Hepatitis C: Making the Diagnosis, Latest Treatment Guidelines

ABSTRACT

Acute hepatitis C virus infection progresses to chronic disease in about 75% of patients. Abnormalities in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are common in patients with chronic hepatitis C; however, ALT levels often fluctuate—sometimes into the normal range. AST levels that are higher than ALT levels suggest advanced fibrosis in a nonalcoholic patient. A thirdgeneration enzyme-linked immunosorbent assay (EIA) decreases the time needed for detection of seroconversion.

All patients who have a positive EIA result also require a polymerase chain reaction test for hepatitis C virus RNA. A high viral load (2 million copies per milliliter or more) is associated with a lower likelihood of response to treatment. Although a liver biopsy is not essential in making the diagnosis of hepatitis C, it is used to grade and stage the degree of liver disease and guide treatment decisions.

Key words: hepatitis C, diagnosis 

In the 1970s, it became evident that most patients with blood transfusion–related hepatitis did not have hepatitis A or B. The disease was therefore named non-A, non-B hepatitis. The culprit organism in nearly all cases of post-transfusion hepatitis (as well as in most cases of hepatitis in injection drug users and hemophiliac patients, and those with sporadic chronic hepatitis) was identified by molecular cloning techniques in 1989 and designated hepatitis C virus (HCV).^1,2 HCV is a small enveloped virus with a single-stranded RNA genome and an associated RNA polymerase that is responsible for viral replication. It is a member of the flavivirus family, which includes West Nile virus, yellow fever virus, and dengue virus. HCV is the most common cause of chronic liver disease and the leading indication for liver transplantation in the United States. It is responsible for 8000 to 10,000 deaths annually. The overall prevalence of HCV infection has not changed during the past decade, but the age-specific prevalence has shifted to older persons, which indicates a previous hepatitis C epidemic.³ In this article, we review the principal diagnostic guidelines for hepatitis C. In a companion piece, we discuss treatment approaches.

TRANSMISSION

Before HCV was identified and screening was initiated, blood transfusion was a common source of HCV transmission.⁴ Specific blood-product screening with HCV antibody testing has been in place since 1990; it was further refined in 1992. Consequently, the risk of transfusion-acquired hepatitis has been reduced to about 1 in 100,000. Even when transmission by transfusion was common, however, most infections probably occurred as a result of exposure by way of injection drug and intranasal cocaine use.  The principal risk factors for HCV infection are listed in the Table.⁵

NATURAL HISTORY

The percentage of patients who progress to cirrhosis once chronic hepatitis C is established is unknown, nor is it possible to predict the course in any individual patient. Most patients with HCV infection do not succumb to their disease, but the high prevalence of infection in the population ensures a major burden of morbidity and mortality. Cirrhosis develops within 20 years in about 20% of patients after transfusion.⁶ Patients with cirrhosis not only face the usual risks of hepatic failure and portal hypertension but also have a substantial risk (1% to 4% per year) of hepatocellular carcinoma (HCC). However, the risk of HCC is remote in the absence of cirrhosis. Periodic screening (eg, every 6 months) of cirrhotic patients with -fetoprotein tests and sonography to detect early cancer is essential. Risk factors for more rapid progression of hepatic fibrosis in patients with chronic hepatitis C include age more than 40 years at acquisition of infection, male sex, heavy alcohol consumption (more than 30 to 50 g/d), and coinfection with HIV or hepatitis B virus.

DIAGNOSIS

Acute HCV infection is usually asymptomatic. Most patients with hepatitis C present long after chronic infection has become well established. The most common scenario is for patients to have unexpected elevations in liver enzyme levels at the time of routine examinations, evaluations for other conditions, or attempted blood donations. When this occurs, subsequent specific testing will reveal HCV infection. Elevated liver enzyme levels without a history of exposure do not in themselves constitute a diagnosis of hepatitis C. However, unexplained liver enzyme elevations mandate an HCV antibody test. There is no such thing as an elevation that is “too mild” to warrant concern. It is also imperative to ask patients about previous risk factors and tests for HCV even if liver enzyme levels are normal, because up to 30% of HCV-infected patients have persistently normal serum alanine aminotransferase (ALT) levels.⁷ Although these patients are more likely to have mild disease than are those with elevated ALT, mild disease is by no means ensured, and such patients require individualized evaluation.

The symptoms of acute HCV infection include nausea, generalized malaise, loss of appetite, arthralgias, jaundice, and dark urine.⁶  Peak serum ALT elevations may be higher than 2000 U/L but are usually lower,⁸ and illness may persist for 2 to 12 weeks. Acute infection progresses to chronicity in about 75% to 80% of patients, but recent studies have shown that those who present with clinical illness, especially jaundice, have a better chance of clearing infection spontaneously than those who remain asymptomatic.⁹ Fulminant hepatitis from acute HCV infection is extremely rare. DIAGNOSTIC

TESTING

Liver enzymes. In patients with chronic hepatitis C, as in patients with hepatocellular injury from other causes, abnormalities in ALT and aspartate aminotransferase (AST) levels are more frequent than abnormalities in levels of cholestatic markers such as alkaline phosphatase. Isolated alkaline phosphatase elevations should always raise the possibility of other types of liver disease, such as primary biliary cirrhosis, granulomatous hepatitis, infiltrative disease, or biliary tract obstruction. There is at best only a partial correlation between liver enzyme abnormalities and liver pathology.⁷ Fluctuations in ALT levels—sometimes into the normal range—are common in chronic hepatitis C.⁸ Conflicting data exist on the predictive value of an AST:ALT ratio of 1 or higher for advanced fibrosis or cirrhosis,^10,11 but an AST level that is higher than an ALT level in a nonalcoholic patient suggests advanced fibrosis, as does a reduced platelet count or low albumin level.

Anti-HCV antibody. The initial diagnostic step in the identification of hepatitis C infection is the measurement of anti-HCV antibody by enzyme- linked immunosorbent assay (ELISA or EIA). This test screens the patient’s serum against 3 different viral antigens. Although the EIA in current use is 99% sensitive in chronic hepatitis C, it is less reliable in acute infection, and a negative EIA result does not exclude the diagnosis of HCV infection in a patient with acute hepatitis. A third-generation test, EIA-3, decreases the time needed for detection of seroconversion.^12,13 Nevertheless, in patients with acute hepatitis, a polymerase chain reaction (PCR) test for HCV RNA should be performed along with an EIA (see below), because patients with acute HCV infection become viremic before antibody appears. The specificity of EIA is a greater problem than the sensitivity. Many patients who have cleared the infection spontaneously continue to express the antibody. Because antibody may persist in patients with resolved infection, a positive EIA result does not necessarily denote active viremia. Moreover, some patients (including those with autoimmune liver disease or other causes of hyperglobulinemia) appear to express HCV antibody even if they do not have a history of or risk factors for HCV infection. A recombinant immunoblot assay, which tests serum against 4 different antigen bands on nitrocellulose, eliminates such false-positive findings because its results are negative in patients with no history of actual infection. Ultimately, however, all patients with positive EIA results should undergo further testing—including a PCR—for HCV RNA, irrespective of the presence or absence of risk factors or levels of ALT.

PCR. This test confirms the presence of the virus by detecting viral RNA in the serum or liver. If a quantitative PCR is ordered, it will also provide a viral load. The cutoff for many commercial versions of this test is a viral load of 50 IU/mL, or about 100 HCV RNA copies/mL. It is extremely rare for a patient with untreated chronic hepatitis C to have a viral load anywhere near this low; thus, negative test results essentially rule out the presence of active infection. A viral load of 2 million copies or more (800,000 IU/mL) is classified as a high viral load; a number lower than this is considered a low viral load. This cutoff is somewhat arbitrary, but it has been used in many trials to distinguish levels of viremia that are associated with a greater or lesser response to treatment. Thus, a high viral load is associated with a lower chance of response to treatment in patients with genotype 1, the most common HCV genotype in the United States. It is useful to record the viral load before the initiation of antiviral therapy because measurements of viral decline at critical time points are used to predict the likelihood of cure. Branched-chain DNA (b-DNA). B-DNA testing is another way to quantify the viral load. The cutoff for this test is 500 IU/mL; this number signifies that the virus may be present at low levels, but the test is not sensitive enough to detect it. This test is relatively cost-effective and measures linearity over a broad dynamic range, which has been a limitation of past PCR assays.

Genotype. Currently, 6 genotypes and several subtypes of HCV are known; there is a substantial degree of geographic variation.¹ In the United States, genotypes 1, 2, and 3 are common and genotype 1 is predominant. HCV genotype is the most important determinant of response to interferon-based antiviral therapy and helps decide the duration of treatment: 12 months of therapy are recommended for genotype 1, while 6 months are recommended for genotypes 2 and 3. We strongly recommend that quantitative PCR results and genotype be obtained before the patient is referred to a specialist, because this information is critical in the initial discussion with the patient.

Liver biopsy. A liver biopsy is not essential in diagnosing HCV infection, but it is an invaluable tool used to grade and stage the degree of chronic liver disease with regard to inflammation and, even more important, fibrosis (Figures 1, 2 and 3). Many hepatologists perform liver biopsies in nearly all consenting patients with chronic hepatitis C to assess the degree of damage. This is an important factor in such decisions as whether to initiate therapy, how aggressively to treat in the event of significant adverse effects, whether to prolong treatment in virologic nonresponders because of putative histologic benefits (a topic of much interest at present but no universal consensus), and as a baseline against which to compare future biopsies to assess for interval progression. There is an approximately 1:1000 risk of significant hemorrhage associated with biopsy. Transient postprocedure discomfort is much more common; it is generally manageable with analgesics. Puncture of other organs, including lungs, kidney, and gallbladder, may occur rarely; many clinicians, including the senior author, use ultrasonography in all cases to prevent this possibility entirely. 

Serum fibrosis testing. Recently, several serum fibrosis tests have become widely available. Although not yet FDA-approved, they aid in the evaluation of liver fibrosis without the need for a biopsy. These tests are an alternative for patients in whom the biopsy is contraindicated or when a patient declines a biopsy. A recent study shows that one such test has a specificity of 70% to 89% and a sensitivity of 33% to 80%.¹⁴ Liver biopsy remains the gold standard for the staging and grading of chronic liver disease. In the future, however, it is likely that the use of fibrosis markers will increase, and perhaps substantially supplant, liver biopsy. Liver stiffness measurement. This noninvasive experimental test for the evaluation of liver fibrosis in patients with chronic HCV infection is based on transient elastography. According to a recent report, liver stiffness measurement is a promising and reliable method.15  It is not yet routinely available.

REFERENCES

1. Lau JY, Davis GL, Prescott LE, et al. Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Hepatitis Interventional Therapy Group. Ann Intern Med. 1996;124:868-876.

2. Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244: 359-362.

3. Gregory L, Armstrong, Edgar P, et al. The prevalence of HCV infection in the United States. Hepatology. 2004;40(4 suppl 1):176A.

4. Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med. 1989;321:1494-1500.

5. Murphy EL, Bryzman SM, Glynn SA, et al. Risk factors for hepatitis C virus infection in United States blood donors. NHLBI Retrovirus Epidemiology Donor Study (REDS). Hepatology. 2000;31:756-762.

6. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology. 1997;26(3 suppl 1):15S-20S.

7. Merican I, Sherlock S, McIntyre N, Dusheiko GM. Clinical, biochemical and histological features in 102 patients with chronic hepatitis C virus infection. Q J Med. 1993;86:119-125.

8. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 2001;345:1452-1457.

9. Gerlach JT, Diepolder HM, Zachoval R, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology. 2003;125:80-88.

10. Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1998;93:44-48.

11. Reedy DW, Loo AT, Levine RA. AST/ALT ratio > or = 1 is not diagnostic of cirrhosis in patients with chronic hepatitis C. Dig Dis Sci. 1998;43: 2156-2159.

12. Uyttendaele S, Claeys H, Mertens W, et al. Evaluation of third-generation screening and confirmatory assays for HCV antibodies. Vox Sang. 1994; 66:122-129.

13. Kao JH, Lai MY, Hwang YT, et al. Chronic hepatitis C without anti-hepatitis C antibodies by second- generation assay. A clinicopathologic study and demonstration of the usefulness of a third-generation assay. Dig Dis Sci. 1996;41:161-165.

14. Sebatiani G, Vario A, Boccato S, et al. Predictive value of three non-invasive methods for assessing liver fibrosis in chronic hepatitis C. Hepatology. 2004;40(4 suppl 1):280A.

15. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by liver stiffness measurement (LSM) in patients with chronic hepatitis C: the importance of sampling. Hepatology. 2004;40(4 suppl 1):279A.

LATEST TREATMENT GUIDELINES

ABSTRACT

Combination therapy with pegylated interferon alfa-2a or alfa-2b and ribavirin (RBV) results in a greater rate of sustained virologic response (SVR) than that seen with standard interferon alone. Patients infected with hepatitis C virus genotype 1 require higher doses of RBV and a longer duration of therapy than do patients infected with genotype 2 or 3. Closely monitor patients for neuropsychiatric effects, especially depression, and hematologic and other toxicities. Because of the teratogenicity of RBV, strict birth control must be used throughout the course of treatment and for 6 months afterwards. Patients who have not demonstrated a 100-fold reduction in viral load after 12 weeks of therapy are unlikely to achieve SVR; discontinuation of therapy may be considered.

Key words: hepatitis C, therapy

In most areas of the country, the treatment of hepatitis C generally falls within the purview of specialists in gastroenterology, hepatology, or infectious diseases, although primary care physicians who treat a large number of patients with hepatitis C may also choose to administer treatment. We recommend that only clinicians who are thoroughly familiar with the disease and its management undertake the care of these patients, unless there is no alternative. In this article, we discuss current therapeutic strategies. In a companion piece, we review diagnostic guidelines.

FIRST-LINE TREATMENT

The current standard of treatment for chronic hepatitis C is a combination of pegylated interferon (PEG-IFN) alfa-2a or alfa-2b and ribavirin (RBV). The rationale for binding IFN to a polyethylene glycol (PEG) molecule is that this process delays clearance of the drug, which results in higher peak drug levels and a prolonged half-life, with a much greater pharmacokinetic area under the curve. As a result, PEG-IFN can be given once weekly, with more constant exposure to drug than is possible with the traditional regimens of standard IFN 3 times weekly. PEGIFN alfa-2a is formulated as a fixed dosage of 180 μg/wk; PEG-IFN alfa- 2b is formulated as a weight-based dosage of 1.5 μg/kg/wk. In multicenter trials, the rate of sustained virologic response (SVR) (defined as an absence of detectable virus in the serum 6 months after completion of antiviral therapy) was 54% to 56% for patients treated with PEG-IFN alfa-2b or alfa-2a plus RBV.^1,2  SVR occurred in 42% to 46% of patients with genotype 1 and 76% to 82% of patients with genotype 2 or 3. In the PEG-IFN alfa-2a study, PEG-IFN was dosed at 180 mg/wk and RBV at 1000 to 1200 mg/d (depending on whether body weight was more or less than 75 kg).² The PEG-IFN alfa-2b was dosed at 1.5 mg/kg/wk and RBV at 800 mg/d.1 The different study designs, drug doses, and patient populations in these trials preclude a direct comparison of the results. In both studies, however, higher body weight was associated with a weaker response, possibly because of the fixed dose of PEG-IFN in one study and of RBV in the other. A third pivotal study with PEGIFN alfa-2a showed that patients infected with hepatitis C virus (HCV) genotype 1 had superior results if RBV was dosed at 1000 to 1200 mg/d rather than 800 mg/d and if treatment was given for 48 weeks rather than 24 weeks.³ In contrast, patients with genotype 2 or 3 fared equally well at either dose of RBV and with 24 or 48 weeks of therapy. Hepatitis C therapy has significant adverse effects; these are listed in the Table. Discontinuation because of side effects occurred in 13% of patients in the pivotal trials; dose reductions occurred more frequently, usually because of hematologic adverse effects. Patients require close monitoring for neuropsychiatric effects, especially depression, and hematologic and other toxicities. Because of the teratogenicity of RBV, strict birth control must be used regardless of which partner is undergoing treatment, both throughout the treatment period and for 6 months afterwards. Contraindications to treatment include major depression, autoimmune disease, severe cardiac or pulmonary disease, and moderate to severe cytopenia. Important predictors of a favorable response include non–genotype 1 disease, low viral load (less than 800,000 IU/mL), younger age, and mild or no fibrosis.

EARLY VIROLOGIC RESPONSE

There has long been interest in identification of early time points at which patients destined not to have an SVR can discontinue therapy, confident that they are not being deprived of a meaningful opportunity for cure. The best time point that has been identified in this context is 12 weeks, at which time failure to have achieved at least a 2-log (100-fold) reduction in viral load is associated with a virtually negligible chance of subsequent SVR.^4,5  Thus, a greater than 2-log reduction at week 12 has come to be termed an early virologic response. If the patient is a responder, therapy is continued and a viral load measurement is repeated at 24 weeks. Persistent viremia at that point generally leads to treatment discontinuation, because it, too, is associated with a very low subsequent chance of SVR. In certain settings, however—such as near-complete clearance and a steady decline in viral load from the 12-week point—a clinician might choose to continue therapy despite the small chance of success.

At completion of therapy, the viral load is measured again. If it is undetectable, the patient is considered to have had an end-of-treatment response. A viral load measurement is repeated 6 months after the completion of therapy. If results of a polymerase chain reaction test are still negative, the patient is considered to have had an SVR. Not all patients who achieve early virologic response go on to SVR. About 15% to 20% of patients may clear the virus completely but relapse after the completion of therapy. Others may have a “breakthrough relapse” during treatment, and still others may have a 2-log reduction by week 12 but never entirely clear HCV RNA. A recent study of patients who had achieved SVR showed that some may continue to harbor small quantities of HCV RNA in the liver; this challenges our current notion of “cure,” but for practical purposes, relapse beyond 6 months after cessation of therapy is virtually never seen.⁶

RECENT FINDINGS AND EMERGING TRENDS

Extended therapy. The recommended duration of PEG-IFN and RBV therapy is 48 weeks for genotype 1 infection when there has been at least a 2-log reduction in viral levels by 12 weeks. However, a recent study has shown that prolongation of therapy to 72 weeks in patients who do not achieve complete viral clearance by week 4 results in a significantly higher rate of SVR than that achieved with cessation of therapy at week 48 (48% vs 32%).⁷ In another study of patients with genotype 1 disease who were treated for 48 weeks versus 72 weeks, 72 weeks of treatment in patients still viremic at week 12 significantly reduced the relapse rate compared with 48 weeks of treatment.⁸ Thus, some experts favor an extended course of treatment in patients with “slow virologic response” (ie, delayed clearance of HCV RNA). HIV and HCV coinfection. This is a major problem because one third of HIV-infected persons in the United States have HCV infection, and these patients are at risk for more rapidly progressive liver disease than monoinfected patients. Recent studies have demonstrated that in coinfected patients, as in monoinfected patients, combination therapy with PEG-IFN and RBV is superior to that with standard IFN and RBV.^9,10  Although SVR rates are lower in coinfected than in monoinfected patients, HCV-HIV coinfection mandates serious consideration of HCV therapy. Ethnicity. Studies have shown that significant differences in treatment response exist among various ethnic groups. For example, in one study involving African Americans and non-Hispanic whites infected with HCV genotype 1, the responses to treatment were 19% and 52%, respectively.¹¹ More recently, it was reported that weight-based RBV (800 to 1400 mg) combined with PEG-IFN alfa-2b doubles the rate of SVR in African Americans, compared with a fixed dose of RBV (800 mg). However, even with weight-based dosing, the rate of SVR was lower (21%) than that seen in many studies of non–African American patients.¹² A large NIH-sponsored study is currently evaluating HCV therapy in 200 African American and 200 white patients. It is also assessing the scientific mechanisms that underlie an impaired response, such as the possibility of inadequate activation by IFN of IFN-response genes.

REFERENCES:​

1. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

2. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

3. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140;346-355.

4. Davis GL, Wong JB, McHutchison JG, et al. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.

5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

6. Radkowski M, Gallegos-Orozco JF, Jablonska J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology. 2005;41:23-25.

7. Sanchez-Tapias JM, Diago M, Escartin P, et al. Longer treatment duration with peginterferon alfa- 2a (40KD) (PEGASYS) and Ribavirin (COPEGUS) in naïve patients with chronic hepatitis C and detectable HCV RNA by week 4 of therapy: final results of the randomized, multicenter TERVIC-4 study. Hepatology. 2004;40(4 suppl 1):218A.

8. Berg T, von Wagner M, Hinrichsen H, et al. Reduction of the relative relapse rate by prolongation of the duration of a therapy with peginterferon alfa- 2a plus ribavirin in patients with genotype 1 infection up to 72 weeks. Hepatology. 2004;40(4 suppl 1): 238A.

9. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438-450.

10. Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/ HCV co-infected patients. AIDS. 2004;18:F27-F36.

11. Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265-2271.

12. Jacobson I, Brown R, McCone J, et al. Weightbased ribavirin dosing improves virologic response in HCV-infected genotype 1 African Americans compared to flat-dose combination therapy. Hepatology. 2004;40(4 suppl 1):217A.