Lesson 1. HCV Epidemiology in the United States

Definitions of HCV Incidence

The incidence of hepatitis C virus (HCV) infection is defined as the number of new infections in a specific region over a specific time period; the incidence data is typically reported out for a 1-year period, often in conjunction with cumulative and comparative multiyear data (Figure 1). The Centers for Disease Control and Prevention (CDC) defines the incidence of HCV in the United States (or in each state) as the number of acute HCV cases that occur per year, which is the closest proxy of actual new infections. The incidence rate is the number of cases per total population (typically defined as number of cases per 100,000 persons).

Method of Estimating HCV Incidence

Most individuals with acute HCV infection do not have a clinically-evident illness and most do not seek medical care. In addition, many cases of diagnosed acute hepatitis C are not reported. Thus, determining the true incidence of new HCV infections per year based on the number of reported cases requires highly complex epidemiology modeling techniques.[1] For each new acute HCV case that is reported in the United States, the CDC estimates there are approximately 13.9 actual new acute HCV cases (reported and unreported) that have occurred.[1,2] This high ratio (total estimated cases to actual reported cases) is primarily a result of the large proportion of persons with acute HCV who have asymptomatic or minimally symptomatic infection and do not seek medical care, or have undiagnosed infection (Figure 2); the passive HCV reporting system likely also contributes to the low number of reported acute HCV cases. The CDC provides several numbers related to the incidence of hepatitis C in the United States, including number of reported acute cases, estimated number of acute clinical cases, estimated number of new infections, and rates per 100,000 persons at the state and national level.[2]

HCV Incidence Data

The CDC HCV surveillance data from 1982 to 2019 shows a peak in the estimated number of acute HCV cases in 1989, a steady decline from 1990 to 2005, a relative leveling off between 2006 and 2010, and then an increase from 2010 to 2019 (Figure 3).[2] In 2019, a total of 4,136 new cases of acute hepatitis C were reported to the CDC from 44 states; based on this number, the CDC estimated a total of 57,500 new acute cases of HCV in 2019.[2] From 2010 to 2019, the number of estimated annual acute HCV infections increased by 387% (Figure 4).[2] This steady and significant increase in new HCV infections from 2010 to 2019 is attributed primarily to the opioid epidemic, and associated injection drug use, particularly among young adults.[3,4,5,6] The following summarizes CDC HCV surveillance data in 2019 based on specific groups and demographic factors.[2]

• Gender: The number of reported cases of acute HCV infections in 2019 was higher in males (2,471) than in females (1,653), with males accounting for 60% of the acute HCV infections in 2019 (Figure 5).[2] 
• Age Group: For 2019, the reported number and rate of acute HCV infections was highest among persons aged 30-39 years followed by those 20-29 years of age; the lowest number and rate was among those 0-19 years of age (Figure 6).[2] 
• Race/Ethnicity: In 2019, the highest number of reported cases of acute HCV by race/ethnicity occurred in White persons, followed by Hispanic and Black persons (Figure 7).[2] Among all reported acute cases in 2019, persons of White race comprised 65% (2,683 of 4,136) of the cases.[2] The highest rate for acute HCV cases was in American Indian/Alaska Native persons, followed by White persons (Figure 8).[2] The trend from 2003 to 2019 shows a dramatic increase in the rate of reported acute HCV among American Indian/Alaska Native individuals during the years 2010 through 2019, as well as a steady increase in White persons during this time (Figure 9).[2]
• State: In the United States for the year 2019, the 5 states with the most number of reported cases of acute HCV were (in descending order): Florida (616), Indiana (325), New York (306), Ohio (281), and Pennsylvania (210).[2] Together, these 5 states comprised approximately 42% (1,738 of 4,136) of the total reported number of acute cases in the United States. In 2019, the 5 states with the highest rate (per 100,000 persons) of reported cases of acute HCV were (in descending order): Indiana, West Virginia, Utah, South Dakota, and Maine.[2]

Importance of HCV Incidence Data

The United States HCV incidence data provide important information for monitoring trends in transmission patterns, developing hepatitis C prevention strategies, monitoring the effectiveness of any implemented plans, and identifying focal outbreaks or regional patterns of infection. In addition, valuable information emerges when data is categorized by age group, gender, race/ethnicity, and risk factor for acquiring hepatitis C virus; these data may inform major prevention strategies.

Definition of HCV Prevalence

The HCV prevalence is defined as the number (or percent) of persons in the total population living with HCV (Figure 10). Most often, the HCV prevalence specifically refers to persons with active (HCV RNA-positive) HCV infection. The HCV prevalence in the United States is dynamic and is impacted by five factors: (1) number of new HCV infections, (2) number of persons who experience spontaneous cure of HCV, (3) number of treatment cures, (4) number of deaths, and (5) number of persons cured who become reinfected (Figure 11). Less frequently, the HCV prevalence data is given for all individuals who have ever been infected with HCV, which includes those with active HCV, persons who spontaneously resolved HCV, and those with HCV treatment-related cure. The prevalence rate of chronic hepatitis C is the number of persons living with HCV per population (typically defined as number of persons per 100,000 population).

HCV Prevalence Estimates

In the United States, HCV infection is the most common bloodborne infection. The best estimates of HCV prevalence derive from analysis of serum specimens taken from participants in the National Health and Nutrition Examination Survey (NHANES) (Figure 12).[7,8,9,10,11] The NHANES surveys require some adjustments since they do not sample certain populations, such as persons who are incarcerated, homeless individuals, nursing home residents, persons on active military duty, and immigrants. The most recent estimate of HCV prevalence in the United States was generated from analysis of 2013 to 2016 NHANES survey data.[11] In this time period, there were an estimated 4.1 million persons living in the United States who were HCV antibody-positive and 2.4 million persons who were HCV RNA positive (1% prevalence among adults).[11] When compared with earlier NHANES studies, the number of persons with a positive HCV antibody has remained relatively stable, whereas the number of HCV RNA-positive persons has decreased significantly from the estimated 3.2 million HCV RNA-positive persons in the 1999 to 2002 time period.[8,11] The declining HCV RNA-positive prevalence likely has resulted from a significant number of persons obtaining cure of chronic HCV infection with direct-acting antiviral therapy.

• Sex: In the United States, the estimated HCV prevalence for adult males is 1.31%, which is 2.3-fold higher than the 0.57% prevalence in adult females; this corresponds with a male to female HCV prevalence ratio of 2.3.[12]
• Birth Cohort: Age data for HCV prevalence has been typically analyzed and reported as birth cohort prevalence. Recent analysis of birth cohort HCV prevalence estimates in the United States showed the highest rates in persons born during 1945-1965 (1.63%), followed by persons born after 1965 (0.51%), and lowest in persons born prior to 1945 (0.21%) These data are consistent with earlier published data that also show highest HCV prevalence among persons born during 1945 to 1965 (Figure 13).[9,13] The relatively high prevalence of HCV infection among persons born between 1945 and 1965 corresponds with the high HCV incidence (new infections) that occurred among young adults using or experimenting with injection drugs in the 1970s and 1980s.[2] In recent years, the proportion of cases involving persons born after 1965 has steadily increased.
• Race/Ethnicity: In the United States, during the years 1999-2016, the highest HCV prevalence, based on race/ethnicity was among Black persons, followed by White persons (Figure 14).[12]
• State and Region: In the United States, 9 states each have more than 65,000 persons living with HCV; these states are California (318,900), Texas (202,500), Florida (151,000), New York (116,000), Pennsylvania (93,900), Ohio (89,600), Michigan (69,100), Tennessee (69,100), and North Carolina (66,400).[12] Five of these states (New York, Pennsylvania, Ohio, Tennessee, and North Carolina) are in the Appalachian region.[12] Together, these 9 states account for an estimated 52% of all persons living with HCV nationally.[12]

Newly Reported Chronic Hepatitis C Cases

In 2019, the CDC reported 137,713 persons in the United States with a new diagnosis of chronic HCV.[2] Cases were clustered in a biphasic age distribution, with a primary peak in persons aged 20-39 years (peak: 29 years) and a second apex among persons aged 55-70 years (peak: 59 years) (Figure 15).[2] Among the newly reported chronic HCV cases, 64% were male and 36% female.[2]

Awareness of HCV Infection Status

Using the most recent NHANES data, investigators estimated only 55.6% of persons infected with HCV in the United States were aware of their HCV infection status.[14] Awareness of infection status was lower in persons who were foreign-born and in persons with income below the poverty level.[14] These most recent NHANES data do not show a major improvement from a prior analysis of NHANES data (from 2001-2008) that reported 50% of persons infected with HCV were aware of their HCV infection status.[15] Awareness of HCV status may be higher among persons engaged in the private health care sector—a study involving persons with access to medical care in four private health care organizations during the years 2006 to 2008 showed an estimated 57% were aware of their HCV infection.[16]

HCV Genotype

In the United States, approximately 75% of chronic HCV infections are caused by hepatitis C genotype 1 (subtypes 1a or 1b), 15 to 20% by genotype 2 or 3 and less than 5% by genotypes 4, 5, or 6.[17,18,19] Among the genotype 1 infections, genotype 1a is more common than 1b.[19]

The CDC reports for HCV-related deaths in the United States are based on death certificate data and likely underestimate the true number of HCV-related deaths.[20] During the years 2010 to 2018, the annual deaths attributed to HCV in the United States peaked in 2014 and 2015, followed by significant subsequent declines from 2016 through 2019 (Figure 16).[2]  In 2019, approximately 72% of the deaths attributed to HCV occurred in males versus 28% in females (Figure 17).[2] The total number of HCV-related deaths was highest in White persons (Figure 18), but the HCV-related death rate was highest in American Indian/Alaska Native persons (Figure 19).[2]

Overview of Risk Factors for HCV Acquisition

Investigators and public health officials have identified multiple risk factors for acquiring HCV in the United States: injection drug use, history of receiving a blood product transfusion prior to July 1992, receipt of a solid organ transplantation, hemophilia with receipt of factor concentrates made before 1987, male-to-male sex, body tattoos, and intranasal cocaine use.[17,21,22,23] Among these, injection drug use is the most common and important risk factor for acquiring HCV in the United States. Several studies have indicated that approximately 45% of persons with HCV infection do not report an exposure. Many of these patients, after undergoing careful questioning, eventually identified injection drug use as a risk factor. In the 1970s and 1980s, receipt of HCV-infected blood products or organs accounted for nearly 50% of new cases of HCV, but after the discovery of HCV as the cause of non-A, non-B hepatitis in 1989 and introduction of blood screening tests in the early 1990s, the proportion of new HCV cases caused by contaminated blood or organs dramatically declined.[7,22,24,25] Persons in different ethnic groups may have relatively different routes of acquiring HCV.

Injection Drug Use

Injection drug use remains the most common risk factor for acquiring HCV in the United States, accounting for more than 60% of all cases of HCV.[26] Approximately 20 to 30% of persons who inject drugs become infected with HCV within the first 2 years of starting to inject drugs and 50% within 5 years.[27] Transmission risk is greatest with “direct sharing” of needles and syringes, but may also occur indirectly via sharing of injection paraphernalia, such as water, cookers, and cotton filters.[28,29,30] The incidence of HCV in persons who inject drugs markedly declined from early 1992-2002, likely due to increased availability of needle exchange programs that arose in response to the HIV epidemic.[29,31] Since about 2002, however, multiple reports have documented a surge in HCV infections in the United States among young persons who inject drugs.[3,4,5,32] This surge in HCV infections in the United States is intricately connected with the ongoing opioid epidemic and its associated injection drug use.[3,5,6] These reports identified a new cohort of persons diagnosed with HCV who inject drugs and have the following characteristics: age younger than 30 years, White race, residence in nonurban areas, and use of oral prescription opiates prior to using heroin.[5,6] Regions of the United States east of the Mississippi River have been most heavily impacted, with a particularly high intensity of new HCV cases in the central Appalachian region.[3,5] 

Noninjection Drug Use

The role of noninjection drug use, such as snorting crack cocaine, powder cocaine, methamphetamines, or heroin, as a risk factor for acquiring hepatitis C remains controversial.[33] The risk of acquiring HCV is plausible with use of pipes that may cause burns in the oral mucosa (with possible open mouth sores) or use of straws or tubing that causes erosion of nasal membranes (with bleeding in the nasal passage). Sharing these blood-contaminated devices could then lead to HCV transmission. The prevalence of HCV in people who use noninjection drugs ranges from 2.3 to 35.3%. It is possible that use of noninjection drugs is a surrogate for other risk activities associated with HCV acquisition.

Sexual Exposure

The risk of acquiring HCV through sexual contact with a person who has HCV infection remains highly controversial. Overall, sexual transmission has accounted for up to 15% of cases of HCV in the United States, but very close interrogation revealed that most cases of sexual transmission also involved injection drug use as a risk factor. Multiple studies involving monogamous heterosexual couples have shown a rate of HCV transmission less than 1% per year.[34,35,36,37] In a study involving 500 anti-HCV-positive, HIV-negative subjects and their long-term monogamous heterosexual partners, investigators reported transmission of HCV by sex at a rate of 0.07% per year among the couples, which translates to approximately 1 per 190,000 sexual contacts.[38] In recent years, multiple reports have identified cases of sexual transmission among men who have sex with men (MSM), particularly men with HIV who have sex with other men.[39,40,41,42] Specific factors identified with HCV transmission among MSM include coinfection with HIV, use of recreational drugs during sex, and certain sex practices that result in rectal bleeding or damage to the rectal mucosa, including fisting and use of shared sex toys.[39,43]

Chronic Hemodialysis

The prevalence of HCV infection in persons receiving hemodialysis is approximately 8%, which is nearly 5-fold higher than the general United States population.[44] Several risk factors have been identified for dialysis patients acquiring HCV, including number of blood transfusions received, number of years on dialysis, mode of dialysis (hemodialysis poses greater risk than peritoneal dialysis), and the prevalence of HCV in the dialysis unit. In the United States, multiple dialysis-associated HCV outbreaks have occurred. In most cases, HCV transmission likely resulted from inadequate infection control practices, particularly in situations when patients received dialysis immediately after a patient with HCV infection received dialysis.[45,46,47,48] The CDC does not recommend using dedicated dialysis machines for patients with HCV, but recommends universal precautions and strict sterilization procedures for all dialysis machines.[49]

Receipt of Clotting Factor Concentrates

Two types of clotting factor concentrates are used in clinical practice: plasma factor concentrate and recombinant factor concentrate. Most often, these involve use of factor VIII or factor IX concentrates. In the late 1970s through the mid-1980s, most persons with hemophilia acquired HCV infection via the receipt of contaminated plasma clotting factor concentrates.[50,51,52] In 1985, several companies introduced virus inactivation procedures for hemophilia blood products and by 1987 these procedures were uniformly used, virtually eliminating the risk of transmission of HCV via clotting factor concentrates. Use of recombinant factor concentrate also provides an option for providing factor concentrate with no risk of viral contamination. 

Receipt of Transfusion of Blood Products

In the 1960s, the risk of acquiring HCV from a blood transfusion was approximately 33%. The universal screening of blood and organ donors with routine use of second-generation HCV antibody tests in 1992 nearly eliminated subsequent risk of transfusion-associated HCV.[25,31,53] In the mid-1990s, the risk of acquiring HCV from a blood transfusion had declined to less than 0.3%.[25,54] The estimated risk of acquiring HCV from a blood transfusion decreased further following the introduction, in 1999, of HCV nucleic acid testing (NAT) as a supplement to HCV antibody testing of blood products.[54,55] Blood banks in the United States now use a combination of the third-generation enzyme-linked immunosorbent assay (ELISA) and NAT screening of mini-pool testing (16 samples). The current estimated risk of acquiring HCV from a transfusion in the United States is approximately 1 in 2 million.

Receipt of Immune Globulin

Scattered cases and outbreaks of HCV transmission via gamma globulin have occurred in the United States and in Europe.[56,57,58] In 1993 and 1994, a major outbreak of HCV transmission in the United States occurred following patient receipt of HCV-contaminated lots of intravenous immune globulin, with a total of 23 persons acquiring HCV.[56] Advances in virus inactivation procedures have nearly eliminated any risk of HCV transmission with immune globulin, and the manufacturers of intravenous immune globulin use vigorous viral inactivation and removal procedures. No cases of HCV transmission have been documented with administration of intramuscular immune globulin. All immune globulin products undergo solvent detergent.

Organ and Tissue Transplantation

Rare cases of inadvertent HCV transmission via organ or tissue transplantation have occurred in the United States.[59,60] Most cases of transmission have involved HCV antibody-negative, HCV RNA-positive donors.[59,60] Among transplant recipients who receive HCV-infected organs or tissues, the risk of developing chronic HCV infection is high. With the advent of more accurate testing methods for donors, the risk of HCV transmission in this setting has markedly declined. In 2013, the U.S. Public Health Service drafted updated guidelines for prevention of HCV transmission through organ transplantation and these guidelines recommend HCV RNA testing (NAT) of all organ and tissue donors.[61]

Perinatal

In the United States, due to the opioid epidemic, there has been a significant increase in HCV infection in recent years among women of childbearing age; this trend has raised concerns for a potentially significant increase in perinatal HCV infections.[62,63] Among pregnant women with chronic HCV infection, approximately 6% will transmit HCV to their child.[64,65,66] Nearly all cases of perinatal HCV transmission have involved mothers who had detectable HCV RNA in plasma during pregnancy. Women coinfected with HIV and HCV have an approximately twofold higher risk of perinatal HCV transmission when compared with women who have HCV monoinfection.[64] The risk of HCV transmission via breastfeeding appears to be negligible.[64,65,66]

Household Contact

Acquiring HCV via nonsexual household contact with a person infected with HCV can occur, but the number of documented cases is extremely low.[67,68] Transmission in this setting would most likely involve sharing a razor or toothbrush, since this process could involve transmission via a blood-tainted device.

Tattoos and Piercings

In the United States, the risk of acquiring HCV from a licensed, regulated professional tattoo or piercing center is extremely low.[69] Tattoos performed in unregulated and unlicensed tattoo centers, such as with tattoos applied by friends or in prison, increases the risk for HCV acquisition.[69,70]

CDC Hepatitis C Case Definitions

The CDC has established case definitions and reporting criteria for acute and for past (resolved) or present (chronic) hepatitis C infection.

Acute Hepatitis C—2020 Case Definition

The CDC 2020 Case Definition for Acute Hepatitis C infection includes clinical and laboratory criteria (Figure 20), along with a case classification as probable or confirmed.[71] Of note, a patient can have a confirmed case of acute hepatitis C based on laboratory data alone (a hepatitis test conversion documented by a negative HCV antibody, HCV antigen, or NAT laboratory test result, followed within 12 months by a positive result with any of these tests). Symptomatic cases often go unreported and for multiple reasons, including many persons with symptomatic acute HCV do not seek medical care, the diagnosis may be missed, and medical providers may fail to report diagnosed cases. It is important not to report cases that have already been reported. A more detailed discussion of the Acute Hepatitis C 2020 Case Definition is included in the lesson Diagnosis of Acute HCV Infection.

Chronic Hepatitis C Virus Infection—2020 Case Definition

The CDC 2020 Case Definition for Chronic Hepatitis C includes clinical and laboratory criteria (Figure 21), as well as a case definition.[72] These cases pertain to persons with current (active) hepatitis C infection and do not represent persons who spontaneously cleared hepatitis C infection. Also, it is important not to report cases that have already been reported.

Perinatal Infection Hepatitis C Infection—2018 Case Definition

The CDC 2018 Case Definition for Hepatitis C, Perinatal Infection includes clinical criteria, laboratory criteria for diagnosis, criteria to distinguish a new case from an existing case, and a case definition.[73] A confirmed case definition requires the following:

• Infant who has a positive test for HCV RNA nucleic acid amplification test (NAAT), HCV antigen, or detectable HCV genotype at ≥2 months and ≤36 months of age and is not known to have been exposed to HCV via a mechanism other than perinatal.

Reporting Criteria

Persons identified with acute hepatitis C should undergo an interview to determine an identifiable risk factor in the 2-week to 6-month time frame that preceded the onset of their illness. Similarly, the individual with past (resolved) or present (chronic) hepatitis C infection should be interviewed to determine lifetime risk factors for hepatitis C. The Viral Hepatitis Case Report form should be filled out for persons identified with either acute hepatitis C infection or past/present hepatitis C. Cases of hepatitis C should be reported to a health department, which in turn submits reporting data to the CDC via the Nationally Notifiable Diseases Surveillance System (NNDSS).

• The estimated number of annual acute HCV infections in the United States increased significantly from 11,800 in 2010 to 57,500 in 2019.
• The recent increases in new HCV infections have primarily resulted from the ongoing opioid epidemic and the associated injection drug use.
• From 2013 through 2019, the highest number and rates of new HCV infections have occurred in persons 20 through 39 years of age.
• In 2019, the highest number of new HCV infections occurred among White persons, but the highest rate was among American Indian/Alaska Native persons.
• Based on CDC estimates, 2.4 million persons are living with active HCV infection, corresponding to a 1.0% HCV prevalence among the adult population in the United States.
• The HCV prevalence is dynamic and impacted by the number of new HCV infections, the number of persons that spontaneously resolve their infection, the number of treatment cures, the number of deaths, and the number of cured persons who become reinfected.
• Approximately 45% of persons with HCV infection are unaware of their HCV status.
• Injection drug use is the most common risk factor for HCV acquisition; sexual transmission of HCV can occur, but this most often involves MSM; the risk among MSM is substantially higher in those with HIV infection.
• The number of annual deaths attributed to HCV has declined significantly in recent years, falling from 19,613 in 2014 to 14,242 in 2019, with the majority of the deaths involving males.
• The CDC has established a clear definition of acute, chronic, and perinatal HCV infection for reporting purposes as well as reporting guidelines.