HCV treatment in patients with decompensated liver disease

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Abbreviations

AUC

area under the curve

CTP

Child‐Turcotte‐Pugh

DAA

direct‐acting antiviral

DCV

daclatasvir

EBV

elbasvir

GFR

glomerular filtration rate

GRZ

grazoprevir

HCV

hepatitis C virus

LDV

ledipasvir

LT

liver transplant

MELD

Model for End‐Stage Liver Disease

PrOD

paritaprevir/ritonavir/ombitasvir plus dasabuvir

SMV

simeprevir

SOF

sofosbuvir

SVR

sustained virological response

VLP

velpatasvir

The approval of safe and effective direct‐acting antiviral (DAA) agents has dramatically changed the care of patients with hepatitis C virus (HCV) infection. This may be particularly true for traditionally difficult‐to‐treat populations, including those with advanced liver disease. Remarkably, increasing availability of safe and effective treatment may have already led to a decline in liver transplant (LT) wait listing for HCV‐related decompensated liver disease.1 However, although sustained virological response (SVR) rates in the general population currently exceed 90% to 95% with first‐line regimens,2 for those who have already developed Child‐Turcotte‐Pugh (CTP) class B and C liver disease, SVR rates remain suboptimal. In addition, controversy remains regarding the impact of viral eradication on the clinical course of these patients and the optimal timing of treatment in the context of anticipated liver transplantation.

Currently Available Treatment for Patients with Decompensated Cirrhosis

There are three available NS5A polymerase inhibitor plus NS5B inhibitor combinations that are recommended for use in patients with CTP B or C cirrhosis: sofosbuvir with ledipasvir, velpatasvir or daclatasvir (for HCV genotypes 1 or 4), or sofosbuvir with velpatasvir or daclatasvir (for HCV genotypes 2 or 3) (Table 1).2, 3, 4, 5, 6, 7, 8 Ribavirin is still recommended in many cases (Table 1), but patients who are ineligible for ribavirin or experienced prior DAA treatment failure are treated with an extended course of therapy.2 In phase 2 and 3 clinical trials of these regimens, patients with CTP B and C disease achieved overall SVR rates of 83% to 88%, with diminished response rates in CTP class C (Table 2; Figure 1). Similar effectiveness has been reported in numerous real‐world cohorts, and the overall safety of these regimens in this high‐risk population has led to widespread enthusiasm to treat.

Table 1.

Current Guidance for HCV Treatment in Patients With Decompensated Liver Disease2

	Regimen
Genotype	Ribavirin Eligible	Ribavirin Ineligible	Prior NS5A Treatment Failure
1 or 4	LDV/SOF with ribavirin (600 mg/day, increased as tolerated) for 12 weeks	LDV/SOF for 24 weeks	LDV/SOF with ribavirin (600 mg/day, increased as tolerated) for 24 weeks
	VLP/SOF with ribavirin (weight‐based) for 12 weeks	VLP/SOF for 24 weeks	VLP/SOF with ribavirin (weight‐based) for 24 weeks
	DCV + SOF with ribavirin (weight‐based) for 12 weeks	DCV + SOF for 24 weeks
2 or 3	VLP/SOF with ribavirin (weight‐based) for 12 weeks
	DCV + SOF with ribavirin (weight‐based) for 12 weeks
5 or 6	LDV/SOF with ribavirin (600 mg/day, increased as tolerated) for 12 weeks	LDV/SOF for 24 weeks	LDV/SOF with ribavirin (600 mg/day, increased as tolerated) for 24 weeks
	VLP/SOF with ribavirin (weight‐based) for 12 weeks	VLP /SOF for 24 weeks	VLP/SOF with ribavirin (weight‐based) for 24 weeks

Abbreviations: DCV, daclatasvir; LDV, ledipasvir; SOF, sofosbuvir; VLP, velpatasvir.

Table 2.

Prospective Clinical Trials for HCV Treatment in Patients With Decompensated Liver Disease

			SVR12 (%)
Trial	Regimen	Patients	CTP B	CTP C
SOLAR‐13	LDV/SOF + ribavirin for 12 or 24 weeks	Genotype 1 or 4, CTP B (n = 59) and C (n = 49)	12 weeks: 87% 24 weeks: 89%	12 weeks: 86% 24 weeks: 87%
SOLAR‐25	LDV/SOF + ribavirin for 12 or 24 weeks	Genotype 1 or 4, CTP B (n = 46) and C (n = 43)	12 weeks: 87% 24 weeks: 96%	12 weeks: 85% 24 weeks: 78%
ALLY‐16	SOF + DCV + ribavirin for 12 weeks	Genotypes 1‐6, CTP B (n = 32) and C (n = 16)	94%	56%
C‐SALT9	GRZ/EBVa for 12 weeks	Genotype 1, CTP B only (n = 30)	90%	N/A
ASTRAL‐44	VLP/SOF with or without ribavirin for 12 or 24 weeks	Genotypes 1‐6, CTP B only (n = 267)	12 weeks: 83% 12 weeks + ribavirin: 94% 24 weeks: 86%	N/A
IMPACT	SMV + SOF + DCV for 12 weeks	Genotype 1 or 4, CTP A (n = 19) or B (n = 21)	100%	N/A

Abbreviations: DCV, daclatasvir; EBV, elbasvir; GRZ, grazoprevir; LDV, ledipasvir; NA, not applicable; SMV, simeprevir; SOF, sofosbuvir; VLP, velpatasvir.

^aDosing adjusted to grazoprevir 50 mg/day plus elbasvir 50 mg/day because of hepatic impairment.

Figure 1.

SVR12 rates among patients with decompensated cirrhosis in prospective clinical trials. Abbreviations: DCV, daclatasvir; EBV, elbasvir; GRZ, grazoprevir; LDV, ledipasvir; Riba, ribavirin; SOF, sofosbuvir; VLP, velpatasvir.

Due to hepatic metabolism and reports of drug‐induced liver injury, NS3/4A protease inhibitors are not recommended for use in patients with moderate‐to‐severe hepatic impairment. In a small phase 2 study, 30 patients with genotype 1 HCV and CTP class B were treated with grazoprevir 50 mg daily (reduced from the approved 100 mg daily dose) and elbasvir 50 mg daily with 90% SVR12.9 However, there are no data on the currently approved dosage. The paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD) regimen is also contraindicated in patients with CTP class B and C cirrhosis because of the up to 945% increase in area under the curve (AUC) of paritaprevir among patients with severe hepatic impairment.10 Although PrOD has been used with high response rates in a small number of patients with CTP B cirrhosis in real‐world cohorts, there are several reports of hepatic decompensation in patients with CTP A and B cirrhosis, including an US Food and Drug Administration Drug Safety Communication reporting 26 cases of liver injury considered possibly or probably caused by PrOD administration.11 In addition, both of the recently approved pangenotypic DAA combinations (sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir) contain protease inhibitors that are hepatically metabolized and have increased AUCs in the setting of decompensated cirrhosis, and are therefore currently contraindicated.

Clinical Response and Optimal Timing of Treatment

HCV treatment in the setting of decompensated cirrhosis should be performed with consideration of whether the patient is an LT candidate. There is significant interest in determining the optimal timing of treatment in transplant candidates, both in terms of patient outcomes and cost‐effectiveness. Treatment before transplant may improve liver function, treat extrahepatic manifestations of HCV, and prevent recurrent disease posttransplant. However, for some patients, treatment may lead to a decline in Model for End‐Stage Liver Disease (MELD) without resolution of transplant indications, perhaps diminishing access to transplant and discouraging the use of HCV‐seropositive grafts in this setting. In addition, very few patients with MELD scores >20 have been treated in trials to date, limiting our ability to extrapolate safety and efficacy data in this group. Patients with CTP C disease and MELD scores >27 tend to have lower SVR rates than CTP B patients and are more likely to be cured if treatment is delayed until after transplantation. Modeling to identify the optimal approach has been attempted,12 although significant uncertainty remains around key variables, including treatment response among the sickest patients, predictors of clinical improvement post‐SVR, and the dynamics of organ allocation including the availability of HCV‐positive donors.

A central issue is whether broader treatment of patients with decompensated cirrhosis will lead to clinical improvement in a substantial proportion such that transplant is no longer needed for prolonged survival. Approximately 60% of patients in the major clinical trials experienced a short‐term improvement in liver function after SVR as measured by MELD or CTP scores, while 17% had no change and 23% experienced worsening in liver function.13 However, the median improvement in MELD was two points, which may have variable clinical significance, and data are not available for those with the most significant hepatic impairment (CTP score > 12 and MELD > 20 were exclusionary for clinical trials). Unfortunately, accurate prediction of clinical improvement is not currently possible, and longer‐term follow‐up for these patients is not yet available.

Thus, viral eradication in patients with advanced liver disease remains an important goal and is now possible in most patients. The timing of HCV treatment in the setting of decompensated cirrhosis should be individualized, taking into account both the patient's severity of liver disease and the patient's access to transplant (Figure 2). For patients with CTP class A disease and/or low MELD scores, treatment to improve liver function and/or avoid transplant or posttransplant recurrence is an accepted approach. For those with the highest MELD and greatest urgency for transplant, treatment can likely be safely postponed until after transplant. Because sofosbuvir is needed in all currently recommended regimens, for patients with decompensated liver disease and advanced renal impairment (glomerular filtration rate [GFR] < 30 mL/min), posttransplant treatment may also be the best option. For patients with moderate MELD scores and a range of complications of liver disease, treatment can be considered on an individualized basis.

Figure 2.

Algorithm for the approach of HCV treatment in patients on the LT wait list.14 *MELD < 20 is based on the limited data on safety and efficacy of treatment in patients with MELD > 20; however, treatment above this MELD may be beneficial in some patients. **GFR > 30 mL/min/1.73 m² is based on the need for use of sofosbuvir in all currently recommended treatment regimens for patients with decompensated cirrhosis and the contraindication to use of sofosbuvir in patients with severe renal impairment. ***MELD > 27 is based on the simulation of LT, which found that even if treatment is assumed to be safe and effective above this MELD, there may be a survival benefit by delaying therapy to the posttransplant setting.12 Abbreviation: LDLT, living donor LT.

Conclusions

The remarkable efficacy and safety of several currently available DAA regimens in patients with decompensated liver disease has dramatically changed the management and prognosis of these patients. Fewer patients are being listed for transplant because of HCV‐related cirrhosis, and many are now being removed from the list with clinical improvement after SVR. Although it is now possible to cure most of these patients, treatment decisions should continue to occur in the context of evaluation for liver transplantation.