1. 1
    Current diagnosis

    • Hepatitis C virus (HCV) is a common infection in the United States with major morbidity and mortality.

    •   Incidence of HCV is rising, linked to the opioid epidemic.

    Given the asymptomatic presentation and long period before complications, screening is warranted: undiagnosed persons born between 1945 and 1965 with no previous history of antibody testing, and people who inject drugs (Table 1).

    Table 1

    Recommendations for One-Time Screening

    Modified from http://hcvguidelines.org.

    Abbreviation: HCV = hepatitis C virus.

    Diagnosis is made with two-stage testing: initial screening for anti-HCV antibodies followed by HCV RNA testing to confirm the presence of virus.

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  2. 2
    Current therapy

    • Novel therapeutic approaches that are safe and highly effective have revolutionized the care of HCV.

    • The goal of therapy is cure of virus, which prevents liver-related complications and further transmission.

    • Regimens of combination antivirals typically given for 12 weeks can cure over 95% of those living with HCV infection.

    The diagnosis, management, and therapeutic approaches for patients living with HCV have dramatically transformed in recent years. Most people (over 95%) living with HCV infection can be cured after 8 to 12 weeks of safe oral regimens combining antiviral agents.

    The availability of novel therapies enhances the effectiveness of screening patients for HCV infection who may otherwise be unaware of infection owing to its asymptomatic presentation.

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  3. 3
    Virology, Pathogenesis, and Natural History

    HCV is a single-strand RNA virus whose genome encodes several viral proteins, including nonstructural proteins (NS3/4A, termed protease; NS5A, and NS5B, termed polymerase) that may each be specifically targeted by medications. There are seven known families of virus, commonly known as genotypes 1 through 7, many with subtypes (e.g., genotype 1a or 1b).

    After acute infection, in the majority of individuals the virus establishes a chronic lifelong infection characterized by high levels of viremia easily detected in plasma; in a minority the virus is spontaneously cleared. In the latter scenario, HCV is permanently eradicated as the polymerase is an RNA-RNA polymerase and there is no DNA intermediate to establish latency in the host. Those who achieve clearance of virus, whether spontaneously or via treatment, are susceptible to reinfection if exposed again.

    Both the acute and chronic phases of HCV infection are largely asymptomatic. A minority of those with acute infection may present with nonspecific symptoms such as abdominal pain and malaise, with less than 10% presenting with jaundice. Rarely, those with chronic infection may experience extrahepatic manifestations of HCV infection, such as cryoglobulinemic vasculitis, proteinuria or glomerulonephritis, or lymphoma. Otherwise, alanine transaminase (ALT) levels may be persistently or intermittently elevated, but may also be within normal range in up to 20% of infected individuals; thus, ALT is considered an imperfect screening test for HCV.

    After establishment of chronic HCV infection, fibrosis occurs at a variable rate and may progress to cirrhosis in about 15% to 20% over a 20-year period. Fibrosis may be accelerated by other liver insults, such as alcohol use, nonalcoholic steatohepatitis, and coinfection with HIV or hepatitis B virus (HBV). Those with HCV-related cirrhosis may experience significant morbidity and mortality from various complications; screening for varices and hepatocellular carcinoma is recommended (see chapter on cirrhosis).

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  4. 4

    HCV is estimated to infect at least 100 million people worldwide. In the United States, it is the leading bloodborne pathogen and infects over 3 million Americans. The highest-risk groups are those born between 1945 and 1965 (so-called baby boomers), people who inject drugs, and HIV-positive men who have sex with men. In the United States, the incidence reached a peak in the 1970s and 1980s and then steeply declined; in the last decade there has been a resurgence of new incident cases linked to a widespread opioid epidemic.

    Owing to the high number of infections that occurred decades ago, a large number of Americans within the baby-boomer cohort are now at risk for unidentified long-standing HCV infection, cirrhosis, and death; at present the mortality related to HCV exceeds that related to all other notifiable infectious diseases in the United States. HCV remains the leading indication for liver transplantation.

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  5. 5
    Risk Factors

    HCV is most efficiently transmitted via exposure to contaminated blood or its components. In the United States, injection drug use (IDU) is the most common mode of transmission. Nosocomial exposure to contaminated blood or blood products and poorly sterilized or reused contaminated medical equipment remains an important risk, especially if strict universal precautions are not instituted. Mother-to- child transmission is not efficient, as about 5% of children born to HCV-infected women are infected, with higher rates if HIV/HCV coinfection is present. Sexual transmission is considered very rare in the context of heterosexual relationships but does occur at higher rates in men who have sex with men, particularly with HIV and/or practices that result in bloody exposures.

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  6. 6

    There are two tests utilized for the diagnosis of HCV infection: testing for anti-HCV antibodies and measuring HCV RNA. The suggested algorithm is initial serologic testing to assess exposure followed by HCV RNA testing to determine current or cleared infection. Currently available anti-HCV testing is highly sensitive (> 99%) but may be falsely negative in the earliest stages of infection (typically the first 4– 12 weeks) or in the setting of immunosuppression (such as dialysis or HIV if CD4 counts are below 200 cells/mm3). HCV RNA testing may be utilized to confirm current HCV RNA infection after an initial positive anti-HCV test or in settings when anti-HCV may be falsely negative. There are two types of HCV RNA tests: qualitative HCV RNA tests that do not quantify the level of viral replication and quantitative HCV RNA tests. Quantitative testing has improved in recent years and exhibits sensitivity similar to qualitative testing; therefore, it is preferred in most situations.

    Those with confirmed current HCV infection (positive HCV RNA) should also be tested for HIV and HBV (the latter typically by HBsAg). Follow-up evaluation includes HCV genotype, which defines therapeutic options. Discovery of advanced fibrosis or cirrhosis may affect the specifics of recommended antiviral regimens but also has prognostic implications. The likelihood of cirrhosis is dependent on various factors, including advancing patient age, duration of infection, and cofactors such as significant alcohol use or HIV. Noninvasive assessment with serologic testing (such as Fibrosure) or with novel imaging technologies (such as transient elastography) has largely replaced liver biopsies.

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  7. 7

    Prevention of HCV infection should be targeted to the highest-risk groups. For people who inject drugs, clean injecting equipment, including needles, syringes, and other components of drug preparation, is paramount. Risk reduction should also be achieved after viral clearance to prevent reinfection.

    Prevention of fibrosis progression includes minimization or abstinence from regular alcohol use, avoidance of fatty liver, and avoidance of primary infection with or control of coexisting viruses (HIV or HBV). If not immune, vaccines against hepatitis A virus and HBV are recommended. Patients with coexisting substance use disorder should be referred for appropriate care.

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  8. 8

    Antiviral treatments for hepatitis C have been revolutionized with combination regimens of direct-acting antivirals (DAAs). These new drugs are used in combination with the goal to eradicate HCV. Cure is known as a sustained virologic response (SVR), defined as a negative HCV RNA test 12 or more weeks after cessation of therapy. This definition represents a durable cure in the absence of reinfection.

    Benefits of SVR include a significant reduction in future liver-related events, especially for those with advanced fibrosis or cirrhosis.

    Additional benefits include abrogation of further HCV transmission, amelioration of extrahepatic manifestations (if present), and improvement in quality of life. Virtually all patients with current HCV infection are candidates for therapy.

    Available agents may be classified by the viral protein they target: NS3/4A protease inhibitors: simeprevir, paritaprevir (which requires pharmacologic boosting with ritonavir), and grazoprevir; NS5A inhibitors: daclatasvir, elbasvir, ledipasvir, and ombitasvir; the NS5A nonnucleoside inhibitor dasabuvir; and the NS5B nucleotide polymerase inhibitor sofosbuvir. Simeprevir (Olysio), daclatasvir (Daklinza), and sofosbuvir (Sovaldi) are available as single agents, but the majority are parts of combination regimens, as described in Table

    1. The Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD) maintain guidelines for providers at http://www.hcvguidelines.org, which provides updates with approval of novel agents and as new data become available.

    Table 2

    First-Line Combination Antiviral Regimens for Chronic Hepatitis C as of March 2017, Genotypes 1–4

    Abbreviations: FDC = fixed-dose combination; NS5A = nonstructural protein 5A; RASs = resistance-associated substitutions; RBV = ribavirin; SOF = sofosbuvir. Daclatasvir may need dose adjustments with certain medications with cytochrome P450  interactions.

    One major consideration in choosing a regimen is the genotype of the virus, although certain regimens are able to treat all genotypes (termed pan-genotypic). Other potential influences include presence of cirrhosis, the potential for concomitant drug interactions (including those with HIV coinfection on antiretrovirals), prior treatment experience, and adherence to therapy. Certain regimens have been tested for those with advanced renal impairment. Insurance formulary preferences may also dictate the choice. One regimen in particular, elbasvir/grazoprevir (Zepatier), requires testing of genotype 1a virus for resistance-associated substitutions (RASs) that are associated with decreased response; if present the duration should be increased and ribavirin (Ribasphere) added. In general, almost all patient groups can be offered a regimen with a rate of SVR at or above 95%.

    These combinations have favorable safety profiles, with phase III trials reporting very low discontinuation rates. The most common side effects of these regimens are headache and fatigue. At times, ribavirin may be added to the regimen, particularly in the cases of relapse after previous treatment and/or cirrhosis (especially if decompensated or previously decompensated).

    Drug–drug interactions are also potentially problematic.

    Sofosbuvir-containing regimens should not be coadministered with amiodarone (Cordarone), owing to reports of symptomatic bradycardia with poor outcomes. Medications may significantly decrease absorption of HCV antivirals, especially rifampin (Rifadin), carbamazepine (Tegretol), oxcarbazepine (Trileptal), and St. John’s wort.7 For the combinations of ledipasvir/sofosbuvir (Harvoni) and sofosbuvir/velpatasvir (Epclusa), care must be taken if coadministered with medications that decrease gastric pH. Involvement of clinical pharmacists may be very useful, along with resources such as the website maintained at the University of Liverpool: http://hep- druginteractions.org.

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  9. 9

    Compared with previous regimens that were associated with far more side effects and complications, current treatments are far more tolerable. Clinical visits to monitor for side effects and to promote adherence are often performed monthly while on treatment. A negative HCV RNA at approximately week 4 into therapy confirms adherence. Certain regimens may require more intensive monitoring in the presence of cirrhosis, as cases of decompensation have been reported. Those with active HBV replication who are untreated are at risk for reactivation of this virus once HCV is suppressed, with rare cases of liver failure reported; cotreatment of both viruses or very close monitoring is recommended for this subgroup. At this time there are no data for the use of these agents in pregnancy or breastfeeding.

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  10. 10

    1   Kim A. Hepatitis C, virus. Ann Intern Med. 2016;165(5):ITC33– ITC48.

    2   Edlin B.R., Eckhardt B.J., Shu M.A., et al. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62(5):1353–1363.

    3   Suryaprasad A.G., White J.Z., Xu F., et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012. Clin Infect

    Dis. 2014;59(10):1411–1419.

    4   Ly K.N., Hughes E.M., Jiles R.B., Holmberg S.D. Rising mortality associated with hepatitis C virus in the United States, 2003-2013. Clin Infect Dis. 2016;62(10):1287–1288.

    5   AASLD/IDSA. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62(3):932–954.

    7  Available as dietary supplement.

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