Hepatitis C is caused by the hepatitis C virus (HCV). HCV causes an acute infection which may lead to chronic infection in an estimated 55% to 85% of patients.1 Chronic infection is defined as at least 6 months of detectable viral HCV RNA in the blood.2 There are no commercially available vaccines for HCV, but there are many highly successful curative treatment options.
Chronic HCV infection carries many life-threatening sequelae including both end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC).2 An estimated 185 million worldwide have chronic HCV, with 3.5 million cases in the United States.3 More than half of those infected are unaware of their infection.4,5
HCV is blood-borne, with the leading route of transmission for acute infection being intravenous drug use (IDU). Other potential risk factors include mother-to-child transmission, intranasal drug use, and long-term hemodialysis.4
There are currently seven identified genotypes of HCV that are further subdivided into 67 subtypes.6 Genotypes 1, 2, and 3 are most common in the United States, accounting for 75.8%, 12.0%, and 10.4% of cases, respectively.6 The American Association for the Study of Liver Diseases and Infectious Diseases Society of America (AASLD-IDSA) released HCV treatment guidelines that are organized by genotype.4 Guideline-directed therapy for HCV involves several levels of subgrouping to further optimize the probability of treatment success. Figure 1 illustrates this classification process. Recommendations for patients outside the groups listed (e.g., patients with decompensated cirrhosis) are made in the following sections.
The goal of treatment is to reduce all-cause mortality and liver-related morbidity, including ESLD and HCC. Successful treatment involves curing the infection. Clinically, this is done by achieving a sustained virologic response (SVR12), defined as an undetectable HCV RNA count (viral load) at least 12 weeks after completion of therapy.4
Treatment is accomplished with the use of combinations of direct-acting antivirals (DAAs) for 8, 12, or 24 weeks. DAAs target one of three key proteins of the HCV viral replication cycle: NS3/4A protease enzyme, NS5A replication complex, or NS5B polymerase enzyme. Inhibition of NS5A or NS5B prevents RNA replication, while NS3/4A inhibition alters protein modification.6 Current guideline-recommended regimens are designed to inhibit at least two of these proteins. Generally speaking, the cure rate for all DAA regimens is above 90% for any given regimen and population, and, in most cases is above 95%.7
DAA treatment regimens in the current guidelines include: glecaprevir/pibrentasvir (GLE/PIB, Mavyret), elbasvir/grazoprevir (EBR/GZR, Zepatier), ledipasvir/sofosbuvir (LDV/SOF, Harvoni), sofosbuvir/velpatasvir (SOF/VEL, Epclusa), sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX, Vosevi), sofosbuvir/daclatasvir (SOF + DAC), simeprevir/ sofosbuvir (SIM + SOF), and ombitasvir/paritaprevir/ritonavir with dasabuvir (PrOD, Viekira Pak) or ombitasvir/paritaprevir/ritonavir without dasabuvir(PrO).4 Ribavirin (RBV) is an RNA antimetabolite that is commonly used to augment regimens in patients with compensated cirrhosis or who have failed prior HCV therapy.4 Pegylated interferon alpha (PEG-IFN) together with RBV was the mainstay of all hepatitis C therapy until introduction of the first DAAs in 2011.8 The recent introduction of GLE/PIB has replaced the final guideline recommendations for PEG-IFN-based regimens (end-stage renal disease [ESRD] patients with genotype 2, 3, 5, or 6).
Screening, Diagnosis, and Monitoring
Diagnosis of HCV is made in two steps. Screening is done by testing for HCV antibodies. If positive, confirmation of active infection is done by testing for viral load. Patients may test positive for HCV antibodies and negative for viral load under two circumstances: spontaneous clearance of the virus, or successful treatment with antiviral therapy.4 For those who initially test negative for HCV antibodies and are suspected of having liver disease, the guidelines recommend testing for viral load or retesting for HCV antibodies if exposure to HCV occurred within 6 months.4 If the viral load is negative there is no active infection, but the patient is not immune to reinfection.9
AASLD-IDSA guidelines recommend a one-time HCV test for the following at-risk groups:4
- All persons born between 1945 and 1965 regardless of country of origin
- Injection-drug users, including one-time users
- Intranasal illicit drug users
- Long-term hemodialysis
- Persons with percutaneous exposures in an unregulated setting (especially tattoo and piercing)
- Healthcare workers who have become exposed to infected blood
- Children born to infected mothers
- Persons who were ever incarcerated
- Recipients of blood components before July 1992 or clotting factor recipients before 1987
- HIV infection
- Sexually active persons about to start pre-exposure prophylaxis for HIV
- Unexplained chronic liver disease and/or cirrhosis hepatitis including elevated alanine aminotransferase (ALT)
- Solid organ donors
Patients who have tested negative for viral load but who continue to engage in high-risk behaviors, such as IDU and HIV-positive men having unprotected sex with other men, should be tested annually.4
The viral load is also used to track therapeutic success during and after treatment. It is repeated 4 weeks after start of therapy to track virologic response and 12 weeks after treatment to assess for SVR12. Other tests done prior to treatment are HCV genotype testing, liver fibrosis/cirrhosis assessment, screening for HIV and hepatitis B, and resistance-associated substitution (RAS) testing when required, usually before initiation of elbasvir/grazoprevir as described below.
- World Health Organisation. WHO | Hepatitis C Fact Sheet. www.who.int/topics/hepatitis/factsheets/en. 2016.
- Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol. 2017;61(1):S58-S68.
- World Health Organization. Guidelines for the Screening Care and Treatment of Persons with Hepatitis C Infection. http://apps.who.int/iris/bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1&ua=1. 2014.
- AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. 2017.
- Centers for Disease Control and Prevention. What is viral hepatitis? www.cdc.gov/hepatitis/abc/index.htm. 2016.
- Smith DB, Bukh J, Kuiken C, et al. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: Updated criteria and genotype assignment web resource. Hepatology. 2014;59(1):318-327.
- Burstow NJ, Mohamed Z, Gomaa AI, et al. Hepatitis C treatment: where are we now? Int J Gen Med. 2017;10:39-52.
- Strader DB, Seeff LB. A brief history of the treatment of viral hepatitis C. Clin Liver Dis. 2012;1(1):6-11.
- Young J, Rossi C, Gill J, et al. Risk factors for hepatitis C virus reinfection after sustained virologic response in patients coinfected with HIV. Clin Infect Dis Am. 2017;64(9):1154-1162.
- Dick TB, Lindberg LS, Ramirez DD, Charlton MR. A clinician’s guide to drug-drug interactions with direct-acting antiviral agents for the treatment of hepatitis C viral infection. Hepatology. 2016;63(2):634-643.
- Harvoni (ledipasvir/sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences Inc. 2016.
- Epclusa (sofosbuvir; velpatasvir) [package insert]. Foster City, CA: Gilead Sciences. 2016.
- Talavera Pons S, Boyer A, Lamblin G, et al. Managing drug–drug interactions with new direct-acting antiviral agents in chronic hepatitis C. Br J Clin Pharmacol. 2017;83(2):269-293.
- Mavyret (glecaprevir/pibrentasvir) [package insert]. North Chicago, IL: AbbVie Inc. 2017.
- Gane E, Lawitz E, Pugatch D, et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment. N Engl J Med. 2017;377(15):1448-1455.
- Zepatier (elbasvir and grazoprevir) [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp. 2017.
- Tong X, Kwong AD. Editorial commentary: Barrier to resistance: Lessons from 2 direct-acting hepatitis C virus inhibitors, MK-5172 and sofosbuvir. Clin Infect Dis. 2014;59(12):1675-1677.
- Kowdley K V, Gordon SC, Reddy KR, et al. Ledipasvir and Sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.
- Vosevi (sofosbuvir, velpatasvir, voxilaprevir) [prescribing information]. Foster City, CA: Gilead Sciences Inc.
- Daklinza (daclatasvir) [prescribing information]. New York City, NY: Bristol-Myers Squibb. 2015.
- Olysio (simeprevir) [prescribing information]. Titusville, NJ. Janssen Therapeutics. 2013.
- Viekira XR (paritaprevir; ritonavir; ombitasvir; dasabuvir) [package insert]. North Chicago, IL: AbbVie Inc. 2015.
- Technivie (ombitasvir, paritaprevir and ritonavir) [package insert]. North Chicago, IL: Abbvie Inc. 2015.
- Smith MA, Lim A. Profile of paritaprevir/ritonavir/ombitasvir plus dasabuvir in the treatment of chronic hepatitis C virus genotype 1 infection. Drug Des Devel Ther. 2015;9:6083-6094.
- Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci U S A. 2001;98(12):6895-6900.
- Copegus(ribavirin) [package insert]. San Franciso: Genentech.; 2002.
- CDC. WHO | HIV and Viral Hepatitis fact sheet. https://www.cdc.gov/hiv/pdf/library/factsheets/hiv-viral-hepatitis.pdf. 2017.
- University of Washington in partnership with International Antiviral Society - USA. Hepatitis C Online. Website. https://www.hepatitisc.uw.edu/. 2017.