Online Medical Reference

Hepatitis C

Robert S. O'Shea

Naim Alkhouri

William Carey

Published: April 2014


Chronic hepatitis C infection remains one of the most important clinical and public health problems facing modern medicine. In 1999, the World Health Organization estimated a worldwide prevalence of about 3%, which suggests that as many as 170 million persons world-wide may be infected with hepatitis C virus (HCV).1 It is estimated that between 2.7 and 3.9 million people–or about 1.3% of the U.S. population–have chronic hepatitis C infection.2,3

In the Western world, hepatitis C cirrhosis with or without liver cancer has killed more Americans per year since 2007 than human immunodeficiency virus (HIV).4 The clinical impact will continue to escalate as will the societal cost–estimated to double over the next 20 years.5

As many as 20% of patients exposed to hepatitis C do not develop chronic infection. Some studies suggest the development of jaundice during acute infection is associated with spontaneous clearance. Even in those with chronic infection, only 20% develop cirrhosis and its complications, usually over a 10- to 20-year time frame.6 Various epidemiologic risk factors may influence the risk and rate of progression including age at acquisition, male sex, alcohol exposure, genetic factors, and other comorbidities.7,8


HCV was first characterized in 1989. It is a ribonucleic acid (RNA) virus classified in the Flaviviridae family and genus Hepacivirus. It is a double-shelled, enveloped, positive sense, single-stranded RNA virus, 50 to 60 nm in diameter. HCV replicates in the liver and in peripheral blood mononuclear cells, and it is detectable in serum during acute and chronic infection.9

The exact mechanism of viral entry into liver cells is not known, but it is associated with several viral and cellular factors including tetraspanin CD81, human scavenger receptor SR-BI, and tight junction molecules Claudin-1 and occludin. During HCV assembly and release from infected cells, virus particles associate with lipids and very-low density lipoproteins, and circulate in the blood in the form of triglyceride-rich particles.10

The HCV genome codes for the synthesis of a single large polyprotein of about 3,000 amino acids that is then cut by specific enzymes into structural and nonstructural proteins. A schematic of the hepatitis C viral structure is shown in Figure 1, along with the proteins that each section encodes.11

HCV polymerase is an RNA-dependent RNA polymerase and lacks error correcting mechanisms, leading to a high mutation rate and likely contributing to the virus’ ability to escape immune pressure.12,13

HCV is classified into 6 major genotypes (G1–G6).

Genotype (G) has considerable importance in determining the outcome of treatment, although it probably does not affect the natural history of the disease. In the United States, the predominant genotype is G1, constituting approximately 75% of individuals, with 20% to 25% G2 or G3, and smaller proportions with genotypes 4, 5, or 6.14,15

Figure 2 indicates the geographic prevalence of HCV genoypes.

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In the past, a major route of infection was via blood transfusion; screening blood donations for HCV (begun in 1992) has reduced the risk of transfusion-associated HCV to less than 1 per 100,000 units transfused.16 The prevalence of infection (the total population of patients still infected) continues to rise. Currently the most common route of transmission is related to intravenous drug use. Other avenues of infection include having multiple sexual partners, tattooing, body piercing, and sharing straws during intranasal cocaine use.17

Maternal-fetal transmission occurs in approximately 5% to 10% of cases and is more likely to occur in a mother who is co-infected with HIV.18,19 No data exist to support elective Caesarean vs. spontaneous vaginal delivery as a means to avoid vertical transmission; similarly, there are no good data to advise against breastfeeding for women with HCV infection.20 The rate of infection after an HCV-contaminated needlestick injury has ranged from 0% to 10% in various studies, although not all infections may lead to long-term infection.21

Transmission to a sexual partner in a monogamous relationship is very uncommon with rates as low as 0.01% per year.22,23 Accordingly, the Centers for Disease Control and Prevention (CDC) does not suggest any change in sexual practice amongst such couples.

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Screening for HCV

The CDC and other public health experts recommend screening patients with specific risk factors, including the following (Table 1):

  • Patients who have previously used drugs
  • Patients with HIV or hemophilia
  • Patients on dialysis in the past, or those who received transplants or transfusions before 1992
  • Health care workers after a needlestick injury
  • Possibly children of HCV-infected mothers or sexual partners of HCV-infected persons

Based on the high prevalence of chronic hepatitis C infection among “Baby Boomers” (i.e., the birth cohort born between 1945 and 1965), the CDC has suggested that one-time screening of all patients in this age range is a cost-effective approach to find patients who might not be aware that they had acquired an infection, even decades earlier.24-26

Table 1: Hepatitis C Screening Recommendations from the Centers for Disease Control and Prevention (CDC), US Preventive Task Force (USPTF), and Veterans Administration Hospital (VA)
History of intravenous drug use
Blood transfusion before 1992
Clotting factor use prior to 1987
Long-term hemodialysis
Health care worker exposure
Chronic liver disease
Children of HCV mothers
Intranasal drug use (shared paraphernalia)
Alcoholic hepatitis, alcohol abuse, dependence
Age cohort 1945-1965
Military service 1964-1975

HCV, hepatitis C virus

Signs and Symptoms

Acute HCV infection is uncommonly recognized because it is usually asymptomatic, or accompanied by mild flu-like symptoms. Weight loss, fatigue, muscle or joint pain, irritability, nausea, malaise, anorexia, and jaundice occur after the 2- to 26-week incubation period. In chronic HCV infection, many have no specific symptoms, and the finding of abnormal hepatic transaminase levels on routine testing often prompts specific testing for hepatitis C.

Fatigue is a common symptom. The degree of fatigue is unrelated to the severity of liver disease. Other complaints can include depression, nausea, anorexia, abdominal discomfort, and difficulty with concentration. Extrahepatic manifestations of HCV may include: mixed cryoglobulinemia, arthralgias, porphyria cutanea tarda, membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, focal lymphocytic sialadenitis, and idiopathic pulmonary fibrosis.

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Diagnosis of HCV infection is usually a two-step process: identification of HCV antibodies followed by demonstration of viremia. The most common serologic test for detecting HCV antibodies is by an enyzyme-linked immunosorbent assay (ELISA) which has a sensitivity and specificity of 95%.27 A positive ELISA almost always represents either active viral infection or resolved HCV. Confirmation of active infection in any patient with a positive anti-HCV ELISA assay requires the detection of HCV RNA by PCR. A small percentage of those infected with HCV are unable to mount an immune response, and do not produce a measurable antibody. These false negatives might occur in patients with early acute HCV, HIV-co-infection, renal failure, or HCV-associated mixed cryoglobulinemia.

HCV viral quantitative assays can detect a viral count as low as 9.6 IU/L. If this test is negative and HCV viremia is still suspected a HCV RNA qualitative TMA assay, may detect even lower levels of viremia. The quantitative HCV RNA test defines the presence and amount of virus. Viral load does not define the likelihood of disease progression.

Patients commonly come to medical attention based on elevated alanine aminotransferase (ALT) levels, which are indirect markers of liver cell injury. HCV infected individuals may have normal or elevated ALT values, limiting the value of this test in the diagnosis of HCV. While the majority of HCV infected individuals with persistently normal ALT values have no hepatic fibrosis, it may be present in up to 25%.28

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The Role of Liver Biopsy in HCV

Liver biopsy plays no role in the diagnosis of HCV. It is of value in assessing the degree of hepatic fibrosis in HCV-infected individuals. In patients with documented HCV infection, a liver biopsy is often helpful in determining the need for therapy. Although not considered mandatory before initiating treatment, it defines the amount of ongoing destruction (grade) and degree of fibrosis (stage) of disease.

In turn, a decision for or against institution of antiviral therapy often turns on the presence and extent of hepatic fibrosis.  Patients with more advanced fibrosis are at high risk for progressive liver disease and therefore should be considered for therapy. Conversely, patients with minimal or no fibrosis might choose to forgo immediate therapy, weighing the likelihood of progressive scarring of the liver against the side effect profile of current treatment, as well as the likelihood of response.

Alternatives to Liver Biopsy

Liver biopsy is associated with some risk–bleeding occurs in 0.35% to 0.5% of all procedures, and severe complications such as perforation in 0.57%, and even death in ~0.03%. Most deaths are from uncontrolled bleeding. Because of low patient and physician acceptance of liver biopsy, alternative means to assess hepatic fibrosis are needed. A detailed discussion about alternatives to liver biopsy is available.29

The need for a staging liver biopsy is clearly in flux; although traditionally used to decide on need for treatment, with the evolution of more effective treatment, potentially shorter courses of therapy and less attendant toxicity, its role will likely diminish.

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General Principles of Treatment

The goal of treatment is permanent elimination of virus. This is achieved in almost all when there is no detectable virus in the blood 6 months after cessation of antiviral treatment. This is referred to as sustained virologic response (SVR). Increasingly, SVR and “cure” are used interchangeably and will be so used in this chapter. Those with genotype 2 or 3 HCV are more likely to achieve SVR compared with those with genotype 1 or 4.

Current practice guidelines provide in-depth information about diagnosis and general management of hepatitis C; however, the introductions of newer simpler and more effective pharmacologic agents have not yet been incorporated into these guidelines.30 Patient Selection: The decision to initiate treatment reflects a balance achieved after weighing the risks and benefits of treatment. This also must take into account the urgency and timing of initiating therapy: immediate treatment vs. delaying therapy vs. holding off, given the considerable financial costs and toxicity of therapy. A critical assessment of the risks, benefits, and alternatives of treatment must take into account the odds of success, as well as the likely adverse events, all in the context of the patient’s preferences. Thus, the ability to estimate prognosis is critically important in counseling patients.

Baseline predictors of response, before initiating therapy, can be broken down into virus specific vs. patient characteristics. In addition, patient-specific factors might be further broken down into those that are modifiable vs. those that are fixed. Viral-specific markers include viral genotype, and viral load, which are also important in directing the duration of treatment.

Patient-specific factors that impact outcome include the presence of advanced fibrosis or cirrhosis. The presence of a specific genetic variant, a single nuclear polymorphism in the gene coding for IL28B is a strong predictor of response in patients with older treatment regimens. Patients with the favorable IL28B genotype are at least twice as likely to respond to treatment with interferon and ribavirin.31 This test is not as relevant in the current era of treatment described later in this chapter.These predictors of response, however, are largely unmodifiable–with no chance to impact them prior to initiation of treatment.

A number of other host-related, less potent predictors of response, which may be modifiable, have been studied including iron status, insulin resistance, cholesterol levels, and vitamin D stores (Table 2).

Table 2: Predictors of Response to Treatment with Interferon + Ribavirin
A. Viral Factors Influencing Treatment Success
Selected Clinical Viral Factors Impact On Cure Rate
HCV viral load <800,000 IU/mL Better
HCV genotype G2 highest response rate
G3 almost as good
G1, 4, 5, 6 lesser response

HCV quasispecies diversity, structural variability, interferon sensitivity determining region also influence outcome but are not clinically useful

B. Host Factors Influencing Treatment Success
Host Factors Impact On Cure Rate
Higher age
SNP IL28B CC genotype
Adherence to treatment

Asian vs. white
White vs. black
White vs. hispanic

Previous failed treatment
GGT Response
Ferritin elevated at baseline
Obesity/BMI, insulin resistance, steatosis
Advanced fibrosis/cirrhosis
Alcohol abuse
HIV co-infection
HBV co-infection
Tobacco abuse/cannabis
Vitamin D level
C. Treatment Factors Influencing Treatment Success
Major Treatment Factors Impact on Cure Rate
No virus after 4 and 12 weeks of treatment
Ribavirin dose

BMI, body mass index; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HBV, hepatitis B virus

The impact of most of these factors has been studied best in patients who were treated with peginterferon and ribavirin therapy; by comparison, not as much data are available for current first-line therapy. Many markers of responsiveness to treatment may also reflect the extent of disease progression. Accordingly the likelihood of advanced fibrosis increases with a higher number of these markers.

The most important prediction of long-term SVR to pegylated interferon and ribavirin therapy, however, relates to the virologic response on treatment. Patients who clear the virus after 4 weeks of treatment (termed a rapid virologic response, RVR)–and subsequently remain virus negative throughout the initial 12-week course of therapy (termed an extended RVR, or eRVR)–are much more likely to develop a SVR (cure).32

Pre-treatment assessment of the patient with chronic hepatitis C should include:

  1. Viral load
  2. HCV genotype (once per lifetime)
  3. Complete blood count (CBC) including platelet count

During treatment employing interferon or ribavirin hematologic parameters need to be monitored carefully. Typically, labs are obtained weekly for a month then monthly. Additional testing and intervention may be required depending on abnormalities encountered. In addition, serial viral loads should be measured after 4 and 12 weeks of therapy, at the end of therapy, and if negative at the end of therapy, 6 months later. These measures are generally considered markers for appropriateness and quality of care.33

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Treatment of Acute Hepatitis C

Acute HCV infection is uncommonly diagnosed because of lack of specific symptoms.34 Early treatment with interferon therapy is highly effective in viral eradication. Multiple drug therapy is not needed in acute hepatitis C treatment. The outcome for patients treated for acute hepatitis C with pegylated interferon alone tends to be very good, with cure rates of 71% to 95%.35 Since as many as 50% of acutely-infected individuals will spontaneously clear infection, a balance must be struck between watchful waiting and early treatment.

Health care workers accidentally exposed to HCV-infected blood via a needlestick injury should have immediate testing done to establish the absence of pre-existing infection. There is no value to administration of either serum immune globulin or prophylactic antiviral treatment. Follow up viral testing (HCV RNA) should be done 12 weeks later and treatment initiated if virus is still present.

Studies of the predictors of spontaneous clearance of HCV infection have suggested that clearance may be more likely to occur in younger patients, and in those with a more symptomatic presentation, particularly with jaundice. In addition, a favorable IL28B genotype polymorphism is a strong predictor of spontaneous clearance. Regardless of ethnicity, those with the favorable IL28C/C genotype are three times more likely to clear HCV spontaneously than those with other genotypes.36

Treatment of Chronic Hepatitis C

Those whose chronic hepatitis C has been successfully treated demonstrate an improved clinical course, demonstrated in patients with all stages of fibrosis at baseline. Patients with advanced fibrosis or cirrhosis who respond to treatment and develop an SVR have as much as an 80% reduction in the risk of developing clinical decompensation compared with patients with a persistent viral infection.37 A number of studies have also shown a decrease in the risk of specific complications, including a decrease of as much as 77% in the risk of development of hepatocellular carcinoma (HCC).38,39 Fibrosis may also improve. Among patients with lesser degrees of liver damage, several studies have suggested a decrease in the degree of liver fibrosis among patients who achieve an SVR, and perhaps in a minority of patients, even regression of cirrhosis.40,41

Secondary aims of treatment are symptom control, improvement in liver function, and prevention of complications of progressive liver disease, including cirrhosis, decompensated liver disease, and HCC.

Regardless of whether a patient elects to be treated or not, practice guidelines recommend that all patients with hepatitis C and no evidence for immunity be vaccinated for hepatitis A and, if risk factors exist, for hepatitis B as well.32

The decision to treat must be individualized, based on the overall risks and benefits of therapy. Patients with chronic HCV infection and evidence of damage, including elevated serum aminotransferase levels, chronic hepatitis and fibrosis on liver biopsy, absence of decompensation, and no other contraindications, should be considered for treatment. Specific contraindications include severe concurrent disease, previous solid organ transplantation (other than liver transplant), autoimmune hepatitis, hyperthyroidism, pregnancy, or uncontrolled depression. Previous contraindications, such as HIV infection or an otherwise immunocompromised status, are no longer considered obstacles to treatment. These indications and contraindications, however, are all relative, and it is likely that they may not be applicable in the emerging non-interferon era of treatment.

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Contra-Indications to Treatment

Because of the cost, complexity, and toxicity of treatment, multiple concerns must be weighed before committing a patient to therapy. Interferon therapy is an immune modulatory therapy. In addition it may provoke or worsen depression. If depression, anxiety, or other psychiatric illness is evident by history or exam, psychiatric consultation should be sought for evaluation, treatment, and follow-up during the interferon-treatment period. As depression and psychiatric effects of interferon treatment can adversely affect the ability of patients to complete therapy, several studies have administered formal testing, and have detected a high prevalence of depression among patients at baseline.42-46 Rarely, serious cardiac or eye events may be caused by interferon. Ribavirin is teratogenic. Accordingly, if these agents are used to treat hepatitis C it is important to survey:

  • Psychiatric history
  • Substance abuse disorder, or alcohol use
  • Screening for depression
  • Autoimmune disorders
  • Pregnancy
  • Presence of other severe/advanced disease that may affect survival

Specific testing in the course of evaluation should include:

  • Ophthalmology exam to exclude retinopathy in patients with a history of hypertension or diabetes
  • Lab testing, including liver function tests, baseline HCV viral load and genotype; CBC with differential; thyroid function tests; HIV serology; hepatitis B and hepatitis A antibody status; metabolic panel, including markers of renal function; iron markers, and autoimmune markers.47,48

There are no fixed criteria that define the minimal acceptable parameters that are necessary before initiating therapy–for example, specific white blood count or platelet levels, but clinicians often use the general baseline parameters that were established as part of clinical trials to decide on candidacy for interferon-based treatment.


Premature cessation of treatment, largely due to side effects occurs in 10% to 14% in patients treated with pegylated interferon or combination pegylated interferon and ribavirin,49 and underscores the importance of counseling, and careful patient selection before beginning treatment. Adverse events of some degree or another are almost universal in treated patients. Relative frequencies of these particular adverse events in a study of peginterferon alfa-2a and ribavirin include50:

Fatigue 64%
Headache 62%
Pyrexia 46%
Myalgia 56%
Rigors 48%
Insomnia 40%
Nausea 43%
Alopecia 36%
Irritability 35%
Arthralgia 34%
Anorexia/weight loss 32%
Weight loss 29%
Depression 31%
Injection site reaction 58%
Injection site inflammation 25%

Treatment can also provoke other illnesses including: symptomatic thyroid disease, impotence, systemic autoimmune disease, immune mediated dermatologic disease, diabetes mellitus, cardiovascular disease, psychosis, seizures, peripheral neuropathy and hemolytic anemia.51

Toxicity of ribavirin is generally additive, with a substantial rate of hemolytic anemia, and skin rashes. The most common side effect is fatigue, occurring in about 15% of patients, resulting partly from hemolytic anemia, which in turn, may provoke symptoms related to heart disease. Ribavirin is a teratogen and is therefore strictly contraindicated in pregnancy when either the woman or the male partner is receiving this drug and for 6 months following cessation of therapy.

The dose of ribavirin used depends on body weight and HCV genotype, and needs to be modified in those with significant renal impairment. Patients with genotype 2 or 3 and normal renal function can be treated effectively with 800 mg per day; patients with genotype 1 or 4 are dosed based on their weight: <75 kg: 1,000 mg daily in two divided doses for 48 weeks, and if ≥75 kg: 1,200 mg daily in two divided doses for 48 weeks.

Ribavirin is cleared by the kidneys and therefore is relatively contraindicated in patients with significant renal dysfunction (a creatinine clearance <50 mL/min). Such patients should be treated in specialized centers.

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Toxicity and Monitoring on Therapy

Patients on therapy need to be monitored closely for complications or the emergence of adverse reactions to combination therapy. This should include evaluation for depression, symptoms of irritability, sleep disturbance, and visual disturbances, as well as evidence of hyper- or hypothyroidism. Blood counts should be monitored frequently at the beginning of treatment and at least monthly afterward, if stable. Although support of the bone marrow with erythropoietin for anemia and granulocyte colony- stimulating factor (GCSF) for neutropenia can allow continuation of therapy, even in patients with significantly affected counts, the safety and cost effectiveness of this approach is uncertain.52,53 Current practice is to dose-reduce ribavirin in cases of severe anemia.

Contemporary Treatment Regimens for Chronic Hepatitis C

The field of HCV treatment witnessed a significant change in 2011 with the approval of the first direct-acting antiviral (DAA) agents, the NS3/4A protease inhibitors boceprevir and telaprevir to treat patients with chronic HCV genotype 1 infection.54 These medications significantly improved treatment outcomes with overall cure rates of approximately 65% to 75% for those receiving a first course of therapy (treatment-naïve).55,56 However, both medications had major drawbacks that made them less than ideal treatment options including:

  1. Low barrier to viral resistance57
  2. Lack of efficacy against other HCV genotypes (genotypes 2-6)
  3. Low cure rates in cirrhotics and those who have not responded to previous treatment
  4. The high pill-burden and the need for three times daily dosing accompanied with food
  5. Additional side effects such as skin rash, serious skin reactions (including fatal reactions to telaprevir), pruritus, severe anemia and dysgeusia
  6. Significant drug-drug interactions as both medications inhibit the cytochrome P450 3A (CYP3A) and they are contraindicated in combination with drugs that are highly dependent on CYP3A for clearance

Treatment regimens using boceprevir or telaprevir will not be further discussed in this chapter, as they have been replaced by two new medications that were approved by the US Food and Drug Administration (FDA) in late 2013 and are now the standard of care for patients with chronic HCV infection. These are the second wave NS3/4A protease inhibitor simeprevir and the first-in-class NS5B polymerase inhibitor, sofosbuvir. The simplest shortest treatment regimen employs sofusbuvir. Regimens using this agent require no tracking of viral loads and have very few drug-drug interactions. Many specialists believe that sofosbuvir used in combination with ribavirin, especially when interferon is not part of the regimen is suitable for use by non-specialists, especially in HCV-infected individuals without evidence of cirrhosis induced hypersplenism. Such individuals, along with and those with renal failure and other co-morbidities that might complicate treatment are best managed in specialty clinics.

Health care providers who plan to treat HCV-infected individuals are cautioned to become familiar with common drug side effects of each agent used.

Sources for complete prescribing information for the drugs approved for treatment of hepatitis can be found in Table 3.

Table 3: U.S. Food and Drug Administration Approved Drugs for Hepatitis C
Drugs used to treat HCV Prescribing information
Pegylated interferon alfa 2a
Pegylated interferon alfa 2b¤tpage=2
For chronic hepatitis C treatment two or three drugs are used simultaneously as described in the text; single-drug regimens are not used.

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Sofosbuvir-Based Regimens

Sofosbuvir is a uridine nucleotide analogue which selectively inhibits the HCV NS5B polymerase. This is particularly important, as inhibition of the viral polymerase has an impact across a number of genotypes. Sofosbuvir has been tested in combination with pegylated interferon and ribavirin, and in interferon-free regimens. Sofosbuvir is an oral medication used once daily (400 mg/day) and may be taken with or without food. The results of phase III clinical trials assessing the efficacy of sofosbuvir for treating chronic HCV infection are summarized in Table 4.

Table 4: Major Phase III Clinical Trial Assessing the Efficacy of Sofosbuvir Regimens for Chronic Hepatitis C Infection
Study (Reference) Population (n) Cirrhotics (%) Regimen SVR

G 1, 4, 5, 6

17% (1) Sofosbuvir/peg/riba x 12 weeks

Overall = 90%
G1a = 82%
G1b = 92%
G4 = 96%
G5/6 = 100%


G 2 and 3


(1) Sofosbuvir/riba x 12 weeks
(2) Peg/riba x 24 weeks

(1) Overall = 67%
G2 = 97%
G3 = 56%
(2) Overall = 67%


G 2 and 3


(1) Sofosbuvir/riba x 12 weeks
(2) Sofosbuvir/riba x 16 weeks

(1) Overall = 50%
G2 = 86%
G3 = 30%
(2) Overall = 73%
G2 = 94%
G3 = 62%


G 2 and 3
Interferon unable


(1) Sofosbuvir/riba x 12 weeks
(2) Placebo x 12 weeks

(1) Overall = 78%
G2 = 93%
G3 = 61%
(2) Overall = 0%


G 3 (250)
G 2 (73)

21% (1) Sofosbuvir/riba x 24 weeks
(2) Sofosbuvir/riba x 12 weeks

Overall = 85%
Overall = 93%

G, genotype; peg, pegylated interferon; riba, ribavirin; SVR, sustained virologic response

The utility of sofosbuvir in treatment-naive patients with genotypes 1, 4, 5, and 6 was studied in a 12-week trial using sofosbuvir in combination with peg/riba (the NEUTRINO trial).58 Eighty-nine percent of the patients were genotype 1, 9% genotype 4, and only 2% had genotype 5 or 6; a total of 17% had cirrhosis. The FISSION trial recruited treatment-naïve patients with genotype 2 or 3, and randomized them to treatment with either dual therapy with sofosbuvir + weight-based ribavirin for 12 weeks, or 24 weeks of peg/riba therapy.58 In both trials, there was a rapid decrease in viral load among all patients treated with sofosbuvir, irrespective of genotype, IL28 status, race, or the presence or absence of cirrhosis. By week 4 of therapy, 99% of those with genotypes 1, 4, 5, or 6 had an undetectable HCV RNA level (<25 IU/mL), along with 100% of those with genotype 2 or 3. This effect extended to the likelihood of SVR: 90% of the genotypes 1, 4, 5, 6 patients achieved an SVR. Although the rate of SVR did not vary much across the different genotypes, there was an effect seen among patients with cirrhosis (with an SVR in 92% of the non-cirrhotics vs. 80% among the patients with cirrhosis), and non-CC IL28 genotype (with a 98% SVR rate among patients with the IL28 CC genotype, but only 87% among the non-CC patients). The results of the FISSION study showed that there was no significant difference in the likelihood of SVR among patients treated with sofosbuvir + ribavirin compared with peg/riba–each of whom had an SVR rate of 67%. This did vary by HCV genotype; among genotype 2 patients, the SVR rate in the sofosbuvir + ribavirin arm was 97%, compared with 78% in those treated with peg/riba. Among genotype 3 patients, the similar comparisons were 56% and 63%. In the subgroup with cirrhosis, 47% of patients treated with sofosbuvir achieved SVR vs. 38% in the peg/riba arm. Importantly, in both these studies, there was a very low rate of discontinuation, with higher rates of most of adverse events occurring among patients treated with peg/riba.

The POSITRON study was aimed at treating genotype 2 or 3 patients who were not candidates for interferon therapy–based on previous side effects from interferon or contraindications (predominantly psychiatric contraindications or autoimmune disorders).59 Patients were treated with sofosbuvir plus either ribavirin or a placebo for 12 weeks. Approximately one half of the patients had genotype 3, and 16% of patients had cirrhosis. The overall SVR rate was 78% among the 207 patients treated with dual therapy, and 0% among the 71 placebo patients. This included 93% of patients with genotype 2, and 61% of the genotype 3 patients. The presence of cirrhosis was also a risk factor for non-response: only 61% of patients with cirrhosis achieved an SVR, compared with 81% of patients who did not have cirrhosis.

The FUSION study enrolled genotype 2 or 3 patients who had failed to respond to peg/riba, retreating them with either 12 weeks or 16 weeks of sofosbuvir + weight-based ribavirin.59 Approximately two thirds of the patients had genotype 3, and 34% of patients had cirrhosis. The overall SVR was 50% in the patients treated for 12 weeks, and 73% among those treated for 16 weeks. Evaluated by genotype, 86% of genotype 2 patients, treated for 12 weeks, and 94% of those treated for 16 weeks achieved an SVR, compared with the genotype 3 patients, where 30% and 62% of patients treated for 12 and 16 weeks developed an SVR. Cirrhosis was again seen as a predictor of lack of response: of those treated for 12 weeks, the SVR rate among patients with cirrhosis was only 31%, compared with 61% in those without cirrhosis. Among those treated for 16 weeks, the comparable figures were 61% among those with cirrhosis, and 76% among those without.

Due to the lower SVR rate in patients with genotype 3 treated with 12 weeks of sofosbuvir + ribavirin and the improvement in SVR noted by extending the duration to 16 weeks in the FUSION study, the VALENCE trial evaluated extending sofosbuvir + weight-based ribavirin to 24 weeks in patients with genotype 3 infection. The results were encouraging with an SVR rate of 84% (210/250 patients).60

Based on interim analysis from a recent study, treatment we most often recommend for genotype 1 hepatitis both in those who have not been previously treated and those with prior treatment failure is a regimen of two oral agents, sofosbuvir and simeprevir. Each of these agents is FDA-approved, although not specifically in combination with one-another. The apparent cure rate is between 93% - 100%. This high efficacy, even in those with advanced fibrosis or cirrhosis, combined with ease of administration, and freedom from side effects makes this the current best choice in our view. The major stumbling block in the management of hepatitis C is no longer toxicity, complexity or duration of treatment. The cost of a 12 week course of treatment with sofosbuvir and simeprevir is estimated to be well in excess of $120,000 (2014). We expect rapid changes to occur in “best practices” for hepatitis C. The International Anti-viral Society in conjunction with the American Association for the Study of Liver Disease and the Infectious Disease Society of America have developed a website providing updated information (


Sofosbuvir FDA-Approved Regimens

Sofosbuvir in patients with HCV genotype 1 or 4 infection: Sofosbuvir + pegyaleted interferon and ribavirin for 12 weeks. Sofosbuvir + ribavirin for 24 weeks (interferon-free regimen) can be considered for patients with genotype 1 infection who are not candidates for interferon-based regimen.

Sofosbuvir in patients with HCV genotype 2 infection: Sofosbuvir + ribavirin for 12 weeks (Figure 5).

Sofosbuvir in patients with HCV genotype 3 infection: Sofosbuvir + ribavirin for 24 weeks (Figure 6).

  • The ribavirin dose is weight-based for all genotypes (<75 kg = 1,000 mg daily and ≥75 kg = 1,200 mg daily).

Adverse Events and Drug-Drug Interactions

Based on safety assessments of sofosbuvir in phase III trials, the most common adverse events for sofosbuvir + ribavirin combination were fatigue and headaches. In the sofosbuvir + pegylated interferon and ribavirin regimen, common adverse events were fatigue, headaches, anemia, nausea, and insomnia.61 After taking sofosbuvir orally, it is rapidly converted to the circulating metabolite GS-331007. Drugs that are potent P-glycoprotein inducers in the intestine may lead to a reduction in sofosbuvir plasma concentration including anticonvulsants (e.g., phenytoin), antimycobacterials (e.g., rifampin), HIV-protease inhibitors (e.g., ritonavir), and herbal supplements (St. John's wort).

Simeprevir-Based Regimens

Simeprevir is a potent, once daily (150 mg/day) oral protease inhibitor that is indicated in combination with peg/riba for treatment-naïve and -experienced patients with compensated HCV genotype 1 infection. Similar to the first generation protease inhibitors, issues with virologic resistance caused by amino acid substitutions at multiple NS3 positions can reduce susceptibility to simeprevir. Importantly, the efficacy of simeprevir-based triple therapy was substantially decreased in subjects with GT1a infection with a baseline NS3 Q80K polymorphism which prompted the FDA to recommend testing for this polymorphism prior to starting therapy in this subset of patients.62 This test is commercially available.

The safety and efficacy of simeprevir combination therapy in treatment-naïve patients with chronic HCV genotype 1 infection were assessed in two large randomized clinical trials, QUEST 1 and QUEST 2 (Table 5) which compared 12 weeks of simeprevir + 24 or 48 weeks of pegylated interferon and ribavirin versus placebo + pegylated interferon and ribavirin (control arm). Treatment duration was determined according to response-guided therapy (RGT) criteria that included HCV RNA <25 IU/mL at week 4 and undetectable HCV RNA at week 12. Patients that met the RGT criteria completed treatment in 24 weeks; otherwise they were treated for 48 weeks.

Table 5: Phase III Clinical Trials of Simeprevir
Trial Population (n) Regimen SVR


Treatment-naïve (394)

(1) Simeprevir x 12 weeks + peg/riba x 24-48 weeks
(2) Peg/riba x 48 weeks

(1) Overall = 80%
G1a = 71%
G1b= 90%
(2) Overall = 50%


Treatment-naïve (391)

(1) Simeprevir x 12 weeks + peg/riba x 24-48 weeks
(2) Peg/riba x 48 weeks

(1) Overall = 81%
G1a = 80%
G1b= 82%
(2) Overall = 50%


Treatment-experienced (relapsers) (393)

(1) Simeprevir x 12 weeks + peg/riba x 24-48 weeks
(2) Peg/riba x 48 weeks

(1) Overall = 79%
G1a = 70%
G1b = 86%
(2) Overall = 37%

G, genotype; peg, pegylated interferon; riba, ribavirin; SVR, sustained virologic response

The pooled SVR rate was at 80% in the simeprevir arm compared with 50% in the control arm (75% for GT1a and 85% for GT1b, 58% in GT1a patients with Q80K mutation). The relapse rate was 11% in the simeprevir-based arms compared with 23% in the control group. The rate of virologic failure was lower among patients receiving triple therapy (8%) than among those who received pegylated interferon and ribavirin alone (33%).

The PROMISE phase III placebo-controlled study included 393 patients with prior relapse after pegylated interferon and ribavirin treatment who were randomly allocated into one of two arms, 12 weeks of simeprevir 150 mg daily or placebo + pegylated interferon and ribavirin, followed by additional 12 or 36 weeks of pegylated interferon and ribavirin according to RGT criteria.63 The overall SVR rate was 79% in the simeprevir arm compared with 37% in the placebo arm (70% for G1a and 86% for GT1b, 47% in G1a patients with Q80K mutation). Patients with advanced fibrosis (stage 3-4) had a lower SVR rate with simeprevir-based triple therapy at 73%. The ASPIRE trial was another randomized controlled, phase IIb trial in treatment-experienced patients with HCV G1 infection that included prior relapsers, partial responders, and null responders. SVR rates in the simeprevir 150 mg daily for 12 week arm were 77%, 65%, and 53%, respectively.64

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Simeprevir FDA-Approved Regimens


Simeprevir in treatment-naïve patients and prior relapsers with HCV genotype 1 infection: Triple therapy with simeprevir will be given for the first 12 weeks and then patients will take pegylated interferon and ribavirin for an additional 12 weeks (Figure 7).

Simeprevir in prior partial and null responder patients with HCV genotype 1: Triple therapy with simeprevir for 12 weeks followed by pegylated interferon and ribavirin for an additional 36 weeks (Figure 8).

Stopping rules for simeprevir: Discontinuation of therapy is recommended in all patients with HCV RNA levels ≥25 IU/mL at treatment weeks 4, 12, or 24.

Side Effects

Overall, simeprevir is tolerated well by patients and the most common side effects of triple therapy are those usually seen with interferon and ribavirin such as flu-like symptoms and fatigue. Adverse events that occurred with more frequency in simeprevir-based combination therapy compared with pegylated interferon and ribavirin included skin rash (including photosensitivity reactions), pruritus, nausea, myalgia, and dyspnea.65 Elevation in both direct and indirect bilirubin was noted early after starting therapy in some patients; however, this was rapidly reversible after stopping simeprevir. Treatment with simeprevir can inhibit the intestinal (but not hepatic) CYP3A4 activity and the OATP1B1/3 and P-glycoprotein transporters which may lead to higher plasma concentration of drugs either metabolized or transported by these proteins. The reader is directed to full prescribing information for details of important drug-drug interactions with simeprevir (Table 3).

A summary of the current recommendations for treating the most common HCV genotypes in the U.S. (GT1-3) is provided in Table 6.

Table 6: Summary of HCV Guidance Recommendations for Treating HCV Genotypes 1-3 (available at:
  Population Recommended Alternative
Genotype 1 Treatment-Naïve and Prior PegIFN + RBV Relapser (± Compensated Cirrhosis)
IFN Eligible SOF + PegIFN + RBV x 12 weeks, regardless of subtype

SMV 12 weeks + PegIFN + RBV  x 24 weeks
HCV GT 1a, if Q80K not detected HCV GT 1b (IIa, A)

IFN Ineligible SOF + SMV ± RBV x 12 weeks, regardless of subtype SOF + RBV  x 24 weeks, regardless of subtype
Prior PegIFN + RBV Failure (partial or null response to treatment with PegIFN + RBV)
  SOF + SMV ± RBV x 12 weeks

SOF x 12 weeks + PegIFN + RBV x 12 weeks
SMV x 12 weeks + PegIFN +RBV x 48 weeks

Prior PI + PegIFN + RBV Failure  (partial or null response to treatment with PegIFN + RBV + TVR or BOC)
GT 1a SOF x 12 weeks + PegIFN + RBV x 24 weeks SOF + RBV x 24 weeks
GT 1b SOF x 12 weeks + PegIFN + RBV x 12-24 weeks SOF + RBV x 24 weeks
Genotype 2

Treatment-Naïve and
Prior PegIFN + RBV Relapser

SOF + RBV x 12 weeks None
Prior PegIFN + RBV Failure (partial or null response) SOF + RBV x 12 weeks (cirrhotics may extend to 16 weeks) SOF + PegIFN + RBV x 12 weeks
Genotype 3

Treatment-Naïve and
Prior PegIFN + RBV Relapser

SOF + RBV x 24 weeks SOF + PegIFN+ RBV x 12 weeks
Prior PegIFN + RBV Failure (partial or null response) SOF + RBV x 24 weeks SOF + PegIFN+ RBV x 12 weeks

Key: SOF = sofosbuvir; PEGIFN = pegylated interferon; RBV = ribavirin; SMV = simeprevir


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Difficult-to-Treat Populations

Table 2 identifies host and viral factors associated with suboptimal response to treatment. Management of selected groups is discussed here.


Across all genotypes patients with cirrhosis are 10% to 50% less likely to respond to treatment. The presence of hypersplenism in these patients makes treatment more difficult. Such patients are best served by referral to a specialist for treatment.

Post Liver Transplant HCV

Infection of the new liver is almost universal post-transplant, and the subsequent rate of hepatic fibrosis can be quite rapid. The likelihood of a patient developing cirrhosis in the newly transplanted liver, over the course of 3 to 5 years post-transplant, is as high as 10% to 30%.66-68

In a small subgroup of patients, perhaps 4% to 7% of all patients with hepatitis C undergoing transplant, the pattern of recurrence is even more aggressive, with predominantly cholestatic features, and the rate of disease progression is even more accelerated–leading to cirrhosis or death within 1 to 3 years in as many as 60% of patients.69

This same group at high risk of progression has also traditionally been more difficult to treat successfully: their immunosuppression may make it more difficult to tolerate treatment, particularly in the early post-transplant period, due to overlapping side effects such as anemia and bone marrow suppression, and patients with HCV recurrence post-transplant tend to have elevated viral loads–on average, 10- to 20-fold greater than pre-transplant levels.70 In addition, many of these patients have previously failed treatment (another poor marker for successful treatment). As a result, the likelihood of SVR in treating these patients with pegylated interferon and ribavirin is frequently less than 30%, particularly among those with genotype 1.71,72

Lastly, the use of interferon in the post-transplant setting has also been associated with the risk of developing acute cellular rejection, with rates as high as 40% in patients who undergo peg/riba therapy.73 This makes treatment for patients who have had recurrent disease after liver transplant somewhat precarious; the situation is even worse, however, in those who have had other solid organ transplant, where the high risk of rejection and subsequent graft loss may absolutely preclude interferon treatment.

Powerful drug-drug interactions exist in patients treated with either boceprivr or telaprevir and either of the two most commonly used immunosuppression regimens, cyclosporine (CSA) or tacrolimus. This, in turn, can lead to massive elevations of the blood levels of tacrolimus or CSA in patients who continue at their routine dosing–up to 70 fold elevations in tacrolimus levels, for example.74 Concern about these findings have prompted some to advise against treating this population.75

Despite this, with close monitoring, several studies have attempted to treat this desperate population using telaprevir or boceprevir; the precise likelihood of SVR, and optimal strategy, however is still evolving.76 Experience with sofosbuvir and with simeprevir in this population is limited and no evidence-based conclusions can be drawn.

HIV/Hepatitis C Co-Infected Patient

Patients with HCV infection often share risk factors for co-infection with both hepatitis B virus (HBV) and HIV, which presents unique challenges. For example, HIV is known to accelerate HCV disease progression; a substantial percentage of patients are either not referred for care or for medical or psychosocial reasons not eligible for treatment, and of those treated, co-infected patients tend to have a lower rate of SVR compared with patients infected with hepatitis C alone. Among co-infected patients with genotype 1 in the APRICOT trial,77 the average SVR in patients treated with peg/riba was 29%–but only 14% in a similar multicenter study done by the Aids Clinical Trials group78–both substantially lower than might be expected in patients in a non-HIV cohort.79-82

The importance of treatment, however, is also clear–as is the case in patients who are not HIV infected, those patients who are able to be successfully treated are clearly at a substantially lower risk of developing liver disease complications or suffering a liver-related death.83

As in patients with cirrhosis, therefore, the introduction of the protease inhibitors was closely watched, as it promised significant improvement in response rates in a population at high risk for progression. However, there are major issues with drug-drug interactions with most of the medications used for control of HIV in this population, the highly active antiretroviral therapies, which significantly impact on the efficacy of treatment.

More recently, the safety and efficacy of sofosbuvir combination therapy in patients with HCV and HIV co-infection was assessed in a large open-label clinical trial (PHOTON-1) that included patients with HCV genotypes 1, 2, and 3. The overall SVR rates with 24 weeks of sofosbuvir + ribavirin were 76% for subjects with genotype 1 and 92% for genotype 3. Treatment with only 12 weeks of sofosbuvir + ribavirin resulted in an SVR rate of 88% for genotype 2 patients. Importantly, the percentage of CD4+ cells did not change during therapy with sofosbuvir + ribavirin and no dose adjustment was needed for commonly used HIV medications (efavirenz, raltegravir, rilpivirine, emtricitabine, and tenofovir). These results led the FDA to approve the use of sofosbuvir combination therapy in co-infected patients and we expect this regimen to become the new standard of care for this population.

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Future Directions in Treatment

Although the overall likelihood of curing HCV has dramatically improved treatment duration, toxicity and cost continues to dampen the enthusiasm of patients contemplating treatment.

This may be especially true in patients who are typically classified as difficult to treat, such as those who were non-responders to previous therapy, patients who are immunosuppressed post-transplant, or have a low likelihood of response as estimated by their IL28 genotype, viral load, etc.

The possibility of interferon-free regimens, with the promise of improved efficacy and lower toxicity, has been a major goal of drug development and hope for these patients.

Numerous agents are currently in all phases of development. It is anticipated that the next few years will see the introduction of many new agents, some of which promise to greatly expand the universe of hepatitis C infected individuals who will benefit from treatment.

Complementary and Alternative Medicine and Hepatitis C

Not surprisingly, given the prevalence of HCV infection and the low efficiency of treatment in the past, many patients have explored complementary and alternative medicine–perhaps as many as 30% to 40%–often without the knowledge of their health care providers.84,85 The usefulness of most of these other therapies, including dietary supplements, herbs, and unconventional treatments, has not been rigorously studied, and the results are extremely varied. Many patients who are interested in complementary or alternative medicine (CAM) take milk thistle, whose active ingredient is silymarin, which may function as an anti-oxidant. Although it has been shown to have multiple effects on the virus lifecycle, including inhibition of specific viral enzymes and cell entry,86,87 clinical trials have not shown consistent benefit.88 Other CAM options that have been studied, albeit in studies of varying degrees of methodologic rigor and with variable sample sizes, have tested vitamin E, thymic extract, zinc, traditional Chinese medicine, glycyprotein, glabra and oxymarine. Apart from interferon-based therapy, most interventions have only marginal benefit, and the National Center for Complementary and Alternative Medicine review of the use of herbal treatment concludes that no CAM treatment has been scientifically proven to successfully treat hepatitis C.89

Recent studies have examined also the role of diet and response to treatment or progression of disease. Although an extremely common issue, there are very limited data to suggest a role for specific dietary modification, although it may be reasonable to minimize intake of polyunsaturated fatty acids, fats and carbohydrates while on treatment.90,91


HCV infection typically progresses to chronic infection in more than 60% of patients, and it can lead to cirrhosis in as many as 20% over a 20-year period. Serum aminotransferase levels reflecting hepatocellular injury can fluctuate, as does the viral load.

As the disease evolves, hepatocytes are progressively destroyed and replaced by fibrosis, insidiously leading to the development of bridging fibrosis and ultimately cirrhosis. The course of any individual patient is affected by various factors, such as age at onset of infection, sex, co-infection with other viruses (hepatitis A virus, HBV or HIV), or other medical conditions, as well as risk behavior, such as alcohol consumption. Interferon-based treatment has a varying success rate in clearing the virus, depending on host and viral factors. Careful selection and monitoring of patients are essential in undertaking therapy. Because of the “cohort effect,” where the bulk of patients with hepatitis C have been infected chronically for >20 years, there is a significant burden of disease-related complications that is likely to continue over the next several decades. Severe complications usually occur only in those with established cirrhosis. The risk of developing HCC in chronic HCV patients with cirrhosis is as high as 4% per year. HCV-infected patients with cirrhosis should be screened at intervals with ultrasound and alpha-fetoprotein testing. Although successful treatment with interferon-based regimens is associated with a lower rate of liver-related complications or mortality, and perhaps even regression of fibrosis/cirrhosis, patients may still be at risk of development of HCC, even years after SVR.

Although HCV remains a major global health problem, significant advances in the understanding of its basic biology have allowed improvements in treatment over the last several years. Interferon-based treatment regimens, although difficult, have been shown to prolong life, and the pace of discovery in this field gives hope that patients will be able to be treated even more effectively in the future with noninterferon-containing regimens, with even greater efficacy.

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