Liver Fibrosis Progression and Mortality in Hepatitis B– and C–Coinfected Persons Treated With Directly Acting Antiviral Agents: Results From ERCHIVES

Abstract

For persons with baseline Fibrosis-4 1.46–3.25, cirrhosis incidence/1000 patient-years was 49.3 among hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfected and 18.2 among HCV monoinfected (P = .03). Cirrhosis risk was numerically higher but statistically nonsignificant among HBV/HCV coinfected (hazards ratio [HR] 1.51; 95% confidence intervals [CI], .37–6.05) but lower among those who attained sustained virologic response (HR, .52; 95% CI, .42–.63).

Persons with hepatitis C virus (HCV) and hepatitis B virus (HBV) coinfection are at a higher risk of liver cirrhosis and hepatocellular carcinoma compared with persons with HCV monoinfection [1, 2]. Treatment of HCV with directly acting antivirals (DAAs) is associated with a significant reduction in overall mortality and the risk of developing liver cirrhosis or hepatocellular carcinoma (HCC) in persons with HCV monoinfection [3, 4]. There are scant data regarding the effect of treatment with DAA regimens upon liver fibrosis progression and clinical outcomes in persons with HBV/HCV coinfection. We determined the incidence rate of liver cirrhosis and hepatic decompensation and mortality in persons with HBV/HCV coinfection and compared it with persons with HCV monoinfection

METHODS

Cohort Construction and Study Population

Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) is a well-established national cohort of persons with and without HCV derived from the US veterans population who have received care at any of the Department of Veterans Affairs’ healthcare facilities. ERCHIVES is updated regularly to include those with newly diagnosed HCV infection and has been described in more detail in numerous previous publications [4–6]. We used ERCHIVES to identify persons with HCV who were treated with a DAA regimen. We excluded the following groups: those previously treated for HBV infection with an approved treatment regimen for more than 90 days; those with human immunodeficiency virus (HIV) coinfection; those missing hepatitis B surface antigen (HBsAg) or HBV DNA, or both; those with an HCC diagnosis at baseline; and those missing baseline HCV RNA values.

Definitions

All persons in the final dataset thus created were HCV positive and were subcategorized into those with HBV/HCV coinfection or HCV monoinfection. HBV/HCV coinfection was defined as having HBsAg and/or HBV DNA available and positive in persons with HCV. Hypertension, cardiovascular disease events, and alcohol and drug abuse or dependence were defined as the presence of 1 or more inpatient or 2 or more outpatient International Classification of Diseases, 9th/10th revision (ICD-9/10), codes [7]. Diabetes was defined using a combination of blood glucose, ICD-9/10 codes, and use of oral hypoglycemic medications or insulin [8]. Liver disease severity was calculated using the Fibrosis-4 (FIB-4) score and categorized as mild (FIB-4 <1.45), moderate (FIB-4, 1.46–3.25), or severe (FIB-4 >3.25) fibrosis/cirrhosis [5, 6]. Hepatic decompensation was defined using a primary hospital discharge diagnosis or 2 or more outpatient diagnoses for ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage, as proposed and validated by Lo Re et al [9]. Chronic kidney disease was defined by calculating the estimated glomerular filtration rate using the CKD-EPI equation [10].

Statistical Analyses

Our primary outcome measures were incidence rates for cirrhosis, first hepatic decompensation event, and mortality. Our secondary outcomes were rate of fibrosis progression over time and time to first cirrhosis diagnosis, hepatic decompensation event, or mortality. The treatment initiation date for HCV with a first course of DAA regimen was set as the baseline. Baseline characteristics were compared for HCV/HBV-coinfected persons versus HCV-monoinfected persons. Categorical variables were compared using chi-square test, and continuous variables were compared using Student’s t test for normally distributed and Kruskal-Wallis test for nonnormally distributed variables. For supplementary analyses, Cox proportional hazards regression analysis was used to generate hazards ratios (HRs) and 95% confidence intervals (CIs) for factors associated with incident cirrhosis. Assumptions for proportional hazards were checked using Schoenfeld residuals. We used SAS version 9.4 (SAS Institute, Inc) for analyses.

Ethical Approval

The study was approved by the Institutional Review Board at the VA Pittsburgh Healthcare System.

RESULTS

We identified 71 132 persons with HCV who were initiated on HCV treatment with a DAA regimen. After excluding those with prior HBV treatment (n = 1644), HIV (n = 808), HCC (n = 1274), and missing data (n = 6111), our final evaluable data consisted of 151 persons with HBV/HCV coinfection and 40 658 with HCV monoinfection. The mean age was 60.9 years in the HBV-coinfected and 60.0 years in the HCV-monoinfected group; 96% in both groups were male. Median (interquartile range) FIB-4 scores were 2.2 (1.6–3.6) and 1.9 (1.4–3.0), respectively, and cirrhosis (defined as FIB-4 >3.25) was observed in 29.3% of HBV/HCV-coinfected and 22.5% of HCV-monoinfected persons. The incidence rate for all events (cirrhosis, hepatic decompensation, mortality) increased with increasing liver fibrosis score (FIB-4) at baseline in both groups (Table 1). Incidence rates for cirrhosis per 1000 person-years of follow-up for persons with a baseline FIB-4 score of 1.46–3.25 were 49.3 for persons with HBV/HCV coinfection and 18.2 for persons with HCV monoinfection. Incidence rates for hepatic decompensation for persons with a baseline FIB-4 score of 1.46–3.25 were 29.5 for persons with HBV/HCV coinfection and 6.9 for persons with HCV monoinfection. For those with a baseline FIB-4 greater than 3.25 at baseline, these rates were 66.5 and 83.1, respectively. Mortality rates in the group with FIB-4 scores less than 1.45 were 23.0 for persons with HBV/HCV coinfection and 13.3 for persons with HCV monoinfection. For those with a baseline FIB-4 score greater than 3.25 at baseline, mortality rates were 49.5 and 38.5, respectively (Table 1).

Table 1.

Incidence Rates (95% Confidence Intervals) per 1000 Patient-Years of Follow-up for Cirrhosis, Hepatic Decompensation, and Mortality, by Study Group and Baseline FIB-4 Score

	n	HBV/HCV Coinfection	n	HCV Monoinfection	P value
Cirrhosis (using FIB-4 >3.25 to define cirrhosis)
FIB-4 <1.45	0	0	54	3.3 (2.6–4.4)
FIB-4 of 1.46–3.25	5	49.3 (20.5–118)	525	18.2 (16.7–19.8)	.03
Cirrhosis (using ≥1 inpatient or ≥2 outpatient ICD-9/10 codes to define cirrhosis)
FIB-4 <1.45	0	0	212	13.9 (12.2–15.9)
FIB-4 of 1.46–3.25	5	57.7 (24–139)	870	36.2 (33.9–38.7)	.30
Hepatic decompensation
FIB-4 <1.45	0	0	23	1.4 (.9–2.1)
FIB-4 of 1.46–3.25	3	29.5 (9.5–91.4)	199	6.9 (6–7.9)	.01
FIB-4 >3.25	5	66.5 (27.7–160.0)	1151	83.1 (78.5–88.1)	.62
Mortality
FIB-4 <1.45	1	23.0 (3.2–164.0)	215	13.3 (11.6–15.2)	.58
FIB-4 of 1.46–3.25	4	38.3 (14.4–102.0)	489	16.8 (15.4–18.4)	.10
FIB-4 >3.25	4	49.5 (18.6–132.0)	598	38.5 (35.6–41.8)	.62

Abbreviations: FIB-4, Fibrosis-4; HBV, hepatitis B virus; HCV, hepatitis C virus; ICD-9/10, International Classification of Diseases, 9th/10th revision.

In multivariable Cox regression analysis, HBV/HCV coinfection was associated with increased hazards of developing liver cirrhosis (HR, 1.51; 95% CI, .37–60.5) compared with HCV monoinfection), although this did not reach statistical significance. Attainment of sustained virologic response (SVR) was associated with a significantly reduced hazards of incident cirrhosis (HR, 0.51; 95% CI, .42–.63) (Supplementary Table 1).

DISCUSSION

There are scant prior data regarding liver disease progression after treatment with newer DAA regimens in persons with HBV/HCV coinfection and how that compares with persons with HCV monoinfection. We report liver fibrosis progression and clinical outcomes from one of the largest studies in persons in these populations, all of whom were treated with a DAA regimen for HCV. Our main observations were a higher incidence rate of cirrhosis among persons with HBV/HCV coinfection and a reduced risk of cirrhosis in persons who attained SVR.

There are some important differences in baseline characteristics between these populations. We observed a slightly higher baseline FIB-4 score and HCV RNA in persons with HBV/HCV coinfection, compared with those with HCV monoinfection, which would suggest a higher risk of liver fibrosis progression and development of cirrhosis in persons with HBV/HCV coinfection. On the other hand, the SVR rate in persons with HBV/HCV coinfection was higher compared with those with HCV monoinfection (88.8% vs 82.8%; P = .04), which would be expected to favor lower progression of liver fibrosis in those with HBV/HCV coinfection. We observed a higher risk of incident cirrhosis among those with HBV/HCV coinfection. To provide some context, patients with HBV and hepatitis delta coinfection are less likely to be HBV e-antigen positive and have lower HBV viral loads compared with HBV-monoinfected persons [11]. While HCV viral load was higher among persons with HBV/HCV coinfection, whether HBV viral loads are lower in these persons and whether this affects clinical and virologic outcomes are not known.

In the Cox regression model adjusting for baseline characteristics, HBV/HCV coinfection was associated with a numerically higher but statistically nonsignificant hazard of developing incident cirrhosis compared with those with HCV monoinfection. Attainment of SVR significantly reduced this risk, thus providing strong evidence in favor of treating these persons for HCV infection. While we did not study the optimal time for initiating HCV treatment, we observed a significantly higher incident rate of cirrhosis in those with a baseline FIB-4 of 1.46–3.25, while no cases of cirrhosis were observed in persons with HBV/HCV coinfection and an FIB-4 less than 1.45, thus suggesting a benefit of early treatment.

Strengths of our study include a large national population and longitudinal follow-up in a well-established cohort. Limitations include the observational nature of the study, nonuniform testing of all HBV biomarkers, and the possibility of unmeasured confounders. Since we excluded those who received any HBV treatment, the effect of HBV treatment upon clinical outcomes could not be ascertained. In the current study we did not determine the rate of HBV reactivation, but in a previous study in a similar population we have demonstrated no significant short-term increase in HBV reactivation after DAA treatment [12]. The number at risk in the HBV/HCV-coinfected group was small at the end of the study period, which may have masked any true association, thereby limiting any strong conclusions.

In conclusion, after treatment of HCV with a DAA regimen, persons with HBV/HCV coinfection are at a higher risk of liver disease progression compared with those with HCV monoinfection. The attainment of SVR significantly reduces that risk. Treatment with DAA regimens should be considered standard of care for all HBV/HCV-coinfected persons.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions: A. A. B.: study concept and design, acquisition of data, analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, and obtained funding; P. Y.: acquisition of data and statistical analysis; S. A., A.-B. A.-S., K. E. S., and O. S. S.: critical revision of the manuscript for important intellectual content; A. A. B. had complete access to data at all times and accepts the responsibility of the integrity of this article.

Acknowledgments: This material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System and the central data repositories maintained by the VA Information Resource Center, including the National Patient Care Database, Decisions Support System Database, and Pharmacy Benefits Management Database.

Disclaimer. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.

Potential conflicts of interest: A. A. B. has received grant support (to the institution, Veterans Research Foundation of Pittsburgh) from Gilead Sciences. K. E. S. has served on advisory boards for Abbott Laboratories and Inovio and on Data Safety Monitoring Boasrd for Medpace and Watermark and received grant support (paid to the institution) from Abbvie, Merck, Gilead Sciences, and Intercept. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.