Hepatitis C cirrhosis: New perspectives for diagnosis and treatment

Table 1 Centers of disease control recommendations on hepatitis C virus infection screening in the general population[17]

Birth between 1945-1965 without identifiable risk factors

History of illegal drug use

Receipient for clotting factors before 1987

Receipients for blood transfusion or solid organ transplantation before 1992

Received hemodialysis

Health-care workers after needle sticks

All HIV-positive individuals

Signs and symptoms of liver disease

Children born to HCV positive mothers

Elevated liver function tests

HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.

Table 2 Various scoring system for the histological staging for liver fibrosis

Stage	IASL score	Bats-Ludwig score	Metavir	Ishak score
0	No fibrosis	No fibrosis	No fibrosis	No fibrosis
1	Mild fibrosis	Fibrous portal expansion	Presence of periportal fibrotic expansion	Fibrous expansion of some portal areas with or without short fibrous septae
2	Moderate fibrosis	Rare bridges or septae	Periportal septae 1 (septum)	Fibrous expansion of most portal areas with or without short fibrous septae
3	Severe fibrosis	Numerous bridges or septae	Porto-central septae	Fibrous expansion of most portal areas with occasional portal to portal bridging
4	Cirrhosis	Cirrhosis	Cirrhosis	Fibrous expansion of most portal areas with marked bridging (portal to portal and portal to central)
5				Marked bridging (portal to portal and portal to central) with occasional nodules (incomplete cirrhosis)
6				Cirrhosis

Adapted from Ghany et al[21].

Table 3 The recommended for treatment of hepatitis C virus infection by genotype in treatment-naïve patients and in treatment naïve patients with compensated cirrhosis[22]

Genotype	Recommended regimen and duration	Recommended regimen for compensated cirrhosis (CP-A) and duration
1a	Three options with similar efficacy:	Three options with similar efficacy:
	(1) Daily fixed dose LDP (90 mg)/SOF (400 mg) for 12 wk	(1) Daily fixed dose LDP (90 mg)/SOF (400 mg) for 12 wk
	(2) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 12 wk	(2) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 12 wk
	(3) Daily SOF (400 mg) plus SMV (150 mg) with or without weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 12 wk	(3) Daily SOF (400 mg) plus sMV (150 mg) with or without weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 24 wk
1b	Three options with similar efficacy:	Three options with similar efficacy:
	(1) Daily fixed dose LDP (90 mg)/SOF (400 mg) for 12 wk	(1) Daily fixed dose LDP (90 mg)/SOF (400 mg) for 12 wk
	(2) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 wk	(2) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 12 wk
	(3) Daily SOF (400 mg) plus SMV (150 mg) with or without weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for12 wk	(3) Daily SOF (400 mg) plus SMV (150 mg) with or without weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 24 wk
2	SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 12 wk	SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 16 wk
3	(1) SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 24 wk
	(2) Alternative for IFN eligible: SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] plus weekly peg IFN for 12 wk
4	Three options with similar efficacy and 2 alternatives available:
	(1) Daily fixed dose LDP (90 mg)/SOF (400 mg) for 12 wk
	(2) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 12 wk
	(3) Daily SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 24 wk
	(4) Alternative 1 for IFN eligible: Daily SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] plus weekly peg IFN for 12 wk
	(5) Alternative 2 for IFN eligible: Daily SOF (400 mg) plus SMV (150 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] for 12 wk
5	(1) Daily SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] plus weekly peg IFN for 12 wk
	(2) Alternative 1 for IFN eligible: Weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] plus weekly peg IFN for 48 wk
6	(1) Daily fixed dose LDP (90 mg)/SOF (400 mg) for 12 wk
	(2) Alternative 1 for IFN eligible: Daily SOF (400 mg) and weight-based RBV [1000 mg (< 75 kg) to 1200 mg (≥ 75 kg)] plus weekly peg IFN for 12 wk

LDP: Ledipasvir; SOF: Sofosbuvir; SMV: Simeprevir; Peg IFN: Pegylated interferon alfa-2a; RBV: Ribavirin; CP-A: Child-Pugh class A.

Table 4 Factors that determine ineligibility to interferon based regimens for treatment[22]

Intolerance to IFN in the past

Autoimmune hepatitis or other autoimmune disorders

Hypersensitivity to PEG or any of its components

Decompensated hepatic disease

Major uncontrolled depression

A baseline neutrophil count below 1500/μL, a baseline platelet count below 90000/μL or baseline hemoglobin below 10 g/dL

A history of pre-existing heart disease

IFN: Interferon; PEG: Percutaneous endoscopic gastrostomy.

Table 5 Summary of sofosbuvir trials and enrollment of cirrhotic patients

Trial	Regimen	Duration (wk)	Patient population (patients withcirrhosis in treatment group)	SVR and additionalfindings	SVR for cirrhoticpatients
NEUTRINO[36]	SOF + peg IFN + RBV	12	327 treatment naïve (54) with G1, 4-6	90% overall	80%
			G1: 292	89%
			G4: 28	96%
			G5-6: 7	100%
FISSION[36]	SOF + RBV	12	253/499 treatment naïve with G2, G3 (49 cirrhotic) assigned to treatment arm	67%	47%
			G2: 70/253	97%	91%
			G3: 183/253	56%	34%
POSITRON[37]	SOF + RBV	12	207/278 IFN intolerant or ineligible with G2, G3 (31 cirrhotic) assigned to treatment group	78%	61%
			G2: 109	93%	94%
FUSION[37]	SOF + RBV	12	G3: 98	61%	21%
			100 treatment experienced with G2, G3 (26)	50%	42%
			G2: 36	86%	60%
	SOF + RBV	16	G3: 64	30%	19%
			95 treatment experienced with G2, G3 (32)	73%	66%
			G2: 32	94%	78%
VALENCE[38]	SOF + RBV	12	G3: 63	62%	61%
			73 patients with G2 (10)	93%	90%
			Treatment naïve G2: 32	97%	100%
	SOF + RBV	24	Treatment experienced G2: 41	90%	88%
			250 patients with G3: (58)	85%	67%
			Treatment naïve G3: 105	93%	92%
			Treatment experienced G3: 145	79%	60%

SOF: Sofosbuvir; Peg IFN: Pegylated interferon alfa-2a; RBV: Ribavirin; G: Hepatitis C virus genotype; SVR: Sustained virologic response.

Table 6 Sustained virologic response achieved in the COSMOS study[43]

Cohort	Regimen	Duration (wk)	SVR12
Cohort 1: Prior non-responder HCV	SMV/SOF + RBV	24	79%
patients with METAVIR scores (F0-F2)	SMV/SOF	24	93%
	SMV/SOF + RBV	12	96%
	SMV/SOF	12	93%
Cohort 2: Prior non-responder and	SMV/SOF + RBV	24	93%
treatment naïve HCV patients with	SMV/SOF	24	100%
METAVIR scores (F3-F4)	SMV/SOF + RBV	12	93%
	SMV/SOF	12	93%

SOF: Sofosbuvir; SMV: Simeprevir; RBV: Ribavirin; SVR12: Sustained virologic response at 12 wk; HCV: Hepatitis C virus.

Table 7 Summary of sofosbuvir and ledipasvir trials and enrollment of cirrhotic patients

Trial	Regimen	Patient population (% with cirrhosis)	Duration (wk)	SVR12
ION-1[45]	SOF + LDP	212 naïve (16%)	12	99%
	SOF + LDP + RBV	211 naïve (15%)	12	97%
	SOF + LDP	214 naïve (15%)	24	98%
	SOF + LDP + RBV	215 naïve (17%)	24	99%
ION-2[46]	SOF + LDP	109 treatment experienced (20%)	12	94%
	SOF + LDP + RBV	111 treatment experienced (20%)	12	96%
	SOF + LDP	109 treatment experienced (20%)	24	99%
	SOF + LDP + RBV	111 treatment experienced (20%)	24	99%
ION-3[47]	SOF + LDP	215 naïve (0%)	8	94%
	SOF + LDP + RBV	216 naïve (0%)	8	93%
	SOF + LDP	216 naïve (0%)	12	95%

SOF: Sofosbuvir; LDP: Ledipasvir; RBV: Ribavirin; SVR12: Sustained virologic response at 12 wk.