Regression in hepatic fibrosis in elderly Chinese patients with hepatitis C receiving direct-acting antiviral treatment

Chronic hepatitis C (CHC) is a prevalent disease resulting from infection with hepatitis C virus (HCV), a hepatotropic RNA that can cause fibrosis, liver cirrhosis, and even hepatocellular carcinoma [1]. Approximately 71 million people across the world are infected with HCV, where the global prevalence of CHC is estimated to be 1.0%, and the reported incidences in China were 0.43% [2, 3]. Currently, the rate of increase in CHC is a relatively higher among elderly people, who typically have a longer course of disease, suffer from a higher amount of comorbidities and are more prone to adverse reactions. These factors significantly impact economic costs, morbidity and mortality on a global scale [4, 5].

Prior to 2011, the standard treatment for CHC was pegylated interferon (PEG-IFN) therapy [6]. However, PEG-IFN based therapy consistently leads to treatment intolerance, especially among elderly patients. Ever since the Food and Drug Administration (FDA) approved the first direct-acting antiviral agents (DAAs), new regiments involving DAAs have revolutionized the treatment of CHC. In fact, various forms of DAAs therapy have been recommended for all patients with chronic HCV infection [7‐10]. DAAs were introduced in 2017 in most parts of mainland China, but the application has been limited due to the economic ability of patients in different regions, the relevant research data is lacking as well. However, thanks to the capitated payment policy in Tianjin, each HCV patient with Tianjin medical insurance can receive medical reimbursement for the total treatment cost. Not only is this financially convenient for patients, but it also provides good conditions for carrying out HCV-related research.

Currently, the degree of liver fibrosis is considered useful for predicting the development of liver fibrosis,cirrhosis, hepatocarcinoma even death in CHC patients following treatment, where its extent serves as an indicator of disease progression [11‐13].

Although liver biopsy remains the gold standard for the evaluation and management of patients with fibrosis, its clinical application is largely limited in due to its invasiveness, inter-observer variability at pathologic evaluation, inadequate sampling size and sampling variations [14, 15].Instead, many non-invasive fibrosis indices have been applied to fibrosis assessment, these methods generally involve a physical approach based on the liver stiffness measurement (LSM) or a biological approach based on serum biomarkers [16, 17]. Of these techniques, transient elastography (TE) has gradually become the mainstay for non-invasive liver fibrosis evaluation, TE can be performed with excellent diagnostic accuracy and independent of the underlying liver disease for cirrhosis diagnosis [18]. Non-invasive scoring systems based on laboratory blood tests include the γ-GT-to-PLT ratio (GPR), AST-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) score. FIB-4 and APRI have demonstrated reliability in predicting cirrhosis during mass HCV treatment [19]. Although GPR scoring is a relatively new noninvasive evaluation method, this system has proven to be no less accurate than FIB-4 or APRI in staging liver fibrosis among patients with chronic hepatitis B [20].

However, the impact of DAAs on the elderly population has not garnered much attention. Existing research on DAAs rarely uses the elderly population as the main research object, rendering knowledge on DAA treatment among the elderly very limited.

Currently the available DAA regimens are well-tolerated and achieve high rates of sustained virological response (SVR) among elderly Chinese adults [21]. The purpose of this study was to evaluate liver fibrosis improvement resulting from DAA treatment in elderly patients with chronic HCV infection using various non-invasive measurements, and to further investigate the factors associated with these changes.

In this study, we found that LSM, GPR, FIB-4, and APRI in CHC patients decreased after DAAs treatment whether the patient is elderly or not, which indicates regression of fibrosis. Besides, the CAP did not change significantly in the elderly group. Among the elderly, the correlations between three noninvasive serological evaluation markers and LSM were positive and significant. Meanwhile, this study also showed that age, LSM and CAP were independent predictors of fibrosis regression based on multivariate analysis.

To the best of our knowledge, this was the first study to explore the effect of DAA treatment on liver fibrosis in elderly Chinese patients with CHC. The main reasons for using DAAs to treat CHC include preventing the development of liver fibrosis and improving existing liver fibrosis status [5]. According to current knowledge, the regression of fibrosis is mainly achieved through the elimination of HCV. [27] Treatment with either IFN or DAAs has the capacity to achieve SVR, and many articles have proven that IFN-based treatment can significantly improve the degree of fibrosis [28‐30]. Nevertheless, IFN-based therapy has been largely replaced by DAA treatment, which has caused the treatment of CHC to enter a pan-genotypic era. Our experience with and knowledge of DAA treatment is still rapidly evolving.

Since DAAs were first approved by FDA, multiple studies have demonstrated their role in improving the degree of liver fibrosis. Bachhofner et al. observed a significant reduction in liver stiffness after DAA-based treatment, which corresponded to a TE regression of more than 30% [31]. Similarly, Knop V et al. found that DAA treatment caused 88% of their patients to experience a reduction in liver stiffness [32]. Notably, most of the relevant studies were carried out in European and American countries. There is a lack of relevant data in China, and especially in the mainland region. However, some clinical trials conducted in China have confirmed the improvement in liver fibrosis resulting from DAAs. In their cohort of 102 patients with CHC, Kang Q et al. observed a decrease in median LSM from a baseline value of 10.45 kPa to 7.60 kPa following DAA treatment; significant decreases were also observed for FIB-4 and APRI scores [33]. In their study, Huang R et al. enrolled 40 patients treated with DAAs, finding that LSM, FIB-4, and APRI achieved statistically significant improvements by liver biopsy [34].

Currently, it has been proven that the available DAAs regimens are well-tolerated and could achieve high rates of sustained virological response (SVR) in Chinese elderly adults [21]. However, none of these studies paid special attention to elderly patients – in fact, the oldest participant was only 67 years old. Since elderly patients often suffer from a variety of basic diseases or take a variety of drugs at the same time, this group does not typically partake in clinical trials. Therefore, the current body of research may not be applicable to this specific sub-population. Our study aimed to fill the lack of data in this area.

Although liver biopsy is recommended prior to antiviral treatment, it may cause complications and is limited by relatively high costs, meaning it is not typically used in the routine management of CHC patients receiving DAAs. To replace biopsy, several noninvasive tests have been created, which are reproducible, and validated in several published studies [35, 36]. Accordingly, we applied TE to measure LSM, and GPR, FIB-4, and APRI scores to evaluate the degree of liver fibrosis.

Consistent with the results of the aforementioned reports, we found that the baseline level of LSM was higher in elderly patients compared to young patients, but no significant difference was observed between the subgroups of patients over 60 years old. Regardless of whether the patients were elderly, this study showed that DAA treatment improves LSM. However, although patients over 70 were found to achieve fibrosis regression, they did not demonstrate a statistically significant decrease in LSM. Among all patients, GPR, FIB-4, and APRI were significantly improved after DAA treatment. We also evaluated the correlations between serum biomarkers and LSM in elderly patients. GPR, FIB-4, and APRI were found to have correlations with TE measurement both before and after treatment, although these relationships were not particularly strong.

While the GPR, APRI, and FIB-4 values rapidly improved after DAA therapy from baseline to 12 weeks, these changes partly reflect improvement of necroinflammation rather than fibrosis regression completely because of the limitations of biochemical indicators. Similarly, TE measurement has been proven to be affected by necro-inflammatory activity to a certain extent, and especially during the onset of acute hepatitis [37]. However, the patients in this study had relatively stable liver disease, and most of their liver enzymes were less than three times the normal upper limit, meaning these factors can be considered to have little on LSM [38]. Furthermore, Lens S, et al. conducted a multicenter study, in which the hepatic venous pressure gradient (HVPG) of patients with HCV-associated cirrhosis significantly decreased after antiviral therapy [39]. Despite the lack of evidence of liver histology, this study reasonably speculated that DAAs did improve the degree of liver fibrosis and not simply inflammation and necrosis.

HCV infection can activate the sterol regulatory element-binding protein (SREBP) signaling pathway, resulting in a temporary increase in its expression level that further increases the adipogenesis of cholesterol and membrane lipids [40]. Theoretically, HCV eradication by DAA treatment is expected to regulate the expression of SREBP and reduce adipogenesis in the liver, which subsequently reduces CAP, an alternative marker of hepatic steatosis. Some previous studies have confirmed this conjecture [41, 42]. However, recent reports have also shown that successful HCV eradication by DAA therapy may cause an elevation in CAP [43, 44]. In this study, we assessed the degree of hepatic steatosis using CAP, finding that the CAP value was higher in elderly patients compared to young patients both before and after treatment. Additionally, the CAP value for patients over 70 years old was higher than that of younger elderly patients. This finding may be related to the relatively long course of disease in elderly patients, which leads to a more serious degree of steatosis. We also found that the CAP value in the younger population significantly increased following DAA treatment. The CAP value for elderly patients showed the same trend, but without statistical significance. There was no significant difference in CAP improvement between the two groups, which is consistent with the results of previous studies. We think this phenomenon could be explained, because elderly patients were always accompanied with sarcopenia and had worse nutritional status, but the specific mechanism between the two is still unclear. Therefore, hepatic steatosis improvement and changes in blood lipid levels after HCV clearance by DAAs should be more actively monitored [45]. Meanwhile, for the elderly, nutritional status assessment can be carried out during the treatment with DAAs, such as body composition analysis and skeletal muscle content determination and other relevant tests, to further clarify the potential causes of CAP changes in the elderly after DAAs treatment.

In this study, we also evaluated various factors associated with the regression of liver stiffness after the end of treatment in elderly patients. Among these factors, age, LSM at baseline, and CAP value were found to be independently associated with LSM improvement.

Almost all relevant studies have shown that LSM is an independent predictor for fibrosis regression in chronic HCV patients who achieve SVR after DAA treatment [41, 46, 47]. Similarly, our results indicate that the higher the baseline LSM, the better the improvement in fibrosis following DAA treatment. Considering that a higher baseline LSM value may reflect a higher degree of liver inflammation, improvements in liver enzyme indices for these patients should be more obvious, and the change in LSM should be more significant. In this study, we found that the CAP value was negatively and independently associated with fibrosis regression. Similarly, the work from Lackner C et al. also identified steatosis as a predictor for failed LSM improvement [48]. Soliman H et al. found that the steatosis degree, as measured by TE, was related to fibrosis regression in patients after receiving DAAs [49]. We determined that the hepatic steatosis of CHC patients may increase with DAA treatment, which may have a negative impact on hepatic fibrosis improvement and worsen long-term prognosis. At the same time, we emphasize that further research is needed to explore the mechanism that explains how degree of steatosis affecting fibrosis regression. Advanced age is also considered to be a predictor of poor prognosis. Therefore, on the premise of ensuring good health, it is important to begin antiviral treatment as early as possible. Recently, some studies have suggested that diabetes is a ‘bad trip companion’ of HCV, and that hyperglycemia is significantly associated with poorer stiffness regression [50, 51]. In the present work, we found that elderly patients were more likely to have diabetes than younger patients, so we included diabetes in our regression analysis. However, this term was not statistically significant.

In addition, factors such as low platelet counts, low or high ALT levels, high serum angiopoietin-2 levels, high FIB-4 score, and previous treatment history have also been identified as predictors associated with improved liver fibrosis [32, 47, 51‐53]. However, these findings were not observed in this study. The impact of these predictors needs to be further evaluated in a larger population with a longer follow-up period.

This research has several limitations worth discussing. First, this study is retrospective in nature and has the potential for misinformation or missing data. To address these concerns, a more prospective study is necessary. Second, this study lacked histological evidence to examine the degree of liver fibrosis in CHC patients before and after DAA therapy. This primary reason for this was patient reluctance to undergo invasive procedures. Finally, the limited period of 12 weeks after treatment only allowed us to assess the temporary benefits of fibrosis after DAA therapy. Thus, future studies involving more patients and with longer follow-up periods are needed to better clarify the long-term benefits of DAAs in elderly patients.

In conclusion, LSM evaluated by TE, GPR, FIB-4, and APRI significantly decreased in elderly patients with CHC after HCV eradication. However, the degree of hepatic steatosis expressed by the CAP value did not significantly change as a result of treatment for the elderly group. Conversely, for younger patients, the CAP value significantly increased after DAA treatment. In addition, for elderly patients, we observed significant correlations between these three noninvasive serological evaluation markers and LSM, both before and after treatment. We found that age, LSM, and CAP at baseline were independent predictors of fibrosis regression in elderly CHC patients treated with DAAs. However, for elderly HCV patients at higher risk for liver fibrosis and HCC development, studies with more long-term follow-up periods are still necessary.