Decrease in Apri Score in Compensated Liver Cirrhosis Patients Due to Hepatitis C After a Combination Therapy of Sovosbuvir and Daclatasvir

Dolvy Girawan1, Ony Wiraswati2, Aditya Herbiyantoro1, Yovita Hartantri3

1 Gastroenterohepatology Division, Department of Internal Medicine, Faculty of Medicine, Padjadjaran University / Dr. Hasan Sadikin General Hospital Bandung.
2 Department of Internal Medicine, Faculty of Medicine, Padjadjaran University / Dr. Hasan Sadikin General Hospital Bandung.
3 Infectious Disease and Tropical Medicine Division, Department of Internal Medicine, Faculty of Medicine, Padjadjaran University / Dr. Hasan Sadikin General Hospital Bandung.

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Dolvy Girawan, Consultant of Gastroenterohepatology, Division of Gastroenterohepatology, Department of Internal Medicine Dr. Hasan Sadikin General Hospital / Faculty of Medicine University of Padjadjaran, Jl. Pasteur 38, Bandung 40161, Indonesia.
Email: imeldg2@gmail.com
Telephone: + (022) 82021011
Fax: + (022) 82021011

Received: December 29, 2020
Revised: January 15, 2021
Accepted: January 19, 2021
Published online: February 21, 2021


AIM: Hepatitis C is a hepatitis C virus (HCV) infection that targets the liver and can cause fibrosis, cirrhosis, and eventually death. The treatment of hepatitis C has progressed considerably, the combination of sofosbuvir and daclatasvir with 92-100% SVR (Sustained Virologic Response) can increase reversibility of compensated liver cirrhosis after sofosbuvir and daclatasvir therapy.

MATERIALS AND METHODS: This study used observational analytic study design. The subjects were hepatitis C compensated liver cirrhosis patients who received combination therapy sofosbuvir and daclatasvir in the Gastroentero-hepatology clinic of Dr. Hasan Sadikin Hospital Bandung from October 2017 until October 2018. In this study, measurement of liver fibrosis was carried out by using AST to Platelet Ratio Index (APRI) before therapy and SVR-12.

RESULTS: The study involved 23 patients. Most of the subjects were women, with an average age of 59.43 years (SD 11.31). All patients in this study have achieved SVR-24. According to the results, 91% of patients experienced a decrease in APRI scores after being treated with sofosbuvir/daclatasvir. There was a decrease in APRI score before therapy and after SVR 12 from 1.51 to 0.79, the change was 0.878 (95% CI: 0.536 - 1.480). There is a reversal in liver cirrhosis to be non-cirrhosis after being treated with sofosbuvir/daclatasvir which is characterized by a decrease in the APRI score < 1 by 80%.

CONCLUSION: The study concluded that the combination of sofosbuvir and daclatasvir in patients with compensated liver cirrhosis with hepatitis C had particularly good effectiveness and could reduce APRI scores.

Key words: APRI score; Compensated liver cirrhosis; Sofosbuvir; Daclatasvir

© 2021 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Girawan D, Wiraswati O, Herbiyantoro A, Hartantri Y. Decrease in Apri Score in Compensated Liver Cirrhosis Patients Due to Hepatitis C After a Combination Therapy of Sovosbuvir and Daclatasvir. Journal of Gastroenterology and Hepatology Research 2021; 10(1): 3435-3440 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/3062


Hepatitis C is an infection of the hepatitis C virus (HCV) which targets the liver and can cause fibrosis, most hepatic fibrosis that occurs are asymptomatic unless hepatic cirrhosis has developed[1,2]. In Indonesia it is estimated 25 million people suffering from hepatitis B and C, as many as 50% of them develop into a chronic form of the disease and 10% develop into hepatic cancer[1]. According to the 2013 Riset Kesehatan Dasar, the Indonesian basic health survey, hepatitis C prevalence increased from 2.1% to 2.5%[3]. Hepatitis C mortality rates are also relatively high, those due to hepatocellular carcinoma is estimated as high as 12-16% in Caucasians[2].

Aims of therapy in chronic hepatitis C is the eradication of the virus and prevention of complications such as fibrosis, cirrhosis, hepatocellular carcinoma, and eventually death. Antiviral therapy target is sustained serologic response, specifically Sustained Virologic Response (SVR) that is measured through HCV RNA examination. Therapy is administered to naïve patients and failed treatment patients with both compensated and decompensated liver disease[3]. Antiviral therapy is given in patients with decompensated hepatic cirrhosis and at the risk for hepatocellular carcinoma[1,4]. Therapy for hepatitis C has had advantages especially after the distribution of Direct Acting Anti Virus (DAA) medications[3-5]. In Indonesia, there are 2 types of DAAs included in the hepatitis C eradication program which are sofosbuvir and simeprevir and a combination of sofosbuvir and daclatasvir.

Measurement of hepatic fibrosis grading is important in determining the length of therapy, prognosis, and risk factors that may occur throughout the disease progress. Liver biopsy is still the gold standard in determining hepatic fibrosis grading, but this method has several disadvantages as it is invasive, subjective, reasonably expensive, and there are often errors in sample collection[5-11]. Thus, a non-invasive method was developed to grade hepatic fibrosis [3,6,9].

There are other non-invasive markers, such as biomarkers from the blood that may replace liver biopsy, the AST (Aspartate Amino Transferase) score/platelet ratio (APRI). These examinations are easy to conduct as it only utilizes 2 indicators, AST and thrombocyte without complicated equations[3,12].

DAA therapy development with considerably high SVR values provides hope for hepatitis C patients with fibrosis[13]. Several studies stated that necroinflammation and hepatic fibrosis were decreased by SVR[7,10,14,15]. Numerous studies mentioned a significant decrease in fibrosis in hepatitis C patients undergoing DAA therapy, which measured through liver biopsy, transient elastography, or biomarkers, however, there were very little studies on a population with hepatic cirrhosis measured using their APRI score. There are differences in the fibrotic changes in compensated and decompensated cirrhosis, SVR values are also lower than decompensated patients[16].

This study aimed to assess the decrease in APRI score in the compensated hepatic cirrhosis population due to HCV who receiving a combination of sofosbuvir and daclatasvir. Henceforth, the result of this study is expected to be utilized as evaluation material for government intervention in managing hepatitis C infection.


Study population

This was an observational analytic study. Subjects were HCV compensated liver cirrhosis patients receiving a combination of Sofosbuvir and daclatasvir in the Outpatient Gastroentero-hepatology clinic of Dr. Hasan Sadikin General Hospital Bandung from October 2017 to October 2018, with an inclusion criteria of 18 years old. Patients with eGFR < 60mL/minute, HIV and Hepatitis B coinfection, and incomplete laboratory data such as SGOT level data, thrombocyte, and HCV RNA before therapy and during SVR-12 examination were excluded from the study. HCV infection was diagnosed both through anti-HCV antibody examination using electrochemiluminescence assay, ECLIA (Elecsys 2010, Roche), and HCV RNA examination, then APRI score was determined afterward. The study was designed as a retrospective cohort from medical record data. The subjects were graded using the AST Score to Platelet Ratio Index (APRI) before therapy and on SVR-12. In this study, from October 2017 to October 2018, as many as 23 patients fulfilling the inclusion criteria were included.

Operational definition and data collection

The operational definition of compensated liver cirrhosis are patients marked with APRI examination > 1 but from history taking there were no previous history of decreased consciousness, history of melena and hematemesis, and edema. In addition, during physical examination, there were no hepatic encephalopathy, ascites, icteric, flapping tremor, and edema found. A combination intervention of sovobuvir and daclatasvir were administration of 400 mg sovosbuvir under the myHep trade name under the license of Gilead science Ireland UC to Gilead science India and myDekla 60mg under the license of Gilead science Ireland UC to Gilead science India in a period of 6 months. Thrombocyte levels were examined through a method of flow cytometry using Sysmex SN HE-038. AST levels were examined through a method of enzymatic calorimetric using Siemens Dimension EXL.

Statistical Analysis

Analysis to test the hypothesis in seeing the difference in APRI score before and after combination therapy of sovosbuvir and daclatasvir using the paired t-test if the data is distributed normally, and the Wilcoxon test if the data is not distributed normally. Normality test using the Saphiro-wilk test, if p > 0.005 is considered normal distribution.


This research was conducted in the Outpatient Gastroentero-hepatology clinic of Dr. Hasan Sadikin General Hospital Bandung in 2017-2018. Subjects of this study were HCV compensated liver cirrhosis patients administrated a combination of sofosbuvir and daclatasvir in the outpatient Gastroentero-hepatology polyclinic of Dr. Hasan Sadikin General Hospital Bandung fulfilling the inclusion and exclusion criteria. The total number of hepatic cirrhosis HCV patients administered a combination treatment of sofosbuvir and daclatasvir was 41 patients, 2 of which with decompensated cirrhosis and 39 of which with compensated cirrhosis. From a total of 39 patients, 1 patient died, 2 patients did not complete full treatment and 13 patients did not have complete data sets at 12 weeks after the end of treatment so only 23 patients were included in the study (Figure 1).

The normality test using the Shapiro-Wilk One sample test shows that only the thrombocytes had normal distribution while the other variables are not normally distributed (p < 0.05), hence the statistical analysis for thrombocytes was done differently using the t-test, while the other variables were analyzed using the Wilcoxon test (Table 2).

Figure 1 Research Chart.

Table 2 Normality test data before and after combination therapy of sovosbuvir and daclatasvir in hepatitis c compensated liver cirrhosis patients.
Variable  P-valueDescription
Analysis using the Shapiro-Wilk Test

The median value of pre-treatment SGOT and SGPT were 56 U/L and 63 U/L then declined after treatment of sovosbuvir and daclatasvir to 42 U/L and 27 U/L respectively (Figure 2). The increased of mean thrombocyte before and after treatment were observed, from 112,348 + 45004 /uL to 157,870 + 13,966 / uL (Figure 3). Figure 4 revealed that APRI score had decreased from 1.51 to 0.79 between before and after treatment.

Figure 2 Scatter plot Differences in SGOT before and after sofosbuvir/daclatasvir administration.

Figure 3 Scatter plot of Platelet Differences before and after sofosbuvir/daclatasvir administration.

Figure 4 Scatter plot APRI Score Differences before and after sofosbuvir/daclatasvir administration.

Table 3 shows results of the statistical test using the Wilcoxon test on the 95% confidence level indicate that there are significant differences in the values of SGOT, SGPT and APRI after combination therapy of sovosbuvir and daclatasvir with a value of p < 0.001 (p-value < 0.05). The statistical test using a t-test that there is an improvement in the median platelet value before combination therapy of sovosbuvir and daclatasvir in hepatitis c compensated liver cirrhosis patients at a 95% confidence level indicating that there are significant differences in thrombocyte value after combination therapy of sovosbuvir and daclatasvir in hepatitis c compensated liver cirrhosis patients with a value of p = 0.007 (value p ≤ 0.05).

Table 3 Overview of research subjects based on the values of SGOT, SGPT, Thrombocytes and APRI before and after combination therapy of sovosbuvir and daclatasvir.
Variable Before Median (Min-Max) After Median (Min-Max) Difference (95% CI)P value
SGOT56 (30 - 273)42 (17 - 108)25 (12 - 47) <0.001 b
SGPT63 (19 - 272)27 (12 - 219)25 (4 - 43) <0.001 b
Thrombocytes*112.348 ± 45.004157.870 ± 103.96645.522 (8.714 - 82.330) 0.007 a
APRI1,512 (1.011 - 8.817)0,793 (0.138 - 2.162)0,878 (0.536 - 1.480) <0.001 b
*mean ± standard deviation, analysis using, a: Paired t-test, b: Wilcoxon test


This was an observational analytic, retrospective cohort study conducted through obtaining secondary data from medical records. Patients fulfilling the criteria for compensated cirrhosis in this study were judged based on their history of symptoms and physical examination performed at the Outpatient Gastroentero-hepatology Polyclinic in Dr. Hasan Sadikin General Hospital Bandung. Not all included patients had supporting examinations conducted such as ultrasound or transient elastography, while the gold standard in distinguishing compensated from decompensated cirrhosis is through liver biopsy[17,18].

The results showed that from the total samples used in this study, all 23 patients achieved 100% SVR-12. This was consistent with several studies which state that SVR rates in monoinfected hepatitis C patients administered a combination therapy of sofosbuvir and daclatasvir reach 100%. The combination of these two drugs has a potent antiviral ability, capable of handling all viral genotypes, and can achieve 92-100% SVR in hepatitis C monoinfected patients[4,5,19-21].

This study found that sex-wise there were more females (58.8%) than males (42.2%). This is inconsistent with research conducted by Barden, which stated that males were more exposed to hepatitis C virus infection compared to females. Productive-age women are said to have protection for their liver cells due to the hormones estrogen and estradiol, protecting their livers from fibrosis through a protective mechanism against oxidative stress, liver inflammation, and cell death[22].

The hormones are also said to help spontaneous healing of hepatitis C infection, but this protection mechanism is not present in menopausal females. The same was stated in a research conducted in Europe, hepatitis C infection is more prevalent in males than females with a ratio of 2.1% and 1.1%[22-24]. A study conducted by Poynard et al stated that being male is one of the risk factors of hepatitis C progression[25]. However, several studies suggest that there is an increase in the incidence of liver fibrosis in menopausal females, hence the incidence of cirrhosis isn’t significantly different between the two sexes[25].

A study by Hayashi mentioned more specifics about the relationship of age with hepatitis C treatment outcomes in females, where they stated that females under the age of 40 years old with interferon alfa treatment have a higher SVR rate than females over 40 years old, this is consistent with the results of this study where the females are aged is 55 years old, with the eldest being 77 years old, although this study did not further examine the number of menopausal subjects in the study sample[23,26,27].

The average age in this study was 59.43 with a standard deviation of 11.31, while the median age is 63 years old with the youngest age being 36 years old and the oldest being 77 years old (Table 1), consistent with the results of a study conducted by Gordon et al in 2015 which stated the average age of patients suffering from liver cirrhosis due to hepatitis C is 58.5 ± 8.9, with the incidence increasing along with age[28].

Table 1 Characteristics of research subjects based on Demographic and Laboratory Data of hepatitis c compensated liver cirrhosis patients administered a combination of sofosbuvir and daclatasvir.
Demographic data  
Average (SD) :59,43 (11.31)  
Median (Minimum-Maximum) : 63 (36-77)  
36-45 years old313
46-55 years old521.7
56-65 years old730.4
>65 years old 834.8
Laboratory Data
Pre-treatment SGOT  
Within normal limit (<37)417.3
Above normal (>37)1982.7
Pre-treatment SGPT
Within normal limit (<63)1147,8
Above normal (>63)1252.2
Pre-treatment Thrombocyte
Within normal limit (>150000)522
Below normal (<150000)1878

In the results of this study, there was a significant change in response to liver function enzymes before and after treatment. As many as 20 of the total 23 patients or as much as 86% experienced a decrease in SGOT value. The median SGOT before treatment amounted to 56, decreased after treatment to 42 or decreased by 25%, and the average value of SGPT, 63 became 27 or decreased by 57%, this is consistent with the results of a study conducted by Deterding et al where they stated that the liver enzymes have a near-normal improvement in 77% of the overall study sample, as well as the SGPT results, which declined in value as much as 82%. This is associated with the cessation of the inflammatory processes that occur in the liver, which is characterized by a decrease in inflammatory cytokines in line with reduced damage to liver cells[29-32]. Patients who did not experience a decrease in liver function enzymes, both SGOT and SGPT, around 14-18%, experienced an increase in function, but the increase was no more than 2 times the upper limit of the normal values[29].

Thrombocytopenia in hepatitis C is a problem caused by various factors, an autoimmune reaction with antiplatelet antibody production, enlargement of the spleen, and hepatitis C virus can also cause suppression of the bone marrow, causing thrombocytopenia. In this study, as many as 73% of the patients experienced an increase in thrombocyte value, thrombocyte average before the combination therapy of sofosbuvir and daclatasvir of 112,348 / uL with a standard deviation of 45,004 / uL[30,33].

Thrombocytes after combination therapy of sofosbuvir and daclatasvir increased to 157,870 / uL with a standard deviation of 103,966 / uL. The average increase in thrombocytes is 45,522 / uL with 95% CI 8,714 - 82,330 / uL, using the Paired t-test statistical test with p values < 0.05 (0.007). These results are in line with studies conducted by Deterding where thrombocytes improved both during treatment and at the end of treatment to SVR 12. Research conducted by Dahal also revealed the same thing, that DAA treatment and achievement of SVR in hepatitis C patients could include thrombocyte repair. A study by Vandermeer involving 646 patients with 76% being cirrhotic patients, after achieving an SVR, experienced a platelet increase of 35,000 with p < 0.001[29-31,33,34].

In this study, 91% or 21 out of 23 patients experienced a decrease in APRI score, and from the decreasing number, as much as 80% experienced a change from APRI score of cirrhosis (> 1) to non-cirrhosis (< 1), as a whole. There was a significant decrease in APRI scores from the median APRI score of 1.51 before treatment to 0.79 at 12 weeks after the end of treatment, with p < 0.001. This is consistent with the research conducted by Domazahvii et al in 2017 which stated that SVR can reduce the rate of liver fibrosis. The study involved 304 patients, comparing liver fibrosis before and 24 weeks after SVR using Transient Elastography (TE), which found a decrease in Liver Stiffness Measurement (LSM) from 16.9 (range 11.8-27.7) to 11.9 (range 8.2-20.9). 198 study participants (65.1%) experienced a decrease in liver fibrosis of at least 20%. Research in Switzerland by Bachofner et al. Also stated the same thing that SVR can reduce liver fibrosis, involving 549 patients, in which all patients received DAA. The median TE before DAA treatment was 12.65 kPa (IQR 9.45-19.2 kPa), while 18 months after treatment decreased to 8.55 kPa (IQR 5.93-15.25), with p < 0.001. The median FIB-4 index and APRI score also decreased significantly from 2.54 (IQR 1.65-4.43) and 1.10 (IQR 0.65-2.43) to 1.80 (IQR 1.23-2.84, p < 0.001) and 0.43 (IQR 0.3-0.79), p < 0.001) [7,32,35,36].

The concept of liver fibrosis reversal as reflected in a decrease in APRI score may be associated with a decrease in active hepatic stelate cells both experiencing apoptosis and re-becoming quiescent. This can be due to the loss of inflammatory signals, one of which originates from chronic viral inflammation. Therefore, it is very important for the target of hepatitis C therapy for virus eradication which is characterized by SVR. The mechanism of sofosbuvir and daclatasvir is to prevent viral replication by inhibiting the formation of protein viruses and inhibiting the replication of new RNA viruses. Hepatic stellate cells that turn into myofibroblasts during fibrogenesis will become inactive and can eliminate all pathways that cause fibrogenesis, such as lipopolysaccharide, inflammatory cytokines (TNF-α and interferon γ), and production of ROS (Reactive Oxygen Species) in kuppfer cells. All of these pathways will impact the degradation of the extracellular matrix which was previously induced by myofibroblast and is also a component that forms fibrosis. This concept of reversal fibrosis indirectly improves liver function marked by a decrease in APRI score[37].


There is a significant decrease in the APRI score after combination therapy of sovosbuvir and daclatasvir in compensated hepatic cirrhosis patients in the Outpatient Gastroentero-hepatology Polyclinic in Hasan Sadikin General Hospital Bandung. There was a decrease in the median APRI value as much as 0,878 with 95% CI 0.536 - 1.480. There was a decrease in the median SGOT value as much as 25 U/L with 95% CI 12 - 47 U/L, statistically tested using the Wilcoxon test with a p-value < 0.001. There was a decrease in the median SGPT value as much as 25 U/L with 95% CI 4 - 43 U/L, statistically tested using the Wilcoxon test with a p-value of 0.001. There was a significant increase in the thrombocyte mean increase as much as 45.522 /uL with 95% CI 8.714 - 82.330 /uL, statistically tested using the Paired t-test with a p-value of p = 0.007.


DG, OW, AH and YH conceived and designed the study. OW acquired the data. All authors contributed to the writing of the manuscript.


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