STRUCTURE

The HCV virion has been visualized by electron microscopy and is an enveloped virus 50 nm in diameter.⁸ The two envelope proteins, E1 and E2, heterodimerize and assemble into tetramers, which create a smooth outer layer. This layer has a “fishbone” configuration with icosahedral symmetry. The envelope proteins are anchored to a host cell–derived lipid bilayer envelope membrane that surrounds the nucleocapsid. The nucleocapsid is believed to be composed of multiple copies of the core protein and forms an internal icosahedral viral coat that encapsulates the genomic ribonucleic acid (RNA). HCV circulates in various forms in the serum of an infected host, including (1) virions that are bound to very-low-density and low-density lipoproteins and appear to represent the infectious fraction; (2) virions bound to immunoglobulins; and (3) free virions. In addition, viral particles that exhibit physicochemical, morphologic, and antigenic properties of nonenveloped HCV nucleocapsids have been detected in plasma.⁹

GENOMIC ORGANIZATION

HCV is a single-stranded positive-sense RNA virus that belongs to the Flaviviridae family and has been classified as the sole member of the genus Hepacivirus.¹⁰ The genome of HCV contains approximately 9600 nucleotides with an open reading frame (ORF) that encodes one large viral polypeptide precursor of 3008 to 3033 amino acids. The HCV ORF is flanked upstream by a 5′ untranslated region (UTR) that functions as an internal ribosome entry site (IRES) to direct cap-independent translation (i.e., without the addition of an extra ribonucleotide to the 5′ end of the viral messenger RNA) and downstream by a 3′ UTR that is critical for initiation of new RNA strand synthesis.^11–13 The 5′ and portions of the 3′ UTR are the most conserved parts of the HCV genome.

VIRAL REPLICATION AND LIFE CYCLE

Although peripheral blood mononuclear cells, B cells, T cells, and dendritic cells have been reported to support HCV replication, hepatocytes are the major site of viral replication.^14,15 Understanding of the mechanisms of viral replication comes from studies in chimpanzees, extrapolation of the mechanisms used by other flaviviruses, and infection of cells in vitro with subgenomic replicons (segments of HCV RNA that are capable of amplification and synthesis of viral proteins but that do not produce mature viruses).

Early events in viral binding to the hepatocyte surface are still not completely understood (Fig. 79-1). HCV entry involves the attachment of envelope proteins E1 and E2 to cell surface molecules. The expression and function of CD81, a member of the tetraspan superfamily, are essential for HCV entry into hepatocytes.¹⁶ In addition, human scavenger receptor class B type 1 (SR-B1), a selective importer of cholesteryl esters from high-density lipoproteins (HDL) into cells, has been shown to interact with E2 and is essential for HCV entry.¹⁷ Whereas CD81 and SR-B1 are required early in the process of viral entry, claudin-1 (CLDN1), a tight junction component that is highly expressed on hepatocytes, is required later in the cell entry process.¹⁸ Heparin sulfated proteoglycans have also been shown to be essential for HCV cell entry.¹⁹ Other receptors are also likely required for viral entry.¹⁸ There is some evidence that the low-density lipoprotein (LDL) receptor is involved during endocytosis of HCV.²⁰

Figure 79-1. Putative life cycle of hepatitis C virus.

(Reproduced with permission from Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 2007; 132:1979-98.) (See text for details and Fig. 79-2 for functions of the hepatitis C virus proteins.) NS, nonstructural; RdRp, RNA-dependent RNA polymerase.

Not only do viral receptors on hepatocytes play a role in entry of HCV into the cell, but also other cofactors affect the efficiency of viral infectivity. C-type lectins DC-SIGN (dendritic cell–specific intercellular adhesion molecule-3-grabbing nonintegrin; CD209) and L-SIGN (DC-SIGNr, liver and lymph node specific; CD209L) are expressed on dendritic cells and liver sinusoidal endothelial cells, respectively.²¹ Both receptors bind E2 on the HCV virus and facilitate infection of adjacent hepatocytes by acting as a capture and delivery mechanism. In addition, HDL increases infectivity of hepatocytes ten-fold, although the mechanism is not understood.²²

Once the HCV virus attaches to the cell, endocytosis of the bound virion is presumed to occur, as in other flaviviruses. A pH drop in the vesicle causes conformational changes in the glycoproteins that lead to fusion of the viral and cellular membranes²³ and release of viral RNA into the cytoplasm. In the cytosol, the 5′ UTR contains several highly conserved and structured domains that function as an IRES, which directs the RNA to its docking site on the endoplasmic reticulum and mediates cap-independent internal initiation of HCV polyprotein translation by recruiting both cellular proteins, including eukaryotic initiation factors (eIF) 2 and 3, and viral proteins.^24,25

The large polyprotein generated by translation of the HCV genome is co- and post-translationally processed proteolytically into at least 11 viral proteins, including both structural (nucleocapsid [C], or p21; envelope 1 [E1], or gp31; and envelope 2 [E2], or gp70) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins (Fig. 79-2).^11,13 The functions of these specific proteins are described later in the chapter.

Figure 79-2. Schematic representation of the hepatitis C virus polyprotein. The structural proteins C (core), E1, and E2 (envelope proteins) are cleaved from the polyprotein by the host signal peptidase. p7, a viroporin protein, is cleaved by the endoplasmic reticulum signal peptidase and forms an ion channel that is essential for assembly and release of infectious virions. The NS2 cysteine protease autocatalytically cleaves itself from the polyprotein. The NS3 protease cleaves the remainder of the nonstructural proteins: NS3 (serine protease and RNA helicase), NS4A (NS3 protease cofactor), NS4B, NS5A (RNA binding site), and NS5B (RNA-dependent RNA polymerase).

After polyprotein processing, NS4B expression causes the membrane alterations that are seen on electron microscopy as a membranous web.^26,27 The replication complex associates viral proteins, cellular components, and nascent RNA strands and is essential for HCV replication, as demonstrated in replicon cell culture systems.²⁸ HCV replication is catalyzed by the NS5B RNA-dependent RNA polymerase (RdRp). The positive-strand genomic RNA serves as a template for the synthesis of a negative-strand intermediate. Negative-strand RNA serves as a template for production of numerous strands of RNA of positive polarity that are used for polyprotein translation and synthesis of new intermediates of replication and are packaged into new virus particles.²⁹

Finally, viral particle formation is initiated by the interaction of the core protein with genomic RNA in the endoplasmic reticulum, although the details of this process and subsequent export of mature virions from the hepatocyte are poorly understood.^30,31 By analogy with pestiviruses, HCV packaging and release are likely to be inefficient because much of the virus remains in the cell. Following release, viral particles may infect adjacent hepatocytes or enter the circulation, where they are available for infection of another cell or host.

GENOTYPES AND QUASISPECIES

HCV has an inherently high mutational rate that results in considerable heterogeneity throughout the genome.⁵⁶ This high mutational rate is in part a consequence of the RNA-dependent RNA polymerase of HCV, which lacks 3′-to-5′-exonuclease proofreading ability that ordinarily would remove mismatched nucleotides incorporated during replication. An average of one error occurs for every 10⁴ to 10⁵ nucleotides copied. This phenomenon is favored by a high viral turnover rate; 10¹⁰ to 10¹² virions are produced per day.⁵⁷ A substantial proportion of newly synthesized viral genomes have alterations. Because of the functional differences in HCV proteins, genetic variation in some parts of the genome confers advantages by evading or inhibiting the host immune system, whereas other mutations may be lethal to the virus if they lead to defective replication machinery. Therefore, genetic variation is distributed irregularly along the genome. Each new genetic variant is produced in a single cell and may or may not spread through the liver and into the serum. The result is not only genetic diversity in the serum, but also compartmentalization of variant virions in different parts of the liver and perhaps in extrahepatic sites.

Because of the vast genetic variation, a classification scheme was devised whereby viral sequences are given a genotype and subtype. The first division used to describe the genetic heterogeneity of HCV is the viral genotype, which refers to genetically distinct groups of HCV isolates that have arisen during the evolution of the virus. Nucleotide sequencing has shown variation of up to 34% between genotypes.⁵⁶ The most conserved region (5′ UTR) has a maximum nucleotide sequence divergence of 9% between genotypes, whereas the highly variable regions that encode the envelope proteins (E1 and E2) exhibit a nucleotide sequence divergence of 35% to 44% between genotypes. The sequences cluster into 6 major genotypes (designated by numbers), with sequence similarities of 60% to 70%, and more than 70 subtypes (designated by a lower case letter) within these major genotypes, with sequence similarities of 77% to 80%.⁵⁶ In this scheme, the first variant, which was cloned by Choo and colleagues, is designated type 1a.⁵⁸ The HCV genotype is an intrinsic characteristic of the infecting HCV strain and does not change over time; therefore, the genotype only needs to be determined once in an infected person. Mixed-genotype infections may be seen and reflect either coinfection with more than one HCV virus or methodologic problems in genotype testing. In addition, inter-genotypic HCV recombinants have been described⁵⁹; these are thought to arise because of recombination between different genotypes in patients with repeated exposure. The recombination events have been reported to occur in or between NS2 and NS3.⁶⁰

Global geographic differences exist in the distribution of HCV genotypes, as well as in the mode of acquisition. In the United States, genotype 1a is the most prevalent, accounting for approximately 57% of HCV infections, followed by genotype 1b in 17%, genotype 2 in 14%, genotype 3 in 7%, and genotype 4, 5, or 6 in less than 5%.⁶¹ Racial differences are seen in the prevalence of genotypes; approximately 90% of African Americans are infected with HCV genotype 1, whereas only 70% of whites and 71% of Hispanics are infected with genotype 1.⁶² In Europe, the most prevalent genotype is 1b (47%), followed by 1a (17%), 3 (16%), and 2 (13%).⁶³ Genotype 4 is found mainly in Egypt, the Middle East, and Central Africa.⁶⁴ In Egypt, approximately 15% of the population is infected with HCV, and more than 90% have HCV genotype 4. Because of the high prevalence rate in Egypt, genotype 4 represents 20% of the world’s HCV-infected population. Genotype 5, although originally isolated in South Africa, is also seen in specific regions of France, Belgium, and Spain.⁶⁵ Genotype 6 is found predominantly in Asia. The distribution of genotypes is ever changing with immigration and alterations in the primary modes of viral transmission. Therefore, the frequencies of viral genotypes change over time.⁶⁶

An important clinical correlation with HCV genotype is response to treatment (see later). HCV genotype does not, however, appear to influence the severity of liver disease, as defined by the stage of fibrosis, or the likelihood of progression of acute to chronic HCV infection.

The second component of genetic heterogeneity is quasispecies generation.⁵⁶ Quasispecies are closely related, yet heterogeneous, sequences of HCV RNA within a single infected person that result from mutations that occur during viral replication. The rate of nucleotide changes varies significantly among the different regions of the viral genome. The highest proportion of mutations is found in the E1 and E2 regions, particularly in HVR1. Even though this region represents only a minor part of the E2 region, it accounts for approximately 50% of the nucleotide changes and 60% of the amino acid substitutions within the envelope region.

The development of quasispecies may be one mechanism by which the virus escapes the host’s immune response and establishes persistent infection.⁶⁷ During acute infection or during treatment, the lack of quasispecies is associated with viral clearance, and the development of numerous quasispecies is associated with viral persistence.⁶⁸ In acute disease, patients in whom genetic variation in the HVR1 region develops after antibody seroconversion progress to chronic disease, whereas those in whom such genetic variation does not develop are more likely to achieve viral clearance.⁶⁷ Genetic variation before seroconversion does not correlate with outcome, indicating that quasispecies formation results from antibody-mediated immune pressure. Interestingly, no intrinsically interferon-resistant variants of HCV have been defined, indicating that both viral and host factors play important roles in determining whether the virus persists or is cleared. An increased number of quasispecies has also been associated with more rapid progression to cirrhosis and the development of HCC.⁶⁹

INCIDENCE AND PREVALENCE

The worldwide seroprevalence of HCV infection, based on detection of antibody to HCV (anti-HCV), is estimated to be 3%, with more than 170 million people infected chronically. Marked geographic variation exists, with infection rates ranging from 1.3% to 1.6% in the United States to 15% in Egypt.^1,64 Currently, between 3.2 and 5 million persons are infected with HCV in the United States.¹ The prevalence rate is higher in persons 40 to 49 years old than in older or younger persons, in males (2.1%) than in females (1.1%), and in African Americans (3%) than in whites (1.5%).¹ Other risk factors for HCV infection and the associated frequencies of infection are injection drug use (57.5%), blood transfusion before 1992 (5.8%), greater than 50 lifetime sexual partners (12%), and family income below the poverty level (3.2%). The current prevalence of HCV infection in the United States may be underestimated because the National Health and Nutrition Examination Survey (NHANES) data did not evaluate persons who are homeless, incarcerated, or in the military. Among incarcerated persons, 12% to 35% are positive for HCV RNA serum,⁷⁰ whereas those in military service have a seroprevalence rate for anti-HCV of 0.5%.⁷¹

Worldwide, three different epidemiologic patterns of HCV infection have emerged: (1) previous exposure through health care with a peak prevalence in older persons; (2) exposure through intravenous drug use, the major risk factor since data first became available in about 1960, with a peak prevalence among middle-aged persons; and (3) ongoing high levels of infection in areas where high rates of infection occur in all age groups.⁶³

Given the factors that influence viral diversity (see earlier), estimating the site of origin and age of HCV by phylogenetic analysis is difficult. The best estimate is that HCV originated in western and sub-Saharan Africa.⁷² Subsequent global spread probably occurred coincident with trade and human migration. Evolution of the virus led to a geographic distribution of genotypes, so that genotypes 1, 2, and 3 are most common in North America and Europe, genotype 4 is most common in the Middle East, and genotypes 5 and 6 are most common in Southeast Asia. In Japan, HCV transmission transitioned from constant to exponential growth in the 1920s, and the prevalence of HCV infection is highest in older persons.⁷³ In Japan, and later in southern and Eastern Europe, health care–related procedures—particularly reuse of contaminated syringes—played a major role in viral spread. In the United States, Australia, and other developed countries, peak prevalence is in persons ages 40 to 49 years, and analysis of risk factors suggests that most HCV transmission occurred between the mid-1980s and the mid-1990s, through intravenous drug use. In Egypt, the spread of HCV increased exponentially from the 1930s to the 1980s because of mass vaccination campaigns with reuse of medical equipment.⁶⁴ In Egypt and other developing countries, high rates of infection are observed in all age groups, suggesting that an ongoing risk of HCV acquisition exists.

In the United States, the incidence of acute hepatitis C is falling. The peak incidence was estimated to be 180,000 cases per year in the mid-1980s, but the rate declined to approximately 19,000 new cases by 2006.⁷⁴ Many factors have contributed to the falling incidence of acute hepatitis C. In the 1980s, when blood was purchased from donors, 2% to 10% of blood units were infected with HCV, leading to a high rate of transfusion-acquired HCV infection.⁷⁵ The institution of volunteer blood donation, creation of recombinant clotting factors, and implementation of HCV blood testing (between 1990 and 1992) dramatically decreased transfusion-acquired HCV infection.⁶⁶

An important mechanism of transmission worldwide has been the lack of sterilization of medical instruments such as syringes. Although the incidence of HCV transmission by medical instruments has also decreased markedly, the risk has not been eliminated, even in the United States. Currently, new HCV infections in the United States and other developed countries occur primarily as a result of injection drug use.

TRANSMISSION

Modes of transmission of HCV can be divided into percutaneous (blood transfusion and needlestick inoculation) and nonpercutaneous (sexual contact and perinatal exposure). Patients are often unwilling to disclose percutaneous risk factors, and therefore “nonpercutaneous” transmission may represent occult percutaneous exposure.

VIRAL MECHANISMS

In chronically infected patients, the pathogenesis of liver damage is largely immune mediated. In a small subset of immunocompromised HCV-infected patients among both HIV-infected patients and organ transplant recipients, however, a syndrome termed fibrosing cholestatic hepatitis develops.^97,98 Such cases are thought to result from direct viral hepatotoxicity of infected cells because viral levels are typically greater than 30 million copies/mL and hepatocytes contain enormous concentrations of virus and viral proteins.⁹⁹ Survival in such patients is quite poor.

The majority of patients with HCV infection have a variable immune response that, although inadequate to eradicate acute infection, appears to regulate the vigor of persistent infection and avoid the development of fibrosing cholestatic hepatitis. The immune response to HCV is incompletely understood because animal models are not readily available and most studies in man rely on observations in peripheral blood rather than the hepatic immune environment.

IMMUNE-MEDIATED MECHANISMS

HCV infection elicits an immune response in the host that involves both an initial innate response as well as a subsequent adaptive response. The innate response is the first line of defense against the virus and includes several arms such as natural killer (NK) cell activation and cellular antiviral mechanisms triggered by pathogen-associated molecular patterns (PAMPs) recognized by the cell.^100–102 These processes can lead to apoptosis of infected cells within the first few hours of infection. NK cells, as the effector cells of the innate immune system, also produce tumor necrosis factor (TNF)-β and interferon-α, cytokines that are critical for dendritic cell maturation and subsequent induction of adaptive immunity.⁹⁴ After this, however, the virus initiates a number of mechanisms that undermine the ability of the host to control the infection.

Virus-related disruption of the innate, and later adaptive, immune response occurs at several levels.⁹³ NK cell function is slowed possibly because NK cell–mediated cytotoxicity and production of cytokines are interrupted when the HCV E2 protein binds its cellular receptor CD81.^103,104 PAMPs activate several cellular processes including the JAK-STAT pathway and Toll-like receptor-3 (TLR-3), activation of both of which ultimately results in production of cellular interferons and interferon-regulated factors that convey antiviral properties to the cell.⁹³ NS3/4 protease degrades TRIF, an essential intermediate in this pathway, and cleaves interferon promoter stimulator-1 (IPS-1), an intermediate in the signaling cascade, to activate interferon when retinoic inducible gene-1 (RIG-1) binds viral intermediates.^47,105,106 In addition, HCV core protein promotes STAT-1 degradation, inhibits STAT-1 phosphorylation, promotes suppressor of cytokine signaling (SOCS) induction (an inhibitor of JAK-STAT signaling), and impairs interferon-stimulated gene factor-3 (ISGF3), a heterotrimer of STAT-1, STAT-2, and interferon-β promoter stimulator (IRF-9) from binding to the promoter regions of interferon-stimulated response elements (ISRE), thereby inhibiting transcription of interferon-response genes. Even when interferon-response genes are activated, NS5A and E2 both can disrupt protein kinase R (PKR) function to suppress translation, thereby allowing viral replication to continue.⁹³ In addition, NS5A inhibits 2′-5′-oligoadenylate synthetase (OAS). 2′-5′-OAS is expressed in response to HCV infection and leads to HCV RNA degradation.⁹³ Taken together, HCV is able to disorient the innate immune response at several levels, and these strategies appear to be pivotal in establishing the chronicity of infection.

The ability of HCV to impair the innate immune response prevents development of a vigorous adaptive immune response to the infection. NK cells do not adequately activate dendritic cells, and as a result, the priming of CD8⁺ and CD4⁺ T cells in HCV-infected patients is inadequate.^107–109 Dendritic cells from HCV-infected patients are more likely to produce IL-10, a cytokine that inhibits antigen-specific T-cell responses. In addition, CD4⁺ T cells primed from dendritic cells of HCV-infected patients are more likely to produce IL-10. Even if an adequate T-cell response is created, HCV-infected patients have a large number of regulatory T cells in their portal tracts¹¹⁰; intrahepatic immune regulation by these cells has not been demonstrated but is presumed.

HCV-specific T cells are enriched at the site of viral replication, with an increased number in the liver when compared with the peripheral blood.^95,111 CD8⁺ lymphocytes predominate, suggesting that cytotoxic T lymphocytes are the main perpetrators of hepatocellular injury. The T-cell immune response in the liver may result in direct lysis of infected cells and inhibition of viral replication by secreted antiviral cytokines.^95,111

Whereas the cellular immune response plays a pivotal role in the pathogenesis of HCV infection, the importance of the humoral immune response is less clear. Antibodies to viral proteins are produced in low levels and do not appear to correlate with the stage of infection or immune reactivity. Furthermore, administration of high-titer HCV-enriched or HCV-specific immunoglobulin has little effect on viral levels or persistence in humans.¹¹²

In summary, viral products play an integral role in the immune regulation that leads to chronic infection instead of viral clearance. Both the virus and the immune response probably play a role in the development of hepatocellular injury.

ACUTE AND CHRONIC HEPATITIS C

HCV accounted for an estimated 20% of cases of acute hepatitis in 2006.⁷⁴ Acute hepatitis C is rarely seen in clinical practice because nearly all cases are asymptomatic.^87,113 Jaundice probably occurs in about 10% of patients with acute HCV infection, whereas 20% to 30% of patients present with nonspecific symptoms such as fatigue, nausea, and vomiting. HCV RNA is detectable within 2 to 3 weeks of exposure, and anti-HCV seroconversion occurs between day 15 and month 3. Serum aminotransferase levels peak at about the first month after exposure (Fig. 79-3), exceed 1000 IU/L in 20% of cases, and generally follow a fluctuating pattern for the first few months. In patients in whom jaundice develops, peak serum bilirubin levels usually are less than 12 mg/dL, and jaundice typically resolves within one month. Severe impairment of liver function and liver failure are rare. The presentation may be more apparent and the clinical course more severe when acute HCV infection occurs in patients who drink large amounts of alcohol or have coinfection with HBV or HIV.

Figure 79-3. Serologic pattern of acute hepatitis C virus (HCV) infection followed by recovery. Symptoms may or may not be present during acute infection. ALT, serum alanine aminotransferase level; anti-HCV, antibody to hepatitis C virus.

(Modified from the Centers for Disease Control and Prevention, www.cdc.gov/hepatitis/Resources/Professionals/Training/Serology/training.htm#one.)

The rate of viral persistence after acute infection varies, ranging from 45% to more than 90%. Age and gender clearly influence the risk of chronicity, with younger and female patients having the lowest rates of chronicity. Other factors that may play a role include the source of infection and size of inoculum (chronicity may be less common in injection drug users than in those who acquire HCV infection by blood transfusion), immune status of the host (chronicity rates are higher in persons with immunodeficiency states such as agammaglobulinemia and HIV infection), and the patient’s race (rates of viral persistence are higher in African Americans than in whites and Hispanic Americans in the United States). Finally, the rate of spontaneous clearance is higher in symptomatic patients in whom jaundice develops during acute infection than in those who remain asymptomatic.^87,113,114 In patients with community-acquired hepatitis C in whom the infection resolves spontaneously, loss of HCV RNA from serum usually occurs within three to four months of the onset of clinical disease.¹¹⁴

Serum alanine aminotransferase (ALT) levels are usually elevated in patients with chronic HCV infection. Because levels commonly fluctuate, however, as many as one half of patients may have a normal ALT level at any given time.¹ The ALT level may remain normal for prolonged periods of time in about 20% of cases,¹¹⁵ although transient elevations occur even in these cases.¹¹⁶ Persistently normal ALT levels are more common in women, and such cases typically are associated with lower serum HCV RNA levels and less inflammation and fibrosis on liver biopsy specimens.¹¹⁵

Most patients with chronic hepatitis C are asymptomatic before the onset of advanced hepatic fibrosis. Patients who have been diagnosed with chronic infection, however, often complain of fatigue or depression, and they consistently score lower than HCV-negative persons in all aspects of health-related quality of life (HRQL).^117,118 Whether the decrease in HRQL is related to viral factors, social factors (e.g., intravenous drug use), social stigmatization, or worry related to the diagnosis itself is unclear. Nonetheless, HRQL scores improve if the patient achieves a sustained response to antiviral therapy (see later). Less common symptoms may include arthralgias, paresthesias, myalgias, sicca syndrome, nausea, anorexia, and difficulty with concentration. The severity of these symptoms may be, but is not necessarily, related to the severity of the underlying liver disease.

EXTRAHEPATIC MANIFESTATIONS

Patients with HCV infection may present with extrahepatic conditions, or these manifestations may occur in patients known to have chronic hepatitis C. Classification of the extrahepatic manifestations of HCV is shown in Table 79-1 and is based on the strength of available data to prove a correlation.¹¹⁹ Types 2 and 3 cryoglobulinemia, characterized by polyclonal immunoglobulin G (IgG) plus monoclonal IgM and polyclonal IgG plus polyclonal IgM, respectively, can both be caused by HCV infection. Among HCV-infected patients 19% to 50% have cryoglobulins in serum, but clinical manifestations of cryoglobulinemia are reported in only 5% to 10% of these patients and are more common in patients with cirrhosis. Symptoms and signs include fatigue, arthralgias, arthritis, purpura, Raynaud’s phenomenon, vasculitis, peripheral neuropathy, and nephropathy. The diagnosis is clear when a rheumatoid factor is detected, cryoglobulins are present, and complement levels are low in serum; however, the reliability of cryoglobulin measurements is dependent on proper handling and processing of the sample.

Table 79-1 Extrahepatic Manifestations of Hepatitis C Virus Infection

Glomerular disease generally manifests as cryoglobulinemic nephropathy, membranoproliferative glomerulonephritis (MPGN), and membranous nephropathy.^119,120 Cryoglobulinemic nephropathy manifests as hematuria, proteinuria, edema, and renal insufficiency of varying degrees, and on renal biopsy specimens it has features of MPGN. At diagnosis, 20% of patients with type 2 cryoglobulinemia have renal involvement, and renal involvement develops in another 35% to 60% over time. In about 15% of patients, cryoglobulinemic nephropathy progresses to end-stage kidney disease requiring dialysis.

Therapy should be considered in patients with symptomatic cryoglobulinemia. Cryoglobulinemia resolves in patients who achieve an SVR with pegylated interferon and ribavirin therapy (see later).¹¹⁹ Unfortunately, patients with significant renal involvement are at a disadvantage with respect to antiviral therapy because administration of ribavirin is generally contraindicated if the creatinine clearance is less than 50 mL/min. In these patients, treatment with rituximab should be considered.^121,122 A durable clinical response to four doses of rituximab has been reported, although no prospective clinical trials have been completed to date. Prednisone, cyclophosphamide, other chemotherapeutic agents as well as plasmapheresis have been used with variable success; however, these approaches do not treat the underlying HCV infection.¹¹⁹ If cryoglobulinemia and renal disease improve with such treatment, then subsequent treatment of the HCV infection with pegylated interferon-α and ribavirin should be reconsidered.

HCV infection is associated with the development of B-cell non-Hodgkin’s lymphoma and monoclonal gammopathy of uncertain significance.^119,123,124 The relative risk of lymphoma is small (1.28) in the United States.¹²³ The most prevalent forms of lymphoma found in patients infected with HCV are follicular lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma. In addition, marginal splenic lymphoma has been reported to regress after therapy for HCV infection alone. An estimated 8% to 10% of patients with type 2 cryoglobulinemia evolve into lymphoma over time. Despite the known association of HCV infection with lymphoma, HCV RNA does not integrate into the host genome and cannot be considered a typical oncogenic virus. Rather, HCV shows lymphotropism and may facilitate the development and selection of abnormal B-cell clones by chronic stimulation of the immune system. In addition, genetic rearrangements in B cells, specifically the Bcl2/J_H rearrangement and the t(14;18) translocation, have been found in HCV-infected patients.^125,126 Patients with B-cell genetic alterations are less likely to respond to antiviral therapy.¹²⁷

Other extrahepatic manifestations of HCV infection include porphyria cutanea tarda, lichen planus, and sicca syndrome.¹¹⁹ In addition, insulin resistance and diabetes mellitus are associated with HCV infection. The SVR to antiviral therapy for HCV infection is reduced in insulin-resistant patients; however, if HCV can be eradicated, insulin resistance often improves, an observation that further supports the relationship between HCV infection and insulin resistance.¹²⁸ Although associations between HCV infection and both thyroid cancer and idiopathic pulmonary fibrosis have been described, data about the effect of HCV eradication on disease progression are lacking (see Table 79-1). A myriad of other conditions have been observed in association with HCV infection, but a true link has not been firmly established for these disorders.¹¹⁹

Although not associated with disease, seropositivity for autoantibodies is found in many HCV-infected persons (e.g., antinuclear antibodies with a titer greater than 1 : 40 in 9%, smooth muscle antibodies with a titer greater than 1 : 40 in 20%, anti-liver-kidney microsomal antibodies in 6%).¹²⁹ In addition, anti-thyroid peroxidase is found in serum in 5% to 12% of HCV-infected patients, although associated thyroid disease is found in only 2% to 5% of patients.¹¹⁹ Therefore, the diagnosis of an autoimmune condition in a patient with HCV infection can never be based on serology alone.

INDIRECT ASSAYS

EIAs detect antibodies against different HCV antigens. The time course of the development of symptoms, detection of anti-HCV, and appearance of HCV RNA after acute infection is shown in Figure 79-3. Three generations of EIAs have been developed. The latest, third-generation, EIAs detect antibodies against HCV core, NS3, NS4, and NS5 antigens as early as 7 to 8 weeks after infection, with sensitivity and specificity rates of 99%.¹³¹ Despite ongoing viral replication, serologic test results can be negative in patients who are on hemodialysis or are immunocompromised.⁸⁰ Because the performance characteristics of third-generation EIAs are so good, confirmation with a recombinant immunoblot assay (RIBA) is no longer required. Instead, patients who are anti-HCV positive should undergo HCV RNA testing to determine if they have active viremia or have cleared the infection.

DIRECT ASSAYS

Two general types of direct assays exist: qualitative and quantitative HCV RNA tests.¹³⁰ Qualitative HCV RNA nucleic acid tests (NAT) only report whether HCV RNA is found in serum or not and do not quantitate the amount of HCV RNA. These tests should be used only for screening purposes now (e.g., screening of blood donated to a blood bank) and should not be used in clinical practice. As a result of NAT technology, transfusion-related HCV infection has decreased to less than one case per two million units of blood transfused.^76,77

Unlike NAT testing, quantitative HCV RNA tests are essential for monitoring the response to antiviral therapy (see later). Currently “real-time” tests, such as Taqman, are performed using polymerase chain reaction (PCR) methodology, with a lower limit of detection of 10 to 15 international units (IU)/mL.¹³² These assays have a linear dynamic range of 1 to 7 log₁₀ IU/mL and are the preferred testing method in practice. Transcription-mediated amplification (TMA) is also extremely sensitive, but available assays are not quantitative in the lower dynamic range of the test. The advantages of these very sensitive tests include positivity within one to three weeks after acute infection and detection of low-level residual infection during antiviral therapy.

A disadvantage of all quantitative tests is the lack of comparability among different assays. Although conversion to a standard IU/mL concentration attempted to resolve such discrepancies, results are still variable. Thus, conversion factors vary from 0.9 copies/mL to 5.2 copies/mL per IU/mL reported. For this reason, the same laboratory and assay should be used during antiviral treatment when comparisons of levels at different points in time are critical to decision making about treatment.

SELECTION OF SEROLOGIC AND VIROLOGIC TESTS

For patients at low risk for HCV infection, a negative result on an EIA for anti-HCV is sufficient to exclude HCV infection. A positive anti-HCV result is sufficient to confirm the diagnosis if the serum ALT level is elevated. If the serum ALT level is not elevated, HCV RNA should be measured. In high-risk patients, such as those with an elevated ALT level who have a known risk factor for HCV, have experienced recent exposure, or are either immunocompromised or on dialysis, a positive anti-HCV result is sufficient to confirm HCV infection. If the anti-HCV result is negative, then HCV RNA testing should be done.

FACTORS ASSOCIATED WITH PROGRESSION OF CHRONIC HEPATITIS C

Numerous host and environmental factors contribute to the presence or absence of histologic progression of HCV infection (Table 79-4). Identification of these factors is important because modifiable factors can be altered and high-risk patients can be treated promptly.

Table 79-4 Factors Associated with Progression of Hepatic Fibrosis in Patients with Chronic HCV Infection

ALT, alanine aminotransferase; HIV, human immunodeficiency virus.

Age at infection is a strong predictor of outcome, as discussed earlier. Natural history studies also suggest that progression of fibrosis is not linear over time and that the progression is slower at younger ages and increases over time, with the greatest acceleration after the age of 50 years.¹⁵⁹ This phenomenon likely explains some of the discrepancies seen in natural history studies. Accelerated fibrosis seen in older persons is independent of the age at acquisition. The mechanisms behind the accelerated rate of progression of fibrosis with aging are poorly understood.

Male gender is associated with more rapid progression to cirrhosis and HCC.^157,159 The reason for this association is not clear, and hormonal effects on fibrogenesis have been suggested. Estrogen inhibits proliferation and activation of hepatic stellate cells in vitro.¹⁶⁰ In addition, fibrosis appears to accelerate in postmenopausal women, and this acceleration may be attenuated with use of estrogen.^157,161,162

Race also has been implicated in disease progression. African Americans have a higher prevalence of HCV infection than whites,¹ but their risk of progression of the disease to cirrhosis is lower.^163,164 Because African Americans have a higher prevalence of disease, decreased response to therapy, and possibly decreased access to health care and liver transplantation, they have higher rates of HCV-related inpatient mortality.¹⁶⁵ Unlike African Americans, HCV-infected Hispanics have a higher rate of progression of fibrosis than do whites.¹⁶⁶ Whether the higher risk is explained by a higher prevalence of alcohol abuse, fatty liver disease, or other factors is unclear.

Alcohol use of greater than 20 g/day clearly increases the risk of progression of fibrosis and development of HCC in patients who are chronically infected with HCV.^167–171 Whether occasional or lesser amounts of alcohol also contribute to disease progression is less clear; however, in the absence of definitive evidence, most hepatologists recommend that HCV-infected patients avoid alcohol altogether.

In addition to alcohol, smoking cigarettes or cannabis leads to an increased rate of progression of fibrosis in HCV-infected patients.^172,173 Daily users of cannabis also have a higher risk of liver steatosis. In experimental models, cannabinoid receptor antagonists have been shown to decrease hepatic steatosis.¹⁷⁴

Several metabolic abnormalities and comorbid conditions, including insulin resistance or type 2 diabetes mellitus, obesity, and liver steatosis have been associated with accelerated progression of fibrosis.¹⁵⁷ The frequencies of insulin resistance and of type 2 diabetes mellitus are markedly increased in patients infected with HCV genotypes 1 or 4.^175–178 HCV infection results in down-regulation of IRS-1 and 2 through up-regulation of SOCS-3, an effect that is independent of other factors such as obesity that can also cause hepatic steatosis.^179,180 Either insulin resistance or hepatic steatosis alone increases the risk of progression of fibrosis.^179,180 Weight loss is associated with reductions in hepatic steatosis and the rate of fibrosis.¹⁸¹ Steatosis is also common in patients infected with HCV genotype 3, but this effect is virally induced and not associated with progression of fibrosis.^182,183 Patients with insulin resistance have a lower SVR to HCV therapy.¹⁸⁴

Mild-to-moderately increased hepatic iron stores are associated with more advanced fibrosis. A consistent relationship between C282Y or H63D heterozygosity and increased progression of fibrosis has not been established, however (see Chapter 74).^185,186 Reduction of hepatic iron concentrations does not reduce the risk of progression of fibrosis or improve the response to antiviral treatment.¹⁸⁷

Polymorphisms in genes implicated in the immune response and fibrogenesis have been studied extensively and may account for some of the variability in progression of fibrosis in patients who are otherwise similar, as reviewed elsewhere.¹⁵⁷ The candidate genes are numerous, and most studies are limited by small sample sizes and lack of reproducibility; larger scale, genome-wide investigations are in progress.¹⁸⁸

PATIENTS WITH PERSISTENTLY NORMAL SERUM AMINOTRANSFERASE LEVELS

Up to one half of anti-HCV-positive persons have a normal serum ALT level at any given time,¹ and the ALT level will remain normal for at least six months in 8% to 20% of them.^145,189 Serum HCV RNA levels are lower in these persons than in persons with elevated ALT levels, and they tend to have lesser degrees of hepatic inflammation and fibrosis. In one series, 86.5% of HCV-infected persons with a normal serum ALT level had METAVIR stage 0 or 1 fibrosis, 12% had stage 2 fibrosis, and just 1.5% had cirrhosis.¹⁸⁹ In a study of 159 patients with persistently normal serum ALT levels, the mean Ishak fibrosis score was 0.87.¹¹⁶ Therefore, these patients tend to have less fibrosis, with the implication that fibrosis progresses more slowly in these patients than in those with an elevated ALT level.^116,157,189 Progression to cirrhosis, although far less common in those with a normal ALT level, remains possible, and antiviral therapy may still be indicated.

IMMUNOCOMPROMISED PATIENTS

Studies of HCV-infected patients with humoral or cellular immune impairment have shown rates of progression to cirrhosis that are significantly higher than those observed in immunocompetent patients.^98,190,191 Given the apparent predominance of cellular immunity in the pathogenesis of chronic hepatitis C (see earlier), it is fascinating that HCV-infected patients with common variable immune deficiency (CVID), which is characterized by a humoral immune defect, have an accelerated rate of progression of fibrosis. In patients with CVID who received pooled plasma products before the initiation of HCV screening, the frequency of HCV infection is high, and the rate of progression of liver disease is accelerated in these patients.¹⁹⁰ During a follow-up period of approximately 10 years, 40% of 71 such patients progressed to decompensated cirrhosis.¹⁹⁰

Cellular immune impairment is far more common than humoral immune impairment. The most common cause is iatrogenic as a result of exogenous immunosuppression following transplantation. Unfortunately, many patients with cellular immune impairment already have HCV infection before becoming immunosuppressed. Chronic HCV infection is the most common indication for liver transplantation and is present, either alone or in association with alcoholic liver disease, in 40% of patients who undergo liver transplantation in the United States. Recurrence of HCV infection is almost universal in patients who undergo transplantation and who are positive for HCV RNA in serum. Typically, levels of viremia increase at least one log following transplantation. The clinical course in patients with recurrent HCV infection after liver transplantation is variable; overall, however, the disease progresses more quickly to cirrhosis than in nontransplanted persons. Rapid recurrence of HCV infection and graft loss resulting from fibrosing cholestatic hepatitis occur in 1% to 10% of patients, and most of these persons die within one year.⁹⁸ Of those without fibrosing cholestatic hepatitis, cirrhosis develops in 20% to 40% in five years.¹⁹¹ High serum HCV RNA levels before or early after liver transplantation, older age of the organ donor, severe and early recurrence of HCV infection after transplantation, and the use of high doses of prednisone or lymphocyte-depleting drugs to treat acute graft rejection are factors that most consistently are associated with a poor outcome.¹⁹¹ In patients in whom the disease progresses to cirrhosis after liver transplantation, decompensation occurs in 40% within one year, of whom 50% die in the following year.^191,192 As a result, long-term survival of patients with HCV infection who undergo transplantation is inferior to long-term survival of patients who undergo transplantation for other indications.¹⁹³ Fibrosing cholestatic hepatitis is generally accepted as a contraindication to retransplantation because of the rapid destruction of the new graft. For the same reason, most liver transplant centers are reluctant to consider retransplantation in patients with severe recurrent HCV infection within the first year. Because progression to cirrhosis is quicker after retransplantation, no consensus has been established as to whether retransplantation should be offered to a patient with recurrent HCV infection, even to a patient with slowly progressive disease (see also Chapter 95).¹⁹⁴

Transmission of HCV to other solid-organ transplant recipients has been described. Before testing for HCV infection became widely available, such transmission was thought to occur infrequently in patients who underwent transplantation. In one large study of cardiac transplant recipients,¹⁹⁵ survival of the 261 recipients of hearts from HCV-positive donors was significantly lower at 1, 5, and 10 years (83%, 53%, and 25%), respectively, than survival in recipients of hearts from HCV-negative donors (92%, 77%, and 53%, respectively). The additional risk of death was not affected by the recipients’ pretransplant HCV status or age. Excess mortality was attributable to liver disease and coronary vasculopathy.

Patients on hemodialysis and renal transplant recipients have a higher prevalence of HCV infection (up to 11% to 14% in some series in the United States) than that in the general population (1.6% in the United States).^1,79,196 The higher prevalence is attributed to a higher frequency of risk factors, particularly prior blood transfusion, and possibly nosocomial spread within dialysis units. Survival is lower in HCV-infected patients on hemodialysis than in uninfected hemodialysis patients, with a relative risk of death of 1.57.^197,198 Most mortality is related to HCC and complications of cirrhosis. Antiviral treatment is difficult in these patients, but the chance of response to treatment occurs in about 30% in genotype 1–infected patients, a surprisingly high rate considering that ribavirin is typically avoided in this group (see later).¹⁹⁹ The impact of HCV infection on renal transplant recipients is controversial. HCV is the leading cause of liver disease in the postrenal transplant setting, and the rate of histologic progression is more rapid than in immunocompetent persons.²⁰⁰ Although the effect of HCV infection on short-term survival appears to be minimal, early studies found that the rate of late survival is reduced because of infectious complications rather than complications of liver disease mellitus. Moreover, HCV increases the risk of postrenal transplant glomerulopathy and diabetes mellitus. Long-term patient and graft survival rates are lower in renal transplant recipients for reasons that require further study. Despite the risks, renal transplantation still confers a survival benefit over hemodialysis in both HCV-positive and HCV-negative recipients.

Heart transplant recipients with preexisting chronic HCV infection appear to do well, although the experience is limited.²⁰¹ On the other hand, as noted earlier, uninfected heart transplant recipients who receive a graft from an HCV-infected donor have poorer outcomes, with a reduction in the one-year survival rate from 92% to 83% and a reduction in the five-year survival rate from 77% to 55%.^195,201 Fibrosing cholestatic hepatitis also has been reported.⁹⁹ Few data are available on outcomes in lung and small bowel transplant recipients who are acutely or chronically infected with HCV.¹⁹⁶

Interferon is generally contraindicated in recipients of solid organ transplants other than liver transplants because of the risk of graft rejection and loss.¹⁹⁶ Therefore, treatment of HCV infection should be considered before solid organ transplantation is undertaken in transplant candidates with chronic hepatitis C (see later).

Liver disease is common in the first several weeks after allogeneic bone marrow transplantation (BMT), but most cases are the result of sinusoidal obstruction syndrome or graft-versus-host disease (see Chapter 34). Chronic hepatitis C is the most common cause of chronic liver disease after BMT. The cumulative frequency of cirrhosis has been estimated to be 11% after 15 years and 24% after 20 years.²⁰² HCV is a major cause of cirrhosis and of liver-related mortality in this population. Unlike the case of solid-organ transplant recipients, however, antiviral treatment appears to be safe in BMT recipients.²⁰³ Graft-versus-host disease is a contraindication to interferon therapy, and cytopenias may limit the doses of interferon-α or ribavirin that can be used safely.

HCV infection is common in HIV-infected persons because the two infections share similar routes of transmission. Approximately 25% of HIV-infected persons are coinfected with HCV, and up to 8% of HCV-infected patients are coinfected with HIV.²⁰⁴ Differences in the efficiency of transmission of HCV and HIV by parenteral or sexual routes explain the wide variation in HCV seropositivity among HIV-infected persons. Higher rates of coinfection are seen among injection drug users and recipients of blood transfusions than among sexual contacts of HIV-infected persons. HIV infection decreases the spontaneous rate of HCV clearance during acute HCV infection and leads to a correspondingly higher rate of chronic HCV infection. Before the introduction of HAART, HCV had little impact on morbidity and mortality in HIV-infected persons. The reduction in the rate of mortality from the acquired immunodeficiency syndrome (AIDS) since the introduction of HAART, however, has allowed the sequelae of chronic HCV infection to become apparent. Indeed, complications of liver disease, mostly related to hepatitis C, are now almost as common as AIDS-related complications, and a major cause of mortality, in patients with HIV infection.^204,205 Progression of hepatic fibrosis is accelerated in HIV-HCV-coinfected patients when compared with HCV-monoinfected patients. In a large study,²⁰⁶ 10.6% of HIV-HCV coinfected patients with hemophilia progressed to decompensated cirrhosis over a median of 12.1 years as compared with 1.6% of HCV-monoinfected patients with hemophilia.²⁰⁶ Potential mechanisms of increased progression of fibrosis have been investigated. HIV increases the production of TGF-β1 in the liver and leads to increased HCV replication.²⁰⁷ HIV-positive patients with a low CD4⁺ count have greater gastrointestinal bacterial translocation, leading to increased levels of lipopolysaccharide in the portal circulation and greater progression of fibrosis.²⁰⁸ HIV proteins may also cause activation of collagen production by hepatic stellate cells.²⁰⁹ In addition, steatosis and steatohepatitis are common in HIV-HCV-coinfected patients, and both are associated with an increased risk of advanced fibrosis on liver biopsy specimens.²¹⁰

All forms of immunosuppression, whether endogenous or exogenous, appear to result in more rapid progression of fibrosis in HCV-infected persons. More research is needed to elucidate the mechanisms and determine whether different immunosuppressive agents or regimens might make transplantation safer for HCV-infected persons.

GENERAL MEASURES AND TREATMENT OF ACUTE INFECTION

Because neither an effective vaccine nor post-exposure prophylaxis against HCV infection is available, major efforts should be placed on preventing HCV infection. Needle exchange and methadone programs have decreased the rate of HCV transmission among injection drug users.²¹¹ In addition, universal precautions, disposable equipment, and rigorous sterilization of reusable medical and surgical equipment have reduced nosocomial HCV infections. Nonetheless, HCV infection is common among patients, and exposure to these patients is common in hospital workers. In one study, the frequency of hepatitis C was 15-fold higher in hospitalized patients than in the general population.²¹² Needlesticks are common in the health care setting and are under-reported. Almost all surgical house staff will sustain at least one needlestick, and in nearly one half the needlestick will be from a high-risk patient.⁸⁴ Fortunately, the risk of transmission of HCV is about 0.3% when exposure occurs from hollow bore needles used to draw patients’ blood, although deep injuries increase the risk of transmission.^83,213 Postexposure treatment with interferon-α has been used after occupational exposure to HCV, but the experience to date is uncontrolled and no benefit has been shown (not surprisingly given the low risk of transmission in this setting).²¹⁴

Although postexposure prophylaxis is not effective, early treatment of acute HCV infection is effective.^215–217 Treatment should be strongly considered in patients with acute HCV infection. Therapy with pegylated interferon alone should be started between weeks 8 and 12 after presentation if HCV RNA has not cleared spontaneously from serum by then.^216,217 The addition of ribavirin to pegylated interferon does not increase the SVR in patients with acute HCV infection.²¹⁵ Patients with acute HCV genotype 1 infection who are treated for 24 weeks have a greater than 80% chance of an SVR. A shorter duration of therapy may be acceptable for patients with acute HCV genotype 2 or 3 infection, but data are limited.

Because most patients with HCV infection are asymptomatic or minimally symptomatic, the vast majority of HCV-infected persons are not detected during acute infection. Therefore, screening of groups at high risk of HCV infection is recommended (see earlier). Persons at high risk include recipients of blood and blood products before 1992, past or present injection drug users (including those with a single exposure), persons with multiple sexual partners, patients on hemodialysis, infants of HCV-infected mothers, persons with occupational exposure to HCV-positive blood, and patients with persistently elevated serum ALT levels.¹ HCV-infected patients should be instructed to avoid sharing razors. In addition, “safe sex” practices, such as the use of latex condoms, should be encouraged in persons with multiple sexual partners.⁸⁷ Monogamous sexual partners who do not engage in high-risk sexual activity have a negligible risk of transmission.⁸⁶ In view of the low rate of vertical transmission, pregnancy and breastfeeding are not contraindicated in HCV-infected women.^88–90 HCV-infected patients are advised to undergo vaccination against hepatitis A and B because of the high risk of severe liver disease if superinfection with either of these viruses occurs.

IMMUNOPROPHYLAXIS

In contrast to hepatitis B, for which immunoprophylaxis or vaccination that results in a high level of envelope antibodies leads to protective immunity, the presence of anti-HCV in serum as a result of either administration of HCV-specific immunoglobulin or experimental vaccination does not prevent HCV infection effectively. HCV has an inherently high mutational rate that results in considerable heterogeneity in the envelope proteins and facilitates rapid escape from antibody recognition (see earlier). Therefore, traditional viral envelope or multiprotein vaccines have had limited success in preventing reinfection with homologous strains of HCV and no effect in preventing reinfection with heterologous strains of HCV. Monoclonal and polyclonal immunoglobulins have been used intra- and postoperatively in liver transplant recipients in the hope of avoiding reinfection of the graft, but this approach has been repeatedly unsuccessful.^218,219

Given these difficulties, work on developing an HCV vaccine has focused instead on stimulating both humoral and cellular immune responses against the virus.²²⁰ If a vaccine were able to produce both neutralizing antibodies and a cellular immune response, it might have a role as both a prophylactic and therapeutic vaccine. Several strategies have been used to create a vaccine. Combining HCV proteins with an adjuvant such as the Toll-like receptor agonist dipalmitoyl-S-glyceryl cystine lipid moiety elicit CD8⁺ T-cell responses.²²¹ Similarly, DNA vaccines lead to antibody production and cross-strain protective immunity by cytotoxic T lymphocytes in vivo. Dendritic cell vaccines have been created by transducing protein or transfecting viral constructs into dendritic cells. The source of the dendritic cells used and the mechanisms of maturation are crucial to their function. All of these approaches require further investigation to determine whether protective immunity is induced. Combinations of techniques are likely to be studied.

GOALS

The primary goal of therapy for HCV infection is eradication of the virus. A consequence of achieving this goal is prevention of liver-related deaths associated with the development of HCC and decompensated cirrhosis. SVR—the absence of detectable virus in blood 24 weeks after completion of therapy—is an excellent surrogate marker for the resolution of HCV infection. Seven retrospective follow-up studies that collectively included more than 500 patients, many of whom were immunosuppressed, followed for a mean of three and one half years found the risk of recurrent or new infection following SVR to be just 0.1% per year.^223–229 SVR is also associated with a reduction in hepatic inflammation, regression of fibrosis, and improvement in HRQL.^117,118 The risk of liver failure is essentially eliminated in patients with cirrhosis who achieve an SVR.^158,230,231 Although the risk of HCC after an SVR in patients with cirrhosis is reduced by more than one half, the risk is not eliminated, and therefore, screening for HCC must continue.¹⁵⁸

END POINTS

Although SVR is considered the endpoint of therapy, other indicators of response are often monitored during therapy because they may help guide and refine treatment (Figs. 79-7 and 79-8). A rapid virologic response (RVR), defined as undetectable HCV RNA in serum after the first 4 weeks of antiviral therapy, identifies those patients who are most sensitive to treatment and is associated with an 80% to 90% SVR rate in genotype 1–infected patients who complete 48 weeks of therapy or in genotype 2– or 3–infected patients who complete 24 weeks of therapy.²³² An early virologic response (EVR), defined as a greater than 2-log drop in viral load at 12 weeks of therapy, is needed to continue therapy beyond 12 weeks because the absence of an EVR predicts failure of treatment in more than 98% of cases.²³³ An EVR can be subdivided further into a complete EVR (cEVR), defined as undetectable HCV RNA in serum at 12 weeks of therapy, and a partial EVR (pEVR), defined as a greater than 2-log decrease in the level of HCV RNA in serum despite residual detectable HCV RNA after 12 weeks of therapy. An end-of-treatment response (ETR) is defined as undetectable HCV RNA in serum at the end of treatment; a small and variable proportion of patients with an ETR will relapse when treatment is stopped. The absence of an ETR is considered nonresponse to treatment.

Figure 79-7. Viral responses to therapy of hepatitis C virus (HCV) infection with peginterferon and ribavirin (beginning at week 0). Rapid virologic response (RVR) is defined as undetectable HCV RNA in serum at 4 weeks. Early viral response (EVR) is defined as a 2-log decline in HCV RNA levels from baseline; it can be further defined as a complete EVR (undetectable HCV RNA at week 12) or partial EVR (HCV RNA still detectable at week 12 but undetectable by week 24) or a partial viral response (a 2-log decline in HCV RNA levels by week 12 but with residual virus detectable at week 24). A null response (or nonresponder) signifies failure to achieve an EVR.

Figure 79-8. Viral responses to therapy of hepatitis C virus (HCV) infection with peginterferon and ribavirin (beginning at week 0). Sustained virologic response is undetectable HCV RNA in serum six months after discontinuation of therapy (at 48 weeks) for HCV infection. Relapse is a return of HCV RNA in serum after discontinuation of therapy. A null response (or nonresponder) signifies failure to achieve an EVR.

DRUGS

Interferon-based regimens are, and for some time will continue to be, the cornerstone of antiviral therapy for HCV infection. Interferons are naturally occurring glycoproteins that exert a wide array of antiviral, antiproliferative, and immunomodulatory effects. Pegylated interferons consist of interferon bound to a molecule of polyethylene glycol (PEG) of varying length. The large size of the molecule increases the half-life of the interferon, thereby allowing once-weekly dosage. Two pegylated interferons are licensed for use in the United States and elsewhere. The first is 40-kd peginterferon alfa-2a, which is used in a fixed dose of 180 µg per week. The second is 12-kd peginterferon alfa-2b, which is prescribed according to the patient’s body weight in a dose of 1.5 µg/kg per week. Pegylated interferons have replaced standard interferon, used in the past, and have resulted in a significant increase in the SVR.

Ribavirin is an oral guanosine analog with activity against DNA and RNA viruses. When ribavirin is used in combination with interferon, the ETR improves and the relapse rate decreases. Several mechanisms to explain the synergistic effect of ribavirin when administered in combination with interferon have been proposed, including (1) alterations of the cytokine milieu leading to a change from a type 2 T-helper cell (Th2) to a Th1 immune response; (2) depletion of intracellular guanosine triphosphate through inhibition of the host enzyme inosine monophosphate dehydrogenase (IMPDH); (3) inhibition of the action of the HCV RNA-dependent RNA polymerase; and (4) induction of lethal mutagenesis during HCV RNA replication.²³⁴ Ribavirin generally is well tolerated, although it results in a dose-dependent hemolytic anemia. The dose administered is based on the patient’s weight, and the patient’s hemoglobin level must be monitored during treatment. Furthermore, in patients with a history of cardiopulmonary disease who cannot tolerate a sudden fall in the hemoglobin level, ribavirin must be used with caution, if at all. In addition, ribavirin is teratogenic; patients taking ribavirin and their partners are required to avoid pregnancy during therapy and for six months after cessation of the drug. Ribavirin has a long cumulative half-life in serum and is excreted by the kidneys; as a result it can lead to severe side effects, particularly hemolysis, in patients with kidney disease. The dose of ribavirin must be adjusted for renal function, and the drug should be administered with extreme caution to patients with a creatinine clearance less than 50 mL/min. Ribavirin is not removed by hemodialysis.

EFFICACY

The current standard of care for the treatment of HCV infection is the combination of a pegylated interferon administered subcutaneously once per week and ribavirin taken orally every day. A treatment algorithm is depicted in Figure 79-9. The dose of interferon is the same for all HCV genotypes, but the dose of ribavirin is based on the patient’s weight for genotypes 1 and 4 (13.3 mg/kg/day divided twice daily) and is fixed at 800 mg per day (in two divided doses) for genotypes 2 and 3. Treatment is administered for 48 weeks in patients with genotype 1 or 4 infection and 24 weeks in those with genotype 2 or 3 infection. In genotype 1–infected patients, treatment should be stopped if an EVR is not achieved. The SVR in genotype 1–infected patients is 42% to 52%.^6,7,222 In the Individualized Dosing Efficacy versus Fixed Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) trial, 3070 genotype 1–infected patients were randomized to one of the two pegylated interferons, and no difference in SVR was noted between the two formulations.²³⁵

Figure 79-9. Algorithm for the treatment of hepatitis C virus (HCV) infection. Patients infected with HCV genotype 2 or 3 and with a low viral load (level of viremia <400,000 IU/mL) may be treated with pegylated interferon (PEG-IFN) and weight-based ribavirin (RBV) for 12 to 16 weeks, with sustained virologic response (SVR) rates similar to those for patients treated for 24 weeks with PEG-IFN and 800 mg/day of RBV; either regimen is acceptable for this group. Patients at higher risk of relapse or nonresponse (those with genotype 1 or with cirrhosis or a high viral load) should not be considered for a shortened course of therapy. Patients with HCV genotype 1 infection and advanced fibrosis (stage 3-4 according to the METAVIR system) should be treated, but patients infected with genotype 1 who have stage 0-2 fibrosis may not require immediate therapy. (Dotted arrow indicates that treatment is an option in these patients.) The viral load should be checked at weeks 4 and 12 of treatment because the likelihood of response is determined by the viral load at these time points (see Figure 79-7). cEVR, complete early virologic response; pEVR, partial early virologic response; RVR, rapid virologic response; IU, international units.

(Based on Mangia A, Minerva N, Bacca D, et al. Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial. Hepatology 2008; 47:43-50; Pearlman B, Ehleben G, Saifee S, et al. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1–infected slow responders. Hepatology 2007; 46:1671-4; Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357:124-34.)

Higher doses of pegylated interferon or ribavirin may be helpful in some patients. In one study,²³⁶ patients with HCV genotype 1 infection, high viral load, and a weight greater than 85 kg—all factors that predict a poor response to treatment—had a higher SVR when the dose of peginterferon alfa-2a or the dose of ribavirin was increased. In this difficult-to-treat patient population, peginterferon alfa-2a in a dose of 270 µg/week improved the SVR rate when compared with a standard dose of 180 µg/week. When higher doses of ribavirin are used (15.2 mg/kg/day) in genotype 1–infected patients, the relapse rate decreases (from 38% for standard-dose to 8% for high-dose ribavirin); however, hemolysis can limit treatment with high doses of ribavirin.^236,237

Some patients may not require the standard duration of treatment to achieve an SVR. Patients with HCV genotypes 2 or 3 infection may achieve an SVR in some cases with just 12 to 16 weeks of treatment.^238–240 If a truncated course of treatment is anticipated, the patient should be given a ribavirin dose based on weight rather than a fixed dose of 800 mg/day and should only be treated with a shortened course if an RVR is achieved.²⁴¹ In general, patients with HCV genotype 1 infection should not have the treatment duration shortened, even if they achieve an RVR because SVR rates are about 10% less than those that follow a full year of therapy. Occasionally, however, drug intolerance may make a shorter course of treatment preferable.^242,243

A longer than standard course of therapy appears to be helpful in genotype 1–infected patients who have a slow response to antiviral therapy. In patients with a pEVR, extending the duration of therapy from 48 to 72 weeks improves the SVR rate from 30% to 45.5% (with use of weight-based ribavirin).²⁴⁴ Furthermore, if genotype 1–infected patients are unable to tolerate the full dose of ribavirin, extending treatment to 72 weeks increases the SVR rate from 32% to 45%, a rate similar to that for 48 weeks of treatment with a weight-based dose of ribavirin and pegylated interferon.²⁴⁵

Mangia and colleagues examined the effect of tailoring the duration of treatment–either longer or shorter than usual—to the time when HCV RNA first became undetectable in serum. They randomized patients to 48 weeks of therapy or a variable length of therapy of 24, 48, or 72 weeks based on a first negative HCV RNA result at weeks 4, 8, and 12, respectively.²⁴⁶ If HCV RNA was negative in serum at week 4, the SVR rate was 87% with 48 weeks and 77% with 24 weeks of therapy. When HCV RNA became negative after eight weeks, all patients received 48 weeks of treatment, and the SVR rate was 70% to 72%. When the HCV RNA first became undetectable at week 12, the SVR rate was 38% with 48 weeks and 64% with 72 weeks of therapy.

FACTORS THAT PREDICT A SUSTAINED VIROLOGIC RESPONSE

The best predictor of response to pegylated interferon and ribavirin is the rate of the initial fall in serum HCV RNA levels during treatment. The highest SVRs occur in patients with an RVR, followed respectively by those with a cEVR, those with a pEVR, and those without an EVR. Patients are usually interested in an estimate of their chances of a response before making a decision to proceed with therapy. Pretreatment factors associated with a greater chance of an SVR include infection with non-genotype 1 HCV, a low baseline serum HCV RNA level, absence of bridging fibrosis or cirrhosis on a liver biopsy specimen, age younger than 40 years, absence of obesity, lack of hepatic steatosis or insulin resistance, absence of HIV infection, and white race (Fig. 79-10). Although the likelihood of an SVR is marginally lower in patients without these favorable factors, patients should not be discouraged and treatment should not be withheld because of the presence of any or all of these factors.

Figure 79-10. Sustained virologic response to pegylated interferon and weight-based ribavirin in relation to patient and virus characteristics. AA, African American; cEVR, complete early virologic response; high viral load ≥400,000 IU/mL; HOMA, homeostatic model assessment, a measure of insulin resistance (higher value indicates greater insulin resistance); IU, international units; low viral load, <400,000 IU/mL; pEVR, partial early virologic response; RVR, rapid virologic response. *METAVIR system.

Of known pretreatment variables, the most powerful predictor of a response to treatment is the viral genotype. Genotype 2 is the most responsive to therapy. Response rates for genotype 3 infections are close to those of genotype 2, although genotype 3–infected patients with a high viral load have been shown to have lower response rates (86% for those with a serum HCV RNA level less than 600,000 IU/mL and 70% for those with a HCV RNA level of 600,000 IU/mL or greater).²⁴⁷ Genotype 4 infection is associated with an SVR similar to that for genotype 3 infection but requires drug doses and a duration of therapy similar to those for genotype 1 infection. Of the common HCV genotypes, HCV genotype 1 is the least responsive to therapy.

Pretreatment viral load also predicts the SVR. Studies have used different cutoff values to define a “low” viral load, with a range of <400,000 IU/mL to <800,000 IU/mL. A low viral load has consistently been associated with a higher SVR, independent of HCV genotype.^241–243246

Obesity, insulin resistance, and hepatic steatosis all decrease the chance of SVR.¹⁸⁴ These factors appear to affect the SVR independently. Weight reduction leads to an improved SVR to HCV therapy.

African Americans respond poorly to standard therapy for HCV infection, with SVR rates ranging from 19% to 28%.^248–250 African Americans have a higher proportion of genotype 1 infections than do whites, but this difference does not explain the difference in SVR rates. Some evidence suggests that African Americans have improved response to higher doses of interferon.²⁵¹

Advanced hepatic fibrosis is a negative predictor of SVR to therapy.²⁵² Patients with advanced fibrosis, however, are most in need of antiviral therapy and should be treated. Patients who have advanced fibrosis should expect a 10% reduction in SVR compared with patients who do not have advanced fibrosis.¹⁵⁸ Thrombocytopenia and neutropenia occur more frequently in these patients and may necessitate a reduction in the dose of pegylated interferon or discontinuation of therapy, further limiting the success of therapy in cirrhotic patients (see later).

Finally, strict adherence by the patient to the prescribed regimen improves the likelihood of an SVR, and compliance must be emphasized at each visit. Adherence to therapy appears to be particularly relevant in the first months of therapy; the impact of a reduction in dose is less if it occurs after an RVR has been achieved.^253,254

INDICATIONS AND CONTRAINDICATIONS

Antiviral therapy should be considered in all patients with chronic hepatitis C. In most cases, the decision as to whether or not to proceed with treatment is based on the patient’s desire and need for therapy. The degree of need is a subjective risk-benefit or cost-benefit decision that is made after considering the histologic stage of disease, presence or absence of favorable factors for a response to treatment, and comorbid conditions that might preclude any potential benefit of eradication of the virus. As treatments have become more effective, these decisions have become easier, and more patients have been considered to be appropriate candidates. Physicians who are not comfortable with administering and monitoring the therapy should refer patients to a gastroenterologist or hepatologist experienced in treating patients with hepatitis C.

The best time to treat a patient with chronic hepatitis C is before the development of cirrhosis because response rates are better and the risk of later complications of cirrhosis can be eliminated if treatment is successful. Treatment of patients with decompensated cirrhosis can still be successful but should only be undertaken by an experienced clinician. Managing patients with decompensated cirrhosis who are treated for HCV infection is labor intensive and requires reductions in dose because of cytopenias in 50% to 75% of cases as well as administration of growth factors in some cases; however, the treatment is generally poorly tolerated. Many prescribers prefer to begin with low doses of both drugs and increase the dose as tolerated by the patient.²²⁴ The chance of an SVR is low in patients with decompensated cirrhosis (13% in those with genotype 1 and 50% in those with genotype 2 and 3 infections).²²⁴ Nonetheless, the risk-benefit ratio clearly favors treatment in most of these cases. If these patients subsequently require liver transplantation, those who have achieved an SVR will avoid recurrence of HCV infection.²²⁴

Relative and absolute contraindications to interferon and ribavirin therapy are listed in Table 79-5. In general, more patients with relative contraindications to treatment have been treated successfully as practitioners have gained experience and familiarity with the treatment. Many relative contraindications to therapy may resolve over time or as a result of a specific intervention. A few absolute contraindications remain. Because ribavirin is a teratogen, unwillingness of the patient and his or her partner to practice adequate contraception and avoid pregnancy during treatment or for six months after the discontinuation of therapy is an absolute contraindication to starting or continuing treatment. Any severe or uncontrolled psychiatric condition is considered an absolute contraindication to therapy. If a patient’s psychiatric disorder is treated appropriately and is stable, however, the patient may become a candidate for HCV therapy. Severe cardiac or pulmonary disease is an absolute contraindication to HCV therapy because of the risk of worsening tissue hypoxia if severe hemolytic anemia occurs because of ribavirin. Moreover, in most patients with severe comorbid disease, successful antiviral therapy would offer no survival benefit. Patients with an underlying autoimmune condition are at risk of experiencing an exacerbation of the condition on pegylated interferon. Although previously considered an absolute contraindication, an autoimmune disorder should probably be considered a strong relative contraindication, and the risk of an exacerbation of the underlying autoimmune disease must be weighed against the potential benefit of clearing the HCV infection.

Table 79-5 Contraindications to Therapy with Pegylated Interferon and Ribavirin

MONITORING AND SAFETY

Before antiviral therapy is started, baseline liver biochemical test levels, a complete blood count (CBC), and a thyroid-stimulating hormone (TSH) level should be obtained. A pregnancy test is required in women before ribavirin is initiated. The HCV genotype and serum HCV RNA level are necessary to determine the dose of ribavirin and duration of therapy (see earlier).

Most hematologic side effects, particularly hemolytic anemia, occur within the first month of therapy, and initially a CBC should be performed weekly. Approximately 10% of patients will have a fall in hemoglobin levels to less than 10 g/dL, with a mean decrease of approximately 3 g/dL. After the first month, a serum ALT level and a CBC should be obtained monthly, and a TSH level should be obtained every three months. Drug doses should be reduced according to the severity of side effects.

A serum HCV RNA level should be obtained at baseline in all patients. Assessment of the decline in HCV RNA level during treatment predicts the likelihood of an SVR, can be used to determine the duration of therapy (see earlier), and is essential for determining treatment failure in genotype 1–infected patients. Therefore, quantitative HCV RNA levels should be drawn at baseline and at weeks 4 and 12. If HCV RNA is still detectable in serum at week 12, a level should also be drawn at week 24. If the HCV RNA level has not fallen by at least 2 logs (99%) after 12 weeks of treatment or is still detectable at week 24, treatment should be stopped. Use of the serum HCV RNA level at week 12 to indicate an EVR does not apply to patients with genotype 2 or 3 infection. The HCV RNA level should be measured at the end of treatment in all patients. If HCV RNA is undetectable, a level should be repeated six months after completion of therapy to determine whether an SVR or relapse has occurred. If an SVR is achieved, HCV RNA testing should be performed annually for at least two years. In nonresponders or relapsers in whom no additional treatment is considered, follow-up testing should be similar to that in patients who receive no treatment, with at least yearly check-ups and laboratory testing and a repeat liver biopsy every four to five years to assess disease progression, particularly if retreatment is considered.

Drugs are discontinued consequent to an adverse event or laboratory test abnormality in approximately 5% and 16% of patients who receive a combination of pegylated interferon and ribavirin for 24 and 48 weeks, respectively.^6,7,222,255 A reduction in the dose of pegylated interferon is required in 26% to 36% of patients and of ribavirin in 19% to 38%, depending on the initial dose and anticipated duration of therapy. Neutropenia, anemia, and thrombocytopenia are the most frequent reasons for reductions in dose. To ensure maximal response rates, dose reductions should be avoided, and the patient’s adherence to therapy should be encouraged.

The most frequent side effects of interferon include flu-like symptoms (in greater than 90% of patients) and alopecia (in 10% to 30%). Flu-like side effects are common but usually do not necessitate dose adjustments. Other adverse events include depression and hypothyroidism or hyperthyroidism. Because adherence to therapy is an important factor in optimizing efficacy, the various drug-related toxicities—in particular, psychiatric symptoms and thyroid dysfunction—should be managed medically as soon as they are detected.

With ribavirin, anemia, cough, pharyngitis, insomnia, dyspnea, pruritus, rash, nausea, and anorexia are the most common side effects. The most serious side effects are anemia and teratogenic effects. Hemolytic anemia is reversible and usually resolves within the first month after therapy is stopped. If anemia is severe or slow to recover, the patient’s iron stores should be assessed by laboratory testing.

Administration of hematopoietic growth factors (e.g., erythropoietin, filgrastim) may enable a patient to continue full-dose pegylated interferon and ribavirin. Use of growth factors may improve the patient’s subjective well-being but has not been shown to have an effect on response to antiviral treatment.²⁵⁶

RETREATMENT

The decision to retreat a patient who failed to respond to an earler course of antiviral therapy should take into consideration the previous regimen used, the appropriateness of the doses given throughout the course, the patient’s ability to tolerate therapy, and the response to treatment, especially whether and when HCV RNA became undetectable. Generally, retreatment with the same regimen, even with a different brand of interferon, is not justified. In nonresponders to an initial course of therapy consisting of either standard interferon monotherapy or standard interferon and ribavirin, the response rate to retreatment with pegylated interferon and ribavirin is 21% to 28% and 12% to 29%, respectively (Fig. 79-11).^257–259 Persons who relapsed after a course of standard interferon alone or a combination of interferon with ribavirin achieve an SVR rate with pegylated interferon and ribavirin of 40% to 58% and 42%, respectively.^257–259 Response rates are higher in patients who are infected with genotypes 2 and 3, have lower baseline levels of serum HCV RNA, and have lesser degrees of hepatic fibrosis.

Figure 79-11. Sustained virologic response rate to retreatment with pegylated interferon and weight-based ribavirin in HCV genotype 1–infected patients who had been treated previously and either did not respond (nonresponders) or relapsed (relapsers). IFN, standard interferon; PEG, pegylated interferon; RBV, ribavirin.

Other strategies for retreating nonresponders include use of higher doses of drugs or maintenance therapy. In the prospective Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy (DIRECT) trial, 343 patients, who were previous nonresponders to pegylated interferon and ribavirin, were randomized to interferon alfacon-1, a non-pegylated recombinant interferon, 9 mg or 15 mg daily, and ribavirin for 48 weeks.²⁶⁰ The SVR rates were 5% and 9%, respectively.²⁶⁰ In the Retreatment with Pegasys Plus Ribavirin in Patients Not Responding to Prior Peg-Intron/Ribavirin Combination Therapy (REPEAT) trial, 942 nonresponders to pegylated interferon and ribavirin were randomized to pegylated interferon and ribavirin for 48 or 72 weeks. A subset of each group also received a higher (induction) dose of interferon for the first 12 weeks. The SVR rate was 7% to 9% in the patients in the 48-week arms and 14% to 16% for those in the 72-week arms.²⁶¹ The use of an induction dose made no difference.

Maintenance therapy for nonresponders to pegylated interferon and ribavirin with low-dose (e.g., half of the usual dose) pegylated interferon has been studied in two large randomized prospective trials.^155,262 In the Colchicine versus Peg-Intron Long-Term (COPILOT) trial, a decrease in the frequency of variceal hemorrhage was observed in treated patients in the subset with portal hypertension, but no differences in the frequency of liver failure, liver transplantation, HCC, or liver-related death after four years were observed.²⁶² In the HALT-C trial (see earlier), no differences in these end points were observed after three and one half years.¹⁵⁵ Although neither study was adequately powered to detect a benefit in the subset of patients in whom HCV RNA was suppressed throughout therapy, the conclusion can be drawn that maintenance therapy with low-dose peginterferon confers no benefit in nonresponders to full-dose therapy.

HIV-HCV COINFECTED PATIENTS

Patients with HIV-HCV coinfection probably progress more rapidly to cirrhosis than do HCV-monoinfected patients, and therefore treatment of HCV infection should always be considered in this group.²⁶³ Patients are at even higher risk of progression of fibrosis if they are female, older than age 33 years, have an increase in the CD4⁺ count of less than 100/mm³ with HAART, continue to have a detectable HIV viral load during antiretroviral therapy, or have untreated HCV infection.

SVR rates were lower in HIV-HCV coinfected patients in clinical trials than in HCV-monoinfected historical controls.^264–266 SVR rates with pegylated interferon and ribavirin (800 mg/day) for 48 weeks are 44% to 73% in genotype 2– or 3–infected patients and 14% to 29% in genotype 1– and 4–infected patients.^264–266 One reason for a lower SVR in coinfected patients is the use of lower doses of ribavirin in most of the studies. In one study,²⁶⁷ however, standard weight-based dosing of ribavirin was used, and the SVR rate in genotype 1–infected patients was 35%. No doubt other factors played a role in the lower response rates, including high dose-reduction and drug-discontinuation rates and the presence among study subjects of factors that predict a poor response to treatment, including a high viral load, preponderance of genotype 1, a high rate of advanced hepatic fibrosis, concurrent alcohol use, and a high proportion of African Americans. Despite a lower SVR among HIV-HCV coinfected patients, however, an RVR is still associated with a high SVR, and failure to achieve an EVR signifies nonresponse.²⁶⁸ The safety and efficacy of pegylated interferon and ribavirin have not been established in patients with a CD4⁺ count less than 200/mm³.²⁶⁹ Ideally, therapy for HCV infection should be started before antiretroviral therapy for HIV is initiated. When HCV therapy cannot be started first, zidovudine, stavudine, and didanosine should not be used in combination with ribavirin because of the additive risk of mitochondrial toxicity. Contraindications to antiviral therapy for HCV infection in HIV-HCV-coinfected patients do not differ from those for monoinfected patients.

LIVER TRANSPLANT RECIPIENTS

Complications of chronic hepatitis C are the most common indication for liver transplantation (see Chapter 95). Patients who have detectable HCV RNA in serum at the time of liver transplantation almost universally experience reinfection of the allograft. Therefore, therapy with interferon and ribavirin should be considered in cirrhotic patients, preferably before liver failure or HCC occurs. Treatment is difficult to tolerate in this setting, and response rates are poor when cirrhosis is decompensated (see earlier). Another option in these patients is to initiate antiviral treatment after transplantation. Preemptive therapy of all HCV-infected patients within the first few weeks after transplantation is associated with substantial toxicity and a low chance of an SVR; it is not recommended.²⁷⁰ Still another option is to follow the patient expectantly post-transplantation and begin antiviral therapy when surveillance liver biopsy specimens demonstrate progression of disease, usually to grade 3 inflammation or stage 2 fibrosis. Often, this degree of liver injury occurs at least one year post-transplantation, but initiating treatment before then is not contraindicated. Treatment is better tolerated more than one year post-transplantation, but reductions in drug doses are required in most patients. Few patients tolerate full doses of ribavirin because of the renal dysfunction associated with calcineurin inhibitors. Nonetheless, 23% to 26% of genotype 1–infected patients achieve an SVR with 48 weeks of pegylated interferon and ribavirin. The SVR rate may be higher than 80% in patients infected with HCV genotype 2 or 3.^270–272 Although patients tolerate therapy poorly and SVR rates are low, a survival advantage has been demonstrated for patients who achieve an SVR compared with those who remain viremic.²⁷³

Although triple therapy with pegylated interferon, ribavirin, and a protease inhibitor will likely become available to nontransplant patients with HCV infection in the near future (see later), protease inhibitors such as telaprevir alter the metabolism of immunosuppressants. Therefore, transplant recipients are unlikely to benefit from these newer agents, at least initially.

FUTURE THERAPIES

A greater understanding of the HCV replication machinery has led to the identification of numerous potential drug targets. Several HCV-specific protease and polymerase inhibitors are in clinical trials, and two of the former class of agents are in phase III trials. These drugs promise to improve the chances of eradication of HCV in coming years. Nonetheless, the same issues that have plagued these classes of drugs in the treatment of HIV infection, including intolerance and viral resistance, will be important considerations in the treatment of HCV infection as well. Therefore, initial trials have used these novel agents in combination with pegylated interferons and ribavirin to reduce the chances of drug resistance and viral breakthrough during treatment.

Several inhibitors of the NS3/4A serine protease are currently in clinical trials. Telaprevir (VX-950) and boceprevir (SCH503034) are the two that are furthest along in development. Initial monotherapy studies demonstrated early selection of preexisting drug-resistant strains of the HCV virus, particularly if the dose of the drug was insufficient or the dosing interval was greater than eight hours.²⁷⁴ The combination of peginterferon alfa-2a and ribavirin with telaprevir, given orally three times a day for 12 weeks, followed by 12 weeks of peginterferon alfa-2a and ribavirin, in previously untreated genotype 1–infected patients led to a rapid reduction in serum HCV RNA levels that prevented the emergence of resistance and resulted in an SVR rate of 61%, compared with 41% in those treated with pegylated interferon and ribavirin alone for 48 weeks (standard treatment).²⁷⁵ A second trial in previously untreated genotype 1-infected patients showed an SVR rate of 68% with the 24-week triple-drug regimen and an SVR rate of 48% with standard treatment.²⁷⁶ Ribavirin remains a critical component of the regimen because telaprevir and pegylated interferon dual therapy produce an inferior SVR compared with triple-drug therapy. Side effects of telaprevir include rash, gastrointestinal complaints, and anemia, although most are mild to moderate and do not require a dose reduction or discontinuation.

Boceprevir, a second protease inhibitor, is also given orally three times a day, and, in combination with peginterferon alfa-2b and ribavirin, led to an SVR rate of 55% in previously untreated genotype 1–infected patients after 28 weeks of therapy.²⁷⁷ Because of concerns about resistance, a second group of patients was treated with a 4-week lead-in phase of pegylated interferon and ribavirin to reduce HCV RNA levels before the introduction of boceprevir. The SVR rate was 57% after completion of an additional 24 weeks of triple-drug therapy.

A second target of HCV replication, the RNA-dependent RNA polymerase, was inhibited by R1626, a nucleoside analog, given orally twice daily, in combination with peginterferon alfa-2a and ribavirin.²⁷⁸ Triple-drug therapy in previously untreated genotype 1–infected patients resulted in undetectable HCV RNA levels in serum at four weeks in 74% of patients, compared with 5% of patients treated with standard therapy. Another orally bioavailable nucleoside analog inhibitor of the RNA-dependent RNA polymerase, R7128, reduced serum HCV RNA levels in patients by 5.1 log when used in combination with pegylated interferon and ribavirin, compared with a 2.5-log reduction with standard treatment, after 28 days.²⁷⁹ Other non-nucleoside inhibitors target allosteric sites on the RNA-dependent RNA polymerase and lead to modest reductions in serum HCV RNA levels when given as monotherapy; studies of combination therapy with pegylated interferon and ribavirin have not yet been undertaken.

Another strategy for impairing viral polymerase function is to inhibit cyclophylin B, which facilitates attachment of HCV RNA to the replicase complex. The cyclophilin inhibitor DEBIO-025, given daily in combination with pegylated interferon, caused a 4.75-log drop in serum HCV RNA levels in 29 days, compared with a 2.49-log decline in HCV RNA levels with pegylated interferon alone and a 2.2-log decline in HCV RNA levels with DEBIO-025 alone.²⁸⁰ Other approaches to antiviral therapy include targeting the HCV helicase and viral assembly; these approaches to antiviral therapy are in the early stages of development.

Ultimately, combination therapy with several virus-specific agents, similar to the strategy used to treat HIV infection, will likely become the favored approach to treating HCV infection and hopefully will achieve eradication of the virus in most cases. Drug interactions, viral resistance, and drug side effects will all be major hurdles to overcome.