Hepatitis C: A review and update

CONTINUING

MEDICAL EDUCATION

Hepatitis C: A review and update Herbert L. Bonkovsky, MD,a,b and Savant Mehta, MDa Worcester, Massachusetts The hepatitis C virus is an RNA virus that is a major cause of acute and chronic hepatitis. It is contracted chiefly through parenteral exposure to infected material such as blood transfusions or injections with dirty needles. Those at highest risk for development of hepatitis C are injection-drug users, people who snort cocaine with shared straws, and health care workers who are at risk for needle-stick and other exposures. Although the incidence of acute hepatitis C infection has fallen dramatically in the United States during the past decade, the prevalence of infection remains high (approximately 2.7 million Americans) because chronic hepatitis C develops in about 75% of those infected. Both acute and chronic hepatitis C are asymptomatic in most patients. However, chronic hepatitis C is a slowly progressive disease and results in severe morbidity in 20% to 30% of infected persons. Chronic hepatitis C is associated with a host of extrahepatic manifestations, many of which may be seen by dermatologists. The most frequent of these are mixed cryoglobulinemia with leukocytoclastic vasculitis and porphyria cutanea tarda. (J Am Acad Dermatol 2001;44:159-79.)

Learning objective: At the conclusion of this learning activity, participants should be familiar with the essentials of the virology of the hepatitis C virus and the major features of the human diseases caused by hepatitis C viral infection; the extrahepatic manifestations of hepatitis C viral infection, with particular emphasis upon dermatologic manifestations, including leukocytoclastic vasculitis, porphyria cutanea tarda, and lichen planus; and the current methods of management of hepatitis C and its extrahepatic manifestations.

HISTORY AND OVERVIEW Although descriptions of diseases typical of epidemic or sporadic acute viral hepatitis date back to antiquity, clear descriptions of epidemics of enterically transmitted hepatitis (formerly called “infectious” hepatitis) and parenterally transmitted hepatitis (formerly called “serum” hepatitis) were first described within the past 100 to 200 years. The first clear association of blood transfusion with the development of hepatitis was not reported until 1943.1 Infectious serum and hepatitis (hepatitis A and B) The classic studies of Saul Krugman and colleagues at the Willowbrook State School in New York established transmissibility of hepatitis by means of a viral agent in human plasma and clearly delineated

From the Departments of Medicinea and Biochemistry and Molecular Biology,b University of Massachusetts Medical School. Supported by a National Institutes of Health grant (RO1DK 38825) and contract (No1-DK-9-2326) (to H. L. B.). Reprints not available from authors. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/2/109311 doi:10.1067/mjd.2001.109311

Abbreviations used: ALT: CHC: HCC: HCV: IFN: MC: PAN: PCT:

alanine aminotransferase chronic hepatitis C hepatocellular carcinoma hepatitis C virus interferon mixed cryoglobulinemia polyarteritis nodosa porphyria cutanea tarda

the clinical syndromes of infectious hepatitis and serum hepatitis.2 During the ensuing 30 years, many investigators tried unsuccessfully to identify the specific agents responsible for these forms of hepatitis. The key breakthrough was the identification of the Australia antigen by Blumberg in 1965, although its association with serum hepatitis was not established until 2 years later.3 Later, it was established that the Australia antigen was, in fact, the major protein of the surface coat of what is now called the hepatitis B virus (ie, the hepatitis B surface antigen). A few years after this, detection of a second virus associated with enterically transmitted epidemics was described by Feinstone, Kapikian, and Purcell.4 This virus was termed hepatitis A. 159

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Fig 1. Structure of HCV. (From Amgen, Inc. Used with permission.)

Non-A, non-B hepatitis (hepatitis C) Shortly after the identification of the hepatitis A and B viruses, it became clear that most cases of posttransfusional hepatitis could not be attributed to either of these agents. This led to the description of another form of hepatitis, called “non-A, non-B” hepatitis. An infectious origin for non-A, non-B hepatitis was strongly suspected, on the basis of clinical observations in humans who had received blood transfusions and of experimental observations in chimpanzees that had been inoculated with serum from patients with chronic non-A, non-B hepatitis. After an incubation period of 1 to 3 months, these chimpanzees developed all the clinical features of hepatitis, which often became chronic (lasting more than 6 months). In the early 1980s, the putative agent of non-A, non-B hepatitis was characterized as a filterable microorganism believed to be a virus, approximately 50 nm in diameter. Because its infectivity was abolished by treatment with chloroform, it was assumed to have a lipid envelope. It was also inactivated by exposure to formalin, heat, and ultraviolet light.5,6 These initial studies formed the basis for a molecular biologic approach for identifying and characterizing the etiologic agent responsible for the great majority of non-A, non-B viral hepatitis, now called the hepatitis C virus (HCV). The approach taken was to harvest viruses from large volumes of serum of one of the experimentally infected chimpanzees. Because the genomic nature of the putative virus was not known, both DNA and RNA were extracted and converted to complementary DNA (cDNA).

Restriction fragments of this cDNA were cloned into a recombinant bacteriophage vector to form a cDNA library, and these phages were then inserted into Escherichia coli capable of transcribing and expressing the peptides encoded by the restriction fragments. These expression products were screened with the use of sera from patients with chronic nonA, non-B hepatitis. It was assumed that the sera from such patients would contain antibodies against peptide products of the infectious agent. More than one million clones were screened in this way and 5 were found to be consistently and strongly reactive. Identification of other clones with overlapping regions of cDNA eventually allowed investigators to establish the sequence of the entire viral genome. This triumph of modern molecular biology and recombinant DNA techniques was first described in 1989.7,8 Hepatitis C viral structure and life cycle Our current understanding of the structure of the HCV is shown in Fig 1. It consists of a positive-sense, single-stranded RNA genome within a nucleocapsid. The nucleocapsid and RNA are packaged in an envelope, derived from host membranes, into which viral-encoded glycoproteins are inserted (the spikes and knobs shown in Fig 1). Based on density gradient analyses, two populations of virus have been described in sera of infected hosts. A high-density fraction is believed to be composed of free or immunoglobulin-bound viral particles, whereas a low-density fraction appears to be bound to low-density lipoproteins.9,10

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Image available in print version only

Fig 2. The genome of HCV. A, General organization. B, Genome showing sites of proteolytic cleavage by viral and host proteases. (Adapted from Davis GL. Hepatitis C. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Schiff ’s Diseases of the liver. 8th ed. Philadelphia: Lippincott, Williams & Wilkins; 1999. p. 793-823. Reprinted with permission.)

The structure of the genome of the HCV is typical of that of flaviviruses. It contains highly conserved 5´ and 3´ terminal regions that flank a large nucleotide open reading frame, which encodes a polyprotein of approximately 3300 amino acids (Fig 2, A). Within infected cells, this polyprotein is cleaved by both viral and host proteases to produce the protein products of the virus. In this way, the polyprotein, expressed from the open reading frame of the HCV, is processed cotranslationally and posttranslationally into at least 9 different polypeptides. These peptides have been given the names of the core peptide, the envelope peptides (E1 and E2), and a total of 6 nonstructural proteins (NS2, NS3, NS4a, NS4b, N5a, and NS5b). The core peptide has a sequence that is highly conserved. In contrast, the amino terminal end of the E2 protein contains two regions that exhibit marked amino acid variations among different viral strains (called genotypes) and even within a single genotype (giving rise to what have been called “quasispecies” of a single viral strain). These areas are termed the hypervariable regions (HVR1 and HVR2). HVR1 peptides are expressed on the surface of mature virions, and their high degree of variability is

probably one of the major reasons why the HCV escapes neutralizing antibodies and so often causes chronic infections. As shown in Fig 2, B, the nonstructural proteins include sites that act as serine proteases or metalloproteases that are capable of producing autocatalytic cleavage of the nascent viral polyprotein. Host proteases also cleave the polyprotein with the eventual formation of peptides that include a helicase and an RNA-dependent RNA polymerase. These latter enzymes play key roles in the replication of viral RNA, which is essential for production of new viruses. Our current understanding of the life cycle of the HCV is shown schematically in Fig 3. As is true for other RNA viruses, action of the RNA polymerase of the HCV introduces random nucleotide errors that the polymerase is not able to correct because it lacks a proofreading function. Because of the enormous rate of HCV replication, the frequency with which such errors occur is very high, estimated at between 1/100 to 1/1000 substitutions per nucleotide site per year.11 Many of these substitutions are lethal and therefore are not reproduced. Others do not result in changes in amino

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Fig 3. The life cycle of HCV. (Courtesy of L. Kaplan, MD.)

acids, whereas still others may decrease the ability of the virus to replicate or increase its susceptibility to elimination by the immune system. However, over time, other mutations can result in changes that allow the virus to replicate and to escape immune surveillance. The net result is that HCVs that infect humans are remarkably heterogeneous, with only about 70% similarity among all known isolates. This level of variability is similar to that of other known flaviviruses.12

currently the Simmonds classification continues to be most widely accepted and used. On the basis of considerations of geographic segregation and phylogenetic distances for genotypes 4 and 6, it has been suggested that these genotypes diverged and evolved in isolation beginning 500 to 2000 years ago. In contrast, it appears that the more common genotypes 1 and 2 evolved more recently, perhaps within the past 50 to 300 years, and have been spread widely by migration of infected hosts.14,15

Types and subtypes of hepatitis C When different HCV isolates have been analyzed further and their genomes sequenced (a lengthy and arduous process), it has been found that they can be subclassified into a finite number of strains or genotypes. Based on sequencing of relatively well-conserved regions (E1, NS4, or NS5), isolates of the same genotype have an average sequence similarity of 95%, with a range of 88% to 100%. Subtypes within the same genotype have an overall average sequence similarity of about 80%, whereas different genotypes have sequence similarities of the less well-conserved regions of only about 65% (range, 55%-70%). This has led to a classification scheme, first proposed by Simmonds et al,13 which is now widely accepted. According to this system, major genotypes are assigned arabic numbers and subtypes are assigned small letters (Table I). In other schemes, 10 or more types and up to 40 to 50 subtypes are proposed, but

EPIDEMIOLOGY Worldwide epidemiology Worldwide, it is estimated that there are approximately 170,000,000 persons infected with HCV.16 This is nearly 3% of the world population. In developed nations, prevalence rates of antibodies to HCV are generally less than 3%, whereas among volunteer blood donors they are less than 1%. In some highly endemic areas of the world (eg, in Egypt), the prevalence rates range from 10% to 30%.17 In the most highly endemic areas of the world, HCV infection is prevalent among persons older than 40 years but is uncommon in those younger than 20 years.18,19 This cohort effect suggests a time-restricted exposure, which in many instances appears to have been related to medical procedures (eg, vaccinations, parenteral drug treatment). A similar phenomenon has been reported in certain regions of Japan where, in one region, 45% of persons older than 41 years had

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Table I. Genotypes and subtypes of the hepatitis C virus Genotype/Subtype

% Patients in US

1a 1b

~50-60 ~15-20

1c 2a/b/c 3a/b 4 5 6

<1 ~10-15 ~4-6 <5 <5 <5

Comments

Difficult to eradicate with currently available therapies Difficult to eradicate with currently available therapies; 1b most prevalent in Europe, Turkey, Japan, Taiwan Widely distributed; respond best to currently available therapies Found mainly in India, Pakistan, Australia, Scotland Found mainly in Middle East, Africa Found mainly in South Africa Found mainly in Hong Kong, Macao

HCV infection, whereas in another, the prevalence in persons of the same age was only 2%.20 Traditional practices such as acupuncture with nonsterile needles and cutting of skin with nonsterile knives were identified as likely modes of transmission. Epidemiology in the United States In a landmark study in the United States between 1988 and 1994, serum samples from 21,241 persons 6 years or older who participated in the Third National Health and Nutritional Examination Survey (NHANES II) were tested for antibodies to HCV.21 The overall prevalence of positivity was 1.8%, corresponding to an estimated 3.9 million persons nationwide who had acquired HCV infection. Sixty-five percent of antibody-positive persons were 30 to 49 years old, and 74% were positive for HCV RNA, indicating that an estimated 2.7 million people in the United States were chronically infected, of whom 57% were infected with genotype 1a and 17% with genotype 1b. The strongest risk factors independently associated with HCV infection were illicit drug use and high-risk sexual behavior. Other factors independently associated with infection included poverty, having 12 or fewer years of education, or having been divorced or separated. Neither sex nor racial/ethnic group was independently correlated with HCV infection, although incidence rates were highest among nonwhite persons. The estimated annual incidence of newly acquired hepatitis C remained high throughout much of the 1980s, with an average rate of 50 per 100,000 (about 135,000 new cases per year), but declined by more than 80% between 1989 and 1993, down to an estimated 28,000 new cases per year (Fig 4). Although the number of cases of transfusion-associated acute hepatitis C declined significantly after 1985, this change has had little impact on overall disease incidence. The dramatic decline observed in 1989 is due mainly to a decrease in acute cases associated with injection drug use, the reasons for which are not clear.

Currently in the United States there are 8000 to 10,000 deaths per year from chronic hepatitis C, and it appears that the risk of complications of chronic hepatitis C, such as hepatoma, are increasing.22 Modes of transmission Transfusion of blood or blood products. When blood is transfused from an anti-HCV antibody-positive donor, more than 80% of the recipients will become infected with HCV.23 The high infectivity of direct intravenous administration of a large inoculum of HCV is also evident in the high HCV prevalences that are found in patients requiring repeated infusions of blood or blood products, such as persons with thalassemia and hemophilia. Several outbreaks have resulted from the use of contaminated blood products other than whole blood (eg, immunoglobulins and clotting factors). Before the introduction of routine screening for HIV and HCV antibodies and surrogate markers (serum alanine aminotransferase [ALT], anti–hepatitis B core antigen), approximately 17% of the HCV infections in the United States were caused by transfusion. Since the advent of routine screening of blood for antiHCV antibodies, the transmission of hepatitis C by blood product transfusion has decreased markedly and now causes fewer than 4% of the new HCV infections in the United States.24 Transmission through infusion of blood products still remains a remote possibility (<1 in 100,000) from patients who have not yet developed antibodies or who test negative by the currently available assays for HCV RNA because of the limited sensitivity of the tests. Illicit drug use. A majority of the new HCV infections now occurring in the United States and other developed countries are related to intravenous drug use. Since 1992, at least two thirds of the new HCV infections in the United States have been ascribed to such drug use, and similar data have been adduced for new HCV infections worldwide.22,25 Apparently, the transmission of hepatitis C occurs most often within the first few months of initiating illicit intravenous drug use.

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Fig 4. Annual incidence rates of new hepatitis C infections in the United States, 1982-1993. (From CDC; used with permission.)

Nosocomial transmission. Small outbreaks of HCV have been reported in hospitals. For example, in one Swedish hematology ward, 5 clusters of patients infected with identical or closely related viruses were found.26 The patients in each cluster had overlapping hospitalizations but did not have any common blood source. Transmission of infection has been well documented in hospitals within certain groups, especially patients undergoing long-term hemodialysis, in whom the yearly incidence of HCV infection (before the introduction of screening for hepatitis C and the introduction of universal precautions) was 4.5% to 6%.27 Receiving dialysis next to an HCV-infected patient was a risk factor, as was the duration of hemodialysis. Since the introduction of universal precautions and screening of blood products for HCV, the annual incidence of hepatitis C in hemodialysis units has been reduced to 0.44%.28 The incidence is even lower in patients who are receiving ambulatory peritoneal dialysis. Although in large epidemiologic studies the recent receipt of health care has not been identifiable as a risk factor for HCV transmission,22 transmission of HCV from health care providers to patients has also been documented. In one report, HCV infection was detected in 6 patients after they had had open-heart surgeries performed by a surgeon who was infected.29 All blood used for these patients was anti-HCV

negative. Five of 6 patients had a genetically similar, unusual HCV strain that was later also found in the surgeon. It was thought that the infection occurred as a result of penetration of gloves and skin of the surgeon, especially during wire closure of the sternum. Needlestick exposure also constitutes a risk factor for the transmission of HCV to health care workers. Two percent to 8% of needlestick exposures from HCV-infected patients are followed by the development of HCV infection in health care workers.30 Exposures involving hollow-bore needles account for most of these, although HCV infection has also been reported as occurring after solid-bore needlesticks or blood splashes into the conjunctivae.31 Not surprisingly, therefore, the prevalence of hepatitis C is higher in older health care workers who perform invasive procedures and have been in practice longer. Sexual transmission. The frequency of sexual transmission of HCV is low (~5%), unlike that of HIV transmission (10%-15%) or HBV transmission (~30%).32 Based on these data, the Centers for Disease Control and Prevention (CDC) have not recommended barrier precautions (eg, latex condoms) between stable, monogamous sexual partners when one is HCV positive. Emphasis instead should be placed on avoidance of potential exposure to blood (no sharing of razors, combs, or toothbrushes). Coinfection with HIV increases the risk of sexual transmission of HCV. In a study of 147 HCV-infected

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patients, 98 of whom were also HIV infected, the prevalence of anti-HCV antibodies was 9.2% in the partners of the HIV-infected index cases but only 4.1% in the partners of the HIV-uninfected index cases.33 Another study showed a transmission rate of 9.5% among HIV-positive persons as compared with zero if they were HIV negative.34 In addition to HIV, the severity of liver disease may also play a role in the risk of transmission. In one study, nearly 15% of household contacts of patients with HCV-related chronic liver disease due to HCV developed HCV positivity, as compared with no infections among the household contacts of 30 asymptomatic HCV-infected blood donors.35 Thus the stage of the liver disease, and not the length of relationship, may chiefly influence the risk of household transmission. Vertical transmission. The risk of perinatal transmission of HCV from mother to infant is low. In one study from Japan, the risk of HCV transmission from mother to infant was 6% in babies born to mothers with anti-HCV and 10% in babies born to mothers with HCV RNA.36 There was no risk of transmission if the maternal viral load in serum was less than 105 copies/mL. In contrast, for mothers with serum levels of viral HCV RNA more than 106 cm3/mL, the rate of transmission to newborns was 36%. HIV coinfection also plays a role. In 12 studies of 105 babies born to mothers with HCV plus HIV coinfection, 18% became infected with HCV, as against an incidence rate of 4.5% of among 310 babies born to mothers with HCV but without HIV. The higher HCV loads in patients infected with HIV may partly explain this. Cesarean section does not appear to decrease the risk for HCV transmission as it does in the case of hepatitis B, although the lower rate of perinatal vertical transmission of HCV means that very large prospective studies would be needed to provide statistically powerful data. Such studies have not been done. HCV transmission by breast-feeding is unusual. In a case-control study of 65 mother-infant pairs in whom mothers were anti-HCV positive, compared with 42 patients who were anti-HCV negative, 3 infants developed hepatitis C by 3 months of age.37 All 3 babies were born to symptomatic mothers with high serum viral loads, ranging from 2.5 × 108 to 4.5 × 109 copies/mL. The HCV genotypes were concordant within each of these 3 mother/baby pairs. These 3 infants were delivered by elective cesarean section at term and had been breast-fed regularly. On the basis of these data, asymptomatic mothers do not seem to transmit the infection by breast-feeding, although symptomatic women, especially with high viral loads, may pose some risk to their infants. Consensus rec-

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ommendations of the CDC do not proscribe breastfeeding by mothers with HCV infection. Household transmission of HCV remains an unlikely mode of transmission based on the currently available data, although one study reported a positive correlation with duration of exposure to the virus.38 Solid organ transplantation. If organ or bone marrow donors are HCV RNA positive, there are high rates of HCV infection among recipients of solid organs (liver, kidney, heart, lung) or bone marrow. This infection nearly always becomes chronic and leads to hepatitis in about half of the recipients.39 HCV infection has been transmitted by tissue transplantation of bone, ligament, and tendon allografts as well.40 Infection in recipients already infected with the HCV with a second strain of the virus from a donor organ has been demonstrated.41

NATURAL HISTORY OF HEPATITIS C INFECTIONS The study of the natural history of hepatitis C is confounded by the fact that both acute and chronic hepatitis C often produce no or only mild nonspecific symptoms. Thus it is difficult to date the onset of infection accurately. Although the acute infection is usually mild, in at least 75% of cases, chronic hepatitis develops. By convention, chronic hepatitis is defined as persistently abnormal serum aminotransferases (aspartate aminotransferase, ALT) for at least 6 months. In addition, some subjects with chronic HCV infection have persistently normal serum aminotransferases but have evidence of persistent infection as shown by detectable HCV RNA in serum and compatible histopathologic abnormalities on liver biopsies. In those with chronic hepatitis, cirrhosis often develops (~20%-50%) and may culminate in the development of liver failure or hepatocellular carcinoma (HCC). Acute hepatitis C After transfusion or accidental needlestick exposure, the incubation period for acute hepatitis C averages 6 to 7 weeks but may range from as short as 2 weeks to as long as 26 weeks. Among adults with acute HCV infection, only 30% to 40% have symptoms (usually mild) and/or develop jaundice. Acute hepatitis C infection is usually milder than, but otherwise indistinguishable from, other types of acute viral hepatitis (HAV, HBV), and serologic and virologic testing is necessary to establish the origin. The majority of asymptomatic patients with HCV infection will have fluctuating serum aminotransferase levels. Normalization of these levels may occur and may be followed later by elevations again, indicating chronic disease.

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Presentation of hepatitis C as fulminant hepatitis is rare. In one study HCV RNA was detected in 5 of 26 patients with fulminant hepatic failure,42 although it was not clear that HCV caused the hepatic failure. Hence acute hepatitis C infection is not believed to be a major cause of fulminant hepatic failure. Hepatic histopathologic features in acute hepatitis C are similar to those of acute hepatitis from other viral causes, although fatty change in hepatocytes is more commonly seen in acute hepatitis C. Other typical features are pleomorphism of hepatocytes, foci of lobular necrosis and inflammation, acidophilic (apoptotic) bodies, and portal tract inflammation with interface hepatitis (erosion of the limiting plates). Chronic hepatitis C The likelihood of development of chronic hepatitis C (CHC) is a function of several factors, including the virus itself, the mode of acquisition of infection, and the host immune response. Viral factors. HCV genotype is a factor that has been implicated in the evolution of CHC. In a study from Italy in 42 patients with diagnoses of acute hepatitis C who were followed up for up to 1 year, there was an overall rate of development of chronicity of 59.5%. However, this rate was 92% in persons infected with genotype 1b HCV. By multivariate analysis the age-adjusted odds ratio for development of chronicity after infection with genotype 1b, as compared with all other genotypes, was 14.4. Moreover, those with type 1b chronic infections had more severe histologic changes.43 This suggests that the HCV virus genotype 1b is independently associated with development of chronic hepatitis and greater likelihood of progression. Mode of acquisition. Large inocula of HCV, as in posttransfusion hepatitis C, are associated with more severe disease. For instance, in a study from France, 6664 patients were surveyed to identify epidemiologic factors that affect the severity of CHC. Among the patients enrolled, 21% had biopsy-proven cirrhosis. The prevalence of cirrhosis varied markedly according to the modes of transmission of HCV. It was significantly more frequent in recipients of blood transfusions (23%) than in users of illicit drugs (7%). Although the development of cirrhosis was directly correlated with disease duration, cirrhosis was more frequent in blood recipients than in drug users with similar durations of CHC.44 Host immune responses. There are obviously important factors in host immune responses, which also influence the development of chronic hepatitis C. For example, when 5 patients who spontaneously cleared HCV were compared with 10 who had per-

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sistent viremia, the quasispecies complexity was higher and the apparent immune pressure was lower in those with persistent viremia. The presence of both characteristics increased the likelihood of chronic infection.45 In another study, 142 patients with history of illicit drug use were followed up semiannually from 1988 through 1996. HCV infection was detected serologically in 43 (30%) of the participants over a median follow-up of 72 months. Spontaneous viral clearance was noted in 6 (14%) of the 43 who became infected, whereas viral persistence was observed in 37 (86%). Those who spontaneously cleared the virus were more likely to be Caucasian, to have developed jaundice (suggesting more severe acute hepatitis), and to have had a lower peak viral titer. However, the outcome for any given person could not be predicted reliably by analyses of these clinical features.46 These and other results indicate that the more vigorous the antibody and T-cell responses to acute HCV infection, the more likely will be spontaneous resolution of viral infection, and vice versa. Progression of CHC. Several studies have addressed the progression of CHC among patients with established chronic liver disease.47-50 The follow-up periods ranged from 4 to 11 years. Cirrhosis was found in 8% to 46% of the patients, and HCC developed in 11% to 19%. Given the fairly high rate of development of HCC, it can be presumed that the mortality rate would also be high. The two studies from Japan48,49 reported the development of HCC in 15% or 19% of 155 and 100 patients, respectively, as compared with the study from the United States, which reported this development in 11% of 131 patients. However, the duration of follow-up (4 years) was also shorter in this latter study.47 In a more recent study from Germany, 838 patients with CHC were followed up for 50 ± 27 months.50 During follow-up 62 patients died (31 from liver disease, 31 from other causes), and 12 needed liver transplantation. When compared with an age- and sex-matched control population, those with CHC had increased mortality mainly when cirrhosis was present at baseline and in patients who were younger than 50 years at entry. During followup, an additional 30 patients developed nonlethal complications of cirrhosis. By multivariate analysis, survival was decreased by the presence of cirrhosis, long duration of disease, history of intravenous drug use, and excessive alcohol consumption, whereas interferon therapy was associated with improved survival. The risk of HCC was increased by cirrhosis and to lesser degrees by long duration of infection and early elevations of serum bilirubin levels, even when cirrhosis was absent at diagnosis.

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Fig 5. Rates of progression of chronic hepatitis C to cirrhosis and hepatocellular carcinoma. (From Amgen, Inc; used with permission.)

Among 627 nonalcoholic North American patients with CHC, 282 patients (45%) were transfusion recipients, 262 patients acquired the disease by other routes of percutaneous exposure, and 83 were without identified risk factors. The duration of follow-up was 1 to 25 years. Four hundred sixty-three patients had liver biopsies; these showed no cirrhosis in 59%, cirrhosis in 37%, and HCC in 4% (all the latter also had underlying cirrhosis). Of the patients with cirrhosis, 68% had acquired the infection via transfusion as compared with 23% who acquired it through other percutaneous exposures. Of the 215 patients with blood transfusions for whom histologic findings were available, cirrhosis was present in 55%, whereas in the nontransfusion parenteral exposure group the corresponding figure was 21%. During the follow-up period, hepatic decompensation developed in 31% of the patients with cirrhosis. By logistic regression analysis, only the mode of transmission (not the age or estimated disease duration) predicted the risk of liver failure. Patients with posttransfusion hepatitis C were more likely to develop decompensation than those who were not transfusion recipients, with a relative risk of 3.92.51 Other studies addressed the natural history of cirrhosis due to CHC. In a study from the United States, a total of 112 patients with compensated HCV cirrhosis and a documented history of either intravenous drug use or transfusion were followed up for a mean duration of 4.5 years. The cumulative probabilities of

hepatic decompensation and development of HCC were 22.2% and 10.1%, respectively, with estimated yearly incidences of 4.4% and 2.0%. The cumulative 5year survival probability was 83% from entry and 51% from onset of hepatic decompensation. The actuarial yearly rate of mortality was 3.4% and the yearly rate of liver transplantation was 9.8%. The incidence of decompensation was significantly lower in patients treated with interferon.52 In a somewhat similar study, 384 European patients with cirrhosis were enrolled and followed up for a mean period of 5 years.53 Entry criteria included biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of HAV or HBV infections and other metabolic and toxin-induced liver diseases. During 5 years of follow-up, HCC developed in 7% and hepatic decompensation in 18%. Death occurred in 51 patients, constituting 13% of the cohort, with 70% dying of liver disease. The survival probabilities were 91% and 79% at 5 and 10 years, respectively. The general pattern of these results is similar to those of other studies.44,47-54 There are some data to suggest that the natural history of hepatitis C may be somewhat benign, especially if infection is acquired in childhood or early adulthood. In a retrospective study of 8568 military recruits when serum was available from 1968 to 1954, a total of 17 were found to be anti-HCV positive, of whom only 2 developed liver disease (relative risk, 3.56) and one died of liver disease.55 In an even more remarkable

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Table II. Extrahepatic manifestations of hepatitis C Listed alphabetically

Listed according to presumed pathogenetic mechanism

Antiphospholipid syndrome (anticardiolipin antibodies) Autoimmune thyroiditis Autoimmune thrombocytopenia B-cell lymphoma Behçet’s syndrome Canities (graying of hair) Glomerulonephritis Hyde’s prurigo nodularis Leukocytoclastic vasculitis Lichen planus MALT (mucosal-associated lymphoid tumors) Mixed cryoglobulinemia Mooren’s corneal ulcer Plasmacytoma Polyarteritis nodosa Porphyria cutanea tarda Sialoadenitis (Sjögren’s-like) Vitiligo

Abnormal B-cell/immunoglobulin production and/or deposition Antiphospholipid syndrome Autoantibodies B-cell lymphoma Cryoglobulinemia Glomerulonephritis Leukocytoclastic vasculitis MALT syndromes (mucosal-associated lymphoid tumors) Plasmacytoma Autoimmune Behçet’s syndrome Canities Hyde’s prurigo nodularis Lichen planus Mooren’s corneal ulcer Sialoadenitis Thyroiditis Thrombocytopenia Vitiligo Unknown mechanism Porphyria cutanea tarda

study of children infected at the time of cardiac surgery and followed up for nearly 20 years, approximately 45% cleared the virus; in the remaining patients, only one had elevated liver tests. Biopsy specimens in 17 of these 67 patients showed histologic damage in only 3.56 Not surprisingly, excessive alcohol intake by patients with CHC increases the risk of development of cirrhosis (39.4% vs 18.2%), as does concurrent HBV infection (24.6% vs 21.1%).44 These factors acted independently of the mode of acquisition. HCC was observed in 3.6% of all patients and in 17.8% of patients with cirrhosis. Its occurrence was strongly and mainly related to the presence of cirrhosis. The natural history of hepatitis C is one of rapid progression among chronically immunosuppressed patients (ie, long-term hemodialysis and bone marrow transplant recipients).57,58 Taken together, these data suggest that, in the typical patient, the progression of CHC is slow and protracted, and overtly serious disease typically first presents 2 to 3 decades after the initial infection (Fig 5). Among contributing factors, heavy alcohol use is most important, although other comorbid factors, such as concurrent HBV infection, iron overload (especially homozygous hemochromatosis),59,60 and/or α1-antitrypsin deficiency60 may play an important role in progression to cirrhosis or HCC in some patients. Once the late phase is reached, symptoms, complications, and liver-related deaths become common.

EXTRAHEPATIC MANIFESTATIONS OF HEPATITIS C INFECTION Many extrahepatic diseases and manifestations have been associated with HCV infection (Table II). Most of these are thought to be immune mediated, perhaps as a result of viral-dependent proliferation of monoclonal or polyclonal lymphocytes. Disease manifestations appear to be chiefly due to the deposition of immune complexes in a variety of organs, particularly the skin and the kidney (glomerulonephritis) or to the tissue deposition of specific T lymphocytes. In most cases, the details of pathogenesis of these disorders remain uncertain. Occurrence of autoantibodies in chronic hepatitis C Autoantibodies, particularly elevations in rheumatoid factors and smooth muscle antibodies, occur extraordinarily commonly in patients with CHC61 (Fig 6). Such autoantibodies also occur frequently in noninfectious autoimmune hepatitis, which is one of the other forms of liver disease that must be considered in the differential diagnosis of chronic viral hepatitis. On the whole, the titers of such autoimmune markers are higher in patients with autoimmune hepatitis than in those with CHC. Then, too, autoimmune hepatitis is chiefly a disease of women, occurring in a bimodal age distribution with one peak in the second to third decades and a second peak in the fifth to sixth decades of life, whereas CHC is predominantly a dis-

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Fig 6. Prevalence rates of autoantibodies in patients with CHC. (From Clifford BD, Donahue DG, Smith L, Cable E, Luttig B, Manns M, et al. Hepatology 1995;21:613-9. Used with permission.)

ease of young to middle-aged men with a history of previous injection-drug use or other high-risk behaviors. For the most part, the presence of autoantibodies in patients with CHC does not influence the clinical presentation, the course of the disease, or its response to treatment. The propensity for development of autoimmune hepatitis has been associated with certain HLA types of the host, particularly HLAA1, -B8, -DR3. In contrast, the association of autoimmune serologic tests in CHC has been associated with HLA-DR4.62 Although the presence of autoimmune antibodies is not considered a contraindication to antiviral therapy of CHC, patients have been described who clearly deteriorated during interferon therapy for CHC, and these patients developed evidence of autoimmune hepatitis.63-65 In addition, exacerbation of other diseases that may have an autoimmune component has been described during interferon treatment of chronic viral hepatitis. Of particular importance to dermatologists are reports of exacerbation of psoriasis.66 Autoimmune disorders Thyroid disease. Autoimmune thyroid disease is the most common autoimmune disorder found in patients with CHC. There is an increased prevalence of antithyroid antibodies in patients with hepatitis C, even before treatment with interferon. These are particularly prevalent in older women, in whom Hashimoto’s thyroiditis is common, regardless of hepatitis C infection. Interferon alfa (IFN-α) therapy may induce a variety of autoimmune phenomena, the

most common of which is autoimmune thyroiditis. It develops more often in patients with pre-existing antithyroid antibodies than in those without. The thyroiditis may resolve after cessation of IFN-α therapy or it may persist even after IFN-α has been discontinued. Sialadenitis. HCV infection is not associated with typical primary Sjögren’s syndrome, but a lymphocytic sialadenitis does occur with increased prevalence in patients with CHC. This is often associated with xerostomia (8%-36%), but it is not associated with xeropthalmia or with anti-Ro(SS-A) antibodies. Histologically, patients who have CHC with xerostomia have a relatively mild form of lymphocytic capillaritis of the salivary glands, and the infiltrating lymphocytes are predominantly CD8+, in contrast to those in primary Sjögren’s syndrome.67 Autoimmune thrombocytopenic purpura. An increased prevalence of antibodies to HCV has been found in patients with autoimmune idiopathic thrombocytopenic purpura. Elevated titers of platelet-associated IgG were described in 88% of patients with CHC, compared with 47% of patients with chronic hepatitis B, and the titers were significantly higher in patients with CHC.68 Typically, IFN-α therapy leads to a decrease in the platelet count. However, we and others have observed a few patients who at baseline had rather strikingly low platelet counts, high levels of antibodies against platelets, and who experienced both a reduction in CHC and in their thrombocytopenia during therapy with IFN-α. Therefore the presence of pre-existent thrombocytopenia is not an absolute contraindication to the use of IFN-α for treatment of CHC.

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Image available in print version only

Fig 7. Typical skin rash of mixed cryoglobulinemia and serum containing precipitated cryoglobulins, both from a patient with CHC. (From Shakil AO, Di Bisceglie AM. Images in clinical medicine: vasculitis and cryoglobulinemia related to hepatitis C. N Engl J Med 1994;331:1624. Copyright © 1994 Massachusetts Medical Society. All rights reserved.)

Lymphoma A high prevalence (20%-40%) of antibodies against HCV has been described in patients with non-Hodgkin’s B-cell lymphomas, but not in other hematologic malignancies. The association has been strongest in those with low-grade malignancies associated with cryoglobulinemia (see below) and in those with mucosal-associated lymphoid tumors of the gastrointestinal tract (MALT syndrome). These disorders are thought to be related to chronic antigen-driven B-cell proliferation with the eventual development of monoclonality. Other factors such as Helicobacter pylori infection may also play a role in some cases. IFN-α may be effective as therapy for these disorders.

DERMATOLOGIC MANIFESTATIONS OF HEPATITIS C Mixed cryoglobulinemia The syndrome of essential mixed cryoglobulinemia (MC) was first described in 1966.69 It is characterized clinically by systemic vasculitis with variable manifestations, ranging from the classical triad of

palpable purpura, arthralgias, and weakness, to lifethreatening forms involving vital organs such as the kidney, brain, and other parts of the nervous system (Fig 7). The disorder takes its name from the fact that it is associated with the presence of serum immunoglobulins that precipitate in the cold and which, in contrast to cryoglobulins composed of a single immunoglobulin class (type I), are “mixed” in composition, consisting of polyclonal IgG and IgM rheumatoid factors. The rheumatoid factors may be either polyclonal (type III) or monoclonal (type II). Most cases of MC, including those associated with CHC, are of the type II variety. It is now well established that about 80% of MC is secondary to HCV infection.70,71 Evidence of HCV RNA has been found with high frequency in organs affected in cryoglobulinemia, particularly in skin and kidney.71 Naturally, HCV RNA has also been found in the liver of such patients, but no evidence of immune complex–mediated liver disease has been found. Two major hypotheses have been proposed for the cause of MC. One is that a low-grade malignant

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Fig 8. Photographs of lower extremities of another patient with cryoglobulinemia complicating CHC. A, Before interferon therapy. B, Improvement after interferon therapy. (From Levey JM, Bjornsson B, Banner B, Kuhns M, Malhotra R, Whitman N, et al. Mixed cryoglobulinemia in chronic hepatitis C infection: a clinicopathologic analysis of 10 cases and review of recent literature. Medicine 1994;73:53-67. Reprinted with permission.)

lymphoproliferative disorder is the basis for the disease. In support of this, monoclonal T-cell populations have sometimes been found in patients with MC. However, in long-term follow-up studies, few patients with MC have been found to develop frank malignancies, and there have been no reports of the detection of HCV RNA in the malignant cells of those whose disease has progressed. The second hypothesis is that the disorder results from chronic stimulation of the immune system produced by a variety of infections, including HCV. The monoclonal rheumatoid factors that generally occur in the type II MC associated with CHC are thought to result from chronic stimulation of the immune system by complexes consisting of IgG bound to HCV antigens. This type of pathogenesis is well established from experimental models and from rheumatoid factor production in such chronic immune complex diseases as rheumatoid arthritis, systemic lupus erythematosus, and subacute bacterial endocarditis. Therapy for MC. Antiviral treatment of CHC is the therapy of first choice for all patients with MC

complicating hepatitis C infection.71 The great majority of these patients will have improvement in the manifestations of cryoglobulinemia, as well as improvement in levels of viral RNA and evidence of hepatitis. An example of such improvement, in a patient from our center, is shown in Fig 8. Porphyria cutanea tarda Porphyria cutanea tarda (PCT) is the most common form of porphyria. A full account of its features is beyond the scope of this review. For additional information, readers are referred to recent reviews.72,73 PCT usually occurs in people of middle age who have one or more of the major risk factors for development of the disease (Table III). The typical patient is a middle-aged man who is a heavy user of alcohol with evidence of liver disease and of iron overload. The earliest clinical manifestation is the typical skin rash characterized by the development of blisters, vesicles, and/or milia on the dorsal aspects of the hands (Fig 9). Other skin manifestations include increased fragility, hypertrichosis (especially involving the lateral aspects

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A

B Fig 9. Typical cutaneous features of PCT.

Table III. Major risk factors for development of PCT Chemical or toxic exposure • Hexachlorobenzene • 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) • Other halogenated aromatic hydrocarbons • (Chemicals that deplete reduced glutathione or ascorbate or otherwise increase oxidative stress)* Iron overload • Heterozygosity for HLA-linked hemochromatosis • Homozygosity for HLA-linked hemochromatosis • Inheritance of other genetic abnormalities that lead to increased hepatic iron (eg, African, non-HLA-linked iron overload, iron-loading heritable anemias) Heavy intake of alcohol Chronic liver diseases • Alcoholic liver disease • Chronic hepatitis C Drug exposure • Estrogens • (Barbiturates) • (Other inducers of hepatic cytochrome(s) P-450, especially CYP1A2) Adapted from Bonkovsky HL, Lambrecht RW. Hemochromatosis, iron overload, and porphyria cutanea tarda. In: Barton JC, Edwards CQ, editors. Hemochromatosis: genetics, pathophysiology, diagnosis and treatment. Cambridge (UK): Cambridge University Press; 1999. p. 453-67. *Factors listed within parentheses have been shown to trigger or exacerbate experimental uroporphyria that resembles PCT biochemically. Thus they are considered theoretical risks in humans.

of the face), chloracne, chronic hyperpigmentation and/or hypopigmentation, sclerodermoid changes, dystrophic calcifications with ulceration, scarring, alopecia, and onycholysis. A minority of patients (approximately one third to one half) have hepatomegaly. This is especially prevalent in those who drink

alcohol heavily and is typically due to a combination of hepatic steatosis, cell swelling, inflammation, and fibrosis. The specific laboratory features typical of PCT are the marked hepatic overproduction of uroporphyrins and heptacarboxyl porphyrins. After binding and storage sites within hepatocytes have been saturated, these porphyrins leak into the plasma and are carried to and deposited in other tissues, including skin, bones, teeth. They are also excreted by the renal glomerulus and may cause the urine to become dark-red. Patients with PCT may also have mild increases in urinary 5-aminolevulinic acid, but they always have normal excretions of porphobilinogen. These findings are useful to differentiate PCT from other forms of cutaneous porphyria that may present with similar clinical findings (hereditary coproporphyria and variegate porphyria).72,74 Fecal porphyrin analyses in patients with PCT often reveal a moderate increase in coproporphyrin, more than 30% of which is an unusual isomer called “iso-coproporphyrin.” Patients with PCT also have increased levels of uroporphyrins and heptacarboxyl porphyrins in the plasma, and the fluorescent spectra of porphyrins in plasma are valuable for differential diagnosis.74 Pathogenesis of PCT. Decreased activity of the enzyme uroporphyrinogen decarboxylase is an essential feature of the biochemical abnormalities of PCT. This is the enzyme that normally converts uroporphyrinogen into coproporphyrinogen in the heme biosynthetic pathway (Fig 10). In patients with type 2 or hereditary PCT, there is an inherited 50% decrease in activity of uroporphyrinogen decarboxylase that occurs in all tissues. However, this defect in itself is not sufficient to produce a PCT phenotype because most persons with this degree of decrease have no symptoms or signs of PCT.

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Fig 10. The biochemical pathogenesis of PCT. (From Bonkovsky HL, Lambrecht RW. Hemochromatosis, iron overload, and porphyria cutanea tarda. In: Barton JC, Edwards CQ, editors. Hemochromatosis: genetics, pathophysiology, diagnosis and treatment. Cambridge (UK): Cambridge University Press; 1999. p. 453-67. Used with permission.)

Another important factor is an increase in the rate or tendency of uroporphyrinogen to be oxidized to uroporphyrin within hepatocytes. This rate of oxidation can be influenced by many factors, including the activity of cytochrome P-4501A2, metabolically active iron within hepatocytes, CHC, long-term alcohol intake, and perhaps estrogens. As already noted (Table III), all of these factors are important risk factors for the development of PCT. Another potential factor important in the pathogenesis of PCT is increased activity of hepatic 5aminolevulinic acid synthase, the first and normally the rate-controlling enzyme of heme synthesis. An increase in activity of this enzyme will cause increased amounts of uroporphyrinogen to form in hepatocytes, and this may undergo oxidation to uroporphyrin and formation of nonporphyrin products that inhibit uroporphyrinogen decarboxylase. The ways in which these multiple factors may give rise to uroporphyrin overproduction are summarized in Fig 10. PCT and hepatitis C. In addition to the wellknown association of alcoholic liver disease with PCT, recent work has made it clear that CHC is also an important risk factor. In southern Europe (Italy, Spain, southern France) 70% to 90% of patients with

PCT have CHC. In contrast, where CHC is less prevalent (eg, northern Europe, Australia, New Zealand) but hemochromatosis is more prevalent, up to 20% of patients with PCT have CHC. In the United States, we have found the prevalence of CHC in patients with PCT to be intermediate (56%).75 It is known that CHC infection increases oxidative stress within hepatocytes and does so to a greater extent than for other chronic viral infections such as chronic hepatitis B. This appears to be the major mechanism whereby CHC infection may act as a trigger for development of PCT, although the possibility that other factors, such as formation of autoantibodies that inhibit uroporphyrinogen decarboxylase, may also contribute have not yet been excluded. The frequent association of both CHC infection and HLA-linked, hereditary hemochromatosis with PCT has two important implications: all patients with PCT should be screened for HCV infection with measurement of antibodies against HCV, and all should undergo HFE gene mutational analysis to look for either of the two mutations (C282Y or the H63D) that have been linked with iron overload; and the initial management of PCT should continue to be vigorous iron removal, to the point of mild iron defi-

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ciency.72,73,75 After this has been accomplished, patients who are HCV positive should be considered for treatment of HCV infection with interferon-based therapies. All patients with active PCT should avoid alcohol, estrogens, or other chemicals that may precipitate or exacerbate the disorder.

OTHER DERMATOLOGIC MANIFESTATIONS OF CHC Lichen planus Isolated case reports first suggested an association of lichen planus with CHC. A recent study compared the prevalence of antibodies to HCV in 263 patients with oral lichen planus to a control group of 100 patients who were receiving routine dental care. Twenty-nine percent of those with lichen planus were positive for HCV antibodies, as compared with 3% in the control group.76 Positivity for hepatitis B virus markers were found in 12% of patients and for the hepatitis A virus marker in 16%. The prevalence of HCV infection in patients with lichen planus varies considerably from one geographic area to another, ranging from 4% in northern France77 to 62% in Japan.78 On the other hand, studies from Great Britain have failed to reveal any association. In a report from Germany, 2.4% of 127 HCV-positive patients had oral lichen planus, but only 1 of 24 consecutive patients with lichen planus was anti-HCV seropositive.79 When chronic liver disease is associated with lichen planus, CHC is generally the cause of that liver disease. There does not appear to be a difference in prevalence of HCV between erosive and nonerosive forms of lichen planus as demonstrated by a recent study by Mignogna et al,76 although it is somewhat controversial. Polyarteritis nodosa In contrast to MC, polyarteritis nodosa (PAN) is rarely found in patients with CHC. Prevalences of 5% to 20% for HCV markers have been reported in patients with PAN. The presence of anti-HCV antibodies should be confirmed by HCV RNA because falsepositive serologic tests may occur in patients with PAN. In one study of 56 patients with PAN, 11 patients had anti-HCV antibodies by enzyme-linked immunoassay II, but only 3 were positive by recombinant immunoblot assay II tests and HCV RNA by polymerase chain reaction.80 Overall 4 of the 56 study patients were positive for hepatitis B surface antigen. Of the 11 patients who had positive serology for hepatitis C, only 1 was positive for hepatitis B surface antigen. Pruritus Pruritus is well recognized as being associated with hepatitis C. In one study 978 consecutive

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patients presenting to a dermatology clinic were tested for serum markers of HCV infection. Of the 28 patients with prurigo, 11 (39%) had evidence of HCV infection by enzyme-linked immunosorbent assay compared with the remaining 950 patients of whom 49 (5%) had evidence of HCV infection.81 It appears that CHC with moderate to severe fibrosis may result in low-grade cholestasis with pruritus, possibly in association with bile duct disappearance, as suggested by a recent study that compared 8 patients with CHC with 8 controls having primary biliary cirrhosis and 7 controls with CHC without pruritus.82 Other manifestations There have been several case reports of other dermatologic manifestations associated with acute hepatitis C. There has been one case report of urticaria83 associated with acute hepatitis C infection. There has been a case report of erythema nodosum84 associated with acute HCV infection and another case of erythema multiforme85 in association with hepatitis C. None of these is specific for hepatitis C infection. Hyde’s prurigo nodularis has been associated with CHC, and it has responded to interferon therapy.86 One of the distinctive skin lesions that appears to be associated only with acute hepatitis C is necrolytic acral erythema.87 It is a distinctive skin lesion that affects the dorsa of the feet. In a recent report of 7 patients with necrolytic acral erythema, all were found to have the HCV infection by enzyme-linked immunoassay and polymerase chain reaction.87 In addition to the HCV itself, a variety of skin manifestations may be related to therapy with IFN-α, the most common of which are erythema at sites of injection and transient alopecia, which occur in about 25% of treated patients. Dry skin has been reported in 8% to 13% of patients receiving IFN-α, and excessive sweating has been reported in about 2% to 8%. Other less common manifestations include acne, nail disorders, epidermal necrolysis, photosensitivity, skin discoloration, and exfoliative dermatitis. As already noted, therapy can exacerbate other autoimmune skin disorders, including psoriasis. Finally, there have been case reports of cutaneous necrosis as a result of accidental injection of IFN-α into an artery. There appears to be a higher prevalence of cutaneous reactions seen in association with the combination of IFN-α and ribavirin, as compared to IFN-α alone. In a recent study that compared 33 patients receiving combination therapy to 35 age-matched controls treated with IFN-α alone, cutaneous adverse reactions, often of a lichenoid type, were observed in 33% of the former, as compared with 5.7% of the lat-

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ter. In 6 of these 11 patients, all cutaneous adverse effects reversed fully after the course of the therapy. One of the patients had to discontinue treatment temporarily because of adverse cutaneous effects.88

MANAGEMENT OF HCV INFECTION Overview Current therapies for HCV infection are not particularly efficacious. Type 1 interferons. The cornerstone of therapy is type 1 interferons (Table IV). In the United States, 3 such preparations currently are approved for routine use in previously untreated patients (IFN-α2a [Roferon, Roche Pharmaceuticals], IFNα2b [Intron-A, Schering-Plough], and alfacon-1 [Infergen, Amgen, Inc]). IFN-α2a and IFN-α2b are naturally occurring interferons that differ by a single amino acid, whereas alfacon-1 does not occur naturally. The primary structure of alfacon-1 (also called consensus interferon) provides a sequence of amino acids found most often among all known sequenced type 1 interferons. All 3 of the approved interferons are made by recombinant techniques and are produced in E coli or other microorganisms transfected with constructs containing expression clones of the interferons. The interferons are purified from the cultures. Unfortunately, the anti-HCV effects of interferon are modest, especially for patients with genotype 1a or 1b viruses and chronic infections. In the United States, such patients account for approximately 75% of all patients with known HCV infection. The usual doses and durations of initial therapy are summarized in Table IV. Response rates during therapy are 20% to 35%, but sustained virologic response rates are disappointingly low (~10%).89 In addition to limited effectiveness, side effects of interferon are numerous and severe. Interferon predictably causes fever, chills, headache, fatigue, arthralgias, and myalgia, especially during the initial week of use. They can be diminished somewhat by instructing patients to take interferon in the evening along with an analgesic and sedative (eg, ibuprofen and diphenhydramine). Other major adverse effects that often require cessation of therapy are depression, moodiness, insomnia, and other neuropsychiatric problems. Symptoms are sufficiently severe to require discontinuation of therapy in 2% to 10% of patients. Other predictable effects include granulocytopenia and thrombocytopenia. Leukopenia responds to granulocyte-macrophage colony-stimulating factor. Ribavirin. Ribavirin is one of several nucleoside analogues that has antiviral activity against several DNA and RNA viruses. It has been available for a generation, although in the United States until recently it was approved for use only as an inhaled form, for

Table IV. Type 1 interferons approved for use in HCV infection in the United States (January 2000)* Generic name

IFN-α2a IFN-α2b Alfacon-1

Brand name

Manufacturer

Roferon Intron-A Infergen

Roche, Inc Schering-Plough, Inc Amgen, Inc

*Approved regimens of therapy: For previously untreated HCV infection with elevated serum ALT: IFN-α2a (3 MU 3 times/wk × 48 wk); IFN-α2b (3 MU 3 times/wk × 48 wk); Alfacon-1 (9 µg 3 times/wk × 48 wk). For previously treated HCV and relapse or nonresponse: Alfacon-1 (15 µg 3 times/wk × 48 wk).

therapy of acute bronchitis due to respiratory syncytial virus in infants. In the early 1990s, orally ingested ribavirin was found to decrease serum ALT levels in patients with CHC, but to have little effect on serum viral loads. Several recent studies have shown that adding ribavirin to standard IFN-α2a or IFN-α2b markedly improves the responses during and after therapy for 6 to 12 months90,91 (Fig 11). As a result, therapy with this combination is now in widespread use. The major side effects of ribavirin are teratogenic effects, hemolytic anemia, and skin rash. Because of its severe teratogenicity, there are large “black box” warnings against its use by men or women of childbearing potential, without their using two different effective methods of contraception and without regular pregnancy tests for women before, during, and for 6 months after therapy. A decrease in hemoglobin occurs in nearly everyone because of accumulation of ribavirin-triphosphate in red blood cells, which shortens their survival. The drug is contraindicated in patients with ischemic disease (eg, coronary artery disease, ischemic cerebrovascular disease, or peripheral vascular disease), renal insufficiency, or both. The severity of such side effects is diminished by use of lower doses; in fact, the optimal dose of ribavirin has not been established. A high and often toxic dose (1200 mg/d) has been used, but our recent results indicate that lower doses (600 mg/d) are as effective and are better tolerated.92 Acute hepatitis C Because of the high likelihood that HCV will not be cleared spontaneously by those who become infected, therapy to help eradicate acute HCV infections is rational. Few prospective, randomized, controlled trials have been performed because most patients who contract acute hepatitis C do not seek medical attention in the acute phase of illness. However, IFN-α is of significant benefit if given with-

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Fig 11. Response rate to standard IFN-α2b versus interferon and ribavirin in chronic hepatitis C. (Adapted from McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-92.)

Table V. Pretreatment factors correlated with response to interferon therapy for CHC Better response

Host factors Age Sex Duration of HCV infection Use of alcohol Status of immune system Hepatic histopathology Scar tissue Inflammation History of previous response to therapy Viral factors Genotype Serum HCV RNA

Worse response

Younger Female Shorter No alcohol >4 mo (<4 mo) use of alcohol Intact

Older Male Longer Current or recent

Mild—no cirrhosis; little fibrosis More vigorous Yes

Severe fibrosis or cirrhosis Less vigorous No

Non-type 1 Lower (<3 × 106 copies/mL)

Type 1 Higher (≥3 × 106 copies/mL)

in the first 3 to 4 months of infection, leading to normalization of serum ALT in more than two thirds of patients (vs
Compromised (HIV-positive, taking immunosuppressants)

Chronic hepatitis C Several factors have been correlated with responses to interferon therapy for CHC (Table V). Those most likely to respond are young women who have not been infected for long; who have little or no iron in the liver; who do not drink alcohol; have

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intact immune systems, low serum ferritins, little or no hepatic fibrosis, robust hepatic inflammatory (Tcell) responses; and who are infected with non-type 1 strains of HCV, which are present in low numbers in the serum at baseline. The most effective therapy for CHC (IFN-α2b and ribavirin or high-dose alfacon-1) currently available produces virologic “cure” in about 30% to 50% of patients. Approximately 50% of those who previously responded to standard-dose interferon, but relapsed after cessation of 6 months or less of therapy (“relapsers”), will have sustained responses to IFN-α2b and ribavirin or to high-dose alfacon-1 (15 µg 3 times/wk × 48 weeks). “Cure” is now usually defined as lack of detectable HCV RNA in serum by sensitive polymerase chain reaction assay at least 6 months after cessation of therapy. If patients achieve this, their chances of remaining free of detectable viral RNA during the ensuing several years are greater than 90%. It is important to keep in mind that in addition to viral eradication, there are other worthwhile goals of therapy. These include prevention of progression to cirrhosis, to decompensation, to need for liver transplant, or to development of HCC. Recent results suggest that interferon and/or ribavirin have anti-inflammatory and antifibrotic effects on the liver even when they are not able to eradicate HCV. Therefore antiviral or other antifibrotic therapies may still be of considerable importance in management. These considerations have led to testing of numerous other therapies for CHC, recently reviewed by one of us.93 Among several approaches, the removal of iron from the liver by therapeutic venesection has been studied perhaps most extensively and with generally encouraging results.94,95 Use of antioxidants such as N-acetylcysteine or Sadenosylmethionine also deserves further trial.93

REMAINING CHALLENGES As for the future, the development of an effective, low-cost vaccine to prevent new HCV infections would be a major advance. However, this development will be complicated by the lack (in general) of anti-infective protection of most anti-HCV antibodies and by the rapid mutation rate of the virus, especially when under immune pressure. More effective and less toxic therapies for those patients already infected are needed as well. Longacting, pegylated interferons will likely be approved for use in the United States during the first half of this year, and much work is now devoted to the development and testing of inhibitors of HCV protease and RNA polymerase. In early trials, the antiinflammatory interleukin 10 has shown promise for

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decreasing the systemic symptoms and hepatic inflammation and fibrosis so often associated with CHC. Combinations of these and other therapies may emerge in coming years. We thank Cathy DeCaire, Dawn Dorschel, and Mary Taubert for their tireless efforts in aiding us in the preparation of the figures and the typescript for this article. REFERENCES 1. Beeson PB. Jaundice occurring one to four months after transfusion of blood or plasma: report of 7 cases. JAMA 1943;121: 1332. 2. Krugman S, Giles JP, Hammond J. Infectious hepatitis: evidence for two distinctive clinical, epidemiological, and immunological types of infection. JAMA 1967;200:365-73. 3. Blumberg BS, Gerstley BJ, Hungerford DA, London WT, Sutnick AI. A serum antigen (Australia antigen) in Down’s syndrome, leukemia, and hepatitis. Ann Intern Med 1967;66:924-31. 4. Feinstone SM, Kapikian AZ, Purcell RH. Hepatitis A: detection by immune electron microscopy of a virus like antigen associated with acute illness. Science 1973;182:1026. 5. Bradley DW, Maynard JE, Popper H, Cook EH, Ebert JW, McCaustland KA, et al. Posttransfusion non-A, non-B hepatitis: physicochemical properties of two distinct agents. J Infect Dis 1983;148:254-65. 6. Bradley DW, McCaustland KA, Cook EH, Schable CA, Ebert JW, Maynard JE. Posttransfusion non-A, non-B hepatitis in chimpanzees: physicochemical evidence that the tubule-forming agent is a small, enveloped virus. Gastroenterology 1985;88: 773-9. 7. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne nonA, non-B viral hepatitis genome. Science 1989;244:359-62. 8. Kuo G, Choo QL, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:362-4. 9. Choo QL, Richman KH, Han JH, Berger K, Lee C, Dong C, et al. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci U S A 1991;88:2451-5. 10. Thomssen R, Bonk S, Thiele A. Density heterogeneities of hepatitis C virus in human sera due to the binding of betalipoproteins and immunoglobulins. Med Microbiol Immunol 1993;182:329-34. 11. Okamoto H, Kojima M, Okada S, Yoshizawa H, Iizuka H, Tanaka T, et al. Genetic drift of hepatitis C virus during an 8.2-year infection in a chimpanzee: variability and stability. Virology 1992;190:894-9. 12. Bukh J, Miller RH, Purcell RH. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis 1995;15: 41-63. 13. Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, Brechot C, et al. A proposed system for the nomenclature of hepatitis C viral genotypes [letter]. Hepatology 1994;19:1321-4. 14. Simmonds P, Smith DB. Investigation of the pattern of diversity of hepatitis C virus in relation to times of transmission. J Viral Hepat 1997;1(Suppl 4)1:69-74. 15. Smith DB, Pathirana S, Davidson F, Lawlor E, Power J, Yap PL, et al. The origin of hepatitis C virus genotypes. J Gen Virol 1997; 78:321-8. 16. World Health Organization. Hepatitis C: global prevalence.Wkly Epidemiol Rep 1997:341-8. 17. El-Sayed NM, Gomatos PJ, Rodier GR, Wierzba TF, Darwish A, Khashaba S, et al. Seroprevalence survey of Egyptian tourism

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75. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, Obando J, DiBisceglie A, Tattrie C, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998;27:1661-9. 76. Mignogna MD, Muzio LL, Favia G, Mignogna RE, Carbone R, Bucci E. Oral lichen planus and HCV infection: a clinical evaluation of 263 cases. Int J Dermatol 1998;37:575-8. 77. Jubert C, Pawlotsky JM, Pouget F, Andre C, Deforges D, Bretagne S, et al. Lichen planus and hepatitis C virus-related chronic active hepatitis. Arch Dermatol 1994;130:73-6. 78. Nagao Y, Sata M, Tanikawa K, Itho K, Kameyama T. Lichen planus and hepatitis C virus in the northern region of Japan. Eur J Clin Invest 1995;25:910-4. 79. Grote M, Reichart PA, Berg T, Hops U. Hepatitis C virus (HCV)infection and oral lichen planus. J Hepatol 1998;29:1034-5. 80. Carson CW, Conn DL, Czaja AJ,Wright TL, Brecher ME. Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa. J Rheumatol 1993;20:304-9. 81. Kanazawa K, Yaoita H, Murata K, Okamoto H. Association of prurigo with hepatitis C virus infection. Arch Dermatol 1995;131:852-3. 82. Chia SC, Bergasa NV, Kleiner DE, Goodman Z, Herfnagle JH, DiBisceglie AM. Pruritus as a presenting symptom of chronic hepatitis C. Dig Dis Sci 1998;43:2177-83. 83. Reichel M, Mauro TM. Urticaria and hepatitis C. Lancet 1990;336:822-3. 84. Domingo P, Ris J, Martinez E, Casas F. Erythema nodosum and hepatitis C. Lancet 1990;336:1377. 85. Antinori S, Esposito R, Aliprandi CA, Tadini G. Erythema multiforme and hepatitis C. Lancet 1991;337:428. 86. Neri S, Racih C, D’Angelo G, Ierna D, Bruno CM. Hyde’s prurigo nodularis and chronic HCV hepatitis. J Hepatol 1998;28:161-4. 87. Darouti ME, Ela ME. Nerolytic acral erythema: a cutaneous marker of hepatitis C. Int J Dermatol 1996;35:252-6. 88. Sookoian S, Neglia V, Castano G, Frider B, Kien MC, Chohuda E, et al. High prevalence of cutaneous reactions to interferon alpha plus ribavirin combination therapy in patients with chronic hepatitis C virus. Arch Dermatol 1999;135:1000-1. 89. Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, Opolon P, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996;24:778-89. 90. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-92. 91. Davis GL, Estebon-Mur R, Rustgi V, Hoefs J. Gordon SC, Trepo C, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493-9. 92. Bonkovsky HL, Stefancyk D, LeClair P, Zucker G, Israel J, Stagias J, et al. Low doses (600 mg/d) of ribavirin are superior to high doses (1000-1200 mg/d) with interferon for chronic hepatitis C: results of a controlled, randomized, multi-center trial [abstract]. Hepatology 1999;30:265A. 93. Bonkovsky HL. Therapy of hepatitis C: other options. Hepatology 1997;26(Suppl 1):143S-151S. 94. Bonkovsky HL, Banner BF, Rothman AL. Iron and chronic viral hepatitis. Hepatology 1997;25:759-68. 95. Fontana R, Israel J, LeClair P, Banner BF,Tortorelli K, Grace N, et al. Iron reduction prior to and during interferon therapy of chronic hepatitis C: results of a multi-center, randomized, controlled trial. Hepatology 2000;31:730-6.

Answer sheets are bound into the Journal for US members. Request additional answer sheets from American Academy of Dermatology, Member Services Department, PO Box 4014, Schaumburg, IL 60168-4014. Phone 847-330-0230; E-mail [email protected]

CME examination Identification No. 801-102

Instructions for Category I CME credit appear in the front advertising section. See last page of Contents for page number.

Questions 1-29, Bonkovsky HL, Mehta S. J Am Acad Dermatol 2001;44:159-79.

Directions for questions 1-18: Give single best response. 1. Of the currently approved therapies for the initial treatment of chronic hepatitis C (CHC), the most effective therapy in terms of virologic response is a. interferon alfa-2a (Roferon), 3 MU administered subcutaneously 3 times a week for 48 weeks b. interferon alfa-2b (Intron-A), 3 MU administered subcutaneously 3 times a week for 48 weeks c. consensus interferon (Alfacon-1, Infergen), 9 µg administered subcutaneously 3 times a week for 48 weeks d. interferon alfa-2b, 3 MU administered subcutaneously 3 times a week plus ribavirin 600 mg taken orally twice daily for 48 weeks e. ribavirin alone, 600 mg taken orally twice daily for 48 weeks 2. The standard dose of interferon currently approved by the Food and Drug Administration for the initial treatment of CHC is a. 3 MU or 9 µg 3 times a week b. 6 MU or 18 µg 3 times a week c. 9 MU 3 times a week d. 1.5 MU 3 times a week 3. Which of the following statements about consensus interferon (Alfacon-1) is true? a. It is a complex mixture of naturally occurring interferon. b. It is a recombinant interferon. c. It is much less toxic than other interferons. d. It is effective if taken orally. 4. Which of the following statements about ribavirin is true? a. It is only active against RNA viruses. b. It is given parenterally. c. Intravenous dose needs to be adjusted frequently. d. Its mechanism of action is clearly delineated. e. It is a nucleoside analogue. 5. By consensus, a sustained virologic response to treatment of hepatitis C virus (HCV) is defined as a. absence of detectable HCV in serum at the end of treatment

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b. absence of detectable HCV in serum 3 months after the completion of therapy c. absence of virus detectable HCV in serum 6 months after completion of therapy d. absence of virus detectable HCV in serum 1 year after completion of therapy 6. Interferon may cause all of the following side effects except a. leukopenia b. hemolysis c. depression d. thyroiditis e. myalgia 7. Which of the following constitutes a relative contraindication to the use of interferon? a. Hemochromatosis b. History of alcoholism c. CHC with positive smooth muscle antibodies in serum d. History of depression 8. The approximate percentage of patients who fail to recover spontaneously from acute hepatitis C is a. 75% b. 60% c. 40% d. 20% 9. Which of the following statements regarding acute hepatitis C is false? a. It rarely, if ever, causes fulminant hepatitis. b. It can be diagnosed distinctively from other hepatitides by its clinical course. c. The majority of patients are without symptoms. d. It does not cause unusually severe hepatitis in chronic hepatitis B carriers. 10. Concerning CHC, each of the following statements is true except a. it is often asymptomatic. b. it results in a slow but usually progressive chronic liver disease. c. its course is not modified by interferon therapy.

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d. its course is often influenced by the mode of acquisition of HCV. 11. Which of the following statements is true regarding the relationship between autoimmune hepatitis and hepatitis C? a. Most patients with autoimmune hepatitis are HCV RNA positive. b. Patients with CHC, positive titers of serum autoimmune markers, and mixed cryoglobulinemia should be treated first with antiviral therapy, not with immunosuppressants. c. Patients with antitissue antibodies and hepatitis C should be treated with a combination of corticosteroids and interferon. d. The hepatic histologic picture in all patients with CHC and positive autoimmune markers resembles that of typical autoimmune hepatitis. 12. Which of the following statements is false? a. Thyroiditis is equally common in patients with chronic hepatitis B and CHC. b. Antithyroid autoantibodies are sometimes detected in patients with CHC even before the initiation of therapy. c. There is a high prevalence of HCV infection in patients with thyroid disorders. d. Hypothyroidism, hyperthyroidism, Hashimoto’s disease, and isolated autoantibodies may be associated with hepatitis C. 13. Of the following disorders, which one has the weakest link to hepatitis C? a. Thyroiditis b. Glomerulonephritis c. Sialadenitis/sicca syndrome d. Guillain-Barré syndrome 14. Of the dermatologic manifestations of acute hepatitis C, which of the following is most frequently observed? a. Lichen planus b. Polyarteritis nodosa c. Leukocytoclastic vasculitis d. Necrolytic acral erythema 15. Which of the following skin disorders is most often associated with interferon use? a. Acne b. Urticaria c. Eczema d. Transient alopecia

16. The current prevalence of serum antibodies to HCV in the US general population is approximately a. 0.8% b. 1.8% c. 3.6% d. 7.2% 17. Hepatitis C is transmitted most commonly by the parenteral route. Other modes of transmission include each of the following except a. snorting of cocaine with shared straws b. sexual transmission c. perinatal transmission d. household contacts 18. Currently the most prevalent genotypes of HCV in the United States are a. 1b and 3 b. 2 and 4 c. 5 and 6 d. 1a and 1b Directions for questions 19-29: For each of the numbered items, choose the appropriate lettered item. a. Hepatitis A b. Hepatitis B c. Hepatitis C d. Both hepatitis B and hepatitis C e. Both hepatitis A and hepatitis C 19. Mainly spread by fecal contamination of food or water 20. Spread by contaminated blood 21. High risk (>25%) of spread through sexual intercourse 22. Australia antigen—major protein of surface coat 23. Many genotypes 24. Cesarean section decreases risk of transmission 25. Fatty changes more commonly seen in histology of this acute form 26. Increased titers of platelet-associated IgG 27. Often associated with porphyria cutanea tarda 28. Binds to low-density lipoproteins in serum 29. Belongs to family of flaviviruses

Answers to CME examination Identification No. 801-102

February 2001 issue of the Journal of the American Academy of Dermatology

Questions 1-29, Bonkovsky HL, Mehta S. J Am Acad Dermatol 2001;44:159-79.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

d a b e c b d a b c b a d c d

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

b d d a d b b c b c d c c c

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