Comparative risk of hepatitis C virus infection in patients with rheumatoid arthritis receiving target-synthetic disease-modified anti-rheumatic drugs (tsDMARDs) vs. biological DMARDs (bDMARDs): a population-based study

Background: Previous studies, predominately from western countries, suggested tsDMARD may associate with the risk of hepatitis C infection (HCV). However, the risk remained uncertain in Taiwan, especially since the background rate of HCV is relatively high in East Asia.

Objectives: To compare the risk of incident of HCV in patients treated with tsDMARDs v.s. bDMARDs.

Methods: We emulated a pragmatic, two-comparison arm (tsDMARDs v.s bDMARDs), clinical trial by using National Health Insurance Database in Taiwan. We included individuals aged 18 and older, diagnosed with RA from 2014 to 2020, and newly treated with tsDMARDs (tofacitinib and baricitinib) or bDMARDs arms. The outcome was incident HCV, defined as those diagnosed with outpatient claims at least 2 times, or one hospitalization claim. We excluded patients who had a history of serious infection (including HCV), HIV infection, and transplantation or malignancy. We defined the initiation date of drugs as the index date. To mimic randomization in a clinical trial, we performed propensity score (PS) matching to create two arms with similar probability of treatment assignment on 1:4 ratios (tsDMARDs: bDMARDs). PS was generated by logistic regression using 48 covariates including index year, age, sex, comorbidities, analgesics, antibiotics, and healthcare utilization at the baseline. We performed an as-treated analysis and follow-up starting from the index date, until first occurrence of outcome, discontinuation or switching, death, treatment of rituximab, or end of data source. We also conducted ITT analysis for sensitivity analysis. We also considered the outcome of herpes zoster as a positive control for this study. We calculated incidence rates per 100 person-years (PYs) and applied Cox proportional hazard model to estimate the hazard ratios (HR) and 95% CIs.

Results: We included a total of 2033 tsDMARD users and 10289 bDMARDs users. After PS-matching, we included 1632 tsDMARD users and 6114 bDMARDs users. The mean age and proportion of females were similar between the two groups (56.02 years and 80.39% in the tsDMARD users and 55.43 years and 78.02% in the bDMARD users). The incidence rate of HCV for tsDMARDs was 0.71 (95%CI 0.46-1.05) per 100 PYs and for bDMARDs was 0.52 (95%CI 1.03-2.87) per 100 PYs. The risk of HCV was higher in tsDMARDs users than bDMARDs users (HR of 1.72,95% CI 1.03-2.87). The results remained consistent in the sensitivity analysis. The result of positive control outcome remained consistent with our study design (HR of 2.19, 95% CI 1.67-2.87).

Conclusions: The result indicated that, compared with bDMARDs, patients receiving tsDMARDs had a higher incidence rate of HCV. The finding provided a strong ground for future strategies to prevent HCV incidence, especially for patients receiving tsDMARDs in Taiwan.