An Update on Hepatitis C

IntroductionInfection with the hepatitis C virus (HCV) is 3 times as common as the human immunodeficiency virus infection, affecting about 400 million people worldwide and almost 4 million in the United States alone. Approximately 30,000 new infections occur in the United States each year, most of which remain asymptomatic and thus undetected. HCV is directly responsible for about 10,000 deaths in this country per year. It is the single most common causative factor in hepato-cellular carcinoma, liver transplantation, and death from renal failure. Available therapies are successful in only a small portion of those treated.^(1,2)

Risk Factors?Who Gets Hepatitis C?HCV is a blood-borne virus transmitted by percutaneous or transmu-cosal exposure to infectious blood, blood products, or various other body fluids that causes both acute and chronic disease. Acute infection usually provokes the normal immune response of both humoral and cellular components (as with any other viral infection), which can often bring about initial remission of symptoms. The patient typically remains chronically infected, however, because the virus is not eradicated by the immune response. A person may also be a carrier (ie, harbor the specific organisms of the disease and be capable of transmitting the infection without manifesting symptoms). ^(2,3)

Common Risk Factors for HCV Infection⁽³⁾

• Receipt of a blood transfusion before 1989 (HCV) or 1975 (hepatitis B virus [HBV])
• Hemophilia and hemodialysis
• Occupational, household, or sexual contact with a carrier or an infected person
• Organ transplant from an infected donor
• Use of intravenous drugs
• Use of intranasal drugs (HCV)
• Multiple sexual partners or a history of sexually transmitted drugs (more significant for HBV than for HCV)
• Exposure to infected blood
• Tattooing, body piercing, and acupuncture with unsterilized tools
• Birth to an infected mother

The risk may be greater in places where lower standards of hygiene may be practiced or in locations with a high residence density (eg, low-income urban areas, prisons). Exposure is also increased for employees in health care or penal facilities.

Factors Conducive to Progression to Cirrhosis(3)

• Age at time of infection >50 years
• Long duration of infection?usually 20 to 30 years
• Male gender
• Daily alcohol consumption of >50 g
• Viral genotype 1 or 4

EtiologyImmune Response

Chronic HCV infection typically involves failure of the immune system, or perhaps more specifically, successful viral evolutionary evasion of various normal human immune defenses. Although diagnosis often relies on detection of humoral antibodies to the virus, humoral antibodies are recognized as largely ineffective in eradicating the virus and often pathogenic in themselves. In fact, HCV-antibody complexes have been implicated in causing type II mixed cryoglobulinemia and ensuing glomerulonephritis, vasculitis, and arthritis in many patients.^(1,3)

Inhibition of antigen presentation, frequent mutation of antigenic viral components (with 6 major genotypes and >50 subtypes of the HCV virus so far identified), and mimicry of the host?s self-recognized molecular components all contribute to the ability of the virus to remain largely invisible to the normal immune system. Poly-clonal and multispecific cellular immune components involving T cells are insufficient for viral eradication, and HCV is somehow insusceptible to the normal activity of various cytokines. ^(1,3)

The HCV virus itself (like the other viral agents commonly causing hepatitis) is not cytotoxic. Cellular immune response of the host to infection, however, is responsible for hepatocytic damage underlying symptoms. Vigorous CD4+ and CD8+ T-cell responses to core antigens are associated not only with initial rapid resolution of symptoms and prevention of viral persistence, but with symptom severity as well Thus, the prolonged inflammation of infected tissues that characterizes chronic disease leads to tissue damage, fibrosis, and eventual cirrhosis. Mortality is a function of the degree of fibrosis and the rapidity at which it develops, which often bears little relation to viremia. ^(1,3)

Genetic FactorsThis seeming paradox of cellular immune function being responsible for both resolution of infection and perpetuation of hepatocellular damage is now recognized as associated with the genetic intricacies of the infecting virus, dictating the character of the host?s cellular immune response. HCV

genotypes 1a and 1b, responsible for >70% of infections in North America, are associated with more damaging immune response, more rapid disease progression, and less promising response to available therapeutic agents. Genotypes 2 and 3 have been found to be significantly more responsive to therapy. Genotype 4 is relatively rare compared with the others and has so far demonstrated progression and response characteristics more similar to those of genotype 1. ⁽¹⁾

DiagnosisAcute Infection

With a typical incubation period of 6 to 8 weeks from exposure to onset of disease, acute HCV infection is more commonly asymptomatic and thus more rarely seen clinically than chronic disease. It is diagnosed by observation of predictable symptoms of jaundice (seen in only 25% of acute cases), fatigue, nausea, and even itching, with significant increases in serum alanine aminotransferase (ALT), often 10 times normal values. Anti-HCV is detectable in only 30% to 40% of patients and usually not until 2 to 8 weeks after the onset of symptoms. Detection of HCV RNA, however, may be possible, even within a few days of exposure. To emphasize the rarity of detecting acute HCV, most cases are diagnosed in patients who contracted infection 15 to 30 years prior to detection. ⁽¹⁾

Chronic InfectionIn chronic HCV, anti-HCV is usually detectable; serum aminotransferase levels may remain elevated for >6 months; and polymerase chain reaction detection of HCV RNA confirms diagnosis and viremia. It is important to recognize that liver function test results may remain normal in up to 40% of patients despite significant necroinflammation on biopsy. Immunosuppressed or immunoin-competent patients may not produce anti-HCV, so HCV RNA testing may be essential for patients who have undergone solid-organ transplant, who are on dialysis or corticosteroids, or who are suffering from agammaglobuline-mia. Other sources of hepatic dysfunction?such as alcoholism, iron overload, or autoimmunity?may also complicate diagnosis, such that anti-HCV may represent a false-positive reaction, previous HCV infection, or mild hepatitis C occurring in addition to other hepatic dysfunction. Therefore, HCV RNA testing helps confirm HCV as a contributing factor. Up to 35% of patients who are positive for anti-HCV may be negative for HCV RNA. ^(1,3)

Complications

As mentioned earlier, hepatocellular damage, as well as longer term consequences of fibrosis, and cirrhosis are pursuant to immune damage rather than viral toxicity. The risk of developing hepatocellular carcinoma is directly related to the extent of such damage, which is closely correlated with cirrhosis and is increasing by approximately 1% to 4% per year after initial infection. Continued alcohol consumption dramatically increases the incidence and progression rates for all associated complications, as does concurrent infection with HBV. ⁽¹⁾

TreatmentInterferons

Interferons are human immuno-modulatory proteins that exhibit not only antiviral properties, but viral antiproliferative activity as well. Alfa, beta, and gamma interferons have been identified, and, although several have been studied, clinical applications for viral infections, interferon alfa-2a, interferon alfa-2b, and alfa-con-1 are currently FDA-approved. Interferons bind to specific membrane receptors on cellular surfaces to initiate a complex sequence of intracellu-lar events. These events include the production or modulation of various enzyme systems that suppress cell proliferation, enhance phagocytic activity of macrophages, augment specific cytotoxicity of lymphocytes for target cells, and enhance HCV-specific T-helper-cell response. ^(1,3-5)

Although these effects obviously enhance the efficacy of the patient?s immune response to HCV infection (with the limitations of viral genome mentioned previously), dosage, duration of therapy, and thus therapeutic benefit are severely limited by side effects. Flulike symptoms of fever, headache, chills, myalgia, and fatigue are the most common side effects, and these side effects tend to subside with continued therapy. Irritability, alopecia, malaise, weight loss, thyroid dysfunction (necessitating monitoring of thyroid function), bone marrow suppression, and depression are also common. ^(1,4,5)

The flulike symptoms can exacerbate pulmonary conditions, increasing pulmonary infiltrates, pneumoni-tis, and pneumonia. Therefore, patients with existing pulmonary disease require careful monitoring. Such symptoms can also destabilize glycemic control in the diabetic patient and compromise the patient with thromboembolic disorders, and they can destabilize existing cardiovascular disease by increasing the likelihood of hypotension, arrhythmia, tachycardia, cardiomyopathy, and myocardial infarction. Long-term therapy has been associated with retinal damage; although the cause is unclear, it may involve retinal vascu-lopathy, which is another increased concern for the diabetic patient. ^(1,5)

As enhancers of various immune functions, the interferons tend to exacerbate autoimmune diseases and to precipitate symptoms in patients with such subclinical conditions. Although rare, hepatotoxicity has been reported. Because hepatic metabolism of these agents is extensive, liver function should continue to be monitored.

Depression can be a particular concern, especially in patients with a history of depression or other psychiatric illness. Therapy should be discontinued immediately when exacerbation of depression or suicidal tendencies are noted. Elderly or debilitated patients may be particularly vulnerable to obtundation and coma, possibly in conjunction with sedatives, hypnotics, or antianxiety agents. ⁽⁵⁾

Meta-analyses of numerous well-designed clinical studies show little clinical difference between the available nonpegylated products in treatment-naive patient populations with respect to efficacy, relapse rate, or side effects. These analyses do correlate longer terms of therapy and/or higher doses of all products with significant reductions in relapse rate. Therefore, doubling of recommended dosages from 3 million units (MU) 3 times weekly (TIW) to 6 MU (9 mcg TIW to 15 mcg TIW in the case of interferon alfacon-1) or extending therapy to 12 or even 18 months can reduce the relapse rate and/or extend the duration of clinical improvement before relapse. However, side effects are obviously more problematic with both tactics, and they limit efficacy for most patients. Increased dosage and/or duration of therapy are viable and often necessary options for relapses. About one half of all patients experience relapses with initial interferon monotherapy. ⁽²⁾

Combining Interferon With Ribavirin

A synthetic nucleoside analog with broad antiviral activity, ribavirin seems to provide benefit in HCV infection, not by its antiviral action, but by some ill-defined anti-inflammatory action instead. In approximately 30% of patients treated with ribavirin alone, ALT drops significantly with improvements in biochemical function and hepatocyte histology?all benefits that seem to bear little correlation with HCV RNA levels and that virtually disappear upon discontinuation of the agent.(1)

Ribavirin is indicated only for use against HCV in combination with interferon therapy. Because it, too, can cause hemolytic anemia as its primary toxicity, the risks for patients with existing cardiovascular disease are further exacerbated by combination therapy. Combination therapy (interferon with ribavirin) is substantially more effective than monothera-py at reducing relapse rate, and it has thus become the standard recommendation for appropriate patients, presumably because it enhances the patients? own immune efficacy against the infection. Combination therapy is the obvious therapeutic choice for patients who relapse after initial treatment and for those who fail monotherapy. It is important to recognize that even among patients with HCV of genomes 2 and 3, noted as more responsive to therapy than genomes 1 and 4, only about 75% respond to combination therapy. Even the best available therapeutic options fail for a large portion of patients with HCV. ^(1,5)

Whereas monitoring is essential for patients on interferon monotherapy, it is even more crucial for those on combination therapy, providing evidence that dosages may need adjustments, other interventions may be necessary, or therapy should be discontinued. At a minimum, the following should be assessed at baseline, at 6 and 12 months during therapy, and 6 months posttreatment^(1,3-5):

• Baseline HCV RNA quantitation
• Complete blood count with differential
• Hepatic function
• Thyroid function Blood counts should be done at least at 2 and 4 weeks into therapy because of the tendency of ribavirin to produce hemolytic anemia.

Pegylated Interferon

Attaching polyethylene glycol (PEG), a large inert molecule, to a protein such as an interferon retards the compound?s breakdown and elimination, thus extending its systemic endurance and duration of activity. Nonpegylated interferons endure in the body for only about 24 hours, but pegylated interferon provides longer, more constant drug levels and more constant exposure to suppress HCV. Whereas nonpegylated interferons require subcutaneous or intramuscular injection 3 times weekly, pegylated interferon alfa-2b produces comparable efficacy with dosing only once a week, thus enhancing compliance and improving quality of life for the patients who must endure therapy. ^(6,7)

Patients on therapeutic regimens based on pegylated interferon have demonstrated significant reduction in HCV viral load and a more favorable sustained viral response rate (SVR) than those on nonpegylated product?some 23% SVR for the pegylated inter-feron, compared with only 12% for the nonpegylated interferon. It follows logically that utilizing pegylated inter-feron in combination with ribavirin, as with nonpegylated interferon, would produce superior results, even over the older combination, and this has been demonstrated by evidence from clinical studies. Patients on regimens of weekly pegylated interferon alfa-2b and 800 to 1,200 mg of ribavirin qd for 48 weeks have experienced SVRs of 61% to 78%, depending on viral genotype.(2,8)Investigators emphasize that mechanisms involved in initial viral elimination between pegylated and nonpegylated product may differ, accounting for dramatic decreases in viral load noted with the second dose in interferon-sensitive cases. ⁽²⁾

ConclusionInterferon alone or in combination with ribavirin can provide rapid improvement in serum ALT levels in 50% to 75% of patients and undetectable serum HCV RNA in 30% to 50%. Enduring improvement in liver disease, however, is attainable only if HCV RNA remains undetectable post-therapy. Response is considered sustained if posttherapy HCV RNA remains undetectable for ?6 months. With interferon monotherapy, sustained response rates average only 15% to 20%; sustained response rate with combination therapy is 35% to 45%. Combination therapy provides both more effective loss of HCV RNA during treatment and a lower post-therapeutic relapse rate. Clinical trials of pegylated interferon in combination with ribavirin promise improved clinical results over nonpegylated interferons, if for no other reason than ease of compliance.

Available therapeutic options are only marginally effective for most patients, especially with the more prevalent and more treatment-resistant HCV type 1 genomes seen in the United States. Studies are currently under way to evaluate interleukin-12, triple therapies, including amantadine or rimantadine in combination with interferons and ribavirin, and combinations that include protease inhibitors for future use in combating this particularly treatment-resistant viral infection. Although vaccines for hepatitis viruses A and B are available and effective, the genetic variation and mutability of HCV have complicated efforts to develop effective vaccines for HCV.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. G. Henry, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to:

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