Management of Chronic Hepatitis C
Renard A. Rawls, M.D., Louis Lambiase, M.D., Jianjun Li, M.D.
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EpidemiologyHepatitis C virus (HCV) infection is a global public health problem; it is the most common chronic blood-borne infection. Worldwide an estimated 170 million people are infected with the hepatitis C virus. In the United States at least 3.9 million persons (1.8%) are anti-HCV seropositive, and 2.7 million are chronically viremic. Sixty-five percent of antibody-positive persons are 30 to 49 years old. The annual incidence of HCV is approximately 38,000 in the United States. Injection drug use is one of the most efficient routes for HCV transmission and has been the dominant mode of HCV transmission during the past 30 years, accounting for 60-80% of prevalent infection. There has been an 80% decrease in the incidence of new cases of HCV during the past decade, as a result of screening and testing practices in most developed countries. The implementation of more sensitive multi-antigen testing has further reduced the risk of transfusion-associated HCV infection to an estimated 0.01%-0.9% per recipient transfused 1. The frequency of sexual transmission of HCV is low, approximately 5%, and there is no current recommendation as far as barrier precautions for patients in stable monogamous sexual relationships. However, co-infection with human immunodeficiency virus (HIV) or multiple sexual partners increases the risk of sexual transmission of HCV. Perinatal exposures account for a small proportion of HCV infections. A summary of such studies demonstrates an average risk for transmission of 6% (range, 0-42%) for infants born to HCV-positive mothers and 17% (range, 8.5-44%) for infants born to mother coinfected with HCV and HIV. Available data are limited on the relationship between the risk for perinatal transmission of HCV and mode of delivery or type of feeding, neither of which indicates increased risk for transmission. Although healthcare workers with exposure to blood are at risk for being infected with HCV and other blood-borne pathogens, the prevalence of HCV infection among healthcare workers appears to be no greater than that found in the general population. Other risk factors responsible for HCV transmission include solid organ transplantation from HCV donors, hemodialysis patients, needle-stick exposures, nosocomial transmission, household exposure, and high-risk behaviors (body piercing, tattooing and non-IVDA exposure to bloody objects such as intranasal cocaine). Patients with hepatitis C should avoid sharing razors, toothbrushes, and other personal items that could be contaminated with blood. They should also be counseled not to donate blood and to cover open cuts. VirologyThe entire HCV genome sequence was identified by 1989. The viral structure consists of a single-stranded RNA genome within a nucleocapsid packaged in an envelope derived from host membranes. HCV is a member of the flaviviride family, and the structure is typical of the flavivirus. There is a high rate of replication with HCV and because of this there is also an exceedingly high mutation rate. There are 7 different genotypes and more than 50 subtypes in HCV. The same genotype has an overall 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 only about 65%. To date, all genotypes have been found to be both hepatotropic and pathogenic. The critical question of the significance of the HCV genotypes and subtypes for pathogenesis is still controversial. However, more consistent data have been accumulated on the association between genotype and response to viral therapy. Patients infected with genotype 1 and genotype 4 respond poorly to interferon treatment compared with patients infected with genotypes 2 and 3. Different genotypes are associated with differences in geography and differences in the mode of acquisition. In the United States, genotype 1 is most prevalent (about 75%); genotypes 2 (10.8%) and 3 (5.8%) are less common. The second component of genetic heterogeneity is known as quasispecies. Quasispecies are closely related yet heterogeneous sequences of HCV within a single infected individual that result from mutations occurring during viral replication. The clinical significance of quasispecies is an active area of investigation. Natural HistoryThe incubation period after acute exposure to Hepatitis C ranges from 2 weeks to 26 weeks. Only 30% to 40% of adults who are acutely infected develop symptoms, and these symptoms are generally quite mild and non-specific. Fulminant hepatic failure is a rare feature of acute hepatitis C infection. Approximately 25% of patients acutely infected with hepatitis C go on to clear the infection as evident by normalization of aminotransferase levels and undetectable serum HCV RNA. Chronic hepatitis, defined as persistently elevated serum aminotransferase levels for greater than six months, develops in approximately 75% of patients who are acutely infected with hepatitis C 2. In certain cases, chronic hepatitis is manifested by normal liver function tests but with persistent viremia, as determined by detectable HCV RNA in serum and histological changes on liver biopsy. Cirrhosis develops in 20-30% of patients with chronic hepatitis C, usually 2-3 decades after initial exposure. The risk of hepatocellular carcinoma (HCC) is approximately 1-4% per year in patients with cirrhosis and hepatitis C in the United States. The interval to development of histologically recognized chronic hepatitis, cirrhosis, and HCC are 10, 20, and 30 years, respectively. Certain factors may increase the chances of developing chronic Hepatitis C in a patient who is acutely infected. Genotype 1b, large inocula of HCV (as in posttransfusion hepatitis C), and poor host immune response are all independent risk factors associated with an increased chance of developing chronic hepatitis C. Among persons with chronic HCV, older age at the time of infection, alcohol abuse, male gender, and human immunodeficiency virus co-infection have all been associated with rapid disease progression. Pathogenesis of Liver InjuryBoth humoral and cellular immune responses are initiated by HCV infection. CD4 and T helper cells play a major role in organizing the host response. Production and secretion of interleukin 2, interferon gamma, and tumor necrosis factor are all part of the immunologic defense against hepatitis C. Patients with a good cellular immune response are able to clear the infection from the blood. However, 75% of the cases of HCV go on to develop persistent infection. If viral clearance is not achieved with cellular immune response, liver damage may result from chronic destruction of hepatocytes by increased cytokine activity. This process may lead to inflammation, fibrosis and ultimately cirrhosis. The humoral response is responsible for most of the extrahepatic manifestations of HCV. Clinical Manifestations The overwhelming complaint of patients with chronic infection is fatigue. However, the severity of this symptom is not necessarily related to the severity of the underlying liver disease. Other non-specific symptoms include depression, nausea, anorexia, abdominal discomfort, and difficulty with concentration. Once patients develop liver cirrhosis, they are at risk for the complication of portal hypertension (e.g., ascites, gastrointestinal bleeding, encephalopathy, etc.). Most studies involving hepatitis C are limited to its liver manifestations. However, HCV is a systemic illness and many extrahepatic manifestations are. These can include membranoproliferative glomerulonephrititis, essential mixed cryoglobulinemia, porphyria cutanea tarda, leukocytoclastic vaculitis, focal lymphocytic sialadenitis, Mooren corneal ulcers, lichen planus, idiopathic pulmonary fibrosis, and rheumatoid arthritis. Some of these associations are more convincing than others. HCV infection is strongly implicated in the pathogenesis of membranoproliferative glomerulonephritis and essential mixed cryoglobulinemia, presumably by immune complex deposition. Interferon (IFN) therapy has resulted in improvement in symptoms and decrease in viral RNA in patients with HCV-related essential mixed cryoglobulinemia, although this effect appears to be transient. IFN therapy in patients with membranoproliferative glomerulonephritis has been associated with a reduction in proteinuria. DiagnosisThe most commonly used screening test for HCV in the United States is the enzyme- linked immunoassay (ELISA). The sensitivity of this test is approximately 95%. False positive results may be seen in patients with autoimmune disease and alcoholic liver disease. False negative test results may be seen in immunocompromised individuals and in patients who are acutely infected where the patient's immune system has not yet mounted an antibody response. Importantly, the antibodies identified in the diagnosis of HCV infection are not protective against the virus. In patients with abnormal liver blood tests and known risk factors for HCV, a positive antibody test is sufficient for establishing a diagnosis of HCV infection. The recombinant immunoblot assay (RIBA) can be used to confirm the diagnosis since the RIBA is more specific, but not more sensitive, than the enzyme immunoassay. Generally, physicians will measure the virus levels directly if confirmation of the diagnosis is needed. Viral detection is accomplished by amplification methods such as polymerase chain reaction assays (PCR) or quantitative assays such as the branched DNA signal amplification assay (bDNA). These tests are useful in the early diagnosis of acute HCV infection for documenting viremia in seropositive persons and for testing immunosuppressed patients who may have a false negative enzyme immunoassay. Quantification of viral RNA is useful in monitoring the response to antiviral therapy. Liver biopsy is not necessary for the diagnosis of HCV infection but biopsy is the gold standard for grading and staging. The range of histologic findings in patients with chronic HCV infection is broad, from minimal periportal lymphocytic inflammation to active hepatitis with bridging fibrosis, hepatocyte necrosis, and frank cirrhosis. Steatosis, lymphoid aggregates, and bile duct damage are frequently found in the liver biopsies. A liver biopsy is useful in assessing the rate of disease progression and predicting the likelihood of treatment response. Therefore, current recommendations are to perform a liver biopsy prior to treatment of HCV infection, and to treat only those patients with significant fibrosis at biopsy. Observation and biopsy 3 5 years later is generally advised for patients without fibrosis and without symptoms of chronic HCV infection. A liver biopsy is absolutely necessary before treatment when there are any questions about a coexisting disease such as autoimmune hepatitis, hemachromatosis, or pre-existing cirrhosis. Management The goals of therapy are to eliminate HCV RNA in the blood (virological response) and obtain normalization of ALT levels (biochemical response). A sustained virologic response is defined as having undetectable HCV RNA 6 months after treatment is completed. It has been demonstrated that more than 95% of HCV patients who achieved sustained virologic response have undetectable HCV RNA in liver biopsies up to 5 years after completion of treatment. Currently approved treatment options for HCV include interferon alfa-2b (Intron-A), pegylated interferon (PEG-Intron), Imfergen, and ribavirin. Interferon alfa-2b used as monotherapy was approved for HCV therapy in 1991, and was approved in combination with ribavirin since 1998. The usual dose of interferon alfa-2b monotherapy is 3 million international units by subcutaneous injection 3 times a week for 6-12 months. This therapy produces a poor rate viral sustained response (range, 3%-19%), which is defined by negative HCV RNA in 6 months after stopping therapy. This response is significantly improved by combining interferon and ribavirin to achieve viral sustained responses of 30%-45% 3. Imfergen is a laboratory-designed interferon with an active site that takes advantages of the best features of naturally occurring interferons. Imfergen produces results similar to interferon alfa-2b when used as monotherapy and has been used by some clinicians. Imfergen is approved by the US Food & Drug Administration (FDA) for use as monotherapy but not in combination with other agents. Interest in Imfergen has waned since the introduction of clearly superior combination therapies. Peg interferon alfa-2b has been approved for HCV therapy alone since January 2001, and in combination with ribavirin since August 2001. The conjugation of IFN with polyethylene glycol (pegylation, PEG) affords improved delivery of IFN by significantly prolonging the plasma half-life. Pegylation offers a number of clinical advantages: enhanced pharmacological activity, increased half-life, reduced immunogenicity and increased patient compliance. Both PEG-Intron (peginterferon alfa-2b, by Schering Oncology/Biotech) and PEGASYS (peginterferon alfa-2a, by Roche Lab) have been evaluated as monotherapy in HCV patients 4,5. When compared to standard interferon monotherapy, superior efficacy has been observed with peginterferon. More recently, combination therapy with peg interferon plus ribavarin has become the standard of care in HCV therapy. In multi-center clinical trials, peg interferon alfa-2b 1.5 ug/kg per week plus ribavirin 800mg per day administered for 48 weeks is associated with a sustained virologic response of 54%, and the combination of peginterferon alfa-2a at a dose of 180ug once per week and ribavirin 1000-1200 mg per day is associated with a sustained virologic response rate of 56%. A reversal of cirrhosis or fibrosis progression was observed in 49% of patients with baseline cirrhosis. It has been suggested that interferon therapy, even in the absence of sustained viral elimination, decreases the rate of fibrosis progression and may prevent or delay the onset of complications from disease progression, including HCC. A multiple-center clinical trial with low dose of peginterferon maintenance therapy sponsored by the NIH will provide further information on anti-fibrosis therapy. The combination of peginterferon and ribavirin causes significant adverse effects. Treatment regimens for HCV infection are difficult to endure and require a serious commitment on the part of the patients. Adverse effects of the medication are common and often poorly tolerated. The most frequently reported adverse events are flu-like symptoms with fatigue, malaise, myalgia, and fever. This seems to abate over time. Injection site inflammation occurs but is not treatment limiting. Depression is nearly universal and can be severe. Dose modification and dose discontinuation guidelines may limit the incidence of severe problems. Memory loss, hair loss, cardiac disease, and even permanent autoimmune thyroid dysfunction are among the other reported side effects. Ribavarin (1-b-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) is a guanosine analogue that is a broad-spectrum antiviral agent that targets both DNA and RNA viruses. The most common side effect of ribavirin is a dose-related hemolysis that is usually mild and is reversible when therapy is stopped. It can be anticipated that greater than 50% of patients will experience a >2 g/dl reduction in hemoglobin. Most of this reduction occurs during the first 8-12 weeks of therapy and is of lesser clinical impact if the baseline hemoglobin is normal. Ribavarin has been shown to have teratogenic and embryo toxic effects at low doses in all animal species tested; birth control is mandatory for men and women receiving ribavarin if there is the possibility of a pregnancy occurring. Factors which are predictive of a sustained viral response including genotype other than Types1 or 4, low stage of fibrosis, low HCV viral load, and patient's ability to tolerate treatment. Alcohol abuse and injecting drug abuse have been suggested as predictors of poor outcome in treatment. Adherence to therapy is crucial to the success of HCV therapy and was recently confirmed as a key factor in determining outcome to combination treatment. It is important for patients to take at least 80% of their peginterferon dose and at least 80% of their ribavirin dose for at least 80% of the recommended duration of treatment ("80+80+80 adherence"). With 80+80+80 adherence to the weight-based dosing regimen of both peginterferon alfa-2b (1.5ug/kg) and ribavirin (>10.6mg/kg), the viral response rate increased from 61% overall to 72%. In our experience, intense physician and nursing support is necessary to insure continuance with therapeutic regimens. Particularly important is the prompt recognition and treatment of mood disorders and depression that result from interferon therapy. Several studies have shown that characteristics of clinicians, the quality of the clinician-patient relationship, aggressive counseling, simplified therapeutic regimens and directly observed treatment (DOT) substantially improves adherence to therapy. Since DOT has been effective in treating TB and HIV patients, it stands to reason that DOT may be effective in the treatment of some special group of HCV, such as substance abusers, who raise concerns over possible non-adherence. Even with the combination therapy of peginterferon and ribavirin, there are still 50% of HCV patients who do not respond to the current therapy. The new drugs that have received the greatest attention thus far are antisense molecules and ribozymes (enzymes composed of RNA). HCV is difficult to eradicate even with long-acting immune modulators and a cocktail of drugs. Thus, HCV vaccine research has been given a high priority. The availability of HCV RNA-derived replicons and chimeric viruses opens the door to the development of anti-HCV RNA drugs analogous to the aminoglycoside antibiotics. Atomic structural maps of HCV RNA elements will also advance this area of pharmaceutical development. References
Jacksonville Medicine / June/July, 2002[dcms-footer.htm]
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