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Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
Cheung MCM, et al. HCV Research UK
J Hepatolology 2016; 65 : 741-747

Background & Aims : Direct-acting antivirals have become widely used for patients with chronic hepatitis C virus infection with decompensated cirrhosis. Virological responses are excellent and early improvements in liver function, at least in a proportion of patients, have been observed but the longer term impact of viral clearance on end-stage liver disease complications is unclear.

Methods : Prospective study of patients with decompensated cirrhosis who received 12 weeks of all-oral direct-acting antivirals through the English Expanded Access Programme. Endpoints were deaths, liver transplantation, hepatocellular carcinoma, serious decompensation events, sepsis or hospitalisations, and MELD scores between start of therapy to 15 months post-treatment start. An untreated cohort of patients was retrospectively studied over 6 months for comparison.

Results : Amongst 317/406 patients who achieved sustained virological response at 24 weeks post-treatment, there were 9 deaths (3%), 17 new liver cancers (5%), 39 transplantations (12%) and 52 with serious decompensations (16%), over 15 months. When compared to the first six months from treatment start and to untreated patients, there was a reduction in incidence of decompensations [30/406 (7%) in months 6–15 and 72/406 (18%) in months 0–6 for treated patients vs. 73/261 (28%) in untreated patients]. There was no significant difference in liver cancer incidence (10/406 (2.5%) in months 6–15 and 17/406 (4%) in months 0–6 for treated patients vs. 11/261 (4%) in untreated patients).

Conclusions : This study suggests that antiviral therapy in patients with decompensated cirrhosis led to prolonged improvement in liver function, with no evidence of paradoxical adverse impact nor increase in liver malignancy.

Lay summary : This is a report of a large group of patients in England who have hepatitis C virus (HCV) infection with advanced liver disease. They have been treated with new anti-HCV drugs, which cured the infection in the majority. This study looks at their outcomes a year following treatment, in terms of deaths, cancers and other complications of advanced liver disease. We conclude that in most patients anti-HCV treatment is beneficial even in advanced liver disease.

Expert's Commentary

This study sheds lights on the role of interferon-free regimens including direct acting antiviral (DAA) on what we consider the final aim of HCV treatment, the possible changes on the natural history of the disease. Previous analyses of registration studies with DAA suggested an improvement in MELD score and in portal hypertension in patients with advanced liver damage ( Afdhal N. J Hepatol 2014 ), these are the first real life data evaluating, (after a median follow-up of 15 months, including the duration of treatment) possible decline in the occurrence of liver cirrhosis complications following achievement of SVR on treatment. It should be emphasized that the study included patients more advanced than those enrolled in the registration studies and significantly more advanced than past candidates to IFN-based treatments. Indeed, Child C patients represented 10% of this cohort of decompensated subjects who were enrolled in this compassionate programm in UK. Of interest, the authors included a control group of untreated patients with similar characteristics to those of patients receiving DAA. Although baseline characteristics of treated patients and controls were not matched, it can be expected that patients with more severe disease received treatment as soon as it was available and therefore, in the worst scenario, treated patients were slightly more advanced than untreated ones. Despite this limitation, results support a higher number of adverse outcome in untreated patients or in patients who did not achieved SVR than in DAA responders. In addition, the study allows to differentiate the benefit by CPT classes. Indeed, the group with the highest number of adverse outcome contained a significant proportion of patients with CPT class C. While such evidence should not be used to deny treatment, it is important to know that the more advanced the disease, the lower might be the benefit of treatment and that this is a reinforcement of the recommendation to treat patients as early as we can.

The final important piece of evidence generated by this work is that HCC rates are not increased after DAA treatment as suggested by recent studies in Europe ( Reig M. J Hepatol 2016; Conti F. J Hepatol 2016 ). Rate of HCC occurrence amongst patients with SVR to DAA was lower than the rates seen in patients who did not eliminate the virus or remained untreated. What is clear from this and other studies is that we have now the opportunity to treat and cure patients with significantly advanced liver disease, a group we could not imagine to cure with IFN-based regimens. Modern anti-HCV regimens are associated with viral eradication in a much larger number of patients, but cannot change the natural history of those with already deteriorated multi-organ conditions who have late access to treatment due either to historical reasons (these potent drugs became available only recently) or personal reasons (lack of awareness or economical restrictions). This consideration is particularly true for HCC where the carcinogenetic process starts 5 years or more before the diagnosis ( Johnson P. Hepatology J Clin Oncol 2014 ).

In conclusion, although not free of limitations, this study helps to understand that DAA reduces but not reset completely the risk of HCC, with the need to continue to regularly monitor patients with HCV-related cirrhosis even after SVR.

Alessandra Mangia, San Giovanni Rotondo, Italy