HCV is a single-stranded RNA virus (hepacivirus) with properties similar to those of flaviviruses. Seven major genotypes of HCV have been identified. In the past, HCV was responsible for over 90% of cases of posttransfusion hepatitis, yet only 4% of cases of hepatitis C were attributable to blood transfusions. Over 50% of cases are transmitted by injection drug use, and both reinfection and superinfection of HCV are common in people who actively inject drugs. Body piercing, tattoos, and hemodialysis are risk factors. The risk of sexual and maternal–neonatal transmission is low and may be greatest in a subset of patients with high circulating levels of HCV RNA. Having multiple sexual partners may increase the risk of HCV infection, and HIV coinfection, unprotected receptive anal intercourse with ejaculation, and sex while high on methamphetamine increase the risk of HCV transmission in men who have sex with men. Transmission via breastfeeding has not been documented. An outbreak of hepatitis C in patients with immune deficiencies has occurred in some recipients of intravenous immune globulin. Hospital- and outpatient facility–acquired transmission has occurred via multidose vials of saline used to flush Portacaths; through reuse of disposable syringes; through drug “diversion” and tampering with injectable opioids by an infected health care worker; through contamination of shared saline, radiopharmaceutical, and sclerosant vials; via inadequately disinfected endoscopy equipment; and between hospitalized patients on a liver unit. In the developing world, unsafe medical practices lead to a substantial number of cases of HCV infection. Covert transmission during bloody fisticuffs has even been reported, and incarceration in prison is a risk factor, with a seroprevalence of 26% in the United States and rates as high as 90% in some states. In many patients, the source of infection is unknown. Coinfection with HCV is found in at least 30% of HIV-infected persons. HIV infection leads to an increased risk of acute liver failure and more rapid progression of chronic hepatitis C to cirrhosis; in addition, HCV increases the hepatotoxicity of antiretroviral therapy. The number of cases of chronic HCV infections in the United States is reported to have decreased from 3.2 million in 2001 to 2.3 million in 2013 with a small increase to 2.4 million between 2013 and 2016, although estimates of at least 4.6 million exposed and 3.5 million currently infected have also been reported. The incidence of new cases of acute, symptomatic hepatitis C declined from 1992 to 2005, but an increase was observed in persons aged 15 to 24 after 2002, as a result of injection drug use. An increase has also been observed in women of reproductive age. Worldwide, 71 million people are infected with HCV, with the highest rates in central and east Asia, north Africa, and the Middle East.
Figure 16–3 shows the typical course of HCV infection. The incubation period for hepatitis C averages 6–7 weeks, and clinical illness is often mild, usually asymptomatic, and characterized by waxing and waning aminotransferase elevations and a high rate (greater than 80%) of chronic hepatitis. Spontaneous clearance of HCV following acute infection is more common (64%) in persons with the CC genotype of the IFNL3 (IL28B) gene (which encodes interferon lambda-3 on chromosome 19) than in those with the CT or TT genotype (24% and 6%, respectively). In persons with the CC genotype, jaundice is more likely to develop during the course of acute hepatitis C. Patients with the CC genotype and chronic hepatitis C are also more likely to respond to therapy with pegylated interferon (see Chronic Viral Hepatitis). Polymorphisms of genes encoding the killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands (HLA-C1) and the interleukin-1 receptor-associated kinase 4 (IRAK4) are associated with spontaneous clearance and reduced clearance, respectively, of viremia following HCV exposure. In pregnant patients with chronic hepatitis C, serum aminotransferase levels frequently normalize despite persistence of viremia, only to increase again after delivery.
The typical course of acute and chronic hepatitis C. (ALT, alanine aminotransferase; Anti-HCV, antibody to hepatitis C virus by enzyme immunoassay; HCV RNA [PCR], hepatitis C viral RNA by polymerase chain reaction.)
Diagnosis of hepatitis C is based on an enzyme immunoassay (EIA) that detects antibodies to HCV. Anti-HCV is not protective, and in patients with acute or chronic hepatitis, its presence in serum generally signifies that HCV is the cause. Limitations of the EIA include moderate sensitivity (false-negatives) for the diagnosis of acute hepatitis C early in the course and low specificity (false-positives) in some persons with elevated gamma-globulin levels. In these situations, a diagnosis of hepatitis C may be confirmed by using an assay for HCV RNA. Occasional persons are found to have anti-HCV without HCV RNA in the serum, suggesting recovery from HCV infection in the past.
HCV is a pathogenic factor in mixed cryoglobulinemia and membranoproliferative glomerulonephritis and may be related to lichen planus, autoimmune thyroiditis, lymphocytic sialadenitis, idiopathic pulmonary fibrosis, sporadic porphyria cutanea tarda, and monoclonal gammopathies. HCV infection confers a 20–30% or more increased risk of non-Hodgkin lymphoma, and chronic HCV infection (especially genotype 1) is associated with an increased risk of end-stage renal disease. A previously reported association between HCV infection and insulin resistance and type 2 diabetes mellitus has been disproved. Hepatic steatosis is a particular feature of infection with HCV genotype 3 and may also occur in patients infected with other HCV genotypes who have risk factors for fatty liver. On the other hand, chronic HCV infection is associated with a decrease in serum cholesterol and low-density lipoprotein levels.
Testing donated blood for HCV has helped reduce the risk of transfusion-associated hepatitis C from 10% in 1990 to about 1 case per 2 million units in 2011. The US Preventive Services Task Force recommends that asymptomatic adults ages 18–79 be screened for hepatitis C virus infection. The CDC now recommends HCV screening for all persons over age 18 and all pregnant women (in both cases except in settings where the prevalence of HCV infection is less than 0.1% [very rare]). Screening of all pregnant women for HCV infection has also been recommended by professional societies. HCV-infected persons should practice safe sex, but there is little evidence that HCV is spread easily by sexual contact or perinatally, and no specific preventive measures are recommended for persons in a monogamous relationship or for pregnant women. Because a majority of cases of HCV infection are acquired by injection drug use, public health officials have recommended avoidance of shared needles and access to needle exchange programs for injection drug users. As yet, there is no vaccine for HCV. Vaccination against HAV (after prescreening for prior immunity) and HBV is recommended for patients with chronic hepatitis C, just as vaccination against HAV is recommended for patients with chronic hepatitis B, although the cost-effectiveness of vaccination has been questioned.
In the past, treatment of patients with acute hepatitis C with a peginterferon-based regimen (see later) for 6–24 weeks was shown to appreciably decrease the risk of chronic hepatitis in patients in whom serum HCV RNA levels had failed to clear spontaneously after 3 months. Ribavirin was added if HCV RNA failed to clear after 3 months of peginterferon, but some authorities recommended using ribavirin with peginterferon from the start of therapy. Oral direct-acting agents have supplanted interferon-based therapy (see Chronic Viral Hepatitis), and a 6-week course of ledipasvir and sofosbuvir has been shown to prevent chronic hepatitis in patients with acute genotype-1 hepatitis C. Treatment of acute hepatitis C may be cost effective.
In most patients, clinical recovery is complete in 3–6 months. Laboratory evidence of liver dysfunction may persist for a longer period. The overall mortality rate is less than 1%, but the rate is reportedly higher in older people. Acute liver failure due to HCV is rare in the United States.
Chronic hepatitis, which progresses very slowly in many cases, develops in as many as 85% of all persons with acute hepatitis C. Ultimately, cirrhosis develops in up to 30% of those with chronic hepatitis C; the risk of cirrhosis and hepatic decompensation is higher in patients coinfected with both HCV and HBV or HIV. Patients with cirrhosis are at risk for hepatocellular carcinoma at a rate of 3–5% per year. Long-term morbidity and mortality in patients with chronic hepatitis C is lower in black than in white patients and lowest in those infected with HCV genotype 2 and highest in those with HCV genotype 3.