Hepatitis - The Naive Patient

Interferon mono therapy was the first antiviral regimen approved for chronic hepatitis C. Sustained response lates with IFN mono therapy were similar among the 3 approved IFNs. Sustained response rates for IFN-alfa-2b administered at a dose of 3 million units 3 times per week for 6 or 12 months were 8 % and 12%, respectively. The sustained response rate associated with IFN-alfa con-I given at a dose of 9 mcg 3 times per week for 6 months was 12.1%. Higher doses of (FN mono therapy were associated with increased end-of-treatment responses but without any improvement in sustained response. Induction trials using IFN mono therapy have not shown any increased efficacy over standard 3-times weekly dosing. Therefore, IFN mono therapy is currently recommended only for those patients who do not tolerate combination .therapy with IFN and ribavirin.

Patients should be followed on IFN mono therapy, with serial testing of alanine aminotransferase and HCV-RNA levels. Therapy should be discontinued in those patients who fail to demonstrate undetectable viral levels at week 12 of treatment.

Several factors are associated with a favorable response to therapy with IFN mono therapy. The most important of these factors include the lack of cirrhosis on liver biopsy, the presence of either HCV genotype 2 or 3, and low HCV-RNA levels pretreatment.

Interferon is associated with numerous side effects. The most common of these is flu- like illness that occurs in the first 4 weeks of therapy and which generally resolves on its own. After the first month of therapy, late side effects such as fatigue, headache, and neuropsychiatric changes may occur. Depressionis also a common side effect of IFN, and patients with prior history of depression shoulcibe carefully monitored. Other less common adverse events may include hypothyroidism, hyperthyroidism, arthralgias, rash, and reversible alopecia. Neutropenia, and especially thrombocytopenia, may occur in patients on IFN therapy and can be managed with dose reduction.

Combination therapy: the naive patient. Two large, randomized controlled trials compared combination IFN-alfa-2b plus ribavirin with IFN-alfa-2b mono therapy, given for 24 or 48 weeks to previously untreated hepatitis C patients (see Figure 4).r6970 Individuals treated with the combination regimen had sustained virologic responses at 24 and 48 weeks of 33% and 41%, respectively. This outcome compared favorably with the 6% and 16% sustained response rates achieved with 24 and 48 weeks, respectively, of IFN mono therapy.

ETR = end-of-treatment response; SVR = sustained virologic response

Careful analysis of these trials revealed the importance of genotype in both predicting response to therapy and determining duration of therapy. Genotype 1 patients treated with combination therapy had sustained response rates at 24 and 48 weeks of 17% and 29%, respectively. Genotype 2 and 3 patients had sustained response rates at 24 and 48 weeks of 66% and 65%, respectively. Based on these data, it seems reasonable to treat genotype 2 and 3 patients for a total of 24 weeks. The presence of bridging fibrosis or cirrhosis resulted in reduced response rates in patients treated with combination therapy for 6 months, but not in those treated with combination therapy for 12 months. Genotype 1 patients with high viral loads were the least likely to respond to combination therapy.

The sustained response to 24 weeks of therapy with combination IFN and ribavirin vs IFN mono therapy was evaluated in 112 noncirrhotic hepatitis C patients infected with genotype 4. The sustained response rate in the combinatioji-therapy group was 42% compared with only 8% in the mono therapy group.

Although the prevalence of the hepatitis C antibody is 2-3 times greater among blacks than whites in the United States, blacks have been underrepresented in the many large published hepatitis C treatment trials. In these trials, blacks are reported to have a lower response rate than whites to IFN mono therapy. Of the 1744 patients enrolled in the 2 large, multicenter trials evaluating IFN plus ribavirin for the treatment of previously untreated hepatitis C patients, 53 were classified as black. Among these 53 patients, 96% were genotype 1. The sustained response of these patients to 24 and 48 weeks of combination therapy were 20% and 23%, respectively. None of the black patients treated with IFN mono therapy had a sustained response.

Five independent factors have been identified as predictors of sustained response in patients treated with combination therapy. These factors are genotype 2 or 3, baseline viral load < 3.5 million copies/ml, minimal fibrosis, female sex, and age <40 years. Early loss of HCV RNA while on therapy may also be predictive of a sustained response.

Common side effects of ribavirin include anemia, depression, fatigue, irritability, rash, cough, shortness of breath, and insomnia. The anemia is the result of a dose-dependent hemolysis of red blood cells and occurs in nearly 100% of patients, with patients frequently showing a drop of 2-3 g from baseline hemoglobin. Therefore, ribavirin must be used with caution in patients with pre-existing anemia, diabetes, or coronary artery disease. Also important to note is that ribavirin is teratogenic, so patients and their sexual partners must be carefully counseled prior to initiation of therapy.

Hepatitis - Treatment of the Non responder

Non response to antiviral therapy is defined as the persistence of detectable HCV RNA throughout therapy, with detectable serum HCV RNA at the end of the therapeutic course. The sustained response to re-treatment of non responders to any form of antiviral therapy has been disappointing.

Re-treatment of non responders to IFN mono therapy was evaluated in several small studies. In the consensus interferon trial, non responders to IFN mon otherapy showed a 13% sustained virologic response rate at 48 weeks of therapy with IFN-alfa con-1. The use of combination IFN and ribavirin therapy in FN non responders has resulted in sustained response rates ranging from 0% to 15%. Of interest, a recent trial reported a 42% sustained response to intravenous recombinant IFN-bEIA in previous IFN non responders.

Approximately 60% of all patients treated with combination IFN and ribavirin are non responders. The approach to this group represents a growing challenge to the treating clinician. Although it seems reasonable that higher doses of IEN plus ribavirin or a weight-based system of ribavirin dosing should improve response to treatment in these patients, there are little if any published data to support such an approach. The peginterferons may, however, prove useful in combination with IFN and ribavirin, and clinical trials designed to test this notion are currently ongoing.

Virologic non responders to antiviral therapy may derive some benefit from re-treatment that is aimed at preventing histologic disease progression. Patients with underlying bridging fibrosis or cirrhosis are at a greater risk for developing complications of cirrhosis than are those without fibrosis. In addition to its antiviral effect, IFN was shown to have anti proliferative and anti fibrotic activity through its down regulation of transforming growth factor b. Recent studies showed improvement in underlying histology in non responders to antiviral therapy. Several studies have also demonstrated a significant reduction in the relative risk of developing HCC among non responders to IFN mono therapy.

These studies have brought the issue of IFN maintenance therapy for prevention of fibrotic progression to the fore. Shiffman and colleagues’95’ reported that a 2-year course of IFN mono therapy administered to non responders stabilized fibrosis and improved inflammation on serial biopsies. This concept has now led to the launch of a National Institutes of Health-sponsored trial -- the Hepatitis C Antiviral Long-term Treatment against Cirrhosis or HALT-C trial -- to evaluate the effect of long-term peginterferon-alfa2a therapy in patients with advanced fibrosis or cirrhosis who did not respond to combination pegylated IEN plus ribavirin.

Hepatitis- Concluding Remarks

Progress in the knowledge of the natural history and treatment of hepatitis C has expanded tremendously since the discovery of the hepatitis C antibody in 1989. This viral disease is transmitted primarily in a parenteral manner, with previous recreational drug use and previous blood or blood product transfusion being the greatest risk factors. Diagnosis of hepatitis C is made by the detection of viral particles in the blood, and liver biopsy is essential to determine the extent of damage caused by this virus. Current therapies are based upon dual treatment with IFN and ribavirin. Recently, a new long- acting pegylated IFN has been approved for use as mono therapy in the United States, and any new agents are under development for the treatment of hepatitis C. The next decade hopefully will bring even greater advances in our knowledge of this common liver disease.

Hepatitis - Alternative Medicines

The rate of complementary medicine use by hepatitis C patients dissatisfied with conventional medications is estimated to be as high as 60%. Various types of agents and approaches are used in this setting, including milk thistle, vitamin therapies, Chinese herbal therapies, acupuncture, and lifestyle-modification techniques. Despite the widespread use of these modalities, few -- if any -- well-designed clinical trials evaluating the efficacy of these therapies in hepatitis C have been published.

Silymarin or milk thistle is the most common alternative medication used by patients with hepatitis. Silymarin, which exhibits certain antioxidant properties and may function as a free-radical scavenger, has been used to treat all forms of liver disease for more than 2000 years. It appears to be safe for use in this setting. The effects of this agent on HCV, however, have never been formally evaluated in controlled trials. Recently, results of a controlled trial showed no benefit of silymarin use in patients with primary biliary cirrhosis.

The widespread use of these products does present some serious health risks. Many patients who take alternative therapies either do not seek, or delay the use of, conventional therapies, which may have been effective. In addition, many alternative therapies are associated with significant liver toxicity. Common examples of hepatotoxic agents include chaparral leaf, valerian, skullcap, mistletoe, germander, Jin Bu Huan, and pyrrolizidine alkaloids. These products are available over the counter. Therefore, alternative medicines should be used with caution.

The increasing use of alternative medicines in hepatology has been fueled by patient dissatisfaction with conventional therapies. Physicians must keep an open mind and familiarize themselves with the purported efficacy and potential toxicities of alternative medications in order to provide effective counsel to their patients. Patients must inform their physicians of all their medications, alternative or conventional. Together, patients, pharmacists, and physicians must ensure that hepatotoxic agents are not ingested.

Hepatitis - Quality of Life

The affect of hepatitis C on the quality of life is beginning to emerge as an important parameter in the evaluation of infected patients. Physicians have the perception that patients with hepatitis C are largely asymptornatic, and that having the disease seldom has an impact on patients’ lives. However, studies with large numbers of patients are showing that hepatitis C does indeed negatively affect quality of life.

Until recently, quality-of-life instruments were not validated for use in patients with chronic hepatitis C. Several instruments -- such as the hepatitis quality-of-life questionnaire (HQLQ) and the short-form 36 (SF-36) -- have now been validated for use in this setting. The SF-36 is a simple questionnaire that includes 36 questions that evaluate 8 domains of general well-being. Higher SF-36 scores represent better quality of life.

Foster and colleagues evaluated quality of life in non cirrhotic patients prior to initiation of treatment. In all 8 domains of the SF-36, hepatitis C patients reported a significantly lower quality of life than did controls. The subgroup of patients with hepatitis C who had used intravenous drugs in the past showed the greatest impairment in quality-of-life scores. The amount of inflammation on liver biopsy was not associated with the degree of impairment of quality of life. Bonkovsky and coworkers confirmed in a study of 642 patients that individuals with hepatitis C report lower quality-of-life scores than do healthy controls. Additionally, findings showed that patients who had a sustained response to IFN mono therapy experienced significant improvements in perceived wellness and functional status, which then translated into significant improvements in quality of life. Ware and colleaguest used the HQLQ to evaluate changes in quality of life in IFN mono therapy relapse patients treated with combination IFN and ribavirin therapy. A sustained virologic response was associated with improvements in vitality, social functioning, and health distress.

Antiviral therapies are associated with a decline in quality of life during therapy. This decline returns to baseline with cessation of therapy. This trend was recently demonstrated to be similar for newer agents as well, such as peginterferon-alfa-2a.

Hepatitis C patients have lower quality-of-life scores than the general population, and the evaluation of quality of life thus takes on greater importance in the care of hepatitis C patients. Abnormalities in quality of life are not entirely attributable to histologic disease severity. Newer therapies, such as the pegylated IFNs, may help improve quality of life both during and after therapy.

Hepatitis - Treatment by Liver Biopsy

One of the dilemmas facing clinicians is whether to treat a patient who has hepatitis C and mild disease on liver biopsy. Wong and colleagues evaluated this scenario from the perspective of cost-effectiveness. In a mathematical model, they compared the cost of immediate combination IFN and ribavirin therapy vs watchful waiting for patients with histologically mild disease. While this model suggested that periodic biopsies would avoid institution of therapy in many patients, immediate treatment of these patients was found to be cost-effective by eradicating virus and thereby potentially preventing disease progression.

Hepatitis - Treatment Plan

Several models have been developed in an effort to estimate the cost-effectiveness of both IFN mono therapy and combination IFN/ribavirin therapy for the treatment of patients with hepatitis C. Bennett and associates reported that when using a 5% discount rate, the marginal cost-effectiveness ratio of 6 months of IFN mono therapy in previously untreated patients with mild histologic disease was well within the range of other well-accepted medical interventions. Kim and colleagues, using a 3% discount rate, estimated the marginal cost-effectiveness ratio for 6 months of IFN mono therapy to be $4000 per quality-adjusted life year gained, and $5Q00 per quality-adjusted life year gained for 12 months of IFN mono therapy. Both of these figures are within the range of acceptability to our society, and therefore, therapy is considered cost-effective. This study also found that IFN mono therapy was not cost-effective in patients older than age 60.

Combination therapy with IFN and ribavirin is significantly more expensive than IFN mono therapy. Wong and colleagues evaluated the cost-effectiveness of combination therapy vs IFN mono therapy for treatment duration of 24 and 48 weeks. Both the 24- and 48-week IFN-plus-ribavirin regimens were more cost-effective than 48 weeks of IFN mono therapy. Combination therapy for duration of 24 weeks was found to be more cost-effective in patients with genotype 2 and 3 disease. In all other evaluated parameters, including viral load and underlying histology, combination therapy for a 48- week duration was more cost-effective than the 24-week regimen.

The advent of pegylated IFN has raised questions about its relative cost-effectiveness. This concept is difficult to analyze at present, because pegylated IFN has only just been approved for use in the United States, and therefore, its pricing is unknown. However, assuming that pegylated IFNs significantly improve sustained response rates, cost effectiveness can be estimated in the absence of pricing. Based on this assumption, Wong estimated that if peginterferon-alfa-2b increases the sustained response rate by
10% to 30% and increases relative costs by 10% to 30%, a 48-week course should both prolong life and be cost-effective.

Hepatitis Cost Effectiveness

Screening
Mass screening for hepatitis C by means of hepatitis C antibody testing does not appear to be a cost-effective strategy. However, an abstract presented at the AASLD meeting in October reported that alanine aminotransferase screening for chronic hepatitis C is cost- effective in individuals between 15 and 58 years of age (ie, across broad age groups). Improvements in cost efficiency may be obtained through identification of risk factors for HCV prior to screening.

The Role of Pegylated Interferon

Rationale:
Pegylated IFNs are currently under investigation, and at this time are not approved for the treatment of hepatitis C in the United States. The concept behind the pegylation of IFN is to produce a molecule that can maintain longer-lasting therapeutic concentrations by optimizing both the absorption and distribution while decreasing the rate of clearance and reducing proteolysis at the same time. This is accomplished by the addition of a polyethylene glycol molecule (PEG) to standard IFN by means of a covalent bond. This PEG molecule is a nontoxic polymer that is readily excreted in the urine and this moiety may be either linear or branched. Larger PEG molecules lead to a greater reduction in renal clearance and provide greater subcutaneous absorption. Pegylated IFN is metabolized primarily in the liver, and its excretion is not affected by renal abnormalities.

Clinical Trials:

Two pegylated formulations of IFN are currently under investigation in the United States:
A linear 12-kD peginterferon-alfa-2b (Pegintron) and a branched chain 40-kD peginterferon-atfa-2a (Pegasys).

A double-blind, randomized, controlled trial was presented at the 2000 meeting of the European Association for the Study of the Liver that compared 3 regimens of peginterferon-alfa-2b (0.5, 1.0, and 1.5 mcg/kg per week) with standard IFN-alfa-2b 3 MU given 3 times weekly in previously untreated patients with hepatitis C. The sustained response rates for patients who received 0.5, 1.0, and 1.5 mcg/kg of the pegylated IFN were 18%, 25%, and 23%, respectively, compared with a 12% sustained response rate found in patients who received the conventional IFN. The overall genotype 1 response rate was 14% in both the 1.0- and 1.5-mcg/kg groups.

EOT = end-of-treatment response;
SVR = sustained virologic response

Zeuzem and colleagues reported the results of a trial comparing once-weekly peginterferon-alfa-2a at a dose of 180 mcg with standard-dose interferon-alfa-2a 3 times weekly for 48 weeks in previously untreated patients with hepatitis C. All patients were assessed at week 72 for a sustained virologic response. These investigators obtained a sustained response rate of 39% for the pegylated-IFN group compared with a 19% response rate for the standard-IFN group. A sustained response rate of 28% was seen in patients infected with HCV genotype 1 who received peginterferon-alfa-2a. The frequency and severity of adverse events were similar in both treatment groups. Pretreatment factors associated with a sustained response, in order of significance, included genotype other than type 1, alanine aminotransferase quotient> 3, HCV RNA level <2>

EOT = end-of-treatment response; SVR = sustained virologic response

In the largest trial of cirrhotic hepatitis C patients receiving IFN therapy performed to date, Heathcote and colleagues reported on the use of pegylated IFN-alfa-2a in the treatment of patients with bridging fibrosis or cirrhosis. Patients were randomized to receive IFN-alfa-2a 3 MU 3 times per week, 90 mcg of peginterferon-alfa 2a weekly, or 180 mcg of peginterferon-alfa-2a weekly, for a total of 48 weeks, and were followed up for 24 weeks. In an intention-to-treat analysis, a sustained response (response at week 72) was seen in 8%, 15%, and 30% of patients treated with standard IFN-alfa-2a, 90 mcg of peginterferon-alfa-2a, and 180 mcg of peginterferon-alfa-2a, respectively. The difference in rate of response between the standard-IFN and 180-mcg of peginterferon groups was statistically significant. The sustained response of patients infected with genotype 1 and non-1 who were treated with the higher dose of peginterferon was 13% and 51%, respectively.

A previous small dose-finding study by Glue and coworkers showed that peginterferon-alfa-2b and ribavirin were safe when used in combination. The results of a larger trial using combination peginterferon-alfa-2b plus ribavirin in previously untreated patients with hepatitis C were reported in October 2000 at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Dallas, Texas. Results showed that the overall sustained response of patients to peginterferon-alfa-2b given at 1.5 mcg/kg per week, plus ribavirin 1000-1200 mg/day, was 54%. The response rates of patients with genotype 1 and non-1 to this regimen were 42% and 82%, respectively.

The FDA approved pegylated IFN-alfa 2b mono therapy in January 2001. The use of combination pegylated IFN plus ribavirin is still under investigation, with several large trials currently underway to determine the effectiveness of this new regimen.

Treatment of the Post- Liver Transplant Patient

Hepatitis C is the leading indication for liver transplantation in the United States. In patients who undergo liver transplantation secondary to hepatitis C, the reappearance of HCV RNA post transplantation is an almost universal occurrence.

The natural history of post transplantation hepatitis C appears to be rapid, with as many as 20% of recipients developing cirrhosis within 5 years of transplantation. Studies with IFN mono therapy in this setting have reported biochemical responses in up to 25% of patients, but virologic response is rare. One study reported a sustained response rate of 24% with a 6-month course of combination IFN and ribavirin. After loss of HCV RNA with combination therapy, ribavirin mono therapy has been used as maintenance therapy. Although combination therapy has not been associated with rejection, significant anemia secondary to hemolysis is common. Larger trials are needed to better address the issue of recurrence of hepatitis C after transplantation.

Hepatitis - Treatment of the Non responder:

Non response to antiviral therapy is defined as the persistence of detectable HCV RNA throughout therapy, with detectable serum HCV RNA at the end of the therapeutic course. The sustained response to re-treatment of non responders to any form of antiviral therapy has been disappointing.
Re-treatment of non responders to IFN mono therapy was evaluated in several small studies. In the consensus interferon trial, non responders to IFN mon otherapy showed a 13% sustained virologic response rate at 48 weeks of therapy with IFN-alfa con-1. The use of combination IFN and ribavirin therapy in FN non responders has resulted in sustained response rates ranging from 0% to 15%. Of interest, a recent trial reported a 42% sustained response to intravenous recombinant IFN-bEIA in previous IFN non responders.

Approximately 60% of all patients treated with combination IFN and ribavirin are non responders. The approach to this group represents a growing challenge to the treating clinician. Although it seems reasonable that higher doses of IEN plus ribavirin or a weight-based system of ribavirin dosing should improve response to treatment in these patients, there are little if any published data to support such an approach. The peginterferons may, however, prove useful in combination with IFN and ribavirin, and clinical trials designed to test this notion are currently ongoing.
Virologic non responders to antiviral therapy may derive some benefit from re-treatment that is aimed at preventing histologic disease progression. Patients with underlying bridging fibrosis or cirrhosis are at a greater risk for developing complications of cirrhosis than are those without fibrosis. In addition to its antiviral effect, IFN was shown to have anti proliferative and anti fibrotic activity through its down regulation of transforming growth factor b. Recent studies showed improvement in underlying histology in non responders to antiviral therapy. Several studies have also demonstrated a significant reduction in the relative risk of developing HCC among non responders to IFN mono therapy.

These studies have brought the issue of IFN maintenance therapy for prevention of fibrotic progression to the fore. Shiffman and colleagues’95’ reported that a 2-year course of IFN mono therapy administered to non responders stabilized fibrosis and improved inflammation on serial biopsies. This concept has now led to the launch of a National Institutes of Health-sponsored trial -- the Hepatitis C Antiviral Long-term Treatment against Cirrhosis or HALT-C trial -- to evaluate the effect of long-term peginterferon-alfa2a therapy in patients with advanced fibrosis or cirrhosis who did not respond to combination pegylated IEN plus ribavirin.

Hepatitis - Treatment of the Relapse Patient

Relapse is defined as the reappearance of serum HCV RNA in a patient who had previously undetectable levels at the end of antiviral therapy. Occurrence of relapse following IEN mono therapy is more common than following combination IFN and ribavirin therapy.

While re-treatment of IFN-mono therapy relapse patients with a repeat course of similar therapy is ineffective, treatment with higher doses may improve sustained response rates. A large, multi center trial evaluated the use of high-dose consensus IFN (IFNalfa con-1) in patients who had relapse following a 24-week course of standard dose IFN-alfa-2b or IFN-alfa con-1. Subjects were randomized to receive 15 mcg of IFN alfa con-1 for either 24 or 48 weeks. The sustained viral response was 28% at 24 weeks and 58% at 48 weeks. Re-treatment at this higher dose was not associated with more significant side effects than treatment with the standard IFN regimen. Factors predictive of a sustained virologic response in this trial included low initial viral load, HCV genotype 2 or 3, and the absence of cirrhosis.

A second large study evaluated the use of combination IFN and ribavirin therapy in IFN mono therapy relapse patients. Patients were treated for a total of 6 months and randomized to receive standard-dose IFN-alfa-2b with or without ribavirin. A sustained virologic response was seen in 49% of patients treated with combination therapy and in only 8% of those treated with IFN mono therapy. Genotype other than type 1 and low pretreatment HCV-RNA levels were positive predictive factors of a sustained response in this trial. Twelve percent of subjects treated with ribavirin required a dose reduction or interruption secondary to anemia, whereas only 3% of those receiving IEN mono therapy required dose reduction.

As previously indicated, patients who relapse following IFN mono therapy may be effectively re-treated with either higher-dose IFN mono therapy or with combination IFN and ribavirin. But the increasing problem facing physicians today is how to approach the patient who relapses following combination therapy. At present, there are no large published studies to help answer this question. Several studies are ongoing with either pegylated interferon (peginterferon) alfa-2a or peginterferon alfa-2b in patients who relapsed following treatment with combination therapy of IFN plus ribavirin.

Hepatitis - Goals of Therapy

Goals of Therapy

1. Primary
2. Viral eradication
3. Secondary
4. Slow disease progression
5. Improve underlying histology
6. Prevent the development of hepatocellular carcinoma
7. Improve quality of life after therapy

Three discrete regimens are licensed in the United States for the treatment of chronic hepatitis C. These regimens include 3 approved interferons (IFN) -- IFN-alfa-2a, IFN alfa-2b, IFN-alfa con (consensus)-1 -- and combination IFN-alfa-2b plus ribavirin

Treatment Plan

The primary aim of therapy in the patient with hepatitis C is to achieve a sustained virologic response, which is defined as undetectable HCV RNA 6 months after termination of antiviral therapy. Secondary goals of antiviral therapy include improvement in histology and quality of life, and the prevention of HCC.

Patients with persistently abnormal liver enzymes, detectable HCV RNA, and an abnormal liver biopsy are candidates for antiviral therapy.

MOLECULAR ASSAYS

The demonstration of hepatitis C viral particles in blood confirms the diagnosis of hepatitis C infection. Two principal methods used to detect hepatitis C viral RNA are target amplification and signal amplification.

Target amplification assays such as the polymerase chain reaction (PCR) rely on sequence-specific primers and a heat-stable DNA polymerase to generate a large number of copies of a portion of the viral genome. Signal amplification-as used in DNA assays, uses a series of hybridization reactions between probes specific for several regions of the target molecule and subsequent hybridization to a DNA amplifier.

Viral load may be measured as either a qualitative or quantitative function. Qualitative testing is the most sensitive and specific and, therefore, the most accurate when used for initial diagnosis. Both qualitative and quantitative viral load testing have a role in the evaluation and treatment of patients with hepatitis C. Qualitative testing is important in confirming a positive anti-HCV test and in assessing sustained response to therapy. Quantitative testing is useful in determining diagnosis, predicting response to therapy, and monitoring response while on therapy.

Many different “brands” of quantitative testing are available and until recently, results could not be compared across assays because of a lack of standardization. As of the year 2000, results of all quantitative assays are standardized as international units per milliliter. Viral load testing is useful in evaluating the patient with suspected acute hepatitis C infection because these assays should be positive within 1-2 weeks of initial exposure. These tests, however, do not correlate with disease severity or the rate of disease progression.

Hepatitis C core antigen immunoassays, currently undergoing testing, may approach the clinical sensitivity of HCV-RNA testing.

Genotype:

Genetic analysis of HCV reveals the existence of numerous viral sequences, termed genotypes. These various genotypes differ in genetic composition by as much as 35%. Six major genotypes have been identified and these can be further subdivided into more than 100 subtypes.

Genotype distribution is worldwide. However, 1a and lb are the most common types in the United States, accounting for more than 75% of all infections. Genotype lb is the most prevalent viral species found in Japan. Genotype 3, which is uncommon in the United States except in younger intravenous drug users, is, however, highly prevalent on the Indian subcontinent. Genotype 4 accounts for the majority of HCV infection in Egypt and is also seen in other areas of Africa. Genotype 5 is common in South Africa and accounts for more than 50% of all cases of hepatitis C seen in that region. Finally, genotype 6 is found primarily in Southeast Asia.

Hepatitis C genotype does not appear to affect the rate of disease progression. Genotype is, however, a predictor of response to therapy. Patients with genotype 2 or 3 are more likely to respond to therapy and based on published data, may be treated with combination interferon and ribavirin for a 6-month course. By contrast, patients infected with HCV genotypes 1 and 4 are less likely to respond to therapy and should be treated with combination interferon and ribavirin therapy for 1 year. Genotyping should be performed in all patients with hepatitis C for whom treatment is being considered. Obtaining the results of genotype testing can allow a more cost-effective approach to therapy.

Liver Biopsy:

The grading and staging of liver disease in patients with hepatitis C is crucial in helping guide treatment. Unfortunately, serum aminotransferase levels, HCV viral load, and hepatitis C genotype are all poor predictors of underlying histology. Therefore, despite the cost and discomfort associated with liver biopsy, it is recommended that it be performed in the initial evaluation of all hepatitis C patients, barring obvious contraindications. Information obtained from the biopsy can help exclude other causes of liver disease, help gauge the rate of progression of disease, and aid the treating physician in adjusting or terminating therapies if the patient is experiencing significant side effects.

Hepatitis Diagnostic Testing

Hepatitis C Antibody Testing

Two primary forms of testing are available for the detection of the anti-hepatitis C antibody (anti-HCV Ab): enzyme immunoassays (EIA) and recombinant immuno blot assays (RIE3A). These antibody tests are useful screening tools for hepatitis C, but they do have limitations.

Both of these antibody tests will yield a positive result for current (active) and resolved disease. Antibody testing may not become positive for 3-6 months after exposure, resulting in a delay diagnosis in the acute disease. Immuno suppressed patients such as those with renal failure, those infected with HIV, or those post-organ transplantation – may not express the hepatitis C antibody yet still may have hepatitis C infection. False-positive antibody testing may occur in low-risk blood donors. EIA Three generations of EIA antibody testing have been developed since 1989. The EIA antibody is the main screening test for hepatitis C. The first-generation EIA antibody, which incorporated the c100-3 epitope from the nonstructural NS4 region, was used until 1992, at which time it was replaced by a second-generation EIA. EIA-2 contains hepatitis C antigens from the viral core and from areas of the nonstructural NS3 and NS4 regions.162 A third-generation EIA that contains reconfigured core and NS3 antigens and a newly incorporated antigen from the NS5 region was recently approved by the United States Food and Drug Administration (FDA) for screening blood products and is now in use at some institutions for diagnostic purposes. EIA-3, with a sensitivity of 97%, offers slightly improved sensitivity over the 95% sensitivity seen with ElA-2. Most centers in the United States use EIA-2 testing.

EIA testing offers several distinct advantages in the diagnostic setting because these assays are easy to perform, are relatively inexpensive, and have high sensitivity. A positive EIA-antibody test requires a second confirmatory assay to make the diagnosis of hepatitis C. False-positive EIA testing may occur in low-risk patients and in patients with underlying autoimmune diseases. These patients may benefit from RIBA assay testing to differentiate a false-positive from a true-positive test.

RIBA: These tests are supplemental assays to EIA testing. Both classes of antibody assays contain the same HCV antigens. RIBA testing is currently in its third generation of development. RIBA-2 uses the same recombinant antigens as EIA-2.

Results from a RIBA-2 assay may be interpreted as positive if 2 or more antigens are positive, interpreted as indeterminate if 1 antigen is positive, or finally, interpreted as negative if all antigens are negative. RIBA testing is not more sensitive than EIA testing, but a RIBA-2 test can be used to distinguish between a false-positive EIA test and true previous exposure to hepatitis C. A third-generation RIBA test (RIBA-3) has recently been licensed in the United States. This assay incorporates the NS5 antigen with the standard antigens used in RIBA-2. This third-generation test produces a reduced number of indeterminate results and is more specific than the RIBA-2 assay.

ROLE OF OTHER FACTORS:

Many factors initially considered to be important predictors of disease progression appear, in fact, not to have such a predictive role. These factors include mode of transmission, serum transaminase levels, hepatitis C viral loads, and hepatitis C genotype. The authors of one paper, however, concluded that transfusion- acquired disease was associated with more rapid disease progression than was disease acquisition due to other risk factors.

CLINICAL PRESENTATION

Most patients with hepatitis C are asymptomatic. But if symptoms do occur, the most common complaints are fatigue, abdominal pain, poor appetite, weight loss, and pruntus. The diagnosis of hepatitis C is made following the completion of specific tests requested by the clinician. The primary care physician generally performs this testing if risk factors are identified or abnormal liver chemistries noted. Blood banks and life insurance companies routinely test blood donors and applicants for hepatitis C. Hepatitis C testing, unlike testing for HIV, does not require that consent be obtained.

Hepatitis C can lead to a broad spectrum of liver disease. Patients may develop mild disease as evidenced by mild inflammation and/or fibrosis. Others may develop increasing amounts of inflammation or fibrosis, which can lead to the development of significant fibrosis or cirrhosis.

EXTRAHEPATIC MANIFESTATIONS
In addition to liver disease, hepatitis C is associated with a number of extra hepatic effects, including hematologic, renal, dermatologic, endocrine, and autoimmune disorders.

HEMATOLOGIC DISORDERS

Essential mixed cryoglobulinemia. Essential mixed cryoglobulinemia (EMC) is a condition that results in the deposition of circulating immune complexes in small- to medium-sized blood vessels. Patients with EMC usually present with rash, arthralgias, and weakness.

A review of the literature reveals that hepatitis C can be found in 95% of all patients with EMC. Several investigators have suggested that hepatitis C may have a causative role in EMC. Anti-HCV antibodies can be detected in the vessel walls of skin biopsies taken from patients with EMC and chronic vasculitis. Interferon therapy has been shown to reduce the cryocrit and allow symptomatic improvement of both rash and joint pains. The response is short-lived, however, because symptoms almost universally reappear upon cessation of therapy.

Lymphoma.
Several reports have described an increased incidence of B-cell lymphoma in patients with hepatitis C. Rasul and colleagues studied 16 patients with chronic hepatitis C and cryoglobutinemia for the presence of lymphoma. Results of bone marrow biopsy were consistent with non-Hodgkin’s lymphoma in 2 patients and suspicious for lymphoma in 7. While this finding needs to be evaluated further in larger studies, the development of lymphadenopathy or unexplained chronic anemia in a patient with hepatitis C infection should raise concern about the possibility of underlying lymphoma.

Renal Disorders
Glonierulonephritis has been associated with hepatitis C. These patients are found to have proteinuria, which can be significant and in the nephrotic range. Most cases of glomerulonephritis are associated with cryoglobulinemia. The most common histologic lesion seen is membranoproliferative glomerulonephritis. Interferon therapy may reduce proteinuria, but a sustained response is seldom achieved in these patients. Ribavirin should be avoided in patients with significant renal impairment. Some may benefit from the use of plasmapheresis, although the relief tends to be short-lived.

DERMATOLOGIC DISORDERS

Several dermatologic disorders have been described in association with hepatitis C. These include porphyria cutanea tarda, lichen planus, and cutaneous necrotizing vasculitis.

Porphyria cutanea tarda:
Porphyria cutanea tarda (PCT) is the most common form of porphyria. PCT ha been associated with hepatitis C infection, particularly in those patients with significant alcohol use. Hepatitis C may occur in 58% to 71% of all PCT patients. This dermatologic disorder tends to present at an earlier age in patients with hepatitis C than in those PCT patients without hepatitis C. Despite this association, the clinical changes seen in the setting of PCT do not appear to be a direct consequence of the viral infection.

Lichen planus:
This condition has been associated with hepatitis C, although hepatitis C has not been shown to be the causative agent.

Cutaneous necrotizing vasculitis: This condition has been associated With hepatitis C as well, although hepatitis C has not been shown to be the causative agent.

Endocrine Disorders:
Hepatitis C has also been linked to both diabetes mellitus and an increased incidence of anti-thyroid antibodies.

Diabetes mellitus:
An association between hepatitis C and diabetes mellitus has recently been demonstrated Mason and colleagues retrospectively evaluated patients with chronic hepatitis C and found this infection to be an independent predictor of diabetes.

Additionally, Mehta and associateS58l found that among individuals older than 40 years of age, those with hepatitis C infection were more than 3 times as likely to have type 2 diabetes mellitus than those without hepatitis C infection. The prevalence of type 1 diabetes was not increased. The link between these 2 disorders must be further investigated in an effort to improve available therapies.

Other Extra Hepatic Manifestations
Finally, hepatitis C has been associated with a number of other extrahepatic disorders as well, incluaing sialadenitis, uveitis, corneal ulceration, polyarteritis flodosa, peripheral neuropathy, and the development of autoimmune phenomena.

Extrahepatic Manifestations of Hepatitis C

1. Essential mixed cryogiobulinemia
2. Lymphoma
3. Glomerulonephritis
4. Porphyria cutanea tarda
5. Diabetes mellitus
6. Corneal ulceration
7. Autoimmune phenomena
8. Uveitis
9. Sialadenitis
10. Peripheral neuropathy

The mechanism by which alcohol effects a more rapid progression of disease is not known. The amplification of cytokine signals is believed to play a role in this process by stimulating stellate cells and increasing fibrosis. Alcohol consumption also increases the risk of developing HCC.
Age and gender. Acquisition of hepatitis C after age 40 is associated with a more rapid disease progression. The reasons for this effect are uncertain but may be related to an aging immune system. Male sex is also associated with more rapid disease progression.

Coinfection. Hepatitis C and HIV coinfection appears to lead to rapid progression of liver disease. Progression to cirrhosis or liver failure may occur within 10-15 years after infection with HCV, and this progression occurs at approximately twice the rate as what occurs with hepatitis C infection alone. Hepatitis C and related liver disease are now the leading cause of non-AIDS-associated death in patients with HIV.

NATURAL HISTORY OF HEPATITIS C

The precise natural history of hepatitis C remains unknown because of the lack of prospective data, the inability to determine time of initial onset of disease, and the variable influences of multiple cofactors leading to disease progression. What has been determined, however, is that a subset of hepatitis C patients will progress to cirrhosis and its associated complications. Chronicity is the hallmark of hepatitis C infection. Approximately 15% to 30% of patients exposed to HCV recover spontaneously, while the remaining 70% to 85% develop chronic infectioni. Most patients with chronic hepatitis C infection appear to have mild to moderate histologic disease. Cirrhosis may develop in as many as 15% to 30% of infected patients. Although fulminant disease is rare in hepatitis C, its occurrence has been reported. Several studies have attempted to determine the rate of histologic disease progression in transfusion-acquired disease. Tong and colleagues found a mean interval of 20.6 years from time of infection to development of cirrhosis, and a mean interval of 28.3 years from time of diagnosis to development of hepatocellular carcinoma (HCC).

The infusion of hepatitis C-contaminated anti-D immune globulin in 1977 and 1978 in Ireland has allowed the prospective evaluation of 376 women, 17 years after exposure. Most of the hepatitis C-infected women had evidence of moderate hepatic inflammation on liver biopsy, while 51% had fibrosis, and only 2% had cirrhosis. The results of a similar German study of 152 women infected with hepatitis C-contaminated Rh0 immune globulin showed no evidence of cirrhosis 15 years after exposure.

In a recent study published in the Annals of Internal Medicine, coworkers conducted a 45-year follow-up of hepatitis C infection in healthy young adults. In this retrospective study, stored sera from 8568 US Air Force recruits in Wyoming dating from 1948-1955 were evaluated for hepatitis C. Ten patients were found to be positive for HCV.

FACTORS INFLUENCING DISEASE PROGRAM

Several factors appear to influence the rate of progression of hepatitis C to cirrhosis. These factors include alcohol use, age at time of exposure, sex, and coinfection with either hepatitis B or HIV.

Alcohol. Alcohol ingestion and chronic hepatitis C infection appear to be synergistic in accelerating the progression of liver disease. An increased risk of cirrhosis and decompensated liver disease is associated with sustained alcohol consumption of greater than 40 g/day. Other effects of concomitant alcohol use in the setting of hepatitis C include increased transaminase levels, higher hepatitis C viral loads and increased number of hepatitis C quasispecies. These elevations have been shown to be significantly reduced with a decrease in daily alcohol intake.

HEPATITIS - SEXUAL TRANSMISSION

SEXUAL TRANSMISSION:
Sexual Transmission of hepatitis C remains controversial and probably accounts for less than 5% of cases. Risk factors for sexual transmission include multiple sex partners, prostitute use, rectal intercourse, and traumatic sex. Sexual intercourse during menstruation or without adequate vaginal lubrication may increase the transmission rate. Studies in married couples have indicated a great risk of spousal transmission with increasing duration of married. Whether this risk is secondary to Sexual Transmission, the potential role of more frequent sharing of household (razors, toothbrushes, etc) items or other factors remains to be determined.

Perinatal transmission
Perinatal transmission of hepatitis C occurs in approximately 3% to 5% of infants born to women infected with HCV. Perinatal transmission is associated with 2 independent risk factors: high viral load at time of delivery and having a mother who is HIV – positive.

Italian investigators recently reported the decreased risk of perinatal transmission of hepatitis C with cesarean section when compared with vaginal delivery. The risk of perinatal transmission of hepatitis C in a woman who is HIV-positive is estimated to be 15% to 35%. Infants born to hepatitis C- infected mothers may initially be hepatitis C antibody –positive due to passive transfer of this antibody across the placenta. This antibody may be present throughout thee first year of an uninfected newborn’s life before Disappearing. Therefore, the determination of hepatitis C infection in the newborn requires the demonstration of positive HCV RNA in the serum. Breastfeeding by mothers with hepatitis C appears to be safe, with no reported cases of viral transmission to newborns.

OTHER FACTORS:
Other groups at high risk for Hepatitis C infections include persons who received clothing factor concentrates prior to 1987, persons on hemodialysis, hemophiliacs and individuals who received either a solid organ or bone marrow transplant prior to 1992. Contamination of the ultrafiltrate dialysis membrane may help explain the high rate of hepatitis C infection seen in dialysis units.

Hepatitis Risk Factors:

RISK FACTOR:

BACKGROUND:

Hepatitis C is transmitted parenterally the most common risk factor for Hepatitis C is intravenous drug use. Prior to 1992- before the introduction of blood donor screening and surrogate Hepatitis Tests- transmit ion of blood plasma- derived product was associated with significant risk of transmission of Hepatitis C. Other potential risk factor of hepatitis C include: internal cocaine use, tattooing, body piercing, accidental middle stick injury and the sharing if house hold items, such as nail clipper, razor, blades and tooth brushes.


Common
Intervenes Drug Use
Blood transmission period to 1992
Accidental middle injury
Sexual Transmission
Perinatal Transmission
Kidney Dialysis
Transplant prior to 1992
Hemophilia
Uncommon
Internsal cocaine
Body piercing
Tattooing
Sharing of house hold items
Fistfights involving blood contact

Case reports have also documented transmission of hepatitis C between patients who underwent colon scope with an inadequately disinfected colon scope, between 2 family members who had engaged in a fistfight during which there was blood exposure and during cardio thoracic surgery.

Hepatitis History and Treatment Plan

INTRODUCTION:

The elucidation of the hepatitis C genome in 1989 has led to the realization that this virus is a major health problem worldwide. 1st infection with the hepatitis C virus (HCV) is one of the most common causes of chronic liver disease n the United States and HCV related disease is a leading indication for transplantation. An estimated 3.9 million Americans carry the antibody to HCV, while 2.7 million have detectable virus in the blood (i.e, active infection). This means that about more then 1% of the United States population has hepatitis C.

In the NHANES (National Health and Nuttrition Examination Survey) study, it was determined that 1.5% of whites, 3.2% of black, and 2.1% of Hispanics are infected with HCV. The prevalence of hepatitis C in the Asian American Population is unknown at the time of this study, the greatest prevalence was seen in patent age 20 to 29 years. Because of this study was perform about ten years ago, however, the age of this patents has now shifted 30 to 49 years range.

The hepatitis C virus has very little, in common with the better- known hepatitis viruses Hepatitis A & B. it is a member of the Flaviviradiae family, which includes such viruses as those that cause yellow fever and Dengue. The viral partial consist of an envelop derived from host membrane, into which are inserted the virally encoded glycoprotenis E1, E2, surrounding a nucleocapsid and a positive- sense, single-standard RNA genome of approximately nine thousand nucleotides.