The Impact of Achieving Sustained Virological Response with Direct Acting Antivirals on Gastroesophageal Varices and Variceal Bleeding

INTRODUCTION

Hepatitis C virus (HCV) is a worldwide health problem as HCV is a leading cause of morbidity and mortality that is explained mainly by high incidence of   complications of liver cirrhosis as portal hypertension, liver cell failure and hepatocellular carcinoma. ¹

Gastroesophageal varices are a serious consequence of portal hypertension that happen in about 50 % of cirrhotic patients, Variceal development happens mainly with of Clinically significant portal hypertension CSPH (hepatic venous pressure gradient HVPG ≥10 mmHg), ² and occurs with a rate of 7-8% annually and progresses from small to large varices by a rate of 10-12% annually, more seriously Variceal hemorrhage occurs by a rate of 5% annually

and if happens mortality rate would be as high as 15-25 % . ³

With introduction of Direct-acting antivirals (DAA) a high rate of sustained virological response (SVR) exceeding 95 % with good safety and tolerability profile already achieved even in difficult-to-treat groups,^4,5 accordingly nowadays almost all patients infected       with HCV are advised to receive HCV treatment to decrease or to avoid its serious complications. ⁶

Despite some data from previous studies revealed the beneficial effect of SVR achieved by DAA interferon free regimens on improvement of liver fibrosis,⁷ Moreover improvement of portal hypertension in a short term after SVR had been reported by some studies,⁸ Still scanty data present around the effect of SVR after DAA interferon free regimens on gastroesophageal varices and variceal bleeding. So, we conducted this study to evaluate the effect of achieving SVR with DAA interferon free regimens on gastroesophageal varices.

PATIENTS AND METHODS

In a prospective study that was done at Tanta University Hospital, Hepatology Gastroenterology and Endoscopy unit, from January 2019 to January 2021, we recruited our patients from those who presented to hepatology clinic with chronic hepatitis C virus infection and  came for receiving   HCV treatment ,We included patients with chronic HCV and gastroesophageal varices candidate for DAA interferon-free regimens, after treatment we divided our patients into two groups group A (achieved SVR (defined by undetectable HCV RNA by real-time PCR at 12 weeks after end of treatment)⁹ ,Group B patients failed to achieve SVR from first time treatment (Non SVR ), The most common DAA regimen was sofosbuvir/Daclatasvir followed by sofosbuvir/Ledipasvir.

Our exclusion criteria were:

• Patients with multiple comorbidities as chronic cardiac or renal disease.
• Age more 70 years old.
• Patients with hepatitis B virus, HBV co infection HCV or mixed caused of liver disease.
• Patients with alcohol intake.
• Patients with no gastroesophageal varices.
• Patients with hepatocellular carcinoma (either recently discovered or previously ablated).
• Patients who developed variceal bleeding within 90 days after DAA initiation.

We included 206 chronic HCV variceal patients who were candidate for DAA interferon free regimens. All patients underwent a full history taking, full clinical examination, as well as pretreatment radiological evaluation (ultrasound with or without triphasic liver C.T) prior to treatment and 6 month after treatment with the size of the spleen and portal vein diameter recorded, Esophagogastro-duodenoscopy (EGD) with documentation of the size, site and risky signs of the varices ,patients with risky varices were subjected to variceal band ligation prior to HCV treatment, Investigations as  full liver functions, full blood count, renal functions, alfa fetoprotein were done to all patients  also Child-Pough scoring were applied to all patients before and 6 months after treatment, All patients had real time PCR at 12 weeks after treatment, all patients will be subjected to regular follow up upper endoscopy on 3-6 months interval ,any bleeding episode after 90 days from DAAS therapy will be documented, after starting DAA 6 patients were excluded as(3 patients died, 2 patients stopped  treatment due to development of hepatic decompensation, 1 patient lost stopped follow up), So only 200 patients were enrolled in our study and  divided into two groups : Group A: who achieved SVR (N= 180 patients); Group B: who failed to achieve SVR (non SVR, N=20 patients).

27 patients  from group A  as well as 7 patients from group B developed acute variceal bleeding, patients were presented  to our emergency department with acute upper GIT bleeding episode, those patients underwent resuscitation by administration of colloids, crystalloids and blood transfusion according to hemoglobin level then patients underwent urgent EGD for control of bleeding, still 2 patients from group A and 2 patient from group B  presented with sever bleeding and died before urgent EGD, For other patients Varices were classified by its site according to Sarin classification and by its size according to Japanese classification of varices, ^10,11  The severity of variceal bleeding episode was assessed by APASL (Asian Pacific Association for Study of the Liver score) the APASL severity score is the sum of five parameter’s points, systolic blood pressure, Child-Turcotte-Pugh class, Platelet count, Infection and active bleeding at endoscopy).¹² All data were collected and statistically analyzed.

The research was conducted in line with the ethical principles of the Declaration of Helsinki.

Statistical Analysis:

Data were analyzed using Statistical Program for Social Science (SPSS) version 20.0 Quantitative data were expressed as mean ± standard deviation (SD). Qualitative data were expressed as frequency and percentage. These tests were done in this study: Independent-samples t-test of significance was used when comparing between two means and Chi-square (X²) test of significance was used to compare proportions between two qualitative parameters.

RESULTS

Basic Characteristics of study groups are shown in (table 1), no significant differences founded between the two groups related to age and sex, however significant predominance of Child-Pough A in SVR group A (139 patients 77.2%) versus Non SVR group B (5 patients 25%) with P-value 0.001. The main used DAA regimen in SVR group was sofosbuvir/Daclatasvir (150 patients 83.3%), However the main DAA regimen used in Non SVR group was sofosbuvir/Daclatasvir/Ribavirin (9 patients 45%).

(Table 2) show that significant higher incidence of developing acute variceal bleeding in Non SVR group B versus SVR group A (27 patients 15% in SVR group versus 7 patients 35% in Non SVR group), With significant higher mortality rate in Non SVR group 10 % versus 1.1 % in SVR group.

(Table 3) shows no significant difference regarding changing in Child-Pough scoring and laboratory characters before and after treatment in SVR non SVR groups put for significant improvement in platelet count after SVR (p 0.001).

(Table 4)shows significant improvement variceal size in SVR group A as large varices (F3) become 11.2% six months after treatment versus 29.4% before treatment, still no significant changes regarding variceal size in Non SVR group B before and 6 months after treatment, with overall improvement in variceal size comparing SVR and Non SVR groups (p value 0.001). Also significant improvement in variceal risky signs was found in SVR group A as risky variceal signs were presented in  143 (79.4%) patients before treatment versus 111 (62.4%)  patients six months after treatment , however no significant change regarding variceal risky signs in Non SVR  group B before and 6 months after treatment, surprisingly no  significant overall improvement in variceal risky signs  in SVR group versus Non SVR group.

Table 1: Basic characteristics Distribution of the studied patients according to different parameters: (Sofo=sofosbuvir, Dalca=Daclatasvir, Riba=ribavirin, led=lideprevir), SVR=sustained virological response, P- value significant < 0.05.

Table 2: Acute variceal bleeding among studied groups (APASL= Asian Pacific Association for Study of the Liver score).

Table 3: Laboratory and clinical characters of studied groups before and 6 months after treatment (Significant p< 0.05).

Table 4: Gastroesophageal varices assessment among studied groups before and 6 months after treatment. (GOV=gastroesophageal varices, F1=Small Straight, F2=Moderate, F3=marked enlarged, Risky signs=red cherry spot red whale signs or both).