Hepatitis C infection: a clinical review.

Abstract: Nearly three million persons in the United States are viremic with hepatitis C (HCV). Despite a decreasing incidence of HCV in this country, the prevalence of HCV-related chronic liver disease is increasing. Most infections in the United States are acquired by intravenous drug use. The chronicity rate of HCV is high, reaching 85% in some populations, and the risk of progression to advanced liver disease is as high as 20% within twenty years of infection. Host factors like alcohol use accelerate the rate of progression. The enzyme immunoassay is the preferred initial test for diagnosis; the third generation assay has greater than a 99% specificity in immunocompetent patients. Barring contraindications, the standard of care for treatment of chronic HCV has become pegylated interferon and ribavirin. With this therapy, the cure rate for treatment-naive patients is about 55%, but rates are higher in certain groups. Common side effects of therapy include neuropsychiatric symptoms, influenza-like symptoms and hematological abnormalities.

Key Words: hepatitis C, liver disease, pegylated interferon, ribavirin

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The Virus and its Epidemiology

Originally identified in 1989, hepatitis C (HCV) has become the most important cause of "non-A, non-B" hepatitis. (1) HCV is an RNA virus belonging to the Flaviviridae family. Its genetic code differs substantially among its six genotypes and ninety or more subtypes, with two genotypes having as much as a 34% nucleotide sequence disparity. (2) This genetic heterogeneity may in part explain the difficulty in developing an effective HCV vaccine. (3)

Based on the National Health and Nutrition Examination Survey (NHANES III), it is estimated that 2.7 million Americans are viremic with HCV, and nearly 4 million have the HCV antibody. (4) These numbers are likely underestimates, because groups with high HCV prevalence rates, such as the mentally ill and the incarcerated, were excluded from the survey. According to one Justice Department study, some 1.3 to 1.4 million inmates released from prison in 1996 were infected with hepatitis C. (5) Persons between the ages of 40 to 59 currently have the highest prevalence of HCV infection. (4)

The incidence of acute HCV is approximately 35,000 cases per year, which represents a decline since the late 1980s. (6) Despite the decrease in incidence, HCV is the most common chronic blood-borne pathogen in the United States. (7) Because of a significant lag time between infection onset and hepatic manifestations, the prevalence of HCV-related liver disease is actually increasing. A fourfold increase in the number of adults diagnosed with chronic HCV is expected to occur from 1990 to 2015, (7) and HCV liver-related deaths are expected to nearly triple by the year 2020. (8)

Most HCV-infected patients in the United States acquire the virus by intravenous (IV) drug use; the seroprevalence of hepatitis C in this population is greater than 75%. (9) Some patients acquired the infection from transfusion, but this has become rare following the advent in 1992 of routine HCV testing of the US blood supply. Other routes of transmission include high-risk sexual behavior, occupational exposure, unsafe medical practices, infected donor organs from transplant, and maternal-infant transmission (10,11) (Fig. 1).

Although HCV can be acquired sexually, transmission rates are low. (12-14) Studies examining sexual transmission in monogamous couples often reveal confounding factors for transmission, such as shared parenteral exposures. (15,16) Yet significant nucleotide sequence homology of the virus's RNA from infected monogamous couples without other risk factors suggests the occurrence of interspousal transmission. (17) Sexual promiscuity increases the risk of HCV acquisition, (10,18) and human immunodeficiency virus (HIV) coinfection further increases the likelihood of sexual transmission. (18,19)

[FIGURE 1 OMITTED]

Regarding vertical transmission (mother to infant), rates ranged from 3.3 to 6.4% in two prospective studies of HCV RNA-positive women. (20,21) A correlation exists between high maternal titers of HCV RNA and the probability of infecting the infant. (20,22,23) The risk is also increased if the mother was previously or is currently using drugs intravenously, or is coinfected with HIV. (24-27) In an analysis of eight studies of HIV coinfected women, the weighted risk of maternal-infant transmission was over 20%, versus 8% for HIV-negative mothers. (28) Although HCV RNA is sometimes detectable in amniotic fluid, (29) it is not known if mother-to-infant transmission occurs in utero or at the time of delivery.

Natural History

The first detectable biochemical marker of HCV infection is the presence of HCV RNA, which can be found as early as one week after exposure. (30) Elevation of serum alanine aminotransferase (ALT) levels, reflecting hepatocyte damage, may be seen within 4 to 12 weeks on average. (31) Because 30 to 50% of patients have no detectable antibodies by enzyme immunoassay in early infection, (32,33) antibody testing is unreliable in acute HCV. And although 90% of patients develop HCV antibodies within 12 weeks of infection, some may take over a year to seroconvert. (32) Only about one-third of acute HCV patients have symptoms, which may include fatigue, anorexia, myalgias, arthralgias, jaundice, or right upper quadrant pain. (31,34) Fulminant hepatic failure from HCV is rare. (35,36)

Although some studies of young women and children have reported low rates of chronic HCV viremia (55%), (37,38) prospective studies in more diverse populations have confirmed up to an 85% chronicity rate. (39) Thus, 15 to 45% of patients with acute hepatitis C will experience spontaneous recovery. Aside from younger age and female sex, certain HLA alleles are associated with spontaneous clearance of viremia. (40,41) Those with jaundice or symptoms of acute infection are more likely to clear the virus than acutely infected individuals who are asymptomatic. (42) However, black persons less frequently clear HCV spontaneously. (43) In general, HCV's high rate of chronicity may be related to the virus's high likelihood of mutation and the lack of, or failure to maintain, a vigorous T-lymphocyte response to infection. (31,44,45)

Chronic HCV has been associated with a myriad of extrahepatic conditions. Yet studies linking these conditions to HCV are limited by small sample size, lack of control groups, and retrospective analysis. Nevertheless, in a prospective multicenter study of 321 chronically infected HCV patients, at least one extrahepatic manifestation was present in 38% of patients; 19% had rheumatic symptoms, and 17% had cutaneous problems. (46) In a hospital-based case control study from the Veterans Affairs Hospitals, HCV was significantly associated with porphyria cutanea tarda, vitiligo, lichen planus, cryoglobulinemia, membranoproliferative glomerulonephritis, and non-Hodgkin's lymphoma. (47) Monoclonal gammopathy may also be associated with HCV. In a study of 239 HCV patients, monoclonal bands were detected in 11% of patients compared with 1% of an age-matched control population. (48) Finally, cognitive problems may be more common in chronic HCV patients, even in the absence of clinically significant liver disease or interferon-based therapy. (49,50)

The rate of hepatitis C patients' progression to fibrosis or cirrhosis has been a controversial subject. Cirrhosis rates as high as 50% have been described in cross-sectional studies from liver clinics, (51) although selection bias may have inflated these figures. Estimates of progression after 20 years of chronic HCV infection in prospective analyses range from about 2% in young women in community-based studies (18) to about 20% in middle-aged patients in post-transfusion studies. (52) Although there is generally no correlation between viral factors like genotype and disease progression, (53) host factors contribute strongly to the increased risk of progressive liver disease. Duration of infection, (54) male gender, older age at time of infection, (55) and coinfection with human immunodeficiency virus (56) or hepatitis B (HBV) (57) are all associated with progression of HCV-related liver disease. Coinfection with schistosomes, (58) iron overload, (59) obesity, (60) and coexisting nonalcoholic fatty liver (61) may contribute to the rapidity of HCV progression. Alcohol can also accelerate liver injury, even in small amounts (less than 140 g per week). (62) In fact, alcohol may actually enhance HCV replication. (63)

Once cirrhosis develops, hepatocellular carcinoma (HCC) develops at a rate of about 2% per year (64) (Fig. 2). The risk factors for the development of HCC are similar to those for progression of HCV-related liver disease. (65-68) In the United States, HCV is the most common indication for liver transplantation. (69) Although about 25% of all HCC diagnosed in this country is HCV-related, death from chronic HCV in the United States is more likely to result from end-stage liver disease than from HCC. (70,71)

[FIGURE 2 OMITTED]

Tests for diagnosis, monitoring, and screening

Serum ALT is a readily available and inexpensive test to monitor HCV disease activity. However, a weak correlation exists between the severity of histolysis on liver biopsy and serum ALT levels. (72,73) Furthermore, ALT levels may fluctuate; consequently, a single value in the normal range can neither rule out active infection (74) nor help gauge the severity of underlying liver disease. (75,76) A patient with an initially normal ALT level with confirmed HCV viremia should undergo repeat testing over several months to confirm a persistently normal ALT. Although early normalization of an abnormal ALT level may indicate response to antiviral treatment, (77-79) a decrease or absence of HCV RNA is the most reliable marker to assess the success of therapy.

The preferred screening test and initial test for HCV diagnosis is the enzyme immunoassay (EIA). EIAs detect mixtures of antibodies directed against various HCV antigens including those from the viral core (C), and from nonstructural viral regions 3 and 4 (NS3 and NS4). (80) The third generation EIA detects an additional antigen from the nonstructural region 5 (NS5) and has a very high sensitivity and a specificity greater than 99% in immunocompetent patients. (81) A negative EIA excludes chronic HCV in patients with normal immune systems. Both second and third generation EIAs are commercially available in the U.S.

The development of antibodies against HCV may be impaired in patients on hemodialysis and in those who are profoundly immunodeficient. Conversely, patients with autoimmune diseases may show false positive results. (82,83) In these patient groups, RNA testing should be utilized for diagnosis (Fig. 3). The recombinant immunoblot assay (RIBA) detects similar antigens to those detected by EIA; however, it is technically more demanding and more expensive. The RIBA has been used to confirm positive EIA results in low risk individuals. Yet, given the high sensitivity and specificity of EIA, clinical RIBA testing is essentially obsolete. (84)

[FIGURE 3 OMITTED]

Detection of HCV RNA is important to confirm the diagnosis of active HCV replication and to assess eradication of virus after treatment. To confirm viremia a qualitative RNA assay is recommended. A repeat test should be obtained if the results are negative, since a single negative assay does not exclude HCV replication. On the other hand, a single positive test result affirms active HCV replication. The lower limits of detection for the qualitative test by polymerase chain reaction (PCR) is 50 IU/ml. (85) An alternative test for qualitative HCV RNA detection is the transcription-mediated nucleic acid amplification assay (TMA), which demonstrates comparable specificity and improved sensitivity compared with the PCR assay; it detects as little as 5 IU/mL RNA. (86)

The most important use for the quantitative virologic assays is for monitoring response to treatment. Quantitative HCV assays include PCR and branched chain DNA methods. Regardless of method chosen, it is advisable to use a single method for longitudinal viral load monitoring, because results are not comparable between assays. Moreover, variations of 1 to 2 log units can occur with any assay, so important clinical decisions should not be based on a single RNA determination. (87) The viral load does not predict the likelihood of disease progression or the degree or hepatic injury, (72) but gives prognostic information about treatment. (88,89)

A new enzyme immunoassay capable of quantifying total HCV core antigen has been developed. The HCV core antigen can be used as a marker of viral replication. (90) Preliminary studies show the new assay correlates well with commercially available HCV quantitative RNA tests. (91) However, total HCV core antigen testing is not yet FDA approved.

In attempts to predict HCV disease severity, many authors have analyzed the use of common laboratory tests or serum markers of inflammation and fibrosis. Although an aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio of one or more was useful to diagnose cirrhosis in some studies, (92-94) the ratio failed to predict advanced disease in other studies. (95,96) Nonetheless, the AST/ALT ratio may provide prognostic information in HCV cirrhotic patients that is comparable to that provided by established prognostic scores like Child-Pugh. (94) Products of collagen synthesis and extracellular matrix components like hyaluronic acid have also been investigated, but positive predictive value for cirrhosis is poor. (97) A panel of biomarkers comprised of apolipoprotein A1, haptoglobin, [alpha]-2 macroglobulin, [gamma]-glutamyl transpeptidase (GGT), and total bilirubin appears promising as a surrogate predictor of significant fibrosis. (98) Unfortunately, no single or group of laboratory tests have been well-validated for disease severity prediction in the general HCV population.

Since noninvasive methods are not reliable for determining the activity of HCV-related liver disease, liver biopsy is necessary in most HCV cases. Despite biopsy drawbacks like sampling error and potential complications, histologic analysis is the only reliable predictor of disease progression and prognosis; cirrhosis develops within ten years in nearly all patients with high-grade necroinflammation on liver biopsy. (99) Liver biopsy may also assist in prognostication by providing additional information about steatosis, iron content, and concomitant alcohol use. (100) Finally, information gleaned from the liver biopsy allows patients and their physicians to make better choices with respect to deferring treatment in those with favorable prognoses. In those patients deferring therapy, an initial biopsy can serve as a baseline against which future biopsies could be compared. However, there is no data to suggest an optimal interval in which to rebiopsy.

Despite a paucity of evidence supporting it, semiannual screening for HCC with hepatic ultrasound and alfa-fetoprotein (AFP) is commonly performed in the United States. Only one prospective study from China showed this screening protocol prolonged survival in high risk patients. (101) Although ultrasound has high specificity, (102) it can still detect focal liver lesions other than HCC, (103) sometimes leading to unnecessary invasive testing. Furthermore, AFP misses many HCCs and may inappropriately arouse suspicion of cancer in many patients. (104) If utilized, HCC screening should only be performed in cirrhotic patients, since HCC is rare in those with less advanced stages of liver disease. (70)

Treatment

The absence of detectable serum HCV RNA by qualitative PCR (<50 IU/mL) 24 weeks after completion of therapy, what is known as sustained virologic response (SVR), is the standard measure of a favorable response to treatment; those treated who achieve SVR have a favorable long-term histologic and clinical outcome. (105) However, SVR is a surrogate endpoint, and attaining it has never been well-correlated with improved survival. (106) Nonetheless, the rates of SVR have improved with enhancements in therapy.

The introduction of pegylated interferon has been the most important recent advance in chronic HCV therapy. Covalently bonding a polyethylene glycol (PEG) moiety to an interferon (IFN) molecule backbone enhances interferon's biologic activity and prolongs its half-life. (107) In fact, the standard of care for treatment of chronic HCV for genotype one (approximately 70% of U.S. isolates) (108) has become pegylated interferon (PEG-IFN) and ribavirin, barring contraindications.

Although 48 weeks of treatment with standard interferon with ribavirin resulted in SVR rates as high as 43%, (89) 48 weeks of PEG-IFN with ribavirin increased the sustained response rates to 54 to 56%, as shown in two large, international, randomized, controlled studies, one using PEG-IFN alfa-2b and the other using PEG-IFN alfa-2a. (109,110) In both trials, sustained response rates were significantly higher in the patients with lower baseline HCV RNA levels (under 2 million copies/mL or under 600,000 IU/ml), lesser degrees of fibrosis on pretreatment liver biopsies, lower body weight (under 75 kg), and genotypes two and three.

Treatment is most often recommended for those chronic hepatitis C patients who are at increased risk for progression to cirrhosis, such as those patients with HCV viremia (detectable HCV RNA), elevated aminotransferase levels, and at least moderate inflammation or portal fibrosis on liver biopsy. (111) However, many patients do not fit into the above profile (mild liver disease, persistently normal ALT, etc), and their treatment has been controversial. Therapy for these patients is considered on an individual basis, and details of their treatment are beyond the scope of this article. Nonetheless, more than half of patients with HCV in certain populations are not considered candidates for therapy. The most frequent reasons for exclusion are current alcohol or substance abuse, severe psychiatric illness, and comorbidities like autoimmune or renal disease. (112-114)

Even when patients are offered therapy, an important obstacle to successful treatment is medication intolerability. A critical component of treatment is patient education about potential side effects, and regular follow-up visits during therapy are essential to encourage adherence and to detect adverse effects early.

Side effects of IFN-based combination therapy can be grouped broadly into influenza-like symptoms, neuropsychiatric symptoms, and hematologic abnormalities. In large treatment trials, adverse events prompted therapy discontinuation in 10 to 14% of patients and dose reductions in 32 to 42%. Mild injection site reactions, dose reductions due to cytopenias, and increased flu-like symptoms (in one study), were more common in the pegylated-interferon combination arms compared with the standard interferon combination arms, but the differences were small. (109,110)

Depression can occur in up to one-third of patients on therapy, (109) and many practitioners are treating mild to moderate depression with selective serotonin reuptake inhibitors and other antidepressants. Prophylactic paroxetine has been shown to minimize depression induced by high-dose IFN alfa-2b in melanoma patients. (115) In a more recent prospective trial, nearly 80% of HCV patients developing interferon-induced depression were able to complete therapy successfully when treated concomitantly with paroxetine. (116)

For patients developing significant therapy-related cytopenias, hematopoietic growth factors have become increasingly popular as a means to complete therapy and to prevent both IFN and ribavirin dose reductions. In a prospective, open-label study of HCV-infected patients developing ribavirin-related anemia, patients receiving weekly epoetin alfa had increased hemoglobin levels and maintained ribavirin dosing compared with those patients receiving dose reductions only. (117) In one placebo-controlled study,

(118) HCV patients on treatment using adjunctive epoetin alfa had significantly impoved quality of life scores relative to IFN-treated patients using placebo. Nevertheless, there is currently no evidence that growth factors increase the likelihood of patients achieving SVR. Furthermore, hematopoietic growth factors may be cost-prohibitive.

Prevention and Vaccination

The 2002 National Institutes of Health Consensus Development Panel on Hepatitis C supports methadone treatment programs, needle and syringe exchange programs, and comprehensive education programs for IV drug users as potentially useful means to prevent the spread of the virus. (119) Syringe exchange is independently associated with the cessation of syringe sharing. (120,121) Although some studies suggest that syringe exchange programs can reduce the risk of HCV among IV drug users, the data are not consistent. (122,123)

Regarding the prevention of sexual transmission, the CDC affirms that partners serodiscordant for HCV in monogamous couples need not use condoms. (124) However, if monogamous couples wish to decrease an already low risk of transmission (0.03-0.6% per year; average 0.3% per year), (125) condoms could be used. On the other hand, the use of condoms is advised for infected patients with multiple or short-term sexual partners; sexual promiscuity increases the risk of acquiring HCV. (10,18)

No prospective studies have evaluated the use of cesarean section to prevent HCV transmission from infected mothers to their infants, and there are no data supporting antiviral therapy to prevent vertical transmission. In fact, interferons and ribavirin are contraindicated in pregnancy.

Preventing transmission from healthcare workers to patients has been controversial. Although transmission has been documented, it is rare and limited to case reports. (126-129) Up to half of the reports were confounded by other factors like contamination of patients' narcotics used for healthcare workers' surreptitious habit of IV drug use. (11) The calculated risk for HCV transmission from an RNA-positive surgeon to a patient during an invasive procedure is 0.00018%, which was roughly comparable to the chance of acquiring HCV by transfusion in the United States in the year 2000. (130) The 2002 NIH Consensus Development Panel on the Management of Hepatitis C recommends that no HCV-infected healthcare professional be restricted from his or her work. (119) Despite this recommendation, some health departments have required HCV-infected physicians to obtain informed consent before performing surgery on their patients. (131)

Finally, there is no evidence that casual or household contact with HCV-infected individuals increases the risk of acquiring infection. (132,133) Sharing household items like razors and toothbrushes should be avoided, however.

The CDC recommends that all patients with chronic HCV be vaccinated against hepatitis A and against hepatitis B, if at risk. (124) The recommendations may be based, in part, on a study of 432 patients with HCV who were prospectively followed for 7 years. Of 17 study patients who developed superinfection with hepatitis A, 7 patients developed fulminant hepatic failure, six of whom died. (134) This is a particularly significant rate of morbidity, since monoinfected patients (hepatitis A) develop fulminant hepatic failure in less than one percent of cases. (135,136) Vaccinating HCV patients who are seronegative for hepatitis A has been shown to be cost-effective relative to vaccinating without first checking antibody status or not vaccinating at all. (137) Cost-effectiveness is most favorable for younger patients. (138)

Less supportive evidence exists for recommending hepatitis B vaccination; although, as noted previously, patients with HCV and HBV coinfection may have a higher risk of cirrhosis compared with those monoinfected. (57) No cost analysis on HBV vaccination for HCV patients has been performed.

Acknowledgments

The author would like to thank Tara Douglas-Williams and Claire Campbell in Atlanta Medical Center's Library for their indefatigable efforts in finding his articles.

I Good people are good because they've come to wisdom through failure.
We get very little wisdom from success, you know.
--William Saroyan

Accepted January 15, 2004.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9704-0365

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RELATED ARTICLE: Key Points

* It is reported that almost three million Americans are chronically infected with hepatitis C, but this figure could be a substantial underestimate.

* The preferred screening test and initial test for hepatitis C is the enzyme immunoassay (EIA) which has a high sensitivity and specificity in immunocompetent patients.

* Viral load (HCV RNA) does not predict disease progression or severity of liver damage, but does give prognostic information about treatment.

* The best therapy available for treatment-naive patients is pegylated interferon in combination with ribavirin.

* Vaccination against hepatitis A and B is essential for all HCV-infected patients who are not already immune to these viruses.

Brian L. Pearlman, MD

From the Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA, and the Medical College of Georgia, Augusta, GA

Dr. Pearlman is on the speakers' bureau for Schering-Plough, the company that manufactures one of the two available pegylated interferon products to treat hepatitis C.

Reprint requests to Brian Pearlman, MD, Center for Hepatitis C, Atlanta Medical Center, 315 Boulevard NE, Suite 140, Atlanta, Georgia 30312. Email: [e-mail]