Chronic Hepatitis C: Diagnosis, Treatment, and Preventive Measures
Chronic Hepatitis C: Diagnosis, Treatment, and Preventive Measures
Author: Robert A. Levine, MD, Professor of Medicine, Department of Medicine, Division of Gastroenterology, State University of New York, Health Science Center at Syracuse.
Peer Reviewer: Mitchell I. Shiffman, MD, Associate Professor of Medicine; Chief, Hepatology Section; Medical Director, Liver Transplant Program, Medical College of Virginia at Virginia Commonwealth University, Richmond.
Editor’s Note—Chronic hepatitis C virus (HCV) infection is the liver disease of this era. Predictions for the 21st century are that liver-related deaths from HCV will increase fourfold and orthotoptic liver transplantation sixfold, respectively. This is related to the fact that the currently infected pool of patients with HCV will peak in the next 10-20 years. Patients with chronic HCV are burdened with both the fear of dying of this disease and the stigma of living with it.
The recent National Institutes of Health Consensus Conferences on chronic HCV solidified the justification for a selective approach to treatment. Nevertheless, the high profile of chronic HCV has led to a sense of urgency about treating all newly recognized patients. This approach has caused the variable natural history of this disease to be overlooked. The debate about whom to treat has failed to focus attention on the alternate approach of waiting for better emerging therapies for the subset of patients with histologically minimal or mild chronic HCV. Practitioners may be more confident about postponing treatment in patients with minimal hepatitis on liver biopsy since they are less likely than patients with more moderate or severe necroinflammatory activity or fibrosis to progress to cirrhosis.
Background
Infection with the hepatitis C virus is a global health problem. An estimated 170 million people are chronically infected worldwide. In the United States, the prevalence of antibody to hepatitis C is estimated to be 1.8% and approximately 4 million persons in the United States currently have chronic HCV.1,2
Like acute hepatitis A or B, it is usually subclinical and less than 25% of patients develop jaundice. Fulminant hepatitis is rare, if it occurs at all. The number of acute cases of hepatitis C has decreased during the past decade from more than 150,000 to 30,000. Eighty-five percent of patients with HCV develop chronic infection. HCV contributes to the deaths of 10-12,000 Americans per year and is the principal cause of chronic liver disease, cirrhosis, and hepatocellular cancer (HCC). Among patients with chronic HCV, 20% progress to cirrhosis after 20-50 years and, thereafter, 1-5% develop HCC in 10-20 years.3 Most patients remain asymptomatic for many decades and may never develop progressive or symptomatic liver disease. Approximately 20% of patients at the first time they are evaluated with liver biopsy already have cirrhosis. Alcohol abuse has a deleterious effect on the natural history of chronic HCV.
There remains disagreement as to the prognosis of patients with chronic HCV. In our experience, there is a large subpopulation of chronic HCV in which there is less progression to cirrhosis, if it occurs at all, when patients initially have histologically minimal or mild chronic HCV.4 Those with more moderate or severe hepatitis and/or significant fibrosis are much more likely to develop cirrhosis.
Epidemiology
From a demographic point of view, HCV infection has its highest incidence among persons aged 20-39 years and males predominate slightly.5 African Americans have substantially higher prevalence of HCV infection than do caucasians and probably a lesser response to treatment, although the latter has not been yet established.
Identifying Patients at Risk
One of the problems is to identify individuals at risk for disease progression. Three independent factors have been noted with an increased rate of fibrosis progression: age of infection older than 40 years, daily alcohol ingestion more than 50 g, and male sex. In addition, the histological picture of a liver biopsy is extremely important in prognosticating progression. As shown in Table 1, patients with no significant fibrosis and minimal or mild necroinflammation are at much lower risk of progression than those with moderate or severe necroinflammation and septal fibrosis or nodularity. The liver biopsy remains the cornerstone of risk identification. Strong predictors of progression to cirrhosis in 10 years are patients with a high grade of necroinflammation, septal fibrosis, or incomplete nodularity. The liver biopsy is more likely to identify the risk of progression than is the genotype or viral load. There is no correlation between HCV-RNA level and histology.6 In many ways, a liver biopsy may be cost-effective since current therapy is expensive, is ineffective in the majority of patients, and has side effects that may be significant. It is critical to use the liver biopsy to recommend which patients have a better or worse prognosis. Conceivably, the role of liver biopsy may decrease in the future if emergent therapies become more cost-effective than the current therapies.7 Some have argued that treatment of all patients with chronic HCV is cost-effective and would cut the lifetime incidence of cirrhosis from 66% to 60%.8-9
Alcohol is probably the most important high-risk factor as evidenced by the fact that moderate alcohol consumption is associated with a two- to three-fold greater risk of cirrhosis and decompensated liver disease.10,11 In alcoholic users, 58% develop cirrhosis by the second decade, whereas only 10% of individuals who do not use alcohol develop cirrhosis in that same period.11 Since alcohol is the most important factor to enhance disease progression and more than 10 g/d is addictive, in our center we recommend that patients not have any alcohol intake if they have chronic HCV.
As shown in Table 1, it is questionable whether genotype or viral levels show a correlation with disease activity and outcome strong enough to justify their use in assessing prognosis in individual patients. In general, patients with genotypes HCV-2 and HCV-3 have the best response in contrast with those with HCV-1, who have the worst. Unfortunately, these parameters have a low predictive value compared to the liver biopsy, which is the gold standard for prognostication.
Table 1. Risk of HCV Disease Progression |
|
| Low Risk | High Risk |
Female |
Male |
| Age < 35 years at acquisition | Age > 40 years at acquisition |
| No alcohol use | Alcohol use > 50 g daily |
| Mild necroinflammation | Moderate/severe necroinflammation |
(grades 1-2) |
(grades 3-4) |
| No/minimal fibrosis | Septal fibrosis/nodularity |
(stages 0/1) |
(stages 2-4) |
Since chronic HCV is usually asymptomatic until irreversible liver damage has occurred, it is critical for the primary care providers to make a timely diagnosis and have a high index of suspicion for this disease. In order to obtain proper screening tests to detect asymptomatic infection during routine examinations, the practicing physicians should be familiar with the risk factors for acquiring chronic HCV, which include the patients with elevated alanine aminotransferase (ALT), intravenous drug abuse, hemophiliacs, hemodialysis patients, health care workers with exposure to blood-blood products,12 persons with needle-stick injury, transplant recipients, transfusion/blood product recipients prior to 1990, persons with a tattoo or body piercing, HIV-positive individuals, persons who inhale cocaine, employment in patient care or clinical laboratory work, persons who are sexually active with multiple partners, exposure to a sex partner or a household member who has a history of hepatitis, and a low socioeconomic level. Although hepatitis C is associated with a history of tattoos, it has not been demonstrated that the transmission occurs also from ear piercing, acupuncture, or medical, surgical, or dental procedures.13
Transfusions
Currently, the transfusion rate is extremely rare, being less than 1.5% per recipient or approximately 0.02% per unit transfused.13 Prior to 1990, however, before the advent of a screening test for HCV, there was a high prevalence rate. Persons with hemophilia have extremely high prevalence rates of HCV infection up to 90% because effective procedures to inactivate viruses in patients receiving clotting factor concentrate prepared from plasma pools was lacking.13 Since December 1994, all immune globulin transfusion products are inactivated for HCV RNA.
Injecting and Other Illegal Use
Sharing syringes and needles is associated with high prevalence of HCV. After five years of injecting, as many as 90% of drug users are infected with HCV. The history of intranasal cocaine is one of the more recently recognized modes of transmission through probably epistaxis or contaminated straws. Studies suggest that as many as 14% of the general population have used cocaine at least once.13
Nosocomial and Occupational Exposure
Nosocomial transmission of HCV is possible if infection-controlled techniques of disinfection are inadequate and con- taminated equipment is shared among patients. Reports are rare of such a transmission, other than in chronic hemodialysis units. The latter prevalence ranges from as low as 10% to as high as 60%.13
Health care, emergency medical, and public safety workers who have exposure to blood in the workplace are at risk for being infected with HCV. However, the prevalence of HCV infection among health care workers, including surgeons, is no greater than the general population and averages 1-2%, and is 10 times lower than that for chronic hepatitis B infection.13
The average incidence of antibody seroconversion after unintentional needle sticks for sharp exposures from an HCV-positive source is 1.8% (range, 0-7%).13
Other Exposures
Percutaneous HCV transfusion has been associated with unusual folk medicine practices, tattooing, body piercing, and commercial barbering. High-risk sexual practices have a 6% prevalence of anti-HCV.13 The prevalence among nonsexual household contacts of persons with chronic HCV infection is unknown.
The average rate of perinatal HCV infection among infants born to HCV-positive, HIV-negative women is 5-6%.13-15 These findings are based solely on detection of anti-HCV and HCV RNA, respectively. HCV RNA can be detected in infected infants as early as 1-2 months. The rate of passage of HCV antibodies from mother to child is less than 1%, and the rate of HCV viremia in infants after perinatal transmission is uncommon.13-15
Although injecting-drug use accounts for 60% of HCV transmission, other exposures such as occupational, hemodialysis, household, and perinatal together account for approximately 10% of HCV infections. Thus, potential risk factors can usually be identified if a proper history is asked. Ideally, less than 10% of patients should have no recognized source of infection if the physician pursues with an intensive history, but in practice about 40% remain without a likely source of their disease.
Pathogenesis
The host immune response is activated in chronic HCV, particulary T-cell-mediated activity. The latter contributes to hepatic damage. Unfortunately, humoral, cellular immune, and cytokine responses are not apparently sufficient to eradicate HCV in most patients. Direct viral cytopathicity does not appear to account for the liver damage in this disease.16
HCV demonstrates heterogeneity within the viral genome so that most patients infected have evidence of multiple quasispecies that differ somewhat in nucleotide sequence. Because of the quasispecies phenomenon and the high rate of mutation of the genome, chronic HCV is the ultimate outcome and not the exception. Host factors, in particular the immune system, play a role in the development of chronic infection. A better understanding of the immune system’s contribution to this disease will provide insight into better future therapy.
Clinical Features and Natural History
Approximately 15-20% of persons resolve their infection without sequellae, as shown by the persistent absence of HCV RNA in the serum and normalization of ALT levels. In the remaining 80-85% chronic HCV infection develops, with persistent or fluctuating ALT elevations indicating active liver disease in two-thirds of these patients and in one-third of the remaining patients of chronically infected persons, ALT levels remain normal.
It is critical to recognize that a single ALT determination cannot be used to exclude ongoing hepatic injury or subclinical hepatitis since there is fluctuation in ALT levels in this infection. It is recommended by most experts that patients have at least three separate abnormal ALT determinations over a 6-12 month period at least one month apart to increase the likelihood of the presence of chronic infection.
The cause of this disease is insidious and progressive without physical signs and symptoms in most patients during the first two or more decades after infection. Asymptomatic persons are recognized during blood donor screening by HCV-positive virology or by elevated ALT levels that may be detected during routine physical examinations.
Cirrhosis develops in approximately 20-25% of persons with chronic HCV over 20-50 years and HCC in 1-5%. However, once cirrhosis is established, the rate of HCC may be as high as 1-4% annually.
Many of these patients are associated with various factors that have a synergistic effect on the severity of their liver disease. As cited in Table 1, these factors include alcoholic intake,10-11 male gender, being older than 40 years at infection, and having more necroinflammatory histologic activity on liver biopsy. In contrast, when patients are carefully avoiding certain risk factors, the prognosis seems much improved without progression to cirrhosis. A notable example of this is more than 200 Irish women in Dublin who have been followed two decades after they received HCV-contaminated Rh factor immune globulin in the maternity hospital. Eventually, only 2.4% had evidence of cirrhosis and none died from the disease.17 Thus, longer term follow-up studies are needed to assess the ultimate consequences of chronic HCV.
Extrahepatic manifestations of chronic HCV include cryoglobulinemia, membranoproliferative glomerulonephritis, and porphyria cutanea tarda. There are other suggested extrahepatic conditions, but these have not been established. Recognized extrahepatic manifestations of the disease are probably of immunologic origin.
Diagnosis and Monitoring
A variety of tests are available for diagnosing patients with chronic hepatitis C and monitoring their response to treatment. These include ALT for biochemical determination; enzyme immunoassays (EIAs) and recombinant immunoblot assays (RIBA) for serologic detection of anti-HCV; polymerase chain reaction (PCR) assay and signal amplification assay (branched DNA) for direct detection of HCV RNA in serum; and liver biopsy for assessing histologic activity and stage of disease. (See Tables 2-4 and Figure.)
Serological Tests for Hepatitis C (See Table 2.)
Table 2. Serologic Assays for Hepatitis C Virus (HCV) Infection |
||
Test/Type |
Application |
Comments |
| • Hepatitis C virus antibody (anti-HCV) | ||
| EIA (enzyme immunoassay) | Indicates past or present infection, but does not differentiate between acute, chronic, or resolved infection | Sensitivity ³ 97% |
| Supplemental assay (i.e., recombinant immunoblot assay [RIBA]) | All positive EIA results should be verified with a supplemental assay | EIA alone has low-positive predictive value in low-prevalence populations |
| • HCV RNA (hepatitis C virus ribonucleic acid) Qualitative tests | ||
| Reverse transcriptase polymerase chain reaction (RT-PCR) amplification of HCV RNA by in-house or commercial assays (e.g., Amplicor HCV) | Detect presence of circulating HCV RNA. Monitor patients on antiviral therapy. | Detect virus as early as 1-2 weeks after exposure |
| Detection of HCV RNA during course of infection might be intermittent; a single-negative RT-PCR is not conclusive. False-positive and false-negative results might occur | ||
| • Quantitative tests | ||
| RT-PCR amplification of HCV RNA by in-house or commercial assays (e.g., Amplicor HCV Monitor). Branched chain DNA (bDNA) assaays (e.g., Quantiplex HCV RNA assay) | Determine concentration of HCV RNA useful for assessing the likelihood of response to antiviral therapy | Less sensitive than qualitative RT-PCR. Should not be used to exclude the diagnosis of HCV infection or to determine treatment end point |
| • Genotype | ||
| Several methodologies available (e.g., hybridization, sequencing) | Group isolates of HCV based on genetic differences, into six genotypes and > 90 subtypes | Genotype 1 (subtypes 1a and 1b) most common in United States and associated with lower response to antiviral therapy |
| With new therapies, length of treatment might vary based on genotype | ||
| Source: Adapted from CDC. U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mort Wkly Rep 1998;47(no. RR-19):1039. | ||
Enzyme immunoassay (EIA). A second-generation enzyme immunoassay (EIA-2) for detecting antibody against HCV (anti-HCV) is the key test to suggest chronic HCV. Its antibody is not detected in the serum until months after exposure and may take as long as 6-12 months to appear. The sensitivity of this assay is approximately 92-95% and usually a positive EIA-2 in a patient with elevated ALT and risk factors for HCV is diagnostic. At this point, the patients should be referred to a gastroenterologist or hepatologist for further evaluation.
Recombinant immunoblot assay (RIBA). The RIBA assay is positive when at least two antigens are present and implies that a previous positive anti-HCV test was a true-positive. One positive antigen is considered indeterminate and none negative. If the RIBA is indeterminate or negative, hepatitis C is unlikely. This supplemental test with RIBA is probably not cost-effective. However, if the diagnosis of HCV is in question, a RIBA could be obtained in an individual who is anti-HCV-positive by EIA-2. Specifically, if the patient has hypergammaglobulinemia, the possibility of autoimmune hepatitis, or when liver enzymes are normal and no risk factors are present, then the RIBA may be helpful for confirmation and to exclude the rare false-positive tests from an anti-HCV-negative individual.
HCV RNA detection. This test detects the presence of the virus itself and, therefore, can be used to differentiate patients who have ongoing infection and those who have cleared the virus from the circulation. Qualitative HCV RNA detection uses reverse transcription polymerase chain reaction (RT-PCR), which is the most sensitive technique for the presence of HCV RNA. Quantitative HCV-RNA is especially important when viral counts are low. Thus, measurement of HCV RNA levels can confirm the diagnosis of HCV when it is in doubt.
| Table 3. Persons who Should be Tested for Hepatitis C Virus (HCV) Infection Based on Their Risk for Infection or a Recognized Exposure(HCV) Infection |
| • Persons who injected illegal drugs, including those who injected once or a few times many years ago and do not consider themselves as drug users, who received clotting factor concentrates produced before 1987, who were ever on chronic (long-term) hemodialysis, or have persistently abnormal alanine aminotransferase levels |
| • Prior recipients of transfusions or organ transplants, including: |
| persons who were notified that they received blood from a donor who later tested positive for HCV infection |
| persons who received a transfusion of blood or blood components before July 1992 |
| persons who received an organ transplant before July 1992 |
| • Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-positive blood |
| • Children born to HCV-positive women |
| • Recipients of transplanted tissue (e.g., corneal, musculoskeletal, skin, ova, sperm) |
| • Intranasal cocaine and other noninjecting illegal drug users |
| • Persons with a history of tattooing or body piercing |
| • Persons with a history of multiple sex partners or sexually transmitted diseases |
| • Long-term steady sex partners of HCV-positive persons |
| Source: Adapted from CDC. U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mort Wkly Rep 1998;47(no. RR-19):1039. |
Because there is a lack of standardization between the various PCR assays available, values from different assays cannot be compared. It is critical to use the same laboratory while monitoring viral load during treatment.
Liver biopsy. Biopsy confirms an early diagnosis of chronic HCV and excludes any other alternative or coexisting diseases such as hemochromatosis or alcohol-related illness. It is the only accurate way to determine hepatitis activity, stage of fibrosis and severity, thereby providing important prognostic information by determining the baseline extent of liver damage. As previously mentioned, patients with minimal hepatitis and no significant fibrosis may not be chosen for treatment, while those most likely to have progressive liver damage have at least moderate- to-severe inflammation and necrosis and/or portal bridging fibrosis.4,18,19
Diagnostic Algorithm
All patients with elevated ALT levels, with or without associated risk factors for hepatitis C, should be tested for anti-HCV by enzyme immunoassay (EIA). For those patients without risk factors who are anti-HCV positive, serum HCV RNA should be determined by PCR. If HCV RNA results are positive, a liver biopsy should be performed. If HCV RNA results are negative, retesting should be performed within several months. If again negative, results should be dismissed as a false-positive EIA and other causes of elevated ALT should be evaluated. For those patients with no associated risk factors and with normal ALT levels, confirmation of HCV exposure should be obtained with either the RIBA test for anti-HCV or the PCR assay for HCV RNA. The former is approximately as expensive as the latter test; thus, in our center we prefer PCR. This test is also more reliable than branched chain quantitation of viral load. Patients with HCV risk factors and elevated ALT levels should then, in preparation for treatment, have a liver biopsy performed followed by quantitation of HCV RNA. (See Figure.)
ALT
ALT levels fluctuate greatly and do not necessarily reflect the presence of infection, severity of disease, or degree of disease progression. Most studies have shown only a weak correlation between serum ALT and histologic severity.6 Approximately 10% of patients who lose HCV RNA during treatment continue to have elevated ALT. About 10% of patients who normalize ALT during treatment continue to have HCV RNA in serum.
Treatment
Despite a decade of experience with treatment for chronic HCV, only in the past 2-3 years has significant progress in treating this disease become evident. An expanding armamentarium of treatment options and new insights about the virus and disease progression has led clinicians to be more aggressive in treatment of certain populations of patients with HCV. Although there may be a subgroup of patients wherein the prognosis is relatively good with virtually no progression to cirrhosis (those patients with minimal hepatitis and no significant fibrosis on liver biopsy),4 in others the progress is insidious leading to severe fibrosis, cirrhosis, and HCC. Despite the fact that monotherapy with interferon has been present for the last decade, 6-12 months of such therapy is less than ideal because of its limited effectiveness with less than 15% of patients showing sustained virological responses. A multidrug approach, as in HIV infection, may prove to be useful for patients with more aggressive hepatitis C. Currently, combination interferon/ribavirin therapy has produced sustained virological responses in about 40-50% of patients who either relapse after an initial response to interferon alone or are treatment-naive patients being administered this combination treatment for 6-12 months.4,20-22 Both types of therapy appear to be cost-effective. Patients who experience sustained virological, biochemical, and/or histological responses represent the minority of those treated today. In the future, emerging therapies hopefully will provide better improvement in these parameters.
Table 4. Persons for Whom Routine Hepatitis C Virus (HCV) Testing is not Recommended |
| • Health care, emergency medical, and public safety workers |
| • Pregnant women |
| • Household (nonsexual) contacts of HCV-positive persons |
| • The general population |
| Source: Adapted from CDC. U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mort Wkly Rep 1998;47(no. RR-19):1039. |
There is evidence that longer treatment of 18-24 months might lead to better results, although also to more adverse side effects.23-24 New research with other treatment approaches suggests that higher starting doses (induction dosing),25 longer treatment at a given dose, maintenance therapy, and the use of a prolonged form of interferon may augment the current treatment and possibly increase the sustained response.
Successful treatment, whether defined as sustained eradication of the virus from the blood or sustained normalization of serum ALT, improves the patient’s quality of life.26 Moreover, histological improvement can be measured in patients who have initial liver biopsies before treatment and subsequent follow-up biopsies.26,27 The latter may be the best correlate of good prognosis in patients who respond to therapy and are followed for many years. Even in nonresponders to interferon treatment, liver biopsy usually shows some improvement.27
Interferons
Type 1 interferons (alpha, beta, omega, and consensus) share common biologic activity. Three type 1 interferons are currently licensed for the treatment of chronic HCV in the United States. Interferon alfa-2b and interferon alfa-2a are human recombinant interferons, and interferon alfacon-1 (consensus interferon) is a synthetic interferon derived by scanning the sequences of several natural interferon subtypes and assigning the most frequently observed amino acid in each corresponding position. This latter drug shows promising treatment results for achieving sustained virus eradication in relapsed patients treated with more intensive high-dose regimens.28
Interferon therapy for chronic HCV has been shown to normalize ALT levels, reduce HCV RNA to undetectable levels, reduce hepatic inflammation, and improve liver histology. A secondary goal is to improve the long-term outlook by delaying progression to cirrhosis, reducing the risk of liver failure and HCC, and decreasing the need for liver transplantation.
Interferon and Ribavirin Combination Therapy
Ribavirin appears to work synergistically with interferon to produce superior antiviral effects. The main side effect of ribavirin alone or in combination with IFN has been hemolytic anemia. However, this resolves and hemoglobin baseline levels return upon stopping treatment.
Recent studies report that the combination of interferon and ribavirin for initial treatment of patients with chronic HCV and for treatment in patients with relapsed hepatitis C who previously responded to interferon alone demonstrates success rates, as defined by prolonged (6 months) clearance of plasma viral RNA with presumptive eradication of the virus and concomitant improvement in histopathology.10,20,21,27 The percentages for combination therapy are in the range of 31% for 24 weeks and 38% for 48 weeks, respectively. Such results compare with 6% and 13% for control groups receiving interferon alone, at 24 and 48 weeks, respectively. Sustained rates appear to be maintained for many years if HCV-RNA is found to be undetectable after six months of cessation of therapy.29
It appears that interferon in combination with ribavirin is the treatment of choice for patients with previous responses to interferon and subsequent relapse. Clinical studies are being undertaken to determine whether nonresponders should be treated with combination therapy.
Who Should be Treated?
In general, patients with chronic HCV who are at greatest risk for progression to cirrhosis are those patients with persistently elevated ALTs, positive HCV RNA levels, and a liver biopsy with moderate necroinflammatory changes or fibrosis. On the other hand, for patients with elevated ALT levels but minimal inflammatory changes on the liver biopsy and no significant fibrosis, they may be monitored with repeated measurements of ALT and an occasional liver biopsy every 3-5 years since their progression to cirrhosis is minimal and slow.4,26
Patients with risk of decompensated cirrhosis should not undergo treatment and those with decompensation should be recommended for liver transplantation. Compensated cirrhosis was previously thought to be a negative variable for response, but newer treatments may prove to be as effective in cirrhotic as in noncirrhotic patients. (See Table 5.)
Table 5. Indications for Treatment |
| Persons Recommended for Treatment |
| Treatment is recommended for patients with chronic hepatitis C who are at greatest risk for progression to cirrhosis, as characterized by: |
| • persistently elevated ALT level (although enzyme level may fluctuate between normal and abnormal in a subpopulation of 20%) |
| • detectable HCV RNA by a PCR-based assay |
| • a liver biopsy indicating active hepatitis with either portal or bridging fibrosis or at least moderate degrees of inflammation and necrosis and stage > 1 and grade > 1 |
| Persons for Whom Treatment Is Unclear |
| • patients with compensated cirrhosis (without jaundice, ascites, variceal hemorrhage, or encephalopathy) |
| • patients with persistent ALT elevations, but with less severe histologic changes (i.e., no fibrosis and minimal necroinflammatory) changes in these patients, progression to cirrhosis is likely to be slow, if at all; therefore, observation and serial measurements of ALT and liver biopsy every 3-5 years is an acceptable alternative to treatment with interferon |
| • patients aged < 18 years or > 60 years (note that interferon is not approved for patients aged < 18 years). |
| Persons for Whom Treatment Is Not Recommended |
| • patients with persistently normal ALT values (but this may change in the near future) |
| • patients with advanced cirrhosis who might be at risk for decompensation with therapy |
| • patients who are currently drinking excessive amounts of alcohol or who are injecting illegal drugs (treatment should be delayed until these behaviors have been discontinued for ³ 6 months) |
| • persons with major depressive illness, cytopenias, hyperthyroidism, renal transplantation, evidence of autoimmune disease, or who are pregnant |
| Source: Adapted from CDC. U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mort Wkly Rep 1998;47(no. RR-19):1039. |
It is not clear which factors increase the likelihood of response to therapy for chronic HCV.30,31 Previously, it was thought that low pretreatment HCV RNA levels, viral genotype other than 1, and mild histologic disease were important. While viral genotype 1a or 1b may carry a lower response to therapy, the level of HCV RNA is controversial. On the other hand, in our center, we believe that minimal hepatitis among patients with mild histologic disease separates a subset population may never need subsequent treatment with monotherapy or combination therapy.4
Patients who are drinking excessive amounts of alcohol, who are injecting illegal drugs, and who are noncompliant should not be entered into treatment programs. Other contraindications for treatment with interferon include major depressive illness, cytopenias, hyperthyroidism, renal transplantation, and evidence of autoimmune disease. The best results with interferon monotherapy are 15-25% achievement of a sustained response as measured by normalization of HCV RNA and ALT at least one year after therapy is stopped.23,26 Many of these have histological improvement.23,26,27 The treatment with a standard dose of interferon is rarely effective in those who do not respond at the end of therapy.
The Patient with Normal ALT Levels
Patients with persistently normal ALT values are currently not treated with interferon outside of clinical trials.26,32-36 Patients who have documented persistently normal ALT have a spectrum of histological abnormalities, most of which are associated with minimal or very mild hepatitis.4 Progression of this disease with normal ALT is extremely slow, with the median time to cirrhosis being estimated as long as 80 years and therapeutic response uncertain.4,35 Large, prospective, randomized control trials are needed to assess the effects of various treatments in this group of patients. Currently, most patients are not being treated for HCV if they have normal ALT values.4
With the relative success of combination therapy, there are many hepatologists who do treat this type of patient with combination drugs. The sustained response rate in patients with normal ALT may be shown in the future to be similar to patients with elevated enzymes. At present, in our center, we believe that patients with normal ALT and minimal hepatitis demonstrated on liver biopsy should not be treated because they have a good prognosis.35 In rare instances, treatment could be indicated for this group in a mother-to-be or an active surgeon.
Side Effects of Treatment
It is important for the practicing physician to be aware of the side effects that patients will have after receiving interferon and/or combination therapy. Five to 15% of patients discontinue treatment and 10-40% must take reduced doses because of side effects. The most common of these, which occur in more than 10% of patients, are flulike symptoms (fevers, headaches, fatigue, myalgia, ascenia, rigors, arthralgias, and dizziness), and in 5-10% of patients gastrointestinal symptoms (nausea, anorexia, diarrhea), alopecia, irritability, and depression occur. Severe side effects have been observed in less than 2% of patients but include autoimmune disease, among which most commonly is thyroid dysfunction, including hypo- and hyperthyroidism, seizure disorder, acute cardiac and renal failure, retinopathy, and sepsis. The only irreversible side effect of interferon is hypothyroidism or hyperthyroidism, which occurs frequently but in a ratio of 5:1, respectively.
Bedtime administration and prophylactic acetaminophen may minimize or prevent the flulike symptoms, which generally decrease with continued treatment.
Ribavirin used in combination therapy can produce hemolytic anemia that may be problematic for patients with a pre-existing anemia, bone marrow suppression, or renal failure. Ribavirin is also teratogenic and female patients should avoid becoming pregnant during therapy.
Certain contraindications require cessation or reduction in the dosage of interferon. These include laboratory tests in which reversible reductions are observed during therapy in more than 10% of patients, including hemoglobin, white blood cell counts, and granulocyte counts. In the presence of ribavirin, a hemolytic anemia is expected in virtually all patients but is modest in nature and the drug can be continued in more than 95% of patients without cessation or reduction in dose.
A Minority Cure for HCV
Since interferon is successful in only a minority of patients and there is breakthrough during therapy and relapse after therapy, patients should be treated only if there are clear indications. These indications include elevated ALT enzyme, no contraindications to therapy, compliance, absence of alcohol for at least six months, and the willingness to commit to 6-12 months of therapy. Unfortunately, even in these treated patients, a sustained response is often not obtained in the majority. Nevertheless, for those who do respond it appears that sustained response can be maintained for subsequent years and at least for 3-5 years.23,27,29 In such patients, it is possible that they may be cured of their infection and their risk of further disease progression will be minimal, if at all.
Table 6. Preventive Measures for Patients with Chronic HCV |
| • Do not drink alcohol |
| • Do not start any new medicines, including over-the-counter and herbal medicines, without checking with their doctor |
| • Do get vaccinated against hepatitis A, and, for those at risk for hepatitis B, also with B vaccine |
| • Do not donate blood, body organs, other tissue, or semen |
| • Do not share toothbrushes, dental appliances, razors, or other personal-care articles that might have blood on them |
| • Do cover cuts and sores on the skin to keep from spreading infectious blood or secretions |
| • HCV-positive persons with one long-term steady sex partner do not need to change their sexual practices. They should discuss the risk, which is low but not absent, with their sex partner. If they want to lower the limited chance of spreading HCV to their partner, they might decide to use barrier precautions (e.g., latex condoms). They discuss with their partner the need for counseling and testing |
| Source:Adapted from CDC. U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mort |
The "cure" for chronic HCV remains elusive. However, the outlook for new and more effective therapies is promising and current treatments have been more effective than earlier therapies. The end point of treatment depends on achievement of sustained clearance of serum HCV RNA that is influenced, in turn, by the patient’s viral replication and immune balance.
New Treatments
New formulations of interferon include pegylated interferon that are conjugated with polyethylene glycol (PEG) molecules and have a much longer half-life than conventional interferon. Current trials are under way regarding their ability and effectiveness. Such treatment may make long-term interferon therapy more tolerable. It appears that there may be a four-fold higher rate of viral clearance after 12 weeks of PEG therapy compared to those with nonpegylated monotherapy. Combination therapies like that approved recently for interferon and ribavirin may involve combining PEG interferon with ribavirin and/or other nucleosides in the years to come.
Long-acting interferons are produced by attaching a long "tail" of PEG to interferon. This increases the half-life of interferon from six hours to nearly five days and allows PEG-interferons to be administered once weekly. These agents are currently in Phase 3 clinical trials and, in some of these trials, it appears that the loss of HCV RNA can be achieved in nearly two-thirds of the treated patients (Mitchell L. Shiffman, MD, personal communication). The rate of long-term sustained response has yet to be defined.
The limited success of vaccine strategies has stimulated the search for adjunct therapies and antiviral medications that inhibit viral entry, replication, and assembly. Inhibition of serine protease, helicase, or RNA polymerase activity may be the most promising approach for antiviral treatment of HCV infection. The nonstructural 3/4A serine protease of HCV RNA genome is especially well characterized.37 It is required for viral replication and is the first molecular target for which new antiviral agents are being developed. A protease inhibitor would be likely to block both the establishment of viral infection and viral production in chronically infected cells. Several candidate protease inhibitors are currently under intense preclinical study.
| Table 7. Preventive Measures for Persons with High-Risk Drug or Sexual Practices |
| Persons who use or inject illegal drugs should be advised to: |
| • stop using and injecting drugs |
| • enter and complete substance-abuse treatment, including relapse-prevention programs |
| • use latex condoms correctly and every time to protect themselves and their partners from diseases spread through sexual activity or to have sex with only one uninfected partner or not to have sex at all |
| • get vaccinated against hepatitis B and, if appropriate, hepatitis A |
Preventive Measures
Tables 6-8 illustrate preventive measures for patients with chronic HCV, for high-risk persons, and procedures for post-exposure of health-care personnel.
Summary of Treatment Response
Response to therapy is monitored by complete eradication of HCV RNA from the serum. A negative serum HCV-RNA six months after cessation of therapy (sustained response) is the most useful predictor of long-term virologic response. After 3-6 months of treatment if patients have detectable viral load, then there is a low likelihood of achieving a sustained response with either monotherapy or combination therapy. All of these patients should probably discontinue treatment, since less than 1% will subsequently achieve long-term sustained viral eradication. Patients with biochemical and virological normalization at the end of treatment still have more than a 40% virologic relapse.
Retreatment of relapsers and nonresponders with the same dose of interferon is associated with a low rate of sustained response. In contrast, it is possible that retreatment with higher doses of interferon for a prolonged duration may increase the sustained response in such relapsed patients, even possibly in previous nonresponders. The latter observations need to be confirmed in larger clinical trials.
Combination therapy has been approved currently for patients with a history of relapse, that is in patients who previously responded to treatment but relapsed following discontinuation of therapy. Sustained response is achieved in 40-50% of naive patients and patients following retreatment. Nonresponders are difficult to treat. It is conceivable that as many as 20% of nonresponders may lose their HCV RNA during treatment, but it is yet unclear how many of these will achieve long-term sustained response.
Studies have shown that a six-month sustained clearance of viral load from serum after stopping treatment indicates a long-term favorable outcome.27 More than 90% of these patients remain HCV-RNA negative for 5-10 years, associated with histologic improvement in all patients.29 Patients studied for HCV-RNA in liver tissue specimens were concomitantly found to be nonreactive.29
Treatment strategies for chronic HCV under evaluation involve increasing the duration of therapy, modifying interferons, induction followed by maintenance therapy, and new antiviral drugs. Some of the latter agents may have an even better therapeutic response than currently approved drugs. There is increasing evidence that treatment may decrease subsequent development of complications, such as decompensated cirrhosis and HCC. Future studies may confirm whether the expected incidence of cirrhosis and HCC may be reduced in treated compared to untreated patients.
| Table 8. Postexposure Follow-up of Health Care, Emergency Medical, and Public Safety Workers for Hepatitis C Virus (HCV) Infection |
| • For the source, baseline testing for anti-HCV and ALT, and at months 1, 3, and 6 |
| • For persons exposed to an HCV-positive source, baseline and follow-up testing including: |
| baseline testing for anti-HCV and ALT activity |
| follow-up testing for anti-HCV (e.g., at 4-6 months) and ALT activity. If earlier diagnosis of HCV infection is desired, testing for HCV RNA may be performed at 4-6 weeks |
| • Confirmation by supplemental anti-HCV testing of all anti-HCV results reported as positive by enzyme immunoassay |
| Source: Adapted from CDC. U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mort Wkly Rep 1998;47(no. RR-19):1039. |
References
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2. Alter MG. Epidemiology of hepatitis C. Hepatology 1997; 26(suppl):62S-65S.
3. Tong MJ, et al. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463-1466.
4. Levine RA. Treating histologically mild chronic hepatitis C: Monotherapy, combination therapy, or tincture of time? Ann Intern Med 1998;129:323-326.
5. Alter MJ, et al. Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA 1990;264:2231-2235.
6. Reedy DW, et al. AST/ALT ratio ³ 1 is not diagnostic of cirrhosis in patients with chronic hepatitis C. Dig Dis Sci 1998;43:2156-2159.
7. Carroll L. Interferon suggested for all hepatitis C cases. Selecting patients who would benefit long term may not be cost effective. JAMA 1998;280:2088-2093.
8. Wong JB. Interferon treatment for chronic hepatitis B or C infection: Costs and effectiveness. Acta Gastroenterol Belgica 1998; 61:238-242.
9. Wong JB, et al. Pretreatment evaluation of chronic hepatitis C risks, benefits, and costs. JAMA 1998;280:2088-2093.
10. Pessione F, et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histologic lesions in chronic hepatitis C. Hepatology 1998;27:1717-1722.
11. Wiley TE, et al. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998; 28:805-809.
12. Conry-Cantilena C, et al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 1996;334:1691-1696.
13. CDC. U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mort Wkly Rep 1998;47:1-39.
14. Granovsky MO, et al. Hepatitis C virus infection in the mothers and infants cohort study. Pediatrics 1998;102:355-359.
15. Ohto H, et al. Transmission of hepatitis C virus from mothers to infants. N Engl J Med 1994;330:744-750.
16. Lau DT-Y. Mechanisms of hepatic toxicity. IV. Pathogenetic mechanisms involved in hepatitis C virus-induced liver diseases. Am J Physiol (Gastrointest Liver Physiol) 1998;38:G1217-G1220.
17. Crowe J, et al. Presentation of hepatitis C in a unique uniform cohort 17 years from inoculaton [Abstract]. Gastroenterology 1995;108:A1054.
18. Poynard T, et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-832.
19. Yano M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334-1340.
20. McHutchison JG, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-1492.
21. Davis GL, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493-1499.
22. Reichard O, et al. Randomised, double-blind, placebo-controlled trial of interferon a-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet 1998;351:83-87.
23. Marcellin P, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-a therapy. Ann Intern Med 1997;127:875-881.
24. Poynard T, et al. Randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352:1426-1432.
25. Lee WM, and the Roferon Study Group. Response to 6 or 12 months of treatment using an induction regimen of interferon alfa-2a in non-cirrhotic patients with chronic hepatitis C. Hepatology Submitted, 1999.
26. National Institutes of Health Consensus Development Conference Panel statement: Management of hepatitis C. Hepatology 1997;26(Suppl 1):2S-10S.
27. Sobesky R, et al. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: A dynamic view. Gastroenterology 1999;116:378-386.
28. Heathcote EJ, et al. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 1998;27:1136-1143.
29. Lau DT-Y, Leiner DE, Ghany MG, et al. 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 1998;28:1121-1127.
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Physician CME Questions
8. Patients with the worst outlook for progressive liver damage are those with:
a. elevated HCV viral load.
b. high grade of necroinflammatory activity on liver biopsy.
c. significant fibrosis on liver biopsy.
d. tender liver on palpation.
e. the degree of serum ALT elevations.
9. The most important risk factor associated with development of cirrhosis is:
a. high serum HCV RNA load.
b. older age.
c. alcoholism.
d. hepatitis C genotype 1.
e. household (nonsexual) contacts of HCV-positive persons.
10. The highest incidence of HCV prevalence occurs in which of the following groups?
a. Intranasal cocaine use
b. Intravenous drug use
c. Health care workers exposed to blood in the workplace
d. High-risk sexual practices
e. Vertical (perinatal) HCV infection in infants of HCV-positive women
11. The best serological test to confirm the presence of HCV infection is:
a. HCV-RNA detection by RT-PCR.
b. elevated alanine aminotransferase (ALT).
c. enzyme immunoassay (EIA).
d. recombinant immunoblot assays (RIBA).
e. hepatitis C genotype.
12. A sustained response to treatment is currently defined by:
a. normalization of ALT at the end of treatment.
b. no detectable HCV RNA at the end of treatment.
c. normalization of ALT at the end of treatment and throughout an observation period of at least six months.
d. no detectable HCV RNA at the end of treatment and throughout an observation period of at least six months.
e. absence of antibody to hepatitis C and negative RIBA test at the end of treatment and throughout an observation period of at least six months.
13. Combination therapy with ribavirin, a nucleoside analog, in conjunction with interferon has been shown to:
a. increase the sustained virologic response rate in relapsers.
b. increase the sustained virologic response in naive patients.
c. increase the sustained response rate in treatment of nonresponders.
d. increase the sustained virologic response in patients with cirrhosis.
e. increase the sustained response rate in treatment of naive, nonresponders, and relapsers.
14. The most promising therapeutic option for the clinical management of patients with chronic HCV is:
a. induction therapy with interferon.
b. long-acting interferon.
c. development of hepatitis C vaccine.
d. development of protease inhibitors.
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