HEPATITIS C IN THE UNITED STATES: A THUMBNAIL SKETCH

An Evolving Natural History

Four million Americans carry hepatitis C virus (HCV), which accounts for 25,000 deaths per year. Acute HCV, unlike acute hepatitis A and B, is asymptomatic; silent, chronic infection is the most common form of infection. Vague symptoms may include fatigue, poor concentration, or right upper quadrant aching. HCV causes persistent viremia and chronic hepatitis in over 85% of acutely infected individuals.

HCV is a single-stranded RNA flavivirus similar to HIV. At least 6 known genotypes exist, each with up to 20 subtypes designated by lowercase letters (eg, genotype 1b). Genotypes 1 and 4 are prognostically distinct; they progress more aggressively, require extended therapy, and relapse more often. Since genotype 1 is significantly more common than genotypes 2 or 3 worldwide, the literature often compares genotype 1 to “non-1” (ie, genotypes 2 and 3). As in HIV, extensive antigenic variation allows HCV to elude vaccine developers. Anti-HCV seropositivity does not imply immunity; billions of new quasispecies are produced daily and permit immune escape. Unlike HIV, HCV does not integrate into the host genome, and cure is feasible. However, recent data suggest that in persons infected with HIV, HCV persists in peripheral blood monocytes (a possible latent reservoir for recurrence) after therapy. How this plays a role in relapsed HCV in persons not infected with HIV is unknown.

HCV likely causes liver injury via immune-mediated mechanisms and is affected by host immunodeficiency. Ironically, poorer immunity may be associated with less aggressive disease, and HCV acquired in infancy or childhood may be more indolent due to an underdeveloped immune system. Similarly, advanced HIV disease may be associated with less inflammatory activity in the liver; conversely, flares of hepatitis may occur as an immune reconstitution syndrome in those who begin effective antiretroviral therapy. Overall, however, HIV accelerates progression to cirrhosis, as do iron overload, steatosis, and alcohol. Superinfection with hepatitis A or acute or chronic hepatitis B may further worsen long-term prognosis. Typically, cirrhosis develops in 20% of individuals after 20-30 years of chronic infection; thereafter, hepatic decompensation often occurs within 5 years. HIV may shorten the interval to cirrhosis to 10 years or less. Hepatocellular carcinoma affects 20% of individuals with cirrhosis. The annual rate of progression to hepatocellular carcinoma after cirrhosis develops is 1-7%.

HCV is usually transmitted parenterally. Injection drug abuse with needle-sharing is the most common risk factor worldwide. Sexual transmission is only 1% in heterosexual, monogamous couples. The risk of sexual transmission is greater in male homosexual activity. HIV enhances perinatal transmission of HCV. Perinatal HCV transmission is 4% in mothers not infected with HIV versus 19% in mothers infected with HIV. Breastfeeding is not a factor.

The science of HCV-HIV co-infection is growing exponentially. HCV has had a major impact on liver-related mortality in HIV. Hepatitis-related mortality rates rose from 10% to more than 50% since 1991. These statistics reflect the effectiveness of antiretroviral therapy in reducing AIDS mortality. HCV does not accelerate the progression of HIV but may complicate antiretroviral therapy by worsening hepatotoxicity. New 2005 guidelines have been published regarding management of hepatitis-HIV co-infection.

Genotypes, Risk Factors, and Public Health

HCV genotype distribution varies geographically. Individuals with HCV in Western nations typically carry genotypes 1a, 1b, 2a, 2b, and 3a. Globally, 74% of HCV cases are genotype 1, 17% are genotype 2 or 3, and 9% are other genotypes. In the United States, genotype 1 represents 90% of HCV cases. Approximately 8% of individuals with HCV in the United States carry genotype 2 or 3; up to 2% carry genotype 4.

No standardized surveillance exists among states. The Centers for Disease Control and Prevention (CDC) National Notifiable Disease Surveillance System (NNDSS) captures acute infections, but most cases of HCV are not reported or are chronic or resolved infections. Data extrapolated from the CDC Sentinel Counties Study of Viral Hepatitis indicate that new HCV infections have declined 87% between the 1980s and 2003, reflecting successful HIV prevention efforts and the decline in injection drug use.

In the 1990s, the Third National Health and Nutrition Examination Survey (NHANES III) estimated a 1.8% (3.9 million) HCV seroprevalence in the United States, with 2.7 million individuals chronically infected. (These statistics exclude individuals who are homeless or incarcerated.) According to the findings of NHANES III, African Americans had a higher prevalence of HCV infection than other ethnic groups; future studies of different populations are forthcoming. Men were twice as likely as women to be HCV seropositive. The highest prevalence occurred in individuals aged 30-49 years.
HCV in the correctional system is attracting growing scrutiny. The exclusion of incarcerated and homeless persons in surveys underestimates HCV prevalence. Over 90% of injection drug abusers are HCV seropositive, and homelessness is associated with drug abuse, HIV infection, and HCV infection. The CDC has recommended that incarcerated persons be tested for HCV. The Bureau of Justice estimated that approximately 1.3 million incarcerated persons infected with HCV were released in 1997 (39% of total persons released). The corrections system represents a large reservoir of hepatitis and HIV (including individuals who use injection drugs, who are homeless, or who are at risk for other reasons); prevention efforts in the greater population are unlikely to succeed without targeting these individuals. However, funding for corrections healthcare varies among states, and expensive treatment for incarcerated populations may not garner high priority in state legislatures. Rapid prisoner turnover may also impede programs for long-term care.

HCV appears to be more prevalent in veterans. Approximately 7% of veterans are HCV-seropositive based on a national day of testing in 1997. Of veterans who tested positive for HCV, most were African American. The increased prevalence in the veteran population has been attributed to high rates of injection drug use during the Vietnam era, when two thirds of current veterans were on active duty.

The Economic Burden

HCV accounts for 40-60% of chronic liver disease in the United States. The CDC estimates that over $600 million is spent annually on medical treatment and loss of productivity from HCV-related liver disease. Currently, chronic HCV is the most common indication for liver transplantation in the United States. As the current cohort ages and costly treatments (including transplantation) are refined and increasingly accepted, costs may rise further. Lastly, HCV in individuals infected with HIV and in those in the correctional system may affect the socioeconomics of the epidemic in ways unforeseen.

References

Centers for Disease Control and Prevention. Hepatitis Surveillance Report No. 60. Atlanta, GA: U.S. Department of Health and Human Services, 2005. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/hep_surveillance_60.pdf.

Centers for Disease Control and Prevention. National Hepatitis C Prevention Strategy Surveillance and Research. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/plan/surveillance.htm.

Kuiken C, Yusim K, Boykin L, Richardson R. The Los Alamos HCV Sequence Database. Bioinformatics. 2005;21(3):379-84. Available at: http://hcv.lanl.gov/content/hcv-db/index.

Roselle GA, Danko LH, Kralovic SM, et al. National Hepatitis C Surveillance Day in the Veterans Health Administration of the Department of Veterans Affairs. Mil Med 2002 Sep;167(9):756-9.

Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatology 2005 Jun; 42(6): 799-805.

Sulkowski MS, Moore RD, Mehta SH, et al. Hepatitis C and progression of HIV disease. JAMA 2002 Jul 10;288(2):199-206.

Tedaldi EM, Baker RK, Moorman AC, et al. Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2003 Feb 1;36:363-7