Hubungan antara Polimorfisme CTLA-4 -1661G>A dengan Kadar CTLA-4 dan Respons Virologis terhadap Pengobatan Tenofovir Disoproxil Fumarate pada Pasien Hepatitis B Kronik

Abstract

Background: In chronic hepatitis B infection there is a weakening of T cell activity due to cell anergy which is characterized by poor cytotoxic T cell response, decreased cytokine production due to increased expression of inhibitory molecules such as CTLA-4. The importance of management in chronic hepatitis B patients to achieve treatment targets and to prevent disease progression. Tenofovir Disoproxil Fumarate (TDF) is one of the NA classes that is the first line of treatment. Not only antiviral, TDF is also an immunomodulator. TDF can reduce the levels of Treg cells, proinflammatory cytokines, enhance specific T cell function and improve T cell anergy by regulating CTLA-4. T cell activation itself is largely determined by genetic factors such as CTLA-4 Objectives: to analyze the association between CTLA-4 -1661G>A gene polymorphisms with CTLA-4 levels and response to Tenofovir Disoproxil Fumarate in chronic hepatitis B patients and other related factors. Methods: A retrospective cohort study of 182 chronic hepatitis B patients taking TDF regularly for 24 weeks. The research was conducted in October 2021 – September 2022 at H. Adam Malik Hospital, USU Hospital. Subjects consisted of 91 people who did not achieve a virological response and 91 people who achieved a virological response to TDF. The sampling technique was consecutive sampling. Subjects were taken blood for examination of CTLA-4 serum levels by ELISA technique and CTLA-4 -1661G>A gene polymorphisms with real-time PCR technique. Results: There was a significant association between the CTLA-4 -1661G>A polymorphism and the virological response to TDF. The GG+AG genotype increased 1.42 times the risk of not achieving a virological response to TDF compared to the AA genotype (p=0.031). Patients with the G allele had a 1.27 times risk of not achieving a virological response to TDF compared to the A allele (p=0.025). From multivariate analysis, there was a significant association between high CTLA-4 levels, high HBV DNA, low baseline ALT, and GG+AG genotypes of CTLA-4 -1661G>A polymorphisms and not achieving a virological response to TDF. There were no associations between gender, age, ethnicity, obesity, baseline AST, HBeAg, genotype, liver fibrosis with virological response to TDF (p>0.05). There were significant differences in serum CTLA-4 levels among genotypes of the CTLA-4 -1661G>A polymorphism. CTLA-4 levels were significantly higher in hepatitis B patients with GG and AG genotypes than AA genotype (p<0.001). Serum CTLA-4 levels were significantly higher in patients with the G allele than A allele (p<0.001). Conclusion: There were associations between genotype GG+AG of CTLA-4 -1661G>A polymorphism with high CTLA-4 levels and not achieving a virological response to TDF. Other factors associated with an inadequate virological response to TDF include high HBV DNA and low ALT levels.