Hepatitis B treatment: A Bird's-eye View

Hepatitis B virus (HBV) is a ubiquitous hepatotropic DNA virus with worldwide distribution; it is calculated that there are 350 million people infected around the world. Data show that about 60,000 individuals die each year due to complications of end stage liver disease caused by this agent ^1.

It is important to point that among the hepatotropic viruses, HBV is the only one with a genome conformed by DNA, while the rest of the hepatotropic viruses, such as hepatitis A, hepatitis C and hepatitis delta, have RNA genomes.

One of the peculiarities of HBV is that after it enters the hepatocyte, its genome can penetrate the nucleus of the cell and insert its own genetic material into the human DNA in the form of a sequence of genetic material known as circular close and covalent DNA (cccDNA.) This phenomenon can cause mutagenesis by insertion and it has been hypothesized that this is the origin of HBV-induced hepatocellular carcinoma; this neoplasm can be found in chronic carries of the virus, even in the absence of cirrhosis that is commonly the premalignant condition in other etiologies of chronic liver disease. ^{2, 4}

The hepatitis B infection is blood-borne as well as a sexually transmitted disease and it can also be transmitted vertically from mother to newborn during the delivery. Hepatitis B is also a preventable disease;⁷ recombinant vaccines that are highly effective in preventing the infection are available. In Taiwan, it was possible to decrease the prevalence from 12% to less than 1% in 10 years after the implementation of a universal vaccination program.⁸

There are areas of the world considered to have high prevalence of this disease, which means that the prevalence of HBV infection is about 8% of the population; those areas of the world with prevalence between 2% and 7% are considered having intermediate prevalence and those with less than 2% are areas of low prevalence. The US has low prevalence of HBV. We have to recognize that in the last 20 years international migration and international/intercontinental travel have contributed to a shift in the epidemiology of this disease. It has been estimated that 45% of the new cases observed in the US come from areas where HBV infection is endemic or has high prevalence. Other 43% of these new cases come from the areas with intermediate prevalence, while only 12% of the new cases come from areas with low prevalence of HBV infection.

The mortality of HBV infection in the USA is approximately 5,000 cases per year. The HBV virus is 50 times more infective than the human immunodeficiency virus (HIV) and 10 times more infective than the hepatitis C virus. The risk of transmission is higher when the source of infection is an individual with positive e antigen (HBeAg) in blood ^{1, 3, 5}.

It is important to mention that the HBV is not a cytotoxic virus and the intensity of the response to the infection by this agent will depend on the immune response mounted by the host. The activation of cytotoxic T cells and natural killer cells (NK) can result in the clearance of the HBV or the induction of apoptosis resulting in minimal inflammation and induction of tolerance to the presence of the virus. On the other hand, the presence of proinflammatory cytokines might trigger acute inflammatory response and the development of acute liver necrosis.^{1, 4}

There are 5 different immunological phases of the chronic HBV infection, and they are a continuum of the original infection. These phases have specific recommendations for treatment:

• Immune tolerant phase: This phase is characterized by normal alanino-aminotransferase (ALT), hepatitis e antigen (HBeAg) positivity, and very high viral load. The liver histology is characterized by the absence of fibrosis and no treatment is recommended in this phase.
• Immune active phase: HBeAg can be either positive or negative, the ALT can be elevated more than 2 times the upper limit of normal, and biopsy shows significant necroinflammatory activity and the possibility of mild to moderate fibrosis (stage 1-2). In this case, the recommendation is to start treatment with pegylated interferon, entecavir, or tenofovir, with the aim to prevent complications of chronic liver disease. The presence or absence of the HBeAg needs to be paired with the viral load (HBV-DNA) to decide if the patient requires treatment:
  • Start treatment when HBeAg is positive and the HBV-DNA is >20,000 IU.
  • Start treatment when HBeAg is negative and the HBV-DNA is >2,000 IU.
  • Start treatment in patients with cirrhosis if the HBV-DNA is >2,000 regardless of the ALT value.
• Immune active phase with negative HBeAg and biopsy with grade 4 inflammation and stage 1-2 fibrosis should receive treatment indefinitely.
• Low viremia: If HBV decreases to <2,000 IU during the treatment with entecavir or tenofovir, the medication is to be continued indefinitely regardless of the ALT value.
• Seroconversion to anti-HBe(+) during treatment; continue medication for a period of “consolidation” that extends for about a year after reaching the seroconversion status.

The current treatment for HBV is based on the use of nucleoside or nucleotide analogs (NAs) that will inhibit the postgenomic RNA transcription into HBV-DN. This treatment cannot be considered a cure in the sense of eradication of the virus from the human body. The NAs do not act on the cccDNA that might be the source of a future breakthrough episode of replication; the goals of the treatment for HBV are the suppression of the viral replication followed by normalization of ALT and loss of HBeAg.

There are two different formulations of tenofovir: the tenofovir disoproxil (TDF) and tenofovir alafenamide (TAD). TDF’s therapeutic dose is 300 mg per day while the TAD’s dose is 25 mg per day. The latter is preferred in those individuals with pre-existent renal disease, as it has demonstrated less nephrotoxicity when compared to TDF. On the other hand, TDF is very effective in preventing vertical transmission of HBV when started in the last trimester of the pregnancy in women who are chronic HBV carriers. Tenofovir has also demonstrated efficacy in chronic active hepatitis B and in naïve immune-active disease as compared with entecavir and pegylated interferon (these comparisons have not been documented in a head-to-head study).

Entecavir is also widely used in the treatment of HBV chronic infection. Its dose is 0.5 mg per day for those individuals who are naïve to NA treatment and 1 mg in those who have previously received lamivudine or adefovir.

The pegylated interferon alpha-2A been approved for the treatment of HBV chronic infection in the United States. The dose of this medication is 180 mg administered subcutaneously every week for 48 weeks. The high incidence of side effects and toxicity might limit its use.

Pearls of wisdom:

In patients with immune active HBV infections remember:

• If the ALT is < 2 X upper limit of normal (ULN) consider the stage of the disease. Consider noninvasive vs invasive diagnostic options (elastography vs liver biopsy).
• If HBV-DNA >2,000 IU in cirrhotic patients, continue the treatment indefinitely.
• Patients older than 40 years of age might present with more advanced stages of the disease.
• Consider a positive family history of cirrhosis and hepatocellular carcinoma as risk factors for the patient.
• Previous treatment with NA is a risk factor for the development of resistance to medications.
• Remember that the benefit of pegylated interferon treatment might present even after the treatment was completed.
• Pegylated interferon, entecavir, and tenofovir are preferred medications as there is no long-term documented resistance to them

Dietary supplements and herbal remedies

HBV infection is a chronic disease with the potential of progression to end stage liver disease and hepatocellular carcinoma. The Hepatitis B Foundation has documented the interest of the people with this disease to use substances to “boost their immune system” but the lack of FDA regulation of these substances represent a major problem. Some of these substances and dietary supplements might interfere with the metabolism of NAs and others can even be hepatotoxic. For these reasons, these supplements, otherwise named “remedies”, “natural medicine” or “traditional medicine” are not recommended in the treatment for HBV. ¹²

The most effective strategy to prevent hepatitis B is vaccination. The HBV vaccine is recombinant and for this reason cannot transmit the hepatitis B itself. The vaccination series has excellent record of safety and it is provided as 3 intramuscular injections in the deltoid muscle at baseline, 1 month, and 6 months. There is also combined HBV and hepatitis A vaccine that is provided in a series of 4 injections and more recently a series of 2 vaccines for HBV has been approved.¹³

Hepatitis B and pregnancy

One advantage of the recombinant vaccines is that they can be given during pregnancy. In the case of hepatitis B, all pregnant women who are at risk of acquiring the disease and who have previously tested negative for anti-HBs can receive the vaccination during the pregnancy.¹⁴

In the case of newborns of HBsAg positive mothers, they should receive hepatitis B immune globulin (HBIg) and HBV vaccination immediately after the delivery and the vaccination series should be completed by the age of 6 months.

If a woman with documented HBV infection becomes pregnant, HBV-DNA monitoring during pregnancy is granted and those women with HBV viral load >200,000 IU will need treatment. This treatment should be started in the third trimester and the recommendation by the American Association for the Study of Liver diseases (AASLD)  is to discontinue this treatment after the delivery and up to 4 weeks postpartum. ¹⁰

• Hepatitis B is a high-impact, highly transmissible disease with multiple transmission forms (sexual, parenteral, vertical).
• The best approach for the eradication of this disease is universal vaccination with highly effective recombinant vaccines.
• It is safe to provide HBV vaccination to pregnant women.
• Pregnant women with HBV active infection should start treatment with NA in the third trimester to minimize vertical transmission of the disease to the newborn during delivery.
• The main aim of the treatment of this disease is seroconversion from HBsAg to anti-HBs; HBeAg to anti-HBe.
• A secondary aim of HBV treatment is to maintain a nonreplicative state of the HBV
• The decision to treat the HBV infection with PEG-IFN or NA will depend on the immunological phase of the disease, viral replication, ALT elevation and necroinflammatory activity or fibrosis detected in the liver by noninvasive or invasive methods (elastography or liver biopsy).

Marco Olivera-Martinez, MD, is an associate professor of gastroenterology and hepatology at the University of Nebraska Medicine in Omaha, Nebraska.


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