Hepatitis C

Luciléia Teixeira MD, MS

David Bobak MD, FIDSA

Introduction

About 200 million people worldwide are infected with the hepatitis C virus (HCV) and up to 4 million persons are newly infected each year. Because the majority of infected individuals have persistent, lifelong infection, HCV is associated with considerable global morbidity due to complications such as cirrhosis and hepatocellular carcinoma (HCC). For these reasons, HCV is the leading worldwide indication for liver transplantation as well. Unfortunately, no vaccine is currently available to prevent HCV infection. In addition, the standard forms of treatment for chronic hepatitis C are too costly for practical use in most developing countries. Much like HIV infection then, the greatest impact of hepatitis C continues to be felt among populations with the least amount of health care resources available. Recent advances in HCV cell culture systems and understanding of the virus’ life cycle have given rise to new hope for the successful development of an effective vaccine and more efficacious and more cost-effective treatment regimens.

Table 2.1 Characteristics of the hepatitis C virus

•	Envelope-containing, positive-strand RNA virus
•	Spherical particles approximately 50 nm in diameter
•	Member of the Flaviviridae family, has its own genus Hepacivirus
•	Related to members of the Flavivirus (yellow fever and dengue viruses) and Pestivirus genera
•	Genome is approximately 9.6 kb with an ORF of ˜9 kb
•	Viral ORF encodes a 3000 amino acid residue polyprotein processed into 10 known proteins
•	Highly conserved 5′ and 3′ untranslated regions involved in replication and translation
•	Genomic diversity characterized by the existence of quasispecies and genotypes
ORF: open reading frame

Etiology and pathogenesis

HCV is classified in the Flaviviridae family, although its genome is sufficiently distinct from related viruses to permit it to be placed in its own genus, Hepacivirus (Table 2.1). The structure of HCV is an enveloped ribonucleic acid (RNA) virus contained in a roughly spherical particle approximately 50 nm in diameter. The HCV genome is a positive-sense, single stranded RNA molecule approximately 9.6 kb in
length, with highly conserved untranslated regions. There is a single large open reading frame of about 9 kb in length, which encodes a very large polyprotein (~3000 amino acid residues) (Fig. 2.1). This protein undergoes co- and posttranslational processing by various viral and host cellular proteases to yield the individual structural and non-structural viral proteins. In an infected individual, more than 10 trillion HCV particles are produced per day, even in the chronic phase of infection. HCV exhibits considerable genetic diversity due to the presence of an RNA polymerase that is deficient in proofreading ability. Over the course of infection, large numbers of similar, but distinct, strains of HCV develop. These strains are known as quasispecies and are present in all HCV-infected persons. In addition, families of HCV with more distinct genetic characteristics have also developed over long periods of time into six major and distinct families of HCV known as genotypes. HCV genotype varies considerably in worldwide distribution and, in addition, has clinical implications for predicting response rates to currently available therapy (as discussed in more detail below).

Fig. 2.1 Hepatitis C virus genome.

Fig. 2.2 Time course of acute hepatitis C.

The major target of HCV infection and replication is the hepatocyte. HCV RNA has been detected in several other cell types including B- and T lymphocytes, and monocytes; however, the significance of HCV infection of these cell types is not well understood. The central theme of HCV infection is that of viral persistence and, as such, HCV infection causes little direct cytotoxicity to hepatocytes. In only a minority of individuals (~15%) is the host immune response able to clear HCV infection (Figs. 2.2, 2.3). The majority of HCV-infected individuals (~85%) go on to develop persistent HCV infection (Figs. 2.3, 2.4). The efficiency of the innate and adaptive host immune responses determines whether the acute infection is cleared and, in those with chronic infection, the level of end organ cytotoxicity (i.e. clinical hepatitis) that occurs. The intensity of the host immune and inflammatory response may also be correlated with the risk of developing cirrhosis and/or HCC late in the course of infection. HCV has developed a variety of strategies to evade primary and adaptive immune responses by the host, allowing for persistent infection lasting up to 40 years or longer. Chronic HCV infection causes persistent hepatic inflammation and promotes fibrosis, two pathophysiologic conditions that predispose infected individuals to develop cirrhosis and/or HCC, the two most serious outcomes of chronic hepatitis C (Figs. 2.3, 2.5).

Fig. 2.3 Clinical outcomes for hepatitis C infection.

Fig. 2.4 Time course of chronic hepatitis C.

Fig. 2.5 Histopathologic changes of hepatitis C. A: chronic hepatitis C infection (x10); B: chronic hepatitis C infection (x100); C: normal liver architecture (x20); D: progressive disease with bridging fibrosis (arrows) (x20); E: cirrhosis with regenerative nodules (RN); F: hepatocellular carcinoma (x40). (Reprinted with permission from Lauer GM, Walker BD. Medical progress: hepatitis C infection. N Engl J Med 2001; 345:41-52.)

Global epidemiology

Hepatitis C has been found in essentially every country in the world, indicating that it is a long-standing infection of humans. Based on available data, it is estimated that as many as 200 million people may be infected with HCV worldwide (Figs. 2.6, 2.7). In the United States, as in most developed countries, the prevalence of HCV infection is approximately 2%. This is in contrast with Egypt, a country where up to 30% of the population is believed to be infected with HCV. Based on genomic sequence homology, HCV has been classified into 11 major genotypes (designated 1-11), more than 50 subtypes (designated a, b, c …), and about 100 different strains (numbered 1, 2, 3 …) (Table 2.2). Genotypes 1-4 comprise the majority of HCV infections and genotypes 1-3 have a generally worldwide distribution (Fig. 2.8). Types 1a and 1b are the most common, accounting for about 60% of global infections. These genotypes predominate in Europe, North America, and Japan. Type 3 is endemic in South East Asia and has a variable prevalence elsewhere. Genotype 4 is principally found in the Middle East, Egypt, and central Africa. Other genotypes are generally rare, type 5 is almost exclusively found in South Africa and genotypes 6-11 are widely distributed throughout Asia.

Table 2.2 Hepatitis C genotypes

•	Eleven known genotypes, four major types (1-4)
•	Genotypes 1-4 most common overall, but there is considerable worldwide variation
•	Genotypes are much more genetically diverse than HIV-1 subtypes
•	Marked variability exists in the response rate to interferon/ribavirin therapy between genotypes

Fig. 2.6 Worldwide prevalence of hepatitis C.

Fig. 2.7 Worldwide burden of hepatitis C infection.

Fig. 2.8 Distribution of hepatitis C genotypes.

Transmission of HCV requires entry of HCV into the bloodstream with subsequent infection of hepatocytes. Not surprisingly, parenteral forms of transmission, such as intravenous drug use or transfusion of infected blood products, are the most commonly identified risk factors in individuals with hepatitis C (Figs. 2.9, 2.10 and 2.11, Table 2.3). HCV can be detected with molecular techniques in other body fluids such as semen and saliva, but the significance of these findings related to transmission risk are unclear. Most epidemiological studies indicate that the actual infection risk associated with exchange of body fluids through oral or sexual contact is very low (Table 2.4).

Since the introduction of highly sensitive screening tests for HCV among blood product donors in the early 1990s, infusion-related infections have become extremely rare in most developed countries (Fig. 2.11). Infection risk to health care workers following percutaneous exposure to blood is estimated at between 1 and 2%. No proven prophylactic intervention is currently available for persons sustaining a high-risk type of exposure. Transmission of HCV infection via organ or hematologic transplantation is rare, but recipients of such transplants from a HCV-positive donor have a very high risk of developing hepatitis C. Vertical transmission is uncommon, with most estimates of the risk of perinatal transmission from HCV-infected mother to infant ranging from 3 to 5% (Table 2.5). HIV infection may increase the likelihood of perinatal or sexual transmission. HCV patients infected with HIV share many characteristics with other HCV-infected individuals, but coinfected patients have many other issues related to the pathophysiology and clinical management of their infections. Interested readers are referred to the reference section and specialty journals for detailed information about HCV/HIV coinfection.

Table 2.3 Factors associated with increased risk of hepatitis C virus transmission

High-risk factors:
•	History of intravenous drug use
•	History of blood product transfusion
•	History of sexual activity with an intravenous drug user
Moderate to low-risk factors:
•	Incarceration in a jail or penitentiary
•	Religious scarification
•	Percutaneous blood exposure
•	Body piercing
Listed in estimated descending rank order of relative risk

Table 2.4 Sexual activity and risk of hepatitis C transmission

•	Most likely occurs, although estimated risk appears to be extremely low
•	Probable higher risk in individuals coinfected with HIV
•	Possible higher risk associated with anal intercourse or activities resulting in blood to mucosal surface exposures
•	Potential non-sexual household blood exposures confounds some data analyses (e.g. sharing toothbrushes or razor blades)
•	No clear-cut evidence as yet that ‘safe sex’ practices and condom use decrease rate of transmission
•	Certain organizations, including the United States Public Health Service and the American Association for Liver Diseases, do not currently recommend routine barrier precautions for sexual activity between long-term monogamous partners

Fig. 2.9 Risk factors for hepatitis C infection. (Adapted from US Centers for Disease Control data.)

Fig. 2.10 Risk factors for hepatitis C infection, pre-1992. (Adapted from US Centers for Disease Control data.)

Fig. 2.11 Risk factors for hepatitis C infection, post-1992. (Adapted from US Centers for Disease Control data.)

Table 2.5 Perinatal transmission of hepatitis C virus

•	Occurs uncommonly, risk is estimated at 3-5% but varies widely among studies
•	Increased risk may be associated with extremely high levels of hepatitis C virus viremia at time of delivery
•	HIV coinfected individuals appear to have slightly increased risk of transmission
•	Elective Cesarean section is not routinely recommended for hepatitis C-infected mothers
•	Infants born to hepatitis C-infected mothers need to have negative viral RNA determinations during the at age 12-18 months to confidently exclude infection
•	In contrast to HIV, there is no evidence that breast-feeding by a hepatitis C-infected mother is associated with a significant transmission risk for the infant

Clinical manifestations

Based on infusion-related infections, the incubation period for acute hepatitis C is estimated to average 7-8 weeks with a range of 2-26 weeks (Figs. 2.2). Antibody to HCV can be detected in 80% of patients within 15 weeks after exposure and in ≥97% by 6 months after exposure. Most patients with acute HCV infection are asymptomatic. In cases of symptomatic hepatitis C, most patients display very mild symptoms such as fatigue, malaise, and nausea. Only about 20% of those with acute hepatitis C develop jaundice. Laboratory evaluation usually only consists of mild, fluctuating elevations in serum transaminases. Fulminant hepatitis is rare, although the risk of developing this condition may be increased in those patients with chronic hepatitis B. Only a small number (~15%) of HCV-infected individuals completely resolve the infection with clearance of viremia and normalization of alanine aminotransferase (ALT) levels.

Most HCV-infected individuals (~85%) develop chronic infection (Fig. 2.4). These patients are generally asymptomatic, but infection may be accompanied by nonspecific symptoms such as fatigue, low-grade fever, myalgias and/or anorexia. These patients usually have few specific laboratory abnormalities, the most common being elevated serum transaminase levels. The development of chronic liver disease is usually insidious, progressing at a slow rate in the majority of patients during the first two or more decades after infection. Commonly, chronic hepatitis C is not recognized in asymptomatic individuals until they are found to have HCV-positive serology as part of the screening process for blood donation or during the evaluation of elevated ALT levels detected during routine physical examinations.

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