Hepatitis C Virus - Clinical Tree

Hepatitis C virus (HCV) was first identified in 1989. Although substantially more prevalent among adults, HCV infection does occur in children and should be considered when relevant clinical or epidemiologic factors are present. ^, In recent years, new HCV infections have increased among women of childbearing age and the number of infants born to HCV-infected mothers has risen, resulting in vertically transmitted infections. ^, Curative treatment with HCV direct-acting antiviral (DAA) therapy is now recommended for all HCV-infected children aged ≥3 years, adolescents, and adults, regardless of disease severity or acuity. ^,

Pathogen

HCV is an enveloped, single-stranded RNA virus, of approximately 9500 nucleotides, belonging to the Hepacivirus genus in the Flaviviridae family. There are at least seven genotypes of HCV, numbered 1 through 7, the nucleic acid sequences of which differ by >30%. More than 67 subtypes that differ by 20%–25% also have been described. The most common subtypes are 1a, 1b, 2a, and 2b. The prevalence of the genotypes varies by continent and region of the world. Genotype 1 is most prevalent worldwide, comprising 46% of all hepatitis C cases globally and accounting for >75% of cases in the US. Genotype 3 is the next most prevalent worldwide with 30% of cases. Genotype 4 is prevalent in Africa and the Middle East, especially Egypt. Genotype 5 is prevalent in southern Africa. Genotype 6 is the least prevalent genotype worldwide and is found in a few Southeast Asian countries. Genotype 7 was recently discovered as a new lineage distinct from genotypes 1–6 and originated in the Democratic Republic of Congo. Affected children are expected to have the same distribution of HCV genotypes by geographic location.

Universal precautions are recommended to prevent transmission of bloodborne infections, including HCV infection. ^, Use of chemical germicides that are capable of producing at least an intermediate level of disinfection activity (e.g., 0.1% glutaraldehyde or 500 ppm free chlorine from sodium hypochlorite—2 tablespoons of household bleach in 1 gallon of water) or conventional sterilization processing (e.g., steam autoclaving) are suitable for inactivating HCV. Data on survival of HCV on environmental surfaces are inconsistent. One study suggests that HCV in dried plasma can cause infection in experimental animals when left at room temperature for at least 16 hours but not after 4 days. A more recent study suggests that HCV can infect human tissue cultures after remaining at room temperature for up to 6 weeks.

Pathogenesis and Immunity

The primary site of hepatitis C virus replication is the hepatocyte. In the acute phase, histopathologic findings in the liver are typical of acute viral hepatitis and include ballooning degeneration, focal necrosis, and hepatocellular apoptosis. ^, These findings are believed to be due to the immune response to virus-infected cells rather than to a direct cytopathic effect of the virus.

The high rate of progression to chronicity with HCV infection—approximately 50%–80%—is partly attributable to failure of the virus to elicit effective neutralizing antibodies. A high rate of mutation in the single-stranded RNA genome of HCV is believed to play a role in the pathogen’s ability to evade the immune system. In an infected person, several closely related but genetically distinct strains of HCV, termed quasispecies, generally occur. ^, Typically, one dominant variant accounts for the majority of circulating virus at any given time. Over time, this variant often loses dominance and is replaced by a new dominant variant. Presumably, evolution of quasispecies is a result of the immune response to the dominant variant, resulting in sequential selection of resistant mutants. Subsequent infection with different genotypes has been observed in the context of re-infection after clearance, as prior infection does not protect against subsequent disease with the same or different genotypes. Mixed infection with different genotypes concurrently also has been observed among persons who inject drugs. Mechanisms associated with persistence and clearance of HCV are not well understood and likely involve both host and viral factors. The heterogeneity of HCV allows the virus to evade the host’s immune system and impedes development of conventional vaccines.

Epidemiology

Incidence and Prevalence

In 2018, an estimated 50,300 new HCV infections occurred in the US, reflecting a rate 5 times higher than in 2005. The incidence of acute hepatitis C was highest among persons aged 20–29 years, and lowest among persons aged ≤19 years. Incidence rapidly increased for young adults aged 20–39 years from 2009 to 2018, mostly due to injection drug use. ^, During 2006–2012, the rates among persons ≤30 years of age increased 13% annually in nonurban counties versus 5% in urban counties nationwide, and the combined incidence of acute HCV infection in 4 states (Kentucky, Tennessee, Virginia, and West Virginia) increased by 364%. ^, Injection drug use has remained the most commonly reported risk behavior among young persons (72%–75%). ^, ^,

Prevalence estimates among children aged 6–19 years could not be calculated from National Health and Nutrition Examination Survey (NHANES) data because so few HCV infections were identified in this age group. However, an analysis based on census data and literature review estimated that in the US during 2005–2015, there were 23,000–46,000 children living with chronic HCV infection and an estimated 7200 new cases from perinatal transmission. Prevalence of HCV infection among women giving birth varies widely by state ^, and it has been estimated that up to 29,000 HCV-infected women gave birth each year in the US from 2011 to 2014. In Kentucky, one of out every 63 mothers giving birth in the state during 2014 was infected with HCV. ^,

The incidence and prevalence of HCV infection among adolescents who report injection drug use is higher than in the general pediatric population. ^, In a survey of newly incarcerated adolescent detainees, 2% had evidence of HCV infection, 95% of whom reported injection drug use. In a survey of homeless adolescents, one-third reported injection drug use and 4% were infected with HCV.

Transmission

Although older children and adolescents are at risk for HCV infection from injection drug use, vertical transmission from mother to infant currently accounts for most cases of HCV infection in the pediatric population. ^, ^, ^, ^, ^, ^,

HCV is transmitted primarily through parenteral exposures to infectious blood or body fluids that contain blood, most commonly through intravenous drug use. Mucous membrane exposures to blood also can result in HCV transmission, but this route is less efficient. ^, In addition to blood, some body fluids including cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, and amniotic fluid, are considered potentially infectious. Although HCV can be detected in saliva, semen, human milk, and other bodily fluids of some infected persons, these body fluids are not believed to be efficient vehicles of transmission. ^, Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they contain blood. ^, HCV does not penetrate intact skin spontaneously, and airborne transmission does not occur.

Perinatal Transmission and Risk Factors

Among HCV-infected infants and young children in high-income countries, perinatal exposure is the most common source of infection. ^, In a meta-analysis of 109 studies published between 1997 and 2012, the rate of vertical transmission of HCV was estimated to be 6% among mothers without HIV infection, with rates varying between 4% and 8% depending on maternal factors, such as level of HCV viremia. In mothers with HIV coinfection, the rate of transmission was 11%, with a range from 8% to 15%. In two studies of children infected with HCV, 30%–50% of children were positive for HCV RNA shortly after birth, suggesting early intrauterine transmission; the remainder did not test positive until later suggesting late intrauterine or intrapartum transmission. ^, ^,

In 2020, universal HCV testing was recommended for all pregnant women during each pregnancy in settings where the prevalence of HCV infection is >0.1%. ^, At the time of the recommendation, overall prevalence was well over this threshold in all US states. ^, ^, The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) have established guidelines for the management of HCV in pregnant women, including special considerations during pregnancy to reduce the risk of perinatal transmission. HCV treatment during pregnancy is not yet recommended due to the lack of safety and efficacy data. ^,

Maternal Injection Drug Use

Maternal injection drug use has been suggested as an independent risk factor, possibly because of an association with a higher likelihood of acute hepatitis during pregnancy with higher titer viremia and absence of antibodies. ^,

HCV Viremia

Perinatal transmission is almost always limited to women with detectable HCV RNA. ^, The level of viremia has been shown to be a determinant of perinatal transmission in some studies, although a specific threshold has not been identified. For example, women in several studies with viral loads <10 ⁵ copies/mL were less likely to transmit HCV, even if they were coinfected with HIV. However, other studies have failed to demonstrate this association. ^, ^,

Maternal HIV Coinfection

HIV coinfection is the most important predictor of perinatal transmission risk, with a rate of vertical transmission ranging from 8% to 15%. Higher HCV RNA levels among HIV-coinfected women may explain, in part, the increased risk for vertical HCV transmission. HIV infection was also shown to facilitate entry and replication of HCV in blood mononuclear cells, which might increase the risk for perinatal transmission. ^,

Prolonged Rupture of Membranes and Obstetric Procedures

The Society for Maternal-Fetal Medicine recommends several obstetrical practices in women with HCV infection, including preference for amniocentesis over chorionic villus sampling when invasive prenatal diagnostic testing is indicated, as well as avoidance of internal fetal monitoring during labor, prolonged rupture of membranes, and episiotomies. ^,

Factors Not Associated With Perinatal Transmission

Mode of Delivery

Based on well-designed cohort studies, the mode of delivery (vaginal vs. cesarean) does not appear to be associated with the risk for transmission.

Breastfeeding

Currently, both the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists support breastfeeding in HCV-infected women. ^, However, HCV-infected women should abstain from breastfeeding if their nipples are cracked or bleeding. ^, ^, More than 20 prospective cohort studies have not shown any increased risk for HCV infection among breastfed infants compared with formula-fed infants. ^, ^, A single prospective study during 1994–1996 showed potential perinatal transmission of HCV through breastfeeding. In this study, all three women who transmitted the infection to their babies developed symptomatic liver disease during the transmission period and had high HCV RNA titers in serum.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here