Hepatitis B (cont.)
Mary D. Nettleman, MD, MS, MACP
Mary D. Nettleman, MD, MS, MACP
Mary D. Nettleman, MD, MS, MACP is the Chair of the Department of Medicine at Michigan State University. She is a graduate of Vanderbilt Medical School, and completed her residency in Internal Medicine and a fellowship in Infectious Diseases at Indiana University.
Mohamad El Mortada, MD
In this Article
What medications are used to treat hepatitis B?
Acute infection with hepatitis B usually does not require treatment. In rare cases, however, the infection may cause life-threatening liver failure. Patients with liver failure due to acute hepatitis B should be evaluated for liver transplantation. Small studies suggest that the drug lamivudine (Epivir) may be effective in this setting.
If a person is chronically infected with hepatitis B and has few signs or symptoms of complications, medications usually are not used. These patients are watched carefully and given periodic blood tests. One test measures the 'viral load,' that is, the amount of viral DNA in the blood. Doctors will recommend treatment if there are signs that the virus is beginning to cause damage or if the viral load is high. Another reason to prescribe medication is if the patient has a positive test for the Hepatitis B e-antigen (HBeAg) in the blood. HBeAg is associated with an increased risk of progression of liver disease and its complications.
In chronic hepatitis B, the goal of treatment is to reduce the risk of complications including cirrhosis and liver failure. However, it takes decades for complications to occur, which makes it difficult to study the effect of medications. As a substitute for waiting years to find out what happens, scientists have used tests like the viral load or liver function tests to evaluate if medicines are working. This is logical because it is known that people who have large amounts of the virus in their blood are at highest risk to get cirrhosis. Up to one-third of people with very high viral loads (more than one million viral copies per milliliter of blood) will develop cirrhosis over a decade, compared to only 4.5% of those with low viral loads (fewer than 300 viral copies per milliliter).
Medications can reduce the number of viruses in the body and may be able to eliminate the virus from the bloodstream. Logically, this should lead to them having a low rate of progression to cirrhosis (<1% per year), although large, long-term studies have not been done. Even in people who clear the virus from their blood, low numbers of viruses still live in the liver and other cells. Thus, the medications do not cure the disease, but they can prevent or delay complications and symptoms. People who have a good response to treatment can still transmit the virus. Doctors follow blood tests that measure viral load and liver function and they may recommend liver biopsies to evaluate if the medications are working.
The medications in current use for chronic hepatitis B include the interferons and nucleoside/nucleotide analogues. New agents are being developed although they are still under investigation and considered experimental. There are no accepted guidelines that tell how every patient should be treated. As a result, treatment is individualized.
Interferon-alpha has been used to treat hepatitis B for more than 20 years. Interferon-alpha is a naturally occurring protein that is made in the body by white blood cells to combat viral infections. In addition to its direct anti-viral effects, interferon works against the hepatitis B virus by stimulating the body's immune system to clear the virus. Compared to older interferon alpha agents, pegylated interferon alpha, marketed as Pegasys or Pegintron, has a more convenient dosing schedule, may be slightly more effective and suppresses the virus for a longer period of time. Pegylated interferon alpha is given once a week for 48 weeks.
Only 27%-32% of persons who have Hepatitis B e-antigen (HBeAg) in their blood will be able to eliminate HBeAg and produce antibodies against the HBe antigen after treatment with interferon. Relapse may occur after treatment is stopped.
Sustained response (undetectable viral load in the blood, normal liver function tests) occurs in approximately 15% to 30% of patients after the drug is stopped. Although this is not a cure (some virus still lives in the liver and elsewhere), people with sustained response are at low risk for complications of liver disease. If the responder's immune system is compromised, for example through the use of steroids or acquiring HIV, the disease can recur. Periodic monitoring of blood tests can help confirm that the response continues to be sustained.
Interferon side effects
Interferon causes several side effects including:
The side effects may be severe enough that the patient is unable to continue treatment. During treatment, the normal immune response to the virus is stimulated and may cause worsening inflammation in the liver. This is normally a good sign showing that the interferon is working, but more extreme responses may in rare cases cause liver failure. Thus, physicians will monitor blood tests closely during therapy. Persons with unstable liver disease due to cirrhosis usually should not take interferon because of the increased risk of liver failure.
Nucleoside/nucleotide analogues (NAs) are man-made chemicals that mimic the nucleosides and nucleotides that are used for making DNA. When the virus tries to use the analogues to make its own DNA, it is unable to make the DNA and, therefore, cannot reproduce. Examples of these agents include adefovir (Hepsera), entecavir (Baraclude), lamivudine (Epivir-HBV, Heptovir, Heptodin), telbivudine (Tyzeka) and tenofovir (Viread).
In a 2004 study in people who already had cirrhosis from hepatitis B, treatment with lamivudine cut the risk of liver cancer and progressive liver failure by more than 50%. Newer NAs such as entecavir (Baraclude) and telbivudine (Tyzeka) appear to have higher response rates than older agents such as lamivudine (Epivir-HBV, Heptovir, Heptodin), but there is less experience with these NAs.
Unfortunately, the hepatitis B virus may become resistant to NAs over time (see below). Adefovir may be effective against strains of virus that have become resistant to lamivudine and may be added to lamivudine when resistance appears. Simply switching from one NA to another is not recommended because this leads to virus strains that are resistant to multiple medications.
Currently, the optimal duration of treatment with nucleoside/nucleotide analogues is uncertain. Persons with HBeAg may be treated until six months after the HBeAg disappears from the blood and is replaced by antibodies (anti-HBe), if this occurs. In persons without HBeAg, the endpoints are less clear. Some experts advocate treating until the viral load (viral DNA) is undetectable and the surface antigen (HbsAg) has been cleared from the blood. Others suggest continuing medications for prolonged periods to suppress the virus. All of these strategies are hampered by the risk of the virus becoming resistant to the medications. Patients who discontinue treatment with NAs should be monitored carefully for recurrent hepatitis, which may be severe.
Why does hepatitis B virus become resistant to nucleoside/nucleotide analogues?
The major challenge associated with long-term therapy with NAs is the development of viral resistance to the NAs. This resistance results from a change (mutation) in the genetic material of the virus.
Therefore, some guidelines do not recommended lamivudine or telbivudine alone as the first treatment for chronic hepatitis B.
For other NAs such as adefovir (Hepsera), resistance is less common after one year of therapy but rises to 30% after five years. Early results with entecavir (Baraclude) suggest that resistance may be uncommon with this agent. When resistance occurs, the viral load may rise or blood liver tests may become abnormal.
Is there a preferred treatment for chronic hepatitis B?
There are no clear guidelines to recommend which agent to use first in treating chronic hepatitis B. Interferon is given for a defined period of time and may have a more prolonged response after the medication is discontinued than NAs. However, interferon is given as an injection, and side effects often are troublesome. NAs are given as a pill and have few side effects, but the duration of treatment is unclear, and prolonged therapy may be required. NAs may be preferred in patients with unstable disease and cirrhosis because they are thought to be less likely to cause serious flares of hepatitis with more severe liver disease.
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