CON: Patients With Decompensated Cirrhosis Listed for Liver Transplantation Should Be Treated Posttransplant

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Abbreviations

CTP

Child‐Turcotte‐Pugh

DAA

direct‐acting antiretroviral

DAC

daclatasvir

FCH

fibrosing cholestatic hepatitis

GLE

glecaprevir

HCV

hepatitis C virus

LDV

ledipasvir

MELD

Model for End‐Stage Liver Disease

PIB

pibrentasvir

SOF

sofosbuvir

SVR12

sustained virological response rates at 12 weeks

VEL

velpatasvir

Key Points

• Hepatitis C virus (HCV) treatment in patients with decompensated cirrhosis is associated with decreased sustained viral response rates and has not been associated with sufficient improvement to remove patients from the transplant list.

• There are serious safety concerns regarding treating HCV in patients with decompensated cirrhosis, including rapid deterioration and death.

• HCV treatment after transplant is highly effective and allows patients access to an increased pool of potential donors.

A remarkable transformation in the treatment of the HCV has occurred in the last 5 years as treatment transitioned away from year‐long courses of interferon injections to 2‐ to 3‐month courses of oral direct‐acting antiretrovirals (DAAs). These DAAs are associated with such extremely high cure rates and minimal side effects that treatment should be considered for all infected patients, with few exceptions. One of these exceptions is the patient with decompensated HCV cirrhosis (defined here as clinically apparent ascites, encephalopathy, or a Child‐Turcotte‐Pugh [CTP] score ≥7) for whom transplantation is an option. Although these patients should still be treated, treatment should optimally be delayed until after transplantation.

Treatment Effectiveness in Patients with Decompensated Cirrhosis

Although HCV treatment is curative in up to 97% to 98% of patients without cirrhosis, patients with decompensated cirrhosis have significantly lower response rates. The SOLAR‐1, SOLAR‐2, ALLY‐1, and ASTRAL‐4 trials studied the efficacy of sofosbuvir (SOF) with an NS5a inhibitor (ledipasvir [LDV], daclatasvir [DAC], and velpatasvir [VEL], respectively) in patients with decompensated cirrhosis. These studies demonstrated sustained virological response rates at 12 weeks (SVR12) as low as 79% (Table 1).1, 2, 3, 4

Table 1.

Published SVR12 Rates in Patients With Advanced Liver Disease and After Transplant

Study	Regimen	Pretransplant		Posttransplant
		CTP B	CTP C	Noncirrhotic		FCH
Clinical Phase 2 and Phase 3 Trials
SOLAR‐11	LDV + SOF + RBV, 12 weeks	26/30 (80%)	19/22 (86%)	53/55 (96%)	4/4 (100%)
	LDV + SOF + RBV, 24 weeks	24/27 (89%)	20/23 (87%)	55/56 (98%)	2/2 (100%)
SOLAR‐23	LDV + SOF + RBV, 12 weeks	22/26 (85%)	17/21 (81%)	49/52 (94%)	3/3 (100%)
	LDV + SOF + RBV, 24 weeks	24/25 (96%)	19/24 (79%)	49/49 (100%)	2/2 (100%)
ALLY‐14	DAC + SOF + RBV, 12 weeks	50/60 (83%)		50/53 (94%)	—*
ASTRAL‐42	VEL + SOF, 12 weeks	75/90 (83%)	—*	—*	—*
	VEL + SOF + RBV, 12 weeks	82/87 (94%)	—*	—*	—*
	VEL + SOF, 24 weeks	77/90 (86%)	—*	—*	—*
MAGELLAN‐212	GLE + PIB, 12 weeks	—*	—*	98/100 (98%)	—*
Real‐World Cohorts
TOSCAR10	DAC + SOF ± RBV, 24 weeks	76/108 (70%)		—*	—*
HEPA‐C9	Various regimens	112/144 (78%)		—*	—*
ELITA11	Various regimens	96/103 (93%)		—*	—*

^*Data are not available for these populations.

Few patients with Model for End‐Stage Liver Disease (MELD) score greater than 15 are included in these studies. Furthermore, only one‐third of patients in SOLAR‐2 and less than 5% of patients in ASTRAL‐4 had decompensated cirrhosis. The TOSCAR cohort5 enrolled patients with decompensated hepatitis C cirrhosis (MELD score ≥15, CTP B or C) and reported a SVR12 rate of only 70% after 24 weeks of therapy with DAC and SOF.6 Although the mechanistic reasons for these decreased SVR12 rates are not known, they may be related to impaired intestinal drug absorption in the setting of portal hypertension and decreased hepatic drug delivery caused by capillarization of the cirrhotic liver. This is supported by previous clinical observations that lower albumin, elevated bilirubin, and the presence of decompensated cirrhosis all predict DAA failure.7

For most patients with decompensated cirrhosis, however, treating hepatitis C is unlikely to result in a degree of clinical improvement that would make removal from the transplant list possible. Data from ASTRAL‐4 and ALLY‐1 suggest that patients experience only a one‐ to two‐point improvement in their CTP score (Fig. 1).2, 4 These two trials, as well as SOLAR‐1 and SOLAR‐2, similarly suggest a decrease in one to four MELD points (Fig. 2).1, 2, 3, 4 Therefore, in patients with decompensated cirrhosis prior to therapy, decompensation persists after therapy, and transplant is still indicated. With a national median MELD score of 28 at the time of transplant, the likelihood of a patient with a MELD in the high teens or low twenties progressing to receive an organ offer is markedly decreased after viral eradication. This state of permanently decompensated liver disease without the hope of continued improvement or a transplant is often referred to as “MELD purgatory.”

Figure 1.

Changes in CTP scores for patients with decompensated HCV cirrhosis after treatment.

Figure 2.

Changes in MELD scores after treatment in patients with CTP B (A) and CTP C (B) cirrhosis.

Attempts have been made to predict which patients with decompensated cirrhosis might experience significant enough improvement to warrant removal from the transplant list. Early attempts to model this were based on the ALLY‐1, SOLAR‐1, and SOLAR‐2 data, so few patients with a MELD score greater than 15 are included, and the changes in the degree of decompensation in patients are not addressed. More recently, El‐Sherif et al published a study of 622 patients with CTP B or C cirrhosis and found that an ALT ≥60 IU/L, albumin greater than 3.5 g/dL, body mass index less than 25, absence of encephalopathy, and absence of ascites each independently predicted regression to CTP A.8 Each of these factors is given one point, and when added together, it is known as the BE3A (BMI, Encephalopathy, Ascites, Albumin, ALT) score. Patients with more significant hepatic decompensation have a lower BE3A score and are therefore less likely to improve their CTP status to CTP A (e.g., a BE3A score of 0 is associated with a <5% chance of achieving CTP A status).

Safety Issues in Patients with Decompensated Cirrhosis

Outside of concerns over MELD purgatory, multiple real‐world cohorts have also found an increased risk for rapid deterioration and death in patients with decompensated cirrhosis treated with DAAs. For example, the HEPA‐C cohort found 32% mortality at 36 weeks in patients with a MELD ≥18, perhaps related to a high rate of serious adverse events (infectious, incident decompensation, and anemia requiring transfusion) (Fig. 3).9 The previously mentioned Australian TOSCAR cohort found that a baseline MELD ≥19.5 was associated with an increased need for rescue transplantation after HCV treatment.5 This was echoed in findings from the European ELITA cohort, which found that 95% of patients with decompensated HCV cirrhosis and a MELD greater than 20 still needed a liver transplant after treatment. This cohort also found an increased risk for needing early liver transplant and a significant risk for death before and after liver transplant.10

Figure 3.

Kaplan‐Meier survival curves from Fernández Carrillo et al.9 demonstrated decreased survival in patients with decompensated cirrhosis treated for HCV prior to transplant. Reproduced with permission from Hepatology.9 Copyright 2017, American Association for the Study of Liver Diseases.

Treatment After Transplantation

HCV treatment after transplant is extremely effective. SVR12 rates in the early posttransplant period are more than 95%, similar to the rates seen in the general population infected with HCV without cirrhosis (Table 1).1, 3, 11 Even patients who experience development of fibrosing cholestatic hepatitis (FCH) now have good outcomes: a 100% SVR12 rate was seen in the 11 patients in the SOLAR‐1 and SOLAR‐2 trials who had this once dreaded and fatal complication. Treatment options after transplant have recently been expanded and now include the SOF‐free regimen of glecaprevir (GLE) and pibrentasvir (PIB).11 Treatment after transplant also carries the benefit of an expanded donor pool, because patients are able to receive a HCV‐positive organ, something that has been increasingly used in the last 5 years.12

Treating prior to transplant introduces patients with decompensated cirrhosis to real risks, including increased DAA failure fostering viral resistance, increased need for rescue transplantation, loss of access to the pool of HCV‐positive donors, and even increased mortality. The potential benefits, such as potential removal from the transplant list, remain too infrequent to routinely justify the risk. New tools, such as the BE3A score, indicate that patients with early decompensation may benefit from treatment. Nonetheless, the reality for the majority of decompensated patients is that even after successful treatment with DAAs, the decompensation and hence the need for transplant will remain. Hepatologists should recommend that their patients with decompensated HCV cirrhosis be transplanted, and HCV therapy should be administered in the early posttransplant period.