Congnn Zhng ,Jihui Lu ,Yjing Zhng ,Pengyun He ,Jinyu Xi ,* ,Mingxing Hung
a Department of Infectious Diseases,The Fifth Affiliated Hospital of Sun Yat-sen University,Zhuhai,Guangdong,China
b Intensive Care Unit,Jiangmen Central Hospital,Jiangmen,Guangdong,China
c Sino-French Institute of Nuclear Engineering and Technology,Sun Yat-sen University,Guangzhou,Guangdong,China
d Office of the Dean,The Third People"s Hospital of Zhuhai,Zhuhai,Guangdong,China
Keywords:Hepatitis C virus (HCV)Epidemiology Risk factors United States HCV-RNA
ABSTRACT Background and aim: Hepatitis C virus (HCV) infection is one of the major global health challenges,leading to a significant increase in rates of hepatic fibrosis,cirrhosis and hepatocellular carcinoma.A comprehensive nationwide survey of trends in prevalence and associated factors could facilitate preventive behavioral interventions.Herein,we sought to determine prevalence,diagnosis,treatment,and risk factors for HCV infection in the general United States (US) population.Methods: This was a secondary analysis of the publicly available data from the US National Health and Nutrition Examination Survey (NHANES).The prevalence of HCV-RNA-positive (HCV-RNA+) was weighted using patient serum sample data collected from 1999 to 2018.A propensity score matching model was used due to the imbalance in the number of HCV-RNA+and HCV-RNA-negative(HCV-RNA-)patients.Matched variables included gender,age,educational level,marital status,language,household size,alcohol consumption,smoking,number of family members and family income to poverty ratio.Results: The weighted prevalence of HCV-RNA+was 1.11% (95% confidence interval (CI): 1.02-1.20),1.58%(95%CI:1.42-1.74)for men and 0.67%(95%CI:0.57-0.77)for women aged 20 years or older in the US from 1999 to 2018.The weighted prevalence of HCV-RNA+increased from 0.87% (95% CI: 0.62-1.12)in 2013-2014,0.95% (95% CI: 0.68-1.22) in 2015-2016 to 1.00% (95% CI: 0.72-1.28) in 2017-2018,respectively.In propensity-matched analysis,patients with HCV-RNA+were more likely to be non-Hispanic black,and have had drug use and blood transfusions.Meanwhile,the weighted diagnostic and treatment rates were 56.27% (95% CI: 50.90-61.64) and 35.40% (95% CI: 27.64-43.16) from 1999 to 2018,respectively.Conclusions: Active HCV infection rate increased between 2013 and 2018,varied by demographic and risk variables.In the direct-acting antiviral era,affordable treatment and universal screening have the potential to improve overall national health.
Hepatitis C virus (HCV) infection is the most common chronic hepatitis virus.1After an HCV acute infection,50-80% of patients develop chronic hepatitis C,which can lead to liver fibrosis,cirrhosis and hepatocellular carcinoma.2Symptoms in patients infected with HCV may manifest as anorexia,malaise,fatigue and jaundice after incubation,and approximately 85% of them are asymptomatic with the virus silently destroying the liver continuously.3Although >95% of patients infected with HCV are treated with direct-acting antiviral drugs (DAA) (being cured is defined as undetectable HCV-RNA levels in 24 or 12 weeks after completing the treatment,also known as a sustained viral response(SVR)).4The global proportion of deaths caused by hepatitis C without hepatocellular carcinoma increased from 33.80%in 1990 to 48.40% in 2015.Meanwhile,the number of deaths due to liver cancer and cirrhosis caused by hepatitis C increased from 0.90 million in 1990 to 1.45 million in 2013.5
An estimated 1.60%(95%CI:1.30-2.10)of global HCV infections are based on HCV antibody positive,equivalent to 1.15 million individuals.However,patients with HCV antibody positive are not sure if they have previous or current infection.The global prevalence of HCV-RNA+is relatively low,estimated at 1.00% (95% CI:0.80-1.14) or 0.71 million (95% CI: 0.62-0.79).6
In the early 2000s,several articles reported a reduction in the prevalence and incidence of HCV.7-11Since then,there have been few publications on HCV epidemiology in the general population.There is a dearth of literature on long-term prevalence estimates and nationally representative characteristics of HCV.The scarcity of updated articles may reduce attention to hidden hazards of HCV transmission.In this study,we assess trends in prevalence,diagnosis,treatment and risk factors for HCV infection among the US general adult population.
2.1.Study population from NHANES
The data file was collected from the National Health and Nutrition Examination Survey (NHANES),a complex,stratified,multistage probability cluster sampling design that randomly selected individuals from the non-institutionalized US population each year.We not only estimated the prevalence,diagnosis and treatment rates,but also identified the risk factors and serological changes associated with HCV infection.The age range in our study was hindered by the information in the NHANES drug use questionnaire.From 1999 to 2018,9930 and 24,504 patients were removed due to incomplete data and aged ≤19 years.Finally,48,975 patients were statistically analyzed,among which 625 were HCV-RNA+(Fig.1).
Fig.1.Cohort construction flow chart. Flow diagram outlining the process of inclusion in the study.We included participants aged 20 years or older eligible for the presence of HCV-RNA+.Abbreviations: HCV,hepatitis C virus;NHANES,National Health and Nutrition Examination Survey.
2.2.Study variables and definition
To estimate the prevalence of HCV-RNA+,a sample of people was selected with laboratory data sufficient.Each sample was assigned a certain coefficient (weighted coefficient),the inverse ratio of the adjusted probability,to reflect the age,gender,urbanrural distribution,sampling design and examination component participation in the National Center for Health Statistics (NCHS)-provided Mobile Examination Center.
The total family income divided by the poverty threshold was called family poverty income ratio (PIR).PIR was calculated based on the US Department of Health and Human Services" poverty index ratio that varied family size and geographic location specific to NHANES survey year.Economic status was measured by the PIR,which below 1 indicated that the income for the respective family or unrelated individual was below the official definition of poverty,while a ratio of 1 or more indicated income above the poverty level.
In the program used between 1999 and 2012,participants who tested positive for antibody screening underwent antibody confirmation test prior to RNA testing.In 2013,NHANES revised its protocols for HCV testing.During 2013-2016,NHANES participants were first tested for HCV antibody with a screening test;those with a reactive antibody screening test then received an HCV-RNA test and only RNA-negative participants underwent an antibody confirmation test using a third-generation line immunoassay.
In this study,we presented twenty-year trends in HCVRNA+prevalence from 1999 through 2018 and examined risk factor data from 2013 to 2018 among adults aged 20 years old and above.
2.3.Statistical analysis
Kolmogorov-Smirnov test was used to examine the normality of continuous variables.Continuous variables were expressed as the mean ± standard deviation (SD) and median (25thand 75thpercentiles) appropriately.The differences between quantitative variables that were non-normally distributed were analyzed with the Man-WhitneyUtest,while normally distributed variables were analyzed by Student"st-test.Categorical variables were statistically described as numbers(percentages).The Chi-squared test and Fisher"s exact probability test were used to evaluate differences between qualitative variables.Multivariate logistic regression was used to explore the independent factors of HCV-RNA+.Propensity score matching(PSM)was used to match the participants with and without HCV-RNA+with a ratio of 1:2 and a caliper of 0.5.PSM was used to match subjects for their age,gender,the ratio of family income to poverty,educational level,language,marital status,number of people in the household,number of people in the family,alcohol consumption,ever smoked at least 100 cigarettes in life,high blood pressure and other factors.Statistical analysis was performed using the SPSS statistical software package (version 26.0;IBM Corporation,Armonk,NY,US).Statistical significance was defined asP<0.05.
3.1.Prevalence,diagnosis and treatment
The weighted prevalence of HCV-RNA+had steadily increased in the US:0.87%(95%CI:0.62-1.12%)in 2013-2014,0.95%(95%CI:0.68-1.22%) in 2015-2016 and 1.00% (95% CI: 0.72-1.28%) in 2017-2018 (Fig.2,Supplemental Table 1).The overall weighted prevalence of HCV-RNA+was 1.11% (95% CI: 1.02-1.20%) among patients aged 20 years or older (0.23 billion),with 1.58% (95% CI:1.42-1.74%)in men(0.16 billion)and 0.67%(95%CI:0.57-0.77%)in women (0.07 billion) from 1999 to 2018 (Supplemental Table 1).The weighted diagnostic and treatment rates were 56.27%(95%CI:50.90-61.64%) and 35.40% (95% CI: 27.64-43.16%) from 1999 to 2018,respectively.(Fig.2,Supplemental Table 1).
Fig.2.Weighted prevalence of HCV-RNA+by demographic characteristics in the US adults,1999-2018.Dots indicate weighted prevalence,and vertical lines indicate 95%CIs.(A) Trends in prevalence of HCV infection for all participants.(B) Trends in prevalence of HCV infection for adults by gender group.(C) Trends in prevalence of HCV infection for adults by race group.All non-blacks include Mexican American,other Hispanic,non-Hispanic white,non-Hispanic Asian and other races.(D)Trends in prevalence of HCV infection for adults by economic status group.Economic status were calculated based on the PIR that identified participants as living at or above(PIR ≥1)or below the poverty threshold(PIR<1).Abbreviations: CI,confidence interval;HCV,hepatitis C virus;PIR,poverty income ratio.
3.2.Characteristics of the participants
From 2013 to 2018,in the group of non-Hispanic black,38.10%in HCV-RNA+compared to 20.68% in HCV-RNA-(P<0.001).In the group of people ever used cocaine,heroin and methamphetamine,55.95% in HCV-RNA+compared to 12.04% in HCV-RNA-(P<0.001).In the group had received blood transfusion,24.40%in HCV-RNA+compared to 11.49% in HCV-RNA-(P<0.001).Other characteristics associated with HCV-RNA+included older age,below poverty,more males,lower education level,more divorces,more drinking and smoking(Supplemental Table 2).The laboratory results suggested statistical significance,including alkaline phosphatase,aspartate aminotransferase,alanine aminotransferase,albumin and cholesterol(Supplemental Table 2).
3.3.Independent risk factors for HCV infection
Multiple logistic regression was utilized to identify the risk factors for HCV-RNA+,showing that male(odd ratio(OR),1.71;95%CI: 1.16-2.51;P=0.0063),non-Hispanic black (OR,1.65;95% CI:1.15-2.37;P=0.0068),ever used cocaine/heroin/methamphetamine (OR,5.95;95% CI: 4.10-8.64;P<0.0001) and blood transfusion (OR,2.07;95% CI: 1.35-3.16;P=0.0008) were still associated with HCV-RNA+(Table 1,supplemental Table 3).
3.4.PSM analysis
In PSM analysis,136 patients with HCV-RNA+were compared to 272 patients with HCV-RNA-,indicating significant differences in race (P<0.001),drug use (P<0.001) and blood transfusion(P=0.004).Patients with HCV-RNA+were more likely to be non-Hispanic black,have had drug injections and blood transfusions.Hematologic results of aspartate aminotransferase,alanineaminotransferase and gamma-glutamyl transferase were significantly different (Table 2,Supplemental Table 4).
Table 1Univariate and multivariate analysis of HCV-RNA+.
The prevalence of HCV-RNA+was 1.11%in 1999-2018 and 0.94%in 2013-2018.The prevalence of HCV infection seemed to decline.However,the prevalence of HCV-RNA+increased from 0.87% in 2013-2014 to 1.00% in 2017-2018.While adjustment to the HCV protocol played a significant role,epidemic changes in HCV-RNA+were observed in the US during the past 6 years since 2013.
Another important findings of our study were the low diagnostic and treatment rates in those with HCV-RNA+,consistent with previous studies of low awareness among patients with HCV infection.12Multiple oral DAA regimens are of less serious harm than previous treatments,recommended for all HCV-infected persons with few exceptions and of high sustained virologic response(SVR) rates that range between 90 and 100% after their full treatment courses according to the US Food and Drug Administration(FDA).All available information indicates that about half of the persons are more likely undiagnosed with HCV and only a few participants have been prescribed antiviral therapy.13Thus,differences in the prevalence remind us that the dimensions and directions of this epidemic should be determined,which are of great significance for the prevention of HCV infection.14
We also found that in 2013-2018,the prevalence of HCV infection mainly developed in male,non-Hispanic black,drug use and blood transfusion,which were consistent with previous studies.15Compared with traditional social-demographic characteristics and potential risk factors associated with HCV infection,injection drug use and receipt of a blood transfusion remained important risk factors for HCV infection.Furthermore,our results showed that several subgroups were different from previous findings,such as aged 50 years or older,lower education level,drinking 4/5 or more drinks almost every day,smoking at least 100 cigarettes,living alone,lower ratio of family income to poverty and being single.
We defined the participants in data obtained from the NHANES.It was also noteworthy that the average serum levels of alkaline phosphatase,aspartate aminotransferase,alanine aminotransferase,albumin,cholesterol concentrations and other serological results were markedly elevated in 168 HCV-infected adults aged 20 years or older (Table 2),which indicated that both immunological mechanisms and viral damage caused by HCV were responsible for the liver injury and extra-hepatic disorders(EHDs).16,17Those with HCV-RNA-were defined as non-HCV infection and were propensity score matched with HCV-RNA+.One hundred and thirtysix cases of HCV-RNA+and 272 cases of HCV-RNA-were selected as matched cohort following a 1:2 propensity score match.Significant differences were observed in the overall standard biochemistry analysis such as aspartate aminotransferase,alanine aminotransferase and gamma-glutamyl transferase.We hypothesize that these elevated serum biochemical parameters may be relevant to the discovery of HCV.Previous studies have pointed out that these serological results are of statistical and practical significance,but may not positively correlated to liver tissue damage or significant fibrosis until they progressed to severe liver cirrhosis or cancer.18The controversy about screening strategies in patients with HCV and normal liver function tests remains to be explored.A recent article suggests that the universal screening of the national population might be the most population-wide effectively measured than birth-cohort screening or traditional risk-factorguided screening.19
Table 2Differences in demographic and laboratory data between the HCV-RNA+and HCV-RNA-participants.
Several potential weaknesses existed in this study.Nearly 0.26 million people may be excluded from the NHANES sampling with high prevalence of HCV infection,such as incarcerated populations,homeless populations,refugees,prisoners or other marginalizedresidents.20Meanwhile,the sample from NHANES selected to represent the full national population could also have sampling errors as only a small number of the entire US population were analyzed.Likewise,some high-risk behaviors were based on selfreporting and could be prone to various distortions such as the social desirability stigma and patient"s poor recall of past risktaking behaviors.
We observed an upward trend in HCV prevalence in the US,but low rates of diagnosis and treatment.The prevalence of HCV was higher,particularly among male,non-Hispanic black,patients living below poverty and those with a history of drug use or blood transfusions.More effective administration must be coupled with the use of DAA to reduce barriers to access to HCV services and limit dissemination.
Authors’ contributions
C.Zhang,J.Lu,Y.Zhang,and P.He assisted with data acquisition,analyses and manuscript preparation.C.Zhang,M.Huang and J.Xia drafted and critically revised the manuscript.M.Huang provided input regarding methodology.J.Xia provided direct supervision and guidance.All authors agree to the final version of this manuscript.
Declaration of competing interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by grants from Natural Science Foundation of Guangdong Province (2021A1515010458) of China.
Appendix A.Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2022.12.003.
