Hepatitis C

Although hepatitis C accounts for only 20% of acute viral hepatitis infection, it is a leading etiology of chronic liver disease in the United States. It also is the main reason for liver transplantation and an important etiology of hepatocellular carcinoma. Because hepatitis C progresses slowly and usually is asymptomatic until the advanced stage, chronic hepatitis C is under-recognized, especially in the outpatient setting.

Approximately 1.5% of the US population has hepatitis C virus (HCV) infection. However, the prevalence is much higher in certain groups: 3.25% among baby boomers¹ (individuals born between 1945 and 1965), 15% to 40% among prison inmates,² and an estimated 70% among injection drug users.³ Men are more likely to acquire infection than women. Infection is more prevalent among non-Hispanic blacks than among non-Hispanic whites or Mexican Americans.⁴

Although the incidence has decreased to 17,000 per year from a peak of 230,000 per year in the mid-1980s,¹ the rates of cirrhosis and HCV-related mortality are increasing as a result of those now-chronic HCV infections. Middle-aged and older adults are affected disproportionately. In 2007, more mortalities occurred as a result of complications from HCV infection than from HIV infection.⁵ Many individuals with HCV do not know they have the infection, and many are diagnosed late in the disease course. These trends have led to questioning of the adequacy of traditional risk factor-based screening for HCV.

Until 2012, screening for HCV based solely on risk factors was recommended by the Centers for Disease Control and Prevention (CDC),⁶ the American Association for the Study of Liver Diseases,⁷ and other groups. In 2004, the US Preventive Services Task Force (USPSTF) noted insufficient evidence for screening even high-risk individuals and advised against screening the general population.⁸ The USPSTF currently is updating this recommendation to screen adults who are at high risk.⁹

However, in August 2012 the CDC issued a new recommendation for one-time screening for HCV in all individuals born between 1945 and 1965; the USPSTF updated recommendation is expected to concur. While baby boomers comprise 27% of the US population, 75% of individuals with HCV infection are in this demographic. These individuals also have the highest risk of HCV-related cirrhosis, hepatocellular carcinoma, and death. In addition, the CDC recommends screening for alcohol use among those identified as having HCV and intervening to assist with alcohol cessation. The CDC reiterated the need to continue HCV screening in other groups based on known risk factors (see Risk Factors section).¹

The CDC studied the cost effectiveness of birth cohort screening for HCV in the US primary care setting. Assuming that 50% to 74% of individuals with HCV infection were unaware they had acquired the infection, the CDC estimated that universal screening of individuals born in 1945 through 1965 would identify approximately 800,000 new cases at a cost of $2,874 per diagnosis. Appropriate treatment could save 348.8 to 532.2 thousand quality-adjusted life years (QALYs) at a cost of $15.7 to $35.7 thousand per QALY.¹⁰ This data compares favorably with that of widely accepted clinical preventive services such as breast cancer screening.¹¹

Some sexual practices that might increase the risk of HCV transmission are anal-receptive intercourse, unprotected intercourse, intercourse with multiple partners, and intercourse with a partner known to have HCV, HIV, or another sexually transmitted infection. While injection drug use is the major risk factor for transmission (Table 1), potential risk factors include use of intranasal and noninjection drugs, transplantation after 1992 (including tissues such as cornea, skin, and sperm), body piercing, and tattooing. The need for routine HCV screening in these groups is uncertain.

Household contacts are not thought to have a significantly increased risk of HCV infection, assuming toothbrushes or razors are not shared with infected individuals. The risk of transmission by long-term, monogamous, nonanal-receptive intercourse is low.⁷

Acute HCV infection typically is subclinical. When symptoms are present, they include malaise, nausea, right upper-quadrant pain, and jaundice. Acute infection follows a mild clinical course lasting 2 to 12 weeks. For reasons that are not understood, in up to 20% of individuals with HCV infection, it will clear resulting in complete recovery within 12 to 20 weeks of seroconversion^.12

Chronic hepatitis C will develop in 80% of individuals with acute infection.¹ In most of these individuals, the disease is asymptomatic or produces mild, nonspecific symptoms such as fatigue, nausea, myalgias, arthralgias, weakness, and weight loss.¹³ Approximately 70% will have disease that remains stable over time, exhibiting minimal or no progression. However, in at least 20% of individuals with acute infection, the disease will progress to cirrhosis over 20 to 30 years.^1,14

In patients with chronic HCV infection, alanine aminotransferase levels might be normal or only slightly elevated. Alanine aminotransferase levels correlate poorly with clinical symptoms and liver histology in the absence of cirrhosis. Advanced disease is indicated by an elevated aspartate aminotransferase to alanine aminotransferase ratio, hyperbilirubinemia (> 1.4 g/dL), low serum albumin (< 3.5 g/dL), and thrombocytopenia (platelet count < 75,000/µL)^.7,15 The extent of fibrosis and inflammation found on liver biopsy is the best clinical predictor of disease progression.⁷ Other clinical factors predictive of progression are listed in Table 2.

Cirrhosis is clinically silent (compensated) in most individuals, although hepatomegaly, splenomegaly, hyperbilirubinemia, hypoalbuminemia, and thrombocytopenia might be present. HCV-related cirrhosis decompensates at a rate of 4% per year.¹⁶ Decompensated cirrhosis is characterized by the onset of jaundice, ascites, variceal bleeding, or hepatic encephalopathy.

Mortality in patients with hepatitis C does not increase until cirrhosis develops. Five-year survival in patients with compensated cirrhosis is 90% but decreases to approximately 50% in those with decompensated cirrhosis.¹⁷ Patients with cirrhosis due to hepatitis C have a 20-fold, or 2% to 8% per year, risk of developing hepatocellular carcinoma (HCC).¹⁸ However, patients are more likely to die of complications of end-stage liver disease than from HCC.⁷

The diagnostic evaluation for HCV is represented in Figure 1 (1-page PDF; About PDFs) and typically includes hepatic transaminase measurements, liver function tests, antibody tests, confirmatory molecular tests, genotyping, and liver biopsy. Enzyme immunoassay (EIA) is the preferred initial antibody test. Newer generation assays can detect seroconversion 8 to 10 weeks after infection with 95% sensitivity and 99% specificity.^7,13 The positive predictive value of the EIA for HCV is 50% to 95%, depending on prevalence as determined by presence or absence of risk factors. Positive EIA results require confirmatory testing. False-negative results can occur in patients who are severely immunocompromised due to HIV infection, hemodialysis, or transplantation; these patients should undergo nucleic acid testing (see below).^1,7

Reverse transcriptase polymerase chain reaction (PCR) is used to confirm HCV infection. PCR can detect HCV ribonucleic acid (RNA) 2 to 8 weeks after infection. Quantitative RNA assays now have sensitivity similar to that of qualitative assays and can be used to monitor viral load during treatment. A positive HCV RNA test result indicates true infection. A negative HCV RNA test result in the context of a positive EIA result usually indicates resolved infection but also can indicate a false-positive EIA or acute HCV with transiently low viremia. A false-positive EIA is most likely to occur in the absence of risk factors. Recombinant immunoblot assay (RIBA) and a repeat HCV RNA test undertaken 4 to 6 months after a negative or false-positive test result can distinguish among these possibilities.^1,7

Six major HCV genotypes have been identified. Genotype 1 (subtypes 1a and 1b) is most common in the United States, followed by genotypes 2 and 3. (Genotypes 4, 5, and 6 are uncommon in the Western world.) HCV genotyping is useful for making treatment decisions. Identifying the genotype is unnecessary for patients who are not candidates for pharmacotherapy (see Management section).

Prior to treatment for chronic hepatitis C, most patients undergo liver biopsy, which is used to determine the fibrosis and disease stages. This has both diagnostic and prognostic implications and can inform treatment decisions. Biopsy also can detect other disease processes affecting the liver, such as steatohepatitis and hemochromatosis. Patients with HCV genotypes 2 and 3 infection might not require biopsy because of good response to standard treatment^.7

Advice for patients with HCV infection is summarized in Table 3. Sexual transmission is thought to occur rarely. Consequently, couples who are in long-term, monogamous, heterosexual relationships in which one partner has HCV infection do not need to use condoms if they avoid anal-receptive intercourse and vaginal intercourse during menses.^7,19 A prospective study of 776 monogamous heterosexual partners of individuals with chronic hepatitis C who adhered to this advice found no interpartner transmission of HCV over 10 years.²⁰

Women with hepatitis C can conceive and deliver vaginally with a 4% to 6% risk of perinatal transmission.⁷ There is no proven reduction in transmission with elective Cesarean delivery.²¹ Women with hepatitis C may breastfeed unless the nipples are cracked or bleeding.^7,19 According to a 2009 prospective randomized controlled trial conducted over 3.8 years with 766 subjects, consuming at least three cups of coffee per day appears to protect against progression of liver disease.²²

Interferon and Ribavirin
Management of chronic hepatitis C must be individualized after consideration of the patient’s overall health, the HCV genotype, viral load, and stage of liver disease. Standard pharmacotherapy consists of pegylated interferon plus ribavirin. The addition of protease inhibitors improves response rates in patients with genotype 1 HCV infection. However, even with careful selection of patients, treatment is neither always successful nor well-tolerated.

Potential candidates for pharmacotherapy must be at least 3 years old²³ and should have a positive serum HCV RNA and significant fibrosis on liver biopsy. Patients with compensated liver disease may undergo treatment but only in the absence of severe thrombocytopenia, anemia, leukopenia, or kidney disease. Patients also must be willing to adhere to treatment protocols.⁷

Contraindications to therapy include pregnancy, ongoing alcohol or drug abuse, autoimmune hepatitis, and uncontrolled depression or thyroid disease.⁷ Patients undergoing alcohol or drug rehabilitation can qualify for treatment if they remain abstinent for 6 months.²⁴ Other patients who are poor candidates for therapy are heart, lung, or kidney transplant recipients and those with significant medical comorbidities such as severe hypertension, heart failure, coronary artery disease, uncontrolled diabetes, or obstructive lung disease^.7

According to a 2010 Cochrane review, combination interferon plus ribavirin is more effective than interferon monotherapy for clearing HCV and for improving liver histology.²⁵ Pegylated interferon-alfa, alfa 2a (Pegasys) and alfa 2b (PegIntron), is administered as a weekly subcutaneous injection, whereas ribavirin (Copegus, Rebetol) is taken by mouth twice daily. The duration of therapy is 24 or 48 weeks, depending on the HCV genotype.^7,26

Rates of sustained virologic response (SVR) (defined as undetectable HCV RNA 24 weeks after treatment completion) with standard interferon and ribavirin therapy are 45% to 60% for genotype 1, and 75% to 80% for genotypes 2 and 3.^27-29 In patients with sustained response of 6 months’ duration, 98% will remain in remission at 5 years. Success rates are generally lower in black and Hispanic patients compared with whites, independent of genotype.³⁰ SVR rates are approximately 20% lower if insulin resistance is present.⁷

Adverse effects from interferon and ribavirin therapy are common and significant. Ten to 14% of patients do not complete treatment due to adverse effects. Eighty percent of patients experience flu-like symptoms such as fever, headache, and myalgia. Forty percent develop clinically significant depression and irritability. Other common side effects include autoimmune thyroiditis, anemia, neutropenia, and thrombocytopenia. Interferon and ribavirin also can be teratogenic if either partner is undergoing pharmacotherapy.⁷

Protease Inhibitors
Two protease inhibitors, boceprevir (Victrelis) and telaprevir (Incivek), were approved by the Food and Drug Administration in May of 2011 for the treatment of genotype 1 HCV infection. (See important drug safety information about telaprevir.) Both are used in combination with interferon and ribavirin and are taken orally three times daily. Rash and anemia are significant adverse effects that lead to an additional 5% to 10% discontinuation rate. Protease inhibitors work by preventing viral replication and by enhancing viral response to treatment. They might permit a shorter duration of therapy for patients with genotype 1 HCV infection, from 48 to 24 weeks.²⁶

Phase III clinical trials demonstrated that protease inhibitors can improve SVR rates by 20% to 45% compared with standard therapy.^31,32 In one study SVR rates were 69% to 75% for patients treated with triple drug therapy including telaprevir, compared with 44% to 46% for treatment-naive patients who underwent conventional therapy.³³ Even patients who previously had been treated with interferon and ribavirin experienced a 51% SVR rate when re-treated with a regimen that included telaprevir (69% SVR rate for those with recurrent disease versus 39% for those who did not respond to previous treatment).³⁴

Complementary Therapies
Consumption of three or more cups of coffee per day predicts improved virologic response to peginterferon and ribavirin therapy for chronic hepatitis C.³⁵

Milk thistle (Silybum marianum) is the most commonly used herbal product among patients with hepatitis. According to a 2007 Cochrane review, milk thistle appears to be safe, but high quality evidence to support its use is lacking.³⁶ Another Cochrane review found no evidence to support or refute the use of the Chinese synthetic anti-hepatitis drug bicyclol.³⁷

Investigational Agents
Research is underway to develop new medications for HCV. These efforts include modifications of current treatments (interferon and ribavirin derivatives), direct-acting antiviral therapy (e.g., other NS3/4A protease inhibitors, NS5B polymerase inhibitors, NS5A inhibitors, and noninterferon direct-acting antiviral combination therapy), and enhancements of host defense mechanisms (e.g., cyclophilin inhibitors, microRNA inhibition, and nitazoxanide [Alinia], an antiprotozoal agent).^38,39

Efforts to develop a vaccine against HCV have been challenging. With six genotypes, there is considerable sequence diversity. Viral escape mutations can occur. And patients with HCV infection naturally develop antibodies against HCV, but for reasons not well understood, most still are unable to clear the virus.⁴⁰

Regardless of whether patients undergo pharmacotherapy, family physicians should monitor patients’ alcohol and drug abstinence; evaluate for depression, especially with interferon use; review risks of transmission; and monitor for disease progression (Table 4). Physicians should ask about constitutional and hepatic symptoms and periodically monitor alanine aminotransferase and markers of hepatic synthetic function (i.e., albumin, bilirubin, platelets, and prothrombin time). In patients with cirrhosis, physicians should monitor for signs of decompensation (i.e., jaundice, ascites, variceal bleeding, and hepatic encephalopathy).⁷

Endoscopic screening for gastroesophageal varices should be undertaken at the time of diagnosis of cirrhosis.⁴¹ These patients also should be screened for HCC every 6 to 12 months using ultrasound.18 Indications for subspecialist referral are listed in Table 5.

Decompensated cirrhosis and HCC are potential indications for liver transplantation. In fact, HCV-associated cirrhosis is the most common reason for liver transplantation among adults. Despite a 95% rate of recurrent infection, transplantation can increase 5-year survival to as much as 60% to 80%.^42,43

The CDC has launched a national education campaign called “Know More Hepatitis.” This effort is aimed at raising public awareness about hepatitis C and supporting the new screening guidelines. An online risk assessment tool and downloadable fact sheets and posters are available at http://www.cdc.gov/knowmorehepatitis.

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