Hepatitis ฺc virus /Disease/ HCV / โรคไวรัสตับอักเสบ ซี

Hepatitis C virus (HCV) is a heterogeneous, single-stranded, positive-sense RNA virus belonging to the Flaviviridae family. Like many other RNA viruses, HCV has an inherently high mutation rate, resulting in considerable genetic heterogeneity throughout the genome. This genetic heterogeneity subdivides the hepatitis C virus into six major genotypes that vary in distribution worldwide (47). Genotype 1 appears to be the predominant type in Canada (46-49). Quasispecies are closely related variants of a single genotype within a single individual, which arise from mutations that occur during viral replication. Quasispecies diversity may increase with time and contribute to interferon resistance and viral persistence.

Information on the rates of development of chronicity after an initial HCV infection comes largely from studies of post-transfusion hepatitis. In these studies viral clearance from serum occurred in about 20-30% of patients initially infected with hepatitis C. It is not known whether this is also true for hepatitis C acquired through other routes. To be confident that viral clearance has been achieved PCR-based assays must be used. Negative HCV RNA by PCR assays indicate viral clearance from serum, but give no information about the state of HCV in the liver or in other privileged niches (e.g., lymphocytes). Thus, given the current state of knowledge complete viral clearance cannot be ascertained with certainty. Therefore, patients who are anti-HCV-positive who have spontaneously developed negative HCV RNA by PCR should continue to be monitored at intervals for the presence of liver disease.

The outcome of chronic hepatitis C virus infection is not well defined. A proportion of patients will ultimately develop cirrhosis and hepatocellular carcinoma (50-52). However, the proportion of patients at risk for this outcome has not been accurately determined. Various reports have suggested that the lifetime risk of cirrhosis in HCV carriers is between 20-50%. Although several factors have been identified which increase this risk, e.g., alcohol consumption (53-55), the magnitude of increase in risk has not been well defined. Furthermore, the rate at which disease progresses has also not been completely defined (56-58). Some studies have indicated that after 17 years of infection the prevalence of cirrhosis is no more than 2% (60). Other studies have indicated that the mean duration between infection and the first diagnosis of cirrhosis is about 20 years (50). The differences in these studies are accounted for by referral bias.As a result there is considerable uncertainty about the rate of disease progression.

Factors that increase the risk of progression to cirrhosis include age over 40, consumption of even moderate amounts of alcohol (53-55), and increased age of acquisition of infection.Patients infected by transfusion are also thought to have more aggressive disease, but in this cohort having a transfusion may be a surrogate marker for increased age at acquisition of disease, since the transfused population is considerably older than the average population. The risk of progression to cirrhosis also appears related to the degree of liver inflammation and fibrosis seen at the time of a biopsy. Patients with persistently normal ALT have a lower likelihood of progression to cirrhosis (56,60,61).There is no clear association of disease progression with genotype or viral load. Co-infection with HIV is associated with higher viral loads, and a more rapid progression to cirrhosis. Co-infection with hepatitis B is associated with a greater risk of HCC than either disease alone.

Predictions of disease progression depend on the assumption that the rate of disease progression is linear, and that it takes an equal amount of time to progress from e.g., stage 1 fibrosis to stage 2 fibrosis as from stage 3 to stage 4 fibrosis. This assumption may not be correct.

Once cirrhosis has developed the 10 year survival is about 80%. However, the rate of development of complications of cirrhosis over the same time period is about 40% (62).

Over the next 10-20 years chronic hepatitis C is predicted to be come a major burden on the health care system in Canada as patients who are currently asymptomatic with relatively mild disease progress to end-stage liver disease and develop hepatocellular carcinoma. Predictions in the USA indicate that there will be a 60% increase in the incidence of cirrhosis, a 68% increase in hepatoma incidence, a 279% increment in incidence of hepatic decompensation, a 528% increase in the need for transplantation, and a 223% increase in liver death rate. There are no comparable studies to assess the future health burden in Canada, but since the demographics in the US and Canada are similar, we can expect a similar increase in these disease states in Canada.

Acute hepatitis C

Since 1991, the routine screening of blood products has decreased the prevalence of acute HCV following
transfusion to negligible levels. Therefore, acute HCV infection is now seen mainly in individuals who have received an accidental needle stick injury. Although a risk for infection is relatively low at < 5%, because the majority of these individuals are health care workers, every effort should be made to make an early diagnosis, and thereby minimize the risk of nosocomial transmission. There are no data to indicate which testing algorithms, using serological tests or PCR assays, are more cost effective. HCV RNA may become positive as early as 2 weeks after exposure. Anti-HCV usually becomes positive 10 weeks after exposure. There has been a suggestion that early treatment of acute hepatitis C with interferon monotherapy C may enhance the likelihood of response compared to chronic hepatitis C (85-87). There is no information as to whether this is true for interferon and ribavirin. The possibility of an enhanced response to early therapy has to be balanced against the theoretical 20% chance of spontaneous clearance of the virus. No recommendations can be made about the timing of therapy of acute hepatitis C. The following recommendation is therefore based on expert opinion, rather than evidence from the medical literature. Healthcare workers or others subjected to needle-stick injury or equivalent exposure should be tested by anti-HCV at the time of the injury and at 12 weeks or later to detect infection. Treatment should be with standard combination therapy of interferon and ribavirin for the standard duration despite the lack of prospective studies proving efficacy. Given the urgent need to gather data on such cases it is strongly recommended that patients with acute hepatitis C be treated in the setting of a clinical trial or a registry

The prime indication for treatment in chronic hepatitis C is an ALT level more than 1.5 times the upper limit of normal on three consecutive occasions over more than three months.

Patients with ALT levels below 1.5 times the upper limit usually have mild disease and an excellent prognosis (60). Treatment may not be required. Interferon monotherapy treatment in this group is largely ineffective. There are no data on the use of interferon and ribavirin combination therapy in this group.

Although the ALT is the trigger for considering treatment, other factors may also influence the decision whether to treat or not. A liver biopsy is recommended for grading and staging of the liver disease. When treating immunosuppressed patients such as renal or bone marrow transplant recipients, a biopsy is mandatory to confirm the diagnosis. If the biopsy is normal or shows minimal disease then treatment may not be necessary. An adequate biopsy consisting of at least 3-5 portal zones is necessary for assessment. Many other factors have to be taken into consideration before deciding to treat a particular patient. Most important is to try to make an assessment of whether the patient will ever develop cirrhosis and liver failure, or particularly in patients over age 50, whether completing causes of mortality are more or less likely to cause death.

Liver biopsy may also be required in patients in whom treatment is not being considered, in order to assess the extent of liver injury.

It is recommended that response to treatment be defined in virologic terms. The use of ALT levels to define response to treatment is no longer recommended. Successful treatment is indicated by clearance of hepatitis C virus RNA from serum (by sensitive PCR-based assays) 6 months after the completion of therapy (sustained response). There is now evidence showing that this response is durable, in that serum HCV RNA remains negative for years (74). ALT levels return to normal, and the incidence of complications of cirrhosis and hepatocellular carcinoma are reduced. Survival is improved.

Dose and Duration of Treatment

The recommended treatment for chronic hepatitis C is with a combination of interferon alpha 2b and ribavirin. The dose of interferon is 3 mu TIW, and the dose of ribavirin is 1000 mg for patients weighing less that 75 kg, and 1200 mg daily for patients weighing more than 75 kg (75-77). The use of interferon alpha 2a or other interferons in combination with ribavirin has not been reported.

Overall, about 40% of patients treated with this combination will have a sustained response. Patients with genotype 2 or 3 have about a 65% response rate (76,77). Patients with genotype 1 have about a 30% response rate. The response rates in other genotypes are not as well defined. Response rates are also improved with lower viral loads (< 2x10⁶ copies/ml by the NGI assay), age less than 40 years, absence of fibrosis and female gender (77).

Treatment duration with interferon and ribavirin is determined by the viral genotype. Patients who carry genotypes 2 or 3 may be treated for 24 weeks. Patients carrying any other genotype should be treated for 48 weeks (53,54). Viral load may be used to predict response to therapy, but the data on viral load as an indicator of duration of treatment were weaker than for genotype, and viral load should not at this stage be used to determine duration of therapy. An algorithm has been developed using several of the favourable response factors listed above (77). However, the algorithm has not been prospectively validated, and should not be used to determine treatment duration.

Unlike interferon monotherapy, a small number of patients treated with interferon and ribavirin who ultimately become long term responders first clear HCV RNA between 12 and 24 weeks of therapy. There is as yet insufficient data to recommend whether the 12 week stop rule described for interferon monotherapy (see below) also applies to combination therapy. Approximately 14% of patients with positive HCV RNA assays at 12 weeks will become sustained responders. However, it is clear that patients who fail to clear HCV RNA by 24 weeks of treatment will not become sustained responders. Therefore, a positive HCV RNA assay after 24 weeks of therapy is an indication to stop treatment.

Interferon monotherapy should now be reserved for patients who cannot tolerate ribavirin (e.g., patients with anemia). The intended treatment duration of interferon monotherapy is 48 weeks. Response is assessed at three months using the qualitative HCV RNA test. Failure to clear HCV RNA after three months of therapy predicts inability to develop a sustained response. Treatment should be stopped if the HCV RNA is positive at three months.

Monitoring During Therapy

The addition of ribavirin to the therapy increases the likelihood of side effects. Ribavirin predictably causes hemolysis. The hemoglobin level falls within the first 2-4 weeks, then stabilizes in most patients. Ribavirin dose reduction is recommended if the hemoglobin falls below 100 gm/l. Routine monitoring for adverse effects includes a CBC weekly for the first month then CBC monthly and TSH every 3 months (there is a increased incidence of thryroiditis on interferon therapy, particularly in patients with chronic hepatitis C). Symptoms should be monitored monthly during treatment.

Treatment response is monitored by the ALT and the HCV RNA concentration. ALT is an imperfect surrogate marker for viral clearance, so that HCV RNA testing is mandatory at the appropriate time points (12 or 24 weeks of therapy, and 24 weeks after completion of therapy). Qualitative HCV RNA testing is adequate to determine response. Quantitative HCV RNA is not required.

Contraindications to therapy

In assessing whether a patient is a good candidate for therapy with interferon and ribavirin, it is essential to consider the benefits and risks for that individual. Factors that may decrease the likelihood of long term benefit from treatment include shorter life expectancy e.g. older age, co-morbid conditions, decompensated liver disease, and active alcohol abuse (abuse within previous 6 months). Ideally patients should abstain from alcohol completely while on treatment.

Factors that may predispose to a higher risk of adverse events include major psychiatric disorders, cardiovascular diseases such as significant arrhythmias, major congestive heart failure, uncontrolled hypertension or ischemic heart disease, active autoimmune diseases, poorly controlled seizure disorders, diabetic retinopathy (interferon can exacerbate diabetic retinopathy), thyroid disease (relative contraindication). Interferon can cause an autoimmune thyroiditis. However, patients who are hypothyroid cannot suffer any further harm. Other factors increasing the risk of adverse events include myelosuppression, such as thrombocytopenia and neutropenia. Therapy should not be instituted if the platelet count is less than 80x10⁹/l or the neutrophil count is less than 1.0x10⁹/l. Renal failure and anemia increase the risk of adverse effects from the ribavirin. Ribavirin is teratogenic. Patients on combination therapy and their partners must use adequate contraception.

Patients in whom poor compliance is expected, or in whom there is a significant risk of re-infection e.g. active substance abuse may not be suitable candidates for treatment.

Other conditions, which are relative contraindications, include severe asthma, psoriasis and past history of autoimmune diseases or psychiatric disorders.

Absolute contraindications to therapy with interferon and ribavirin are decompensated liver disease, active alcohol abuse, pregnancy or lack of appropriate contraception and expected non-compliance.

Combined infections

Special Cases

Since many patients with hepatitis C are asymptomatic, presentation may be incidental or fortuituos. Some patients may progress to the point of cirrhosis or even decompensated liver disease without any antecedent symptoms. Some patients may present with a wide variety of symptoms, not all necessarily due to hepatitis C. Some of the ways in which patients present are:

abnormal Ast or Alt on routine screening:
- insurance exams
- prenatal clinic
- assessment for various symptoms, e.g. abdominal pain

positive anti hepatitis C on screening:
- Blood donor clinics
- Red Cross Lookback Program

contacts of positive case:
- partner: but sexual transmission has a lifetime risk of about 3% and most partners have contracted hep C by sharing needles
- children of positive mothers (Hepatitis Knowledge Network Vol.1 No. 2)

screening of high risk persons:
- previous blood transfusion or blood products (prior to 1990)
- previous or present IVDU
- multiple sexual partners (particularly if other STD's present)
- previous body piercing, tattoos
- snorting of cocaine with common straw

fatigue:
- a small number of persons present with fatigue (subsequent newsletter)

decompensated liver disease:
- cirrhosis
- portal hypertension with varices and ascites

autoimmune diseases accentuated by hep C:
(see Hepatitis Knowledge Network Vol. 1 No. 1)
Although this means of presentation is not common, some presenting conditions are: - arthritis
- lichen planus
- diabetes
- thrombocytopoenia

Although the diagnosis of chronic hepatitis C can be made by checking for the antibodies and determining the presence of the HCV RNA, patients must be thoroughly assessed relative to their liver disease and other complications. A good progressive approach is as follows:

a history of liver disease:
- jaundice, pale stools, dark urine
- bleeding (nose bleeds, bleeding gums), bruising
- pruritus
- abdominal swelling, peripheral oedema

examination for signs of liver disease:
- spider angiomata
- jaundice
- gynecomastia, loss of body hair
- hepatomegaly
- testicular atrophy
- nail changes

examination for signs of portal hypertension:
- splenomegaly
- varices
- abdominal and chest wall veins
- ascites with or without peripheral oedema

hematological tests indicating liver disease:
- thrombocytopoenia (and possibly neutropoenia)
- prolonged INR or prothrombin time
- macrocytic anemia, often with target cells biochemical tests of liver disease: - Ast, Alt over one and a half times normal for three months (alkaline
phosphatase and gamma GT are cholestatic enzymes not hepatocellular
enzymes)
- decreased albumin
- elevated bilirubin
- polyclonal increase in gamma globulins serological tests for hepatitis C:
- antibody poistive (anti hepatitis C by ELISA then by RIBA)
- HCV RNA (usually by PCR, qualitative adequate)
rule out other causes of liver disease: (subsequent newsletter)
pathological confirmation by liver biopsy: (subsequent newsletter)

Prevention:
Treatment is important, prevention is vital. Hepatitis C is spread predominantly by blood to blood and other ways are infrequent. Logical means of prevention are:

ฎ personal health measures:
- avoid sharing toothbrushes, razors, etc.
- avoid unprotected sex during menstrual period (Hepatitis Knowledge
Network Vol.1 No. 2)
- clean all blood contamination with bleach
- cover open sores and burns with a bandage

ฎ general health measures:
- do not share needles or rigs
- do not share straws to snort cocaine
- avoid unprotected, promiscuous sex
- only use tattoo parlours which use disposable needles
- do not share body piercing needles

Consumption of alcohol makes hepatitis C more active and progress more rapidly. Thus, all patients with chronic hepatitis C should be advised to minimize, if not elimate, alcohol use.

Direct percutaneous inoculation is the most efficient mode of transmitting HCV, although sexual, household occupational and vertical transmission of HCV may also occur (63-67). HCV intra-spousal transmission appears to be rare in the absence of a parenteral risk in the partner. In case-control studies sexual co-habitation with an anti-HCV-positive person was not identified as a risk for infection. Therefore HCV is not considered to be a sexually transmitted disease. Some factors, however, such as sexual promiscuity, HIV and HSV2 co-infections are associated with sexual transmission of hepatitis C (66,67). It is not clear whether the probability of transmission between partners increases with decades of marriage and/or age (68,69). This does not necessarily represent sexual transmission.

The infected person should inform sexual partners. Testing should be offered to the sexual partner. Patients should be advised to avoid sharing items of personal hygiene. In short-term sexual relationships condom use is advised. Unprotected sex during menstruation should be avoided. Couples should be given information about the risks of transmission, and about precautions which may reduce the risk of transmission. The committee neither recommends nor recommends against the use of condoms in stable monogamous relationships. It is up to the couple to make a decision, based upon the best information that can be provided to them.

Mother-to-Infant Transmission of the Hepatitis C Virus

Rates of transmission of hepatitis C from mother to newborn infant vary between 0 and 3% according to different reports (70-73).Two risk factors have been identified, HIV infection in the mother, and high maternal viral load (70,73). It is controversial whether caesarian section prevents transmission of HCV. Results of testing breast milk for HCV RNA are conflicting. However, transmission from breast milk has not been documented.

Breast feeding is considered safe and is not contraindicated.

Anti-HCV testing in the neonate is not helpful, because there is passive transfer of antibody across the placenta. This may take 12-18 months to clear. Testing for hepatitis C infection within the first 18 months of life should be by PCR assays. There is very limited information in the literature concerning the rate of chronicity after neonatal transmission. Clearance of the virus may occur more frequently than in adult infection.

Management of Hepatitis C in the Patient With Normal ALT
Ira M. Jacobson, MD

Prior to the advent of techniques to detect and quantify hepatitis C virus (HCV) RNA in serum, the status of HCV infection in patients with HCV antibodies and normal alanine aminotransferase (ALT) levels was unclear. Once these techniques became available, it became clear that many such persons are viremic, and that about 25% of patients with chronic hepatitis C have persistently normal ALT levels. Levels of viremia in these patients are not significantly different from those of patients with elevated ALT levels. Moreover, normal ALT levels are usually not paralleled by normal liver histology. Qualitatively, at least, these patients are subject to the same type of necroinflammatory activity and, potentially, fibrosis as the more typical patient with enzyme elevations.

The abundance of published experience suggests that, quantitatively, the patient with persistently normal ALT levels is more likely to have mild inflammation and fibrosis than other HCV-infected patients. In a 1997 review by Hoofnagle, 37% of HCV-infected patients with normal ALT levels had no inflammation or minimal change, 63% had portal hepatitis or mild chronic hepatitis, and only 0.5% had significant fibrosis or cirrhosis. In a French study led by Mathurin in 1998, 102 patients with normal ALT levels were compared with 102 patients with elevated ALT levels. The grade of inflammation and stage of fibrosis were significantly lower in the normal ALT group, and over time the rate of progressive fibrosis in the normal ALT group was half that in the other group. The most recent contribution to this field, echoing the theme of slow progression, came from a just-published Italian study by Persico and colleagues, in which 35 patients with initially normal ALT levels were followed for 5 years. According to their protocol, the few patients who developed de novo ALT elevations during the observation period were place don antiviral therapy, while the 73% who maintained normal ALT levels were rebiopsied. In these patients, no change in mean grade or stage was found.

In perhaps the most notable exception to these conclusions, Puoti et al (1997) found no difference in histology between patients with normal versus high ALT levels. A preponderance of genotype 2a was found among the normal ALT patients. Although not a comparative study, in 1997 Gholson et al reinforced the potential for progressive fibrosis in 50 patients with normal ALT, 70% of them female (a gender ratio that reflects the experience of others, as well). Nine of the patients had stage 3 fibrosis, while one had stage 4. Equally notable was the presence of grade 2 or 3 inflammation in more than half the patients.

The potential for normal ALT patients to have progressive liver disease led to a number of studies with interferon monotherapy. Each of these studies was relatively small, and while some created the impression of poor efficacy, when reviewed cumulatively, the data indicate rates of sustained virologic response (SVR) similar to those seen in other patients. In Marcellin and coworkers' 1997 analysis of seven prior studies presented at the National Institutes of Health (NIH) Consensus Conference, the SVR rate was 19%. Beyond efficacy considerations, the factor that led to diminished enthusiasm for treating normal ALT patients with interferon was the observation of de novo ALT elevations, while on therapy, in more than half the patients. It has been speculated that these ALT elevations may be related to stimulation by interferon of immunologic activity against infected hepatocyles. The NIH Consensus Statement, published in 1997, concluded, "Current studies suggest that treatment of patients with persistently normal ALT is not beneficial and may actually induce liver enzyme abnormalities. Therefore, these patients should not receive therapy outside placebo-controlled trials. "This conclusion was accepted by some hepatologists; others felt that these patients, like others with hepatitis C, need to be evaluated individually and therapy considered on the basis of liver histology and other factors, such as the mind-set of the patient.

Interest in combination therapy for normal ALT patients has been an inevitable outgrowth of the recent adoption of interferon/ribavirin as standard therapy for chronic hepatitis C. A number of trials have been initiated, and preliminary results are available from several of them. In a New York multicenter study, the author and coworkers randomized patients to 12 months of interferon 5 MU versus 3 MU t.i.w. plus ribavirin 1,000 to 1,200 mg/day. Eighteen patients have thus far been followed up for 6 months after cessation of treatment, with seven (39%) showing sustained virologic response. Only one transient ALT elevation was seen.

Another trial from San Diego was reported preliminarily by Hassanein et al at the last annual meeting of the American Association for the Study of Liver Diseases. In this ongoing study, 75% of patients responded to treatment, but data on SVR are still pending. These researchers pointed out that ALT reductions within the normal range were characteristic responses to antiviral therapy.

At the most recent International Symposium on Viral Hepatitis held in Atlanta, Bacon et al presented data on 24 interferon nonresponders with normal ALT levels who were given a course of combination therapy. They showed an SVR rate of 25%, with a reduction in mean ALT from 42 to 19IU/I. This is similar to the response rate to combination therapy noted in their larger series of monotherapy nonresponders with high ALT levels.

As further data on SVR rates are expected from these trials, clinicians regularly continue to see HCV-infected patients with normal ALT. Some researchers maintain that these patients should be biopsied so that the same kind of individualized therapeutic decision making that applies to other patients with hepatitis C can be applied to this group as well. The alternative view is that treatment of these patients is still investigational, and that biopsies and therapy should be withheld until some consensus emerges from the ongoing trials. The shortcoming of the latter position is that those patients with high grades of inflammation or fibrosis will not be identified and may experience further progression. Early data suggesting equivalent rates of SVR to combination therapy in this population further support an individualized approach, with biopsy playing an important role.

A 45-year-old woman learned that she was positive for HCV antibodies when she attempted to donate blood 3 years ago. The patient, who works with institutionalized children, has no risk factors for HCV infection. Although she says she used to consume one glass of wine per day, she says she is now consuming less alcohol. Her past medical history includes a hysterectomy 4 years ago (with no blood transfusion), cholecystectomy, and tonsillectomy. She is currently taking hormone replacement therapy.

Current physical examination reveals no jaundice, spiders, palmar erythema, hepatosplenomegaly, or ascites. Laboratory findings are shown in Table 1. A liver biopsy performed 1 year ago showed mild chronic inflammation, focal mild piecemeal necrosis, and bridging portal-to-portal fibrosis (ie. Grade 1-2, stage 3).

The patient was treated with interferon a-2b 3 MU t.i.w. plus ribavirin 1,000 mg/day. Laboratory values over the first 24 weeks of treatment are shown in Table 2. Adverse effects of therapy included flu-like symptoms with initial dose, mild fatigue, mild exertional dyspnea, and anemia. At week 4, hemoglobin was <10 g/dL, so the ribavirin dose was reduced to 600 mg/day. At week 24, the patient developed tremulousness and mild insomnia, and experienced a 5-lb weight loss. Physical examination revealed a pulse rate of 92 beats/minute (up from 72 beats/minute at her last examination).

At week 24, the patient's thyroid-stimulating hormone (TSH) level was 0.03 and free T4 level was 13.2 ng/dL. At week 28, treatment was discontinued. Propranolol (40 mg/day) was administered to control symptoms of hyperthyroidism, and an endocrine.

Cholson CP, Morgan K, Catinis G, et al. Chronic hepatitis C with normal aminotransferase levels, a clinical histologic study. Am J Gastroenterol. 1997;92:1788-1792.

Hassanein TI, Monson P, Behling C, et al. Combination therapy results in a significant reduction of transaminase levels in patients with normal pretreatment transaminase levels. Hepatology. 1999;30(pt 2):205A.

Hoofnagle JH. Hepatitis C the clinical spectrum of disease. Hepatology 1997;26(suppl 1):15S-20S.
Jacobson JM, Russo M, Lebovics E, et al. Interferon alfa-2b and ribavirin in treatment-na๏ve patients with chronic hepatitis C and normal ALT levels. Hepatology. 1999:30:459A.

Marcellin P, Levy S, Frlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology 1997;26(suppl 1):133S-136S.

Mathurin P, Moussalli J, Cadranel JH, et al. Slow progression rate of fibrosis in hepatitis C virus in patients with persistently normal alanine transaminase activity. Hepatology 1998:27:868-872.

National Institutes of Health Consensus Development Conference Panel statement: management of hepatitis C. Hepatology. 1997;26(suppl 1):2S-10S.

Persico M, Persico E. Suozzo R, et al. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels. Gastroenterology 2000;118:760-764.

Puoti C, Magrini A, Stali T, et al. Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels. Hepatology. 1997;26:1393-1398.

Serfaty L, Chazouilleres O, Pawlotsky JM, Andreani T, Pellet C, Poupen R. Interferon alpha therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity. Gastroenterology. 1996;110:291-295.

Shindo M, Araj K, Sokawa Y, Okuno T. The virological and histological states of anti-hepatitis C virus-positive subjects with normal liver biochemical values. Hepatology. 1995;22:418-425.

By Howard J. Worman, M. D.
This page provides general information on treatment options for
viral hepatitis B and C.
It is not an endorsement of the any of the products by the author or by any institution with which the author is affiliated.
Various type I interferons administered by intramuscular or subcutaneous injection are indicated for the treatment of chronic hepatitis B and chronic hepatitis C. Interferon alfa is a naturally occurring glycoprotein that is secreted by cells in response to viral infections. It exerts its effects by binding to a membrane receptor. Receptor binding initiates a series of intracellular signaling events that ultimately leads to enhanced expression of certain genes. This leads to the enhancement and induction of certain cellular activities including augmentation of target cell killing by lymphocytes and inhibition of virus replication in infected cells. Various recombinant forms of interferon alpha (interferon alpha-2a and interferon alpha-2b) and a recombinant non-naturally occuring type I interferon (interferon alfacon-1) are approved to treat viral hepatitis.

THIS PAGE PROVIDES ONLY AN INTRODUCTION TO TREATMENT OF CHRONIC HEPATITIS B OR HEPATITIS C WITH INTERFERON. YOU SHOULD CONSULT A PHYSICIAN EXPERIENCED IN THE CARE OF PATIENTS WITH LIVER DISEASES FOR ADDITIONAL INFORMATION.

Chronic Hepatitis B
Interferon alfa-2b is effective in the treatment of adults with chronic hepatitis B virus infection and evidence of viral replication. The patient should have evidence of infection with hepatitis B virus, documented by the presence of hepatitis B surface antigen in the blood, for six months. The patients should also have evidence of virus replication, documented by the presence of hepatitis B e antigen in the blood. Ongoing inflammation of the liver should also be present as documented by an elevation in serum aminotransferase activities. A liver biopsy should also be performed prior to treatment. Patients with severe, decompensated liver disease (eg. encephalopathy, ascites, very high serum bilirubin, prolonged prothrombin time, etc.) should not generally be treated with interferon alfa-2b except in the setting of an approved clinical study.
The recommended dose of interferon alfa-2b for the treatment of chronic hepatitis B is 5,000,000 units daily, administered by subcutaneous or intramuscular injection, for a total of 16 weeks. The patient must be monitored carefully during the treatment period for side effects including flu-like symptoms, depression, rashes, other reactions and abnormal blood counts.

A meta-analysis of several randomized trials of interferon alfa-2b in the treatment of patients with chronic hepatitis B showed such treatment to be cost-effective (Wong et al. Annals Intern. Med. 1995;122:664-675). This analysis showed that treatment with interferon alfa-2b decreased viral replication, documented by loss of serum hepatitis B e antigen, in about 45% of patients compared to less than 10 % of untreated patients. About 8% of patients also lost hepatitis B virus surface antigen (cured) within one year of treatment compared to a rate of about 1% a year for untreated patients.

Interferon alfa-2b treatment of chronic hepatitis B requires careful medical attention. Consult a physician who has experience with this type of treatment for more information.

Chronic Hepatitis C
Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough) and interferon alfacon-1 (Infergen; Amgen) are all approved in the United States for the treatment of adults with chronic hepatitis C. The patient should have evidence of chronic liver disease and infection with hepatitis C virus as documented by the presence of serum antibodies against this virus or serum viral RNA. Inflammation of the liver should also be present as documented by elevations in the serum aminotransferase activities and liver biopsy. Treatment of patients without evidence of inflammation (e.g. normal serum aminotransferase activities), or treatment of patients with decompensated liver disease (e.g. encephalopathy, ascites, very high serum bilirubin, abnormal prothrombin time, etc.), should only be considered in the setting of an approved clinical study.
The recommended dose of interferons alfa-2b and alpha-2a for the treatment of chronic hepatitis C is 3,000,000 units three times a week, administered by subcutaneous or intramuscular injection. For interferon alfacon-1, the recommended dose is 9mcg three times a week for first time treatment. Six months of treatment was originally recommended for interferons alpha 2a and 2b, however, several studies have shown that treatment for a year or longer may be more effective (Poynard et al. Hepatology. 1996;24:778-789). Treatment times of 1 to 2 years with these drugs are now approved by the FDA. For interferon alfacon-1, a six month treatment course of 9 mcg three times a week is approved and a dose of 15 mcg three times a week for another six months is approved for patients who do not respond or relapse. During the treatment periods with any of these recombinant interferons, the patient must be monitored carefully for side effects including flu-like symptoms, depression, rashes, other unusual reactions and abnormal blood counts.

The results of several published clinical studies demonstrate that about 50% to 70% of patients with chronic hepatitis C respond to treatment with interferon alfa-2b as documented by reductions in the serum aminotransferase activities to near normal. Several studies have also shown that about 70% of patients have a decrease in liver inflammation on follow-up liver biopsy. Unfortunately, most patients relapse and have recurrent liver inflammation after treatment is discontinued.

Several studies have tested a combination of interferon alfa-2b and ribavirin. This drug combination was approved by the United States Food and Drug Administation in June, 1998 for patients with chronic hepatitis C who have been treated perviously with interferon alone and "relapsed" after treatment was discontinued. It may also be useful in patients never treated previously or in those who did not respond at all to previous interferon treatment. Study results suggest that a combination of interferon alpha-2b and ribavirin induce a sustained response in more patients than treatment with interferon alpha-2b alone. Patients interested in such treatment should consult their physician.

Interferon treatment of chronic hepatitis C requires careful medical attention. Consult a physician who has experience with this type of treatment for more information.

ไวรัสตับอักเสบ ซี
ต้นฉบับจาก สคต.3 ชลบุรี

โรคตับอักเสบ ซี เป็นโรคติดต่อสำคัญ โรคหนึ่งซื่งเกิดจากเชี้อ ไวรัสตับอักเสบ ซี (Hepatitis C virus)
ทำให้เซลล์ตับเสียหาย และก่อให้เกิดโรคตับอักเสบ และประมาณครึ่ง หนึ่งของผู้ป่วยตับ อักเสบ ซี แบบ
เฉียบพลัน จะกลายเป็นพาหะของเชื้ออย่างเรื้อรัง และประมาณร้อยละ 20 ของกลุ่มนี้จะกลายเป็นโรค
ตับแข็งและ มะเร็งตับภายในระยะเวลา 5-40 ปี จากการสำรวจความชุกของการติดชี้อไวรัสนี้ในคนไทย
โดยกรมวิทยาศาสตร์การแพทย์ กระทรวง สาธารณสุข พบว่าในกลุ่มคนที่มาบริจาค โลหิตมีอัตราการ
ติดเชื้อ ไวรัสนี้ ร้อยละ 1.5 และในกลุ่มผู้ติดยาเสพติดชนิดฉีดเข้าเส้นที่ติด เชื้อโรคเอดส์ พบว่ามีไวรัส
ตับอักเสบ ซี สูงถึงร้อยละ 99.1 สำหรับการสำรวจในกลุ่มผู้ที่ป่วยโรคตับอักเสบซึ่งมีสาเหตุได้หลาย
ประการ นั้น พบว่าเกิดจากไวรัสตับอักเสบ ซี ร้อยละ 12.5

อาการ โรคไวรัสตับอักเสบ ซี มีระยะฟักตัว 6-10 สัปดาห์ ผู้ติดเชื้อส่วนใหญ่ไม่แสดงอาการ
อาการที่พบระยะเเรก ได้แก่ อาการอ่อนเพลีย ไข้ เบื่ออาหาร คลื่นไส้ อาเจียน ปวดท้อง ตามด้วยตัวเหลีอง
ตาเหลือง ปัสสาวะสีเหลืองเข้ม

การติดต่อ โรคไวรัสตับอักเสบ ซี ติดต่อเช่นเดียวกับไวรัส ตับอักเสบ บี และ ไวรัสเอช ไอ วี คือติคต่อจาก
การรับเลือด หรือ ผลิตภัณฑ์จากเลือดที่มีเชื้อ ไวรัสตับอักเสบ ซี ปนเปื้อน การใช้เข็ม ฉีดยาร่วมกันในกลุ่ม
ผู้ติดยาเสพติดชนิดฉีดเข้าเส้น นอกจากนี้ยัง สามารถติดต่อได้ทางเพศสัมพันธ์ ส่วนการติดต่อจากมารดา
สู่ทารก นั้นพบ ได้น้อย

การป้องกันและรักษา เนื่องจากไวรัสตับอักเสบ ซี ที่ระบาด ในแต่ละภูมิภาคของโลกมีความแตกต่างทาง
พันธุกรรมค่อนข้างมาก การศึกษาวิจัยเพื่อผลิตชุดน้ำยาตรวจวินิจฉัยและการผลิตวัคซีนจึงทำ ได้ยาก
ในปัจจุบันการรักษาด้วยสาร Inteferon ให้ผลเพียงร้อยละ 40-50 และมีผลข้างเคียงค่อนข้างมาก
ดังนั้น จึงควรเน้นที่การ ป้องกัน ซึ่งวิธีที่ดีที่สุดในขณะนี้คือการตรวจคัดกรองเลือดบริจาคก่อนนำ ไป ให้
กับผู้ป่วย และการหลีกเลี่ยงพฤติกรรมเสี่ยง

Dose and Duration of Treatment

Monitoring During Therapy

Contraindications to therapy

Mother-to-Infant Transmission of the Hepatitis C Virus

Management of Hepatitis C in the Patient With Normal ALT Ira M. Jacobson, MD

Management of Hepatitis C in the Patient With Normal ALT
Ira M. Jacobson, MD