Interferon lambda 4 (IFNL4) gene polymorphism is associated with spontaneous clearance of HCV in HIV-1 positive patients

Abstract

Approximately one-third of the individuals infected with human immunodeficiency virus type 1 (HIV-1) are co-infected with hepatitis C virus (HCV). Co-infected patients have an increased risk for developing end-stage liver diseases. Variants upstream of the IFNL3 gene have been associated with spontaneous and treatment-induced clearance of HCV infection. Recently, a novel polymorphism was discovered, denoted IFNL4 ΔG > TT (rs368234815), which seems to be a better predictor of spontaneous clearance than the IFNL4 rs12979860 polymorphism. We aimed to determine the prevalence of the IFNL4 ΔG > TT variants and to evaluate the association with spontaneous clearance of HCV infection in Brazilian HIV-1 patients. The IFNL4 ΔG > TT genotypes were analyzed by polymerase chain reaction followed by restriction digestion in 138 HIV-1 positive patients who had an anti-HCV positive result. Spontaneous clearance of HCV was observed in 34 individuals (24.6%). IFNL4 genotype distribution was significantly different between individuals who had spontaneous clearance and chronic HCV patients (p=0.002). The probability of spontaneous clearance of HCV infection for patients with the IFNL4 TT/TT genotype was 3.6 times higher than for patients carrying the IFNL4 ΔG allele (OR=3.63, 95% CI:1.51-8.89, p=0.001). The IFNL4 ΔG > TT polymorphism seems to be better than IFNL4 rs12979860 to predict spontaneous clearance of the HCV in Brazilian HIV-1 positive patients.

Pharmacogenomics research and clinical implementation in Brazil

“…Figure shows a flowchart of our search results. After filtering PubMed entries and publications from REFARGEN members, 72 articles were selected, 22 of which examined both pharmacogene(s) and drug(s) from a CPIC guideline (Table ). The remaining 50 articles investigated one or more genes comprised in the guidelines.…”

“…Their results indicated that carrying the variant alleles in heterozygosis or homozygosis was associated with failure to obtain a sustained viral response (SVR) and/or relapse. These results were verified in another cohort of Brazilian patients and extended to a third polymorphism, namely rs368234815, located upstream to IFNL3 and in extensive linkage disequilibrium with rs12979860. Nastri et al reported that the haplotype G/T/ΔG, comprising the minor alleles at rs8099917, rs12979860 and rs368234815, was related to non‐response to PEG‐IFN‐α‐based treatment and to a higher chance of developing chronic infection when compared to the wild‐type haplotype T/C/TT.…”

Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay?

“…Similarly, in a swiss cohort of 540 HCV infected patients, the IFNL4 TT/-ΔG was a better marker of spontaneous clearance compared with rs12979860 [126]. Also, in Brazilian HIV infected patients with the IFNL4 TT/TT genotype, the probability of a spontaneous clearance of HCV infection was 3.6 fold higher than for patients carrying the IFNL4 ΔG, while the CC genotype of the IFNL4 polymorphism had a 2.8 higher probability for spontaneous clearance [138]. However, other studies reported that IFNL3.rs12979860 and IFNL4.ss469415590 variants have comparable effects on spontaneous resolution of HCV in Egyptians, Iranian, and Chinese populations [139,140].…”

IFNL4 rs368234815 and rs117648444 variants predict off‐treatment HBsAg seroclearance in IFN‐treated HBeAg‐negative chronic hepatitis B patients

“…The search for a host genetic marker of IFN responsiveness regained interest following the identification of the new IFNL4 gene that harbours the dinucleotide frameshift variant rs368234815 TT/ΔG in strong linkage with the rs12979860 polymorphism (commonly referred to as IL28B ), a genetic marker of outcome to IFN‐based therapy of hepatitis C virus (HCV) infection . The IFNλ4 protein, which can be generated only by carriers of the IFNL4 rs368234815 ΔG allele, correlates with a substantially worse treatment response and spontaneous clearance rate in HCV patients . Recently, it has been shown that the amino acid substitution in IFNλ4 protein changing a proline at position 70 to a serine (following named as IFNλ4‐P70 and IFNλ4‐S70 respectively) because of the rs117648444 variant, alters its antiviral activity leading to an improve of HCV clearance .…”

“…8 The IFNλ4 protein, which can be generated only by carriers of the IFNL4 rs368234815 ΔG allele, correlates with a substantially worse treatment response and spontaneous clearance rate in HCV patients. [8][9][10][11][12][13][14] Recently, it has been shown that the amino acid substitution in IFNλ4 protein changing a proline at position 70 to a serine (following named as IFNλ4-P70 and IFNλ4-S70 respectively) because of the rs117648444 variant, alters its antiviral activity leading to an improve of HCV clearance. 15 In support, patients harbouring the impaired IFNλ4-S70-coding rs117648444 T allele display a faster HCV RNA decline at week 4 of Peg-IFN/ribavirin treatment compared to those predicted to produce the fully active IFNλ4-P70 variant.…”