In this multicenter retrospective real-world cohort study, we aimed to assess the effectiveness and safety of HCV treatments in patients with cirrhosis, both with and without EV. Our findings reveal that among patients infected with HCV and cirrhosis, those exhibiting the presence of EV achieved a SVR rate of 91.5%. In contrast, a higher SVR rate of 96.3% was observed in the subgroup of patients without EV.
During the era of IFN-based antiviral regimens, the effectiveness of IFN-based antiviral therapies was markedly low, particularly in patients with CSPH (HVPG ≥10 mm), with a success rate below 20% in patients infected with GT1 [12]. Moreover, the administration of IFN-based therapies was often impeded by the prevalence of hematologic complications, including leukopenia, thrombocytopenia, and anemia, which were attributed to the myelosuppressive effects of IFN [22]. However, portal pressure also played a significant role in exacerbating these complications [23]. The aforementioned hematologic complications, particularly thrombocytopenia and leukopenia, frequently necessitated treatment discontinuation in this patient population [24].
The introduction of DAAs was a breakthrough in the treatment of patients with HCV, including those with cirrhosis, significantly improving treatment effectiveness and safety profile [25]. There is a notable dearth of studies comparing the efficacy and safety of IFN-free therapies in patients with and without CSPH [26–29]. This gap in research not only underscores the scarcity of evidence regarding treatment outcomes in this specific high-risk subgroup but also accentuates the necessity for comprehensive investigation and analysis in forthcoming studies.
In a prospective study conducted on an Italian cohort of patients infected with GT3 HCV and liver cirrhosis, who were treated with SOF (Sofosbuwir)/VEL (Velpataswir) without RBV for 12 weeks, it was demonstrated that the presence of EV does not significantly impact the effectiveness of SOF/VEL treatment [26]. This study revealed similarly high SVR rates of 98.4% in patients without EV and 97.1% in those with varices, moreover in the subgroup of patients deemed at high risk of PH (determined by non-invasive evaluation), the SVR rate was 99.1%, compared to 95.8% in patients without such risk. In our analysis patients with GT3 achieved a lower SVR as compared to those infected with other genotypes (75.5%). However, it should be noted that our analysis involved all patients with HCV, regardless of therapeutic options, including suboptimal regimen of SOF+RBV used predominantly in GT3-infected individuals, in contrast to the above mentioned study, which focused solely on the new pangenotypic option—SOF/VEL. The effectiveness of various IFN-free therapeutic options was analyzed in a retrospective study conducted among 104 patients with PH (HVPG ≥ 6 mmHg), with 100 out of these patients achieving SVR, indicating a success rate of 96.2%. However, it is noteworthy that researchers did not report the effectiveness of treatment specifically within the subgroup of patients with CSPH [27].
In a minor study which targeted HIV/HCV-coinfected patients with advanced liver fibrosis and PH (HVPG ≥ 6 mmHg), all subjects achieved SVR following treatment with IFN-free therapy based on SOF including 11 individuals diagnosed with CSPH (HVPG ≥ 10 mmHg) [28]. Our study, which included patients with HIV coinfection, demonstrated that 16 out of 19 (84.2%) individuals with EV achieved SVR. This compares to 55 out of 57 (96.5%) individuals without EV within the same subgroup.
In a large-scale RWE study, it was observed that DAA therapy was less effective in patients with EV [30]. Additionally, another study covering a patient population of nearly a thousand identified EV as an independent predictive factor for the lack of virological response to HCV treatment [31]. In our analysis, during the univariable analysis, factors such as male gender, GT3 infection, decompensation of liver function at baseline (B in the CP scale), and documented EV were identified as negative predictors of achieving SVR.
The DAA regimens evaluated in our study had a good safety profile, characterized by a low rate of treatment discontinuation due to adverse events, in line with clinical trials and other RWE studies [32,33]. It is noteworthy, however, that the tolerability of DAA regimens was found to be less favorable in patients with EV. Our analysis revealed a significantly higher prevalence of complications such as ascites, hepatic encephalopathy, and gastrointestinal bleeding in patients with EV compared to those without this complication. These findings are consistent with the natural progression of liver disease, where the presence of EV often signifies more advanced liver pathology and a higher risk of clinical decompensation [34]. These observations suggest a need for heightened vigilance and closer monitoring of patients with EV undergoing DAA therapy, particularly given the increased risk of liver decompensation and other complications associated with advanced liver disease. Such patients should not be treated with regimens containing protease inhibitors (PI), according to current guidelines and the FDA (Food and Drug Administration)'s position, because of the potential risk of exacerbating liver dysfunction or liver failure [20,35]. In our study, which has the character of a retrospective project from real-world clinical practice, not being a randomized clinical trial with a protocol, the decision on the choice of therapy was entirely on the part of the treating physician, who in making it was guided by the provisions of the drug program and the current state of medical knowledge.
Although the first signals of the possibility of worsening liver function in patients with decompensated cirrhosis appeared in 2016, being the basis for a provision against their use in this population in the EASL recommendations 2016 published in 2017, the 2015 and all subsequent AASLD guidelines include the phrase "not recommended" for PI use in CP B and C patients[36–38]. Finally, the safety warning for PI-containing regimens was issued by the FDA in the second half of 2019, 107 patients with decompensated liver function at the very beginning of our study were treated with such regimens, mainly ombitasvir/ paritaprevir boosted with ritonavir ± dasabuvir ± RBV. Although 92 of them achieved SVR, 12 patients in this group discontinued treatment due to safety concerns related to deterioration of liver function. Six deaths were also reported, four of which were attributed to liver-related complications. Thus our observations support recommendations suggesting that PI-containing regimens should be avoided in patients with decompensated cirrhosis qualified as CP class B or C.
In the studied population, the prevalence of so classified individuals was significantly higher among patients with EV compared to those without varices, with rates exceeding 25% as opposed to 6.8%, respectively. Notably, within the varices group, the SVR rate was below 90%. These findings resonate with those from another retrospective study, wherein patients with decompensated cirrhosis exhibited higher SVR rates in PP analysis, reaching 92.9% [33]. Patients with a low platelet count have an important impact on the patient's prognosis in the course of cirrhosis [39]. In our analysis, such individuals had worse SVR percentages in patients with EV than in those without EV.
Subgroups analyzed in our study demonstrated variances in the utilization of concomitant medications. Notably, within the EV group, patients were statistically more inclined to receive beta-blockers. The administration of beta-blockers contributes to a proactive approach aimed at reducing portal pressure and mitigating the risk of variceal bleeding, a hallmark complication of portal hypertension [40]. Additionally, there was an increased utilization of rifaximin within the EV subgroup, which corresponded to a higher baseline incidence of encephalopathy. It's noteworthy that this medication not only address complication associated with liver cirrhosis but also potentially improve overall prognosis [41].
As such the diagnosis and treatment of HCV infection are crucial in the management of this patient population, as successful treatment can significantly impact disease progression and patient outcomes. The regression of liver fibrosis and CSPH following treatment with DAAs is a topic of considerable interest but remains controversial. While some studies indicate rapid declines in liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) following SVR, others suggest minimal changes [14,42–44]. Conversely, improvements in MELD scores and liver function, along with reductions in HVPG, suggest benefits of treatment in this population [43,45]. These findings underscore the complexity of assessing treatment outcomes and the need for comprehensive evaluation in patients with HCV-related liver disease.
The accurate assessment of liver disease severity is crucial prior to initiating treatment for HCV infection, as recommended by the European Association for the Study of the Liver (EASL) [20]. Specifically, individuals diagnosed with cirrhosis sholud be undergo a comprehensive assessment to determine the presence of PH, which includes the evaluation for EV [20]. Additionally, individuals with EV identified during endoscopy before treatment should also undergo endoscopic examination to diagnose variceal recurrence after viral eradication. Traditionally, the measurement of HVPG has been considered the "gold standard" for assessing portal pressure. However, due to its invasiveness, there has been a growing interest in noninvasive methods to predict the presence of CSPH. Liver stiffness measurement has been identified as a useful tool in assessing liver fibrosis [6]. Additionally recent studies have shown promising results regarding the use of noninvasive techniques such as spleen stiffness measurement (SSM) in predicting CSPH. SSM, particularly using Acoustic Radiation Force Impulse (ARFI) imaging, has demonstrated a significant correlation with PH and the presence of EV [46,47]. These methods offer clinicians valuable insights into the severity of liver disease without subjecting patients to the risks associated with invasive procedures. It is imperative to consider the long-term implications of HCV treatment, particularly in patients with PH. A previous report has shown that the risk of HCC development remains clinically significant in patients with PH complicated by advanced fibrosis even after successful eradication of HCV [16]. Variceal bleeding, a principal complication of cirrhosis associated with PH, continues to be a significant concern despite advancements in its management. Despite major improvements, mortality rates as high as 15% persist after a first episode of bleeding, emphasizing the critical need for effective preventive measures and treatment strategies in patients with CSPH [48]. This underscores the importance of ongoing surveillance and management strategies to address complications such as variceal bleeding and reduce mortality rates in this population.
Our study exhibits several limitations warranting attention. Primary, it is imperative to acknowledge that our study did not employ HVPG measurements for the diagnosis of PH, relying instead on the presence of EV, which may not represent the gold standard in PH diagnosis. Additionally, in this study we did not analyse all manifestations of PH, focusing mainly on EV. As a retrospective analysis of the real world, our study inevitably is burdened with inherent flaws, such as incomplete data, potential biases, data entry errors, data misclassification and under-reporting of safety information, particularly the lack of detailed data on causes of death. In addition, the observational nature of the study may have introduced variability in treatment adherence, as the assessment of adherence was based solely on patient reports, with no objective method. Finally, in our analysis, we do not have information on the improvement in liver function as a result of HCV eradication, as we do not have long-term data on patients' scores on the CP and MELD scales.
However, the strength of our investigation lies in the extensive analysis of a sizable cohort of patients with EV across multiple hepatology centres, facilitating the generalization of conclusions. Moreover, the relatively low percentage of patients lost to follow-up (3.5%) is noteworthy, resembling values typically observed in controlled clinical trials rather than real-world studies.