Hepatitis C

Practice Essentials

Hepatitis C is an infection caused by the hepatitis C virus (HCV) that attacks the liver and leads to inflammation. The World Health Organization (WHO) estimates that about 71 million people globally have chronic hepatitis C, with approximately 399,000 dying from this infection, primarily due to cirrhosis and hepatocellular carcinoma. The image below depicts the HCV genome.

Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.View Media Gallery

Signs and symptoms

Initial symptoms of hepatitis C are often extrahepatic, most commonly involving the joints, muscle, and skin. Examples include the following:

• Arthralgias

• Paresthesias

• Myalgias

• Pruritus

• Sicca syndrome

• Sensory neuropathy

Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension, such as the following:

• Mental status changes (hepatic encephalopathy)

• Ankle edema and abdominal distention (ascites)

• Hematemesis or melena (variceal bleeding)

Physical findings usually are not abnormal until portal hypertension or decompensated liver disease develops. Signs in patients with decompensated liver disease include the following:

• Hand signs: Palmar erythema, Dupuytren contracture, asterixis, leukonychia, clubbing

• Head signs: Icteric sclera, temporal muscle wasting, enlarged parotid gland, cyanosis

• Fetor hepaticus

• Gynecomastia, small testes

• Abdominal signs: Paraumbilical hernia, ascites, caput medusae, hepatosplenomegaly, abdominal bruit

• Ankle edema

• Scant body hair

• Skin signs: Spider nevi, petechiae, excoriations due to pruritus

Other common extrahepatic manifestations include the following:

• Cryoglobulinemia

• Membranoproliferative glomerulonephritis

• Idiopathic thrombocytopenic purpura

• Lichen planus

• Keratoconjunctivitis sicca

• Raynaud syndrome

• Sjögren syndrome

• Porphyria cutanea tarda

• Necrotizing cutaneous vasculitis

Diagnosis

General baseline studies in patients with suspected hepatitis C include the following:

• Complete blood cell count with differential

• Liver function tests, including levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, albumin, and total and direct bilirubin

• Calculated glomerular filtration rate (eGFR)

• Thyroid function studies

• Screening tests for coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV)

• Screening for alcohol abuse, drug abuse, or depression

• Hepatitis B virus (HBV) testing with hepatitis B surface antigen (HBsAg) (to identify coinfection), as well as hepatitis B surface antibody (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) (for evidence of previous infection)

• Serum pregnancy testing in women of childbearing age before initiating a treatment regimen that includes ribavirin or that includes direct-acting antiviral agents (DAAs) without ribavirin

Tests for detecting HCV infection include the following:

• Hepatitis C antibody testing: Enzyme immunoassays (EIAs), rapid diagnostic tests (RDTs), and point-of-care tests (POCTs)

• Qualitative and quantitative assays for HCV RNA (based on polymerase chain reaction [PCR] or transmission-mediated amplification [TMA])

• HCV genotyping

• Serologic testing (essential mixed cryoglobulinemia is a common finding)

Liver biopsy is not mandatory before treatment but may be helpful. Some restrict it to the following situations:

• The diagnosis is uncertain.

• Other coinfections or disease may be present.

• The patient has normal liver enzyme levels and no extrahepatic manifestations.

• The patient is immunocompromised.

Management

Treatment of acute hepatitis C has rapidly evolved and continues to evolve. HCV infection has become a curable disease, although a vaccine does not yet exist.

Background

Hepatitis C is a worldwide problem. The hepatitis C virus (HCV) is a major cause of both acute and chronic hepatitis. The World Health Organization (WHO) estimates about 71 million people globally have chronic hepatitis C, with approximately 399,000 dying from this infection, primarily due to cirrhosis and hepatocellular carcinoma (HCC). [1] The prevalence of HCV infection varies throughout the world. For example, Frank et al reported in 2000 that Egypt had the highest number of reported infections, largely attributed to the use of contaminated parenteral antischistosomal therapy. [2] This led to a mean prevalence of 22% of HCV antibodies in persons living in Egypt. In the United States, the incidence of acute HCV infection has sharply decreased during the past decade, but its prevalence remains high. According to US Centers for Disease Control and Prevention (CDC) estimates, 2.7-3.9 million people (most of whom were born from 1945 through 1965) in the United States have chronic hepatitis C which develops in approximately 75% of patients after acute infection. [3] This virus is the most common blood-borne pathogen in the United States [4] and a leading cause of morbidity and mortality, primarily through the development of liver fibrosis and cirrhosis; persons with chronic infection live an average of 2 decades less than healthy persons. [4] Infection due to HCV accounts for 20% of all cases of acute hepatitis, an estimated 30,000 new acute infections, and 8,000-10,000 deaths each year in the United States. [5] HCV has rapidly surpassed human immunodeficiency virus (HIV) as a cause of death in the United States. An examination of nearly 22 million death records over 9 years revealed an HCV mortality rate of 4.58 deaths per 100,000 people per year and an HIV mortality rate of 4.16 deaths per 100,000 people. Almost 75% of HCV deaths occurred among adults between the ages of 45 and 64 years. [6] Medical care costs associated with the treatment of HCV infection in the United States are high. Treatment with a 12-week regimen of HCV antiviral agents can cost up to $95,000. [7, 8] The incremental cost-effectiveness ratio (ICER) for direct-acting antiviral agents (DAAs) remains up to $100,000 across all HCV genotypes and fibrosis stages. [7, 9] With an estimated 2.7-3.9 million people having chronic infection, the potential medication costs alone could range from $257 billion to $371 billion per year. Because most patients infected with HCV have chronic liver disease, which can progress to cirrhosis and HCC, chronic infection with HCV is one of the most important causes of chronic liver disease (see the image below) and, according to a report by Davis et al, the most common indication for orthotopic liver transplantation (OLT) in the United States. [10]

Hepatitis C. Causes of chronic liver disease. Courtesy of the US Centers for Disease Control and Prevention. Most patients with acute and chronic infection are asymptomatic. Patients and healthcare providers may detect no indications of these conditions for long periods; however, chronic hepatitis C infection and chronic active hepatitis are slowly progressive diseases and result in severe morbidity in 20-30% of infected persons. Astute observation and integration of findings of extrahepatic symptoms, signs, and disease are often the first clues to the underlying HCV infection. [11] Although acute HCV infection is usually mild, chronic hepatitis develops in at least 75% of patients. [12] (See Prognosis.) Although liver enzyme levels may be in the reference range, the presence of persistent HCV-RNA levels discloses chronic infection. Biopsy samples of the liver may reveal chronic liver disease. Cirrhosis develops in 20-50% of patients with chronic hepatitis C infection. Liver failure and HCC (11%-19%) can eventually result.

Pathophysiology

Hepatitis C virus (HCV) is a spherical, enveloped, single-stranded RNA virus belonging to the family Flaviviridae, genus Flavivirus. Lauer and Walker reported that HCV is closely related to hepatitis G, dengue, and yellow fever viruses. [13] HCV can produce at least 10 trillion new viral particles each day. The HCV genome consists of a single, open reading frame and two untranslated, highly conserved regions, 5'-UTR and 3'-UTR, at both ends of the genome. The genome has approximately 9500 base pairs and encodes a single polyprotein of 3011 amino acids that are processed into 10 structural and regulatory proteins (see the image below).

Hepatitis C viral genome. Courtesy of Hepatitis Resource Network The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells. In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Findings from studies suggest that at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C. The proteolytic cleavage of the virus results in two structural envelope glycoproteins (E1 and E2) and a core protein. [14] Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, believed to result from selective pressure by virus-specific antibodies. The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV. HCV core protein is an important risk factor in the development of liver disease; it can modulate several signaling pathways affecting cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress, and lipid metabolism. [15] Other viral components are nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7), whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown. These nonstructural proteins are necessary for viral propagation and have been the targets for newer antiviral therapies, such as the direct-acting antiviral agents (DAAs). NS2/3 and NS3/4A are proteases responsible for cleaving the HCV polyprotein. NS5A is critical for the assembly of the cytoplasmic membrane-bound replication complex; one region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity–determining region. NS5B is an RNA dependent RNA polymerase required for viral replication; it lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies. These represent minor molecular variations with only 1%-2% nucleotide heterogeneity. HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development. Genotypes HCV genomic analysis by means of an arduous gene sequencing of many viruses has led to the division of HCV into six genotypes based on homology. Numerous subtypes have also been identified. Arabic numerals denote the genotype, and lower-case letters denote the subtypes for lesser homology within each genotype. [12] Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40%-80% of all isolates. Genotype 1 also may be associated with more severe liver disease and a higher risk of hepatocellular carcinoma. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent. Genotype details are as follows:

• Genotype 1a occurs in 50%-60% of patients in the United States.

• Genotype 1b occurs in 15%-20% of patients in the United States; this type is most prevalent in Europe, Turkey, and Japan.

• Genotype 1c occurs in less than 1% of patients in the United States.

• Genotypes 2a, 2b, and 2c occur in 10%-15% of patients in the United States; these subtypes are widely distributed and are most responsive to medication.

• Genotypes 3a and 3b occur in 4%-6% of patients in the United States; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland.

• Genotype 4 occurs in less than 5% of patients in the United States; it is most prevalent in the Middle East and Africa.

• Genotype 5 occurs in less than 5% of patients in the United States; it is most prevalent in South Africa.

• Genotype 6 occurs in less than 5% of patients in the United States; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao.

Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among persons in Scotland who abuse injection drugs.

Etiology

Transmission Transfusion of blood contaminated with hepatitis C virus (HCV) was once a leading means of HCV transmission. Since 1992, however, the screening of donated blood for HCV antibody sharply reduced the risk of transfusion-associated HCV infection. With the advent of more advanced screening tests for HCV such as polymerase chain reaction (PCR), the risk is considered to be less than 1 per 2 million units transfused. The newer assays have decreased the window after infection to 1-2 weeks. Persons who inject illicit drugs with nonsterile needles are at the highest risk for HCV infection. In developed countries, most of the new HCV infections are reported in injection drug users (IDUs). The most recent surveys of active IDUs in the United States indicate that approximately one third of young (aged 18–30 years) IDUs are HCV-infected. [16] Older and former IDUs typically have a much higher prevalence (approximately 70%-90%) of HCV infection, attributable to needle sharing during the 1970s and 1980s, before greater understanding of the risks of blood-borne viruses and the implementation of public educational strategies. The additional risk of acquiring hepatitis C infection from noninjection (snorted or smoked) cocaine use is difficult to differentiate from that associated with injection drug use and sex with HCV-infected partners. [16] Transmission of HCV to healthcare workers may occur via needle-stick injuries or other occupational exposures. Needle-stick injuries in the healthcare setting result in a 3% risk of HCV transmission. According to Rischitelli et al, however, the prevalence of HCV infection among healthcare workers is similar to that of the general population. [17] Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope, via dialysis, or during surgery, including organ transplantation before 1992. HCV may be transmitted via sexual transmission. However, studies of heterosexual couples with discordant serostatus have shown that such transmission is extremely inefficient. [18] A higher rate of HCV transmission is noted in men who have sex with men (MSM), particularly those who practice unprotected anal intercourse and have infection with the human immunodeficiency virus (HIV). [19] HCV may also be transmitted via tattooing, sharing razors, and acupuncture. The use of disposable needles for acupuncture, now the standard practice in the United States, should eliminate this transmission route. Maternal-fetal HCV transmission may occur at a rate of approximately 4%–5%. [20] Breastfeeding is not associated with transmission. [21] Casual household contact and contact with the saliva of those infected are inefficient modes of transmission. No risk factors are identified in approximately 10% of cases.

Epidemiology

Worldwide, more than 170 million persons have hepatitis C virus (HCV) infection, [27] of whom 71 million have chronic infection. [1] The Eastern Mediterranean region and Europe have the highest prevalence (2.3% and 1.5%, respectively), with other regions having an estimated prevalence of 0.5%-1.0%. [1] Jeddah City, Saudi Arabia, has a reported HCV prevalence of 0.38%. [28] The prevalence rates in healthy blood donors are 0.01%-0.02% in the United Kingdom and northern Europe, 1%-1.5% in southern Europe, and 6.5% in parts of equatorial Africa. [29] Prevalence rates as high as 22% are reported in Egypt and are attributed to the use of parenteral antischistosomal therapy. [2] Race-, sex-, and age-related differences in incidence In the United States, HCV infection is more common among minority populations, such as black and Hispanic persons in association with lower economic status and educational levels. In addition, in the United States, genotype 1 is more prevalent in black individuals than in other racial groups. Racial disparity has also been reported in the all-cause mortality in patients with HCV infection. A 2017 National Health and Nutrition Examination Survey (NHANES) III report found that having chronic HCV was associated with a 2.63-fold higher all-cause mortality rate ratio (MRR) compared with being HCV negative. [30] The highest MRR of having chronic HCV compared to being HCV negative was 7.48 among Mexican Americans, 2.67 among non-Hispanic white persons, and 2.02 among non-Hispanic black persons. Mexican Americans with chronic HCV had approximately a seven-fold higher mortality than HCV-negative individuals. [30] No sex preponderance occurs with HCV infection. [5] In the United States, 65% of people with HCV infection are aged 30-49 years. Those who acquire the infection at a younger age have a somewhat better prognosis than those who are infected later in life. Infection is uncommon in persons aged 20 years and younger but is more prevalent in persons older than 40 years. [31, 32] Data suggest that an association exists between age and transmission route, such as nonsterile medical procedures, including vaccination and parenteral drug treatment. [33]

Prognosis

Infection with hepatitis C virus (HCV) is self-limited in 15% to 50% of patients. [1, 16, 34, 35] In a review of HCV infection, it was reported that chronic infection developed in 70%-80% of patients. [12] Cirrhosis develops within 20 years of disease onset in 20% of persons with chronic infection. [36] The onset of chronic hepatitis C infection early in life often leads to less serious consequences. [32, 33] Hepatitis B virus (HBV) coinfection, iron overload, and alpha 1-antitrypsin deficiency may promote the progression of chronic HCV infection to HCV-related cirrhosis. [34, 35] Two studies of compensated cirrhosis in the United States and Europe showed that decompensation occurred in 20% of patients and that hepatocellular carcinoma (HCC) occurred in approximately 10% of patients. [37, 38] The survival rate at 5 and 10 years was 89% and 79%, respectively. HCC develops in 1-4% of patients with cirrhosis each year, after an average of 30 years. The risk of cirrhosis and HCC doubles in patients who acquired HCV infection via transfusion. [39] Progression to HCC is more common in the presence of cirrhosis, alcoholism, and HBV coinfection. Bellentani et al [40] and Hourigan et al [41] reported that the rate and likelihood of disease progression is influenced by alcohol use, immunosuppression, sex, iron status, concomitant hepatitis, and age of acquisition. In an observational study of Veterans Affairs (VA) HCV clinical registry data on 128,769 patients, McCombs et al found that those who achieved an undetectable HCV viral load had a decreased risk of subsequent liver morbidity and death. [42, 43] Viral load suppression reduced the risk for future liver events by 27% (eg, compensated/decompensated cirrhosis, HCC, or liver-related hospitalization), as well as reduced the risk of death by 45%, relative to patients who did not achieve viral load suppression. [42, 43] Additionally, patient race/ethnicity and HCV genotypes affected the risk of future liver events and death. The risk for all liver events and death was higher in white patients relative to black patients, and those with HCV genotype 3 had a higher risk for all study outcomes compared to patients who had HCV genotype 2 (lowest risk) or genotype 1. [42, 43]

Patient Education

Patients with hepatitis C virus (HCV) infection should be advised to abstain from alcohol use, as it accelerates the onset of cirrhosis and end-stage liver disease. Patients should be informed about the low but present risk for transmission to sex partners. Optimally, patients should use barrier protection during sexual intercourse. [44] Sharing personal items that might have blood on them, such as toothbrushes or razors, should be avoided. Patients with hepatitis C should not donate blood or organs. One exception is in patients with HCV who require liver transplantation. Arenas et al showed that liver transplant recipients who received liver grafts from HCV-positive donors had 5-year survival rates comparable to recipients who received grafts from HCV-negative donors. [45] Given the shortage of organs and the long waiting list, this strategy has proven safe and effective. Patients should also check with a healthcare professional before taking any new prescription pills, over-the counter drugs, or supplements, as these can potentially damage the liver.

Presentation

History Acute hepatitis C virus (HCV) infection becomes chronic in 70% of patients, which represents a high rate of chronicity for a viral infection. Most patients with chronic hepatitis C are asymptomatic or may have nonspecific symptoms such as fatigue or malaise in the absence of hepatic synthetic dysfunction. Patients with decompensated cirrhosis from HCV infection frequently have symptoms typically observed in other patients with decompensated liver disease, such as sleep inversion and pruritus. Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension. These include mental status changes (hepatic encephalopathy), ankle edema and abdominal distention (ascites), and hematemesis or melena (variceal bleeding). Symptoms often first develop as clinical findings of extrahepatic manifestations of HCV and most commonly involve the joints, muscle, and skin. In a large study of the extrahepatic manifestations of HCV, 74% of medical workers with HCV infection demonstrated extrahepatic manifestations, of which the following were the most common [46] :

• Arthralgias (23%)

• Paresthesias (17%)

• Myalgias (15%)

• Pruritus (15%)

• Sicca syndrome (11%)

In addition, sensory neuropathy has been reported as an extrahepatic manifestation in 9% of patients with HCV infection. [47] Risk factors for manifestations of extrahepatic chronic hepatitis C infection include advanced age, female sex, and liver fibrosis. Patients also present with symptoms that are less specific and are often unaccompanied by discrete dermatologic findings. Pruritus and urticaria are examples of less specific clues to underlying HCV infection in the appropriate setting (eg, posttransfusion, organ transplantation, surgery, injection drug use, injury of the nasal mucosa from snorting cocaine through shared straws). Patients with ongoing pathology associated with chronic hepatitis C that eventually results in organ failure can present with symptoms and signs in the skin. Pruritus, dryness, palmar erythema, and yellowing of the eyes and skin are examples of less specific findings in patients with end-stage liver disease with cirrhosis; these findings provide clues that lead to further evaluation of the underlying causes. Chronic hepatitis C has a strong association with pruritus. Indeed, some authorities believe that all patients with unexplained pruritus should be investigated for HCV infection. [48]

Physical Examination Most patients with hepatitis C virus (HCV) infection do not have abnormal physical examination findings until they develop portal hypertension or decompensated liver disease. One exception is patients with extrahepatic manifestations of HCV infection, such as porphyria cutanea tarda or necrotizing vasculitis. Signs in patients with decompensated liver disease include the following:

• Hand signs: Palmar erythema, Dupuytren contracture, asterixis, leukonychia, clubbing

• Head signs: Icteric sclera, temporal muscle wasting, enlarged parotid, cyanosis

• Fetor hepaticus

• Gynecomastia, small testes

• Abdominal signs: Paraumbilical hernia, ascites, caput medusae, hepatosplenomegaly, abdominal bruit

• Ankle edema

• Scant body hair

• Skin signs: Spider nevi, petechiae, excoriations due to pruritus

Other common extrahepatic manifestations include the following:

• Cryoglobulinemia

• Membranoproliferative glomerulonephritis

• Idiopathic thrombocytopenic purpura

• Lichen planus [49] (see the images below)

• Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology

• 
  

Lichen planus (oral lesions). Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus (volar wrist). Courtesy of Walter Reed Army Medical Center Dermatology

• Keratoconjunctivitis sicca

• Raynaud syndrome

• Sjögren syndrome

• Porphyria cutanea tarda

• Necrotizing cutaneous vasculitis

Approximately 10%-15% of affected patients have symptoms/signs such as weakness, arthralgias, and purpura; these are often related to vasculitis. The precise pathogenesis of these extrahepatic complications has not been determined, although most are the clinical expression of autoimmune phenomena.

Differential Diagnoses

• Autoimmune Hepatitis

• Cholangitis

• Viral Hepatitis

Workup

Approach Considerations

Please note that guidelines for the current diagnostic workup and management of hepatitis C (HCV) infection continue to evolve rapidly. Clinicians are advised to refer frequently to HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (ISDA). Other resources can also be found at the IDSA website.

AASLD/ISDA guidelines The AASLD/ISDA recommend the following for initial HCV testing and followup [9] :

• Initial HCV testing: HCV-antibody test; if the result is positive, confirm current infection with a sensitive HCV-RNA test.

• Negative HCV-antibody test but clinical suspicion of liver disease: Test for HCV RNA or followup testing for HCV antibody if HCV exposure occurred within the past 6 months; consider testing for HCV RNA in immunocompromised individuals.

• Reinfection after previous spontaneous or treatment-related viral clearance: Obtain initial HCV-RNA testing (because an HCV-antibody test is expected to be positive).

• Before initiation of antiviral therapy: Obtain quantitative HCV-RNA testing to document baseline viral load.

• Selection of the most appropriate antiviral regimen: Use HCV genotype testing for guidance.

• Positive HCV-antibody test with negative HCV RNA by polymerase chain reaction (PCR): Inform patients they do not have evidence of current (active) HCV infection.

All patients with HCV infection are recommended to have an evaluation for advanced fibrosis with the use of liver biopsy, imaging, and/or noninvasive markers to aid in decision making regarding treatment strategies and to determine whether additional measures for the management of cirrhosis should be initiated (eg, screening for hepatocellular carcinoma). [9] Patients in whom therapy is deferred should undergo repeat liver assessment on an ongoing basis.

WHO guidelines The World Health Organization (WHO) recommends nucleic acid testing for qualitative or quantitative HCV RNA detection as well as for test of cure at 12 or 24 weeks following antiviral treatment completion. [50] In areas with limited resources, the WHO suggests using the aminotransferase/platelet ratio index (APRI) or the fibrosis-4 (FIB-4) score for evaluating hepatic fibrosis rather than other noninvasive tests that require more resources (eg, elastography, FibroTest), as follows [50] :

• APRI = [(AST (IU/L)/AST_ULN (IU/L))×100]/platelet count (10 9 /L)

• FIB-4= age (years) × AST (IU/L)/platelet count (10 9)/L × [ALT (IU/L)1/2]

where ALT is alanine aminotransferase, AST is aspartate aminotransferase, IU is international unit, and ULN is the upper limit of normal. Serologic screening for HCV involves an enzyme immunoassay (EIA). These assays are 97% specific but cannot distinguish acute from chronic infection. A rapid antibody test for HCV is available. The recombinant immunoblot assay is used to confirm HCV infection. A meta-analysis comparing point-of-care screening tests (POCTs) with rapid diagnostic tests (RDTs) indicated that POCTs are highly accurate for diagnosing hepatitis C. [51, 52] POCTs do not require special equipment or electricity and are more robust than RDTs at high temperatures; thus, they may enable expanded screening. Healthcare personnel who sustain a needle-stick injury involving an HCV-infected patient should undergo PCR testing for HCV immediately and then every 2 months for 6 months. If HCV infection is diagnosed, therapy can be instituted. Other baseline studies include the following [9] :

• Complete blood cell (CBC) count with differential

• International normalized ratio (INR)

• Liver function tests, including levels of ALT and AST, alkaline phosphatase, albumin, and total and direct bilirubin

• Calculated glomerular filtration rate (eGFR)

• Thyroid function studies

• Screening tests for coinfection with human immunodeficiency virus ( HIV) or hepatitis B virus (HBV)

• Screening for alcohol abuse, drug abuse, and/or depression

• Hepatitis B virus (HBV) testing with hepatitis B surface antigen (HBsAg) (to identify coinfection), as well as hepatitis B surface antibody (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) (for evidence of previous infection)

• Serum pregnancy testing in women of childbearing age before initiating a treatment regimen that includes ribavirin or that includes direct-acting antiviral agents (DAAs) without ribavirin

The CBC demonstrates thrombocytopenia in approximately 10% of patients. Low thyroxine levels are found in approximately 10% of patients, as well. Stress testing may be necessary in appropriate patients. An ophthalmologic examination may also be necessary. In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a one-time blood test for HCV infection in baby boomers, the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965). [53] In June 2013, The US Preventive Services Task Force (USPSTF) also updated its 2004 HCV screening and treatment recommendations, advocating a one-time screening for all persons born between 1945 and 1965. The new recommendation arose from the fact that a lack of universal blood screening for the virus prior to 1992 placed those born between the mid-1940s and mid-1960s at an increased risk of exposure to HCV. [54, 55, 56] It was estimated that one-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. [53] Screening for HCV in the emergency department (ED) has been found to be feasible, albeit costly. [57, 58] All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventive and/or treatment services, as appropriate. [53]

Hepatitis C Antibody Test

Hepatitis C virus (HCV) infection is diagnosed through the detection of antibodies to recombinant HCV polypeptides. However, antibody assays do not distinguish past from current HCV infection. For this reason, follow-up testing for HCV RNA is necessary to distinguish between ongoing or prior infection in persons with HCV antibodies. Several generations of US Food and Drug Administration (FDA)-approved enzyme immunoassays (EIAs) to measure antibodies against NS4, core, NS3, and NS5 sequences are commercially available. [59] The third-generation assay is 97% sensitive. It can detect HCV antibody at an average of 8 weeks after the onset of infection. The recombinant immunoblot assay, previously used to confirm HCV infection, is not necessary owing to the improved sensitivity of the positive EIA tests with currently recommended higher cutoff values. False-negative results for the presence of HCV antibody can occur in persons with compromised immune systems, such as those with human immunodeficiency virus (HIV) infection, renal failure, or HCV-associated essential mixed cryoglobulinemia. False-positive EIA results can also occur; the likelihood of a false-positive result is greater in persons without risk factors and in those without signs of liver disease, such as blood donors or healthcare workers. In 2010, the FDA approved the OraQuick HCV Rapid Antibody Test, which can be used for persons at risk for hepatitis or for those with signs or symptoms of hepatitis. The test strip can be used with a sample collected from a fingerstick or venipuncture whole blood. [60]

Qualitative and Quantitative Assays for HCV RNA

Qualitative assays Qualitative assays can be used to test for hepatitis C virus (HCV) RNA. HCV RNA can be detected in blood using amplification techniques such as polymerase chain reaction (PCR) or transcription-mediated amplification (TMA). The following are a few of the FDA-approved PCR-based tests for qualitative HCV RNA detection [61] :

• COBAS AmpliScreen HCV Test, version 2.0: PCR with a lower limit of detection of 50 IU/mL

• Hepatitis C Virus Reverse-Transcriptase (RT) PCR Assay

• UltraQual HCV-RT PCR Assay

• Versant HCV RNA Qualitative Assay: TMA with a lower limit of detection of 9.6 IU/mL

Quantitative assays Quantitative assays ascertain HCV RNA quantity in blood, using signal amplification (branched DNA [bDNA] assay) or target amplification techniques (PCR, TMA). RT-PCR is more sensitive than bDNA testing. The HCV RNA level in blood helps predict the likelihood of a response to treatment, and the change in HCV RNA level can also be used to monitor the therapeutic response. The same quantitative test should be used throughout therapy to avoid confusion, and results should be reported in international units (IU) to standardize data. The Versant HCV RNA Assay, version 3.0, is based on bDNA technology and has a dynamic range of 615-7,700,000 IU/mL. Another FDA-approved HCV quantitative test is the Aptima HCV Quant Dx Assay; its limit of detection is 3.9 IU/mL in plasma and 3.4 IU/mL in serum. [62] The following are the best laboratory evidence of acute HCV infection:

• A positive HCV RNA test in the setting of a negative HCV antibody test (seronegative “window” period)

• A positive HCV antibody test after a prior negative HCV antibody test (seroconversion)

It should be noted that impaired antibody production in immunosuppressed individuals may result in misleading information.

HCV Genotyping Hepatitis C virus (HCV) genotyping is helpful for predicting the likelihood of response and duration of treatment. Genotyping can be performed by direct sequence analysis, reverse hybridization to genotype-specific oligonucleotide probes, or restriction fragment length polymorphisms (RFLPs). In June 2013, the FDA approved the Abbott RealTime HCV Genotype II test, which, by analyzing a sample of an infected patient’s blood plasma or serum, can differentiate HCV genotypes 1, 1a, 1b, 2, 3, 4, and 5. This test is approved for use in adult, non-immunocompromised patients with known chronic HCV infection but has not been approved for diagnostic use or as a screening test for HCV genetic material. FDA approval was based partly on a comparison of the test's accuracy with that of a validated gene-sequencing method. [63, 64] Other genotype tests are available, including the following, although none have been approved by the FDA [65] :

• Trugene HCV 5'NC Genotyping Kit: Based on direct sequencing followed by comparison with a reference sequence database

• Line Probe Assay (Inno LiPA HCV II): Based on reverse hybridization of PCR amplicons on a nitrocellulose strip coated with genotype-specific oligonucleotide probes

• Versant HCV Genotyping Assay (INNO-LiPA) 2.0: Next-generation line-probe assay

In addition to HCV genotype, a growing body of research indicates that patient genetics play a role in the response to treatment. The single-nucleotide polymorphism (SNP) rs12979860, located near the IL28B gene on chromosome 19, which encodes type III interferon, is associated with more than a two-fold difference in the rate of sustained virologic response (SVR) to antiviral treatment with pegylated interferon and ribavirin. This SNP can be detected by PCR and is an independent predictor of SVR regardless of HCV genotype. [66]

Other Testing

Della Rossa et al reported that cryoglobulins are found in as many as 50% of persons with hepatitis C viral infection. [67] Hepatitis C virus (HCV) is the primary cause of essential mixed cryoglobulinemia (ie, type 2 cryoglobulinemia); as many as 90% of affected persons have HCV viremia. Cryoprecipitates usually contain large amounts of HCV antigens and antibodies. Vasculitis, arterial hypertension, purpura, lichen planus, arthralgias, and low thyroxine levels were associated with titers positive for cryoglobulin. Other common serologic findings in patients with chronic HCV infection include one or more of the following [68] :

• Antinuclear antibody (ANA)

• Rheumatoid factor

• Anticardiolipin antibody

• Antithyroid antibody

• Anti–smooth muscle antibody

Additional evaluations may include testing for infection with human immunodeficiency virus (HIV), screening for susceptibility to hepatitis A and hepatitis B virus infections, and for other underlying causes of liver disease (eg, autoimmune liver disease, hemochromatosis, Wilson disease, α1-antitrypsin deficiency).

Liver Biopsy

Liver biopsy is not considered mandatory before the initiation of treatment for hepatitis C, but it may be helpful for assessing the activity and severity of hepatitis C virus-related liver disease. However, some experts recommend biopsy only in the following situations:

• The diagnosis is uncertain

• Other coinfections or disease may be present

• The patient being considered for treatment has normal liver enzyme levels and no extrahepatic manifestations

• The patient is immunocompromised

Histologic Findings Lymphocytic infiltration, moderate degrees of inflammation and necrosis, and portal or bridging fibrosis are noted in hepatitis C. Regenerative nodules are seen in patients with cirrhosis. Some patients also may have findings indicative of hepatocellular carcinoma (HCC). Most pathologists provide separate measurements of disease activity (grade) and fibrosis (stage). Many scoring systems are used, including the Ishak (6-point scale) and the Knodell histologic activity index (18-point score); although both scoring systems are useful for assessing improvements in histologic findings in studies, they are impractical for clinical use because of interobserver disagreement. The METAVIR score was developed by the French METAVIR Cooperative Study Group and reported by Bedossa and Poynard in 1996 [69] ; it is frequently used in European trials. This score consists of a 3-point activity scale and 4-point fibrosis score, with good agreement among pathologists. In the United States, many pathologists use a scale described by Batts and Ludwig (Batts-Ludwig score) in 1995, [70] which consists of an activity grade (0-4) and a fibrosis stage (0-4). HCC may occur rapidly following treatment with direct-acting antiviral agents (DAAs) in HCV-related cirrhosis; thus, patients with cirrhosis should be closely monitored after DAA therapy. [71] Most of the neoplastic HCC nodules appear to have aggressive imaging features of microvascular invasion in this setting. [71] Noninvasive methods of assessing hepatic fibrosis are in development. Current serum assays are directed at measuring breakdown products of extracellular matrix constituents (eg, glycoproteins, propeptides) and their regulatory enzymes (eg, lysyl oxidase, lysyl hydroxylase, propyl hydroxylase).

Radiologic Studies

A liver stiffness test (FibroScan) is available as a noninvasive method of staging liver disease in persons with chronic hepatitis C. Obesity, female sex, operator inexperience, and age older than 52 may give invalid results. Falsely high estimates of liver fibrosis have also been reported with acute inflammation and recent food intake. On December 17, 2014, the FDA gave marketing approval for the Hepatiq radiologic image processing system. [72, 73] The software application uses quantitative analysis of nuclear medicine liver-spleen images to determine the severity of liver disease and to predict clinical outcomes. [73] The developer noted that Hepatiq "automates the Quantitative Liver Spleen Scan (QLSS) that has been proven to be an accurate predictor of clinical outcomes in the recently concluded HALT-C [H epatitis C A ntiviral L ong-term T reatment against C irrhosis] trial." [73] The HALT-C trial was a multicenter, randomized controlled study that evaluated whether long-term interferon would suppress HCV, prevent progression to cirrhosis, prevent liver cancer, and reduce the need for liver transplantation. [74] In a study that compared abdominal computed tomography (CT) and laboratory data from 469 HCV-infected patients with those of histopathlogic METAVIR fibrosis scores, investigators found that the use of multiparametic CT evaluation of HCV-associated liver fibrosis further improved its diagnostic performance over that of individual parameters. [75] These parameters included hepatosplenic volumetrics, texture features, liver surface nodularity (LSN) score, and linear CT measurements, as well as the fibrosis-4 (FIB-4) score and aspartate transaminase-to-platelets ratio index (APRI). The diagnostic performance of LSN plus FIB-4 scores approached that of panels with more parameters and compared favorably with elastography. [75]

Treatment & Management

Approach Considerations

Please note that the guidelines for the current diagnostic workup and management of hepatitis C (HCV) infection continue to rapidly evolve. Clinicians are advised to refer frequently to HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (ISDA). Spontaneous resolution of acute HCV infection may occur in 15% to 50% of patients. [1, 16, 34, 35] Monitoring for spontaneous clearance for a minimum of 6 months before initiating treatment is therefore recommended. Patients with acute HCV infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). However, IFN-sparing regimens are safer and are currently recommended for the treatment of acute HCV infection as with chronic HCV infection. Hepatitis C has become a curable disease with the use of antiviral agents (>95%). [1] Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). [9, 34] These guidelines are updated often. The AASLD/ISDA guidelines previously proposed that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need. The recommendations included the following [34] :

• Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extrahepatic complications are to be given the highest priority for treatment.

• Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment.

• Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis).

More recently, the AASLD/ISDA guidelines have removed their prioritization tables but continue to strongly recommend treatment for all patients with chronic HCV infection, barring those with shortened life expectancies that cannot be resolved by HCV treatment, liver transplantation, or another directed therapy. [9] With the exception of pregnant women, the World Health Organization recommends treatment be offered to all individuals aged 12 years or older diagnosed with HCV, regardless of their disease stage. [50] Initiating treatment earlier for patients with lower stage fibrosis may extend the benefits of sustained virologic response (SVR). In a long-term follow-up study, 820 patients with METAVIR stage F0 or F1 fibrosis confirmed by biopsy were followed for up to 20 years. The 15-year survival rate was statistically significantly better for those who experienced SVR (93%) compared to those whose treatment had failed (82%) or for those who remained untreated (88%) (P =.003). [76] Treatment of chronic HCV infection has two goals. The first is to achieve sustained eradication of HCV (ie, SVR), which is defined as the persistent absence of HCV RNA in serum 12 weeks after completing antiviral treatment. The second goal is to prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver transplantation. In a prospective study of 158 patients with chronic HCV infection and liver cirrhosis who received interferon-free therapies with direct-acting antiviral agents (DAAs) and 184 control HCV patients with untreated liver cirrhosis, the short-term risk (1.5 years) for de novo HCC did not change. [77] Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is widely recommended for patients with elevated serum alanine aminotransferase (ALT) levels who meet the following criteria [6] :

• Age older than 18 years

• Positive HCV antibody and serum HCV RNA test results

• Compensated liver disease (eg, no hepatic encephalopathy or ascites)

• Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm 3, serum creatinine < 1.5 mg/dL)

• Willingness to be treated and to adhere to treatment requirements

• No contraindications for treatment

A further criterion is liver biopsy findings consistent with a diagnosis of chronic hepatitis. However, a pretreatment liver biopsy is not mandatory. It may be helpful in certain situations, such as in patients with normal transaminase levels, particularly those with a history of alcohol dependence, in whom little correlation may exist between liver enzyme levels and histologic findings. Viral load suppression reduces the risk of hepatitis C liver morbidity and mortality. In an observational study of Veterans Affairs (VA) HCV clinical registry data from 128,769 patients that spanned more than a decade, researchers found that those who achieved an undetectable HCV viral load had a decreased risk of subsequent liver morbidity and death. [78, 79] Viral load suppression reduced the risk for future liver events by 27% (eg, compensated/decompensated cirrhosis, HCC, or liver-related hospitalization) as well as reduced the risk of death by 45%, relative to patients who did not achieve viral load suppression. Among the entire study population, only 24% had been treated previously for HCV; of these patients, only 16% (4% of all patients) achieved an undetectable viral load. [78, 79] Patient race/ethnicity and HCV genotypes also affected the risk of future liver events and death. The risk for all liver events and death was higher in white patients relative to black patients, and those with HCV genotype 3 had a higher risk for all study outcomes compared to patients who had HCV genotype 2 (lowest risk) or genotype 1. [78, 79]

Interferons and Pegylated Interferons The two most frequently used recombinant interferon (IFN) preparations in clinical trials have been IFN alfa-2b (Intron-A) and IFN alfa-2a (Roferon-A), which differ from each other by only a single amino acid residue. IFN alfacon-1 (Infergen), or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs. Roferon-A was discontinued from the market in 2007 and Infergen was discontinued from the market in 2013. The addition of propylene glycol (PEG) molecules to IFN has led to the development of long-lasting IFNs that have better sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C. Two PEG-IFN preparations are available for the treatment of chronic hepatitis C. PEG-IFN alfa-2b (PEG-Intron) consists of IFN alfa-2b attached to a single 12-kd PEG chain; it is excreted by the kidneys. PEG-IFN alfa-2a (Pegasys) consists of IFN alfa-2a attached to a 40-kd branched PEG molecule; it is metabolized predominantly by the liver. IFN monotherapy in acute hepatitis C Although the short courses of standard IFN monotherapy introduced in the 1980s by Hoofnagle et al, [80] Davis et al, [10] and Di Bisceglie et al [81] led to sustained improvement in liver disease and loss of virus in less than 10% of patients, these therapies were the first to cure chronic viral hepatitis. Jaeckel et al reported that treatment with IFN alfa-2b prevented chronic infection in 98% of a group of 44 German patients with acute hepatitis C. [82] In this study, patients received 5 million U/day of IFN alfa-2b subcutaneously for 4 weeks and then three times per week for another 20 weeks; the IFN alfa-2b was well tolerated in all patients but one. [82] Because it has the poorest safety profile of all the HCV antiviral agents, with few exceptions PEG-IFN is no longer recommended in combination regimens. Spontaneous resolution of acute HCV infection may occur in 15% to 50% of patients. [1, 16, 34, 35] Monitoring for spontaneous clearance for a minimum of 6 months before initiating any treatment is therefore recommended.

Interferons and Ribavirin A major advance in the treatment of chronic hepatitis C was the addition of the oral nucleoside analogue ribavirin to the interferon (IFN) regimen. As reported in the landmark 1998 studies by McHutchison et al [83] and Poynard et al, [84] IFN alfa-2b and ribavirin combination therapy for 6-12 months resulted in sustained eradication rates of 30%-40%. However, patients with HCV genotype 1 who were treated for 12 months had a much less favorable response than patients infected with genotypes 2 and 3 who received a 6-month course of therapy. PEG-IFN therapy with ribavirin The addition of ribavirin to PEG-IFN heralded a new era in the treatment of chronic HCV. The benefits of combination therapy were documented in three landmark trials: Manns et al in 2001, [85] Fried et al in 2002, [86] and Hadziyannis et al in 2004. [87] Manns et al reported a significantly higher sustained virologic response (SVR) rate in patients given higher-dose PEG-IFN alfa-2b plus ribavirin than in patients given lower-dose PEG-IFN alfa-2b plus ribavirin or those who received IFN alfa-2b plus ribavirin. [85] Adverse-effect profiles in the three treatment groups were similar. Secondary analyses identified body weight and HCV RNA viral load less than 1 million copies/mL as important predictors of SVR. (See the image below.)

Pegylated interferon alfa-2b plus ribavirin therapy for chronic hepatitis C

Fried at al found that patients who received PEG-IFN alfa-2a plus ribavirin had a significantly higher SVR rate than patients who received IFN alfa-2b plus ribavirin (56% vs 44%) or PEG-IFN alfa-2a alone (56% vs 29%). [86] The SVR rates for patients with HCV genotype 1 were 46%, 36%, and 21%, respectively, for the three regimens. Hadziyannis et al reported that in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks, and standard-dose ribavirin was statistically superior to low-dose ribavirin. [87] In this study, 1311 persons were randomized to PEG-IFN alfa-2a at 180 mcg/wk for 24 or 48 weeks plus a low dose (800 mg/day) or standard weight-based dose (1000 or 1200 mg/day) of ribavirin. [87] In patients with HCV genotypes 2 or 3, there were no statistically significant differences in SVR rates in the four treatment groups. In a study of ribavirin in combination with either PEG-IFN alfa-2b or PEG-IFN alfa-2a for the treatment of chronic HCV infection, Ascione et al reported a higher SVR rate with PEG-IFN alfa-2a (68%) than with PEG-IFN alfa-2b (54.4%). [88] SVR rates were not statistically different in patients with a baseline HCV RNA of 500,000 IU/mL or below or in those with cirrhosis. [88] In a similar trial, Rumi et al reported that treatment with ribavirin plus PEG-IFN alfa-2a resulted in a significantly higher SVR rate than ribavirin plus PEG-IFN alfa-2b. The two regimens showed a similar safety profile. [89] In a study of patients coinfected with HCV and human immunodeficiency virus (HIV) with compensated cirrhosis, Mira et al found that SVR to PEG-IFN plus ribavirin significantly reduced the incidence of liver-related decompensations and overall mortality. [90] The probability of hepatic decompensation was 0% at 1 year and 4% at 3 years for SVR patients, compared with 15% and 32%, respectively, for non-SVR patients. The probability of overall mortality was 0% at 1 year and 4% at 3 years for SVR patients, compared with 12% and 20%, respectively, for non-SVR patients. [90] In conclusion, treatment with PEG-IFN alfa-2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotype 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks. [91] Response to therapy of HCV genotype 1 (ie, achievement of SVR) can be predicted by identifying the single nucleotide polymorphisms (SNPs) located in the region of interleukin (IL)-28B gene through genome-wide association studies (GWAS). Patients with the CC genotype of the IL-28B have a much more favorable response as compared to the CT or TT genotype (70% vs 25%-30%). Testing for IL-28B genotype is thus a useful tool in the management of patients with interferon and ribavirin combination therapy. [92] Adverse effects

Adverse effects are common with IFN and ribavirin combination therapy. Approximately 75% of patients experience one or more adverse effects. Adverse effects of IFN include the following:

• Hematologic complications (ie, neutropenia, thrombocytopenia)

• Neuropsychiatric complications (ie, memory and concentration disturbances, visual disturbances, headaches, depression, irritability)

• Flulike symptoms

• Metabolic complications (ie, hypothyroidism, hyperthyroidism, low-grade fever)

• Gastrointestinal complications (ie, nausea, vomiting, weight loss)

• Dermatologic complications (ie, alopecia)

• Pulmonary complications (ie, interstitial fibrosis)

Adverse effects of ribavirin include the following:

• Hematologic complications (ie, hemolytic anemia)

• Reproductive complications (ie, birth defects)

• Metabolic complications (ie, gout)

Because of the risk of reproductive complications from ribavirin, it is recommended that patients and their partners not become pregnant while either is on therapy as well as for 6 months after the completion of treatment. [9] Growth factors, such as granulocyte-stimulating factor (GSF) and erythropoietin, are frequently used to counteract the adverse hematologic effects of IFN and ribavirin, respectively. Despite the encouraging early results reported by Afdhal et al [93] and Van Thiel et al, [94] the cost-effectiveness data supporting the routine use of these agents as a means of avoiding IFN and ribavirin dose reductions are insufficient. In November 2012, the FDA approved eltrombopag (Promacta), an oral thrombopoietin agonist, for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of IFN-based therapy. The approval was based on results from the phase 3 E ltrombopag to IN itiate and Maintain Interferon A ntiviral Treatment to B enefit Subjects with Hepatitis C related L iver DiseasE (ENABLE) 1 and 2 trials, which showed eltrombopag significantly reduced the time to the first IFN dose reduction compared with placebo. [95, 96] Because of this, a significant improvement in the virologic response was observed in the eltrombopag group compared with placebo. These randomized, double-blind, placebo-controlled, multicenter studies collectively enrolled 1521 patients with platelet counts less than 75,000/mcL. ENABLE 1 utilized PEG-IFN alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilized PEG-IFN alfa-2b plus ribavirin. In patients who are at risk of depression or who develop depression during treatment, any antidepressant is better than none. Because available evidence suggests that all antidepressants will have an effect, Schaefer et al reported that treatment must be individualized on the basis of the adverse effect profile, drug-to-drug interactions, and general considerations (eg, speed of onset, efficacy). [97] Fatigue is common in patients with chronic hepatitis C, but it is poorly associated with biochemical parameters. Sustained response is accompanied by substantial improvement of fatigue. [98] With the availability of newer directly acting agents (DAAs), and due to the poor safety profile of PEG-IFN, PEG-IFN is no longer recommended in combination regimens. However, in resource-limited settings, PEG-IFN alfa-2a continues to have a role in the management of acute and chronic HCV, as well as in those with end-stage renal disease and individuals who don't have access to or who are not candidates for DAA therapy. [99] Ribavirin continues to be used in combination with sofosbuvir alone or other combinations.

Direct-Acting Antiviral Agents (DAAs) Relatively recently, several antiviral agents have been developed to specifically target various sites of hepatitis C (HCV) viral replication. Similar to the antiretroviral drugs, these agents have been approved by the FDA in various combinations to interrupt HCV replication at different sites, with reported 90%-95% sustained virologic response (SVR) rates in treated patients versus 40%-55% in those completing treatment with dual-therapy pegylated interferon (PEG-IFN) plus ribavirin. [100] However, clinicians should be aware that baseline resistance-associated substitutions (RASs) may impair treatment response to direct-acting antiviral agents (DAAs), particularly baseline NS5A resistance in DAA-naïve HCV patients. [101] Currently available agents and their target sites are outlined below. NS3/4 targeting protease inhibitors

• Simeprevir

• Paritaprevir

• Grazoprevir

• Glecaprevir

NS5B targeting polymerase inhibitors

• Nucleotide: Sofosbuvir

• Non-nucleotide: Dasabuvir

NS5A targeting agents

• Ledipasvir

• Ombitasvir

• Elbasvir

• Velpatasvir

• Pibrentasvir

Overview of WHO and AASLD/IDSA guidelines The World Health Organization (WHO) recommends the use of pangenotypic DAA regimens to treat chronic HCV-infected individuals aged 18 years and older. [50] All pangenotypic DAAs (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, sofosbuvir/velpatasvir/voxilaprevir) showed similar SVR12 rates. SAEs and DAEs also were comparable between the pangenotypic DAAs and ledipasvir/sofosbuvir. There are very limited data in treatment-naïve patients for the triple DAA combination (sofosbuvir/velpatasvir/voxilaprevir). WHO recommends preserving this regimen for patients who have failed previous DAA treatment (in line with AASLD/IDSA recommendations). [50] WHO and AASLD/IDSA recommendations for chronic HCV-infected teens aged 12-17 years or weighing at least 35 kg (77.16 lb) are as follows [50] :

• Genotype 1, 4, 5, and 6: Sofosbuvir/ledipasvir for 12 weeks (treatment naïve without cirrhosis or with compensated cirrhosis; treatment experienced without cirrhosis) or 24 weeks (treatment experienced with compensated cirrhosis)

• Genotype 2: Sofosbuvir/ribavirin for 12 weeks (treatment naïve or experienced, without cirrhosis or with compensated cirrhosis)

• Genotype 3: Sofosbuvir/ribavirin for 24 weeks (treatment naïve or experienced, without cirrhosis or with compensated cirrhosis)

• Genotypes 4, 5, or 6: Sofosbuvir/ledipasvir for 12 weeks (treatment naïve or experienced, without cirrhosis or with compensated cirrhosis)

In chronic HCV-infected children younger than 12 years, the WHO recommends deferring DDA treatment until they are aged 12, as well as to discontinue the use of interferon-based regimens in this population. As physicians await approval and availability of DAAs for children younger than 12 years of age, treatment with IFN plus ribavirin may be considered for those children with genotype 2 or 3 infection, and severe liver disease. This also includes children at higher risk of progressive disease, including those with HIV coinfection, thalassemia major, and childhood cancer survivors. Clinical trial results of DDAs in children aged 6-12 years are starting to emerge. [50] NS3/4 targeting protease inhibitors These agents target the NS3/4 serine protease to inhibit HCV replication. In 2011, boceprevir and telaprevir were approved to treat genotype 1 HCV infection. However, treatment with these two agents is no longer recommended and they have been discontinued from the market. Their use has been superseded by the more recently approved protease inhibitors active against a broader range of viruses. Simeprevir (Olysio) was FDA approved in November 2013. The QUEST 1 and QUEST 2 phase 3 trials assessed the efficacy of simeprevir in 785 adult, treatment-naïve patients with chronic HCV genotype 1. Results showed that 80% and 81% of patients treated with simeprevir (plus PEG-IFN alfa and ribavirin) achieved SVR at 12 weeks (SVR12) compared with the PEG-IFN alfa and ribavirin control groups (50%). [102] In the PROMISE study, 393 patients who had previous relapse after completing HCV treatment with PEG-IFN and ribavirin, were randomized to receive either 150 mg of once-daily simeprevir for 12 weeks plus PEG-IFN and ribavirin for 24 or 48 weeks based on response guided treatment criteria (simeprevir group) or PEG-IFN and ribavirin alone for 48 weeks (control group). In this study, the SVR12 was 79% in the simeprevir treatment group compared to 37% with PEG-IFN and ribavirin alone. [102] The presence of the Q80K HCV genotype (GT) 1a polymorphism (commonly found in GT1a patients in the United States) at baseline had a substantial negative impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. [103] In the HPC3007 trial of HCV, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group. [103] Simeprevir was approved by the FDA for the treatment of HCV genotype 4 monoinfected and HCV/human immunodeficiency virus (HIV)-coinfected patients as a component of a combination antiviral treatment regimen that includes PEG-IFN and ribavirin. [104] The open-label, single-arm study (RESTORE) included 107 patients with HCV GT4 infection. Treatment included simeprevir 150 mg once daily plus PEG-IFN and ribavirin for 12 weeks, followed by PEG-IFN and ribavirin alone (12 or 36 weeks, response guided). Overall, 65.4% of patients achieved SVR12 (82.9% treatment naïve; 86.4% prior relapsers; 60% prior partial responders; 40% prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% and 90.9%), SVR12 rates were high: 93.5% and 95.0%, respectively. These results were similar to previous reports for HCV GT1. [104] As discussed later, simeprevir is used in combination with other agents for the treatment of HCV infection. Paritaprevir given in combination with ritonavir and ribavirin to patients with hepatitis C genotype 1 for 12 weeks resulted in an SVR of 95% at 24 weeks after treatment discontinuation. [105] Paritaprevir is a component of Viekira Pak and Technivie as discussed below. Grazoprevir is active against a range of HCV genotypes, including some that are resistant to the most currently used antiviral medications. It is used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin. Asunaprevir, another agent in this class, is currently not available in the United States. NS5B targeting polymerase inhibitors HCV NS5B polymerase plays an essential role in HCV replication. Sofosbuvir (Sovaldi) is a NS5B polymerase inhibitor that results in suppression of HCV replication and life cycle. Sofosbuvir received FDA approval in December 2013 for the treatment of chronic HCV infection with genotypes 1, 2, 3, and 4 as part of a combination antiviral regimen, including those with hepatocellular carcinoma (HCC) meeting Milan criteria (awaiting liver transplantation) to prevent HCV recurrence and those with HCV/HIV-1 coinfection. Approval for sofosbuvir was supported by data from several phase 3 studies that evaluated 12 or 16 weeks of treatment with the drug combined with either ribavirin or ribavirin plus PEG-IFN alfa. Three of these studies evaluated sofosbuvir plus ribavirin in genotype 2 or 3 patients who were either treatment-naïve, [106] treatment-experienced [107] or PEG-IFN intolerant, ineligible, or unwilling. [107] The fourth study evaluated sofosbuvir in combination with PEG-IFN/ribavirin in treatment-naïve patients with genotypes 1, 4, 5 or 6. [106] In these studies, sofosbuvir-based therapy was found to be superior to historical controls [106] or to placebo, [107] or noninferior to currently available treatment options [106] based on the proportion of patients who had a SVR12 after completing therapy. Patients who achieve SVR12 are considered cured of HCV. Trial participants taking sofosbuvir-based therapy achieved SVR12 rates of 50%-90%. During the FDA’s review, data from two additional phase 3 studies were added to the new drug application (NDA) as a result of the "Breakthrough Designation" status. In the first study, patients with genotype 3 HCV infection were treated with sofosbuvir and ribavirin for 24 weeks. Eighty-four percent of patients in this trial achieved SVR12. [108] The second study evaluated sofosbuvir and ribavirin for 12 weeks in patients with genotype 2 HCV infection coinfected with HIV-1. [109] The efficacy of combined simeprevir and sofosbuvir was investigated in the COSMOS study, an open-label, randomized phase II clinical trial. [110] For all patients (treatment-naïve and treatment-experienced, with or without cirrhosis), 93% achieved an SVR12 after 12 weeks of treatment, and 97% achieved SVR12 after 24 weeks of treatment. [110] Dasabuvir is approved by the FDA only for use in combination with ombitasvir/paritaprevir/ritonavir. In the United States, this combination is marketed as Viekira Pak. NS5A targeting agents Several agents are available for NS5A target inhibition in the replication cycle of HCV. These include ledipasvir, ombitasvir, elbasvir, and velpatasvir. These are all approved as part of combination products as discussed below. Combination products Several anti-hepatitis C agents are currently approved by FDA for treatment as described below. ◊ Ledispasvir/sofosbuvir (Harvoni) Harvoni is a combination oral product containing ledipasvir, an NS5A protein inhibitor, and sofosbuvir that was approved by the FDA in October 2014 for the treatment of HCV genotype 1. Since its original approval in the United States, the indication has been expanded to include genotypes 1, 4, 5, and 6. It is administered once daily and does not need to be administered with IFN. Some regimens may require ribavirin. Studies have shown a high SVR (94%-99%) in all treatment groups (ie, treatment naïve or treatment experienced, with or without cirrhosis, and liver transplant recipients). [111, 112, 113] This fixed-dose combination drug demonstrated efficacy in refractory cirrhotic hepatitis C. In a study of 154 patients with cirrhotic chronic HCV infection whose condition had failed previous protease inhibitor–based therapy, treatment with the fixed-dose combination of ledipasvir and sofosbuvir with or without ribavirin led to an SVR in the majority of patients. [114, 115] Study subjects received either ledipasvir and sofosbuvir plus placebo for 24 weeks or placebo for 12 weeks followed by ledipasvir and sofosbuvir plus ribavirin for 12 weeks. SVR12 was seen in 96% of the 24-week combination group and 97% of the 12-week combination plus ribavirin group. Three patients in the 12-week group and two patients in the 24-week group experienced relapses. [114, 115] For treatment-naïve noncirrhotic patients, with chronic HCV and a viral load below 6 million international units/mL (IU/mL), treatment duration is generally 8 weeks. However, with a viral load above 6 million IU/mL or with cirrhosis, ledispasvir/sofosbuvir is given for 12 weeks. In patients with and without cirrhosis, this therapy results in SVR rates greater than 95%. [110, 116] In a trial of 20 patients with acute hepatitis C genotype 1 monoinfection, a 6-week treatment regimen with ledipasvir plus sofosbuvir resulted in SVR in all patients. [117] Treatment was well tolerated; there were no drug-related serious adverse events. ◊ Elbasvir/grazoprevir (Zepatier) The fixed-dose HCV NS5A and NS3/4A protease inhibitor, elbasvir/grazoprevir (Zepatier) was approved in January 2016 for use with or without ribavirin for adults with HCV genotypes 1 or 4 infection. Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. Grazoprevir is an inhibitor of HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is also essential for viral replication. Efficacy of elbasvir/grazoprevir was evaluated in clinical trials that included nearly 1400 patients. The overall SVR rates ranged from 94% to 97% for genotype 1 and 97% to 100% for genotype 4 across trials. [118, 119] The approved dosage regimens are specific to the characteristics of the patients and their virus genotype. Prior to initiating therapy, patients with HCV genotype 1a should be tested for NS5A resistance-associated substitutions (RASs) to determine the dosage regimen and duration. Those without RASs are treated for 12 weeks, but treatment is given for 16 weeks with weight-based ribavirin in those with RASs. For patients with subtype 1b infection, the regimen is given for 12 weeks without ribavirin. Duration of treatment is the same in patients with and without cirrhosis with SVR rates greater than 95%. [120] However, this regimen is contraindicated in those with Child-Pugh classes B and C cirrhosis. ◊ Ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak) On December 19, 2014, the FDA approved the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira Pak) for the treatment of genotype 1 chronic hepatitis C infection in adults, including patients with compensated cirrhosis. Studies were conducted using two tablets of ombitasvir/paritaprevir/ritonavir tablet once daily (in the morning) plus one tablet of dasabuvir 250 mg tablet twice daily (morning and evening) with a meal with ribavirin (up to six pills divided into two daily doses) for 12 weeks (no cirrhosis) or 24 weeks (compensated cirrhosis) with the cure rates summarized below. [121, 122, 123, 124, 125] HCV genotype 1a infection cure rates for the ombitasvir/paritaprevir/ritonavir and dasabuvir combination included the following:

• No cirrhosis: SVR12 rates were 95% for 12 weeks of treatment with ribavirin (SAPPHIRE-I study) [121] ; SVR12 was 97% for 12 weeks of treatment with ribavirin but 90% without ribavirin (PEARL-IV study) [124]

• Cirrhosis: SVR12 rates were 89% in the 12-week arm and 95% in the 24-week arm; prior treatment null responders had lower SVR rates (TURQOUISE-II study) [125]

HCV genotype 1b infection cure rates for the ombitasvir/paritaprevir/ritonavir and dasabuvir combination included the following:

• No cirrhosis: SVR12 rates were 99% for 12 weeks of treatment with ribavirin (PEARL-III Study) [124]

• Cirrhosis: SVR12 rates were 98.5% in the 12-week arm (with ribavirin) and 100% in the 24-week arm; prior treatment null responders had lower SVR rates (TURQOUISE-II Study) [125]

For treatment-naïve patients with HCV 1a infection, the regimen is given with ribavirin (daily dose 1000 mg for those < 75 kg and 1200 mg for those ≥75 kg) for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis. For patients with subtype 1b infection, the regimen is given without ribavirin for 12 weeks, regardless of the presence of cirrhosis. This regimen is contraindicated in Child-Pugh classes B and C cirrhosis. ◊ Ombitasvir/paritaprevir/ritonavir (Technivie) Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin was studied in treatment-naïve and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I). [126] In previously untreated patients, SVR12 rates were 100% (42/42) in the ribavirin-containing regimen and 90.9% (40/44) in the ribavirin-free regimen. All treatment-experienced patients achieved SVR12 (49/49). In the ribavirin-free group, 2 of 42 (5%) treatment-naïve patients had virologic relapse, and 1 of 44 (2%) had virologic breakthrough; no virologic failures were recorded in the ribavirin-containing regimen. [126] The combination product ombitasvir/paritaprevir/ritonavir (Technivie) was FDA approved in July 2015 for the treatment of genotype 4 chronic HCV without cirrhosis. [127] It is recommended to be used in conjunction with ribavirin. ◊ Sofosbuvir/velpatasvir (Epclusa) On June 28, 2016, the FDA approved the fixed-dose combination tablet containing sofosbuvir and velpatasvir as the first agent to treat all six major forms of HCV in adults with chronic hepatitis C with and without cirrhosis. [128, 129] The safety and efficacy of Epclusa for 12 weeks was evaluated in three phase III clinical trials of 1558 subjects without cirrhosis or with compensated cirrhosis. [128] Cure was noted in 95%-99% of patients. The safety and efficacy of sofosbuvir/velpatasvir was also evaluated in a clinical trial of 267 subjects with decompensated cirrhosis, of whom 87 subjects received this agent in combination with ribavirin for 12 weeks, with 94% cure rates. [128] For patients with decompensated cirrhosis, sofosbuvir-velpatasvir is approved for use in combination with the drug ribavirin. For treatment-naïve patients, sofosbuvir-velpatasvir is given for 12 weeks, regardless of the presence of cirrhosis. This regimen results in SVR rates of approximately 98%-99%. The most common side effects of sofosbuvir-velpatasvir include headache and fatigue. Coadministration of amiodarone with combination sofosbuvir-velpatasvir is not recommended due to the possibility of symptomatic bradycardia.

Treatment-Naive Patients with Chronic Hepatitis C Infection Although quite effective, regimens for the treatment of hepatitis C remain very expensive. In a study of treatment-naïve US veterans with genotype 1 hepatitis C, ombitasvir-based therapy was considered to be the most economically efficient strategy. [130] ​ The following recommendations for treatment-naïve patients are based on HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (ISDA); they are updated frequently. [9] I. Genotype 1 HCV genotype 1a treatment-naïve patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks if no baseline nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) for elbasvir are detected

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 8 weeks for non-black patients, non-HIV-infected persons, and those whose HCV RNA level is below 6 million IU/mL

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) for 12 weeks as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg), with weight-based ribavirin

• Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks in patients who have baseline NS5A RASs for elbasvir

HCV genotype 1a treatment-naïve patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for those with no baseline NS5A RASs for elbasvir

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimen

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks in patients with baseline NS5A RASs for elbasvir

HCV genotype 1b treatment-naïve patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 8 weeks for non-black persons, non-HIV-infected patients, and those whose HCV RNA level is below 6 million IU/mL

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg) for 12 weeks

• Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks

HCV genotype 1b treatment-naïve patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimen

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg) for 12 weeks

II. Genotype 2 HCV genotype 2 treatment-naïve patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

HCV genotype 2 treatment-naïve patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

III. Genotype 3 HCV genotype 3 treatment-naïve patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

HCV genotype 3 treatment-naïve patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks when Y93H is present

IV. Genotype 4 HCV genotype 4 treatment-naïve patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Alternative regimen

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks

HCV genotype 4 treatment-naïve patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Alternative regimen

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks

V. Genotype 5 or 6 HCV genotype 5 or 6 treatment-naïve patients with and without compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks in those without cirrhosis OR for 12 weeks in those with cirrhosis

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks, regardless of cirrhosis status

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks, regardless of cirrhosis status

Treatment-Experienced Patients with Chronic Hepatitis C Infection The following recommendations for treatment-experienced patients are based on HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (ISDA); they are updated frequently. [9] IA. Genotype 1a HCV genotype 1a peginterferon (PEG-IFN)/ribavirin treatment-experienced patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks if no baseline nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) for elbasvir are detected

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) as part of an extended-release regimen or plus twice-daily dasabuvir (250 mg, and weight-based ribavirin for 12 weeks

• Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks for patients with baseline NS5A RASs for elbasvir

HCV genotype 1a PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks if no baseline NS5A RASs for elbasvir are detected

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 16 weeks in patients who have baseline NS5A RASs for elbasvir

IB. Genotype 1b HCV genotype 1b PEG-IFN/ribavirin treatment-experienced patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg) for 12 weeks

• Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks

HCV genotype 1b PEG-IFN/ribavirin treatment-experienced with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg) for 12 weeks

Genotype 1 NS3 protease inhibitor and PEG-IFN/ribavirin–experienced patients HCV genotype 1 nonstructural protein 3 (NS3) protease inhibitor (eg, simeprevir) plus PEG-IFN/ribavirin treatment-experienced patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 12 weeks for all genotype 1b patients, as well as genotype 1a patients without baseline NS5A RASs for elbasvir. Extend this treatment to 16 weeks for genotype 1a patients who have baseline NS5A RASs for elbasvir.

HCV genotype 1 NS3 protease inhibitor (eg, simeprevir) plus PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for 12 weeks for all genotype 1b patients, as well as genotype 1a patients without baseline NS5A RASs for elbasvir. Extend this treatment to 16 weeks for genotype 1a patients who have baseline NS5A RASs for elbasvir.

Genotype 1 non-NS5A inhibitor and sofosbuvir-containing regimen–experienced patients HCV genotype 1 non-NS5A inhibitor, sofosbuvir-containing regimen, treatment-experienced patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks for genotype 1a patients

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks, regardless of HCV subtype

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks for genotype 1b patients

Alternative regimen

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin, except in simeprevir failures, for 12 weeks

HCV genotype 1 non-NS5A inhibitor, sofosbuvir-containing regimen, treatment-experienced patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks for genotype 1a patients

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks, regardless of HCV subtype

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks for genotype 1b patients

​ Genotype 1 NS5A inhibitor DAA–experienced patients HCV genotype 1 NS5A inhibitor, direct-acting antiviral agent (DAA) treatment-experienced patients with or without compensated cirrhosis Recommended regimen

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

Alternative regimen

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg), except NS3/4 protease inhibitor inclusive DAA combination regimens, for 16 weeks

II. Genotype 2 HCV genotype 2 PEG-IFN/ribavirin treatment-experienced patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

HCV genotype 2 PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

HCV genotype 2 sofosbuvir plus ribavirin treatment-experienced patients with or without compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

HCV genotype 2 sofosbuvir plus NS5A treatment-experienced patients with or without compensated cirrhosis Recommended regimen

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

III. Genotype 3 HCV genotype 3 PEG-IFN/ribavirin treatment-experienced patients without cirrhosis Recommended regimen

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 16 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks when Y93H is present

HCV genotype 3 PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose elbasvir (50 mg)/grazoprevir (100 mg) plus sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 16 weeks

HCV genotype 3 DAA treatment-experienced (including NS5A inhibitors) patients with or without compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

• Weight-based ribavirin for 12 weeks for individuals with prior NS5A inhibitor failure and cirrhosis

IV. Genotype 4 HCV genotype 4 PEG-IFN/ribavirin treatment-experienced patients without cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for patients who had virologic relapse after previous PEG-IFN/ribavirin treatment

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) plus weight-based ribavirin for 16 weeks for patients with previous on-treatment virologic failure (failure to suppress or breakthrough) while on PEG-IFN/ribavirin

HCV genotype 4 PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for individuals who had virologic relapse after previous PEG-IFN/ribavirin treatment

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) plus weight-based ribavirin for 16 weeks for patients with previous on-treatment virologic failure (failure to suppress or breakthrough) while on PEG-IFN/ribavirin

• Daily ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks

HCV genotype 4 DAA treatment-experienced(including NS5A inhibitors)patients with or without compensated cirrhosis Recommended regimen

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

V. Genotype 5 and 6 HCV genotype 5 or 6 PEG-IFN/ribavirin treatment-experienced patients with or without compensated cirrhosis Recommend regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks for patients without cirrhosis OR for 12 weeks for patients with compensated cirrhosis

• Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

HCV genotype 5 or 6 DAA treatment-experienced (including NS5A inhibitors) patients with or without compensated cirrhosis Recommended regimen

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

Decompensated Cirrhosis The American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (ISDA) define decompensated cirrhosis as moderate or severe hepatic impairment (ie, Child-Turcotte-Pugh [CTP] class B or C). [9] They recommend referring all patients with hepatitis C virus (HCV) infection and decompensated cirrhosis to clinicians with expertise in this condition, preferable in a liver transplant center. Genotype 1, 4, 5, or 6 infection Decompensated cirrhosis in patients with genotype 1, 4, 5, or 6 infection Recommended regimens

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with a low initial ribavirin dose (600 mg, increase as tolerated) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks

• Genotype 1 or 4 infection only: Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial ribavirin dose (600 mg, increase as tolerated) for 12 weeks

Decompensated cirrhosis in ribavirin-ineligible patients with genotype 1, 4, 5, or 6 infection Recommended regimens

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 24 weeks

• Genotype 1 or 4 infection only: Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 24 weeks

Patients with genotype 1, 4, 5, or 6 infection, decompensated cirrhosis, and previous sofosbuvir- or nonstructural protein 5A (NS5A)–based treatment failure Recommended regimens

• Prior sofosbuvir-based treatment failure only: Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with a low initial ribavirin dose (600 mg; increase as tolerated) for 24 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 24 weeks

Genotype 2 or 3 infection Ribavirin-eligible patients with genotype 2 or 3 infection and decompensated cirrhosis Recommended regimens

• Daily fixed-dose combination sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks

• Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial ribavirin dose (600 mg, increase as tolerated) for 12 weeks

Ribavirin-ineligible patients with genotype 2 or 3 infection and decompensated cirrhosis Recommended regimens

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 24 weeks

• Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 24 weeks

Patients with genotype 2 or 3 infection, decompensated cirrhosis, and previous sofosbuvir- or NS5A-based treatment failure Recommended regimen

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 24 weeks

Moderate or severe hepatic impairment, CTP class B or C The AASLD/ISDA do not recommend the following regimens for patients with decompensated cirrhosis (moderate or severe hepatic impairment, CTP class B or C):

• Paritaprevir- or simeprevir-based regimens

• Elbasvir/grazoprevir-based regimens

• Glecaprevir/pibrentasvir

• Sofosbuvir/velpatasvir/voxilaprevir

HIV-HCV Coinfection Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are at risk for accelerated liver fibrosis and should usually be offered antiviral treatment. [50] HIV/HCV-coinfected persons should be treated and retreated the same as those without HIV infection once any interactions with antiretroviral agents have been identified and managed. [9] Daily daclatasvir plus sofosbuvir (400 mg), with or without ribavirin, is a recommended regimen when antiretroviral regimen changes cannot be made to accommodate alternative HCV direct-acting antiviral medications. However, the combination of ledipasvir/sofosbuvir for 8 weeks is not recommended, regardless of the patient's baseline HCV RNA level. [9] With the availability of newer agents, the efficacy of treatments for coinfected persons is similar to that for their HIV-uninfected counterparts. [131, 132] However, several important points related to drug interactions with antiretroviral medications need to be emphasized, as follows [34] :

• Daclatasvir in combination with other antiviral agents: Reduce daclatasvir to 30 mg/day with ritonavir-boosted atazanavir and with cobicistat-boosted atazanavir; increase daclatasvir to 90 mg/day with efavirenz and with etravirine.

• Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg): This combination should be used with antiviral agents with which it doesn't have clinically significant interactions, such as abacavir, emtricitabine, enfuvirtide, lamivudine, raltegravir, dolutegravir, rilpivirine, and tenofovir.

• Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg): As with combination elbasvir/grazoprevir, combination glecaprevir/pibrentasvir should be used with antiviral agents with which it doesn't have clinically significant interactions, such as abacavir, emtricitabine, enfuvirtide, lamivudine, raltegravir, dolutegravir, rilpivirine, and tenofovir. Monitor for hepatic toxicity.

• Simeprevir in combination with other antiviral agents: Use simeprevir with antiviral agents with which it doesn't have clinically significant interactions, such as abacavir, emtricitabine, enfuvirtide, lamivudine, maraviroc, raltegravir, dolutegravir, rilpivirine, and tenofovir.

• Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg): This combination should not be used with efavirenz, etravirine, or nevirapine. Because velpatasvir may increase tenofovir levels, concomitant use of these agents mandates consideration of the creatinine clearance (CrCl) rate; avoid their use in those with a CrCl level below 60 mL/min.

• Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg): Because ledipasvir increases tenofovir levels, concomitant use of these agents mandates consideration of the CrCl rate; avoid their use in those with a CrCl level below 60 mL/min. Because potentiation of this effect is expected when tenofovir is used with ritonavir-boosted HIV protease inhibitors, avoid using ledipasvir with this combination unless the antiretroviral regimen cannot be changed and the urgency of treatment is high.

• For combination agents expected to increase tenofovir levels, baseline and ongoing assessment for tenofovir nephrotoxicity is recommended.

• Paritaprevir/ritonavir/ombitasvir plus dasabuvir should be used with antiretroviral drugs with which they do not have substantial interactions, such as atazanavir, dolutegravir, emtricitabine, enfuvirtide, lamivudine, raltegravir, and tenofovir.

• The dose of ritonavir used for boosting atazanavir should be held when administered with paritaprevir/ritonavir/ombitasvir plus dasabuvir; restore the dose when the HCV treatment is completed. Atazanavir should be administered at the same time as the fixed-dose HCV combination.

• Sofosbuvir/velpatasvir/voxilaprevir should be used with antiretroviral drugs with which they do not have substantial interactions, such as dolutegravir, emtricitabine, enfuvirtide, lamivudine, rilpivirine, and raltegravir. Monitor for hepatic toxicity. This drug combination may increase tenofovir levels. Thus, concomitant use of these agents mandates consideration of the CrCl rate; avoid their use in those with a CrCl level below 60 mL/min. Monitor renal function.

• Avoid interrupting antiretroviral therapy to allow HCV treatment.

• Avoid the use of elbasvir/grazoprevir or simeprevir with cobicistat, efavirenz, etravirine, nevirapine, or any HIV protease inhibitor.

• Avoid the use of glecaprevir/pibrentasvir with atazanavir, ritonavir-containing antiretroviral regimens, efavirenz, or etravirine.

• Avoid the use of sofosbuvir/velpatasvir with efavirenz, etravirine, or nevirapine.

• Avoid the use of sofosbuvir/velpatasvir/voxilaprevir with ritonavir-boosted atazanavir, efavirenz, etravirine, or nevirapine.

• Avoid the use of sofosbuvir-based regimens with tipranavir.

• Avoid the use of paritaprevir/ritonavir/ombitasvir plus cobicistat, dasabuvir with darunavir, efavirenz, etravirine, nevirapine, rilpivirine, ritonavir-boosted lopinavir, or ritonavir-boosted tipranavir.

• Avoid the use of paritaprevir/ritonavir/ombitasvir, with or without dasabuvir, in HIV/HCV-coinfected individuals who are not taking antiretroviral therapy.

• Avoid the use of ribavirin with didanosine, stavudine, or zidovudine.

HBV-HCV Coinfection Coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV), in the absence of human immunodeficiency virus (HIV) infection, is relatively uncommon in the United States, and optimal treatment regimens have not been established. Globally, an estimated 3-18% of hepatitis B surface antigen (HBsAg)-positive individuals have concurrent HCV infection, and these individuals are at a higher risk for hepatocellular carcinoma for unclear reasons. [50] The World Health Organization recommends offering HCV antibody (anti-HCV) or HBsAg testing, as well as linkage to prevention, care, and treatment services, in all settings to (1) adults and adolescents from populations most affected by HCV infection (ie, population with high HCV seroprevalence, those with a history of and/or high-risk behaviors for HCV exposure) and (2) pediatric, teen, and adult patients clinically suspected to have chronic viral hepatitis. [50] A few important studies are discussed below. Villa et al reported that 9 million U of standard interferon (IFN) three times weekly for 3 months could clear HCV in 31% of patients with HCV-HBV coinfection. [133] Using standard IFN and ribavirin, Liu et al discovered that sustained HCV eradication was achieved at rates comparable to those in patients with HCV alone and, interestingly, up to 21% of their patients lost the hepatitis B surface antigen. [134] Given the superior efficacy of pegylated IFN (PEG-IFN) over standard IFN, Liu et al subsequently conducted a multicenter study using PEG-IFN and ribavirin in HCV-HBC coinfected patients. This regimen proved equally effective in patients with HCV monoinfection and in those with chronic HCV-HBV coinfection. [135]

Management and Monitoring of Acute HCV Infection Acute hepatitis C virus (HCV) infection is defined as presenting within 6 months of the exposure. During this time, there is a 15% to 50% chance of spontaneous resolution of infection. [1, 16, 34, 35] Monitoring for spontaneous clearance for a minimum of 6 months before initiating treatment is recommended. In the past, interferon (IFN)-based treatment was used with high cure rates of acute infection. However, IFN-sparing regimens are safer and are currently recommended for the treatment of acute HCV infection. [34] When the decision is made to initiate treatment after 6 months, the same regimens that are recommended for chronic HCV infection are recommended for acute infection. [34] The following recommendations are based on HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (ISDA). [9] Medical management and monitoring of acute HCV infection Recommendations [9]

• Regularly monitor with laboratory studies in the setting of acute HCV infection. In addition, monitor HCV RNA (eg, every 4-8 weeks) for 6 to 12 months to determine spontaneous clearance versus persistence of HCV infection.

• Counsel patients with acute HCV infection to avoid hepatotoxic insults, including hepatotoxic drugs (eg, acetaminophen) and alcohol consumption, and to reduce the risk of HCV transmission to others.

• Refer to an addiction medicine specialist for patients with acute HCV infection related to substance use.

• If a decision to delay initiation of treatment is acceptable to the clinician and patient, monitor for spontaneous clearance for at least 6 months. If, after 6 months, a decision is made to initiate therapy, treat as previously discussed under the section Treatment-Naïve Patients with Chronic Hepatitis C Infection

• If a decision to initiate treatment is made during the acute infection period, before starting therapy, monitor HCV RNA levels for at least 12-16 weeks for possible spontaneous clearance.

• The same treatment regimens recommended for chronic HCV infection are recommended for acute HCV infection.

Recurrence After Liver Transplantation Recurrent hepatitis C viral (HCV) infection is universal after liver transplantation, can lead to cirrhosis in 30% of patients within 5 years, and is emerging as the most common cause of retransplantation in the United States. [136] Interferon (IFN) is contraindicated after organ transplantation because of its high risk of precipitating rejection, in part due to upregulation of the human leukocyte antigen (HLA) system by IFN. Liver transplantation is a possible exception, however, as allograft rejection is uncommon in liver transplant recipients with recurrent HCV infection who are treated with IFN-based therapies. The following recommendations are based on HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (ISDA). [9] They are subject to change. Treatment-naïve and treatment-experienced patients I. Genotype 1, 4, 5, or 6 post liver transplantation ◊ HCV genotype 1, 4, 5, or 6 allograft patients without cirrhosis, regardless of treatment experience Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based ribavirin for 12 weeks

◊ HCV genotype 1, 4, 5, or 6 allograft patients with compensated cirrhosis, regardless of treatment experience Recommended regimen

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based ribavirin for 12 weeks

◊ HCV genotype 1, 4, 5, or 6 allograft patients with or without compensated cirrhosis, regardless of treatment experience Alternative regimens

• Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

• Genotype 1 or 4 infection only: Daily simeprevir (150 mg) plus sofosbuvir (400 mg) with or without weight-based ribavirin for 12 weeks

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

◊ HCV genotype 1, 4, 5, or 6 allograft patients with decompensated cirrhosis, regardless of treatment experience Recommended regimen

• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

II. Genotype 2 or 3 post liver transplantation ◊ HCV genotype 2 or 3 allograft patients without cirrhosis, regardless of treatment experience Recommended regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

• Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

◊ HCV genotype 2 or 3 allograft patients with compensated cirrhosis, regardless of treatment experience Recommended regimen

• Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

Alternative regimens

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks

◊ HCV genotype 2 or 3 allograft patients with decompensated cirrhosis, regardless of treatment experience Recommended regimens

• Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) with a low initial dose of ribavirin (600 mg; increase as tolerated) for 12 weeks

• Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) with weight-based ribavirin for 12 weeks

HCV and Pregnancy The following recommendations are based on HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (ISDA). [9] They are subject to change. All pregnant women should be tested for infection with hepatitis C virus (HCV), preferably at the start of prenatal care. For risk reduction of HCV transmission to future offspring, women of reproductive age with confirmed HCV infection should receive antiviral therapy prior to pregnancy consideration when possible. There is no currently known intervention to reduce maternofetal transmission in pregnant women with HCV infection. At the initiation of prenatal care, HCV-antibody-positive pregnant women should undergo HCV RNA and routine hepatic function studies to evaluate the risk of maternofetal transmission and severity of liver disease. These women should also receive prenatal and intrapartum care that is appropriate for their individual obstetric risk(s). Clinicians should have a high index of suspicion for intrahepatic cholestasis or pregnancy in gravida with HCV and pruritus or jaundice, and evaluate these women with measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum bile acids. Counsel HCV-infected women with cirrhosis about the higher risk of adverse maternal and perinatal outcomes. In addition, coordinate antenatal and perinatal care with a maternal-fetal medicine obstetrician. Postpartum, HCV- or HIV-HCV–infected mothers may breastfeed, unless she has cracked, damaged, or bleeding nipples. In addition, postdelivery HCV-infected women should be reevaluated for spontaneous clearance of their HCV RNA.

Patients Using Alcohol or Injection Drugs In 1998, Wiley et al reported that significant alcohol use (>40 g alcohol/day in women and >60 g of alcohol/day in men for >5 years) in patients infected with hepatitis C virus (HCV) resulted in a two- to three-fold greater risk of liver cirrhosis and decompensated liver disease. In addition, cirrhosis developed more rapidly in alcohol users. [137] Because of the risk that alcohol use poses for rapid liver fibrosis, hepatoma, and deleterious effects on treatment response, complete alcohol abstinence is recommended during treatment. Practice guidelines from the American Association for the Study of Liver Diseases (AASLD) have recommended that HCV treatment not be withheld from patients who use illicit drugs or who are on a methadone maintenance program, provided they are willing to maintain close monitoring, including practicing contraception. [34, 138] However, the guidelines have also noted that "It is important to consider the individual issues that may affect the risks and benefits of treatment of HCV infection in persons who use illicit drugs, rather than to make categorical recommendations." [139] The complexity of HCV treatment in these patients is aided by a multidisciplinary team approach composed of physicians, nurses, and substance abuse and mental health professionals.

Deterrence/Prevention Currently, no products are available to prevent hepatitis C virus (HCV) infection. The development of immunoprophylaxis for this disease is proving difficult; an effective neutralizing immune response has not been demonstrated. Patients with hepatitis C should be advised to abstain from alcohol use; they should also be advised to use barrier protection during sexual intercourse. Screening high-risk patients and initiating appropriate treatment may decrease the prevalence of cirrhosis and hepatocellular carcinoma (HCC). In an ongoing prospective study of prevention of HCV infection in injection-drug users, researchers recommended six measures that can be used to prevent the spread of hepatitis C [140, 141] :

• Reducing risk from shared ancillary drug preparation equipment, such as containers, rinse water, and filters, in addition to shared syringes

• Using a new rapid test at the point of care that offers results in 20 minutes; it can detect infection before seroconversion occurs and, combined with counseling, can help to stem transmission

• Addressing social and relational contexts of injecting can encourage uninfected individuals to take precautions when injecting drugs with infected sex partners

• Encouraging "taking a break" from injecting drugs

• Developing models to guide delivery of new prevention strategies, including already-available approaches such as increasing syringe availability and future strategies such as direct-acting antivirals that can be used prophylactically, as well as vaccines

• Combining interventions in synergistic ways, such as needle exchange and methadone maintenance programs

The World Health Organization (WHO) recommends offering and providing access to opioid substitution therapy to all opioid-dependent individuals from key populations. [50]

Consultations and Long-Term Monitoring Consultations Consultation with a gastroenterologist and hepatologist is recommended in the treatment of hepatitis C virus (HCV) infection. Consultation with a psychiatrist may be helpful before and during treatment in patients at risk of depression or other psychiatric illnesses. Patients with cirrhosis should be referred for liver transplantation evaluation after decompensation or when their Model for End-Stage Liver Disease (MELD) score rises. Long-term monitoring AASLD/ISDA guidelines For patients who achieved a sustained virologic response (SVR), the AASLD/ISDA recommendations are as follows [9] :

• Those without advanced fibrosis (ie, Metavir stage F0, F1, or F2): Follow up as in never-infected individuals.

• Those with ongoing risk for HCV infection or when otherwise unexplained hepatic dysfunction develops: Assess for HCV recurrence or reinfection with a quantitative HCV RNA test rather than an HCV-antibody test

• Those with advanced fibrosis (ie, Metavir stage F3 or F4): Surveil for hepatocelluar carcinoma (HCC) with twice-yearly ultrasonography.

• Those with cirrhosis: Obtain baseline endoscopy to screen for varices; if found, treat and follow up as indicated.

• Those with persistently abnormal liver studies: Evaluate for other causes of liver disease.

For patients with posttreatment failure to achieve an SVR [9] :

• Assess for disease progression every 6-12 months with hepatic function studies, complete blood cell (CBC) count, and international normalized ratio (INR).

• In those with advanced fibrosis (ie, Metavir stage F3 or F4), screen for HCC with ultrasonography every 6 months.

• In those with cirrhosis, obtain endoscopy screening for varices.

• Evaluate for retreatment as effective alternative therapies become available.

HCV RNA tested at about week 4 after the initiation of therapy should almost always be undetected or detectable only at the limit of the quantification. Higher values at this point in time suggest suboptimum adherence. At week 12 of treatment, the patient should be evaluated for an early virologic response by repeating the quantitative HCV RNA and interferon (IFN)-associated thyroid dysfunction screening. If the HCV RNA level is undetectable or if a greater than 2-log-fold reduction in HCV RNA level is present, therapy should be continued because, according to Fried et al, up to 65% of patients go on to develop a SVR. [86] Conversely, if an early virologic response is not present, treatment should be stopped, because the chance of developing a sustained response of HCV eradication is less than 3%. Poynard et al reported that the one exception is in the context of clinical trials or treatment of recurrent HCV infection in liver transplant recipients [142] ; improved fibrosis scores have been reported in patients in whom the virus has not been eradicated, thus identifying a subgroup of patients who may benefit from maintenance therapy. The HCV RNA level should be rechecked 6 months after the completion of treatment; if HCV RNA is detectable, the patient has had a relapse of the disease and an alternative treatment should therefore be considered. If HCV RNA is undetectable and test results remain negative, the patient has developed an SVR. Patients with HCV infection should be monitored closely for adverse effects as well as response to therapy. Tests to help monitor drug toxicity include the following:

• Complete blood cell count with differential

• Renal function testing

• Liver function tests (including alanine aminotransferase [ALT] level)

• Thyrotropin level

Although measurement of ALT levels is useful for monitoring the effectiveness of therapy for HCV infection, ALT levels can fluctuate. Consequently, a single value in the reference range does not rule out active infection, progressive liver disease, or cirrhosis. ALT normalization with therapy is not proof of cure. Patients with cirrhosis should be screened for hepatocellular carcinoma and esophageal varices. They should also be monitored for the development of decompensated liver disease. Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) before or after completing HCV treatment has been recommended. [143] Patients should be offered vaccination for HAV and HBV before they develop decompensated liver disease (otherwise, if they are vaccinated after decompensation, they may be less likely to mount an immune response).

Medication

Medication Summary The treatment of chronic hepatitis C has evolved rapidly. In the past the backbone of treatment for chronic hepatitis C virus (HCV) infection regardless of genotype was a combination therapy with injectable pegylated interferon-alfa (PEG-IFNa) plus oral ribavirin. Because it has the poorest safety profile of all the HCV antivirals, with few exceptions, PEG-IFN is no longer recommended in combination regimens. Ribavirin continues to be used in combination with sofosbuvir alone or other combinations. The direct-acting antiviral agents (DAAs), first introduced in 2011, offered enhanced efficacy when combined with both PEG-IFN and ribavirin, particularly for genotype 1 infections. The first protease inhibitors, boceprevir and telaprevir, are no longer available for use in the United States and have been supplanted by antivirals with greater efficacy and improved safety profiles. There are three classes of approved DAAs: NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors (nonnucleoside inhibitors and nucleotide inhibitors). The particular combination of antivirals is determined by genotype. Several novel agents are only available as a fixed-dose combination. The following combinations are currently available:

• Ledipasvir/sofosbuvir (Harvoni)

• Elbasvir/grazoprevir (Zepatier)

• Ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak)

• Ombitasvir/paritaprevir/ritonavir (Technivie)

• Glecaprevir/pibrentasvir (Mavyret)

• Sofosbuvir/velpatasvir/voxilaprevir (Vosevi)

• Sofosbuvir/velpatasvir (Epclusa): Combination therapy is required because monotherapy with either agent is not efficacious.

For patients with chronic HCV infection and chronic kidney disease (CKD) stage 1, 2, or 3, the following drug regimens do not require dose adjustments [9] :

• Simeprevir 150 mg

• Sofosbuvir 400 mg

• Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg)

• Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)

• Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg)

• Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)

• Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg)

Although quite effective, regimens for the treatment of hepatitis C remain very expensive. In a study of treatment-naïve US veterans with genotype 1 HCV, ombitasvir-based therapy was considered to be the most economically efficient strategy. [130]

HCV Protease Inhibitors Class Summary These agents interfere with HCV replication by inhibiting a key viral enzyme, NS3/4A serine protease.

HCV Polymerase Inhibitors Class Summary HCV NS5B polymerase plays an essential role in HCV replication. Sofosbuvir (Sovaldi)

Sofosbuvir is a NS5B polymerase inhibitor that results in suppression of HCV replication and interrupts HCV life cycle. It is indicated for the treatment of CHC infection genotypes 1, 2, 3, and 4 as part of a combination antiviral regimen, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) to prevent HCV recurrence and those with HCV/HIV-1 coinfection.

HCV NS5A Inhibitors Class Summary NS5A is integral for HCV RNA viral replication.

Combination Products Class Summary Several combination products have been approved and additional ones are being investigated to provide all oral regimens with high degrees of efficacy. Ledipasvir/sofosbuvir (Harvoni)

Ledipasvir inhibits HCV NS5A protein, which is required for viral replication. Sofosbuvir is an inhibitor of HCV NS5B RNA-dependent polymerase. The oral combination is indicated for treatment of adults with chronic hepatitis C infection with genotype 1, 4, 5, or 6. Duration of therapy ranges from 8 to 24 weeks and depends on if the patient is treatment-naïve or experienced, and if cirrhosis is evident. Ombitasvir/paritaprevir/ritonavir & dasabuvir (Viekira Pak)

This product is indicated for the treatment of chronic HCV genotype 1 infection, including patients with compensated cirrhosis; may be used for patients with HCV/HIV-1 coinfection. It is used in combination with ribavirin in certain patient populations (ie, genotype 1a, with or without cirrhosis; genotype 1b, with cirrhosis). Ombitasvir inhibits HCV NS5A, which is required for viral replication. Paritaprevir is a NS3/4A serine protease inhibitor. NS3/4A protease is needed for proteolytic cleavage of the HCV-encoded polyprotein into mature forms. Ritonavir is a protease inhibitor that is used as a "boosting agent" to increase paritaprevir serum levels. Dasabuvir is a nonnucleoside NS5B RNA-dependent polymerase inhibitor. It's inhibition, in turn, suppresses viral replication. Ombitasvir/paritaprevir/ritonavir (Technivie)

Ombitasvir/paritaprevir/ritonavir is indicated in combination with ribavirin for genotype 4 chronic HCV infection without cirrhosis. Ombitasvir inhibits HCV NS5A, which is required for viral replication. Paritaprevir is a NS3/4A serine protease inhibitor. NS3/4A protease is needed for proteolytic cleavage of the HCV-encoded polyprotein into mature forms. Ritonavir is a protease inhibitor that is used as a "boosting agent" to increase paritaprevir serum levels. Elbasvir/grazoprevir (Zepatier)

Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. Grazoprevir is an inhibitor of HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. It is indicated with or without ribavirin for the treatment of adults with chronic HCV genotypes 1 or 4 infection. Glecaprevir/pibrentasvir (Mavyret)

Combination of glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor). Glecaprevir/pibrentasvir is indicated in treatment-naïve patients aged 12 years and older or weighing at least 45 kg with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). It also is indicated in patients aged 12 years and older or weighing at least 45 kg with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both. An 8-week regimen is approved for treatment-naïve patients with any genotype and for treatment-experienced patients with genotypes 1, 2, 4, 5, or 6 who had prior treatment with peginterferon, ribavirin, and/or sofosbuvir. Sofosbuvir/velpatasvir (Epclusa)

Combination of sofosbuvir (NS5B RNA-dependent polymerase) and velpatasvir (pangenotypic NS5A inhibitor). It is indicated for adults with chronic hepatitis C virus (HCV) infection genotypes 1, 2, 3, 4, 5, or 6. Sofosbuvir/velpatasvir/voxilaprevir (Vosevi)

Combination of sofosbuvir (NS5B RNA-dependent polymerase), velpatasvir (pangenotypic NS5A inhibitor), and voxilaprevir (pangenotypic NS3/4A protease inhibitor). It is indicated for retreatment of chronic hepatitis C virus (HCV) infection in adults with genotype 1, 2, 3, 4, 5, or 6 previously treated with an NS5A inhibitor-containing regimen, or with genotype 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor.

Interferons and ribavirin Class Summary Interferons are naturally produced proteins with antiviral, antitumoral, and immunomodulatory actions. Interferons alfa, beta, and gamma may be given topically, systemically, and intralesionally. Interferons are immunomodulators that may shorten the clinical course, prevent complications, prevent latent and/or subsequent recurrences, decrease transmission, and eliminate established latency. Interferon alfa-2b (Intron-A)

IFN alfa-2b is a protein product manufactured by recombinant DNA technology. The adult dosage is 3 million units subcutaneously (SC) 3 times weekly. Modulation of host immune response by IFN may play an important role in the treatment of viral diseases. Peginterferon alfa-2b (PEG-Intron, Sylatron)

PEG-IFN consists of IFN alfa-2b attached to a single 12-kd PEG chain. It is excreted by the kidneys. PEG-IFN has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing and significantly improves the quality of life for patients. The adult dose is 1.5 mcg/kg SC. Pegylated interferon alfa-2a (Pegasys)

PEG-IFN alfa-2a consists of IFN alfa-2a attached to a 40-kd branched PEG molecule. It is predominantly metabolized by the liver. The adult dosage is 180 mcg/kg SC once weekly. Ribavirin (Rebetol, Virazole, Copegus, Moderiba, Ribasphere)

Ribavirin is an antiviral nucleoside analogue. Its chemical name is D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, ribavirin has little effect on the course of hepatitis C. Given with IFN, it significantly augments the rate of sustained virologic response. The adult dosage is 10.6 mg/kg orally once daily or in 2 divided doses.

Thrombopoietin-Receptor Agonists Class Summary These agents directly stimulate bone marrow platelet production to provide stable platelet counts to allow therapy with interferons. Eltrombopag (Promacta)

Oral thrombopoietin (TPO) receptor agonist. Interacts with transmembrane domain of human TPO receptor and induces megakaryocyte proliferation and differentiation from bone marrow progenitor cells. This agent is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.

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