What is the role of a liver biopsy in the management of chronic hepatitis C?
Blood tests can tell the clinician whether HCV is present but cannot tell the level of liver damage that has occurred. Liver biopsy allows the clinician to determine how much inflammation and scarring is present in a small sample of liver tissue. Liver biopsy may be recommended when the clinician is uncertain about whether to begin treatment or wishes to monitor the response within the liver to therapy.
Patients at risk for cirrhosis should be considered for treatment of HCV. According to a consensus statement from the National Institutes of Health (NIH) these include persons with:
- HCV infection and persistent elevation of ALT (alanine aminotransferase, a liver enzyme in the blood)
- High levels of HCV RNA in the blood
- HCV infection and evidence of fibrosis (scarring) on liver biopsy
- HCV infection and evidence of at least moderate inflammation and liver cell injury (necrosis) on liver biopsy
These are general guidelines. Patients and providers may decide that treatment is needed for other reasons. For example, patients with HIV have a more rapid course of liver injury and may need treatment at an earlier stage. Newer therapies may be offered to selected patients in research settings.
Individuals who should not be treated with antiviral therapy include those who are unable to comply with the treatment schedule, should not take the specific medications (for example, allergy), and have reversible serious untreated conditions such as unstable heart disease, uncontrolled high blood pressure, or untreated major depression.
Patients with unstable (decompensated) cirrhosis are at high risk for complications for treatment and usually do not receive medical treatment, except in research settings. Fundamentally, the decision regarding antiviral therapy in chronic HCV infection should be tailored to the individual patient with careful consideration of the risks and benefits.
All patients with HCV should be vaccinated against hepatitis B and hepatitis A. They also should be counseled on measures to prevent the spread of HCV and eliminating alcohol use. Finally, risk behaviors for HCV overlap with those of HIV, and all patients with HCV should be tested for HIV.
What are the different patterns of response to antiviral treatment?
Treatment responses are mainly defined by results of the HCV RNA testing. Four patterns of response to antiviral treatment have been described:
1. sustained virologic response,
3. partial response, and
Sustained virologic response
The optimal response is a sustained virologic response (SVR), defined as the absence of detectable HCV RNA in serum using a sensitive test at the end of the treatment and six months later. Most of these individuals will remain in remission (no signs of the disease) indefinitely, with no detectable hepatitis C virus RNA in the blood or liver. Moreover, follow-up biopsies show a marked reduction in inflammation and there even can be regression of scarring. Longer follow-up of these patients is necessary, however, to evaluate definitively whether sustained responders will avoid the complications of cirrhosis and live longer.
Relapsers are patients who initially eliminate the RNA from their blood but then develop detectable RNA again shortly after discontinuing therapy. The RNA becomes detectable again within six months and usually within the first three months of stopping treatment.
Patients whose HCV RNA levels decline but never become undetectable are referred to as partial responders.
Patients who have sustained levels of detectable HCV RNA during therapy are known as non-responders. Patients in whom HCV RNA becomes undetectable during the early period of treatment but reappears before the end of therapy, should probably likewise be considered non-responders. This reappearance of HCV RNA during therapy is referred to as a 'break through' of HCV.
What are the goals of therapy for hepatitis C virus?
The ultimate goals of antiviral therapy are to eliminate HCV, improve or normalize the liver tests and histology (microscopic appearance), prevent progression to cirrhosis and liver cancer, prolong survival, and improve the quality of life.
As already indicated, only a sustained virologic response provides the possibility of achieving all of the ultimate goals, since most patients who have an SVR will remain in remission indefinitely. The rest of the patients (non-responders, partial responders and relapsers) may show improvement in blood tests with or without relief of symptoms.
For previously untreated patients without reasons to be excluded from treatment, the optimal treatment is combined treatment with pegylated interferon and ribavirin (Rebetol, Copegus). Patients who have reasons not to receive ribavirin may be treated solely with pegylated interferon. Older preparations of interferon are less effective and less commonly used.
Interferons are a family of naturally occurring proteins that are produced by the body to fight viral infections. To produce pegylated interferon, the interferon is processed by attaching ethylene glycol to it. This process is called pegylation and it slows the elimination of interferon from the body so that its effects are more prolonged. There are currently two types of pegylated interferon: pegylated interferon alpha 2b (Peg-Intron A) and pegylated interferon alpha 2a (Pegasys). Both pegylated interferon alpha 2b and 2a; are given as a subcutaneous injection once a week.
Optimally, pegylated interferon therapy should be combined with ribavirin. In persons who cannot take ribavirin, monotherapy with pegylated interferon may be used. Monotherapy has been shown to achieve sustained virologic response rates of 23% to 25% in patients.
The antiviral agent, ribavirin (Rebetol, Copegus), is a nucleoside analogue that is taken by mouth. Nucleoside analogues are man-made molecules that closely resemble the biochemical units that make up genetic material (RNA and DNA). Ribavirin works by fooling the virus into using it instead of the normal building blocks, thereby slowing viral reproduction. Ribavirin has not worked well when used alone for hepatitis C.
Combined pegylated interferon and ribavirin
- Combined therapy with both pegylated interferon and ribavirin produces a sustained virologic response in 28% to 50% of patients with genotype 1.
- For unknown reasons, response rates are lower in African American persons and higher in Caucasians.
- In patients with genotype 2, sustained response rates are higher (76% to 82%).
- The duration of therapy depends on the genotype of the HCV.
- Hence the recommended duration of treatment for HCV genotype 2 and 3 is 24 weeks and for genotype 1 is 48 weeks.
- Sustained virologic response usually is accompanied by a return to normal serum ALT levels and improvement in inflammation within the liver.
Combination therapy is associated with more side effects than monotherapy (see below). In research studies, up to 20% of patients receiving combination therapy required a reduction in the doses or discontinuation of therapy because of the side effects. Nevertheless, combination therapy represents significant progress in the treatment of chronic HCV and is the current standard of care.
Some patients treated successfully with combination therapy still have detectable virus after 12 weeks of treatment but go on to have a sustained response. Therefore, patients on combination therapy should have hepatitis C virus RNA measured at 24 weeks of therapy. In those who are still positive for the virus at that time, consideration is given to stopping treatment, since the chance of sustained response is small.
How are relapses and nonresponders treated?
- The optimal treatment for nonresponders and relapsers is not well established.
- A minority of nonresponders (6% to 12%) will respond to a second course of pegylated interferon and ribavirin.
- Patients initially treated with older interferon alpha monotherapy can be considered for the therapy of either pegylated interferon alpha monotherapy or pegylated interferon alpha plus ribavirin therapy.
- Newer preparations of interferon such as 'consensus interferon' and albumin interferon are being studied and show promise in persons who did not respond to combination therapy.
Despite the failure to achieve sustained virologic response, treatment may slow the progression of HCV to cirrhosis, although this has not been shown for certain.
When people first acquire HCV, the infection is said to be 'acute'. There is no standard approach to treatment for acute HCV. Most patients with acute HCV do not have symptoms, so they are not recognized as being infected. However, some have low-grade fever, fatigue or other symptoms that lead to an early diagnosis. Others who become infected have a known exposure to an infected source, such as a needlestick injury, and are monitored closely. Treatment decisions should be made on a case-by-case basis. However many experts prefer to hold treatment for several months to see whether the patient eliminates the virus without treatment.
Flu-like symptoms, hair thinning and depression are common side effects of interferon or pegylated interferon. Depression may be serious and is common enough that patients should be monitored for this side effect.
Interferons may cause transient bone marrow suppression resulting in reduced white blood cell counts and hemoglobin. Reductions in white blood cell counts may cause increased susceptibility to infection. Death rarely occurs as a result of therapy, but may occur from progressive liver failure in patients with advanced cirrhosis.
Certain side effects are attributed to the addition of ribavirin to interferon, including nausea, cough, shortness of breath, rash, itching, insomnia, and loss of appetite.
Ribavirin also causes anemia due to the destruction of red blood cells (hemolysis). This anemia is usually mild but can become clinically significant. Ribavirin particularly may cause destruction of red blood cells (hemolysis) in people with kidney failure. Anemia improves with a reduction in the dose of ribavirin.
Ribavirin also accumulates in the testicles and ovaries and causes birth defects in animals. Although no birth defects have been reported in humans as yet, both men and women should use contraceptive measures to avoid pregnancy during and for at least six months after ribavirin treatment.
What about liver transplantation for hepatitis C?
HCV is the leading reason for liver transplantation in the U.S., accounting for 40% to 45% of transplants. HCV routinely recurs after transplantation and infects the new liver. Approximately 25% of these patients with recurrent hepatitis will develop cirrhosis within five years of transplantation. Despite these findings of recurrence, the five-year survival rate for patients with HCV is comparable to that of patients who are transplanted for other types of liver disease.
Treatment for recurrent hepatitis is not a simple issue. Interferon is an immune modulator (modifier) that may promote rejection of the transplanted liver. Furthermore, interferon may not be well tolerated by patients who just underwent transplantation and are taking many different kinds of medications.
As our awareness of HCV infection increases, more and more patients are being diagnosed with this condition. Current research includes diagnosis, natural history, treatment, and vaccine development.
- Diagnosis: More accurate tests are being developed to detect even smaller amounts of the virus.
- Natural history: There is much we do not know about the natural history of chronic HCV. Why do some people clear the virus spontaneously? What makes some people develop cirrhosis when others appear to have little liver damage? What predicts response to treatment or re-treatment?
- Treatment: New formulations of interferon are being developed in the hopes of improving response rates. In addition, new agents are being tested in combination with pegylated interferon and ribavirin. Some of these agents, like telaprevir, inhibit protease enzymes that HCV needs in order to reproduce.
- Vaccine development: Scientists have not been able to develop an effective vaccine against HCV. This is partly due to the ability of the HCV to change (mutate) and evade the body's immune responses.
Hepatitis C at A Glance
- HCV is one of several viruses that cause hepatitis (inflammation of the liver).
- Up to 85% of individuals who are initially (acutely) infected with HCV will fail to eliminate the virus and will become chronically infected.
- HCV is spread most commonly through inadvertent exposure to infected blood. Intravenous drug abuse is the most common mode of transmission. The risk of acquiring HCV through sexual contact is low.
- Generally, patients do not develop symptoms of chronic infection with HCV until they have extensive scarring of the liver (cirrhosis). Some individuals, however, may have fatigue and other non-specific symptoms in the absence of cirrhosis. A minority of patients with HCV have symptoms from organs outside of the liver.
- In the U.S., Infection with HCV is the most common cause of chronic hepatitis and the most common reason for liver transplantation.
- HCV is diagnosed by determining levels in the blood of antibodies to the virus and then confirmed with other tests for viral RNA. The amount of viral RNA in the blood (viral load) does not correlate with the severity of the disease but can be used to track the response to treatment.
- A liver biopsy may be used to assess the amount of liver damage (liver cell injury and scarring), which can be important in planning treatment.
- Considerable progress has been made in the treatment of HCV. Combined therapy with pegylated interferon and ribavirin is the standard treatment regimen.
- Treatment results in reduced inflammation and scarring of the liver in most sustained responders and also occasionally (and to a much lesser extent) in those who relapse or do not respond.