Hepatitis C

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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)[1] estimates that about 50 million people globally have chronic hepatitis C, with approximately 242,000 dying from this infection, primarily due to cirrhosis and hepatocellular carcinoma (sixth most commonly diagnosed malignancy and third leading cause of cancer worldwide[2] ). Although direct-acting antiviral agents cure over 95% of individuals infected with HCV, no effective vaccine exists against hepatitis C.[1] The image below depicts the HCV genome.



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Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.

Signs and symptoms

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

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

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

Other common extrahepatic manifestations include the following:

See Presentation for more detail.

Diagnosis

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

Tests for detecting HCV infection include the following:

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

See Workup for more detail.

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.

See Treatment and Medication for more detail.

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.[3] 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.[4] This virus is the most common blood-borne pathogen in the United States[5] 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.[5]

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.[6] 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.[7]

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.[8, 9] The incremental cost-effectiveness ratio (ICER) for direct-acting antiviral agents (DAAs) remains up to $100,000 across all HCV genotypes and fibrosis stages.[8, 10] 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). The INSIGHT Study, which collected data both retrospectively (n = 1052) and prospectively (n = 1481) from 2533 newly diagnosed patients with hepatocellular cancer across 33 centers and 9 Asia-Pacific countries, found that hepatitis B was the most common risk factor in all countries except Japan, Australia, and New Zealand—the prevalence of hepatitis C and diabetes were more common in the latter 3 countries.[2]

According to a report by Davis et al, the most common indication for orthotopic liver transplantation (OLT) in the United States.[11]  



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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.[12]

Although acute HCV infection is usually mild, chronic hepatitis develops in at least 75% of patients.[13] (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.[14] 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).



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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.[15] 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.[16]

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.[13]

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:

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.[17] 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.[17]

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.[18] 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.[19] 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).[20]

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%.[21] Breastfeeding is not associated with transmission.[22] 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

United States statistics

The growing US opioid epidemic and its attendant rise in injection drug users (IDUs) has contributed to a more than a two-fold increase in the annual incidence rate of acute hepatitis C virus (HCV) infection over a decade (2004-2014), including a near four-fold increase in prescription opioid analgesic injection.[23]

HCV is the major cause of chronic hepatitis in the United States. HCV infections account for 20% of all cases of acute hepatitis and for more than 40% of all referrals to active liver clinics.

The overall prevalence of anti-HCV antibodies in the United States is 1.8% of the population. Approximately 74% of these individuals are positive for HCV RNA, meaning that active viral replication continues to occur. Thus, an estimated 3.9 million persons are infected with HCV and 2.7 million persons in the United States have chronic infection.[6] Genotype 1a occurs in 57% of patients; genotype 1b occurs in 17%.

In 2015, there were 2436 cases of acute hepatitis C reported to the Centers for Disease Control and Prevention (CDC), but this is likely an underrepresentation of the true number.[24] Alter et al reported that HCV infections account for approximately 30,000 new infections and 8,000-10,000 deaths each year in the United States.[6] Of the new infections, 60% occur in IDUs; less than 20% of new cases are acquired through sexual exposure; and 10% are due to other causes, including occupational or perinatal exposure and hemodialysis.

El-Serag et al reported that HCV was largely responsible for the increase in the incidence of hepatocellular carcinoma in the United States during the final decades of the 20th century.[25] In the United States, the number of deaths due to HCV-related complications increased from fewer than 10,000 in 1992 to just under 15,000 in 1999[25] ; by 2010, there were more than 16,600 deaths attributable to HCV,[26] rising to over 19,600 such deaths in 2015.[24] According to Kim, this number is expected to increase in the future because of the current large pool of undiagnosed patients with chronic infection.[27]

International statistics

Worldwide, more than 170 million persons have hepatitis C virus (HCV) infection,[28] 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%.[29]

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.[30] Prevalence rates as high as 22% are reported in Egypt and are attributed to the use of parenteral antischistosomal therapy.[3]

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.[31] 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.[31]

No sex preponderance occurs with HCV infection.[6]

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.[32, 33] Data suggest that an association exists between age and transmission route, such as nonsterile medical procedures, including vaccination and parenteral drug treatment.[34]

A 2022 CDC report noted a 2019 incidence of 0.1 per 100,000 population of HCV infection in those younger than 20 years.[35]  

Prognosis

Infection with hepatitis C virus (HCV) is self-limited in 15% to 50% of patients.[1, 17, 36, 37] In a review of HCV infection, it was reported that chronic infection developed in 70-80% of patients.[13] Cirrhosis develops within 20 years of disease onset in 20% of persons with chronic infection.[38] The onset of chronic hepatitis C infection early in life often leads to less serious consequences.[33, 34] Hepatitis B virus (HBV) coinfection, iron overload, and alpha 1-antitrypsin deficiency may promote the progression of chronic HCV infection to HCV-related cirrhosis.[36, 37]  The INSIGHT Study reported the three most common comorbidities with HCV across 9 Asia-Pacific countries were cirrhosis, hypertension, and diabetes.[2]

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.[39, 40] 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.[41] Progression to HCC is more common in the presence of cirrhosis, alcoholism, and HBV coinfection.

Bellentani et al[42] and Hourigan et al[43] 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.[44, 45] 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.[44, 45] 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.[44, 45]

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.[46] 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.[47] 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.

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[48] :

In addition, sensory neuropathy has been reported as an extrahepatic manifestation in 9% of patients with HCV infection.[49] 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.[50]

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:

Other common extrahepatic manifestations include the following:

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.

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 (IDSA). Other resources can also be found at the IDSA website.

In 2020, the US Public Health Service amended its recommendations to indicate that children aged 12 years and younger at the time of transplantation who have received postnatal infectious disease testing are exempt from pretransplant HIV, HBV, and HCV testing during hospital admission for transplantation.[35]

AASLD/IDSA guidelines

The AASLD/IDSA recommend the following for one-time HCV testing[52] :

Offer periodic repeat HCV testing to everyone who has activities, exposures, or conditions/circumstances associated with a higher HCV exposure risk.[52] Moreover, the AASLD/IDSA recommend annual HCV testing for all individuals who inject drugs, for HIV-infected men who have unprotected sex with men, and for men who have sex with men on preexposure prophylaxis (PrEP).

The AASLD/IDSA recommend the following for initial HCV testing and followup[10] :

All patients with HCV infection are recommended to have an evaluation for advanced fibrosis with the use of noninvasive markers and/or elastography (and, rarely, liver biopsy) 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).[10]  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.[53] 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[53] :

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.[54, 55] 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[10] :

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).[56]

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.[57, 58, 59] It was estimated that one-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection.[56]

Screening for HCV in the emergency department (ED) has been found to be feasible, albeit costly.[60, 61] 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.[56]

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.[62] 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.[63]

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[64] :

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.[65]

The following are the best laboratory evidence of acute HCV infection:

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.[66, 67]

Other genotype tests are available, including the following, although none have been approved by the FDA[68] :

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.[69]

Other Testing

Della Rossa et al reported that cryoglobulins are found in as many as 50% of persons with hepatitis C viral infection.[70] 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[71] :

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:

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[72] ; 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,[73] 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.[74] Most of the neoplastic HCC nodules appear to have aggressive imaging features of microvascular invasion in this setting.[74]

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.[75, 76] The software application uses quantitative analysis of nuclear medicine liver-spleen images to determine the severity of liver disease and to predict clinical outcomes.[76] 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 [Hepatitis C Antiviral Long-term Treatment against Cirrhosis] trial."[76] 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.[77]

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.[78] 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.[78]

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 for the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA).

The treatment goal of HCV-infected individuals is the reduction of all-cause mortality and hepatic-associated morbidity (eg, end-stage liver disease, hepatocellular carcinoma) as achieved by virologic cure, with sustained virologic response.[10]

Spontaneous resolution of acute HCV infection may occur in 15% to 50% of patients.[1, 17, 36, 37] 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).[10, 36] These guidelines are updated often.

The AASLD/IDSA 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[36] :

The AASLD/IDSA guidelines removed their prioritization tables but continue to strongly recommend treatment for all patients with acute or chronic HCV infection, barring those with shortened life expectancies that cannot be resolved by HCV treatment, liver transplantation, or another directed therapy.[10] Consultation with an expert is recommended to manage patients with short life expectancy due to liver disease.

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.[53]

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).[79]

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, 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.[80]

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[7] :

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.[81, 82] 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.[81, 82]

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.[81, 82]

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,[83] Davis et al,[11] and Di Bisceglie et al[84] 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.[85] 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.[85]

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, 17, 36, 37] 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[86] and Poynard et al,[87] 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,[88] Fried et al in 2002,[89] and Hadziyannis et al in 2004.[90]

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.[88] 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.)



View Image

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%).[89] 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.[90] 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.[90] 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%).[91] 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.[91]

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.[92]

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.[93] 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.[93]

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.[94]

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.[95]

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:

Adverse effects of ribavirin include the following:

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.[10]

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[96] and Van Thiel et al,[97] 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 Eltrombopag to INitiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE (ENABLE) 1 and 2 trials, which showed eltrombopag significantly reduced the time to the first IFN dose reduction compared with placebo.[98, 99]

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).[100]

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.[101]

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.[102]

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.[103] 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.[104]

Currently available agents and their target sites are outlined below.

NS3/4 targeting protease inhibitors

NS5B targeting polymerase inhibitors

NS5A targeting agents

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.[53] 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).[53]

Note that  whenthese guidelines were issued, glecaprevir-pibrentasvir had a different regimen and daclatasvir was discontinued from the market as shorter treatment duration options evolved. 

A shorter duration of treatment (ie, 8 weeks) with glecaprevir-pibrentasvir was approved by the FDA in September 2019 for treatment-naïve adults and adolescents with HCV infection genotypes 1-6 who have compensated cirrhosis.

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[53] :

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.[53]

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%).[105]

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.[105]

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.[106] 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.[106]

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.[107] 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.[107] 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.[108] 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,[109] treatment-experienced[110] or PEG-IFN intolerant, ineligible, or unwilling.[110] The fourth study evaluated sofosbuvir in combination with PEG-IFN/ribavirin in treatment-naïve patients with genotypes 1, 4, 5 or 6.[109]

In these studies, sofosbuvir-based therapy was found to be superior to historical controls[109] or to placebo,[110] or noninferior to currently available treatment options[109] 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.[111] The second study evaluated sofosbuvir and ribavirin for 12 weeks in patients with genotype 2 HCV infection coinfected with HIV-1.[112]

The efficacy of combined simeprevir and sofosbuvir was investigated in the COSMOS study, an open-label, randomized phase II clinical trial.[113] 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.[113]

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).[114, 115, 116]

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.[117, 118] 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.[117, 118]

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%.[113, 119]

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.[120] 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.[121, 122] 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%.[123] 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.[124, 125, 126, 127, 128]

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

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

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).[129] 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.[129]

The combination product ombitasvir/paritaprevir/ritonavir (Technivie) was FDA approved in July 2015 for the treatment of genotype 4 chronic HCV without cirrhosis.[130] 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.[131, 132] 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.[131] 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.[131]

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.

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, 17, 36, 37] 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.[36]

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.[36]

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 (IDSA).[10]

In the setting of suspected acute HCV infection due to exposure, clinical presentation, or elevated aminotransferase levels, the AASLD/IDSA recommend HCV antibody and HCV RNA testing.[10]

Pharmacologic pre- or postexposure prophylaxis with antiviral treatment is not recommended.[10]

Medical management and monitoring of acute HCV infection

Initiate HCV treatment without awaiting spontaneous resolution following the initial diagnosis of acute HCV viremia (ie, quantifiable RNA).

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.

Antiviral treatment

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

AASLD/IDSA Simplified Pangenotypic HCV Treatment

The American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) provides simplified hepatitis C virus (HCV) treatment for treatment-naive adults without cirrhosis as well as those with compensated cirrhosis.[10]  (Both sets of recommendations were updated on December 19, 2023.) Select guidance is summarized below.

Treatment-naive adults without cirrhosis

Eligible individuals: Adults with any genotype of chronic hepatitis C, in the absence of cirrhosis and without previous hepatitis C treatment

Ineligible patients (any of the following): Received previous hepatitis C therapy, have cirrhosis, are HBsAg positive, are gravid, have/clinically suspected to have hepatocellular carcinoma (HCC), previous recipient of liver transplant

Pretreatment evaluation

Calculate the fibrosis-4 (FIB-4) score.

Evaluation of cirrhosis: Liver biopsy is not needed. Patients are presumed to have cirrhosis when the FIB-4 score is over 3.25 OR have any of the following findings from a previous test—transient elastography indicating cirrhosis; noninvasive serologic test results over proprietary cutoffs indicating cirrhosis; clinical evidence of cirrhosis; previous liver biopsy showing cirrhosis.

Pretreatment laboratory studies include the following:

Recommended pharmacotherapy regimens

Glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks; take with food 

Sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

On-treatment monitoring

Inform and monitor patients for hypoglycemia if they are taking diabetes medication as well as for changes in their anticoagulation status (international normalized ratio [INR]) if they are on warfarin (assess for subtherapeutic anticoagulation).

Other patients do not require laboratory monitoring.

Posttreatment evaluation of cure (sustained virologic response [SVR])

At 12 weeks or later after treatment completion, obtain quantitative HCV RNA and liver function tests for confirmation of virologic cure (ie, undetectable HCV RNA) and normalized transaminase.

In the setting of elevated transaminase levels after achieving SVR, evaluate for other causes of liver disease.

Follow-up after achieving virologic cure (SVR)

Noncirrhotic individuals who achieve SVR: No liver-related follow-up

Individuals with ongoing risk for HCV infection: Risk reduction counseling, annual testing for HCV RNA, HCV RNA testing in the setting of elevated ALT, AST, or bilirubin

Patients should avoid excess alcohol use.

Follow-up after not achieving virologic cure

Those in whom initial HCV therapy fails to achieve SVR: A specialist should evaluate for retreatment, on the basis of the AASLD/IDSA recommendations.

Until retreatment: Evaulate for disease progression every 6-12 months (liver function test, CBC, INR)

Patients should avoid excess alcohol use.

Treatment-naive adults with compensated cirrhosis

Eligible individuals: Adults with any genotype of chronic hepatitis C, with compensated cirrhosis (Child-Pugh A) and without previous hepatitis C treatment. Liver biopsy is not needed. Patients are presumed to have cirrhosis when the FIB-4 score is over 3.25 OR have any of the following findings from a previous test—transient elastography indicating cirrhosis; noninvasive serologic test results over proprietary cutoffs indicating cirrhosis; clinical evidence of cirrhosis; previous liver biopsy showing cirrhosis.

Ineligible patients (any of the following): Current/previous episode of decompensated cirrhosis, received previous hepatitis C therapy, have end-stage renal disease, are HBsAg positive, are gravid, have/clinically suspected to have HCC, previous recipient of liver transplant

Pretreatment evaluation

Calculate the FIB-4 and the Child-Turcotte-Pugh (CTP) scores. Individuals with a CTP score of 7 or above (ie, CTP B or C) have decompensated cirrhosis and are not recommended to use this simplified management approach.

Pretreatment laboratory studies include the following:

Recommended pharmacotherapy regimens

Genotype 1-6: Glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks; take with food

Genotype 1, 2, 4, 5, or 6: Sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

NOTE: Baseline NS5A resistance-associated substitution (RAS) testing is required for those with genotype 3 HCV. In the absence of Y93H, patients can undergo 12 weeks of sofosbuvir/velpatasvir therapy. In the presence of Y93H, other HCV treatment guidance is recommended.

On-treatment monitoring

Clinicians may monitor for hepatic injury during treatment with blood tests as hepatic decompensation may occur (rare) in those with cirrhosis on HCV antiviral agents.

Individuals should see a specialist in the setting of worsening liver blood tests; jaundice, ascites, or encephalopathy; or new liver-related symptoms

Inform and monitor patients for hypoglycemia if they are taking diabetes medication as well as for changes in their anticoagulation status (international normalized ratio [INR]) if they are on warfarin (assess for subtherapeutic anticoagulation).

Posttreatment evaluation of cure (SVR)

At 12 weeks or later after treatment completion, obtain quantitative HCV RNA and liver function tests for confirmation of virologic cure (ie, undetectable HCV RNA) and normalized transaminase.

In the setting of elevated transaminase levels after achieving SVR, evaluate for other causes of liver disease.

Follow-up after achieving virologic cure (SVR)

Ultrasound surveillance for HCC: Every 6 months, with or without alpha-fetoprotein testing, for those with cirrhosis on the basis of AASLD recommendations.

Ultrasound surveillance for esophageal varices: Follow AASLD recommendations on portal hypertensive bleeding in cirrhosis.

Individuals with ongoing risk for HCV infection: Risk reduction counseling, annual testing for HCV RNA, HCV RNA testing in the setting of elevated ALT, AST, or bilirubin

Patients should not use alcohol to avoid liver disease progression.

Follow-up after not achieving virologic cure

Those in whom initial HCV therapy fails to achieve SVR: A specialist should evaluate for retreatment, on the basis of the AASLD/IDSA recommendations.

Ultrasound surveillance for HCC: Every 6 months, with or without alpha-fetoprotein testing, for those with cirrhosis on the basis of AASLD recommendations.

Evaulate for disease progression every 6-12 months (liver function test, CBC, creatinine, INR).

Patients should not use alcohol to avoid liver disease progression.

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.[133] ​

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 (IDSA); they are updated frequently.[10]

I. Genotype 1

HCV genotype 1a treatment-naïve patients without cirrhosis

Recommended regimens

Alternative regimen

 

HCV genotype 1a treatment-naïve patients with compensated cirrhosis

Recommended regimens

Alternative regimen

 

HCV genotype 1b treatment-naïve patients without cirrhosis

Recommended regimens

 

HCV genotype 1b treatment-naïve patients with compensated cirrhosis

Recommended regimens

 

II. Genotype 2

HCV genotype 2 treatment-naïve patients without cirrhosis

Recommended regimens

 

HCV genotype 2 treatment-naïve patients with compensated cirrhosis

Recommended regimens

See also "AASLD/IDSA Simplified Pangenotypic HCV Treatment," subsection "Treatment-naive adults without cirrhosis"

 

III. Genotype 3

HCV genotype 3 treatment-naïve patients without cirrhosis

Recommended regimens

 

HCV genotype 3 treatment-naïve patients with compensated cirrhosis

Recommended regimens

Alternative regimens

 

See also "AASLD/IDSA Simplified Pangenotypic HCV Treatment," subsection "Treatment-naive adults without cirrhosis"

 

IV. Genotype 4

HCV genotype 4 treatment-naïve patients without cirrhosis

Recommended regimens

 

HCV genotype 4 treatment-naïve patients with compensated cirrhosis

Recommended regimens

See also "AASLD/IDSA Simplified Pangenotypic HCV Treatment," subsection "Treatment-naive adults without cirrhosis"

 

V. Genotype 5 or 6

HCV genotype 5 or 6 treatment-naïve patients with or without compensated cirrhosis

Recommended regimens

Treatment-Experienced Patients with Chronic Hepatitis C Infection

The following recommendations for retreatment of experienced patients in whom prior therapy failed 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 (IDSA); they are updated frequently.[10]

Sofosbuvir-based treatment failures, with or without compensated cirrhosis

Recommended regimen

Alternative regimen

Glecaprevir/pibrentasvir treatment failures (all genotypes), with or without compensated cirrhosis

Recommended regimens

Multiple DAA treatment failures, all genotypes

Sofosbuvir/velpatasvir/voxilaprevir treatment failures, with or without compensated cirrhosis

Recommended regimens

Decompensated Cirrhosis

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA) define decompensated cirrhosis as moderate or severe hepatic impairment (ie, Child-Turcotte-Pugh [CTP] class B or C).[10] 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.

Decompensated cirrhosis in ribavirin-eligible patients with genotype 1-6 infection 

Recommended regimens

Decompensated cirrhosis in patients with genotype 1-6 infection with prievious sofosbuvir- or nonstructural protein 5A (NS5A) inhibitor-based treatment failure

Recommended regimens

Decompensated cirrhosis with moderate or severe hepatic impairment, CTP class B or C

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

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.[10, 53] 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.[10]

With the availability of newer agents, the efficacy and adverse event rates of treatments for coinfected persons is similar to that for their HIV-uninfected counterparts.[10, 134, 135]  Simplified HCV treatment is effective in HIV-infected individuals, and a minimal monitoring approach in those undergoing antiviral therapy for chronic HCV appears to be safe and achieves an sustained virologic response (SVR) rate comparable to that with standard monitoring.[10]

However, several important points related to drug interactions with antiretroviral medications need to be emphasized, as follows[10] :

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.[53]

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.[53]

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.[136] 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.[137]

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.[138]

HCV 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.[139] 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 (IDSA).[10] They are subject to change.

Genotype 1-6 infection in the allograft, without cirrhosis, regardless of treatment experience

Recommended regimens

Genotype 1-6 infection in the allograft, with compensated cirrhosis, regardless of treatment experience 

Recommended regimens

Genotype 1-6 infection in the allograft, with decompensated cirrhosis, regardless of treatment experience 

Recommended regimens

DAA-experienced patients with genotype 1-6 infection in the allograft, with or without compensated cirrhosis

Recommended regimen

HCV-Uninfected Transplant Recipients With Organs From HCV-Viremic Donors

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 (IDSA).[10]  They are subject to change.

HCV-viremic donor organs under consideration in HCV-uninfected recipients

Informed consent

Transplant programs should have a programmatic strategy to:

The following should be included in informed consent:

Timing of DAA therapy for HCV-negative recipients of HCV-viremic liver transplant

In clinically stable patients, treat early with a pangenotypic direct-acting antiviral (DAA) regimen.

HCV-uninfected recipients of liver grafts from HCV-viremic donors

Recommended regimens

Timing of DAA therapy for HCV-negative recipients of HCV-viremic non-liver solid organ transplant

Recommended regimen

HCV-uninfected recipients of non-liver organs from HCV-viremic donors

Recommended regimens

HCV and Renal Impairment or Kidney Transplant

In 2022, the US Public Health Service updated their recommendations for testing of solid organ transplant candidates younger than 12 years for infection with HIV, hepatitis B virus, and hepatitis C virus (HBV) as follows: Candidates aged younger than 12 years at the time of transplantation and who have received postnatal infectious disease testing are exempt from pretransplant HIV, HBV, and HCV testing during hospital admission for transplantation.[35]

The following recommendations are based on 2024 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 (IDSA).[10]  They are subject to change.

Patients with chronic kidney disease stage

When recommended regimens are used, there is no dose adjustment needed in direct-acting antivirals (DAAs).

Kidney transplant patients

Kidney transplant patients with HCV genotype 1-6 infection who are treatment-naive and non-DAA experienced, with or without compensated cirrhosis

Recommended regimens

Alternative regimen

Kidney transplant patients with HCV genotype 1-6 infection who are DAA experienced, with or without compensated cirrhosis

Recommended regimen

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 (IDSA).[10] They are subject to change.

Screening

All pregnant women should be tested for infection with hepatitis C virus (HCV), preferably at the start of prenatal care.

Treatment

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.

Monitoring during pregnancy

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 maternal-to-child transmission (MTCT) and severity of liver disease. These women should also receive prenatal and intrapartum care that is appropriate for their individual obstetric risk(s). No intervention is currently known to lower MTCT.

Clinicians should have a high index of suspicion for intrahepatic cholestasis or pregnancy (ICP) in gravida with HCV and pruritus or jaundice,. 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.

Breastfeeding and postpartum care

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.

HCV and Children (2023 CDC and 2024 AASLD/IDSA Guidelines)

2023 CDC guidelines

In 2023, the Centers for Disease Control and Prevention updated their 2020 recommendations for hepatitis C virus (HCV) testing for all perinatally exposed infants and children .[140]  Their recommendations are outlined below.

Test all infants and children born to pregnant individuals with current or probable HCV infection. Consider pregnant persons with detectable HCV RNA as being currently infected with HCV. In the setting of reactive anti-HCV testing but not-available HCV RNA results, consider pregnant persons as having probable HCV infection.

At age 2-6 months, obtain HCV RNA nucleic acid testing (NAT) for perinatally exposed infants to identify those who might develop chronic HCV infection. Manage infants with detectable HCV RNA in consultation with an expert in management of pediatric hepatitis. For infants without detectabe HCV RNA, no further followup is needed.

Infants and children aged 7-17 months who did not previously undergo testing should receive NAT for HCV RNA. Children aged 18 months or older who did not previously undergo testing should receive an anti-HCV test with reflex to NAT for HCV RNA.

2024 AASLD/IDSA guidelines

The following recommendations are based on HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, 2024 guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA).[10]  They are subject to change.

Testing preinatally exposed children and their siblings

All children born to HCV-infected women should undergo HCV infection testing, using an antibody-based test at or after age 18 months. The AASLD/IDSA do not recommend repetitive HCV RNA testing before age 18 months.

Test anti-HCV-positive children after age 18 months with an HCV-RNA assay after age 3 to confirm chronic hepatitis C infection.

Test siblings of children with vertically-acquired chronic HCV for HCV infection, if born from the same mother.

Transmission and prevention

Inform parents that hepatitis C is not transmitted by casual contact. Thus, HCV-infected children are not a risk to other children and can participate in school, sports, and athletic activities, and they can engage in all other regular childhood activities without restrictions.

Inform parents of HCV-infected children that universal precautions should be followed at school and in the home. Educate families and children about HCV transmission risk and routes, and techniques for avoiding blood exposure (eg, avoid the sharing of toothbrushes, razors, and nail clippers; use of gloves and dilute bleach to clean up blood).

Monitoring and medical management

To evaluate for disease progression, obtain routine liver biochemistries at initial diagnosis and at least annually thereafter.

The AASLD/IDSA recommend appropriate vaccinations for children with chronic HCV infection who are not immune to hepatitis B virus and/or hepatitis A virus to prevent these infections.

All children with chronic HCV infection should undergo evaluation of disease severity with routine laboratory testing and physical examination, as well as use of evolving noninvasive modalities (ie, elastography, imaging, or serum fibrosis markers).

Children with cirrhosis should undergo hepatocellular carcinoma (HCC) surveillance and endoscopic surveillance for varices per standard recommendations.

Cautiously use hepatotoxic drugs in children with chronic HCV infection after evaluating the potential treatment risks versus benefits. Use of corticosteroids, cytotoxic chemotherapy, and/or therapeutic doses of acetaminophen, as well as solid organ transplantation and bone marrow transplantation, are not contraindicated in children with chronic HCV infection.

Anticipatory guidance about the potential risks of ethanol for liver disease progression is recommended for adolescents with chronic HCV infection and their families. Advise abstinence from alcohol and provide interventions to facilitate cessation of alcohol consumption, when appropriate, for all persons with chronic HCV infection.

Children and adolescents

All children and adolescents with HCV infection aged 3 years or older should receive direct-acting antiviral (DAA) therapy with an approved regimen; they will benefit from antiviral therapy, regardless of disease severity.

In the setting of extrahepatic manifestations (eg, cryoglobulinemia, rashes, glomerulonephritis) and advanced fibrosis, initiate early antiviral therapy to minimize future morbidity and mortality.

HCV antiviral treatment

√ Treatment-naive or interferon-experienced children aged 3 years or older and adolescents, without cirrhosis or with compensated cirrhosis (Child-Pugh A) 

√ DAA-experienced children and adolescents, without cirrhosis or with compensated cirrhosis (Child-Pugh A)

◊◊ Genotype 1, 2, 4, 5, or 6, with prior exposure to an interferon-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors

◊◊ Genotype 3, with prior exposure to an interferon-based regimen (± ribavirin) and/or sofosbuvir but no exposure to NS3/4A or NS5A protease inhibitors

◊◊ Genotype 1-6

◊◊ Genotype 4, 5, or 6, for children and adolescents aged 3 years or older with prior exposure to an interferon (± ribavirin) plus an HCV protease inhibitor regimen

◊◊ Genotype 1, for children and adolescents aged 3 years or older with prior exposure to an interferon (± ribavirin) plus an HCV protease inhibitor regimen

Patients Using Alcohol or Injection Drugs

Alcohol

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.[141] 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.

Injection drug use (IDU)

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.[36, 142] 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."[143]

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.

The following recommendations are based on HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, guidelines from the AASLD and the Infectious Disease Society of America (IDSA).[10] They are subject to change.

Screening and treatment

People who inject drugs (PWID) should undergo annual HCV testing in the setting of no previous testing, or past negative testing and subsequent IDU. Testing frequency is based on the individual's level of risk.

It is recommended that substance use disorder treatment programs and needle/syringe exchange programs offer routine, opt-out HCV antibody testing with reflexive or immediate confirmatory HCV RNA testing and linkage to care for infected persons.

Counsel PWID about measures to lower the HCV transmission risk to others.

Offer linkage to harm reduction services (eg, intranasal naloxone, needle/syring service programs, medications for opioid use disorder, other substance use disorder treament programs).

HCV treatment is not contraindicated in those with active or recent drug use or when there is a concern for reinfection.

Testing for reinfection

It is recommended that PWID with recent IDU following spontaneous clearance of HCV infection or treatment success undergo at least yearly HCV RNA testing.

HCV and Men Who Have Sex With Men

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 (IDSA).[10]  They are subject to change.

Testing and prevention

Sexually active HIV-infected adolescent and adult men who have sex with men (MSM) should undergo annual HCV testing. More frequent testing is based on the presence of high-risk sexual or drug use practices.

HIV-uninfected MSM are recommended to undergo HCV testing at the start of HIV preexposure prophylaxis (PrEP) as well as every year thereafter (while on PrEP). More frequent testing is based on the presence of sexual or drug use practices.

Counsel all MSM about the sexual HCV transmission risk with high-risk sexual and drug use practices. Educate these individuals preventive measures for HCV infection/transmission.

Treatment

For HCV-infected MSM, combine antiviral treatment with ongoing counseling regarding the risk of HCV reinfection risk. Educate patients about measures to lower the risk of HCV reinfection following cure.

Testing for HCV reinfection

Following treatment success or spontaneous HCV clearance, sexually active MSM should undergo at least yearly (and risk-based, if indicated) HCV testing with HCV RNA.

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[144, 145] :

The World Health Organization (WHO) recommends offering and providing access to opioid substitution therapy to all opioid-dependent individuals from key populations.[53]

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/IDSA guidelines

For patients who achieved a sustained virologic response (SVR), the AASLD/IDSA recommendations are as follows[10] :

For patients with posttreatment failure to achieve an SVR[10] :

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.[89]

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[146] ; 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:

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.[147] 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 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:

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[10] :

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.[133]

Sofosbuvir (Sovaldi)

Clinical Context:  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.

Class Summary

HCV NS5B polymerase plays an essential role in HCV replication.

Class Summary

NS5A is integral for HCV RNA viral replication.

Ledipasvir/sofosbuvir (Harvoni)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

Class Summary

Several combination products have been approved and additional ones are being investigated to provide all oral regimens with high degrees of efficacy.

Interferon alfa-2b (Intron-A)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

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.

Eltrombopag (Promacta)

Clinical Context:  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.

Class Summary

These agents directly stimulate bone marrow platelet production to provide stable platelet counts to allow therapy with interferons.

What is hepatitis C (hep C)?What are symptoms of hepatitis C (hep C) infection?Which physical finding are characteristic of decompensated liver disease in hepatitis C (hep C) infection?What are common extrahepatic manifestations of hepatitis C (hep C) infection?Which baseline studies are performed in patients with suspected hepatitis C (hep C) infection?Which lab tests detect hepatitis C virus (HCV) infection?What is the role of liver biopsy in the workup of hepatitis C (hep C) infection?How is hepatitis C (hep C) infection treated?What is the prevalence of hepatitis C (hep C) infection?What are medical care costs associated with the treatment of hepatitis C (hep C) infection in the US?What is the role of hepatitis C (hep C) in the etiology of chronic liver disease?What is the onset and progression of hepatitis C virus (hep C) infection?What is the pathophysiology of hepatitis C virus (HCV) infection?What is the role of hepatitis C viral (HCV) proteins in the pathogenesis of infection?What are the most common hepatitis C virus (HCV) genotypes?How is hepatitis C virus (HCV) infection transmitted?What is the prevalence of hepatitis C virus (HCV) infection in the US?What is the global prevalence of hepatitis C virus (HCV) infection?What are the racial predilections for hepatitis C virus (HCV) infection?Which age group has the highest prevalence of hepatitis C virus (HCV) infection?What is the prognosis of hepatitis C (hep C) infection?What is included in patient education for hepatitis C (hep C)?How frequently does acute hepatitis C virus (HCV) infection become chronic?Which symptoms of hepatitis C (hep C) infection are related to synthetic dysfunction and portal hypertension?What are the common extrahepatic manifestations of hepatitis C (hep C) infection?What are dermatologic signs and symptoms of hepatitis C (hep C) infection?What are signs of decompensated liver disease in patients with hepatitis C (hep C) infection?What are extrahepatic manifestations of hepatitis C (hep C) infection?Which physical findings are characteristic of hepatitis C (hep C) infection?What are the differential diagnoses for Hepatitis C?What guidelines have been published for the diagnosis of hepatitis C (hep C) infection?What are the advantages of point-of-care screening tests (POCTs) for the diagnosis of hepatitis C (hep C) infection?How should healthcare workers with needle-stick injury involving an HCV-infected patient be evaluated and monitored?Which baseline studies are performed in the workup of hepatitis C (hep C) infection?What are the guidelines for hepatitis C (hep C) infection screening?How is hepatitis C (hep C) infection diagnosed?Which hepatitis C virus (HCV) RNA assays are approved by the FDA?What is the role of quantitative hepatitis C virus (HCV) RNA assays in the diagnosis of hepatitis C (hep C) infection?What is the role of genotyping in the workup of hepatitis C (hep C) infection?Which hepatitis C genotype tests are available?What is the role of genetic testing in the management of hepatitis C (hep C) infection?What are common serologic findings in patients with chronic hepatitis C (hep C) infection?Which additional lab tests may be indicated in the workup of hepatitis C (hep C) infection?What is the role of liver biopsy in the workup of hepatitis C (hep C) infection?Which histologic findings are characteristic of hepatitis C (hep C) infection?How is hepatitis C (hep C) infection staged?What treatment guidelines are available for hepatitis C (hep C) infection?What are the treatment options for acute hepatitis C virus (HCV) infection?What are the treatment guidelines for chronic hepatitis C (hep C) infection?What are the goals for treatment of chronic hepatitis C (hep C) infection?What are the criteria for antiviral therapy to treat chronic hepatitis C (hep C) infection?Which factors affect the risk of liver morbidity in chronic hepatitis C (hep C) infection?What interferon (IFN) preparations are used in the treatment of hepatitis C (hep C) infection?What is the efficacy of interferon (IFN) monotherapy for the treatment of acute hepatitis C (hep C) infection?What is the efficacy of combined interferon (IFN) and ribavirin for the treatment of hepatitis C (hep C) infection?What are the benefits of combination ribavirin and propylene glycol (PEG)-interferon (IFN) therapy for the treatment of hepatitis C (hep C) infection?What is the efficacy of combination ribavirin and propylene glycol (PEG)-interferon (IFN) therapy for hepatitis C (hep C) infection?How is response to combination ribavirin and propylene glycol (PEG)-interferon (IFN) therapy for hepatitis C (hep C) infection determined?What are the adverse effects of interferon (IFN) for the treatment of hepatitis C (hep C) infection?What are the adverse effects of ribavirin in the treatment of hepatitis C (hep C) infection?What is the role of growth factors in the treatment of hepatitis C (hep C) infection?What is FDA approved for the treatment of thrombocytopenia in chronic hepatitis C (hep C) infection?How is depression managed in patients with hepatitis C (hep C) infection?How does effective treatment for chronic hepatitis C (hep C) infection affect symptoms of fatigue?What is the role of (PEG)-interferon (IFN) in hepatitis C treatment in resource-limited settings?What is the efficacy of elbasvir/grazoprevir (Zepatier) for the treatment of hepatitis C (Hep C) infection?What is the efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak) for the treatment of hepatitis C (Hep C) infection?What is the treatment regimen for ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak) in treatment naïve patients with hepatitis C virus (HCV) infection genotype 1a infection?What is the efficacy of ombitasvir/paritaprevir/ritonavir (Technivie) for the treatment of hepatitis C (Hep C) infection?What is the efficacy of sofosbuvir/velpatasvir (Epclusa) for the treatment of hepatitis C (Hep C) infection?What is the role of direct-acting antiviral agents (DAAs) in the treatment of hepatitis C (hep C) infection?Which direct-acting antiviral agents (DAAs) are currently available for the treatment of hepatitis C (hep C) infection?What is the role of NS3/4 serine protease inhibitors in the treatment of hepatitis C (hep C) infection?What is the role of simeprevir (Olysio) in the treatment of hepatitis C (hep C) infection?What is the role of NS5B targeting polymerase inhibitors in the treatment of hepatitis C (hep C)?What is the efficacy of sofosbuvir in the treatment of hepatitis C (hep C) infection?What is the efficacy of combined NS5B targeting polymerase inhibitors for the treatment of hepatitis C (hep C) infection?Which NS5A targeting agents are available for the treatment of hepatitis C (hep C) infection?What is the efficacy of ledipasvir/sofosbuvir (Harvoni) in the treatment of hepatitis C (hep C) infection?What is the efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak) for hepatitis C virus (HCV) infection genotype 1a infection?What is the efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak) for hepatitis C virus (HCV) infection genotype 1b infection?What are the treatment options for acute hepatitis C (hep C) infection?How is hepatitis C virus (HCV) infection managed in patients with HIV infection?What are considerations for antiretroviral medications used in the treatment of patients coinfected with HIV and hepatitis C virus (HCV)?Which antiretroviral combinations should be avoided by patients coinfected with HIV and hepatitis C virus (HCV)?How is coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) managed?What are the recommendations for the treatment of pregnant women with hepatitis C virus (HCV) infection?What are the treatment guidelines for hepatitis C (Hep C) in patients using alcohol or injection drugs?How can hepatitis C virus (HCV) infection be prevented?Which specialist consultations are required for the management of hepatitis C (hep C) infection?What is the role of RNA testing in the management of hepatitis C (hep C) infection?Which tests may be used to monitor drug toxicity due to hepatitis C (hep C) treatment?What is the role of alanine aminotransferase (ALT) monitoring in the management of hepatitis C (hep C) infection?What screening should patients with hepatitis C (hep C) infection and cirrhosis receive?What is the most economical treatment strategy for chronic hepatitis C (hep C) infection?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 1a patients without cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 1a patients with compensated cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 1b patients without cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 1b patients with compensated cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 2 patients without cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 2 patients with compensated cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 3 patients without cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 3 patients with compensated cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 4 patients without cirrhosis?What are the treatment guidelines for chronic HCV infection in treatment-naïve genotype 4 patients with compensated cirrhosis?What are the treatment guidelines for chronic hepatitis C (hep C) infection in patients with genotype 5 or 6?What are the guidelines for treatment of chronic HCV infection in PEG-IFN/ribavirin treatment-experienced genotype 1a patients without cirrhosis?What are the guidelines for treatment of chronic HCV infection in PEG-IFN/ribavirin treatment-experienced genotype 1a patients with compensated cirrhosis?What are the guidelines for treatment of chronic HCV infection in PEG-IFN/ribavirin treatment-experienced genotype 1b patients without cirrhosis?What are the guidelines for treatment of chronic HCV infection in PEG-IFN/ribavirin treatment-experienced genotype 1b patients with compensated cirrhosis?What are the guidelines for treatment of chronic HCV infection in NS3 PI + PEG-IFN/ribavirin treatment-experienced genotype 1 patients without cirrhosis?What are the guidelines for treatment of chronic HCV infection in NS3 PI + PEG-IFN/ribavirin treatment-experienced genotype 1 patients with compensated cirrhosis?What are the guidelines for treatment of chronic HCV infection in non-NS5A inhibitor, sofosbuvir-containing regimen, treatment-experienced genotype 1 patients without cirrhosis?What are the guidelines for treatment of chronic HCV infection in non-NS5A inhibitor, sofosbuvir-containing regimen, treatment-experienced genotype 1 patients with compensated cirrhosis?What are the guidelines for treatment of chronic HCV infection in NS5A inhibitor DAA-experienced genotype 1 patients with/without compensated cirrhosis ?What are the treatment guidelines for chronic HCV infection in genotype 2 patients without cirrhosis previously treated with PEG-IFN/ribavirin?What are the treatment guidelines for chronic HCV infection in genotype 2 patients with compensated cirrhosis previously treated with PEG-IFN/ribavirin?What are the treatment guidelines for chronic HCV infection in patients with genotype 2 previously treated with either sofosbuvir plus ribavirin or sofosbuvir plus NS5A?What are the treatment guidelines for chronic HCV infection in genotype 3 patients without cirrhosis previously treated with PEG-IFN/ribavirin?What are the treatment guidelines for chronic HCV infection in genotype 3 patients with compensated cirrhosis previously treated with PEG-IFN/ribavirin?What are the treatment guidelines for chronic HCV infection in genotype 3 patients previously treated with a DDA?What are the treatment guidelines for chronic HCV infection in genotype 4 patients without cirrhosis previously treated with PEG-IFN/ribavirin?What are the treatment guidelines for chronic HCV infection in genotype 4 patients with compensated cirrhosis previously treated with PEG-IFN/ribavirin?What are the treatment guidelines for chronic HCV infection in genotype 4 patients previously treated with a DDA?What are the treatment guidelines for chronic HCV infection in genotype 5 or 6 patients previously treated with PEG-IFN/ribavirin?What are the treatment guidelines for chronic HCV infection in genotype 5 or 6 patients previously treated with a DAA?What are the guidelines for the medical management and monitoring of acute hepatitis C (hep C) infection?Why is interferon (IFN) contraindicated following liver transplantation in patients with hepatitis C (hep C) infection?What are the treatment guidelines for hepatitis C genotype 1, 4, 5, or 6 without cirrhosis following liver transplantation?What are the treatment guidelines for hepatitis C genotype 1, 4, 5, or 6 with compensated cirrhosis following liver transplantation?What are posttransplantation alternative treatment regimens for hepatitis C genotype 1, 4, 5, or 6, with or without compensated cirrhosis?What are the treatment guidelines for hepatitis C genotype 1, 4, 5, or 6 with decompensated cirrhosis following liver transplantation?What are the treatment guidelines for hepatitis C genotype 2 or 3 without cirrhosis following liver transplantation?What are the treatment guidelines for hepatitis C genotype 2 or 3 with compensated cirrhosis following liver transplantation?What are the treatment guidelines for hepatitis C genotype 2 or 3 with decompensated cirrhosis following liver transplantation?How has the treatment of chronic hepatitis C (hep C) infection evolved?Which direct-acting antiviral agents (DAAs) are used in the treatment of hepatitis C (Hep C) infection?What is the most economically efficient treatment strategy for hepatitis C (Hep C) infection?Which medications in the drug class HCV Polymerase Inhibitors are used in the treatment of Hepatitis C?Which medications in the drug class HCV NS5A Inhibitors are used in the treatment of Hepatitis C?Which medications in the drug class Combination Products are used in the treatment of Hepatitis C?Which medications in the drug class Interferons and ribavirin are used in the treatment of Hepatitis C?Which medications in the drug class Thrombopoietin-Receptor Agonists are used in the treatment of Hepatitis C?

Author

Vinod K Dhawan, MD, FACP, FRCPC, FIDSA, Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Clinical Professor, Department of Clinical Medicine, Charles R Drew University of Medicine and Science

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine

George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians

Disclosure: Springer Consulting fee Consulting; Gilead Consulting fee Review panel membership; Gilead Honoraria Speaking and teaching; Bristol-Myers Squibb Honoraria Speaking and teaching; Springer Royalty Review panel membership

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.

Hepatitis C. Causes of chronic liver disease. Courtesy of the US Centers for Disease Control and Prevention.

Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.

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.

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

Hepatitis C. Causes of chronic liver disease. Courtesy of the US Centers for Disease Control and Prevention.

Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.

Natural history of hepatitis C virus infection.

Diagnostic algorithm for hepatitis C virus infection.

Evolution of the treatment of hepatitis C virus infection.

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

Cold agglutinin disease indistinguishable from cryoglobulinemia. Courtesy of Walter Reed Army Medical Center Dermatology.

Cryoglobulinemia, palpable purpura, dysproteinemic purpura, and leukocytoclastic vasculitis (small vessel vasculitis). Courtesy of Walter Reed Army Medical Center Dermatology.

Cutis marmorata. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme, bull's-eye lesions. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema dyschromicum perstans. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema dyschromicum perstans. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme of the oral mucosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme (Stevens-Johnson syndrome). Courtesy of Walter Reed Army Medical Center Dermatology.

Palmar erythema. Courtesy of Walter Reed Army Medical Center Dermatology.

Granuloma annulare. Courtesy of Walter Reed Army Medical Center Dermatology.

Disseminated superficial (actinic) porokeratosis. Courtesy of Walter Reed Army Medical Center Dermatology.

Disseminated superficial (actinic) porokeratosis. Courtesy of Walter Reed Army Medical Center Dermatology.

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

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

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

Lichen planus (hypertrophic type). 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.

Lymphoma cutis. Courtesy of Walter Reed Army Medical Center Dermatology.

Henoch-Schönlein purpura. Courtesy of Walter Reed Army Medical Center Dermatology.

Palpable purpura. Courtesy of Walter Reed Army Medical Center Dermatology.

Purpura in hemophilia (factor VIII deficiency). All ecchymoses and bland petechiae are in the differential diagnosis of thrombocytopenic purpuras, including thrombocytopenia secondary to hepatitis C virus in which an autoantibody to platelets is present. Courtesy of Walter Reed Army Medical Center Dermatology.

Progressive pigmented purpuric eruption. Courtesy of Walter Reed Army Medical Center Dermatology.

Progressive pigmented purpura (photo rotated 90°). Courtesy of Walter Reed Army Medical Center Dermatology.

Progressive pigmented purpura (Gougerot-Blum disease). Courtesy of Walter Reed Army Medical Center Dermatology.

Progressive pigmented purpura (Schamberg disease). Courtesy of Walter Reed Army Medical Center Dermatology.

Thrombocytopenic purpura. Courtesy of Walter Reed Army Medical Center Dermatology.

Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Chronic urticaria. Courtesy of Walter Reed Army Medical Center Dermatology.

Urticaria (secondary to penicillin). Courtesy of Walter Reed Army Medical Center Dermatology.

Nodular vasculitis. Courtesy of Walter Reed Army Medical Center Dermatology.

Henoch-Schönlein purpura, palpable purpura, and leukocytoclastic vasculitis. Courtesy of Walter Reed Army Medical Center Dermatology.

Vitiligo. Courtesy of Walter Reed Army Medical Center Dermatology.

Vitiligo. Courtesy of Walter Reed Army Medical Center Dermatology.

Waldenström hypergammaglobulinemic purpura. Courtesy of Walter Reed Army Medical Center Dermatology.