Research Article

Evaluation of Treatment Results with Direct Acting Antiviral Drugs of Cirrhotic/Non-cirrhotic Chronic Liver Disease Caused by Hepatitis C Virus Genotype 1b Infection

10.4274/vhd.galenos.2020.2020.0016

  • Mustafa Doğan
  • Birol Topçu
  • Rıtvan Karaali
  • İlknur Erdem

Received Date: 07.05.2020 Accepted Date: 23.05.2020 Viral Hepat J 2020;26(2):43-48

Objectives:

This study aimed to investigate the effect of treatment with direct-acting antivirals (DAAs) on the virological response and on the some parameters used to evaluate liver function in cases with chronic liver disease due to hepatitis C virus (HCV) genotype 1b.

Materials and Methods:

This study included cases who were treated with DAAs after HCV genotype 1b infection. HCV-RNA levels and biochemical and hematological parameters measured at the beginning of treatment, 12th week and 52th week after the treatment were transferred to the SPSS statistics software. model for end-stage liver disease (MELD) and Child-Pugh scores were also calculated and added to these data.

Results:

The study group consisted of a total of 102 patients, including 33 (32%) males and 69 (68%) females. Compensated cirrhosis was detected in 26.5% of the patients (n=27). There was a significant change in serum albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and alpha-fetoprotein (AFP) parameters in patients with compensated cirrhosis after treatment, and total bilirubin, hemoglobin, ALT, AST, GGT, ALP and AFP parameters in the group without cirrhosis (p<0.05). Only a significant decrease was observed in the MELD score of the patients with compensated cirrhosis (p=0.007).

Conclusion:

The ombitasvir/paritaprevir/ritonavir+dasabuvir and ledipasvir/sofosbuvir regimens are very effective and safe in the treatment of patients who develop chronic liver disease and compensated liver cirrhosis after HCV genotype 1b infection.

Keywords: HCV, PrOD, MELD, Child-Pugh, compansated cirrhosis

Introduction

Hepatitis C virus (HCV) is known as the single-stranded, enveloped, smallest RNA virus of the Flaviviridae family. It is divided into at least six groups and many subtypes according to its genotype. Although different rates are reported regionally in different studies reported from Turkey, the most frequently seen genotype is 1b (1). Chronic HCV infection is one of the most important causes of chronic liver disease, hepatocellular carcinoma, and cirrhosis. More than 185 million people worldwide are thought to be infected with HCV and more than 85.000 people in Turkey (1). About 60-85% of these cases become chronic (2). An effective treatment is of great importance in terms of breaking the infection chain, preventing the spread and reducing the morbidity and mortality caused by the virus. With the introduction of direct-acting antivirals (DAAs), a sustained virologic response (SVR) of up to 99% has been achieved in the treatment of these patients, leading to the beginning of a new period (3). A limited number of cases have been reported to discontinue treatment due to side effects and unforeseen causes during the treatment. However, these drugs provided satisfactory results in the follow-up of the disease with their ease of use, easy tolerance and low side effect profiles (4). This study aimed to investigate the treatment results obtained with DAAs in patients with HCV genotype 1b and the effect of this treatment on some laboratory parameters evaluating liver damage and on the score values obtained from the scoring methods.


Materials and Methods

This is an observational study aimed at collecting retrospective data. This study was carried out with the approval of Ethical Committee of Namık Kemal University Faculty of Medicine (approval number 2020.86.04.10). The procedures were performed in accordance with the Declaration of Helsinki. Since our study was retrospective, informed consent was not used. This study covered the date range of 01.01.2016-31.12.2019. Patients older than 18 years of age, who were evaluated in our outpatient clinic within the specified date range, had anti-HCV positivity and received DAA medication, were included. The study group consisted of 102 cases. Demographic data, serological data, sustainable virological response, treatment regimen and side effects were transferred to the study form. The HCV-RNA values measured before the treatment, end of the treatment and 52th week, as well as biochemical and hematological analysis results, were also recorded in the study form. The model for end-stage liver disease (MELD) and Child-pugh scores of these patients were also calculated and transferred to the form.


Statistical Analysis

Data were transferred to the study form and analyzed using SPSS statistical software. Variables were expressed in frequency, percentage, mean, standard deviation, table, and graph. The normality test was performed and all variables were seen to follow a normal distribution. Paired Samples test was used to compare the pre- and post-treatment values of the continuous variables. A p-value of <0.05 was considered statistically significant.


Results

Of the 153 patients, 15% (n=23) were seen not to come to regular polyclinic controls and 18% (n=28) were other genotypes. The study group consisted of 102 patients with genotype 1b. The mean age of these patients was 59.43±14 years (minimum: 21, maximum: 83). Of the cases, 32% (n=33) were male and 68% (n=69) were female. Of the patients, 82% (n=84) were naive and 17% (n=17) previously received pegylated interferon plus ribavirin treatment and one case received boceprevir with peginterferon alfa-2a-ribavirin treatment. Compensated cirrhosis diagnosis was observed in 26.5% of the patients (n=27). In the treatment of 82% of patients, the ombitasvir/paritaprevir/ritonavir tablet 12.5/75/50 mg once a day two tablets at the same time and dasabuvir (PrOD) tablet 250 mg twice daily regimen was seen to be used whereas Sofosbuvir/ledipasvir 400/90 mg once a day regimen was used in the treatment of 18%. Demographic characteristics and clinic parameters of patients before treatment are shown in Table 1.

There was no statistically significant difference in terms of treatment success in both groups (p>0.05). In 99% of the patients (n=101), HCV-RNA levels were found below the determinable level in the fourth week of treatment. The SVR was found to be 99% at 12 weeks after treatment. In the evaluation of a case where no virological response was seen, it was learned that the patient was anti-human immunodeficiency virus (HIV) positive, received antiretroviral therapy (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil), and was using an intravenous agent. In the evaluation made at the 52th week after treatment, recurrence (HCV-RNA: 4277 IU/mL) was detected in one case, while SVR maintained in other cases. No detectable risk factor was found in the recurrent case. No patient discontinued the treatment due to adverse effects. There was no relationship between advanced age [≥65 years (n=47), <65 years (n=55)] and treatment success among the cases.

Considering the pre- and post-treatment laboratory parameters, there was a significant change in serum albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and alpha-fetoprotein (AFP) parameters in patients with compensated cirrhosis after treatment, and total bilirubin, hemoglobin, ALT, AST, GGT, ALP and AFP parameters in the group without cirrhosis (p<0.05). The MELD and CHILD scores of patients without cirrhosis were seen to decrease after treatment, but this decrease was not significant. However, there was a significant decrease in the MELD score of patients with compensated liver cirrhosis (p=0.007). Descriptive statistics of surveyed variables among patient are shown in Table 2.


Discussion

This retrospective single-center study consists of real-life data obtained between 2016-2019. Chronic HCV infection is one of the most important causes of cirrhosis and related liver diseases. The SVR achieved following an effective treatment significantly reduces morbidity and mortality even in advanced fibrosis (5). High levels of success have been achieved via both PrOD-based and sofosbuvir-based treatment regimens in the treatment of cases with HCV genotype 1b (6). The SVR rate has been reported to vary between 84% and 100% depending on patient groups and risk factors (7,8). The presence of liver cirrhosis stands out as an independent risk factor affecting SVR-12 (6). However, high SVR-12 can be achieved regardless of the liver cirrhosis stage (9). Treatment success (SVR-12) has been found to be higher in patients with albumin >3.5 g/dL, bilirubin <2 mg/dL and Child-pugh scores score 5-6 in the presence of liver cirrhosis (10). Furthermore, in a different evaluation, 100% SVR-12 was obtained with the PrOD regimen in the group, where 98.4% of patients had a Child-pugh score of 5 points, and no side effects that could lead to the discontinuation of treatment were observed (11).

Progression to decompensation can be seen in patients with compensated cirrhosis during the PrOD-based treatment regimen (12). There are some risk factors that facilitate decompensation. The main two predictive factors in progression to decompensation have been reported to be advanced age (>65 years) and albumin level of <3.6 g/dL (13). The development of hyperbilirubinemia during the treatment has been reported to be another facilitating factor (13). Furthermore, the rate of progression to decompensation in patients with compensated cirrhosis varies widely among patient groups. Progression to decompensation was observed in 18.52% of the patients with compensated cirrhosis, who developed hyperbilirubinemia during the PrOD regimen (13). In contrast, there are studies indicating that decompensation may develop at the rate of 2% in patients with compensated cirrhosis treated with a PrOD-based regimen, however, this treatment cannot be associated with mortality (12). The possibility of hepatocellular carcinoma development has been reported to be 1.4% in the follow-up period of these cases (10,12).

It has been demonstrated that there is no difference between the sofosbuvir-based regimen and the PrOD-based regimen in terms of treatment success in patients with genotype 1 in the presence of compensated liver cirrhosis (8). In the present study, no difference has been observed between the sofosbuvir-based regimen and the PrOD-based regimen in terms of SVR-12.

Advanced age is considered as a condition that may affect SVR success. In the HCV genotype 1 cases, the post-treatment SVR-12 rates have been reported to be 94% and 100% in patients aged ≥65 years and <65 years, respectively (14). However, PrOD regimen has been reported to be effective and reliable in patients aged ≥65 years. In the present study, no statistically significant difference has been observed between the patients aged >65 years and <65 years in terms of SVR-12.

In a study comparing PrOD ± RBV treatment results of cases with HIV/HCV coinfection and cases with HCV infection alone, a 2.2% difference was observed in terms of SVR-12, but no statistically lower difference was found. In cases with coinfection alone, HCV genotype 4 has been found to be associated with non-response to treatment (15). In another study, the results of PrOD ± RBV treatment in genotype 1 and 4 patients with coinfection were compared and the results were seen to be similar; SVR-12 was achieved at a rate of 97.8% and 97.6%, respectively (9). When the results of two patients with HIV/HCV coinfection included in the present study were evaluated, no virological response to DAA treatment was observed in a patient with simultaneous IV drug use.

In a study comparing eight-week and 12-week treatment periods in patients with genotype 1b, who were treated with the PrOD regimen, SVR was achieved at a rate of 95% and 99% after eight-week and 12-week treatments, respectively and no factor related to treatment non-response was found (16). The virus may be re-detected in some cases during the HCV-RNA follow-ups after SVR. The recurrence rate is reported to be about 1% (7,17). Recurrence was observed in one of our patients at the 52th week follow-up following the achievement of SVR. No etiological reason associated with recurrence was found.

High virological response success can also be achieved in patients who have had unsuccessful treatment experience with DAA treatment (18). A 100% SVR-12 has been achieved with the PrOD ± RBV regimen in compensated cirrhotic cases, about 70% of whom have treatment experience.

Mild and moderate adverse effects may occur in patients receiving PrOD ± RBV therapy. In particular, fatigue, headache, sleeplessness, itching, diarrhea and anemia have been reported more frequently (19). No toxic changes related to DAA treatment have been observed in laboratory parameters. Furthermore, no cases where the treatment was discontinued due to adverse effects were reported (11). However, severe adverse effects that may cause discontinuation of treatment may develop (6). In the present study, the most common adverse effect was itching and there were no adverse effects causing discontinuation of the treatment or requiring additional treatment.

Treatment of chronic liver disease with DAA can affect the physical and mental scores of the patients. Positive changes can occur in social lives in particular. More cost-effective changes can be seen in the quality of life and conditions of patients after treatment (20).

Treatment success has been found to have no significant relationship with the age, gender, previous treatment, body mass index, platelet count, international normalized ratio, and MELD score (13). However, the MELD score of <10 and the ALT value of 20 U/L in the 8th week of the treatment have been demonstrated to be positive markers for the virological response (21).

Some biochemical parameters that are above the reference range before treatment may return to normal limits after DAA treatment. Moreover, white blood cell count, platelet count, and hemoglobin values may change during and after treatment. These changes have been reported in both cirrhotic and non-cirrhotic cases. Significant changes can be seen in ALT, AST, GGT, ALP, platelet count, serum albumin and total bilirubin values following the DAA treatment (8,10,21,22). In the literature, there are also studies reporting that there is no significant difference in the white blood cell, hemoglobin, and platelet count (22). In the present study, a significant change has been observed in albumin, ALT, AST, GGT and AFP parameters in cirrhotic patients and total bilirubin, ALT, AST, GGT, ALP, AFP and hemoglobin parameters in non-cirrhotic patients after the treatment (p<0.05).

There are scoring criteria used to assess the level of liver damage and the well-being of the patient. It is thought that DAA treatment may lead to positive changes in these criteria and decrease the fibrosis score, resulting in a reduction in the burden of disease. When the initial and post-treatment first-year MELD scores and degree of fibrosis measured using FibroScan were evaluated, a significant change has been observed in both parameters (p<0.05) (10). Furthermore, it has been seen that significant changes may occur in the CHILD score and physical life score of patients following the DAA treatment (10). Contrary to this, progression to decompensation is seen in very few patients with compensated cirrhosis (23). In the present study, a decrease has been observed in the post-treatment MELD and Child-pugh scores of patients with compensated cirrhosis compared to the pre-treatment scores, but there were no significant changes. However, a significant decrease has been seen in the MELD scored of patients without cirrhosis (p=0.007).


Study Limitations

The main limitation of our study is that it has a retrospective design. In addition, subgroup analysis was not performed based on the accompanying risk factors, HCV-RNA levels, and histological activity indices.


Conclusion

This study consists of cases with HCV genotype 1b and chronic liver disease. Regardless of age, gender, viral load, and underlying diseases, a high level of SVR has been achieved in all cases included in the study. Furthermore, returning to normal limits has been observed in indirect markers used to determine the level of liver damage. The retrospective design of this study is its weakness. However, we believe that very valuable data have been presented thanks to the results it has revealed.


Ethics

Ethics Committee Approval: This study was carried out with the approval of Ethical Committee of Namık Kemal University Faculty of Medicine (approval number: 2020.86.04.10).

Informed Consent: Since our study was retrospective, informed consent was not used.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: M.D., B.T., R.K., İ.E., Concept: M.D., B.T., R.K., İ.E., Design: M.D., B.T., R.K., İ.E., Data Collection or Processing: M.D., B.T., R.K., İ.E., Analysis or Interpretation: M.D., B.T., R.K., İ.E., Literature Search: M.D., B.T., R.K., İ.E., Writing: M.D., B.T., R.K., İ.E.

Conflict of Interest: Authors declare no conflict of interest.

Financial Disclosure: There was no aid and sponsor for this study.

Images

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