– đi u tr l n đ uề ị ầ ầ
– không x ganơ
– HCV RNA<6×103
(6.8 log) IU/mL.
• Th i gian đi u tr nên rút ng n m t cách th nờ ề ị ắ ộ ậ
tr ng.ọ
• N u ti u c u <75 x 10ế ể ầ 3
/μL: ph i đi u tr 24ả ề ị
tu n & c n có ribavirin.ầ ầ
53. HBV-HCV
Bn đ ng nhi m HBV và HCV có th đi u tr v i thu cồ ễ ể ề ị ớ ố
kháng virus cho HCV
T l đ t SVR t ng t nh ng bn nhi m đ n đ cỷ ệ ạ ươ ự ở ữ ễ ơ ộ
HCV (66, 237).
Trong và sau đi u tr HCV n u có nguy c tái ho tề ị ế ơ ạ
HBV, c n ph i h p thu c kháng HBVầ ố ợ ố (224).
DDIs c n ki m tra tr c đi u tr .ầ ể ướ ề ị
54. AASLD 2016 Guidance on HBV Reactivation in
Pts Receiving HCV DAA Therapy
• All pts starting HCV DAA therapy should be assessed for HBV
infection (HBsAg, anti-HBs, and anti-HBc testing)
– If HBsAg+, assess HBV DNA prior to, during, and immediately
after HCV DAA therapy
• For active HBV infection: initiate HBV therapy before or
simultaneously with HCV DAA therapy
• For low or undetectable HBV DNA: monitor for HBV
reactivation during HCV DAA therapy
AASLD/IDSA HCV Guidelines. September 2016.
55. VGC TR EMẺ
DAA Không đ c s d ng tr emượ ử ụ ở ẻ
Đ n 2016: Duy nh t pegylated interferon/ribavirinế ấ
đ c khuy n cáo cho tr trên 2 tu i.ượ ế ẻ ổ
56. April 7, 2017/FDA News Release
• FDA approves two hepatitis C drugs for
pediatric patients
• The U.S. Food and Drug Administration
approved supplemental applications for
Sovaldi (sofosbuvir) and Harvoni (ledipasvir
and sofosbuvir) to treat hepatitis C virus (HCV)
in children ages 12 to 17.
57. 7. MỘT SỐ ĐIỀU TRỊ MỚI
• PAN- GENOTYPE
• SHORTER DURATION
• RETREATMENT
60. ASTRAL-1: SVR12 With Sofosbuvir/ Velpatasvir
in GT1, 2, 4, 5, 6 HCV
• Double-blind, placebo-controlled trial
– All pts with GT5 HCV allocated to active Tx because few pts in this group (n = 35)
– Key baseline characteristics: cirrhosis 19%; Tx exp’d 32%; BL NS5A RAVs 42%
• No impact of cirrhosis, Tx experience, BL NS5A RAVs on SVR rates
Feld JJ, et al. AASLD 2015. Abstract LB-2. Feld JJ, et al. N Engl J
Med. 2015;[Epub ahead of print]. Reproduced with permission.
HCV Genotype
99 98 99 100 100 97 100
41/
41
34/
35
116/
116
104/
104
117/
118
206/
210
618/
624
100
80
60
40
20
0
n/N =
SVR12(%)
All Pts 1a 1b 2 4 5 6
61. 100
ASTRAL-3 Open-Label Trial: SVR12, Safety With
Sofosbuvir/Velpatasvir in GT3 HCV
• SVR12 rate numerically lower with vs without BL NS5A RAVs (88% vs 97%)
• Safety profile similar to ASTRAL-1
Mangia A, et al. AASLD 2015. Abstract 249. Reproduced with permission.
Foster GR, et al. N Engl J Med. 2015;[Epub ahead of print].
n/N =
SVR12(%)
80
60
40
20
0
264/
277
221/
275
191/
197
163/
187
73/
80
55/
83
200/
206
176/
204
64/
71
45/
71
95
80
63
909797
87
91
66
86
All Pts No Yes Naive Experienced
Cirrhosis
P < .001
(superiority)
SOF/VEL 12 wks
SOF + RBV 24 wks
Treatment History
62. FDA APPROVES GILEAD’S EPCLUSA® (SOFOSBUVIR/VELPATASVIR)
FOR THE TREATMENT OF ALL GENOTYPES OF CHRONIC HEPATITIS C
• June 28, 2016
• Epclusa is the First and Only All-Oral, Pan-genotypic Single Tablet Regimen for
Chronic Hepatitis C Virus Infection
• Epclusa® (sofosbuvir 400 mg/velpatasvir 100 mg), the first all-oral, pan-genotypic,
single tablet regimen for the treatment of adults with genotype 1-6 chronic
hepatitis C virus (HCV) infection.
• Epclusa is also the first single tablet regimen approved for the treatment of
patients with HCV genotype 2 and 3, without the need for ribavirin.
• Epclusa for 12 weeks was approved :
– in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A)
– in combination with ribavirin (RBV) for patients with decompensated cirrhosis
(Child-Pugh B or C).
63. MK-3682 WITH RUZASVIR (MK-8408)
CHRONIC HEPATITIS C GENOTYPE 1, 2, 3, 4, 5, 6
• MK-3682 450 mg + Ruzasvir 60 mg
• 12 tu nầ
• Đang nghiên c uứ
64. ADDING VOXILAPREVIR TO SOFOSBUVIR/VELPATASVIR FOR 8
WEEKS: EFFECTIVE FOR HCV GENOTYPE 3: AASLD-2016
• Adding voxilaprevir to sofosbuvir and velpatasvir (Epclusa) for 8 weeks: similar
efficacy to sofosbuvir/velpatasvir alone for 12 weeks in the treatment of patients
with hepatitis C virus (HCV) genotype 3 and cirrhosis.
For the phase 3 POLARIS-3 trial, the researchers investigated the addition of voxilaprevir 100 mg/day to
sofosbuvir/velpatasvir 400 mg/100 mg/day for 8 weeks compared with sofosbuvir/velpatasvir 400 mg/100
mg/day alone for 12 weeks in 219 patients with genotype 3 HCV infection and cirrhosis.
The results showed that 96% of patients in each group achieved a sustained virologic response for at least 12
weeks after treatment (SVR12).
In looking at patients according to prior treatment, 96% of treatment-naïve patients in the voxilaprevir group
(72/75) achieved SVR12 compared with 99% of the sofosbuvir/velpatasvir group (76/77). Among those who
received prior treatment, 97% and 91% achieved SVR 12, respectively.
A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/ Voxilaprevir for 8 Weeks and Sofosbuvir/Velpatasvir for 12 Weeks for
Patients With Genotype 3 HCV Infection and Cirrhosis: The POLARIS-3 Study]
7.2 EVEN SHORTER DURATION !
65. CURE HEPATITIS C AFTER ONLY 4 WEEKS OF TREATMENT?
• RG-101: newly developed therapy , injection ; targets the microRNA in
the liver that is essential for hepatitis C virus to continue to replicate.
• 79 participants,
• ledipasvir/sofosbuvir (Group 1)
• simeprevir (Group 2)
• daclatasvir (Group 3).
• 2 mg/kg injection of RG-101 on days 1 and 29.
• SVR 12: 100% Group 1, 96% in Group 2, and 92% in Group 3
• After 24 weeks, 29 patients were available for follow-up:
– 100% in Group 1,
– 80% in Group 2,
– 89% in Group 3 were free of hepatitis C virus.
66. Dec 8, 2016 : GILEAD SUBMITS FDA :
INVESTIGATIONAL SINGLE TABLET
SOFOSBUVIR/VELPATASVIR/VOXILAPREVIR
• If Approved, SOF/VEL/VOX Would Be the First Once-
Daily Single Tablet Regimen Available as a Salvage
Therapy for Patients Infected with HCV Genotype 1-
6 Who Have Failed Prior Treatment with DAA
Regimens Including NS5A Inhibitors -
HCV New Drug Research, 2016
7.3 RETREATMENT
67. KẾT LUẬN
1. Điều trị viêm gan C đã có các bước tiến vượt bậc trong thời
gian qua
2. Các phác đồ uống với các DAA, không có interferon và không
có ribavirine: khả thi, hiệu quả, dung nạp tốt…
3. Các phác đồ hiện có hiệu quả tốt trên các nhóm bn chưa điều
trị/đã thất bại điều trị, có/ko có xơ gan, có bệnh thận mạn…
4. Cần có chiến lược điều trị, theo dõi hợp lý trước, trong và
ngay cả sau điều trị.
5. Các NC điều trị mới theo 3 hướng: điều trị cho tất cả
genotpye, thời gian ngắn hơn, điều trị lại: rất triển vọng!
Editor's Notes
Chronic HCV infection generates inflammation and scarring (fibrosis) of the liver tissue. The level of fibrosis increases with time and can be measured with validated scales like the Metavir scale: F0=no fibrosis, F1=light fibrosis, F2=moderate fibrosis, F3=advanced fibrosis and F4=cirrhosis. The course of infection is highly variable from person to person, however, and can progress rapidly to advanced liver disease over a few years or slowly over 20 years or more.
HCV infection itself is associated with severe fatigue. When fibrosis becomes severe enough, the patient develops cirrhosis. Initially the liver is able to compensate for the damage. With time, cirrhosis distorts the structure and degrades the function of the liver. De-compensated cirrhosis arises when conditions secondary to liver failure develop. Although cirrhosis can remain asymptomatic for several years, once it is established, potential complications include: jaundice, ascites, variceal hemorrhage, and encephalopathy. There is a five-year survival rate for patients with de-compensated cirrhosis.
There is evidence that fibrosis can be reversed or halted if inflammation is controlled (Benyon RC and Iredale JP. Is liver fibrosis reversible? Gut 2000; 46:443446).
Chronic HCV infection is also associated with an increased risk of developing comorbidities such as coronary artery disease, diabetes, steatosis and insulin resistance, which are themselves associated with higher rates of disease progression.
HCV genotype 1 is more difficult to treat in patients with high viral load or advanced fibrosis, thus the importance of treating early.
Khi có phối hợp Ribavirine , ko cần kéo dài lên 24 w!
There are many options currently available, and they are all completely oral-based regimens. No interferon anymore. Now, only 1 currently available single-tablet regimen—the sofosbuvir and velpatasvir you see highlighted at the bottom of the list—is effective against all genotypes. However, if you look above sofosbuvir and velpatasvir, you will see that single-tablet combinations will cover all genotypes. It’s eventually going to be the case that genotypes are not necessarily identified, but currently it’s still recommended that we determine genotypes so we can create the best treatment regimen.
Key finding here –
Relapse – does well, any genotype, with or without cirrhosis, any regimen
Of the nulls and partials – unclear if duration alone or RBV alone is sufficient, but together, efficacy improved to 100%
TN: Death coronary artery disease. Found several days after death.
TE 12 week no R: 1 GT1b CKD patient discon at TW10 due to noncompliance; 1 death due to lymphoma
TE 12 week + R: 1 death due to motor vehicle accident
HCV, hepatitis C virus.
Resistance associated variants can be present at baseline and can be selected for during therapy. The viral population may even develop compensatory variants with additional mutations that allow them to compete in the host because they are more fit.
BL, baseline; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; NGS, next-generation sequencing; RAV, resistance associated variant; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir.
One study to examine the interplay between resistance and efficacy is HCV-TARGET, which determined the prevalence of baseline resistance associated variants and their impact on the efficacy of either ledipasvir/sofosbuvir or simeprevir and sofosbuvir. This was a multicenter, prospective, observational cohort, so these resistance associated variants were not impactful in an algorithmic way. Providers treated these patients the way that they intended to treat them without any intervention from the study itself, but a subset of individuals had consented to baseline serum collection. Using these samples, the resistance associated variants were determined using next-generation sequencing, which captured variants occurring above a 10% threshold. There were 492 patients in the prevalence analysis and 472 in the efficacy analysis.
As we would expect from other populations, the overall prevalence at baseline resistance associated variants was pretty common for the protease inhibitor or NS3 class at 95%. In the NS5A, it was 13%, and they did show 8% in NS5B, or the polymerase inhibitors. Ten percent had 2 classes or more present, so that means that this could be potentially a pretty complicated patient if you’re trying to design a therapy as a result of looking at their resistance associated variants.
NS3 resistance associated variants were more frequent in genotype 1a patients compared to those with genotype 1b while the opposite was true for NS5A resistance associated variants. Overall variant prevalence was similar regardless of cirrhosis status, treatment experience, or liver transplant status.
LDV, ledipasvir; RAV, resistance associated variant; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response.
Ledipasvir/sofosbuvir resistance associated variants with mutations at amino acid positions 28, 30, 31, 58, and 93 numerically associated with SVR12 rate differences between 1% and 7%, though these differences were not statistically significant. However, the Y93 ledipasvir/sofosbuvir RAV, though infrequent at 4% in this population, was associated with a significant decrease in SVR12, going from 96% in those that did not have this mutation down to 75% in those that did.
Because the simeprevir plus sofosbuvir regimen does not contain an NS5A inhibitor, NS5A resistance associated variants would not be expected to be impactful. Simeprevir resistance associated variants, however, contained multiple positions that were impactful with a numeric but nonsignificant decrease of 0% to 9% in SVR12 at positions 80, 122, 155, 168, and 170.
DAA, direct-acting antiviral; DCV, daclatasvir; DSV, dasabuvir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PI, protease inhibitor; PTV, paritaprevir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir.
A very small subset of these patients was retreated, based on knowledge of what therapy they had previously failed and their prevalence of resistance associated variants.
The blue subset at the top of the chart includes genotype 1 patients that had experienced failure of simeprevir plus sofosbuvir with or without ribavirin. They were generally retreated with an NS5A inhibitor–containing regimen and obtained an overall efficacy of 91%. Only 2 patients did not achieve SVR12 in this subset.
The orange subset in the middle of the chart includes genotype 1 patients that had experienced failure of a daclatasvir- or ledipasvir-containing regimen with sofosbuvir with or without ribavirin. They were generally retreated with a protease inhibitor–containing regimen with an 86% SVR12 rate, which reflected only 1 failure.
The green subset at the bottom of the chart includes genotype 3 patients that had experienced failure of sofosbuvir plus ribavirin and were retreated with an NS5A inhibitor–containing regimen, either daclatasvir or ledipasvir with sofosbuvir with or without ribavirin for 12-24 weeks. In these 7 patients, there was 100% efficacy.
CPT, Child-Turcotte-Pugh; FDC, fixed-dose combination; GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; QD, once daily; Tx, treatment.