This is one of a few multicentric cohort studies, representative of patients with chronic HCV infection in care in Italy that prospectively evaluated the medium-term outcomes following HCV eradication by DAA in consecutively enrolled patients with severe liver disease, based on HIV status. Regarding the HIV coinfection our study population consisted of HIV coinfected patients at least 10 years younger than HCV monoinfected patients. This age difference potentially reflect the epidemiology of HIV infection mainly related with a later epidemic wave compared to the post transfusion and nosocomial epidemic wave of HCV monoinfection in Italy (17). The longer duration of chirrosis due to the longer time of infection in monoinfected patients could explain the higher HCC prevalence in monoinfected compared to coinfected patients before therapy (2–6). However, despite the younger age, coinfected patients had more advanced liver cirrhosis which confirm a faster liver disease progression compared to monoinfected patients (C-P class B and C: 28.4% vs 8.4% in coinfected and monoinfected patients, respectively, p < 0.001).
We found that the overall SVR12 rate (93.9% and 94.1% in coinfected and monoinfected patients, respectively) is similar to those reported in clinical trials and in our previous study (18), confirming the high efficacy of DAA therapy in the real-world setting also in patients with advanced liver disease, regardless of HIV coinfection (18–21). The results of this medium-term study confirm that HCV clearance obtained by DAA is feasibly linked to an improved outcome in patients with advanced liver disease, independently by HIV-coinfection.
In our previous study, it has been shown a similar cumulative incidence of HCC in coinfected and monoinfected patients after viral eradication, suggesting that HIV coinfection is not associated with a higher probability of developing liver complications in successfully DAA treated patients with compensated cirrhosis (20). Here, we expand our previous findings, including patients with advanced/decompensated cirrhosis. Data in this group of patients are limited because patients with significant advanced liver disease were not included in clinical trials on DAA efficacy and were either excluded or, if included, their numbers were extremely low in real-life studies. Moreover, there are no long-term studies that prove the extent of clinical benefit for these patients.
Improvements in C-P scores have been noted and predictors of improvement have been described in patients with chronic HCV infection after viral eradication (22–25). We found that a successful DAA therapy for both HCV monoinfected and HIV/HCV coinfected patients with compensated/decompensated cirrhosis was also associated with a decrease of the liver disease severity. Specifically, after successful DAA treatment, an improvement in C-P class was observed in 85% of coinfected and in 64.6% of monoinfected patients, suggesting that viral eradication helps liver function recovery in the majority of patients with liver cirrhosis. Several studies reported liver stiffness regression after successful HCV treatment with the better improvement in patients with higher baseline fibrosis stage, with no significant difference between monoinfected and coinfected patients (13, 14, 26, 27).
As it has been previously reported, in almost 50% of patients with cirrhosis at baseline, who achieved the SVR following an IFN based treatment, a METAVIR score lower than F4 were observed in their post-treatment liver biopsy (28). Other studies which evaluated a longer duration have confirmed these findings, reporting even higher percentages of patients in whom significant decrease of high fibrosis score were observed (29, 30, 31).
However, when IFN-based therapy was used, only patients with low C-P scores were treated with Peg-IFN and Ribavirin for 6 months showing a beneficial clinical outcome during the median follow-up of 30 months after the SVR (32). Different results in terms of clinical outcomes could be observed in patients treated with DAA, because following their use in real-life, more compromised patients in terms of severity of liver damage have been treated (10, 33–35).
In this study, we observed that although most HCV-coinfected patients with baseline cirrhosis that achieve SVR12 experienced improvement of liver function tests, part of those kept the risk of liver disease progression regardless of viral eradication. We found that C-P class worsened in 8.2% HCV-monoinfected patients and in 5.4% HIV/HCV-coinfected patients. Male sex, higher baseline INR and platelets counts lower than 100.000, surrogate markers of severe liver damage and portal hypertension, were independently associated to C-P class deterioration, while HIV coinfection was not an independent factor of liver disease worsening. In previous studies, additional analyses have suggested that patients above the age of 65 with reduced hepatic synthetic function (serum albumin 635 g/L) were less likely to benefit from DAA therapy as well, although these factors were not sufficiently discriminative to identify a subgroup in which antiviral therapy should be deferred in favour of liver transplant (28).
A critical issue for patients with cirrhosis is the prediction of the risk of decompensations. In the present study we found that a new decompensating event occurred in part of patients with a history of previous decompensation: 47% of coinfected and 45.6% of monoinfected patients with a history of hepatic decompensation before treatment start, kept the risk of a decompensating event following viral eradication. In addition, liver disease progression with the appearance of an incident decompensating event was observed after viral eradication, emphasising the finding that the virological efficacy is not always translate in clinical efficacy in patients with advanced liver disease.
Our findings confirm the existence of a point of no return, after which antiviral treatment may be too late to influence the natural history of HCV related liver disease, however more data are needed to better define this patient’s population.