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Year : 2023  |  Volume : 55  |  Issue : 1  |  Page : 14--20

Comparison of patients using lamivudine, entecavir, and tenofovir according to liver fibrosis markers fibrosis-4 and aspartate aminotransferase-to-platelet ratio index scores

Huseyin Dogus Okan1, Oguz Karabay1, Ertugrul Guclu1, Mustafa Baran Inci2, Aziz Ogutlu1,  
1 Department of Infectious Diseases and Clinic Microbiology, Sakarya University, Faculty of Medicine, Sakarya, Turkey
2 Department of Public Health, Sakarya University, Faculty of Medicine, Sakarya, Turkey

Correspondence Address:
Huseyin Dogus Okan
Department of Infectious Diseases and Clinic Microbiology, Sakarya Training and Research Hospital, Central Building, Sakarya - 54100


OBJECTIVES: It was intended to assess the efficacy of lamivudine, entecavir, and tenofovir regimens in the management of chronic hepatitis B (CHB) guided by Fibrosis-4 (FIB-4) and aspartate aminotransferase-to-platelet ratio index (APRI) scores. MATERIALS AND METHODS: Our study was conducted on patients who applied to the hepatitis outpatient clinic between 2008 and 2015 retrospectively. Lamivudine, entecavir, and tenofovir regimens used in the practice of CHB cases were compared by measuring noninvasive FIB tests. RESULTS: Entirely 199 patients involved in the research were evaluated in three treatment arms; 48 used lamivudine, 46 used entecavir, and 105 used tenofovir. Similar statistical characteristics were observed between research arms regarding age, gender, and alanine aminotransferase normalization by years (P > 0.05). Totally 5 (13.5%) of patients developed Hepatitis B e antigen (HBeAg) seroconversion among 36 HBeAg positivity, and similar statistical features were seen by comparing the groups (P > 0.05). In the entecavir and tenofovir arms, a significant decrease was seen in FIB-4, and APRI index values in the 1st year of treatment (P < 0.001). At the graph curve, a plateau was observed in the APRI test after the 1st year, and a plateau was observed in the FIB-4 test after the 2nd year. CONCLUSION: Consistent with the study outcome, when we consider FIB regression, tenofovir and entecavir regimens were found more effective than lamivudine. In addition, entecavir was more effective than the other two drugs after the 1st year.

How to cite this article:
Okan HD, Karabay O, Guclu E, Inci MB, Ogutlu A. Comparison of patients using lamivudine, entecavir, and tenofovir according to liver fibrosis markers fibrosis-4 and aspartate aminotransferase-to-platelet ratio index scores.Indian J Pharmacol 2023;55:14-20

How to cite this URL:
Okan HD, Karabay O, Guclu E, Inci MB, Ogutlu A. Comparison of patients using lamivudine, entecavir, and tenofovir according to liver fibrosis markers fibrosis-4 and aspartate aminotransferase-to-platelet ratio index scores. Indian J Pharmacol [serial online] 2023 [cited 2023 Oct 2 ];55:14-20
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When the decision to start and then evaluate the treatment outcomes is concerned, a liver biopsy may bring some disadvantages in chronic hepatitis B infection (CHB). Complications that may be contraindicated for biopsy, such as ascites and coagulopathy, repeat biopsy necessity in monitoring treatment responses can be given as examples. Today, the accepted method to evaluate the fibrosis (FIB) stage of the lever in CHB is liver biopsy.[1] However, besides being a painful procedure, it can rarely cause life-threatening complications as it is an invasive procedure. In addition, it does not provide a dynamic evaluation of the histopathology of the liver after treatment. Hence, more studies are needed on the validity of noninvasive methods such as FIB-4 and aspartate aminotransferase-to-platelet ratio index (APRI) tests instead of histopathological evaluation.

The study was intended to assess treatment efficiency by comparing the FIB-4 and APRI tests in patients with CHB who received lamivudine, entecavir, and tenofovir regimens.

 Materials and Methods

Our research was carried out retrospectively at Sakarya University Faculty Of Medicine Hospital 2008 and 2015. 199 CHB patients given lamivudine, entecavir, and tenofovir treatments were assessed with noninvasive methods that can be an alternative to biopsy. Information on cases was obtained from electronic data.

Cases of all treatment groups were included according to the following criteria:

To be performed liver biopsy before treatment with the diagnosis of CHBBeing over the age of 18Being naive about treatment and starting one of the study drugsBeing followed regularly for 4 years.

The patients we excluded in our study had the following criteria:

Cases with concomitant hepatitis C, delta hepatitis, and autoimmune liver diseasesCases whose biopsy reports are compatible with cirrhosis.

The characteristics of the cases at the beginning of treatment; before treatment liver biopsy histological activity level and FIB stage, HBV DNA quantity, Hepatitis B e antigen (HBeAg) status, basal aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count values. And their values in the 1st, 2nd, 3rd, and 4th years, anti-HBeAg seroconversion rates, virological, biochemical, and serological response rates, treatment compliance rates, and APRI and FIB-4 scores in years 1, 2, 3, and 4 were calculated separately. Treatment response rates were compared in treatment-naive patient groups receiving lamivudine, entecavir, and tenofovir.

Biochemical analyzes such as ALT and AST were studied in the biochemistry laboratory of Sakarya University Training and Research Hospital. The reference range of ALT and AST was 0–50 U/L.

Noninvasive methods used in the study were FIB-4 and APRI tests. The formulas used for the calculations were as follows:

FIB-4 index: age (year) × AST (U/L)/(platelet count [109/L] × [ALT] 1/2 [U/L]).

APRI index: (AST/Upper reference limit value of AST/platelet count [109/L]) ×100.

The criteria considered when evaluating the treatment results were as follows: biochemical recovery was accepted as ALT normalization. The serological response was accepted as HBeAg negativity in cases HBeAg positive. HBV DNA negativity was accepted as the virological response. The final target was determined as hepatitis B surface antigen (HBsAg) negativity and anti-HBs formation.

Statistical analysis

SPSS version 20 – 2011 was used for data analysis. Categorical variables were expressed as numbers and percentages. Mann–Whitney U hypothesis tests were used to ensure the normal distribution. Kruskal–Wallis hypothesis tests were used in groups of three and above. Logarithmic transformation was made for HBV DNA data. The Pearson's Chi-square analysis was utilized when percentage comparison was required for categorical variables. APRI and FIB-4 score values of treatments given at five different time points (initial and within the next 4 years) were evaluated using Friedman and Willcoxon tests. The statistical significance level of the P value was accepted as < 0.05.

Ethical approval

Ethics approval number obtained from Sakarya University Faculty of Medicine Clinical Research Unit: 71522473/050.1.04/178.


Demographic data

In our study, 199 patients (120 men/79 women) were involved in our evaluation with the following therapies: 48 had lamivudine, 46 had entecavir, and 105 had tenofovir. A total of 48 patients used lamivudine, 46 patients used entecavir, and 105 patients used tenofovir. Age and gender characteristics were similar in all three treatment groups (P > 0.05). The demographic data of the cases are summarized in [Table 1].{Table 1}

Serological and virological findings

Considering the baseline ALT values, the rate of those with high ALT was 97/199 (48.7%). The number of patients with high-ALT levels in the groups was as follows: lamivudine 14/48 (29.2%), entecavir 30/46 (65.2%), and tenofovir 53/105 (50.5%). Baseline means ALT values were lower in patients receiving lamivudine, unlike the other groups (P < 0.001). However, ALT elevation was similar in the entecavir and tenofovir groups (P = 0.056). The groups were statistically similar regarding ALT normalization after the initiation of treatment (P > 0.05).

Thirty-six (18.1%) of the patients were HBeAg positive. HBeAg-positivity rates were as follows: 5/48 (10.4%) in the lamivudine group, 11/46 (23.9%) in the entecavir group, and 20/105 (19%) in the tenofovir group. A statistical discrepancy was not seen between the groups (P > 0.05). The number of cases that developed HBeAg seroconversion was 5/36 (13.5%). HBeAg seroconversion rates were similar in all three groups. HBsAg loss was not detected in any of our cases.

The mean HBV DNA level of all groups before treatment was 5.81 log IU/mL (0.301–9.901). The mean HBV DNA levels of the groups were 4.3 log IU/mL (2.926–7.296), 6.8 log IU/mL (2.590–9.128), and 6.2 log IU/mL (0.301–9.901) for lamivudine, entecavir, and tenofovir, respectively. Statistically, we found a discrepancy between the groups. The average HBV DNA level in the lamivudine arm was lower than in the other two arms (P < 0.001). Serological and virological data are summarized in [Table 2].{Table 2}

Histopathology findings

The average Histological activity index (HAI) score of 199 cases participating in the study was 6.91 (2–16). The average HAI score in the lamivudine group was 5.9 (2–16). The average HAI score in the entecavir group was 7.3 (2–13). The average HAI score in the tenofovir group was 7.2 (2–16). HAI scores were not statistically similar between groups. The average HAI score of the lamivudine arm was lower than the tenofovir and entecavir arms (P = 0.003).

The mean stages of liver FIB according to Ishak score of 199 patients included in the study was 2.2 (0–6). The mean FIB scores were 2.3 (0–5), 2.0 (0–4), and 2.3 (0–6) in the lamivudine, entecavir, and tenofovir groups, respectively. The groups were similar in terms of FIB (P = 0.466). Histopathological data are summarized in [Table 3].{Table 3}

Noninvasive indices

Statistically, we detected a discrepancy between baseline and 1st-year FIB-4 and APRI scores in the treatment groups (P < 0.001). When we look at the charts [Graph 1] and [Graph 2], a plateau was found in the years after the 1st year for the APRI test and a plateau was detected in the years after the 2nd year for the FIB-4 test.[INLINE:1][INLINE:2]

In our study, the average APRI score at the beginning of treatment for lamivudine, entecavir, and tenofovir was 0.37, 0.83, and 0.63, respectively. APRI score of lamivudine arm was lower than tenofovir and entecavir arms (P < 0.05). However, we did not find any statistical discrepancy between the entecavir and tenofovir arms (P = 0.551). When the APRI scores of the 1st year, 2nd year, 3rd year, and 4th year were compared separately, the results were statistically similar. There was a meaningful decrease in the statistical evaluation in all three groups in time intervals. This reduction was significant in the lamivudine, entecavir, and tenofovir groups at the baseline and 1st-year periods (P < 0.05). This reduction was significant in the entecavir and tenofovir groups between the 1st- and 2nd-year periods (P < 0.05).

There was no statistically significant decrease in the 1st-year and 2nd-year time intervals in the lamivudine group. During the 3rd-and 4th-year intervals, there was no significant decrease in APRI scores in the lamivudine entecavir and tenofovir groups. APRI score data are summarized in [Table 4].{Table 4}

FIB-4 scores at the beginning of lamivudine, entecavir, and tenofovir therapies were 1.35, 1.65, and 1.43, respectively (P = 0,295). In terms of the FIB-4 score decrease in the 1st year, there was no difference between lamivudine and entecavir, but the decline in the FIB-4 score was significant in the tenofovir group (P < 0.05). However, in patients who received antiviral medication for at least 1 year, we detected a significant decrease in the entecavir and tenofovir arms regarding the decrease in FIB-4 score, but not in the lamivudine arm. Again, there was a meaningful difference in terms of FIB-4 regression in the entecavir group in patients who had been treated for at least 2 years but not in the other two treatment groups. FIB-4 index score data are summarized in [Table 5].{Table 5}


Liver biopsy still plays a key role in guiding the treatment of patients with CHB. Besides being the gold standard, liver biopsy is an invasive method and carries some risks for the patient. For these reasons, the use of noninvasive methods instead of biopsy has been investigated for a long time.[2] In the treatment of CHB, it is intended to reduce inflammation in the liver and to regress FIB. Changes in these parameters can be detected by liver biopsy or by noninvasive methods. In this study, it was investigated how different antivirals applied to hepatitis B patients caused a change in liver histology.

The histological activity index (HAI) is essential for determining the inflammatory process in the liver. The mean HAI score of the cases we were involved in the study was 6.9 (2–16) [Table 3]. The mean HAI score was 5.9, 7.3, and 7.2 in the lamivudine, entecavir, and tenofovir therapies, respectively. When the initial HAI levels are evaluated, it is understood that the lamivudine group has a significantly lower HAI score than the others. In Turkey, 10 years ago, in the health regulations, high potency drugs such as tenofovir and entecavir were recommended for only patients with high-DNA levels. In contrast, lamivudine was mostly recommended for cases with a low viral load. Because of this retrospective design of our study, it is understood that the patients in the lamivudine group had lower HAI levels. In contrast, the group with higher DNA and more severe liver damage received high-potency antivirals in the foreground. We think that the current situation is related to the legal regulation in the reimbursement system.

When the initial FIB-4 and APRI score values were compared with the 1st-year values, a significant decrease was observed in all three drugs (P < 0.05). For example, the APRI score of the lamivudine group decreased from 0.369 at baseline to 0.227 1 year later. Similarly, we observed a decrease from 0.826 to 0.382 and from 0.634 to 0.303 in the entecavir and tenofovir arms, respectively. However, we did not find this improvement in the 1st year for lamivudine between the 1st year and the 2nd year, nor did we find it in the 2 to 3, 3 to 4 years. In the 1st year, while there is the highest rate of inflammation in the liver, and inflammation decreases shortly after the initiation of treatment. As the viral replication decreases, the FIB process within the liver decreases, and inflammation-related indicators rapidly improve. Whereas, after the 1st year, FIB, which has already reduced to basal levels, can no longer reach significant recovery levels. Therefore, in treating CHB, the most significant improvement in FIB is seen in the 1st year of treatment. Suppose the decline in FIB indicators is to be evaluated as a success criterion. In that case, we think that the 1st-year value after treatment should be taken as a basis. We observed the same findings in the FIB-4 score, and the trend in the graph we obtained for the APRI score was highly similar to the FIB-4 score. We could not see any significant difference between both parameters.

The average FIB level of 199 patients involved in the study was 2.2. Statistically, no difference was observed between the FIB levels of the groups. Again, within the scope of reimbursement arrangements, patients with FIB of <2 cannot be treated. Hence, treatments with two or more FIB values were initiated in all three treatment groups. Therefore, it is expected that there is no discrepancy between the groups regarding FIB.

We found that entecavir was superior to the other two drugs in terms of the decrease in FIB-4 score in patients who were followed up for at least 1 year. When we deepened the statistics, we found a significant discrepancy in the entecavir arm compared to the other two drug arms in patients who had been treated for at least 2 years. According to these findings, entecavir is more successful than the other two drugs in histological improvement. Other researchers have investigated these findings. For example, in a meta-analysis, it has been shown that entecavir is the best of all antivirals in histological improvement.[3]

In a study consisted 1600 cases, two liver biopsies were performed, and the healing efficiency of lamivudine and entecavir in liver inflammation was investigated in HBeAg-positive patients. While there was a 72% improvement in the entecavir group, this ratio was 62% in the lamivudine group.[4] Our findings are similar to the literature.

In another study, two ways were tried because of the complete nonresponsiveness of 286 patients to lamivudine, and they were switched to entecavir, or lamivudine treatment was continued. While there was a 55% improvement in patients who switched to entecavir, this improvement remained at only 28% in the group that continued with lamivudine.[5]

In another study, Schiff et al.,[6] evaluated the improvement with entecavir use, and in this study, the condition of 10 patients with an Ishak FIB score above four was evaluated after 6 years of entecavir treatment. They showed that all patients had a significant improvement in the Ishak score, with an average improvement of 2.2 within 6 years and an improvement of 7.6 in the Knodell necroinflammatory score. In a study involving 348 patients, the liver FIB level at baseline and after 240 weeks was evaluated. It was observed that improvement was 51% with the tenofovir treatment.[7] In another study, 57 patients received entecavir for 6 years, and 96% of the patients in this study had a decrease of at least two points in the Knodell score, while no progression was seen in FIB.[8] Unlike the lamivudine arm, there was a significant discrepancy between the 1st and 2nd years in the tenofovir and entecavir arms. However, there was no significant difference between the years 2 and 3, 3 and 4. Since tenofovir and entecavir were given to patients with more severe liver inflammation and their viral loads were higher due to legal regulations, it was thought that the recovery in these patients spread over 2 years.

ALT normalizations of all three groups were compared during the treatment, but no statistical difference was observed. In a study from Turkey made by Bilge et al. involving 94 patients with CHB under treatment, no significant discrepancy was found between the tenofovir and entecavir groups when ALT normalization was considered in the 1st year of treatment. However, in a meta-analysis conducted in China in 2016, when ALT normalization was evaluated, tenofovir was superior to entecavir in the first 3 months. In contrast, entecavir was superior to tenofovir in ALT normalization in the 6th month. However, no difference was found between these two groups regarding ALT normalization in the 1st year.[9] We evaluated ALT normalization from the 1st year. We could not see a difference between the groups concerning ALT normalization because we were evaluated starting from the 1st year, not the first 6 months. According to this result, there is no statistically significant difference between the three drugs in reducing inflammation in the liver.

In our study, the HBeAg-positivity rate was 18.1%. In the seroprevalence study made by Tozun et al.[10] in Turkey in 2015, HBeAg-positive infection rate was detected as 18.5%. We think that the ratio of 18.1% that we found was similar to data in Turkey.

HBeAg (+) seroconversion was detected in 5/36 (13.5%) cases. However, we did not find a discrepancy between the treatment arms regarding the distribution of these five cases (P = 0.22). Köklü et al.[11] evaluated the long-term efficacy of tenofovir, lamivudine, and entecavir in HBV-related cirrhosis cases in a multicenter study. They found no statistical discrepancy between the groups in terms of HBeAg seroconversion at the end of the 1st year. In a meta-analysis consisting of 22 studies reviewed between 1995 and 2010 in the USA, the effectiveness of oral antivirals in HBV-associated decompensated cirrhosis was evaluated. HBeAg seroconversion rates in the 6th month of lamivudine, entecavir, and tenofovir treatments were found to vary from 11% to 25%.[12] Similarly, a recent study evaluated entecavir and tenofovir efficacy in 200 patients in each arm. It was found that the HBeAg seroconversion rate was 27.4% in the entecavir arm and 33.7% in the tenofovir arm (P > 0.05).[13] In the study of Liang et al.,[14] entecavir was found to have similar efficiency as lamivudine in terms of HBeAg seroconversion. In this study, we could not find a statistical discrepancy between the lamivudine, entecavir, and tenofovir therapies. In literature, it seems that the best results for HBeAg seroconversion are obtained with pegylated interferon treatment.[1] This is due to the effectiveness of interferons based on the principle of eliminating virus-infected cells.

Our study evaluated the change in platelet counts among the lamivudine, entecavir, and tenofovir therapies regarding 1st-year values. According to our results, while there was no statistical discrepancy in platelet change for the entecavir and tenofovir groups, the 1st-year value was significantly reduced in lamivudine. We think that this may be due to the low potency of lamivudine and its late suppression of viral infection. When we reviewed the literature, we found that this effect has not been adequately studied. We think that new research is needed on the subject.

When the three treatment arms were compared regarding HBV DNA level before treatment, the values were 4.3, 6.8, and 6.2 log IU/ml for lamivudine, entecavir, and tenofovir, respectively. The level of HBV DNA in the group receiving lamivudine was statistically lower than the others (P < 0.01). The fact that the lamivudine group started with a lower HBV DNA level is related to the legal regulations in the reimbursement process. According to the Health Implementation Communiqué of that period, while lamivudine was used with an HBV DNA level below seven logarithms, potent antivirals could be used in higher DNA levels. We think these values we have found are related to this legal regulation.

In conclusion, we found tenofovir and entecavir therapies more effective than lamivudine therapy in the regression of FIB in this series of 199 cases. However, based on the 1st-year and 2nd-year data, entecavir was more effective than the other two drugs. We think that our results need to be supported by other prospective studies that will contribute to the use of noninvasive tests more effectively.


According to our research, tenofovir and entecavir were more efficient in terms of liver histopathology improvement. We did not find a significant difference in terms of ALT normalization, HBeAg, and HBsAg seroconversion. Histopathological improvement was evident in the 1st year of the treatment.

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Conflicts of interest

There are no conflicts of interest.


1Terrault NA, Lok AS, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-99.
2Castera L. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease. Best Pract Res Clin Gastroenterol 2011;25:291-303.
3Woo G, Tomlinson G, Nishikawa Y, Kowgier M, Sherman M, Wong DK, et al. Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: A systematic review and Bayesian meta-analyses. Gastroenterology 2010;139:1218-29.
4Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001-10.
5Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006;130:2039-49.
6Schiff ER, Lee SS, Chao YC, Kew Yoon S, Bessone F, Wu SS, et al. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol 2011;9:274-6.
7Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: A 5-year open-label follow-up study. Lancet 2013;381:468-75.
8Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010;52:886-93.
9}Doğan ÜB, Kara B, Gümürdülü Y, Soylu A, Akin MS. Comparison of the efficacy of tenofovir and entecavir for the treatment of nucleos(t)ide-naive patients with chronic hepatitis B. Turk J Gastroenterol. 2012;23:247-52. doi: 10.4318/tjg.2012.0380. PMID: 22798114.
10Tozun N, Ozdogan O, Cakaloglu Y, Idilman R, Karasu Z, Akarca U, et al. Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: A fieldwork TURHEP study. Clin Microbiol Infect 2015;21:1020-6.
11Köklü S, Tuna Y, Gülşen MT, Demir M, Köksal AŞ, Koçkar MC, et al. Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis. Clin Gastroenterol Hepatol 2013;11:88-94.
12Singal AK, Fontana RJ. Meta-analysis: Oral anti-viral agents in adults with decompensated hepatitis B virus cirrhosis. Aliment Pharmacol Ther 2012;35:674-89.
13Sriprayoon T, Mahidol C, Ungtrakul T, Chun-On P, Soonklang K, Pongpun W, et al. Efficacy and safety of entecavir versus tenofovir treatment in chronic hepatitis B patients: A randomized controlled trial. Hepatol Res 2017;47:E161-8.
14Liang J, Tang YF, Wu FS, Deng X. Entecavir versus lamivudine for the treatment of chronic hepatitis B: A systematic review. Pharmazie 2012;67:883-90.