key: cord-0990705-x6jo8afm
authors: Butt, Adeel A.; Yan, Peng; Chotani, Rashid A.; Shaikh, Obaid S.
title: Mortality is not increased in SARS‐CoV‐2 infected persons with hepatitis C virus infection
date: 2021-02-16
journal: Liver Int
DOI: 10.1111/liv.14804
sha: fe800cad322ddc60803be7b8794c6a80a380e4fe
doc_id: 990705
cord_uid: x6jo8afm

BACKGROUND: Impact of SARS‐CoV‐2 infection upon hospitalization, intensive care unit (ICU) admissions and mortality in persons with hepatitis C virus (HCV) infection is unknown. METHODS: We used the Electronically Retrieved Cohort of HCV infected Veterans (ERCHIVES) database to determine the impact of HCV infection upon the rates of acute care hospitalization, ICU admission and all‐cause mortality. We identified Veterans with chronic HCV infection and propensity score matched controls without HCV in ERCHIVES. We excluded those with HIV or hepatitis B virus coinfection. RESULTS: We identified 975 HCV+ and 975 propensity score matched HCV− persons with SARS‐CoV‐2 infection. Mean FIB‐4 score (±SD) was higher in those with HCV (1.9 ± 2.1 vs 1.2 ± 0.9; P < .0001) and a larger proportion of those with HCV had cirrhosis (8.1% vs 1.4%; P < .0001). A larger proportion of HCV+ were hospitalized compared to HCV‐ (24.0% vs 18.3%; P = .002); however, those requiring ICU care and mortality were also similar in both groups (6.6% vs 6.5%; P = .9). Among those with FIB‐4 score of 1.45‐3.25, hospitalization rate/1000‐person‐years was 41.4 among HCV+ and 20.2 among HCV−, while among those with a FIB‐4 > 3.25, the rate‐ was 9.4 and 0.6 (P < .0001). There was no difference in all‐cause mortality by age, gender, FIB‐4 score, number of comorbidities or treatment with remdesivir and/or systemic corticosteroids. CONCLUSIONS: HCV+ persons with SARS‐CoV‐2 infection are more likely to be admitted to a hospital. The hospitalization rate also increased with higher FIB‐4 score. However, admission to an ICU and mortality are not different between those with and without HCV infection.

patients. 8, 9 Conversely, patients with pre-existing cirrhosis are at a higher risk of liver function deterioration and higher mortality. 10 The effect of hepatitis C virus (HCV) infection upon the severity of SARS-CoV-2 infection is not known. We recently demonstrated that persons with HCV are infrequently tested for SARS-CoV-2 infection with a positivity rate of 6.2% among those who were tested. 11 Several reports have suggested that newer antiviral agents for HCV may also be effective against SARS-CoV-2. 12, 13 However, no clinical studies have assessed the impact of HCV upon severity of SARS-CoV-2 illness, rate of hospitalization and mortality compared with an appropriately matched population without HCV infection. We sought to determine these outcomes in a population of Veterans with HCV infection and propensity score matched controls without HCV infection.

We used the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) for the current study. Creation of ERCHIVES has been described in numerous previous publications. 11, [14] [15] [16] [17] [18] [19] Data are updated annually to include Veterans with newly diagnosed 

The diagnosis of SARS-CoV-2 infection was confirmed from the VA CDW, where a standard nasopharyngeal swab is tested using RT-PCR to confirm the diagnosis. 11 If multiple tests were done on a single individual, any positive test was considered to be a positive diagnosis for SARS-CoV-2 infection, with first positive test used as the index date. Each individual could be entered into the respective study group only once. Presence of comorbidities was defined using established and published definitions based on International Classification of Diseases, 9th or 10th edition (ICD-9/10) diagnostic codes, laboratory values and/or pharmacy prescription for specific conditions. 14-19 Liver fibrosis stage was calculated using the FIB-4 score using an average of two values closest to, but be- 

Within the ERCHIVES database, we identified all Veterans with a positive HCV antibody and at least one positive HCV RNA. We excluded those with HIV or HBV coinfection at any time point. For each person with HCV and a positive SARS-CoV-2 test, we identified one propensity score matched control with at least one confirmed negative HCV antibody test or undetectable HCV RNA who remained negative during the duration of recorded follow-up. Propensity score matching was based on age, race, gender, body mass index, and presence of hypertension, diabetes, coronary artery disease, stroke or cancer, smoking status and alcohol use. We used the nearest-neighbour matching (1:1) technique with a calliper of 0.25 standard deviation.

Primary outcome measures were hospitalization and all-cause mortality. Hospitalization was treated as a binary variable and defined as any admission to an acute care facility that occurred within 14 days after a positive SARS-CoV-2 test. Hospitalization was subdivided into those who were admitted to an acute care unit with no intensive care unit (ICU) stay and those who were admitted or transferred to an ICU setting for any duration of time.

Baseline characteristics of those with and without HCV were compared using the chi-squared or student's t-test, as appropriate.

BUTT eT al.

The study was approved by the Institutional Review Board at VA Pittsburgh Healthcare System. A waiver of informed consent requirement has been granted to studies related to ERCHIVES. A larger proportion of persons with HCV+ were hospitalized (24.0% vs 18.3%; P = .002); however, those requiring ICU care was similar in both groups. Mortality was also similar in both groups (6.6% vs 6.5%; P = .9). (Table 1) .

In subgroup comparisons, there was no difference in hospitalization or ICU admission between those with and without HCV by age, race, gender or presence of comorbidities (Tables 2 and 3) .

Hospitalization rates were significantly higher among those with HCV who had more advanced liver fibrosis. Among those with a FIB-4 score of 1.45-3.25, hospitalization rates per 1000 personyears were 41.4 among HCV+ and 20.2 among HCV−, while among those with a FIB-4 score of >3.25, the rates were 9.4 and 0.6 (P < .0001). Hospitalization with ICU stay were similarly higher in those with FIB-4 score of 1.45-3.25 and >3.25 in persons with HCV (Table 3) .

There was no difference in all-cause mortality by age, gender, liver fibrosis score, number of comorbidities or treatment with remdesivir and/or systemic corticosteroids. However, the number of events in each subgroup was relatively small to make meaningful comparisons (Table 4 ).

To our knowledge, this is the first study specifically looking at the impact of HCV infection upon the risk of hospitalization and allcause mortality compared with a well-matched population without HCV infection, and to assess the impact of liver fibrosis stage upon these outcomes. Overall hospitalization was higher among persons with HCV, but admission to an ICU or all-cause mortality were not different in persons with and without HCV.

Based on earlier studies abnormal liver enzymes are present in 22%-40% of hospitalized patients with SARS-CoV-2 infection and associated with a higher rate of admission to ICU, mechanical ventilation and mortality compared with those with normal liver enzymes. 4, 9, 20, 21 Pre-existing liver disease has been reported in up to 6% of those with SARS-CoV-2 infection, although the exact nature and distribution of these has been rarely reported. Patients with SARS-CoV-2 infection who have pre-existing cirrhosis, 96% require hospital admission or a prolongation of hospital stay and infection is frequently associated with deterioration of liver function and higher mortality. 10 In about one third of the 50 patients in this study, the aetiology of cirrhosis is viral hepatitis. 10 Our study is the largest, and to our knowledge the first study to specifically determine the impact of HCV infection upon hospitalization and mortality rates. We found that a higher proportion of persons with HCV required hospitalization, but there was no difference in the proportion requiring admission or transfer to the ICU or mortality. We carefully matched the groups for age, gender, race and multiple comorbidities. It is well documented that the prevalence of several medical, psychiatric and substance use disorders is different in those with HCV compared with those without HCV 22 and comorbidities are associated with poorer outcomes in persons with SARS-CoV-2 infection. The apparent lack of difference in severity of disease (as measured by the need F I G U R E 1 Cohort construction and study flow sheet for ICU care) and mortality indicates that any possible differences in these outcomes in persons with and without HCV may be explained, at least in part, by the differential prevalence of these comorbidities.

In subgroup comparisons, the only factor associated with a higher rate of hospitalization or ICU admission in persons with HCV (compared to those without HCV) was more advanced liver fibrosis as measured by the non-invasive FIB-4 score. When comparing those with and without HCV with similar FIB-4 score, the rates of hospitalization and ICU admission were much higher in those with HCV. This indicates that any potential increased risk Overall mortality was not different between those with and without HCV. In subgroup comparisons, the number of events were generally small in the subgroup to make meaningful comparisons.

However, no large numerical differences were apparent by age, gender, liver fibrosis stage or burden of comorbidities.

Treatment for SARS-CoV-2 is a rapidly emerging field. The strengths of our study include a large national sample, which was carefully matched between the two study groups, racial and geographic diversity of the study population and availability of extensive longitudinal data. Several limitations of our study should also be noted.

This was an observational study, and while we carefully matched the groups on propensity scores, there is always a potential for residual confounding. We did not assess the impact of other interventions, including supplemental oxygen use, mechanical ventilation and other potential therapeutic agents. We also did not assess the improvement in symptomatology, oxygen requirements, functional status or other clinical manifestations of SARS-CoV-2 infection.

In conclusion, persons with HCV who develop SARS-CoV-2 infection are more likely to be admitted to a hospital compared with a wellmatched group without HCV infection. However, admission to an ICU and mortality are not different between those with and without HCV infection. In subgroup comparisons, those with HCV and advanced fibrosis are more likely to be hospitalized and admitted to the ICU, although no difference in mortality was observed between those with and without HCV and the same degree of liver fibrosis. 

All authors have no potential conflicts of interest to disclose. 

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