The Study of Efficacy and Safe of Lamivudine in Patients with Severe Acute Hepatitis B

Objectives: Lamivudin has been approved for the treatment of chronic hepatitis B but experience with lamivudin treatment for acute severe hepatitis B is still limited. Fulminant hepatitis develops in 1% of patients with acute hepatitis B. Severe acute hepatitis B in immunocompetent patients may progress to fulminant hepatitis and death.

Aim: To evaluate the efficasy of lamivudine for the treatment of acute severe hepatitis B virus infection in imunocompetent adults in Clinic for infectious diseases Banja Luka.

Patients and methods: In the period of 2006-2024 years, 12 immunocompetent patients (4 women, 8 men, age 24-77 years) with severe acute hepatitis B were treated with lamivudin. All 12 patients fulfil at least two of the criteria for severe acute hepatitis B infection: 1. hepatic encephalopathy; 2. total bilirubin 210 micromole per litre; and severe coagulopathy (international normalized ratio-INR was 4.5 ± 6.4 or prothrombin time-PT < 40%). All patients had evidence of severe hepatocyte lysis. Nine patients had rapid increase of total bilirubin and contemporary decrease of alanine aminotransferase level, which escalate risk of development of fulminant hepatitis B. All patients received lamivudin at a dose 100 mg per day.

Results: Ten patients responded well to the treatment and their biochemical parameters improved rapidly. Within 1-6 months, the HBsAg was undetectable in 10 out of 12 investigated patients. Protective anti-HBs antibodies developed in 10 of them in 1-6 months. The corticosteroid therapy was short-term in 2 of 12 patients. Two patient developed fulminant hepatitis B and died after the lamivudine therapy was initiated. Lamivudine treatment was well tolerated in all patients.

Conclusion: Lamivudin induces a prompt clinical, biochemical and serological response in immunocompetent patients with severe acute hepatitis B. Early treatment with lamivudine probably decreases the risk of progression to fulminant hepatitis in patients with severe acute hepatitis B.

Objectives

The incidence of acute Hepatitis B (HBV) is largely reduced during the last 25 years as a results of the use of vaccination and routine blood donor screening [1].

Hepatitis B virus infection has three possible outcomes, as follows: acute course with complete recovery and immunity from reinfection, fulminant hepatitis with liver failure and chronic infection with virus persistence.

Acute Viral Hepatitis B (AVH-B) is successfully cleared in more than 95% of immunocompetent patients. Acute Hepatitis B virus infection may take a severe course, which can eventually lead to fulminant hepatic failure in about 1% of all cases with acute hepatitis. Hepatitis B virus infection is one of the most frequent causes of fulminant hepatic failure with mortality rate of up to 80% [2]. Orthotopic liver transplantation has been the only established treatment for fulminant hepatitis B, but in our country this procedure is inpossible to achieve.

The mode of transmission of HBV infection is limited to sexual intercourses, intravenous drug users, in patients undergoing dental therapy, acupuncture, piercing and tatooing. Most symptomatic patients recover and treatment is not necessary, when there are signs of severe liver failure, treatment is recommended in order to reduce the risk of progression to fulminant or subfulminant hepatitis and the need of emergency liver transplantation [3].

Lamivudine is a oral nucleoside analogue with potent inhibitory effect on hepatitis B virus replication. Lamivudine has been established as a safe and effective antiviral agent for the treatment of chronic HBV hepatitis, but expirience with lamivudine treatment for acute severe Hepatitis B is still limite [4,5]. The reports have been published regarding lamivudine treatment in acute hepatitis B are very rare. Lamivudine is a nucleoside analog that acts against the hepatitis B virus. Lamivudine is metabolized intracellularly to the active lamivudine 5'-triphosphate. Lamivudine is metabolized in both infected and uninfected cells to the triphosphate derivative, which is the active form of the parent compound. The intracellular half-life of triphosphate in hepatocytes is 17-19 hours in vitro. Lamivudine triphosphate acts as a substrate for HBV viral polymerase. Creation of new viral DNA is blocked by incorporation of lamivudine triphosphate into the chain and consequent chain termination [6].

Aim

The aim of present study was to evaluate the efficasy of lamivudine in treating immunocompetent adults with severe acute hepatitis B virus infection in Department for infectious diseases Banja Luka.

We report our experience on treament with lamivudine in a series of 12 patients with severe acute HBV infection.

Patients and methods

This study was a retrospective study. In the period of 2006-2024 years, 12 immunocompetent patients in Department for infecious diseases in Banja Luka, Bosnia and Hercegovina were diagnosed acute svere hepatitis B.

The diagnosis was based on recent onset of jaundice and other typical symptoms and biohemical, and virologycal findings. Laboratory test results demonstrated elevated aminotransferase levels, hyperbilirubinemia, prolonged protrombin time, and detection of serum HBsAg, Hepatitis e Antigen (HBeAg), Imunoglobin M Antibody to Hepatitis B core Antigen (IgM HBcAb). None had a history of hepatotoxic drug intake or alcohol use.

Unfortunately we did not demonstrate quantitative HBV DNA by polymerase chain reaction, because tehnical problem in our Clinical center.

Patients were considered to have severe acute hepatitis B if they fulfilled two of the following criteria: 1. hepatic encephalopathy; 2. serum bilirubin equal to or more than 10.0 mg/dL; 3. International Normalized Ratio (INR) more than or equal to 1.6 or prothrombin time-PT < 40% [8,9]. All patients received lamivudine at a dose 100 mg per day.

They were closely monitored during treatment for clinical evidence and grade of hepatic encephalopathy, impaired coagulation and serum liver enzyme and bilirubin levels every week for the first month and then montly. HBsAg, HBeAg, IgM anti-HBc, HBsAb and HBeAb were tested by commercially available enzyme-linked immunoassays and were checked every month for the next 6 month and HBsAb titers were checked at 6 and 12 months. The accepted criteria for defining clinical and serologic recovery from acute hepatitis B are clearance of circulating hepatitis B surface antigen (HBsAg) and appearance of the antibodies to HBsAg (anti-HBs), with normalization of serum aminotransferases [7,9-11].

There were 8 man and 4 women with a median age of 43.1 (range, 24-77) years. All patients were not evidence of pre-existing liver diseases. The mode of HBV transmission predominantly by sexual contact or percutaneous exposure (Table 1). All 12 patients fulffil at least two of three criteria for severe acute hepatitis B infection. We started lamivudine at a dosage of 100 mg daily, becouse all patients had evidens of severe hepatocyte lysis (alanin aminotransferase, total serum biliribin).

Laboratory test demonstrated elevated aminotransferase levels, hyper-bilirubinemia, predominantly direct, prolonged protrombin time and normal ammonia and albumin values. Alanine-Aminotransferase (ALT) was elevated above upper limit of normal rang between 819-6964 IU/L. Falling aminotransferases in combination with deterioration of prothrombin time usually indicates decreasing liver cell function and progression to liver failure. Patients had evidence of severe hepatocyte lysis. Some of patients had rapid increase of total bilirubin and contemporary decrease of alanine aminotransferase level, which escalate risk of development of fulminant hepatitis B. All patients had severe coagulopathy, and 11 patients had grade 1-4 encephalopathy (Table 2).

Serologic tests were positive for Hepatitis B surface Antigen (HbsAg), IgM Antibody to Hepatitis B core Antigen (IgM HBc Ab) and Hepatitis B e Antigen (HBeAg). All patients were serum HBsAg and IgM HBc Ab positive, 11 patients HBeAg positive. Test for IgM antibodies to hepatitis A virus, antibodies to hepatitis C virus and antibodies to hepatitis delta virus were all negative.

At this juncture, because of the progressive clinical and biohemical deterioration and the threat of hepatic failure, we administered lamivudine within 2-30 days of onset of illness at a dosage of 100 mg daily after informed consent had been obtained (Table 3).

Ten patients responded well to the treatment and their biochemical parameters improved rapidly. Encephalopathy disappeared within 3 days of treatment and prothrombin time normalised in all of patients within ten days. The complete normalisation of aminotransferase and bilirubinemia occurred on average after 5.5 weeks and 6 month. Two patients died after two days of treatment with lamivudine.

All HBeAg positive patients lost e-antigen and seronverted to HBeAb, and loss HBeAg within six month from the start of treatment and all of patients developed anti HBs at protective titre (> 10 mU/ml). Lamivudine treatment was continued until HBsAg was cleared.

Lamivudine was discontinued after six months in all the patients. In addition, six months after lamivudine was discontinued the patients remained well with normal results on liver-function tests. Five of all patients cleared HBV DNA (evaluated by PCR).

The corticosteroid therapy was short-term in 2 of 12 patients. two patients died of fulminant hepatic failure after the lamivudine therapy was initiated. Lamivudine treatment was well tolerated in all patients (Table 4).

In the present study, we administered lamivudine 100 mg daily over a short term (1-6 months) to 12 patients who met strict criteria for acute severe hepatitis B infection. A prompt clinical, biohemical, serological response was noted. Tillman et al reported that lamivudine treatment led to fast recovery with the potential to prevent liver failure and liver transplantation when administrated early enough. All tested patients lost serum HBsAg, and developed protective anti HBs titer (100% seroconverted) [8].

Unfortunately, there is not much literature on the role of antiviral therapy in severe acute hepatitis B.

In a small study, 3 patients with acute hepatitis B were treated with lamivudine 150 mg daily. In all the patients, serum HBV DNA became undetectable, and HBsAg and HBeAg disappeared.

Kumar M, et al. reported ″ In conclusion, although lamivudine caused a greater decrease in HBV DNA levels in patients with acute hepatitis B, it did not produce significant biochemical and clinical improvement compared to that in patients who received the placebo″. In a case report, a 74-year-old patient with acute hepatitis B and hepatic encephalopathy responded to lamivudine with the disappearance of serum HBsAg [5].

In a study of 46 patients with severe acute hepatitis B 3 months after lamivudine treatment, serum HBV DNA became undetectable in all the patients, and anti-HBe became positive in 87.5% of the patients [7].

In another study, 15 patients with severe acute HBV infection were treated with lamivudine 100 mg daily for 3-6 months, with 5 patients having grade 1-4 encephalopathy prior to onset of treatment. Thirteen (86.6%) patients responded. Encephalopathy disappeared within 3 days of treatment. Serum HBV DNA became undetectable within 4 weeks, and liver enzymes normalized within 8 weeks. Anti-HBe developed in 9 of 11 HBeAg-positive patients within 12 weeks. [8].

Severe or fulminant acute hepatitis B generally do not evolve to a chronic disease, since the immune response that causes liver damage also leads to the viral clearance. In this setting, with the use of nucleoside analogues we obtained a prompt hepatic biochemical and functional improvement, which probably enforced the ongoing process of recovery. Furthermore, we reduced the risk of fatal outcome which can occur in some of these patients [9,10].

In light of our obtained results, the only ethical choice in patients with severe and fulminant acute hepatitis B seems to be the treatment lamivudine in our country. Orthotopic liver transplantation is unpossible mission in our country and other countries ex-Yugoslavia [9,11].

Many authors have suggested the need for a large placebo-controlled study. This study is retrospective, and the number of our patients was limited, but in our experience, treatment with lamivudine for severe and fulminant hepatitis B is certainly indicated. A large rondomized controlled, double-blind prospective study with a larger number of patients is needed.

Lamivudine induces a prompt clinical, biochemical and serological response in immunocompetent patients with severe acute hepatitis B. Early treatment with lamivudine probably decreases the risk of progression to fulminant hepatitis in patients with severe acute hepatitis B.

Lamivudin can be used safely in acute liver failure. Further investigation with randomized prospective trials for the optimal use of the drug in this. We consider that lamivudine is worth administering to patients with fulminant hepatitis B.

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