Current Treatment Of Chronic Hepatitis B: Clinical Aspects And Future Directions
- 1The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- 2International Institutes of Medicine, Zhejiang University, Jinhua, China
Hepatitis B virus infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases , European Association for the Study of the Liver , and Asian-Pacific Association for the Study of the Liver also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: Who should be treated in the general population according to the guidelines Treatment of specific populations infected with HBV Controversial issues in clinical practice Perspective.
Who Should Get The Hepatitis B Vaccine
All newborn babies should get vaccinated. You should also get the shot if you:
- Come in contact with infected blood or body fluids of friends or family members
- Use needles to take recreational drugs
- Have sex with more than one person
- Are a health care worker
- Work in a day-care center, school, or jail
What Treatments Are Available For Chronic Hepatitis B
First line treatments include antiviral therapies such as tenofovir , entecavir and Vemlidy which are taken once daily. These antivirals are not a cure for chronic hepatitis B, but they work to suppress or control the virus while you are taking them. When the virus is suppressed, liver disease progression is slowed or even stopped, and the liver is often able to heal with time. It is important to see a knowledgeable doctor to determine if you are a good candidate for treatment since treatment is a commitment, and is taken for at least a year, usually for many years or even for life – or until there is a cure found for this disease.
U.S. residents seeking help with medication costs can find resources here.
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Treatment Of Chronic Hepatitis B In Children
Vaccination against HBV among young Chinese individuals decreased the HBV infection rate. In recent years, several studies reported gradually increasing the horizontal transmission of HBV in early childhood, and family members may be the main source of infection. Interferons and NAs are the potential treatment options according to the age of young people .
Approved Drugs For Adults
There are currently 7 approved drugs in the United States for adults living with chronic hepatitis B infection. These include 5 types of antiviral drugs that are taken as a pill once a day for 1 year or longer. And there are 2 types of immune modulator drugs called interferon that are given as an injection for 6 months to 1 year.
It is important to know that not everyone needs to be treated. A liver specialist should evaluate your health through a physical exam, blood tests, and an imaging study of your liver . Then you can discuss together whether you are a good candidate for treatment since the approved drugs are most effective when there are signs of active liver disease. In addition, talk to your provider about HBV Clinical Trials since there are several new drugs being tested that are available for infected adults.
All adults, however, should be seen regularly by a liver specialist whether they are on treatment or not.
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What Will I Need To Do If I Am On Hepatitis B Medications
- Take oral medications every day to avoid developing resistance.
- See your provider on a regular basis
- If you have cirrhosis or high risk of liver cancer, get liver imaging on time as prescribed by your provider
- Have periodic laboratory tests to monitor HBV viral load and liver enzymes to monitor disease activity and response to medications
- You may need blood tests every 3-6 months initially and at least once a year thereafter if virus is undetected in blood.
Candidates In The General Population
Antiviral treatment is an effective therapeutic strategy for CHB patients that efficiently suppresses HBV replication, decreases inflammatory necrosis in the liver, reduces the incidence of liver cirrhosis and related complications, and reduces the fatality rate associated with hepatocellular carcinoma and other liver diseases. In the 2019 China guidelines , HBV infection is divided into four phases: immune tolerance, immune clearance, immune control, and immune reactivity, and it is different from the 2015 version . Additionally, the 2019 China guidelines eased the restrictions on indications for antiviral therapy, and reducing the demand for HBV-DNA load. Conversely, the HBV-DNA load is considered for the performance of antiviral therapy in the 2018 guidelines updated by the 2018 AASLD guideline and the 2017 EASL guidelines . For the treatment of HBV infection with normal ALT , antiviral therapy is recommended in patients > 30-years-old with a family history of liver cirrhosis or cancer in the 2019 China guidelines. In another case > 30-years-old without a family history of liver cirrhosis or cancer, a hepatic biopsy was recommended. Although we can refer to many guidelines, there are many patients failed to fulfill the criteria for treatment at follow-up and eventually developed liver fibrosis, cirrhosis, and cancer .
Table 1. Comparison between 2015 and 2019 guidelines.
Table 2. Indications for chronic hepatitis B treatment in 2017 and 2018 guidelines.
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Us Food And Drug Administration Approves Vemlidy For Treatment Of Chronic Hepatitis B Virus Infection In Pediatric Patients
Approval Expands on Previous FDA Approval of Vemlidy in Adults Living With This Chronic Liver Disease
Efficacy and Safety of Once-Daily Vemlidy Demonstrated in Individuals 12 Years of Age and Older
FOSTER CITY, Calif.—-Gilead Sciences, Inc. today announced that the U.S. Food and Drug Administration has approved the supplemental new drug application for Vemlidy® 25 mg tablets as a once-daily treatment for chronic hepatitis B virus infection in pediatric patients 12 years of age and older with compensated liver disease.
Vemlidy is a novel, targeted prodrug of tenofovir that was previously approved by the FDA in 2016 as a once-daily treatment for adults with chronic HBV infection with compensated liver disease. It is recommended as a preferred or first-line treatment for adults with chronic HBV with compensated liver disease in guidelines from the American Association for the Study of Liver Diseases and European Association for the Study of the Liver .1,2
Vemlidy has a boxed warning in its product label regarding post-treatment severe acute exacerbation of hepatitis B. See below for important safety information.
U.S. IMPORTANT SAFETY INFORMATION AND INDICATION FOR THE USE OF VEMLIDY
BOXED WARNING: POSTTREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B
Warnings and Precautions
Adverse Reactions
Drug Interactions
Consult the full prescribing information for VEMLIDY for more information on potentially significant drug interactions, including clinical comments.
Indication
Patients Who Receive Immunosuppressive Or Cytotoxic Therapy
While receiving immunosuppressive or cytotoxic therapy, patients with HBsAg-positive, anti-HBc-positive or HBsAg-negative, and anti-HBc-positive have the possibility of HBV reactivation. Thus, it is necessary to screen for HBsAg before therapy. In the case of HBsAg-positive, patients should receive anti-HBV prophylaxis before immunosuppression or cytotoxic therapy or consecutively. If HBsAg-negative, HBcAb+ patients undergoing anti-CD20 antibody therapy or stem cell transplantation, should accept anti-HBV prophylaxis for at least 18 months after immunosuppressive therapy, as the rate of HBV reactivation is high, according to 2019 Chinese guidelines.
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Can Hepatitis B Be Prevented
The hepatitis B vaccine is one of the best ways to control the disease. It is safe, effective and widely available. More than one billion doses of the vaccine have been administered globally since 1982. The World Health Organization says the vaccine is 98-100% effective in guarding against the virus. Newborns should be vaccinated.
The disease has also been more widely prevented thanks to:
- Widespread global adoption of safe blood-handling practices. WHO says 97% of the blood donated around the world is now screened for HBV and other diseases.
- Safer blood injection practices, using clean needles.
- Safe-sex practices.
You can help prevent hepatitis B infections by:
- Practicing safe sex .
- Never sharing personal care items like toothbrushes or razors.
- Getting tattoos or piercings only at shops that employ safe hygiene practices.
- Not sharing needles to use drugs.
- Asking your healthcare provider for blood tests to determine if you have HBV or if you are immune.
Injections: Interferon And Pegylated Interferon
Pegylated interferon is given as an injection once per week. It can be used alone or with an oral hepatitis B medication. Patients with both chronic hepatitis B and hepatitis D infection may need pegylated interferon alone or combined with an oral hepatitis B pill.
- Pegylated interferon therapy is usually given for 48 weeks.
- Pegylated interferon may cause many side effects, such as flu-like symptoms, rashes, irritability, and depression.
- Side effects to interferon require close monitoring with routine blood tests.
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What Is Chronic Hepatitis
Hepatitis is an inflammation of the liver. In chronic hepatitis, liver inflammation continues for at least six months. This condition may be mild, causing relatively little damage, or more serious, causing many liver cells to be destroyed. Some cases lead to cirrhosis and liver failure.
Chronic hepatitis from infection is most often caused by these viruses:
- Hepatitis B and C. Often the person infected is unaware of any initial symptoms. Or the symptoms were so mild that the person did not seek medical attention. This is especially true for chronic hepatitis C. Over time, perhaps a decade or more, both types may lead to the serious complication of cirrhosis due to ongoing destruction of liver cells and resultant scarring. A minority of patients with cirrhosis develop liver cancer over time.
- Hepatitis D. Hepatitis D infects only patients already infected with hepatitis B, and it generally results in a flare of active hepatitis.
This information helps to determine the best treatment and to assess your risk of developing cirrhosis and liver failure. A liver biopsy also can help to check for other disorders, such as alcoholic liver injury or fatty liver.
National Institutes Of Health Recommendations
The National Institutes of Health recommends nucleoside therapy for the treatment of patients with acute liver failure, as well as cirrhotic patients who are HBV DNA positive and those with clinical complications, cirrhosis or advanced fibrosis with positive serum HBV DNA, or reactivation of chronic HBV during or after chemotherapy or immunosuppression. In addition, immunoglobulin and vaccination should be administered to newborns born to women positive for hepatitis B surface antigen .
In general, for hepatitis B e antigen -positive patients with evidence of chronic HBV disease, treatment is advised when the HBV DNA level is at or above 20,000 IU/mL and when serum ALT is elevated for 3-6 months.
For HBeAg-negative patients with chronic hepatitis B disease, treatment can be administered when the HBV DNA is at or above 2,000 IU/mL and the serum ALT is elevated for 3-6 months.
In patients coinfected with HBV and HIV, initiate therapy against HBV and administer antiretroviral therapy as well.
The NIH also indicates that immediate therapy is not routinely indicated for patients who have the following :
-
Chronic hepatitis B with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy
-
Low levels of or no detectable serum HBV DNA and normal serum ALT levels
-
Positive serum HBV DNA but not HBsAg , unless the patient is undergoing immunosuppression
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Hbsag Clearance After Na Treatment
There are few large or conclusive studies on the clearance of HBsAg after NA treatment, and some of these studies are single-centre retrospective studies. Kim et al. reported a clearance rate of 1% or less in 110 CHB patients who were treated with ETV/LAM for approximately 1 year. A retrospective study by Yip et al. reported an HBsAg clearance rate of 2.1% after an average follow-up of 4.8 years in 20,263 CHB patients treated with ETV/TDF for longer than 6 months. Wong et al. retrospectively evaluated 1072 CHB patients on antiviral therapy for approximately 6 years and found an HBsAg clearance rate of 4.58%. This study found no significant difference in the clearance rate between HBeAg-positive and HBeAg-negative patients, but the rate in patients with cirrhosis was significantly lower than patients without cirrhosis . These results suggested that the clearance rate of non-cirrhosis patients was higher after NA treatment, which is not consistent with the results of patients who experienced spontaneous clearance. Compared to patients with normal baseline ALT, patients with higher ALT levels had significantly higher rates of achieving HBsAg clearance. In general, the clearance rate may increase with the extension of treatment in CHB patients, but the overall rate with currently available NA treatment is low. The HBsAg clearance rates were 1.45.1% after an average follow-up of 27 years after NA treatment .
Low Response Rates And Nonresponders
Low vaccination response rates have been associated with obesity, smoking, immunosuppression , and advanced age. Approximately 25-50% of persons who initially do not have a vaccine response will show a response to one additional vaccine dose, and 50-75% of individuals will have a response to a fourth higher dose of Engerix B or Recombivax HB, or a second 3-dose series.
Postvaccine antibody titers do not need to be obtained in routine vaccinations of children or adults. It is recommended that testing for anti-HBs be obtained 4-12 weeks after vaccination in the following groups :
- Immunocompromised patients, including those on hemodialysis, HIV patients, and others
- Infants born to HBsAg-positive mothers
- Healthcare professionals
- Sexual partners of HBsAg-positive patients
Nonresponders, should be revaccinated with another series of 3-dose hepatitis B vaccine. Consider delaying revaccination for several months after initiation of antiretroviral therapy in patients with CD4 counts below 200 cells/mm3 or those with symptomatic HIV disease. The delay in these individuals is an attempt to maximize the antibody response to the vaccine.
Do not defer vaccination in pregnant patients or patients who are unlikely to achieve an increased CD4 count. Individuals at increased risk of severe complications due to HBV infection include those unlikely to achieve CD4 counts of 200 cells/mm3 or above after antiretroviral therapy and HIV-infected pregnant women.
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Controversial Issues In Clinical Practice
Nucleoide analogs withdrawal and retreatment
Oral nucleoide analogs used in first-line treatment, such as TDF, entecavir , and tenofovir alafenamide fumarate , have strong anti-virus effects, fewer side effects, convenience, and low resistance. However, long-term duration, especially > 10 years of administration, requires intensive focus on drug safety and may result in reduced compliance in patients . Drug withdrawal can be considered in HBeAg+ patients after e-antigen seroconversion and consolidation therapy, as recommended by guidelines . Conversely, for HBeAg- patients, the 2019 China guidelines recommended drug withdrawal upon serum HBsAg disappearance and HBV DNA below the limit of detection, and the 2018 AASLD guidelines recommended at least 2 years of viral inhibition and consolidation therapy, while the 2017 EASL guidelines recommended a minimal 3-year viral inhibition. The 2015 APASL guidelines recommended drug withdrawal upon serum HBsAg disappearance, followed by 12-month consolidation therapy or undetectable HBV DNA and a minimum of 2 years of treatment.
Low level viremia
Table 3. Recommendations for salvage therapy in resistant patients in 2019 guideline.
How Do I Get Hepatitis B Treatment
Usually for adults, hepatitis B goes away on its own and you wont need treatment. Your doctor might tell you to rest, eat well, and get plenty of fluids. You may also get medicines to help with any symptoms you might have but be sure to talk with your doctor or nurse before taking anything.
If you have chronic hepatitis, there are medicines you can take to treat it. Your doctor will tell you about your options and help you get whatever treatment you need.
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What Are The Risk Factors For Getting Hepatitis B
Due to the way that hepatitis B spreads, people most at risk for getting infected include:
- Children whose mothers have been infected with hepatitis B.
- Children who have been adopted from countries with high rates of hepatitis B infection.
- People who have unprotected sex and/or have been diagnosed with a sexually transmitted infection.
- People who live with or work in an institutional setting, such as prisons or group homes.
- Healthcare providers and first responders.
- People who share needles or syringes.
- People who live in close quarters with a person with chronic hepatitis B infection.
- People who are on dialysis.
What Are The Treatment Options For Chronic Hep B
For people with acute hep B infection experiencing mild symptoms, doctors often recommend rest, a healthy diet, and fluids to speed up recovery. Severe symptoms may need to be treated in a hospital.
According to the Hepatitis B Foundation, there are currently seven drugs approved by the FDA to treat chronic hep B in the United States. Not everybody needs to take medication, but some people will need to take medication for the rest of their lives.
These drugs fall into one of two categories:
- Antiviral drugs. These drugs help reduce inflammation and liver damage. Theyre usually taken daily in pill form for at least a year.
- Immune modulator drugs. These drugs boost your immune system to help your body fight off the virus. Theyre administered as an injection over 6 to 12 months.
Theres no cure for hep B, acute or chronic, at the moment. However, clinical trials continue to investigate new treatment options.
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