Adverse Outcomes in Alaska Natives Who Recovered From or Have Chronic Hepatitis C Infection

doi:10.1053/j.gastro.2009.10.056

Gastroenterology

Volume 138, Issue 3, March 2010, Pages 922-931.e1

https://doi.org/10.1053/j.gastro.2009.10.056 Get rights and content

Background & Aims

The factors associated with adverse outcome from hepatitis C virus (HCV) infection are incompletely understood. To determine the incidence and risk factors associated with the development of end-stage liver disease (ESLD) and liver-related death (LRD), we conducted a retrospective/prospective population-based study in a cohort of Alaska Native persons chronically infected with HCV from 1994 to 2005.

Methods

We followed 960 persons prospectively for an average of 7.2 years and retrospectively for 12.1 years with data from medical records and serum samples. We compared data from subjects that were chronically infected with those who recovered from HCV infection, stratified by alcohol use. Survival models were used to examine factors associated with ESLD and LRD in chronically infected patients.

Results

During prospective follow-up, 80 (8.8%) and 47 (5.2%) patients developed ESLD and LRD, respectively. In examining incidence per 100 person-years, no difference was found among heavy alcohol users in the incidence of LRD (2.28 versus 3.50; P = .34) or ESLD (3.21 versus 5.69; P = .13) in persons with chronic HCV compared with those recovered from HCV infection. In subjects that consumed <50 g alcohol/d, the incidences of LRD were 0.77 and 0.09 (P = .01) and of ESLD were 1.58 versus 0.36 (P = .002), respectively, in subjects with chronic infection versus those that recovered. Multivariate analysis showed that older age, heavy alcohol use, and HCV genotype 3 were associated with ESLD.

Conclusions

A history of heavy alcohol use is associated with the highest incidence of LRD and ESLD, regardless of whether patients are chronically infected or recover from HCV infection.

Section snippets

Recruitment and Follow-up

Since 1992, HCV serologic testing has been available to all AN persons at the Alaska Native Medical Center in Anchorage. Alaska has a population of 660,000 persons of whom approximately 130,000 (20%) are AN persons, who are eligible to receive health care through the AN health system, a statewide tribally operated health delivery system consisting of rural health clinics, regional hospitals, and a tertiary medical center, the Alaska Native Medical Center. The characteristics of the population

Results

Among 1590 anti–HCV-positive persons, 960 (60%) consented for long-term follow-up of HCV outcomes (Figure 1). No significant differences were found in age, sex, or residence in persons who consented and persons who did not consent. These 960 persons were followed prospectively for a mean of 7.2 years and retrospectively for a mean of 12.1 years. The characteristics of the entire cohort and persons who had chronic HCV infection compared with persons who recovered are shown in Table 1. For the

Discussion

With the use of both prospective and retrospective data from a long-term, population-based cohort of AN persons with HCV infection, our study showed that alcohol consumption >50 g/d at the time of enrollment was the greatest predictor of adverse liver outcome, significantly higher than HCV infection alone. A history of heavy alcohol use was associated with the highest incidence of LRD and ESLD, regardless of whether persons were chronically infected or had recovered from HCV. Our survival

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Cited by (37)

The contribution of alcohol use disorder to decompensated cirrhosis among people with hepatitis C: An international study
2018, Journal of Hepatology
Citation Excerpt :
Defining an individual’s risk of liver disease progression is often difficult, due to the non-linear nature of disease progression, and fluctuating lifestyle co-factors.31 However, heavy alcohol use (>50 g/d) has been shown to be associated with end-stage liver disease diagnosis and liver-related mortality, independent of chronic HCV infection or viral eradication by therapy.32 Given its significant impact, where needed, effects of alcohol use disorder should be mitigated to lower the risk of liver disease progression among people with HCV infection.
The advent of direct-acting antivirals (DAAs) has led to ambitious targets for hepatitis C virus (HCV) elimination. However, in the context of alcohol use disorder the ability of DAAs to achieve these targets may be compromised. The aim of this study was to evaluate the contribution of alcohol use disorder to HCV-related decompensated cirrhosis in three settings.
HCV notifications from British Columbia, Canada; New South Wales, Australia, and Scotland (1995–2011/2012/2013, respectively) were linked to hospital admissions (2001–2012/2013/2014, respectively). Alcohol use disorder was defined as non-liver-related hospitalisation due to alcohol use. Age-standardised decompensated cirrhosis incidence rates were plotted, associated factors were assessed using Cox regression, and alcohol use disorder-associated population attributable fractions (PAFs) were computed.
Among 58,487, 84,529, and 31,924 people with HCV in British Columbia, New South Wales, and Scotland, 2,689 (4.6%), 3,169 (3.7%), and 1,375 (4.3%) had a decompensated cirrhosis diagnosis, and 28%, 32%, and 50% of those with decompensated cirrhosis had an alcohol use disorder, respectively. Age-standardised decompensated cirrhosis incidence rates were considerably higher in people with alcohol use disorder in New South Wales and Scotland. Decompensated cirrhosis was independently associated with alcohol use disorder in British Columbia (aHR 1.92; 95% CI 1.76–2.10), New South Wales (aHR 3.68; 95% CI 3.38–4.00) and Scotland (aHR 3.88; 95% CI 3.42–4.40). The PAFs of decompensated cirrhosis-related to alcohol use disorder were 13%, 25%, and 40% in British Columbia, New South Wales and Scotland, respectively.
Alcohol use disorder was a major contributor to HCV liver disease burden in all settings, more distinctly in Scotland. The extent to which alcohol use would compromise the individual and population-level benefits of DAA therapy needs to be closely monitored. Countries, where appropriate, must develop strategies combining promotion of DAA treatment uptake with management of alcohol use disorders, if World Health Organization 2030 HCV mortality reduction targets are going to be achieved.
The burden of liver disease has been rising among people with hepatitis C globally. The recent introduction of highly effective medicines against hepatitis C (called direct-acting antivirals or DAAs) has brought renewed optimism to the sector. DAA scale-up could eliminate hepatitis C as a public health threat in the coming decades. However, our findings show heavy alcohol use is a major risk factor for liver disease among people with hepatitis C. If continued, heavy alcohol use could compromise the benefits of new antiviral treatments at the individual- and population-level. To tackle hepatitis C as a public health threat, where needed, DAA therapy should be combined with management of heavy alcohol use.
Prevalence and correlates of hepatitis C virus–associated inflammatory arthritis in a population-based cohort
2017, Seminars in Arthritis and Rheumatism
The objectives of this study were to determine the prevalence of hepatitis C virus–associated inflammatory arthritis, to describe its clinical and immunologic correlates, and to identify features that are characteristic of arthritis in chronic hepatitis C.
Participants with chronic hepatitis C infection enrolled in a population-based cohort study in Alaska and who had not received anti-viral treatment for hepatitis C were recruited. In a cross-sectional study, we assessed joint symptoms and signs, performed autoantibody and cytokine testing, and abstracted medical records for features of hepatitis C and arthritis.
Of the 117 enrolled participants, 8 (6.8%) had hepatitis C-associated arthritis. The participants with arthritis were younger than those without (median age: 45 vs. 52, p = 0.02). Rheumatoid factor was commonly present among patients with hepatitis C-associated arthritis. The only studied autoantibody found more commonly in patients with HCV arthritis than those without arthritis was anti-nuclear antibody (63% vs. 23%, p = 0.026). The only joint symptom significantly more common in hepatitis C arthritis was self-reported joint swelling (75% vs. 26%, p = 0.007). Features of fibromyalgia were more common and functional status was worse in those with arthritis than those without. No cytokines differed in patients with and without arthritis. There were no associations of arthritis or autoantibodies with liver-related outcomes.
In this study of a cohort of individuals with chronic HCV infection, HCV-associated arthritis was present in less than 10%. Few serologic features distinguished participants with or without arthritis, but self-reported joint swelling was more common in those with arthritis.
Infection With Hepatitis C Virus Genotype 3 Is an Independent Risk Factor for End-Stage Liver Disease, Hepatocellular Carcinoma, and Liver-Related Death
2017, Clinical Gastroenterology and Hepatology
Citation Excerpt :
All participants provided written informed consent. At the time of AK-HEPC study enrollment, study nurses conducted an extensive interview of each participant to obtain information on risk factors and demographic data that were reviewed in our previous publication.5 Information was obtained directly from the HCV registry, by chart review including International Classification of Diseases, 9th revision (ICD-9) liver-related diagnosis, and review of the State of Alaska Death Tapes from 1995 through 2012.
Few studies have examined factors associated with disease progression in hepatitis C virus (HCV) infection. We examined the association of 11 risk factors with adverse outcomes in a population-based prospective cohort observational study of Alaska Native/American Indian persons with chronic HCV infection.
We collected data from a population-based cohort study of liver-related adverse outcomes of infection in American Indian/Alaska Native persons with chronic HCV living in Alaska, recruited from 1995 through 2012. We calculated adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for end-stage liver disease (ESLD; presence of ascites, esophageal varices, hepatic encephalopathy, or coagulopathy), hepatocellular carcinoma (HCC), and liver-related death using a Cox proportional hazards model.
We enrolled 1080 participants followed up for 11,171 person-years (mean, 10.3 person-years); 66%, 19%, and 14% were infected with HCV genotypes 1, 2, and 3, respectively. On multivariate analysis, persons infected with HCV genotype 3 had a significantly increased risk of developing all 3 adverse outcomes. Their aHR for ESLD was 2.1 (95% CI, 1.5–3.0), their aHR for HCC was 3.1 (95% CI, 1.4–6.6), and their aHR for liver-related death was 2.4 (95% CI, 1.5–4.0) compared with genotype 1. Heavy alcohol use was an age-adjusted risk factor for ESLD (aHR, 2.2; 95% CI, 1.6–3.2), and liver-related death (aHR, 2.9; 95% CI, 1.8–4.6). Obesity was a risk factor for ESLD (aHR, 1.4; 95% CI, 1.0–1.9), and diabetes was a risk factor for ESLD (aHR, 1.5; 95% CI, 1.1–2.2). Male sex was a risk factor for HCC (aHR, 3.6; 95% CI, 1.6–8.2).
In a population-based cohort study of American Indian/Alaska Native persons with chronic HCV infection, we found those infected with HCV genotype 3 to be at high risk for ESLD, HCC, and liver-related death.
Association of Hepatitis C Virus With Alcohol Use Among U.S. Adults: NHANES 2003–2010
2016, American Journal of Preventive Medicine
Citation Excerpt :
Complications associated with chronic HCV infection include cirrhosis and hepatocellular carcinoma, which are projected to increase substantially within the next decade and are leading causes for liver transplantation.6–10 Alcohol use has been identified as a primary predictor in the progression of those complications.11 Excessive alcohol use among individuals chronically infected with HCV was associated with an increased risk of all-cause and liver-related mortality compared with infected people without excessive alcohol use.12
Excessive alcohol use exacerbates morbidity and mortality among hepatitis C virus (HCV)–infected people. The purpose of this study was to describe self-reported patterns of alcohol use and examine the association with HCV infection and other sociodemographic and health-related factors.
Data from 20,042 participants in the 2003–2010 National Health and Nutrition Examination Survey were analyzed in 2014. Estimates were derived for self-reported demographic characteristics, HCV-RNA (indicative of current HCV infection) status, and alcohol use at four levels: lifetime abstainers, former drinkers, non-excessive current drinkers, and excessive current drinkers.
Former drinkers and excessive current drinkers had a higher prevalence of HCV infection (2.2% and 1.5%, respectively) than never or non-excessive current drinkers (0.4% and 0.9%, respectively). HCV-infected adults were estimated to ever drink five or more drinks/day almost every day at some time during their lifetime about 3.3 times more often (43.8% vs 13.7%, p<0.001) than those who were never infected with HCV. Controlling for age, sex, race/ethnicity, education, and having a usual source of health care, HCV infection was significantly associated with excessive current drinking (adjusted prevalence ratio, 1.3; 95% CI=1.1, 1.6) and former drinking (adjusted prevalence ratio, 1.3; 95% CI=1.1, 1.6).
Chronic HCV infection is associated with both former and excessive current drinking. Public health HCV strategies should implement interventions with emphasis on alcohol abuse, which negatively impacts disease progression for HCV-infected individuals.
Excess mortality rate associated with hepatitis C virus infection: A community-based cohort study in rural Egypt
2016, Journal of Hepatology
Citation Excerpt :
In contrast to participants with chronic HCV infection, those who cleared HCV infection had a similar all-cause mortality rate compared to those never infected in this study. This differs from reports from Western countries where injecting drug use is the major mode of HCV transmission and people who cleared HCV share the same lifestyle risks (drug overdose, suicide, murder, excessive alcohol consumption, HIV co-infection) as those who became chronically infected with HCV [8,12,14]. In Denmark, all-cause mortality of people who cleared HCV was significantly higher than that of never infected, except in a subgroup of individuals aged 40–69 years without injecting drug use, alcohol abuse and other comorbidities, implying that in the absence of high-risk behaviours there is little excess mortality in people who cleared HCV infection [14].
>80% of people chronically infected with hepatitis C virus (HCV) live in resource-limited countries, yet the excess mortality associated with HCV infection in these settings is poorly documented.
Individuals were recruited from three villages in rural Egypt in 1997–2003 and their vital status was determined in 2008–2009. Mortality rates across the cohorts were compared according to HCV status: chronic HCV infection (anti-HCV antibody positive and HCV RNA positive), cleared HCV infection (anti-HCV antibody positive and HCV RNA negative) and never infected (anti-HCV antibody negative). Data related to cause of death was collected from a death registry in one village.
Among 18,111 survey participants enrolled in 1997–2003, 9.1% had chronic HCV infection, 5.5% had cleared HCV infection, and 85.4% had never been infected. After a mean time to follow-up of 8.6 years, vital status was obtained for 16,282 (89.9%) participants. When compared to those who had never been infected with HCV in the same age groups, mortality rate ratios (MRR) of males with chronic HCV infection aged <35, 35–44, and 45–54 years were 2.35 (95% CI 1.00–5.49), 2.87 (1.46–5.63), and 2.22 (1.29–3.81), respectively. No difference in mortality rate was seen in older males or in females. The all-cause mortality rate attributable to chronic HCV infection was 5.7% (95% CI: 1.0–10.1%), while liver-related mortality was 45.5% (11.3–66.4%).
Use of a highly potent new antiviral agent to treat all villagers with positive HCV RNA may reduce all-cause mortality rate by up to 5% and hepatic mortality by up to 40% in rural Egypt.
Natural history of hepatitis C
2014, Journal of Hepatology
Citation Excerpt :
The impact of ongoing alcohol use in anti-HCV positive, HCV RNA negative individuals remains important: McMahon et al. compared survival data from subjects that were chronically infected with those who recovered from HCV infection, stratified by alcohol use. No difference was discerned among heavy alcohol users in the incidence of liver related deaths or end stage liver disease in those with chronic HCV, compared with those recovered from HCV infection [16]. Treatment is indicated in patients who are deemed to develop chronic hepatitis.
There has long been evidence that hepatitis C can lead to persistent infection in a high proportion of infected individuals, and can progress to chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). The transition from acute to chronic hepatitis C is usually sub-clinical. Accurate studies of the time course for clearance of acute hepatitis C are difficult to carry out because of the silent onset of the acute disease. The likelihood of spontaneous HCV resolution is associated with several genetic factors, including IL28B inheritance and the DQB1^∗0301 allele of the major histocompatibility complex class II. Most data suggest that resolution in the acute phase without progression to chronic disease is not accompanied by significant disease, but minor histological lesions have been observed in anti-HCV positive, HCV RNA negative individuals. The risk of reinfection remains a possibility after clearance of acute hepatitis C. High rates of sexually-transmitted infection are being reported in HIV positive men who have sex with men (MSM). Chronic infection with HCV is the leading cause of end-stage liver disease, hepatocellular carcinoma (HCC) and liver related death in the Western world. The natural history of the chronic disease remains incompletely defined. It is generally a slowly progressive disease characterized by persistent hepatic inflammation, leading to the development of cirrhosis in approximately 10–20% of patients over 20–30 years of HCV infection. However, the published data indicate varying progression rates to cirrhosis. Overall, once cirrhosis has developed there is a 1–5% annual risk of HCC and a 3–6% annual risk of hepatic decompensation. Following an episode of decompensation the risk of death in the following year is between 15% and 20%. The high number of chronically infected individuals, the burden of disease, and the absence of a vaccine indicates that treatment will form part of the disease control but the impact, effectiveness and outcomes of treatment in various groups remain uncertain. Several studies and meta-analysis have concluded that eradication of HCV with antiviral therapy reduces the risk of HCC in patients with chronic hepatitis C, independent of fibrosis stage, but the risk is not eliminated.

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: Conflicts of interest The authors disclose no conflicts.

: Funding Supported by the National Institutes of Health (grant AI 48214 and R01 AI 66209) and by the Alaska Native Tribal Health Consortium and the Arctic Investigations Program, CDC.

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Clinical—Liver, Pancreas, and Biliary TractAdverse Outcomes in Alaska Natives Who Recovered From or Have Chronic Hepatitis C Infection

Background & Aims

Methods

Results

Conclusions

Section snippets

Recruitment and Follow-up

Results

Discussion

Am J Gastroenterol

Lancet

Hepatology

Hepatology

Hepatology

Gastroenterology

Lancet

Blood

The natural history of hepatitis C

Semin Liver Dis

Diagnosis, management, and treatment of hepatitis C

Hepatology

Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulinIrish Hepatology Research Group

N Engl J Med

The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse

Annals of Internal Medicine

The natural history of hepatitis C virus infection—host, viral, and environmental factors

JAMA

Clinical—Liver, Pancreas, and Biliary Tract
Adverse Outcomes in Alaska Natives Who Recovered From or Have Chronic Hepatitis C Infection