Figure 58-9. Clinical course of acute hepatitis B infection.

In Western Europe and North America the prevalence of chronic infection is less than 1% but ranges

between 10% and 20% in endemic areas including southeast Asia, China, and sub-Saharan Africa. It is

estimated that there 1 million deaths each year as a result of cirrhosis and HCC associated with chronic

HBV worldwide.

Treatment

Primary prevention by means of vaccination constitutes the best treatment approach for HBV infection.

Individuals at high risk include health care workers, visitors to highly endemic areas, men who have sex

with men, sex workers, and intravenous drug users. The hepatitis B vaccine is given as a series of three

intramuscular doses and has almost 100% efficacy among immunocompetent persons. Hepatitis B

immune globulin has a reported efficacy of 90% in the prevention of newborn infections and

approximately 75% in cases of needle sticks or sexual infections in people exposed to the virus with no

prior immunity. It is administered as soon as possible after exposure together with the first dose of the

hepatitis B vaccine series.

Figure 58-10. Clinical course of chronic hepatitis B. A: A benign chronic carrier has continued production of hepatitis B surface

antigen but there is an absence of serum markers of viral replication. B: A pattern of continuing liver injury and serum markers of

active viral replication.

Therapy is usually directed at HBeAg-positive cases that have an increased risk of cirrhosis and HCC.

HBeAg-negative patients with high viral load may also benefit from treatment. Effectively controlled

infection is determined by loss of HBsAg and absent viremia by PCR on antiviral treatment. The

endpoint of treatment is loss of HBeAg and seroconversion to detectable HBeAb. In clinical trials about

half of patients achieved this endpoint after 5 years of treatment but many patients will require a longer

duration of therapy, in some cases, lifelong. Patients with chronic hepatitis B and cirrhosis or advanced

fibrosis showed a reduction in the risk of HCC after continuous treatment with lamivudine.35,39

Lamivudine is an orally effective antiviral agent that competitively inhibits the DNA polymerase. Its

administration is associated with a more rapid seroconversion to HBeAg-positive status, a more rapid

loss of HBeAg, improved aminotransferase levels, and a 3 to 4 log reduction in circulating levels of HBV

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DNA in the first 3 months of therapy. It is also associated with improved liver histologic findings in

cases of chronic hepatitis.

Agents available to treat hepatitis B include interferon (IFN), lamivudine, entecavir, adefovir,

telbivudine, and tenofovir. The most widely used, well-tolerated, and effective agents include the

nucleoside analogues lamivudine, entecavir, and tenofovir. Lamivudine is effective and low cost; its

major limitation is the development of drug resistance. Entecavir and tenofovir are active against

lamivudine-resistant variants and can be considered for first-line treatment in individuals if cost is not a

limiting factor. Both lamivudine and tenofovir are active against human immunodeficiency virus (HIV),

so these agents are preferred in individuals coinfected with HIV and HBV.

Liver transplantation is the treatment of choice in patients with hepatic failure. Recurrence of viral

infection in the allograft can be as high as 80% in HBeAg-positive cases where no postoperative

prophylaxis is administered. The combination of lamivudine and hepatitis B immune globulin

posttransplantation reduced the reinfection rate to less than 10% and increased the 5-year survival rate

to 80%.35 Other posttransplant pharmacologic regimens are currently being examined.40

HEPATITIS C VIRUS

Molecular Structure

Hepatitis C virus (HCV) is a lipid enveloped, 9.4-kb, single-stranded RNA virus of the family

Flaviviridae, genus Hepacivirus.41 Six genotypes have been identified, which differ from one another by

as much as 30% at the sequence level. Quasispecies within genotypes demonstrate further genetic

heterogeneity and reflect the high rate of mutation seen in viral replication. Over 70% of US cases are

due to genotype 1 virus.

Epidemiology/Risk Factors for Transmission

There are more than 185 million individuals infected with HCV worldwide, translating to a global

prevalence of 2.8%. In the United States, there are an estimated 3.6 million HCV-infected individuals,

approximately 1% of the population, but this is likely an underestimate as these estimates do not

include high-risk homeless or incarcerated populations.42,43

Figure 58-11. Clinical course in acute hepatitis C.

The most commonly identified risk factors are exposure to blood or blood products prior to 1992 and

intravenous drug use. Other risk factors include intranasal drug use due to mucosal exposure to blood

on drug paraphernalia, anal intercourse in men who have sex with men due to blood-mucosal exposure,

occupational exposure, hemodialysis, tattooing, and perinatal transmission. In the United States, more

than 80% of infections have been identified in adults born between 1945 and 1965.41 Due to this

observation, the CDC now recommends screening all individuals in this birth cohort irrespective of

reported risk factors.

Clinical Features

The usual incubation period of HCV is 5 to 10 weeks. Most acutely infected patients are asymptomatic

and therefore the infection goes unappreciated. Initial laboratory findings after infection include

elevated ALT levels (500 to 1,000 IU/mL) and high HCV RNA titers (Fig. 58-11). HCV clearance is

spontaneous in about 15% to 20% of individuals following primary infection. Hepatitis C infection by

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itself is almost never associated with ALF. Liver damage in the setting of chronic infection is due to host

immune response rather than viral hepatotoxicity. Ongoing chronic hepatic injury leads to progressive

fibrosis and cirrhosis which typically occurs over decades, in most cases undetected until the appearance

of overt liver failure (Fig. 58-12). The incidence of hepatic decompensation (variceal hemorrhage,

ascites, jaundice, encephalopathy) in the setting of cirrhosis is approximately 5% per year. Hepatitis C

cirrhosis is strongly associated with the development of HCC. Extrahepatic manifestations of hepatitis C

include membranoproliferative glomerulonephritis, cryoglobulinemia, diabetes, porphyria cutanea

tarda, lichen planus, vitiligo, and non-Hodgkin lymphoma.44

Figure 58-12. Clinical course in chronic hepatitis C.

The diagnosis of chronic hepatitis C is based on serologic demonstration of persistent HCV RNA and

HCV antibodies. HCV RNA can be detected weeks earlier than antibodies, which typically appear 2 to 8

weeks after the initial infection.

Treatment

With the recent advent of highly effective, well-tolerated antiviral therapy, all individuals who develop

hepatitis C should be offered treatment. The goal of treatment is a sustained virologic response or

absence of HCV RNA in serum 3 to 6 months after stopping treatment. Therefore, unlike HBV, therapy

in HCV is ideally curative.

In the past, the mainstay of therapy included IFN alpha combined with ribavirin (RBV) given for 48

weeks. This combination had poor tolerability and poor efficacy, with SVR rates for genotype 1

infections ranging from 35% to 45% depending on stage of disease and patient characteristics. In 2011,

the first directly acting antivirals (DAAs) designed to specifically inhibit HCV proteins became available.

Inhibitors of the HCV NS3A protease, boceprevir and telaprevir, were the first to be introduced but they

still had to be given in combination with IFN and RBV. These first PI-based regimens increased SVR

rates up to about 60% to 70%, but they compounded the toxicities of IFN and RBV, with high rates of

serious adverse events including death. In 2013, more effective antivirals were introduced which

allowed for IFN-free, ribavirin-free treatment regimens. With 12 to 24 weeks of treatment, DAA

combinations have SVR rates between 95% and 100% and very few side effects. New antivirals include

second-generation protease inhibitors nucleotide and nonnucleotide analog inhibitors of the HCV NS5B

polymerase and inhibitors of the HCV NS5A replication complex. Over the next several years, many

additional DAAs are expected to be approved. Determining the optimal combination for treatment will

depend on factors such as genotype, comorbidities, and drug-drug interactions.

4 Transplantation is the treatment of choice in cases of irreversible decompensated cirrhosis due to

HCV and in cases of HCC due to HCV. Thus, HCV has become the most common indication for liver

transplantation in the United States and many countries worldwide. In many cases, treatment cannot

completely reverse all hepatic damage from HCV and risk of HCC remains. Therefore, even if access to

HCV diagnosis and effective treatment is optimal, the need for liver transplantation due to HCV is

expected to continue for decades.

HEPATITIS D VIRUS

Molecular Structure

The hepatitis D virus (HDV), or delta agent, is an incomplete RNA virus that requires the presence of

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HBV for viral assembly and propagation. The only enzymatic activity of HDV is a ribozyme that cleaves

circular RNA and makes it linear. The HDV genome is a 1,680 nucleotide, single-stranded circular

RNA.45 Eight genotypes have been proposed.46 A single HDV antigen is encoded, it is a structural

component of the virion, and a lipoprotein envelope is provided by HBV.

Epidemiology/Risk Factors for Transmission

HDV is found in approximately 5% of HBV carriers. Due to its dependence on HBV, HDV always occurs

in association with HBV infection. Transmission is similar to that of HBV, via parenteral or sexual

exposure to blood or body fluids. HDV hepatitis occurs only in HBsAg- positive patients.

Figure 58-13. Synchronous infection with hepatitis B virus and hepatitis D virus.

Clinical Features

Acute infection is diagnosed by the presence of anti-HDV IgM. Anti-HBc IgM distinguishes coinfection

from superinfection (Figs. 58-13 and 58-14). The diagnosis in patients with chronic liver disease is made

by the presence of HBsAg and antibodies against HDV in the serum and confirmed by the presence of

HDV antigen in the liver or HDV RNA in the serum (Fig. 58-15). ALF is seen with both coinfection (HDV

and HBV simultaneously infects the host) and superinfection (HDV infects a host already infected with

HBV). Superinfection seems to be associated with a higher mortality rate. Chronic HDV and HBV

infection may coexist. Cirrhosis is observed in at least two-thirds of patients and occurs at a younger age

than in patients infected with HBV alone.47,48

Treatment

Treatment and prevention of HDV are associated with that of hepatitis B, with which it always coexists.

Vaccination for HBV is contributing to the decline in the incidence of HDV. Alpha IFN is the only

currently available treatment for chronic HDV.

Figure 58-14. Superinfection of chronic hepatitis B carrier with hepatitis D.

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