16-06: Chronic Viral Hepatitis

General Considerations

Chronic hepatitis is defined as chronic necroinflammation of the liver of more than 3–6 months’ duration, demonstrated by persistently elevated serum aminotransferase levels or characteristic histologic findings, often in the absence of symptoms. In many cases, the diagnosis of chronic hepatitis may be made on initial presentation. The causes of chronic hepatitis include HBV, HCV, and HDV as well as autoimmune hepatitis; alcoholic and nonalcoholic steatohepatitis; certain medications, such as isoniazid and nitrofurantoin; Wilson disease; alpha-1-antiprotease deficiency; and, rarely, celiac disease. Mortality from chronic HBV and HCV infection has been rising in the United States, and HCV has surpassed HIV as a cause of death. Chronic hepatitis is categorized on the basis of etiology (eFigure 16–11) (eFigure 16–12); the grade of portal, periportal, and lobular inflammation (minimal, mild, moderate, or severe); and the stage of fibrosis (none, mild, moderate, severe, cirrhosis). In the absence of advanced cirrhosis, patients are often asymptomatic or have mild nonspecific symptoms. The World Health Organization has outlined a strategy for eliminating chronic viral hepatitis by 2030 (by measures such as vaccinating against hepatitis B, ensuring blood safety and injection safety, timely birth dosing of hepatitis B vaccine, harm reduction from injecting drug use, and testing and treating persons coinfected with hepatitis viruses and HIV).

Clinical Findings & Diagnosis

Chronic hepatitis B afflicts 248 million people worldwide (2 billion overall have been infected; endemic areas include Asia and sub-Saharan Africa) and up to 2.2 million (predominantly males) in the United States. It may be noted as a continuum of acute hepatitis B or diagnosed because of repeated detection of HBsAg in serum, often with elevated aminotransferase levels.

Five phases of chronic HBV infection are recognized: immune tolerant phase, immune active (or immune clearance) phase, inactive HBsAg carrier state, reactivated chronic hepatitis B phase, and the HBsAg-negative phase. In the immune tolerant phase (HBeAg-positive chronic HBV infection), HBeAg and HBV DNA are present in serum and are indicative of active viral replication, and serum aminotransferase levels are normal, with little necroinflammation in the liver. This phase is common in infants and young children whose immature immune system fails to mount an immune response to HBV.

Persons in the immune tolerant phase and those who acquire HBV infection later in life may enter an immune active phase (HBeAg-positive chronic hepatitis B), in which aminotransferase levels are elevated and necroinflammation is present in the liver, with a risk of progression to cirrhosis (at a rate of 2–5.5% per year) and of hepatocellular carcinoma (at a rate of more than 2% per year in those with cirrhosis); low-level IgM anti-HBc is present in serum in about 70%.

Patients enter the inactive HBsAg carrier state (HBeAg-negative chronic HBV infection) when biochemical improvement follows immune clearance. This improvement coincides with disappearance of HBeAg and reduced HBV DNA levels (less than 10⁵ copies/mL, or less than 20,000 international units/mL) in serum, appearance of anti-HBe, and integration of the HBV genome into the host genome in infected hepatocytes (intrahepatic covalently closed circular DNA, a surrogate marker of the transcriptional activity which has been identified in serum as hepatitis B core–related antigen). Patients in this phase are at a low risk for cirrhosis (if it has not already developed) and hepatocellular carcinoma, and those with persistently normal serum aminotransferase levels infrequently have histologically significant liver disease, especially if the HBsAg level is low.

The reactivated chronic hepatitis B phase (HBeAg-negative chronic hepatitis B) may result from infection by a pre-core mutant of HBV or spontaneous mutation of the pre-core or core promoter region of the HBV genome during the course of chronic hepatitis caused by wild-type HBV. HBeAg-negative chronic hepatitis B accounts for less than 10% of cases of chronic hepatitis B in the United States, up to 50% in southeast Asia, and up to 90% in Mediterranean countries, reflecting in part differences in the frequencies of HBV genotypes. In reactivated chronic hepatitis B, there is a rise in serum HBV DNA levels and possible progression to cirrhosis (at a rate of 8–10% per year), particularly when additional mutations in the core gene of HBV are present. Risk factors for reactivation include male sex and HBV genotype C as well as immunosuppression. Treatment of HCV infection with direct-acting antiviral agents has been reported to lead to instances of HBV reactivation.

In patients with either HBeAg-positive or HBeAg-negative chronic hepatitis B, the risk of cirrhosis and of hepatocellular carcinoma correlates with the serum HBV DNA level. Other risk factors include advanced age, male sex, alcohol use, cigarette smoking, HBV genotype C, and coinfection with HCV or HDV. HIV coinfection is also associated with an increased frequency of cirrhosis when the CD4 count is low. Only 1% of treated and untreated patients per year reach the HBsAg-negative phase, in which anti-HBe may remain, serum ALT levels are normal, and HBV DNA is undetectable in serum but remains present in the liver; in some cases, anti-HBs appears in serum.

Acute hepatitis D infection superimposed on chronic HBV infection may result in severe chronic hepatitis, which may progress rapidly to cirrhosis and may be fatal. Patients with long-standing chronic hepatitis D and B often have inactive cirrhosis and are at risk for decompensation and hepatocellular carcinoma. The diagnosis is confirmed by detection of anti-HDV or HDAg (or HDV RNA) in serum.

Treatment

Patients with active viral replication (HBeAg and HBV DNA [10⁵ copies/mL or more, or 20,000 international units/mL or more] in serum and elevated aminotransferase levels) may be treated with a nucleoside or nucleotide analog or with pegylated interferon. Nucleoside and nucleotide analogs are preferred because they are better tolerated and can be taken orally. For patients who are HBeAg-negative, the threshold for treatment is a serum HBV DNA level of 10⁴ copies/mL or more, or 2000 international units/mL or more. If the threshold HBV DNA level for treatment is met but the serum ALT level is normal, treatment may still be considered in patients over age 35–40 if liver biopsy or a noninvasive assessment of liver fibrosis demonstrates a fibrosis stage of 2 of 4 (moderate) or higher. Therapy is aimed at reducing and maintaining the serum HBV DNA level to the lowest possible levels, thereby leading to normalization of the ALT level and histologic improvement. An additional goal in HBeAg-positive patients is seroconversion to anti-HBe, and some responders eventually clear HBsAg. Although nucleoside and nucleotide analogs generally have been discontinued 6–12 months after HBeAg-to-anti-HBe seroconversion, some patients (especially Asian patients) serorevert to HBeAg after discontinuation, have a rise in HBV DNA levels and recurrence of hepatitis activity, and require long-term therapy, which also is required when seroconversion does not occur and in patients with cirrhosis (at least until HBsAg clears and possibly indefinitely). HBeAg-negative patients with chronic hepatitis B also generally require long-term therapy because relapse is frequent when therapy is stopped.; a low serum HBsAg level identifies patients who are at low risk for relapse and in whom HBsAg is more likely to clear if the nucleoside or nucleotide analog is stopped after 3 years than if it is continued indefinitely.

The available nucleoside and nucleotide analogs—entecavir, tenofovir, lamivudine, adefovir, and telbivudine—differ in efficacy and rates of resistance; however, in HBeAg-positive patients, they all achieve an HBeAg-to-anti-HBe seroconversion rate of about 20% at 1 year, with higher rates after more prolonged therapy. The preferred first-line oral agents are entecavir and tenofovir. Entecavir is rarely associated with resistance unless a patient is already resistant to lamivudine. The daily dose is 0.5 mg orally for patients not resistant to lamivudine and 1 mg for patients who previously became resistant to lamivudine. Suppression of HBV DNA in serum occurs in nearly all treated patients, and histologic improvement is observed in 70% of patients. Entecavir has been reported to cause lactic acidosis when used in patients with decompensated cirrhosis. Tenofovir disoproxil fumarate, 300 mg orally daily, is equally effective and is used as a first-line agent or when resistance to a nucleoside analog has developed. Like entecavir, tenofovir has a low rate of resistance when used as initial therapy. Long-term use may lead to an elevated serum creatinine level and reduced serum phosphate level (Fanconi-like syndrome) that is reversible with discontinuation of the drug. Tenofovir alafenamide, 25 mg orally daily, is an alternative formulation of tenofovir that was approved by the FDA in 2016; it is associated with a lower rate of renal and bone toxicity than tenofovir disoproxil fumarate.

The first available nucleoside analog was lamivudine, 100 mg orally daily. No longer considered first-line therapy in the United States, it still may be used in countries in which cost is a deciding factor. By the end of 1 year of therapy with lamivudine, however, 15–30% of responders experience a relapse (and occasionally frank decompensation). As a result of a mutation in the polymerase gene (the YMDD motif) of HBV DNA that confers resistance to lamivudine. The rate of resistance reaches 70% by 5 years of therapy. Adefovir dipivoxil has activity against wild-type and lamivudine-resistant HBV but is the least potent of the oral antiviral agents for HBV and is now rarely if ever used. The standard dose is 10 mg orally once a day for at least 1 year. As with lamivudine, only a small number of patients achieve sustained suppression of HBV replication with adefovir. Resistance to adefovir occurs in up to 29% of patients treated for 5 years. Patients with underlying kidney dysfunction are at risk for nephrotoxicity from adefovir. Telbivudine, given in a daily dose of 600 mg orally, is more potent than either lamivudine or adefovir but like them is associated with resistance, particularly in patients who are resistant to lamivudine. Elevated creatine kinase levels are common in patients treated with telbivudine.

Nucleoside and nucleotide analogs are well tolerated even in patients with decompensated cirrhosis (for whom the treatment threshold may be an HBV DNA level less than 10⁴ copies/mL and therapy should be continued indefinitely) and may be effective in patients with rapidly progressive hepatitis B (“fibrosing cholestatic hepatitis”) following organ transplantation. Combined use of a nucleoside and nucleotide analog or of peginterferon and a nucleoside or nucleotide analog has not been shown convincingly to have a substantial advantage over the use of one drug alone.

Nucleoside analogs are also recommended for inactive HBV carriers (and those positive only for anti-HBc) prior to the initiation of immunosuppressive therapy (including rituximab or anti-tumor necrosis factor antibody therapy) or cancer chemotherapy to prevent reactivation. In patients infected with both HBV and HIV, antiretroviral therapy, including two drugs active against both viruses (eg, tenofovir plus lamivudine or emtricitabine), has been recommended when treatment of HIV infection is indicated. Telbivudine and tenofovir are classified as pregnancy category B drugs, and lamivudine, a category C drug, has been shown to be safe in pregnant women with HIV infection. Antiviral therapy has been recommended, beginning in the third trimester, when the mother’s serum HBV DNA level is 200,000 international units/mL or higher to reduce levels at the time of delivery.

Peginterferon alfa-2a is still an alternative to the oral agents in selected cases. A dose of 180 mcg subcutaneously once weekly for 48 weeks leads to sustained normalization of aminotransferase levels, disappearance of HBeAg and HBV DNA from serum, and appearance of anti-HBe in up to 40% of treated patients and results in improved survival. A response is most likely in patients with a low baseline HBV DNA level and high aminotransferase levels and is more likely in those who are infected with HBV genotype A than with other genotypes (especially genotype D) and who have certain favorable polymorphisms of the IL28B gene. Moreover, many complete responders eventually clear HBsAg and develop anti-HBs in serum, and are thus cured. Relapses are uncommon in complete responders who seroconvert from HBeAg to anti-HBe. Peginterferon may be considered in order to avoid long-term therapy with an oral agent, as in young women who may want to become pregnant in the future. Patients with HBeAg-negative chronic hepatitis B have a response rate of 60% after 48 weeks of therapy with peginterferon, but the response may not be durable once peginterferon is stopped. A rapid decline in serum HBsAg titers predicts a sustained response and ultimate clearance of HBsAg. The response to peginterferon is poor in patients with HIV coinfection.

In chronic hepatitis D, peginterferon alfa-2b (1.5 mcg/kg/wk for 48 weeks) may lead to normalization of serum aminotransferase levels, histologic improvement, and elimination of HDV RNA from serum in 20–50% of patients, but relapse may occur and tolerance is poor. Nucleoside and nucleotide analogs are generally not effective in treating chronic hepatitis D; prenylation inhibitors (eg, lonafarnib) and HBV-HDV–specific receptor blockers (eg, bulevirtide [formerly myrcludex B]) are under study.

Prognosis

The sequelae of chronic hepatitis secondary to hepatitis B include cirrhosis, liver failure, and hepatocellular carcinoma. The 5-year mortality rate is 0–2% in those without cirrhosis, 14–20% in those with compensated cirrhosis, and 70–86% following decompensation. The risk of cirrhosis and hepatocellular carcinoma correlates with serum HBV DNA levels, and a focus of therapy is to suppress HBV DNA levels below 300 copies/mL (60 international units/mL). In patients with cirrhosis, even low levels of HBV DNA in serum increase the risk of hepatocellular carcinoma compared with undetectable levels. HBV genotype C is associated with a higher risk of cirrhosis and hepatocellular carcinoma than other genotypes. Antiviral treatment improves the prognosis in responders, prevents (or leads to regression of) cirrhosis, and decreases the frequency of liver-related complications (although the risk of hepatocellular carcinoma does not become as low as that in inactive HBV carriers and hepatocellular carcinoma may even occur after clearance of HBsAg). A risk score (PAGE-B) based on a patient’s age, sex, and platelet count has been reported to predict the 5-year risk of hepatocellular carcinoma in white patients taking entecavir or tenofovir.

Clinical Findings & Diagnosis

Chronic hepatitis C develops in up to 85% of patients with acute hepatitis C. It is clinically indistinguishable from chronic hepatitis due to other causes and may be the most common. Worldwide, 170 million people are infected with HCV, with 1.8% of the US population infected. Peak prevalence in the United States (about 4%) is in persons born between 1945 and 1964. In approximately 40% of cases, serum aminotransferase levels are persistently normal. The diagnosis is confirmed by detection of anti-HCV by EIA. In rare cases of suspected chronic hepatitis C but a negative EIA, HCV RNA is detected by PCR testing. Progression to cirrhosis occurs in 20% of affected patients after 20 years, with an increased risk in men, those who drink more than 50 g of alcohol daily, and those who acquire HCV infection after age 40 years. The rate of fibrosis progression accelerates after age 50. African Americans have a higher rate of chronic hepatitis C but lower rates of fibrosis progression and response to therapy than whites. Immunosuppressed persons—including patients with hypogammaglobulinemia or HIV infection with a low CD4 count or those receiving immunosuppressants—appear to progress more rapidly to cirrhosis than immunocompetent persons with chronic hepatitis C. Tobacco and cannabis smoking and hepatic steatosis also appear to promote progression of fibrosis, but coffee consumption appears to slow progression. Persons with chronic hepatitis C and persistently normal serum aminotransferase levels usually have mild chronic hepatitis with slow or absent progression to cirrhosis; however, cirrhosis is present in 10% of these patients. Serum fibrosis testing (eg, FibroSure) or elastography may be used to identify the absence of fibrosis or presence of cirrhosis.

Treatment

The introduction of direct-acting and host-targeting antiviral agents has rapidly expanded the therapeutic armamentarium against HCV (Table 16–6). Standard therapy for HCV infection from the late 1990s to the early 2010s was a combination of peginterferon plus ribavirin, and ribavirin continues to be used in some all-oral regimens. Sustained virologic response rates (negative HCV RNA in serum at 24 weeks after completion of therapy) for peginterferon plus ribavirin were 45% in patients with HCV genotype 1 infection and 70–80% in those with genotype 2 or 3 infection. Response of genotype 1 infection to peginterferon plus ribavirin was associated most strongly with the CC genotype of the IFNL3 (IL28B) gene, with sustained response rates as high as 80%, compared with 40% for the CT genotype and 30% for the TT genotype. Higher rates of response were achieved in persons infected with HCV genotype 1 when a first-generation direct-acting antiviral agent—boceprevir or telaprevir (agents no longer available in the United States), nonstructural (NS) 3/4A serine protease inhibitors—was added to peginterferon plus ribavirin. Sustained response rates were as high as 75% for HCV genotype 1 with a standard three-drug regimen. With the addition of the protease inhibitor, the treatment duration for HCV genotype 1 infection could be shortened to 24 weeks, depending on the rapidity of clearance of HCV RNA from serum—so-called response-guided therapy. Treatment with peginterferon-based therapy is associated with frequent, often distressing, side effects, and discontinuation rates are as high as 15–30%. Peginterferon alfa is contraindicated in pregnant or breastfeeding women and those with decompensated cirrhosis, profound cytopenias, severe psychiatric disorders, autoimmune diseases, or an inability to self-administer or comply with treatment. Men and women taking ribavirin must practice strict contraception until 6 months after the conclusion of therapy because of its teratogenic effects in animals. Ribavirin should be used with caution in persons over 65 years of age and in others in whom hemolysis could pose a risk of angina or stroke.

After the introduction of all-oral regimens, the criterion for a sustained virologic response was shortened from 24 weeks to 12 weeks following the completion of treatment. The definition of clearance of HCV RNA requires use of a sensitive real-time reverse transcriptase-PCR assay to monitor HCV RNA during treatment (the lower limit of quantification should be 25 international units/mL or less, and the limit of detection should be 10–15 international units/mL).

Several types of direct-acting antiviral agents have been developed (Tables 16–6 and 16–7). HCV protease inhibitors (“…previrs”) generally have high antiviral potency but differ with respect to the development of resistance (although resistance-associated substitutions in the HCV genome tend not to persist after therapy with these agents is stopped). Some of the compounds show better response rates in HCV genotype 1b than in genotype 1a infection. Simeprevir is less effective in patients with genotype 1a and a nonstructural protein Q80K mutation than in those without the mutation.

HCV polymerase inhibitors (“…buvirs”) are categorized as nucleoside or nucleotide analog and non-nucleoside polymerase inhibitors. Nucleos(t)ide analogs are active against all HCV genotypes and have a high barrier to resistance. Non-nucleos(t)ide polymerase inhibitors are the weakest class of compounds against HCV because of a low barrier to resistance. Drugs in this class are generally more active against HCV genotype 1b than HCV genotype 1a. They have been developed to be used only in combination with the other direct-acting antiviral agents, mainly protease inhibitors and NS5A inhibitors.

The first approved HCV NS5B nucleotide polymerase inhibitor was sofosbuvir in 2013. Sofosbuvir was initially approved for use in combination with peginterferon and ribavirin in patients with HCV genotype 1 infection and with ribavirin alone in patients with HCV genotype 2 or 3 infection (see Table 16–6). Most patients with HCV genotype 2 or 3 infection, including those with HIV coinfection, are cured with 12 or 24 weeks of therapy, respectively. HCV genotype 2 responds much better to interferon-free sofosbuvir-based therapy than HCV genotype 3, but the sustained virologic response is 20–30% lower in patients with cirrhosis and the combination of sofosbuvir and ribavirin has been reported to cause lactic acidosis in some patients with advanced cirrhosis. Importantly, no sofosbuvir-resistant variants have been selected during therapy. The combination of sofosbuvir and simeprevir was found to be effective in HCV genotype 1 infection and was approved by the FDA; the approval was thereafter extended to HCV genotypes 4, 5, and 6. Sofosbuvir was also approved to be used in combination with ledipasvir.

The combination of paritaprevir (an NS3/4A protease inhibitor), boosted by ritonavir, plus ombitasvir (an NS5A inhibitor) and dasabuvir (an NS5B non-nucleoside polymerase inhibitor) is effective in HCV genotype-1 treatment-naive patients and prior nonresponders to interferon-based therapy, with or without cirrhosis, and has been approved by the FDA. The same combination without dasabuvir has also received FDA approval for HCV genotype 4 infection. Instances of hepatotoxicity have been reported with these regimens in patients with advanced cirrhosis. Daclatasvir in combination with sofosbuvir has proven effective in genotypes 1-, 2-, and 3-infected patients, including those coinfected with HIV, and was approved by the FDA in 2015 for HCV genotype 3 infection.

NS5A inhibitors (“…asvirs”) are characterized by high antiviral potency at picomolar doses. The cross-genotype efficacy of these agents varies. Ledipasvir was the first NS5A inhibitor approved by the FDA in 2014 (see Table 16–6). Ledipasvir has potent activity against genotypes 1, 4, 5, and 6 HCV and has been formulated in combination with sofosbuvir. The combination is highly effective in both treatment-naive and treatment-experienced patients, even those with cirrhosis and is given in a fixed dose of ledipasvir 90 mg and sofosbuvir 400 mg once daily for 12 weeks in HCV genotype 1–infected treatment-naive patients and treatment-experienced patients without cirrhosis and for 24 weeks in treatment-experienced patients with cirrhosis. In treatment-naive patients without cirrhosis, the duration of treatment can be shortened to 8 weeks if the baseline HCV RNA level is less than 6 million international units/mL. Sustained virologic response rates are well above 90%, including in patients coinfected with HIV, and this regimen is a first-line therapy for HCV genotype 1. The combination of ledipasvir, sofosbuvir, and ribavirin achieves high rates of sustained virologic response in patients with HCV genotype 3 as well as in patients with HCV genotype 1 or 4 and advanced cirrhosis. Side effects are mild and include fatigue and headache. Concomitant use of a proton pump inhibitor, particularly twice-daily dosing in patients with cirrhosis, may reduce the effectiveness of the combination of ledipasvir and sofosbuvir. Re-treatment of occasional nonresponders or relapsers with resistance-associated substitutions that persist for years with an alternative regimen that may include sofosbuvir is often effective.

Other highly effective combinations have been approved by the FDA: 100 mg of grazoprevir (an NS3/4A protease inhibitor) plus 50 mg/day of elbasvir (an NS5A inhibitor) for HCV genotypes 1 and 4; 300 mg of glecaprevir (an NS3/4A protease inhibitor) plus 120 mg/day of pibrentasvir (an NS5A inhibitor) for genotypes 1–6 (pangenotypic); and another pangenotypic regimen, sofosbuvir and velpatasvir, with the addition of ribavirin in patients with cirrhosis and with the addition of voxilaprevir (an NS3A/N4 protease inhibitor) as “rescue” therapy in patients with nonresponse or relapse following initial treatment with an NS5A-containing regimen. The combination of glecaprevir and pibrentasvir is approved for 8 (rather than the usual 12) weeks in treatment-naïve, noncirrhotic patients, including those coinfected with HIV. It is also a pangenotypic option for patients with chronic kidney disease, including those receiving dialysis. Other “rescue” regimens are under study, including grazoprevir, ruzasvir (an NS5A inhibitor), and uprifosbuvir (an NS5B polymerase nucleotide inhibitor), with or without ribavirin, for patients who have not responded to NS5A-containing therapy. Where available, testing for resistance-associated substitutions may be helpful in some cases before re-treatment. Use of any regimen containing a protease inhibitor is contraindicated in patients with decompensated cirrhosis, and pretreatment testing for resistance-associated substitutions is recommended.

In late 2019, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommended two preferred combination regimens: glecaprevir plus pibrentasvir for 8 weeks for genotypes 1–6 and sofosbuvir plus velpatasvir for 12 weeks for genotypes 1, 2, 4, 5, or 6.

Overall treatment rates are still less than 20% and lowest among Hispanics and persons with Medicaid or indigent care insurance. The cost of direct-acting antiviral agents has been high (although declining), and lack of insurance coverage has often been a barrier to their use. Additional factors to consider in the selection of a regimen are the presence of cirrhosis or kidney dysfunction, prior treatment, potential drug interactions (of which there are many), and the likelihood that a patient may require liver transplantation in the future. For some regimens, an 8-week course of treatment may be effective in selected cases. Other agents that have been studied include NS3/4A protease inhibitors (eg, danoprevir); polymerase inhibitors (eg, mericitabine); virus entry, assembly, and secretion inhibitors; microRNA-122 antisense oligonucleotides (eg, miravirsen); cyclophilin A inhibitors (eg, alisporivir); interferon lambda-3; and therapeutic vaccines. HCV genotype 1 is now easy to cure with oral direct-acting agents, with expected sustained virologic response rates well above 90%, and virtually all HCV genotype 2 infection is curable with all-oral regimens. HCV genotype 3 infection, particularly in association with cirrhosis, has been the most challenging to treat, but the newest regimens have increased the likelihood of cure. Interferon is now rarely required, and the need for ribavirin is decreasing.

Antiviral therapy has been shown to be beneficial in the treatment of cryoglobulinemia associated with chronic hepatitis C; an acute flare of cryoglobulinemia may first require treatment with rituximab, cyclophosphamide plus methylprednisolone, or plasma exchange. As noted above, patients with HCV and HIV coinfection have been shown to respond well to treatment of HCV infection. Moreover, in persons coinfected with HCV and HIV, long-term liver disease–related mortality increases as HIV infection–related mortality is reduced by antiretroviral therapy. Occasional instances of reactivation of HBV infection, as well as herpesvirus, have occurred with direct-acting antiviral agents for HCV infection, and all candidates should be prescreened for HBV infection, with the initiation of antiviral prophylactic therapy in those who are HBsAg positive when treatment of HCV infection is begun.

Prognosis

Chronic hepatitis C is an indolent, often subclinical disease that may lead to cirrhosis and hepatocellular carcinoma after decades. The overall mortality rate in patients with transfusion-associated hepatitis C may be no different from that of an age-matched control population. Nevertheless, mortality or transplantation rates clearly rise to 5% per year once cirrhosis develops. A risk score combining age, sex, platelet count, and AST-to-ALT ratio has been proposed. There is some evidence that HCV genotype 1b is associated with a higher risk of hepatocellular carcinoma than other genotypes. Antiviral therapy has a beneficial effect on mortality, cardiovascular events, type 2 diabetes mellitus, and quality of life, is cost-effective, appears to retard and even reverse fibrosis, and reduces (but does not eliminate) the risk of decompensated cirrhosis and hepatocellular carcinoma in responders with advanced fibrosis. Even patients who achieve a sustained virologic response remain at an increased risk for mortality compared with the general population. An increased risk of death from extrahepatic cancers has been described in this group, as well as in patients who achieve suppression of HBV infection. Although mortality from cirrhosis and hepatocellular carcinoma due to hepatitis C is still substantial, the need for liver transplantation for chronic hepatitis C is now declining, and survival after transplantation is improving. The risk of mortality from drug addiction is higher than that for liver disease in patients with chronic hepatitis C. HCV infection appears to be associated with increased cardiovascular mortality, especially in persons with diabetes mellitus and hypertension. Statin use has been reported to be associated with improved virologic response to antiviral therapy and decreased progression of liver fibrosis and frequency of hepatocellular carcinoma.

When to Refer

• For liver biopsy.

• For antiviral therapy.

When to Admit

For complications of decompensated cirrhosis.