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Lamivudine Treatment for Chronic Hepatitis B: What You Need to Know

Lamivudine Treatment for Chronic Hepatitis B: What You Need to Know

Lamivudine is a powerful compound that was initially developed as a treatment for human immunodeficiency virus (HIV) infections. However, researchers have discovered that this compound has a vital role to play in the treatment of hepatitis B virus (HBV). When used in the treatment of HIV infections, lamivudine is taken in combination with other medications. However, when used to treat HBV, it is taken alone---the drug works by preventing the replication of the genetic material of the hepatitis B virus. Without being able to reproduce itself, the virus will not be able to cause inflammation and damage to the liver. Lamivudine is available in tablet and liquid forms. Tablets come in two strengths with 100mg and 300mg options. Usually, patients will start with a dosage of 100mg daily and then increase to 150mg daily after one week. The liquid form, however, has a concentration of 5 mg/mL and is prescribed based on body weight. After intake, lamivudine is rapidly absorbed but a significant portion of the drug is converted to an active metabolite so that it can effectively inhibit HBV replication. It is excreted primarily in the urine. The half-life of lamivudine is about 5 to 7 hours, but this could be prolonged in patients with impaired kidney functions. Patients must complete the entire course of the drug as prescribed, even if the symptoms have seemed to improve. This is because premature discontinuation of the medication may cause the infection to relapse, which could be much more difficult to treat.

Mechanism of Action

The process of lamivudine treating hepatitis B is known as selective inhibition. In the early phase of the disease**, specific types of immune cells known as CD8+ cells can effectively "seek and destroy" cells within the liver**. When the hepatitis B virus infects the liver cells, they exhibit a protein called polymerase. This protein is able to convert the genetic material in the hepatitis B virus, known as covalently closed circular DNA, into a form that can be used by the host cell. As a result, the virus is able to effectively "hide" within the genetic material of the liver cells and avoid eradication by the immune system.

Lamivudine is known as a nucleoside analog. This means it is structurally similar to the "building blocks" that make up the genetic material of cells. In the body, these active components are converted into a "triphosphate" or three-phosphate form. When the hepatitis B virus overwrites the genetic material, the polymerase is tricked into using lamivudine instead. However, lamivudine is different in that once the next component is added, the process is terminated. By halting the replication of the virus genetic material, it means the hepatitis B virus is unable to effectively hide within the liver cells. Additionally, by sabotaging the activity of polymerase, it serves to reduce the overall capacity of the virus to infect more cells and continue the progression of the disease.

As the virus is effectively eradicated gradually from the body, it means the inflammation within the liver is reduced and the symptoms of the disease, such as fatigue, abdominal pain, and nausea, are decreased. By simultaneously reducing the effects of the immune response and allowing the liver to recover from the damage caused by the hepatitis B virus, lamivudine is effective in both treating the symptoms and progression of the disease.

Inhibition of Reverse Transcriptase

HBV reverse transcriptase is an enzyme vital to the replication of the HBV genome. Upon infection, the virus inherits a pre-genomic DNA strand -- a long single strand that is identical to one half of the circular DNA genome found within the intact HBV virus. This pre-genomic DNA, through the facilitation of reverse transcriptase, is effectively copied in a 'template' style, producing a complementary strand and leaving the original HBV DNA fully double-stranded; it is this DNA that is subsequently integrated into a host cell's DNA, and that which underpins the production of the viral proteins and RNA required to produce new viral particles. Alas, as a result of the structural similarity between deoxyguanosine (one of the four nucleotides that make up DNA) and lamivudine, the nucleoside analog is able to be mistakenly incorporated into the growing DNA strand during reverse transcription. Lamivudine initially acts as a chain terminator for the reverse transcription process; however, it is also recognized that the incorporation of lamivudine can dramatically reduce the proofreading capabilities of reverse transcriptase. This introduces a random mutagenic element to the reverse transcription process, meaning that a multitude of defects can be introduced into the HBV DNA. This can prevent the formation of fully functional viral genomes and so inhibit the production of new viral particles necessary for the continued infection of host cells. Whilst most research supports the above mechanism, it is important to note that additional inhibitory mechanisms of lamivudine on HBV are cited in the literature. For example, it is suggested that the drug's triphosphate form can inhibit various groups of enzymes called DNA polymerases, as well as cellular enzymes responsible for the replication of mitochondrial DNA. However, as in comparison to the specific targeting of HBV reverse transcriptase, these mechanisms are considered to play a lesser role in the overall efficacy of lamivudine therapy for HBV.

Suppression of HBV Replication

When used as a treatment for HIV, lamivudine suppresses the replication of the virus in the human body by reducing viral load and by increasing the number of CD4+ cells. The impact of lamivudine on the replication of HBV depends on the ability of the drug to interfere with HBV genetic material. Studies have shown that lamivudine forms active phosphorylated products that compete with natural deoxycytidine 5'-triphosphate for incorporation into HBV DNA; this leads to the termination of the proviral DNA chain. Ultimately, lamivudine inhibits HBV DNA polymerase, the enzyme that is essential for the formation of HBV DNA. By doing this, the drug reduces hepatic inflammation and may prevent progression to cirrhosis. Another advantage of the use of lamivudine in the treatment of HBV is the reduction in the transmissibility of the virus. The termination of the DNA chain means that HBV DNA cannot form a stable mRNA-DNA duplex. This is crucial, as HBV utilizes a 'peeling off' mechanism in which it removes the existing strand of mRNA in order to form a duplex with the DNA and, therefore, allow the transcription to continue. With the inhibition of the DNA chain, lamivudine again decreases the amount of viral mRNA. This means that there is less of the virus in the blood due to the production of fewer viral proteins; this leads to a reduction in the ability of the virus to spread to a new host and a reduction in the likelihood of the development of immunity.

Clinical Applications

Treatment of Chronic Hepatitis B

Lamivudine has been widely used to treat chronic hepatitis B since its initial approval in 1998. It operates by inhibiting the reverse transcriptase enzyme in the DNA B virus, interrupting the viral replication and consequently leading to a reduction in inflammation and fibrosis. Studies have shown that a majority of patients tend to respond well to lamivudine therapy, with improvement in both liver histology and seroconversion rates of e-antigen. However, long-term lamivudine therapy may be associated with drug resistance - with reported resistance rates ranging from 16% at year 1 of treatment to 70% at year 5 of treatment. The high rates of resistance are due to the low genetic barrier in the development of resistance while patients are on lamivudine therapy. This means that new virus strains with mutations in the DNA polymerase gene may develop easily during treatment - and once a patient has lamivudine-resistant strains, the drug may need to be replaced with other therapy. Work is currently being done to investigate lower resistance rates using combination antiviral therapies, such as the concurrent use of adefovir and lamivudine. Such strategies may also help to achieve higher rates of HBeAg seroconversion for patients.

Prevention of Mother-to-Child Transmission

The highest risk of becoming infected with hepatitis B is from a mother to her baby during childbirth. To protect the baby from becoming infected, it is important for all pregnant women who are infected with hepatitis B or who are carriers of the virus to tell the doctor so that the baby can be treated at birth to prevent any transmission of the virus. The standard care is for the baby to be given the first dose of the hepatitis B vaccination, the birth dose, and a course of the antiviral medicine such as lamivudine for a period of 4 weeks, starting within 12 hours and no later than 7 days after birth. Lamivudine can be used during the last few months of pregnancy, too. Studies have shown that when a mother who is receiving lamivudine to treat her hepatitis B infection has a high hepatitis B virus count in her blood, giving the birth dose of the hepatitis B vaccine and a course of lamivudine to the baby significantly reduces the actual transmission of hepatitis B virus to the baby.

Combination Therapy with Other Antiviral Agents

Lamivudine has been combined with several other antiviral medications, including adefovir, entecavir, and tenofovir. Antiviral combinations are often used when the hepatitis B virus is resistant to lamivudine. Resistance is particularly common in patients who have already been treated with the medication for an extended period of time**. The simultaneous use of lamivudine and adefovir was extensively researched and shown to be very effective in reducing the viral load and minimizing liver inflammation**. The combination of entecavir and lamivudine has also been used in certain clinical scenarios, but this approach has fallen out of favor because of the potential risk of developing resistance to entecavir. This lack of consensus was highlighted in a study comparing the effectiveness of initial lamivudine monotherapy with initial lamivudine/entecavir combination therapy, which found that while monotherapy was ultimately less successful, combination treatment did not deliver a significant difference in patient outcomes. When considering clinical applications, it is important to recognize that entecavir also has a lower resistance barrier, meaning that there may be a disadvantage to using lamivudine in the long term. Tenofovir, a newer and more effective antiviral agent that directly prevents the replication of viral DNA, has also been used in combination therapy with lamivudine. The data supporting the combined use of tenofovir and lamivudine is strong; studies have shown that long-term treatment can help to reverse advanced liver damage, normalize liver enzyme levels, and prevent complications associated with hep B, such as cirrhosis. Tenofovir is taken orally, once a day, with or without food. The combination of tenofovir and lamivudine is recommended by leading hepatology societies for healthcare professionals and has been shown to be more effective than monotherapy in certain cases, such as in patients who have already been exposed to other antiviral agents.

lamivudine hepatitis b

Safety and Side Effects

The most common side effect of lamivudine is headache, which can be experienced by up to 1 in 5 people taking this treatment. Headache can often be relieved with a simple painkiller such as paracetamol. Other side effects that are not considered serious but are more likely to occur from lamivudine include tiredness, nausea, vomiting, abdominal pain, and cough. These effects are uncommon and can affect between 1 in 10 to 1 in 100 people. There is also a small risk of developing inflammation of the pancreas (pancreatitis) while taking lamivudine. This condition can cause severe abdominal pain, back pain, and generally feeling very unwell. If you develop these symptoms while taking lamivudine, you should inform your doctor immediately. Lamivudine can also cause skin reactions. If you experience a rash, particularly with blistering or ulcers in the mouth, this may be a sign that you are allergic to the treatment, and you should stop taking it and let your doctor know straightaway. If you develop tiredness, a general feeling of being unwell, loss of appetite, nausea (feeling sick), yellowing of the skin or whites of the eyes, and dark urine, you should advise your doctor immediately as these can be signs of liver inflammation**. Lamivudine has been associated with a number of cases of lactic acidosis, a build-up of lactic acid in the body, particularly in people who have fatty liver disease** or other kinds of liver disease, such as hepatitis B or C. Lactic acidosis is a rare but serious side effect of lamivudine and is potentially fatal. If you develop any of the symptoms of lactic acidosis, such as persistent nausea, vomiting, and abdominal pain, you should stop taking the treatment and contact your doctor immediately. Lactic acidosis is generally seen in more advanced liver disease, where these enzymes may be raised. These serious side effects of lactic acidosis can occur suddenly or they can develop gradually over time. Allopurinol is a medicine that is used to reduce the production of uric acid.

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