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ORIGINAL ARTICLE
Year : 2020  |  Volume : 23  |  Issue : 2  |  Page : 226-231

Does regression in treatment-induced liver fibrosis reflect noninvasive tests? Assessing treatment results of hepatitis B patients who took potent antiviral drugs for 5 years


Department of Gastroenterology, Mersin City Hospital Mersin, Turkey

Date of Submission04-Jan-2019
Date of Acceptance27-Oct-2019
Date of Web Publication7-Feb-2020

Correspondence Address:
Dr. S Yalaki
Department of Gastroenterology, Mersin City Training and Research Hospital Mersin; Korukent Mah., 96015 Sok. Mersin Entegre Sağlık Kampüsü, 33240 Toroslar/Mersin
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_7_19

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   Abstract 


Background: Chronic liver disease may be reversed through treatment, and it is crucial to have a definitive diagnosis of liver fibrosis for this treatment. Aims: In this study, we aimed to determine whether regression of liver fibrosis in naive patients undergoing strong antiviral therapy is reflected in noninvasive tests. Materials and Methods: We systematically reviewed and monitored medical records of patients with chronic hepatitis B who underwent liver biopsy for patient qualification. We selected patients with a liver fibrosis score of two or more who had not previously received antiviral treatment. We used previously described formulas to compute the indirect indicators of fibrosis for the patients and noted the values of Aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), age-platelet index (API), fibrosis index-based 4 factor (FIB-4), AST-platelet ratio index (APRI), mean platelet volume (MPV) and platelet count (PLT). Results: We found a significant difference between the three measurements for APRI, AAR and FIB-4 scores and MPV and PLT distributions in patients who were administered entecavir and tenofovir (Friedman P < 0.05). In the post-hoc binary comparison for both entecavir and tenofovir, we found significant differences between the baseline measurements and the 3rd- and 5th-year measurements in terms of APRI, AAR, FIB-4, MPV, and PLT. Conclusion: Liver biopsy is considered the gold standard for the treatment and follow-up of hepatitis B but may not be appropriate in all cases. Non-invasive tests may be effective in monitoring antiviral therapy. We demonstrated that non-invasive tests improved with antiviral therapy, which may be a reflection of treatment-regression in liver histopathology.

Keywords: Hepatitis B, indirect fibrosis markers, noninvasive tests, regression of hepatic fibrosis


How to cite this article:
Yalaki S, Yalcin M S. Does regression in treatment-induced liver fibrosis reflect noninvasive tests? Assessing treatment results of hepatitis B patients who took potent antiviral drugs for 5 years. Niger J Clin Pract 2020;23:226-31

How to cite this URL:
Yalaki S, Yalcin M S. Does regression in treatment-induced liver fibrosis reflect noninvasive tests? Assessing treatment results of hepatitis B patients who took potent antiviral drugs for 5 years. Niger J Clin Pract [serial online] 2020 [cited 2020 Feb 20];23:226-31. Available from: http://www.njcponline.com/text.asp?2020/23/2/226/277872




   Introduction Top


The hepatitis B virus (HBV) is the cause of 10% of all the chronic liver disease (CLD) incidences worldwide, and it is a significant cause of mortality and morbidity.[1] Complications are not observed in all patients with infection; however, hepatic failure, hepatocellular carcinoma (HCC), and cirrhosis are developed in 15–40% of these patients.[2] These complications, along with mortality, are associated with high replication rates detected by high plasma HBV DNA concentrations in infected chronic HBV patients.[3],[4],[5]

Liver fibrosis appears as a regenerative response to liver damage and remains the primary element in the development of cirrhosis. While it had been considered irreversible, it was later proved to be reversible through treatment both for viral and nonviral cases.[6],[7],[8] Hepatic decompensation and HCC incidence in cirrhosis patients also decrease with viral suppression with HBV polymerase/reverse transcriptase inhibitors, possibly due to the decline in fibrosis.[9],[10]

Since the prognosis of CLD is directly associated with the degree of hepatic fibrosis, demonstrating the severity and existence of fibrosis gains much importance.[5],[11] The gold standard for the assessment of fibrosis is a biopsy. However, liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications, including death. Such limitations have encouraged the development of noninvasive methods for the assessment of fibrosis. These noninvasive methods have included numerous serum biomarkers, imaging techniques, and combined indices/scores.

It has been shown in various studies that indirect markers of fibrosis have significant importance in diagnosis. In this study, we aimed to determine whether regression of liver fibrosis in naive patients undergoing strong antiviral therapy is reflected in noninvasive tests.


   Materials and Methods Top


In this retrospective study, we examined the medical records of patients with chronic hepatitis B (CHB) that were characterized by hepatitis B “s” antigen positivity for at least 6 months between 2008 and 2018. The selected patients all had CHB and had undergone liver biopsy. Their fibrosis scores were two or above, and all of them received potent antiviral treatment with no prior treatment history. Exclusions from the study included patients with a BMI above 30, daily alcohol intake above 20 g, accompanying liver diseases (Wilson disease, primary biliary cirrhosis, HCC, hemochromatosis, autoimmune hepatitis), liver transplant and coinfections such as hepatitis C virus, hepatitis D virus, or human immunodeficiency virus.

Indirect markers of fibrosis

We used previously described formulas shown in [Table 1] to determine the indirect markers, including the noninvasive tests of aspartate aminotransferase (AST) to alanine aminotransferase ratio (AAR), age/platelet index (ApI), AST/platelet ratio index (APRI), and fibrosis index-based on four factors (FIB-4).[12],[13],[14],[15] We identified the liver biopsy histories of all the patients and determined these dates as the baseline. Then, we recorded the values in the 3rd and 5th years together with the findings from the following measurements: platelet (PLT) count, mean platelet volume (MPV) and AST, and alanine aminotransferase (ALT) concentrations.
Table 1: The formulas of indirect fibrosis markers

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Statistical analysis

We described the continuous variables by mean and standard deviation, with the minimum, median, and maximum descriptions. Correlation analysis was performed for the correlation between initial noninvasive tests and initial fibrosis values. We used the Wilcoxon test for the comparisons of independent variables with normal distribution, the Mann-Whitney U test for independent variables without normal distribution and the Friedman test for more than two dependent variables with normal distribution.

P values below 0.05 were considered as statistically significant. We conducted the analyses on the MedCalc Statistical Software version 12.7.7 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2013).


   Results Top


The general characteristics of CHB patients are given in [Table 2]. The study population included 29 (30.9%) females and 65 (69.1%) males with a mean age of 48.29 ± 13.79. 40 (42.6%) of the patients received entecavir, while 54 (57.4%) received tenofovir. The median fibrosis score was 3 in both groups.
Table 2: Characteristics of chronic hepatitis B (CHB) patients

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In the correlation analysis [Table 3] between the fibrosis stage and noninvasive test scores, a statistically significant increase in all scores and decrease in PLT count was observed as the fibrosis level increased. There was no correlation between MPV. Among these values, the highest correlation with the fibrosis stage was achieved with ApI (r0.44), APRI (r0.38), FIB-4 (r0.33), and PLT counts (r-0.40) with a significance at P = 0.01. But AAR score had a weaker correlation with fibrosis.
Table 3: Correlation between fibrosis level and initial biochemical scores

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The median of the baseline, 3rd-year and 5th-year parameters are given in [Table 4]. APRI was measured at 1.02, 0.36, and 0.31 in the entecavir group and 0.99, 0.51, and 0.45 in the tenofovir group, respectively. FIB-4 was measured at 1.54, 1.24, and 1.2 in the entecavir group and 1.55, 1.26, and 1.21 in the tenofovir group, respectively. Ap index was measured at 4.42, 3.90, and 3.82 in the entecavir group and 4.35, 3.81, and 3.98 in the tenofovir group, respectively. AAR was measured at 0.86, 0.95, and 1.02 in the entecavir group and 1.07, 1.04, and 0.92 in the tenofovir group, respectively. The average PLT counts at the baseline and 5th year were measured at 166,500 and 199,000 in the entecavir group and 179,000 and 215,000 in the tenofovir group, respectively. It was observed that the MPV values decreased at the end of 5 years compared to the baseline values. In tenofovir patients, these values were measured as 9.39, 10.78, and 7.97. In entecavir patients, these values were measured as 9.38, 10.66, and 8.47.
Table 4: Comparisons of measurements

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We found a significant difference between the three measurements in terms of APRI, AAR, and FIB-4 scores and MPV and PLT distributions in patients who were administered entecavir and tenofovir (Friedman P < 0.05). In the post hoc binary comparison for both entecavir and tenofovir, we found significant differences between the baseline, 3rd-year, and 5th-year measurements in terms of APRI, AAR, FIB-4, MPV, and PLT, which are given in [Table 5] (P < 0.016, Wilcoxon, Bonferroni correction).
Table 5: Post hoc binary comparison

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   Discussion Top


Since the prognosis of CLD is directly associated with the degree of hepatic fibrosis, demonstrating the existence and severity of fibrosis gains much importance.[5],[11] The gold standard for the assessment of fibrosis is a biopsy, which is infeasible in repeated assessments. This method is also invasive and has serious possible complications including death. Therefore, the incorporation of noninvasive methods is encouraged in fibrosis assessments. These noninvasive methods have included numerous serum biomarkers, imaging techniques, and combined indices/scores.[12],[13],[14],[15],[16] It has been shown in various studies that indirect markers of fibrosis have significant importance in diagnosis.

In the study of Wai et al. on patients with CHC, the APRI parameter was stated to be a predictor for cirrhosis and fibrosis (the area under the receiver operating characteristic curve [AUROC] was measured at 0.80). Other studies on patients with CHB reported a correlation between liver fibrosis progression, and low PLT counts and high AST values.[14],[15],[16] Previous research and a certain meta-analysis of 40 studies revealed that APRI scores above 0.7 had 77% sensitivity and 72% specificity for liver fibrosis prediction and APRI scores above 1.0 had 76% sensitivity and 72% specificity for cirrhosis prediction. Scores above 2.0 had higher specificity at 91% but lower sensitivity at 46%. As the scores decreased below 0.5, the negative predictive value increased and brought the possibility of excluding cirrhosis. Similarly, as the scores increased above 1.5, the positive predictive value increased and brought the possibility of including cirrhosis. This hints that midrange values are not as definitive; thus, the APRI score alone is not adequately sensitive to exclude the disease.[17],[18] In the current study, we found a significant difference between the three measurements in terms of APRI in both groups (Friedman P < 0.05). In the post hoc binary comparison for both entecavir and tenofovir, we found significant differences between the baseline, 3rd-year, and 5th-year measurements in terms of APRI (P< 0.016, Wilcoxon, Bonferroni correction). Fibrosis recovery could be reflected by the progress in the APRI measurements.

With the age parameter and ALT value included, the FIB-4 score has matching statistics to APRI. In the study by Vallet et al. on the comparison of FIB-4 index values and biopsy findings in 847 patients, they measured the AUROC value of patients with severe fibrosis at 0.85 (METAVIR F3–F4). In the study, as the FIB-4 score fell below 1.45, the negative predictive value, sensitivity, and specificity were measured at 94.7%, 74.3%, and 80.1%, respectively. As the FIB-4 score increased above 3.25, they were measured at 82.1%, 98.2%, and 37.6%, respectively.[15],[19] In the current study, we found a significant difference between the three measurements in terms of FIB-4 in both groups (Friedman P < 0.05). In the post hoc binary comparison for both entecavir and tenofovir, we found significant differences between the baseline, 3rd-year, and 5th-year measurements in terms of FIB-4 (P< 0.016, Wilcoxon, Bonferroni correction). Liver fibrosis recovery could be reflected by the decrease in the FIB-4 measurements.

It is known that an AST/ALT ratio under 1.0 is characteristic in hepatitis B and C, while a value above that might still include the diseases. The effect of this ratio becomes more recognizable as cirrhosis and fibrosis progress further. AAR is another noninvasive and simple test for the demonstration of prognosis and progression, particularly in cirrhosis cases. The literature emphasizes that cirrhosis cases would be more helpful as opposed to APRI scores.[12],[20] Giannini et al. measured AUROC scores at 0.820 and APRI scores at 0.773.[12] We found a significant difference between the three measurements in terms of AAR in both groups (Friedman P < 0.05). In the post hoc binary comparison for both entecavir and tenofovir, we found significant differences between the baseline, 3rd-year, and 5th-year measurements in terms of AAR (P< 0.016, Wilcoxon, Bonferroni correction). Liver fibrosis recovery could be reflected by the decrease in the AAR measurements.

Some studies have reported greater mean age, serum AST, and serum gamma-glutamyl transpeptidase measurements, and lesser PLT counts in hepatitis B patients with severe fibrosis.[13],[20],[21],[22] In the current study, we found a significant difference between the three measurements in terms of PLT in both groups (Friedman P < 0.05). In the post hoc binary comparison for both entecavir and tenofovir, we found significant differences for PLT between the baseline, 3rd-year, and 5th-year measurements in terms of PLT (P< 0.016, Wilcoxon, Bonferroni correction). Fibrosis regression could be reflected by the increase in the PLT measurements.

Based on the age parameter and PLT value, the Ap index is another noninvasive test that may be utilized for the prediction of fibrosis. It is known that an Ap index at or above 6 means significant histologic findings, including septal fibrosis, moderate to severe necroinflammatory lesions and/or cirrhosis. A patient with a score ≥6 probably can be managed without a liver biopsy but a liver biopsy may be necessary for a lower score. Previous studies showed that the AUROC value of the Ap index was 0.763 ± 0.043. It was measured at 0.74 for CHC and 0.78 for CHB and had 52% sensitivity and 93% specificity for the values at or above 6.[13],[14],[23] In the current study, when we studied the Ap index values alone, we found a significant difference between the three measurements in both groups (Friedman P < 0.05). In the post hoc binary comparison for entecavir, we found significant differences between the baseline, 3rd-year, and 5th-year measurements in terms of the Ap index (P< 0.016, Wilcoxon, Bonferroni correction). No statistically significant differences were observed between any of the measurement times in terms of tenofovir.

MPV defines the PLT size and is routinely measured in blood counts. The PLT life cycle is decreased in CLD patients due to splenic sequestration, which results in an improvement in the release of new PLTs into the circulation and bone marrow PLT production. The latter has been recorded to increase with higher IL-6 values in hepatitis B patients due to inflammation.[21],[22],[23] Considering these reports, as new PLTs are introduced into the circulation and fibrosis score is increased in chronic HPV patients, MPV is also anticipated to increase. In the current study, we found a significant difference between the three measurements in terms of MPV in both groups (Friedman P < 0.05). In the post hoc binary comparison for both entecavir and tenofovir, we found significant differences between the baseline, 3rd-year, and 5th-year measurements in terms of MPV (P< 0.016, Wilcoxon, Bonferroni correction). Fibrosis recovery could be reflected by the change in the MPV measurements.

The use of noninvasive tests to increase the strength has come to the fore. When the literature is examined, it is seen that the accuracy in the diagnosis of fibrosis/cirrhosis increases with combined use. In their study, Ben Ayed et al. Reported that total score using APRI and FIB-4 showed better diagnostic performance than APRI and FIB-4 scores used separately.[24] In another study, Giannini et al. reported that combined use of AAR and PLT values has a high diagnostic value for cirrhosis.[25]

Fibrosis in the liver is known to be reversible with antiviral therapy in CHB patients.[7],[8] However, the literature investigating the effects of antiviral treatments on noninvasive tests in CHB patients is very limited. In the study of Basar et al., they observed significant declines in the noninvasive test values of CHD cases after the treatment following antiviral therapy for an average of 15.8 months.[26] In a study by Koksal et al., a significant decrease in APRI, FIB-4, and red cell distribution width-PLT ratio scores and a significant increase in PLT counts were also detected at months 12 and 24 during both types (entecavir and tenofovir) of treatments.[27] In our study, there was a statistically significant difference between the three measurements in terms of APRI, AAR, FIB-4 score, MPV, and PLT distributions in patients receiving tenofovir and entecavir (Friedman P < 0,05). We think that it is important that the improvement seen in noninvasive tests with antiviral treatment continues in the 5th year.

In conclusion, while the liver biopsy is widely considered as the gold standard in both the treatments and follow-up of hepatitis B, it might not be feasible in all cases. However, noninvasive scores do not replace liver biopsy for diagnosis, they can beused to monitor response in the treatment of chronic viral hepatitis B with oral antiviral drugs. Studies involving prospective randomized end-of-treatment biopsy results are needed for an optimal comparison of treatment efficacy against noninvasive scores.

The noninvasive tests that we propose for fibrosis measurements are all cost-effective, easy to access, repeatable, reproducible, and highly applicable between laboratories. The downside of said tests is that they are not particular for liver measurements, meaning that findings may easily be influenced by comorbid conditions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Giannini E, Botta F, Fasoli A, Ceppa P, Risso D, Lantieri PB, et al. Progressive liver functional impairment is associated with an increase in AST/ALT ratio. Dig Dis Sci 1999;44:1249-53.  Back to cited text no. 12
    
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Giannini E, Risso D, Botta F, Chiarbonello B, Fasoli A, Malfatti F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 2003;163:218-24.  Back to cited text no. 25
    
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Koksal AR, Alkim H, Boga S, Ergun M, Bayram M, Ozguven BY, et al. Effect of entecavir and tenofovir treatment on noninvasive fibrosis scores: Which one ıs better? Am J Ther 2016;23:e429-38.  Back to cited text no. 27
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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