Study Identifies Risk Factors for Liver Enzyme Elevation Following Hepatitis C Virologic Cure

Higher pretreatment alanine aminotransferase (ALT) and pre-treatment cirrhosis are linked to increased odds of liver enzyme elevation among patients with hepatitis C virus (HCV) who achieved a sustained virologic response, new findings suggest.¹ Male sex was also linked to lower odds of liver enzyme elevation.

These findings were the result of recent research conducted to evaluate the subset of patients with chronic HCV infection who demonstrated liver enzyme elevation following their achievement of sustained virologic response. The investigators—led by Helen L. Zhang of the department of medicine at Durham Veterans Affairs Medical Center—noted that factors for liver enzyme elevation had not previously been well characterized.

Nevertheless, there had been some research suggesting those with HIV/HCV co-infection have a greater prevalence of liver enzyme elevation as well as liver fibrosis progression even following sustained virologic response achievement compared to patients with HCV mon-oinfection.²

“In this study, we assessed the prevalence and predictors of liver enzyme elevation (LEE) after HCV virologic cure in a cohort of patients with HCV monoinfection or HIV/HCV coinfection who received DAA therapy,” Zhang et al. wrote.¹

Study Design

The research team conducted a retrospective cohort study within the Duke University Health System (DUHS) in North Carolina, implementing the Duke Enterprise Data Unified Content Explorer (DEDUCE) electronic health record query tool. The team sought to find individuals in the age range of 18 years or older with an HCV infection diagnosis at DUHS, with the diagnoses specifically having occurred between January - 1996 - December 2017.

The investigators looked at those whose medication records suggested they had been treated with a direct-acting antiviral (DAA) regimen for HCV. These subjects would also have documented sustained virologic response 12 weeks following their treatment (SVR12). SVR12 was defined by the team as the recording of an undetectable HCV RNA viral load at least 24 weeks following the beginning of one’s DAA treatment, assuming a 12-week period of treatment.

The subjects were also required to have had at least a single recorded alanine aminotransferase (ALT) or aspartate transaminase (AST) measurement between 10 - 48 weeks following the end of DAA therapy (EOT). The research team retrieved the necessary data from electronic health records through the use of DEDUCE, gathering such information up until September 2020.

The team determined their research’s primary outcome would be the occurrence of at least a single liver enzyme elevation occurrence. This was defined by ALT or AST levels that were shown to exceed the upper limit of normal (35 IU/L for males and 25 IU/L for females), specifically within 10 - 48 weeks following DAA therapy’s conclusion.

As far as secondary outcomes, the investigators included an evaluation of all liver enzyme elevation instances noted between 0 - 410 weeks post-DAA therapy conclusion, in addition to all ALT assessments taken within the same timeframe.

Multivariate logistic regression was implemented by the research team to look at the relationship between potential risk factors and liver enzyme elevation. They evaluated longitudinal relationships between HIV status and liver enzyme elevation through generalized linear mixed-effects models.

Notable Findings

There were a total of 1,356 participants evaluated in the investigators’ analysis, 41.0% having reported experiencing liver enzyme elevation after having achieved a sustained virologic response. Pre-treatment cirrhosis (adjusted odds ratio [aOR] 2.26, 95% CI 1.60–3.21) and increased pre-treatment ALT levels (aOR 1.08 per 10 IU/L increase, 95% CI 1.05–1.11) were linked to increased likelihood of developing liver enzyme elevation.

The research team concluded that male sex, however, was linked to a diminished likelihood of liver enzyme elevation (aOR 0.28, 95% CI 0.21–0.38). The team added that there had not been significant evidence shown in their study of a link between HIV infection and liver enezyme elevation (aOR 0.83, 95% CI 0.47–1.44).

The investigators’ findings suggested that cirrhosis, pretreatment ALT levels, and female sex are major predictors of liver enzyme elevation among those with HCV who achieve sustained virologic responses. This, they explained, could help to identify patients who may be at higher risk of liver injury following treatment.

“...(This) study describes a high prevalence of LEE in patients who have achieved HCV cure and has identified potential risk factors for post-SVR LEE,” they wrote. “Future studies in larger and more balanced cohorts of patients with HCV monoinfection and HIV/HCV coinfection should evaluate the association between HIV infection and LEE, differences in trends in LEE over time and reasons for our observed higher odds of LEE among female patients.”¹

References

1. ^{Zhang HL, Nemeth H, Woodhouse EW, Davenport CA, Chan C, Okeke NL, Naggie S. Prevalence of and Risk Factors for Liver Enzyme Elevation After Hepatitis C Virologic Cure. J Viral Hepat. 2024 Oct 3. doi: 10.1111/jvh.14009. Epub ahead of print. PMID: 39360629.}
2. ^{A Olveira, L Dominguez, J Troya, et al., “Persistently Altered Liver Test Results in Hepatitis C Patients After Sustained Virological Response With Direct-Acting Antivirals,” Journal of Viral Hepatitis 25, no. 7 (2018): 818–824, https://doi.org/10.1111/jvh.12883.}