Hepatitis C treatment threshold in patients with decompensated liver disease
Authors: Duminda Suraweera, Sammy Saab
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Saab consults, advises, and is on the speakers' bureau for AbbVie, Bristol‐Myers Squibb, Gilead, and Merck. See Article on Page 1810 Select patients with decompensated liver disease due to hepatitis B virus have realized marked improved clinical outcomes from continual viral suppression with oral therapy.1 Based on those successes, hepatologists are often faced with the dilemma of whether to treat patients with decompensated liver disease due to hepatitis C virus (HCV) with direct‐acting antiviral (DAA) agents. Although these drug regimens have revolutionized the treatment of HCV, the utility of DAAs in patients with decompensated liver disease is an area of active investigation, particularly among liver transplant candidates.2 There are a number of potential clinical benefits in treating liver transplant candidates with decompensated liver disease, including increased waitlist survival, removal from the transplant list, elimination of the possibility of HCV reinfection in the organ graft, and improved survival after liver transplantation.3 Indeed, a number of studies have highlighted the decreasing proportion of liver transplant candidates with a diagnosis of HCV who are waiting for transplant.4 On the other hand, there is the risk of delaying transplantation because the patient can no longer receive an HCV‐positive graft and the possibility of selecting for resistant variants if a sustained virological response (SVR) is not achieved. In this issue of Hepatology, Fernández Carrillo et al. report on a retrospective, noninterventional, multicenter study investigating the effectiveness and safety of interferon‐free DAA regimens in patients with advanced liver disease from the Spanish Hepa‐C registry.5 The study demonstrates that liver disease severity is important for identifying not only patients who are most likely to have an improved clinical outcome after achieving SVR but also patients who are likely to have suboptimal SVR and a high rate of adverse effects. All patients were treated with interferon‐free DAA regimens, with the specific DAA treatment regimens and duration of use at the discretion of individual physicians. The most common regimens used were sofosbuvir/simeprevir (45% of patients), sofosbuvir/daclatasvir (22% of patients), and ledipasvir/sofosbuvir (16% of patients). The patients were stratified according to severity of cirrhosis: compensated (Child‐Turcotte‐Pugh [CTP] A patients) or decompensated cirrhosis (CTP B/C). Within the CTP B/C group of 175 patients, only 13 were classified as CTP C. In their study, there was a drop‐off in SVR with advanced liver disease. The SVR rates at 12 weeks in the CTP A and B/C groups were 94% and 78%, respectively (P < 0.001). In addition, relapse rates were significantly higher in CTP B/C than CTP A patients (14% versus 4%, P < 0.001). Prior studies have also demonstrated a lower SVR in patients with decompensated liver disease.6 This decrease in SVR is generally considered multifactorial and may be related to increased portal pressure altering drug uptake and metabolism, impaired immune function from inflammatory and fibrotic effects of cirrhosis, and potentially differences in adherence because of the increased likelihood of adverse events. Serious adverse events in the current study were more common in CTP B/C patients (50% versus 12%, P < 0.001). The mortality rate was also higher in the CTP B/C group (6.4% versus 0.9%, P < 0.001). In fact, the rate of serious adverse events in CTP B/C patients was higher in this population than in other studies that have reported on the treatment of HCV in decompensated patients (Table 1).6 The increased rates of serious adverse events and mortality in the study by Fernández Carrillo et al. may be partially explained by the use of simeprevir‐based regimens, which are now contraindicated in patients with decompensated cirrhosis because of the risk of hepatotoxicity. However, no difference was seen in the overall adverse events of pooled CTP A and B/C patients when comparing regimens with and without simeprevir. Table 1 - Treatment Regimens in Patients With Decompensated Liver Disease From Hepatitis C Trial GT MELD DAA Duration SVR Relapse Rate Serious Adverse Events ALLY‐1 (n = 12) Any Overall median 13 DCV/SOF+RBV 12 weeks CTPB:94% Overall 15% Overall 17% CTPC:56% SOLAR‐1 (n = 13) 1/4 <10: 13% LDV/SOF+RBV 12 weeks CTPB:87% CTPB: 10% CTPB: 10% 10‐15: 61% CTPC:86% CTPC:4% CTPC:26% 16‐20: 25% 24 weeks CTPB:89% CTPB:3% CTPB:34% 21‐25: 1% CTPC:87% CTPC:8% CTPC:42% SOLAR‐2 (n = 15) 1/4 <10: 9% LDV/SOF+RBV 12 weeks CTPB:87% CTPB: 12% Overall 22% 10‐15: 43% CTPC:85% CTPC:4% 16‐20: 25% 24 weeks CTPB:96% CTPB:4% 21‐25: 4% CTPC:78% CTPC:4% ASTRAL‐4 (n = 14)a Any Overall median 10 SOF/VEL 12 weeks 83% Overall 7% 19% 24 weeks 86% 18% SOF/VEL+RBV 12 weeks 94% 16% aAll patients were classified as CTP B at screening, with some patients reclassified as CTP A or CTP C at first visit.Abbreviations: DCV, daclatasvir; GT, genotype; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; VEL velpatasvir. A common theme noted in the studies of the treatment of patients with decompensated liver disease is the exclusion of patients with renal insufficiency (Table 1). Indeed, there is usually an element of renal insufficiency associated with Model for End‐Stage Liver Disease (MELD) scores above 20. There are currently two DAA regimens approved for patients with renal insufficiency, but these same regimens are contraindicated in patients with decompensated cirrhosis (ombitasvir/paritaprevir/ritonavir and dasabuvir and elbasvir and grazoprevir). Clearly, the use of DAAs has revolutionized the care of patients with HCV, and clinical improvement can be achieved in patients with advanced liver disease. However, it is equally possible that there exists a point of no return, beyond which there is unlikely to be benefit with DAA treatment. Some studies have attempted to delineate baseline characteristics that would help guide patient selection for antiviral treatment. Foster et al. found that patients with initial serum albumin ≤35 g/L, sodium < 135 mmol/L, or age > 65 were less likely to benefit from therapy.10 The study by Fernández Carrillo et al. further supports the possibility of doing harm by treating a patient beyond a certain MELD score. Regression analysis performed in the study found that a MELD score ≥18 was predictive of death with a specificity of 97%. Although simeprevir‐based regimens are no longer recommended for patients with decompensated cirrhosis, the population‐based data reported in this study are vital if we are to evaluate the true efficacy and safety of DAA agents in actual clinical practice. To this end, the importance of maintaining accurate national registries is highlighted in this study. Data on long‐term outcomes in patients with HCV‐related decompensated liver disease treated with DAAs are still needed. Prior to initiation of DAAs, these patients should be referred to a liver transplant center to thoroughly discuss the timing of DAA therapy and implications of SVR on transplant status and outcomes.