All patients with chronic hepatitis C are potential candidates for antiviral therapy. Treatment is recommended for patients with an increased risk of developing cirrhosis. These patients are characterized by detectable HCV RNA levels higher than 50 IU/mL, a liver biopsy with portal or bridging fibrosis, and at least moderate inflammation and necrosis. The majority also have persistently elevated ALT values. In some patient populations, the risks and benefits of therapy are less clear and should be determined on an individual basis or in the context of clinical trials.

Many patients with chronic hepatitis C have been ineligible for trials because of injection drug use, significant alcohol use, age, and a number of comorbid medical and neuropsychiatric conditions. Efforts should be made to increase the availability of the best current treatments to these patients. Because a large number of HCV-infected persons in the United States are incarcerated, programs should be implemented to prevent, diagnose, and treat HCV infection in these individuals. Based on the NHANES III data that demonstrate high prevalence of HCV in African American and Hispanic populations, individuals who are uninsured or have publicly funded healthcare are more likely to be infected with HCV. Efforts should also be initiated to diagnose and treat infection in these individuals.

All patients with chronic hepatitis C should be vaccinated against hepatitis A, and seronegative persons with risk factors for hepatitis B virus (HBV) should be vaccinated against hepatitis B.

Normal ALT Levels

Approximately 30 percent of patients with chronic HCV infection have normal ALT levels, and another 40 percent have ALT levels less than two times the upper limit of normal. Although most of these patients have mild disease, histologically, some may progress to advanced fibrosis and cirrhosis. Experts differ on whether to biopsy and treat these patients.

Numerous factors must be considered in recommending treatment, including favorable genotype, presence of hepatic fibrosis, patient motivation, symptoms, severity of comorbid illness, and the patient's age. When patients with normal or minimally elevated ALT levels are treated with monotherapy, their SVR rates are similar to those of patients with higher ALT levels. Studies of pegylated interferon with ribavirin have not been completed in patients with normal ALT levels.

Mild Liver Disease

Progression to cirrhosis is likely to be slow in patients who have persistent ALT elevations but no fibrosis and minimal necroinflammatory changes. These patients may not need treatment and should be monitored periodically. However, decisions to treat such patients should be individualized and may be based on the patient's desire to eliminate the HCV infection or unwillingness to undergo subsequent liver biopsies to assess disease progression.

Advanced Liver Disease

Data on safety and efficacy of interferon (standard or pegylated) with or without ribavirin in patients with advanced fibrosis or compensated cirrhosis have largely been derived from subgroup analyses of larger trials. SVR rates are lower in patients with advanced liver disease than in patients without cirrhosis. Further studies are needed to evaluate whether long-term anti-viral therapy will delay histological disease progression to cirrhosis. Liver transplantation offers the primary treatment option for patients with decompensated liver disease. Studies of antiviral therapy are being conducted in patients awaiting liver transplantation, but potentially life-threatening side effects of antivirals have been observed in some patients.

Recurrence After Transplantation

Hepatitis C frequently recurs following liver transplantation, and disease progression is accelerated compared with immunocompetent patients with HCV disease. Once cirrhosis develops in the allograft, the risk of complications is high. While recurrence of HCV replication is almost universal after liver transplantation, the severity of the recurrence of hepatitis C after transplant correlates with the degree of immunosuppression in the posttransplantation period. Treatment of HCV recurrence after liver transplantation should be considered experimental and carried out in the context of clinical trials.

Children

Children should be screened for HCV if they are born to HCV-infected women, received transfusions prior to 1992, or have high-risk behavior since data suggest that response rates to treatment may be higher than in adults. Children and adults with chronic HCV infection generally have no symptoms. Little is known about the treatment of children and adolescents, and further research is needed. Studies of interferon monotherapy in children have been largely uncontrolled, with small numbers of highly selected patients. SVR rates are better than in adults, ranging from 33 to 45 percent (26 percent for genotype 1 and 70 percent for other genotypes). Promising new therapies, including the pegylated interferons, should also be studied in children. Some patients may benefit from treatment even if the liver disease is mild. Given the long life expectancy of children and their better tolerance to drugs, the long-term safety of these medications needs to be studied in children.

Management of Hepatitis C: Evaluating Suitability for Drug Therapy

RAYMOND P. WARD, M.D., PH.D., St. Mary's Family Practice Residency, Grand Junction, Colorado
MARCELO KUGELMAS, M.D., University of Colorado Health Sciences Center, Denver, Colorado
KAREN D. LIBSCH, M.D., St. Mary's Family Practice Residency, Grand Junction, Colorado

Chronic hepatitis C virus infection is a common and serious disease. Although an estimated 2.7 million persons in the United States have this disease, most have not yet been diagnosed. Recent advances in treatment provide successful cure in 50 to 80 percent of cases. Current drug therapy consists of a combination of pegylated interferon and ribavirin. Although all patients with chronic hepatitis C virus infection are potential candidates for treatment, pharmacologic therapy has a number of contraindications. Evaluation of suitability for treatment includes a thorough search for comorbid medical and psychiatric conditions that can be contraindications. Initial testing involves anti-hepatitis C virus antibodies, but definitive diagnosis of active disease requires detection of viral RNA. Most patients require a liver biopsy to determine the amount of hepatic fibrosis and ongoing hepatocellular inflammation. Viral genotype also should be determined: type 1 requires 12 months of treatment and does not respond as well as types 2 and 3, which require only six months of treatment. Common side effects of drug therapy include anemia, anorexia, depression, fatigue, fever, headache, myalgia, nausea, and erythema at the injection site. (Am Fam Physician 2004;69:E1429-E38,1439-40. Copyright© 2004 American Academy of Family Physicians)

Hepatitis C virus (HCV) infection is the most common blood-borne infection. It affects approximately 1.8 percent of the U.S. population (3.8 million persons exposed and 2.7 million persons chronically infected).¹ Most cases of chronic HCV infection have yet to be diagnosed. Therefore, a substantial increase in the number of known cases is projected over the next decade, along with a large increase in the number of patients with complications of HCV infection, such as cirrhosis, liver failure, and hepatocellular carcinoma. HCV infection already is the leading cause of chronic liver disease in patients presenting to gastroenterologists, the leading cause of hepatocellular carcinoma, and the leading diagnosis among patients referred for liver transplantation.²

Because of the increasing prevalence of chronic HCV infection and significant advances in its diagnosis and treatment, this illness has been the subject of several recent reviews^3,4 and a consensus statement from the National Institutes of Health (NIH).⁵ This article reviews factors that should be considered in the evaluation of the suitability of HCV-infected patients for treatment.

Natural History of HCV Infection

Acute HCV infection is rarely severe and usually asymptomatic. Although the immune system occasionally eradicates the virus, up to 85 percent of patients develop chronic HCV infection (Figure 1).^1,2 Over time, liver damage and other sequelae increase, and patients begin to have symptoms. Risk factors for more rapid progression of disease include age over 40 years at the time of infection, male gender, and daily consumption of more than 30 g of alcohol.^5-7

Although most HCV-related deaths occur after the disease has progressed to cirrhosis,⁷ patients can have significant symptoms and reduction in quality of life well before that time.⁸ Chronic HCV infection also is linked to an increased incidence of several extrahepatic diseases, including renal disease, diabetes mellitus, neuropathy, lymphoma, Sjögren's syndrome, mixed cryoglobulinemia, and porphyria cutanea tarda.⁹

Natural History of HCV Infection

FIGURE 1. Natural history of hepatitis C virus (HCV) infection. (MELD = model for end-stage liver disease)

Advances in Diagnosis and Treatment

Over the past 15 years, remarkable advancements have been made in the identification of HCV infection. The screening of donated blood for HCV RNA has reduced the risk of viral transmission through blood transfusions to less than one case per 100,000 units of blood transfused.¹⁰ The efficacy of treatment also has improved. First, interferon was used, then interferon in combination with ribavirin; the latest treatment, a combination of pegylated interferon with ribavirin, is clearly superior to the older regimens and is the current standard of care.^11,12

The NIH guideline⁵ on the management of HCV infection suggests that all patients with chronic infection are potential candidates for antiviral therapy, and especially recommends treatment for patients with an increased risk of developing cirrhosis.

Diagnosis of HCV Infection

A third-generation HCV antibody test (at least 99 percent sensitive, 99 percent specific) is recommended for use as the initial test in patients with clinical or laboratory evidence of liver disease and for the screening of at-risk populations.⁵ The Centers for Disease Control and Prevention (CDC) recommends screening in asymptomatic persons who have any of the following risk factors: history of intravenous drug use, blood transfusion or organ transplant before 1992, receipt of clotting factors before 1987, or long-term hemodialysis.¹³ [SORT C: consensus/expert opinion]

The anti-HCV antibody test determines whether a person ever has been exposed to HCV but not the presence of active infection (because 15 to 20 percent of persons who contract HCV spontaneously clear the infection). False-positive results are possible, especially when the test is used as a screening tool in a population with a relatively low risk of disease. False-negative results may occur in immunosuppressed persons.

Active infection therefore must be confirmed by demonstrating the presence of HCV RNA. Quantitative tests detect and count viral loads as low as 50 to 500 copies per mL, whereas qualitative tests detect (but do not quantify) the presence of HCV in the range of 5 to 50 copies per mL.¹⁴ Confirmation of the diagnosis requires only a single positive test showing the presence of HCV RNA. Because there can be a transient decline in viremia to below the level of assay sensitivity, all negative test results should be reconfirmed with another test approximately one month later to be certain that active HCV infection is not present.⁵

An algorithm for the diagnosis of chronic HCV infection in patients with risk factors or clinical or laboratory evidence of liver disease is provided in Figure 2.^1,2

HCV Testing

FIGURE 2. Testing for hepatitis C virus (HCV) infection. Patients who should be checked for HCV infection include those with clinical evidence of liver disease, those with laboratory evidence of disease (typically, elevated aspartate transaminase and alanine transaminase levels), and those with any of the following risk factors: history of intravenous drug use, blood transfusion or organ transplantation before 1992, receipt of clotting factors before 1987, and long-term hemodialysis. (EIA = enzyme immunoassay; anti-HCV = antibody to hepatitis C virus; RT-PCR = reverse transcriptase polymerase chain reaction.)
Information from references 1 and 2.

Evaluation of Patients with Chronic HCV Infection

HISTORY OF HCV INFECTION

Most patients with HCV infection are asymptomatic, and the diagnosis usually is made after transaminase screening. However, some patients have evidence of advanced disease, with symptoms of liver failure. Fatigue and nausea occur in many patients, but these symptoms are not unique to HCV infection.

An effort should be made to determine the mode and year of infection. The most common ways of acquiring the virus are intravenous drug use and blood transfusion before July 1992. Other risk factors to consider include sexual behavior, occupational exposure to infected blood, body piercing, and tattoos.^5,15,16 The date of original infection, as well as the results of liver biopsy, can be used to make a rough determination of the natural history of the disease in the patient. However, the duration and source of the infection often cannot be determined.

MEDICAL HISTORY

A thorough list of the patient's past and present medical and psychiatric conditions is important because the pegylated interferon ribavirin combination interacts with many body systems. Conditions that are specific contraindications to this treatment should be reviewed carefully (Table 1).

As many as 30 percent of patients with HCV infection have symptoms of depression, but this condition does not necessarily preclude them from treatment for HCV infection. The severity of the symptoms and their impact on the patient's function should be determined. If the depression is severe or recent, psychiatric consultation should be considered.

Many autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, autoimmune hepatitis, psoriatic arthritis) are contraindications to the use of combination drug therapy for HCV infection. Some autoimmune diseases, such as Crohn's disease and ulcerative colitis, do not appear to be exacerbated by pegylated interferon. Depending on the comorbid conditions that the patient has, it sometimes may become necessary to consult with a gastroenterologist, a hepatologist or, in the case of decompensated cirrhosis, a liver transplant team.

TABLE 1
Contraindications to Treatment of HCV Infection with Interferon and Ribavirin

Contraindication	Reason for contraindication
Absolute
Allergy to pegylated interferon or ribavirin	--
Decompensated cirrhosis	Treatment can be considered only in the context of established protocols at liver transplantation centers.
Active intravenous drug use or heavy alcohol use*	Ongoing alcohol consumption greatly reduces the chance of successful treatment; minimal alcohol use does not appear to be harmful. Intravenous drug users are at high risk for reinfection. Alcohol and drug use raise issues about compliance with therapy.
Pregnancy	Ribavirin is highly teratogenic: it damages fetuses, eggs, and sperm. Effective contraception is imperative during treatment and for six months after treatment.
Relative
Anemia, leukopenia, or thrombocytopenia	Combination therapy reduces all hematologic cell lines.
Autoimmune disease	Pegylated interferon acts as a general immune system stimulant and, thus, worsens most autoimmune diseases; however, it does not appear to exacerbate some diseases, such as Crohn's disease and ulcerative colitis.
Coronary artery disease	Ribavirin causes an anemia that can precipitate ischemia in a heart that has little reserve. Coronary artery disease is not an absolute contraindication to the use of pegylated interferon monotherapy.
Severe psychiatric disease, especially severe depression	Pegylated interferon may cause or exacerbate depression; there have been associated instances of suicide. HCV-infected patients with mild depression are candidates for treatment. Consider a psychiatric consultation before treatment is initiated.
Current psychosis or a history of psychosis	Pegylated interferon may exacerbate psychosis. With adequate psychiatric support and close follow-up, some patients with advanced HCV disease may be considered for treatment.

HCV = hepatitis C virus.
*--Stable methadone use is not a contraindication to treatment.

BEHAVIORAL AND SOCIAL ISSUES

Several behavioral and social issues influence the decision to treat a patient with HCV infection. Alcohol consumption should be discouraged. The daily consumption of more than 30 g of alcohol (approximately two drinks) in men and 20 g of alcohol in women is associated with more rapid progression to liver failure.¹⁷ Consumption of a minimal amount of alcohol does not appear to be harmful, but there are no clear data on the amount that is safe.

Sexual activity should be reviewed to identify transmission risk factors (e.g., multiple sexual partners) and because of the highly teratogenic effect of ribavirin. All patients must have a fail-safe plan for contraception during treatment and for six months afterward. Active intravenous drug use is a contraindication to treatment, but stable methadone use is not.

Pharmacologic therapy for HCV infection is quite expensive (approximately $25,000 for a 48-week course), but treatment has been shown to be cost-effective.¹⁸ The manufacturers of pegylated interferon have assistance programs through which medication can be obtained for uninsured patients.

It is important to review the patient's social support network. Pharmacologic therapy for HCV infection can be debilitating and may necessitate absence from work.

PHYSICAL EXAMINATION

The physical examination should include a search for evidence of liver dysfunction and physical conditions that could be contraindications to treatment. Key elements of the physical examination are summarized in Table 2.

TABLE 2
Highlights of the Physical Examination in Patients with HCV Infection

Area of examination	Comments or reason for examination
Abdomen	Evaluate for evidence of hepatic inflammation or hepatomegaly. Note whether ascites or splenomegaly is present.
Cardiovascular	Known, currently symptomatic cardiovascular disease system is a relative contraindication to treatment with the combination of pegylated interferon and ribavirin.
Extremities	Peripheral edema can be a sign of portal hypertension.
General nutrition	Malnutrition can be a sign of advanced liver disease.
HEENT	Check for thyroid abnormalities, because treatment can cause or exacerbate autoimmune thyroiditis. Note whether icterus is present.
Mental status	Check for evidence of psychosis or depression. The patient's level of judgment and insight should be sufficient to understand and tolerate the treatment regimen and its possible side effects.
Respiratory system	Perform a general examination to exclude respiratory disease.
Skin	Note any signs of alcohol abuse or liver failure, such as damaged capillaries over the cheeks, dilated veins over the chest or abdomen (indicative of portal hypertension), spider nevi, and palmar erythema. Note the presence or absence of jaundice and gynecomastia. Look for cutaneous complications of long-term HCV infection, such as palpable purpura (associated with cryoglobulinemia) or blisters and vesicles (porphyria cutanea tarda).
Weight	Weight determines the dosage of pegylated interferon and ribavirin.

HCV = hepatitis C virus; HEENT = head, eyes, ears, nose, and throat.

LABORATORY TESTS

Several laboratory tests should be performed to evaluate the degree of liver disease and determine whether other conditions are present that may be contraindications to treatment of HCV infection (Table 3).^5,11,12,19 Elevated levels of aspartate transaminase (AST) and alanine transaminase (ALT) indicate ongoing hepatocellular necrosis; however, it is important to understand that AST and ALT levels have only a weak correlation with the degree of liver injury.

In extreme cases of decompensated liver disease, the albumin level drops, the serum bilirubin levels rise, the International Normalized Ratio is prolonged, and thrombocytopenia may indicate portal hypertension. Testing for thrombocytopenia in conjunction with determination of an elevated AST/ALT ratio is a fairly accurate and noninvasive way to identify cirrhosis.²⁰

TABLE 3
Laboratory Testing in Patients with HCV infection

Test	Rationale
Albumin level, PT, INR, PTT	Abnormal results may indicate some degree of liver failure.
AST and ALT levels	Elevated levels indicate ongoing hepatocellular necrosis; however, AST and ALT are not good markers of the degree of fibrosis.
BUN and creatinine levels	HCV occasionally can cause renal disease.
Complete blood count	Pegylated interferon may cause leukopenia and thrombocytopenia, and ribavirin may cause anemia. Pre-existing leukopenia or thrombocytopenia is a relative contraindication to treatment of HCV infection. Iron deficiency anemia should be corrected before treatment is initiated.
Hepatitis A and hepatitis B	Immunity to hepatitis A and hepatitis B should be established by reliablesurface antibodies documentation of previous immunization or the presence of hepatitis A and B surface antibodies. If the patient is not immune, vaccination is recommended whether or not the patient is a candidate for treatment of HCV infection.^5,19
HIV	Many risk factors for acquiring HIV and HCV infection are similar; therefore, patients with HCV infection who are at risk for HIV infection should receive appropriate testing.⁵
Iron	In patients with significant iron overload, hemochromatosis should be ruled out, and these patients should be considered for treatment with phlebotomy. Iron overload is a negative predictor for successful therapy, but iron reduction does not necessarily improve outcome.
Pregnancy	Pregnancy is an absolute contraindication to treatment.
TSH	Autoimmune thyroiditis can be caused or exacerbated by pegylated interferon.
Viral genotype	Infections with HCV genotypes 2 and 3 have a better prognosis (cure rates of 70 to 80 percent) and require only six months of treatment, whereas infections with HCV genotype 1 have a cure rate of 40 to 50 percent and require 12 months of treatment.^11,12

HCV = hepatitis C virus; PT = prothrombin time; INR = International Normalized Ratio; PTT = partial thromboplastin time; AST = aspartate transaminase; ALT = alanine transaminase; BUN = blood urea nitrogen; HIV = human immunodeficiency virus; TSH = thyroid-stimulating hormone.
Information from references 5, 11, 12, and 19.

LIVER BIOPSY

The liver biopsy provides the most direct information about the current status of the liver and is recommended in most patients with active HCV infection.^5,19 [SORT C: consensus/expert opinion] Patients infected with HCV genotype 2 or 3 generally respond well to antiviral therapy and may not always require a liver biopsy before treatment is given.

The two central pieces of information from the biopsy are the degree of inflammation and the degree of fibrosis. Inflammation is scored from zero (no inflammation) to 4 (severe inflammation). The degree of inflammation correlates roughly with the amount of ongoing hepatic injury and the natural history of the disease.

Fibrosis is the replacement of functional hepatic tissue with nonfunctional connective tissue. It is triggered by ongoing inflammation and cytokine-related stimulation of hepatic stellate cells. In chronic HCV infection, fibrosis begins to develop in and around the portal triad and then extends to the periportal area; next, it bridges from one portal triad to an adjacent one, and finally proceeds to a complete circle of fibrosis (or cirrhosis) connecting all adjacent portal units. Therefore, fibrosis is scored on a four-point scale: zero (no fibrosis), 1 (portal fibrosis), 2 (periportal fibrosis), 3 (bridging fibrosis), and 4 (cirrhosis).

Liver fibrosis correlates with the natural history of the disease. Patients who have already progressed to cirrhosis have a lower response rate to treatment and a higher rate of hepatic complications during treatment. The liver biopsy also may detect the presence of other liver diseases that may require separate treatments and could affect the timing of the treatment of HCV infection. For example, evidence of fatty liver, alcoholic liver disease, or hemochromatosis would require consideration of weight loss, alcohol cessation measures, and phlebotomy, respectively.

Patient Education

Patients with HCV infection should be educated about the natural history of the disease and the negative impact of alcohol consumption. They should be reassured that there is no evidence of HCV transmission via casual household contact, including the sharing of utensils or food, hugging, kissing, or breastfeeding.²¹ The sharing of razors or toothbrushes should be avoided, because these items may be contaminated with small amounts of blood.

The lifetime risk for sexual transmission of hepatitis C virus in monogamous couples appears to be less than 1 percent.

The lifetime risk for sexual transmission of HCV in monogamous couples appears to be less than 1 percent.^22,23 The CDC does not recommend any changes in sexual practice for HCV-infected persons who are in a long-term, monogamous relationship.^13,22,23Couples should decide whether to use condoms, which may further reduce the already low rate of HCV transmission.

Patients who are considering treatment for HCV infection with pegylated interferon and ribavirin should be made aware of potential side effects²⁴ (Table 4).²⁵ Patients should be reassured that adequate support will be provided at the physician's office, and they should be informed that professional support from the pharmaceutical companies is available through 24-hour hotlines. Patients should be directed to reliable sources of information so they can learn more about their condition (see accompanying patient information handout).

TABLE 4
Side Effects of Treatment of HCV Infection with Pegylated Interferon and Ribavirin

Side effect	Comments or initial management
Alopecia	Alopecia may worsen over the course of treatment but reverses after treatment. Use of gentle shampoos and avoidance of gels and mousse may help.
Anemia	Ribavirin causes hemolytic anemia; in severe cases, medication must be reduced in dosage or discontinued. Hematocrit levels must be monitored throughout treatment.
Anorexia	The patient should be instructed to eat small, frequent meals. Weight should be monitored throughout treatment, and measures to control nausea may help.
Cough	Increased liquid intake and use of a humidifier may be helpful. More severe side effects, such as reduced pulmonary function and pneumonia, can occur and may need to be investigated.
Depression	Baseline and routine assessments for depression should be conducted. Counseling and support groups can be helpful; formal psychiatric consultation and pharmaceutical antidepressant therapy sometimes are necessary.
Erythema at injection site	Before the injection, ice should to applied to the skin; the injection site should not be massaged. Injection sites should be rotated.
Fatigue	The activity level may need to be reduced from the pretreatment level; if possible, the patient should continue a mild exercise routine but avoid strenuous activities and responsibilities on the day after an injection.
Fever	Pegylated interferon can cause influenza-like symptoms, including fever, but episodes tend to decrease over the course of treatment. Acetaminophen (Tylenol) or ibuprofen (Advil) can be administered before injections. If OTC treatments are ineffective, an evaluation for some other cause may be indicated.
Myalgia	Myalgia is another influenza-like symptom that is caused by pegylated interferon. Fluid intake should be encouraged. An OTC analgesic such as acetaminophen or an NSAID can relieve myalgia; warm soaks, compresses, mild exercise, and mild massage also may be helpful.
Nausea	Adequate hydration should be maintained. The patient should be instructed to eat small, frequent meals, and to avoid unpleasant sights, tastes, and smells. If necessary, prescription antiemetics can be used.
Neutropenia	A baseline assessment and continued monitoring during therapy are required. Neutropenia may become so severe that dosage reduction or discontinuation of treatment is necessary.
Pruritus	The patient should be instructed to follow general practices for avoiding dry skin and to avoid taking hot baths and showers. Liver and renal function may need to be checked, and the patient may need to be assessed for autoimmune skin conditions such as psoriasis. Use of a mild topical steroid preparation may be required.

HCV = hepatitis C virus; OTC = over-the-counter; NSAID = nonsteroidal anti-inflammatory drug.
NOTE: The following are rare (less than 1 percent) but serious complications of treatment with pegylated interferon and ribavirin: angina, arrhythmias, autoimmune thrombocytopenia, blindness, bronchiolitis obliterans, cardiomyopathy, emphysema, gastroenteritis, gout, hepatic dysfunction, hyperglycemia, hyperparathyroidism, hypothyroidism, infection, injection site necrosis, interstitial nephritis, loss of consciousness, lupus-like syndrome, myocardial infarction, nerve palsy, neutropenia, optic neuritis, pancreatitis, pericardial effusion, pleural effusion, phototoxicity, psoriasis, psychosis, relapse of drug addiction, retinal ischemia and thrombosis, rheumatoid arthritis, sarcoidosis, suicide attempt, transient ischemic attack, urticaria, and vasculitis.
Information from reference 25.

Determining Who to Treat

The 2002 NIH consensus statement⁵ on the management of HCV infection states that all patients with chronic infection are potential candidates for therapy. This is a marked change from the 1997 NIH consensus statement²⁶ and reflects the availability of more effective treatment regimens and more established treatment expertise.

Important factors to consider include the presence of comorbid conditions that would make treatment dangerous or more difficult, patient motivation and reliability, and HCV viral genotype. Treatment of HCV genotype 1 has a success rate of only 40 to 50 percent, whereas treatment of genotypes 2 or 3 has a success rate of 70 to 80 percent.^11,12 Some patients who are known to have been infected for many years but have minimal hepatic fibrosis and are asymptomatic may choose surveillance rather than treatment.

After a complete evaluation, most patients clearly will be candidates for treatment or have contraindications that preclude treatment. In some patients, however, the decision to treat is not clear based on the work-up alone and must be made on an individual basis. Table 5 presents three clinical scenarios highlighting several factors that must be considered in deciding whether to treat a patient who has chronic HCV infection.

TABLE 5
Clinical Scenarios in Patients with HCV Infection

Case	Treatment decision
Mr. Allen is a 45-year-old man who contracted HCV infection 26 years ago during a period of adolescent drug use. He has not used drugs or alcohol in the past 20 years. He complains of fatigue but is otherwise healthy, with no additional medical concerns. The liver biopsy shows moderate inflammation and bridging fibrosis.	Mr. Allen is high priority for treatment. His liver biopsy shows moderately advanced disease, so he is at high risk for progression to cirrhosis and has no other contraindications to pharmacologic therapy for HCV infection.
Mr. Brown is a 44-year-old man with HCV infection of unknown duration. He is a heavy drinker who has come to the alcoholdetoxification unit three times in the past two years but has missed several scheduled clinic visits. He reports having sex with multiple sexual partners over the previous two years, including prostitutes during drinking binges. His liver biopsy shows moderate inflammation and bridging fibrosis.	Mr. Brown currently is not a candidate for pharmacologic treatment, even though his risk of developing liver failure is quite high. His initial treatment should attempt to reverse and treat his psychosocial issues, especially the alcoholism. If this patient's alcoholism is addressed successfully, the issues of his sexual promiscuity and unreliability probably will improve. When these issues have been addressed successfully, he can be considered for pharmacologic therapy.
Ms. Crown is a 40-year-old single mother with two young children at home. She holds a low-paying job and does not have family support nearby. At age 15, she contracted HCV (genotype 2) from a blood transfusion. She currently complains of chronic fatigue and nausea. Her medical history is significant for depression, for which she was hospitalized last year. She has been taking fluoxetine since that time but still has some mild symptoms of depression. The liver biopsy shows minimal inflammation and portal fibrosis.	Ms. Crown represents a difficult treatment decision. Because she is infected with HCV genotype 2, she has a good prognosis, and treatment could improve some of her debilitating symptoms. However, her liver biopsy shows only minimal damage, and her ability to work and care for her children could be compromised if treatment reactivates her depression. This patient should be approached from a social point of view, by trying to improve psychosocial factors before considering therapy.

HCV = hepatitis C virus.

Treatment of HCV Infection

In the initial evaluation of patients with HCV infection, it is important to consider the history, physical examination, and laboratory work-up, as well as the patient's social situation. Providing treatment for patients with HCV requires that the physician and office personnel be familiar with the side effects of the medications and able to provide close follow-up during therapy. Currently, most patients with HCV infection who are candidates for treatment are referred to a subspecialist. However, with the increasing prevalence of HCV infection, more family physicians may be treating uncomplicated cases, with adequate back-up from an appropriate subspecialist.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

This electronic version supplements the print version of this article and addresses information on drug side effects and clinical scenarios.

The Authors

RAYMOND P. WARD, M.D., PH.D., is a faculty member at St. Mary's Family Practice Residency, Grand Junction, Colo., where he completed his residency. Dr. Ward received his medical degree and a graduate degree in pharmacology from the University of Washington School of Medicine, Seattle.

MARCELO KUGELMAS, M.D., is a faculty member in the hepatology section of the Department of Internal Medicine at the University of Colorado Health Sciences Center, Denver. Dr. Kugelmas received his medical degree from the University of Buenos Aires Facultad de Medicina and completed a gastroenterology and hepatology fellowship at the Cleveland Clinic, Cleveland, Ohio.

KAREN D. LIBSCH, M.D., is a third-year resident at the St. Mary's Family Practice Residency Program. She received her medical degree from the University of Utah School of Medicine, Salt Lake City.

Address correspondence to Raymond P. Ward, M.D., St. Mary's Family Practice Residency, 1160 Patterson Rd., Grand Junction, CO 81506 (e-mail: rward@stmarygj.com). Reprints are not available from the authors.

REFERENCES

Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-62.
Alter MJ. Epidemiology of hepatitis C. Hepatology 1997;26(3 suppl 1):62S-5S.
Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345:41-52.
Herrine SK. Approach to the patient with chronic hepatitis C virus infection. Ann Intern Med 2002; 136:747-57.
Management of hepatitis C: 2002. NIH Consens State Sci Statement 2002;19:1-46.
Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-32.
Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hurter D, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology 1998;28:1687-95.
Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998;27:209-12.
Mayo MJ. Extrahepatic manifestations of hepatitis C infection. Am J Med Sci 2003;325:135-48.
Velati C, Romano L, Baruffi L, Pappalettera M, Carreri V, Zanetti AR. Residual risk of transfusion-transmitted HCV and HIV infections by antibody-screened blood in Italy. Transfusion 2002;42:989-93.
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82.
Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, 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;358:958-65.
Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51(RR-6):64-6.
Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastroenterology 2002;122:1554-68.
Conry-Cantilena C, VanRaden M, Gibble J, Melpolder J, Shakil AO, Viladomiu L, et al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection.
N Engl J Med 1996;334:1691-6.
Williams I. Epidemiology of hepatitis C in the United States. Am J Med 1999;107:2S-9S.
Day CP. Heavy drinking greatly increases the risk of cirrhosis in patients with HCV hepatitis. Gut 2001; 49:750-1.
Wong JB, Koff RS. Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C. A cost-effectiveness analysis. Ann Intern Med 2000;133:665-75.
Booth JC, O'Grady J, Neuberger J, the Royal College of Physicians of London, and the British Society of Gastroenterology. Clinical guidelines on the management of hepatitis C. Gut 2001;49(suppl 1):I1-21.
Giannini E, Risso D, Botta F, Chiarbonello B, Fasoli A, Malfatti F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 2003;163:218-24.
ACOG committee opinion. Breastfeeding and the risk of hepatitis C virus transmission. No. 220, August 1999. Committee on Obstetric Practice. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1999;66:307-8.
Chiaramonte M, Stroffolini T, Lorenzoni U, Minniti F, Conti S, Floreani A, et al. Risk factors in community-acquired chronic hepatitis C virus infection: a case-control study in Italy. J Hepatol 1996;24:129-34.
Rooney G, Gilson RJ. Sexual transmission of hepatitis C virus infection. Sex Transm Infect 1998;74: 399-404.
Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003;124: 1711-9.
Guiding patients through chronic hepatitis C therapy. Kenilworth, N.J.: Schering Corp., 2002.
Management of hepatitis C. NIH Consens Statement 1997;15:1-41.

Treatment for Hepatitis C

PegIntron:

Hepatitis C is the most serious form of hepatitis. It develops into a chronic form in about 85% of infected patients. If left untreated, patients are placed at high risk of developing cirrhosis, liver failure, or liver cancer. Liver failure due to hepatitis C is now the leading cause of liver transplants in the United States. If you have been infected with hepatitis C for 6 months or more, your doctor may initiate medical treatment to avoid the possibility of permanent liver damage.

The current approach to treating chronic hepatitis C is combination therapy with a pegylated alpha interferon and ribavirin. One example is combination therapy with PEG-INTRON® (peginterferon alfa-2b) Powder for Injection and REBETOL® (Ribavirin, USP) Capsules. PEG-INTRON® is a modified form of alpha interferon that works by helping to boost the immune system to fight viruses. REBETOL® is an antiviral drug that is taken orally. This combination therapy was approved by the Food and Drug Administration (FDA) for the initial treatment of patients with chronic hepatitis C. Studies show that more patients with chronic hepatitis C respond to PEG-INTRON/REBETOL combination therapy than to REBETRON® Combination Therapy containing REBETOL® and INTRON® A (Interferon alfa-2b, recombinant) Injection. In clinical trials, about 52% of patients responded to PEG-INTRON/REBETOL combination therapy compared with 46% who responded with REBETRON Combination Therapy.

REBETRON Combination Therapy is a treatment option for chronic hepatitis C patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy.

PEG-INTRON® is a modified form of alpha interferon. PEG-INTRON® stays in the body for a longer time than standard interferon and therefore only has to be taken once weekly instead of three times per week as is the case with standard alpha interferons.

Both PEG-INTRON® and INTRON® A are approved for use alone or in combination with REBETOL® for the treatment of chronic hepatitis C. It is not known how both agents work in combination with REBETOL® against the hepatitis C virus.

See also:

Pegasys

Hepatitis C patients now have a new treatment option. PEGASYS is a pegylated interferon that uses technology to better meet patients' needs. PEGASYS is the only pegylated interferon available as a ready-to-use solution. And no matter what your weight is, patients usually take the same dose of PEGASYS. Pegylation also allows PEGASYS to be a once-weekly medication.

More than 20,000 hepatitis C patients were treated in PEGASYS clinical trials all over the world, and ongoing trials for more uses of PEGASYS continue today. At Roche, we're making a genuine commitment to treating people with hepatitis C.

One of these new uses involves combination therapy. PEGASYS can now be prescribed along with a drug called COPEGUS. The benefit of combination therapy is that more patients tend to respond to combination therapy than they would to PEGASYS alone.

As a PEGASYS patient, you can sign up for a free patient support program. This program, called Pegassist^SM, offers lots of materials, including booklets and newsletters to help you to cope with your disease.

What Is COPEGUS?

COPEGUS is an antiviral medication that is used in combination with PEGASYS to help fight the hepatitis C virus. Although ribavirin cannot fight hepatitis C on its own, studies have shown that it does help alpha interferon work better.

With PEGASYS and COPEGUS combination therapy, the hepatitis C virus can be decreased to a level so low that it cannot be measured by blood tests. Depending on your genotype he virus is decreased and cannot be measured in 5 to 8 out of every 10 people who take PEGASYS and COPEGUS combination therapy for 6 months to 1 year. After 3 to 6 months of therapy, a blood test can help your healthcare professional determine your likelihood of long-term response.

COPEGUS is taken in the form of several pills every day in addition to PEGASYS therapy. Since all medications can cause side effects, it's possible that you could experience side effects while taking COPEGUS and/or PEGASYS. If you have any questions about your treatment options, be sure to speak with your healthcare professional. For more information about COPEGUS, please see the medication guide and full prescribing information.

PEGASYS and COPEGUS combination therapy must not be used by women who are pregnant or by men whose female partners are pregnant. COPEGUS therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during COPEGUS therapy and for 6 months post-therapy. Patients should be advised to notify the physician immediately in the event of a pregnancy (see the medication guides and CONTRAINDICATIONS and WARNINGS in the full prescribing information).

Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded; routine monthly pregnancy tests must be performed during this time (see CONTRAINDICATIONS in the complete COPEGUS prescribing information).

If pregnancy does occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to COPEGUS, the COPEGUS Pregnancy Registry has been established. Physicians and patients are strongly encouraged to register by calling 1-800-526-6367.

For more information, please see Pregnancy and Family Planning.

In this section, you'll find information on:

Important Safety Information

Alpha interferons, including PEGASYS (peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE EVENTS in medication guides ).

Use with Ribavirin. Ribavirin, including COPEGUS™, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen

PEGASYS, peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).

PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and decompensated hepatic disease (Child-Pugh class B and C) before or during treatment with PEGASYS. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).

COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to COPEGUS, the COPEGUS Pregnancy Registry has been established. Physicians and patients are strongly encouraged to register by calling 1-800-526-6367.

The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials (N=451) were fatigue/asthenia (65%), headache (43%), pyrexia (41%), myalgia (40%), irritability/anxiety/nervousness (33%), insomnia (30%), alopecia (28%), neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%), injection site reaction (23%), arthralgia (22%), depression (20%), pruritus (19%) and dermatitis (16%).

Serious adverse events included neuropsychiatric disorders (suicidal ideation and suicide attempt), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including psoriasis and lupus), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).

Please see the medication guides and complete product information for PEGASYS and COPEGUS

Please also see our PegIntron or Pegasys ? pages of our web site.

IS HCV CURABLE?

Reported by Jules Levin

Http://www.natap.org

Over 90% of HCV mono-infected patients who have negative HCV viral load (undetectable) 6 months after stopping therapy remain undetectable. Small studies of perhaps 200 hundred patients in total have followed patients for 3-11 years and find over 90% of these patients continue to have undetectable HCV in the blood. Small studies have shown that these patients do not have HCV in the liver either. The study discussed below found that 98% of patients achieving a sustained viral response (undetectable HCV viral load) did not have HCV in the liver. This of course is good news. Most doctors feel that a patient who achieves and sustains undetectable viral load is likely to remain healthy. Many patients who achieve a sustained viral response (SVR) are able to improve the condition of the liver (fibrosis and inflammation). Studies have also found that a percentage of patients who are not able to achieve an SVR are still able to slow disease progression (inflammation and fibrosis). However, we still need long-term studies which follow large numbers of patients for many years to evaluate long-term clinical outcomes: the development of cirrhosis and other severe complications of HCV, and longevity.

This past year HCV researchers (Poynard, McHutchison, Lindsay et al) reported on the effect of HCV therapy on fibrosis and inflammation. They followed patients who received various regimens including interferon and Pegylated interferon, and they evaluated the outcomes in terms of improved fibrosis and inflammation. They found that inflammation and fibrosis improves in many patients whether or not they achieve an SVR, but of course achieving an SVR results in greater likelihood of improving the liver. They also found that 49% of the 150 patients with cirrhosis in this study were able to "reverse" cirrhosis.

When doctors refer to HCV being "curable" it is often said that this is analagous the situation with cancer. In cancer if they can't find cancer for a certain number of years after therapy has been finished they call the person cured. Does cancer ever re-emerge? We need long-term studies in HCV to evaluate the outcomes of patients who sustain undetectable HCV viral load in order to confirm this.

In summary, if a patient can sustain an undetectable viral load for 6 months to 1 year after stopping HCV therapy this gives them the best opportunity to remain healthy. It's important to bear in mind that these study results apply to patients with HCV mono-infection. We are not certain if these findings apply precisely to HCV/HIV coinfected patients. Studies in coinfected patients are ongoing and soon we will have additional information on them. There is much research going on now into new drugs for treating HCV. For patients who do not achieve a sustained viral response with the current therapy, they may want to consider maintenance therapy if they have advanced liver disease. Maintenance therapy consists of continuing interferon at a half-dose. Studies have found that this slows disease progression. The first study data on a new HCV drug that appears promising was presented recently at the large annual liver conference (AASLD). They studies and reported for the first time results from patients with HCV who received an HCV protease inhibitor (BILN 1061). Patients received this new drug for 2 days and achieved potent reductions in viral of 2-3 logs. There were no apparent safety concerns. Phase II studies are expected to begin in early 2003.

Study title: Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin

"...Of the 400 sustained responders, 393 (98%) had undetectable hepatic HCV RNA, whereas the other 7 (2%) had detectable viral RNA in the liver... Seven (2%) patients with a SVR had persistent hepatic HCV RNA; of these, 5 were followed late after treatment, and 2 relapsed... Five of these 7 patients have subsequently been followed annually. To date, 2 with high and low hepatic HCV-RNA levels, respectively, have relapsed (patients 2 and 7), with serum HCV RNA reappearing 12 months after completion of therapy. Two others (patients 3 and 6) have a durable response at 3.5 years' posttreatment. Patient 5 was still virus-free at 12 months' posttreatment, but has not been followed further. Patients 1 and 4 achieved a sustained response at 24 weeks after treatment, but have not been followed subsequently.."

Abstract summary: The clinical use of measuring hepatic hepatitis C virus (HCV) RNA before and after therapy in patients with chronic hepatitis C has been assessed in a number of small clinical trials. Viral clearance from the liver may be a better marker of long-term response than eradication of serum HCV RNA. The aim of this study was to evaluate quantitative hepatic HCV-RNA measurements before and after antiviral therapy. Two thousand eighty-nine chronic hepatitis C patients were enrolled in 3 published clinical trials evaluating interferon alfa-2b alone or with ribavirin either as initial therapy or for interferon relapse. Hepatic HCV-RNA quantitation was performed with a modified reverse-transcription polymerase chain reaction (RT-PCR) before and 24 weeks after therapy in 951 and 1,316 patients, respectively. Pretherapy hepatic HCV-RNA concentrations correlated best with serum HCV-RNA concentrations (R = .236, P = .0001) and negatively correlated with alanine transaminase (ALT) values (-0.178, P = .0001), duration of infection (-0.09, P = .02), parenchymal injury (-0.135, P = .0001), histologic activity index (HAI) inflammatory score (-0.085, P = .01), Knodell fibrosis score (-0.072, P = .03), and body weight (-0.078, P = .02). In paired liver biopsy specimens (n = 534), change in hepatic HCV RNA correlated with the change in the HAI (R = .346, P = .0001). Of 400 sustained virologic responders (SVR), 393 (98%) had undetectable hepatic HCV RNA, whereas 7 (2%) had detectable hepatic HCV RNA; 5 have been followed and 2 have had reappearance of serum HCV RNA 12 months after therapy. In conclusion, measurement of hepatic HCV RNA before or after therapy reflects changes observed in serum HCV RNA, and correlates inversely with hepatic inflammation and fibrosis, but otherwise has minimal clinical use. (HEPATOLOGY 2002;35:688-693. Author: McHutichison et al)

Hepatitis C is an important cause of chronic liver disease, with an estimated 2.7 million persons infected in the United States and 150 million persons worldwide. Recent studies have shown that 35% to 40% of patients who receive the combination of interferon plus ribavirin achieve the long-term benefits of sustained viral eradication from serum. Therapy, however, is costly and associated with side effects that require discontinuation or dose reductions in up to 20% of patients. Thus, identification of factors that would allow selection of patients most likely to respond or maintain their response would be clinically valuable. Before treatment, young age, female gender, absence of cirrhosis, low levels of pretreatment serum hepatitis C virus (HCV) RNA, and infection with HCV genotypes 2 or 3 have been associated with response. Unfortunately, these variables cannot be used clinically to accurately predict response in any individual patient, rendering it difficult to use these prognostic indicators to deny therapy.

The clinical use of quantifying hepatic HCV RNA before and after interferon therapy in patients with chronic hepatitis C infection has been assessed retrospectively in a number of small clinical studies. Viral clearance from the liver has been thought to be a better marker of long-term response than sustained eradication of serum HCV RNA, and most patients with a sustained virologic response (SVR) after therapy have also been shown to have undetectable liver HCV RNA.

The aim of this study was to prospectively evaluate the clinical use of assessing liver HCV-RNA quantitation before therapy as a predictor of sustained response, and after therapy as an indicator of durable response, in patients with chronic hepatitis C infection.

Two thousand eighty-nine patients with chronic hepatitis C infection were enrolled in 3 published clinical trials, comparing the safety and efficacy of interferon alfa-2b (INTRON A, Schering-Plough, Kenilworth, NJ) alone or combined with ribavirin (REBETOL, Schering-Plough) for 24 or 48 weeks for initial therapy or for relapse after interferon. At the time of liver biopsy (before and 24 weeks after therapy), a portion of liver tissue was immediately snap-frozen in liquid nitrogen and stored at -70¡C for HCV-RNA analysis.

A SVR was defined as loss of serum HCV RNA by reverse-transcription polymerase chain reaction (RT-PCR) 24 weeks after completion of therapy. Pre- and posttherapy liver tissue was available for analysis from 951 and 1,316 patients, respectively.

RESULTS

Of the 2,089 patients evaluated, pre- and posttherapy liver tissue was available for analysis from 951 and 1,316 patients, respectively. The discrepancy in the lower number of patients with pretreatment biopsies available for this study resulted from the fact that this protocol was introduced after some patients had already undergone their pretreatment liver biopsy. Thus, patients with a biopsy obtained within a few months of these clinical trials did not undergo a repeat pretreatment liver biopsy before study entry. Most pretreatment liver-biopsy specimens (903 of 951 [95%]) contained detectable HCV RNA.. Of the remaining 48 (5%) that were negative, 37 (77%) were associated with reduced amplification of the internal assay controls, indicating that there was insufficient remaining viable tissue to perform RT-PCR.

Of the 1,316 liver biopsies tested for HCV RNA 24 weeks after therapy, 400 were from sustained responders and 916 from nonresponders (those who did not achieve a sustained response). Of the 400 sustained responders, 393 (98%) had undetectable hepatic HCV RNA, whereas the other 7 (2%) had detectable viral RNA in the liver. The remaining 916 liver biopsies tested were from nonresponders, of which 850 (93%) had detectable HCV RNA, but in 66 (7%) biopsies, HCV RNA was undetectable. However, 34 (52%) of these specimens from nonresponders, and 17 of 393 (4%) from sustained responders, had reduced amplification of internal controls, consistent with viable tissue inadequate to assess whether HCV RNA was present or absent.

Pretreatment hepatic HCV-RNA values correlated closely with baseline serum HCV-RNA levels (r = 0.236, P = .0001).

A significant negative correlation was observed with the baseline ALT ratio (ALT value at baseline expressed as a ratio to the upper limit of normal) (r = -0.178, P = .0001), body weight (r = -0.078, P = .019), and duration of infection (r = -0.088, P = .017). However, the date of acquisition of infection was based on the patient's reporting; therefore, the duration of infection represents an estimated value in the majority of cases. Analysis of subgroup means by ANOVA also showed a statistical association between hepatic HCV-RNA levels and the reported mode of acquisition (P = .0001), as well as a higher hepatic HCV-RNA level in patients with genotype 1 compared with non-1 ( P = .0007).

When we evaluated the relationship between hepatic HCV-RNA concentrations and histologic changes before treatment, we found a negative correlation between pretreatment hepatic HCV-RNA values and parenchymal injury (r = -0.135, P = .0001), HAI inflammatory score (r = -0.085, P = .012), and Knodell fibrosis score (r = -0.072, P = .034); however, we found no association with other components of the HAI.

Although pretreatment hepatic HCV-RNA values were predictive of response to antiviral therapy when analyzed alone or after controlling for treatment, when other prognostic factors such as genotype and serum HCV RNA were included in the logistic regression, the effect of the hepatic HCV RNA in predicting response became nonsignificant.

There were 534 patients with paired liver biopsies available before and after therapy. Of these, 364 (68%) were nonresponders and 170 (32%) sustained responders. Overall, the observed change in liver HCV RNA correlated significantly with the change in the HAI (r = .346, P = .0001). However, this correlation was not observed when either nonresponders (r = .026, P = .62) or sustained responders (r = -.062, P = .42) were analyzed separately. Seven patients achieved a SVR to therapy but had detectable hepatic HCV RNA at the 24-week posttreatment biopsy. One of these (patient 3) was from the interferon-relapse retreatment trial, and most had low levels of detectable hepatic HCV RNA at follow-up.

Five of these 7 patients have subsequently been followed annually. To date, 2 with high and low hepatic HCV-RNA levels, respectively, have relapsed (patients 2 and 7), with serum HCV RNA reappearing 12 months after completion of therapy. Two others (patients 3 and 6) have a durable response at 3.5 years' posttreatment. Patient 5 was still virus-free at 12 months' posttreatment, but has not been followed further. Patients 1 and 4 achieved a sustained response at 24 weeks after treatment, but have not been followed subsequently.

Discussion By Authors

When this study was initiated, the clinical value of measuring hepatic HCV RNA as a predictor of response, relapse, or disease severity was unclear. Smaller studies have demonstrated that changes in hepatic HCV RNA with therapy reflect changes in serum HCV RNA, and that the persistence of hepatic HCV RNA at the end of therapy may predict relapse. Other studies using non-PCR-based techniques for the detection of intrahepatic HCV RNA, such as branched-chain DNA target amplification or in situ hybridization, have also demonstrated a correlation between hepatic HCV-RNA levels and serum HCV RNA. This large trial allowed a careful prospective evaluation of these issues.

Our results indicate that measurement of hepatic HCV RNA before or after therapy reflects levels of serum HCV RNA.

Seven (2%) patients with a SVR had persistent hepatic HCV RNA; of these, 5 were followed late after treatment, and 2 relapsed. Combination therapy for previously untreated patients with chronic hepatitis C results in posttreatment virologic relapse rates of 20% to 40% depending on the duration of therapy. Accurate, early identification of these relapsing patients is not possible and cannot be predicted at this time. Most relapses occur during the first 3 months following treatment. After this period, the late relapse rate over several years in patients with a SVR is approximately 5% to 10%. Small studies of hepatic HCV RNA have documented that hepatic viral clearance correlates with long-term SVR. In our study, only 2 of 7 patients with a SVR, but detectable posttreatment hepatic HCV RNA, have relapsed within 12 months.

In this study, the posttreatment liver biopsies were obtained 24 weeks after the end of therapy. Whether earlier relapse, within the first 6 months after therapy, could be predicted by assessing hepatic HCV RNA at the end of treatment was not evaluated in this study. Presumably, residual virus within the liver (or other extrahepatic reservoirs) is responsible for most early relapses, and this might have been detectable if hepatic HCV-RNA estimation had been performed at the end of treatment, as indicated in a previous small trial. Larger prospective trials would be required to further evaluate this concept, but end-of-therapy biopsies are rarely obtained either in clinical trials or in routine clinical practice.

Hepatic HCV-RNA concentrations before treatment correlated with both serum HCV-RNA concentrations and HCV genotype, and were higher in genotype 1-infected patients, as previously noted. In addition, hepatic HCV-RNA concentrations were associated with certain demographic variables. A strong inverse correlation existed between pretreatment hepatic HCV-RNA concentrations and the degree of liver parenchymal injury, and with baseline ALT values; a weaker correlation was found with the estimated duration of infection, body weight, HAI inflammatory, and Knodell fibrosis scores. Reasons for these negative correlations are speculative. The precise mechanisms of hepatocyte injury in chronic hepatitis C are unknown but presumably immune-mediated. This study did not indicate an association between hepatic HCV-RNA levels and the degree of histologic activity as would be expected if a direct viral cytopathic mechanism were the predominant factor in hepatic injury.

In this study, 5% of pretreatment and 7% of posttreatment liver specimens were falsely negative (HCV RNA detected in the serum but not in the liver), and most of these could be explained by reduced amplification within the assay. Whereas sampling could be a potential explanation, other studies suggest that HCV is distributed evenly throughout the liver, but may only infect 5% to 25% of hepatocytes. Technical factors could explain these occasional negative samples, but in most instances, the accompanying internal controls were also negative, suggesting that the liver tissue was insufficient or improperly stored to maintain nucleic-acid viability.