Patients with compensated cirrhosis: how to treat and follow-up Thomas Berg Sektion Hepatologie Klinik und Poliklinik für Gastroenterologie und Rheumatologie Universitätsklinikum Leipzig Leber- und Studienzentrum am Checkpoint, Berlin
Patients with compensated cirrhosis: how to treat and follow-up How to diagnose and define compensated cirrhosis Safety of DAAs in compensated cirrhosis How does compensated cirrhosis affects DAA efficacy The role of HCV genotypes The role of compensated cirrhosis sub-classification Do treatment strategies differ with respect to presence/absence of early compensated cirrhosis? The role of ribavirin (RBV) an treatment duration How to follow patients with SVR Topics to discuss Long-term HCC risk and surveillance strategies
How to diagnose compensated cirrhosis EASL CPG J Hepatol 2016, EASL homepage
The HCV journey HCV infection = A fibrotic liver disease normal liver Disease progression predictable by fibrosis measurement over time Compensated Cirrhosis F1 F2 F3 Decompensated Cirrhosis Time bar for treatment initiation
The HCV journey HCV infection = A fibrotic liver disease normal liver Disease progression predictable by fibrosis measurement over time Compensated Cirrhosis F1 F2 F3 Decompensated Cirrhosis Time bar for treatment initiation A homogeneous stage?
The HCV journey HCV infection = A fibrotic liver disease normal liver Disease progression predictable by fibrosis measurement over time Compensated Cirrhosis F1 F2 F3 Decompensated Cirrhosis Time bar for treatment initiation A transition stage How to diagnose?
Figure from Chhatwal et al. Hepatology 2016 How to define compensated cirrhosis
Compensated cirrhosis a spectrum of morphological and biological changes rather than a homogeneous entity 5 or 6 points can make a difference Bilirubin between 1 2 x ULN Albumin levels between 35 and > 40 g/l Does not reflect: presence of portal hypertension and varices degree of HVPG history of variceal bleeding Platelet count Histologic severity of cirrhosis (Laennec staging F4A-C)
The Laennec staging system for histological sub-classification of compensated cirrhosis Kim MY et al. J Hepatol 2011; 55:1004
The Laennec staging system for histological sub-classification of compensated cirrhosis as a predictive marker HVPG = hepatic venous pressure gradient Kim MY et al. J Hepatol 2011; 55:1004 Kim SU et al. J Hepatol 2012; 57:556
A clinical scoring model for staging compensated cirrhosis according to the Laennec system Zhang EL et al. J Surg Res 2016; 204:274
Feld JJ, et al. N Engl J Med 2015; Poordad F et al. N Engl J Med 2014 How to define compensated cirrhosis Standards in clinical trials Cirrhosis was defined as one of the following: A) ASTRAL-1 Phase III study (Velpatasvir/Sofosbovir) Liver-biopsy (Metavir score of 4 or an Ishak score 5 or 6) FibroTest score > 0.75 and APRI (ratio of aspartate aminotransferase to platelets) > 2 FibroScan value > 12.5 kpa B) TURQUOISE-II study (3D regimen) Liver biopsy (Metavir score >3 or Ishak score >4) FibroScan 14.6 kpa Child Pugh class A score < 7
In clinical trials (compensated disease) appr. 80% of patients with cirrhosis had early stage cirrhosis TURQUOISE-II study patients characteristics at baseline: Parameter Numbers/Percent of patients Platelet count (median) 140 /nl (IQR 104.0 188.5) Platelets < 100/nL 20% Serum albumin (median) 40 g/l (IQR 37 42) Albumin < 35 g/l 11% Child Pugh score > 5 18% Poordad F et al. N Engl J Med 2014; 370:1973
Pharmacokinetics and Safety of DAAs in compensated cirrhosis?
Pharmacokinetics of DAAs: Effects of hepatic impairment on drug exposure Drug Exposure change in hepatic impairment groups versus controls Mild (CTP-A) Moderate (CTP-B) Severe (CTP-C) Action required Protease inhibitors Simeprevir x < 2 x 2,6 x 5,2 Not recommended in CTP-B or C patients Paritaprevir/r x < 2 x < 2 x 18 Not recommended in CTP-B or C patients Grazoprevir x < 2 x 1,71 unknown Not recommended in CTP-B or C patients (1/2 Dosage) Asunaprevir x < 2 x 9.8 x 32.1 Not recommended in CTP-B or C patients NS5B inhibitors Sofosbuvir x < 2 x < 2 x < 2 No Dasabuvir x < 2 x < 2 x < 2 No NS5A inhibitors Daclatasvir x < 2 x < 2 x < 2 No Ledipasvir x < 2 x < 2 x < 2 No Ombitasvir x < 2 x < 2 x < 2 No Velpatasvir x < 2 x < 2 x < 2 No Elbasvir x < 2 x < 2 unknown Not recommended in CTP B or C patients Lens S et al. Semin Liver Dis 2014; 34: 58
Safety of two different DAA regimens in patients with compensated cirrhosis LDV = Ledipasvir; SOF = Sofosbuvir SVR12 = sustained virologic response Calleja JL et al. J Hepatol 2017; 66: 1138
Safety of the 3 D regimen in Child A cirrhosis A pooled analysis of 1066 patients from 12 clinical phase II/III trials Risk factors for decompensation Evidence of advanced cirrhosis low baseline albumin ( 3.6 g/dl) HCV RNA 6.4 log10 IU/mL prior history of non-selective beta blocker use for varices These data support the use of OBV/PTV/r ± DSV ± RBV in patients with cirrhosis, but these regimens should be avoided in patients with a history of hepatic decompensation Poordad F et al. J Hepatol 2017; in press
Efficacy of DAAs in compensated cirrhosis?
Efficacy of the 3D-regimen (OBV/PTV/r + DSV ± RBV) in HCV type 1 according to stage of fibrosis (N=1,567) OBV = Ombitasvir; PTV/r = Paritaprevir/ritonavir; DSV = Dasabuvir SVR12 = sustained virologic response Calleja JL et al. J Hepatol 2017; 66: 1138
Efficacy of LDV + SOF ± RBV in HCV type 1 according to stage of fibrosis (N=1,758) LDV = Ledipasvir; SOF = Sofosbuvir SVR12 = sustained virologic response Calleja JL et al. J Hepatol 2017; 66: 1138
Do we need to intensify treatment regimens in HCV type 1 compensated cirrhosis? Adding ribavirin Treatment extension
3D-regimen (OBV/PTV/r + DSV) with ribavirin for 12 or 24 weeks in HCV type 1 compensated cirrhosis Poordad F et al. N Engl J Med 2014; 370:1973
SVR12 (% Patients) TURQUOISE II SVR rates in HCV subtype 1a according to surrogate parameters of portal hypertension and liver function Poordad F et al. N Engl J Med 2014 88,9 97,0 92,6 95,7 84,0 88,9 92,9 96,8 3D + RBV 12 Weeks 24 Weeks 40/45 32/33 151/163 133/139 <100 100 Baseline Platelet count (x10 3 /µl) 21/25 16/18 170/183 149/154 <35 35 Baseline Albumin level (g/l)
Extending 3D treatment duration to 24 weeks only for HCV type 1a with negative predictors Relapse rates according to negative predictors AFP 20 ng/ml, Platelets < 90 x 10 9 /L; Albumin < 35 g/l at baseline Relapse rate (%) 12 week arm (N=135) 24 week arm (N=113) No negative predictor 1 % 0 % At least one negative predictor 21 % 2 % SMP viekirax and exviera
3D-regimen (OBV/PTV/r + DSV) without ribavirin for 12 weeks in HCV type 1b compensated cirrhosis OBV = Ombitasvir; PTV = Paritaprevir; DSV = Dasabuvir RVR = rapid virologic response; SVR12 = sustained virologic response Treatment-naive and Peg-IFN/RBV-experienced patients Feld JJ et al. J Hepatol 2016; 64: 301
Efficacy of LDV + SOF ± RBV in HCV type 1 according to RBV and cirrhosis status (N=1,758) LDV = Ledipasvir; SOF = Sofosbuvir SVR12 = sustained virologic response Calleja JL et al. J Hepatol 2017; 66: 1138
LDV/SOF ± RBV in compensated cirrhosis importance of certain baseline characteristics Treatment Naïve Treatment Experienced Overall SVR12 98% 95% Cirrhosis determination method 100 <125 FibroScan FibroTest + APRI 97% 100% 92% 95% 98% 87% Albumin (g/dl) <3.5 3.5 95% 98% 98% 95% <75 90% 82% Platelets (x 10 3 /µl) 75 <100 100 <125 100% 98% 98% 93% 125 98% 98% FibroScan >12.5 20 >20 100% 100% 99% 95% 80 90 100 80 90 100 Bourliere M et al. AASLD 2014; Oral #82
Efficacy of DAAs in Veterans Affairs healthcare system (N=17,487) Ioannou GN et al. Gastroenterology 2016; 151: 457
How cirrhosis status affects current treatment recommendations in HCV type 2 Regimen No cirrhosis Compensated cirrhosis TN TE TN TE SOF + VEL 12 weeks 12 weeks 12 weeks 12 weeks Daclatasvir + Sofosbuvir 12 weeks 12 weeks 12 weeks 12 weeks 16 24 weeks for cirrhosis (AASLD 2017 guideline) TN = PEG-IFNa/RBV treatment naive, TE = PEG-IFNa/RBV treatment experienced *EASL CPG J Hepatol 2016 and AASLD
Intergenotypic recombinant HCV variants (chimera) Genomic region used for HCV typing/subtyping Genomic region used for HCV drug design Hedskog C et al. Hepatology 2015
Phylogenetic tree based on HCV NS3 sequences and geographical distribution of origins from patients with 2k/1b virus St. Petersburg Susser S et al. J Hepatol 2017; epub
SVR rates in patients with recombinant HCV genotype 2k/1b chimera Susser S et al. J Hepatol 2017; epub
SVR12 (%) ASTRAL-3: SVR12 in relation to cirrhosis status in HCV type 3 SOF/VEL 12 W SOF + RBV 24 W 100 80 98 93 91 89 90 73 71 58 60 40 20 0 160/163 141/156 40/43 33/45 31/34 22/31 33/37 22/38 Non-Cirrhotic Cirrhotic Non-Cirrhotic Cirrhotic Treatment Naïve Treatment Experienced Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med. 2015. DOI: 10.1056/NEJMoa1512612
How cirrhosis status affects current treatment recommendations in HCV type 3 Regimen No cirrhosis Compensated cirrhosis TN TE TN TE SOF + VEL 12 weeks 12 weeks + RBV 1 12 weeks + RBV 1 12 weeks + RBV 1 Daclatasvir + Sofosbuvir 12 weeks 12 weeks + RBV 1 24 weeks + RBV 24 weeks + RBV 1 if no resistance testing is performed Patients without Y93H RAS should be treated for 12 weeks without ribavirin 16 24 weeks for cirrhosis (AASLD 2017 guideline) TN = PEG-IFNa/RBV treatment naive, TE = PEG-IFNa/RBV treatment experienced *EASL CPG J Hepatol 2016 and AASLD/IDSA guideline 2017
Summary: DAA regimens in which treatment modality needs to be adapted according to compensated cirrhosis status and HCV type Regimen* 1a 1b 2 3 4 5 and 6 SOF/LDV - - NR NR - - SOF/VEL - - - YES - - 3/2 D YES - NR NR (YES) NR GRZ/EBV - - NR NR - NR DCV/SOF - - - YES - - SMV/SOF YES YES NR NR - NR NOTE: 8-week regimens not recommended in cirrhosis *With or without ribavirin depending on regimen and patients characteristics/ HCV type NR = regimen not recommended/licensed for this HCV type - = cirrhosis status does not lead to a change in the treatment modality as compared to patients without cirrhosis YES = cirrhosis status will lead to a change in the treatment modality
Management beyond SVR in patients with compensated cirrhosis at baseline? HCC Surveillance?
Post-treatment follow-up of patients who achieve SVR EASL CPG J Hepatol 2016, EASL homepage
HCC risk and SVR SVR and HCC risk HCC risk after SVR importance of cirrhosis Janjua NZ et al J Hepatol 2017; 66: 504
Case presentation Male patient, 56 years old, architect, self-employed HCV-induced cirrhosis Child A (blood transfusion in 1984) Fibroscan 17 kpa Several interferon-based treatment courses without SVR 2009/2010 clinical trial with an IFNa-free DAA regimen Developed hepatic decompensation under DAA treatment with ascites, jaundice 04/2010 SVR
Case presentation - five years after SVR US no change, no focal lesion Platelets 117/nL Albumin 4.2 g/dl Bili 0.61 mg/dl Transaminases normal AFP 41.6 ng/ml (< 10 ng/ml)
MRI
MRI
Who is at risk to develop HCC after SVR? Is it possible to individualize HCC surveillance?
Risk factors for HCC development after the cure of the HCV infection (SVR) Studies Parameter HR All Cirrhosis 6.7 1, 2, 6, 7 Age > 64 years 4.5 or 1.1 for each year 1, 2, 3 Diabetes 1.8-6.2 1 Alcohol 1.67 1 HCV type 3 1.6 2, 4 Albumin < 35-36 g/dl 6.2 5, 6, 7 AFP > 10-20 ng/ml 5, 8 ALT > 40 IU/mL and/or GGT elevated after EOT 1 El-Serag HB et al. Hepatology 2016; 64: 130; 2 Hedenstierna M et al. Clin Infect Dis (CID) 2016; June 21, epub, 3 Toyoda H et al. J Gastroenterol Hepatol 2015; 30: 1183; 4 Zeng Q-L et al. Gut Liver 2016; June 3, epub; 5 Asahani Y. et al. Hepatology 2013;58:1253; 6 Lee HW et al. Gut Liver 2016; 10: 429; 7 Nagaoki Y et al. J Gastroenterol Hepatol 2016; 31: 1009; 8 Huang C. F. et al. J Hepatol 2014;61:67-74
HCC Risk after SVR Importance of metabolic risk factors SVR1/Non-SVR1 = no metabolic risk factors SVR2/non-SVR2 = with metabolic risk factors Non-SVR, no metabolic risk factors Non-SVR, with metabolic risk factors SVR, with metabolic risk factors SVR, no metabolic risk factors Nahon P et al. Gastroenterology 2017; 152: 142
Summary In early compensated cirrhosis: Efficacy of the approved DAA regimen given for 12 weeks is very high and not different from patients without cirrhosis In most patients no adaptation of the antiviral regimen is required (Note, 8-week regimens not recommended in any patients with advanced fibrosis) Only in certain subgroups ribavirin should be added (TE, HCV type 3, 3D in GT1a) Response to SOF + RBV is less robust, and this regimen should not be used anymore in type 3 and 2 For more advanced compensated cirrhosis (with negative predictors) either adding RBV and/or extending treatment duration seems reasonable HCC screening MUST continue long-term in those with advanced fibrosis/cirrhosis