拉米＋疫苗治疗HBV失败一例

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Late Failure of Combined Recombinant Hepatitis B Vaccine and Lamivudine in Treatment of a Patient with Chronic Hepatitis B
Posted 05/25/2004

Kendal Yalcin, MD; Halil Degertekin, MD; Mithat Bozdayi, MD, PHD

Abstract and Introduction
Abstract
We report the first case of a woman having chronic hepatitis B treated with a combination therapy of recombinant hepatitis B vaccine and lamivudine for 18 months. The main aims of such a combined therapy were to assess whether the concomitant anti-hepatitis B virus (HBV) vaccination might prevent the emergence of a mutant HBV and lead to sustained hepatitis B e antigen seroconversion with undetectable serum HBV DNA. The data from the present case demonstrated that combination of anti-HBV vaccine and lamivudine did not eliminate viral DNA despite prolonged treatment and did not have any effect on preventing resistant-type HBV. Although the combined therapy failed to reach the therapeutic endpoints, it concerned a single and unique patient. Hepatitis B vaccine and lamivudine for HBV treatment should be further investigated in randomized controlled trials.

Introduction
The development of new nucleoside analogues that inhibit hepatitis B virus (HBV) reverse-transcriptase activity, such as lamivudine, famciclovir, and others, has recently provided an alternative to interferon therapy for chronic hepatitis B.[1] However, antiviral therapy of HBV infection faces the problem of viral persistence and resistance to nucleoside analogues.[2] In view of the limited efficacy of lamivudine monotherapy for chronic hepatitis B infection, the capacity of new antiviral strategies based on combination of new inhibitors, including adefovir and entecavir, with immune modulators needs to be further evaluated to prevent the emergence of resistant viral strains.

Administration of vaccine containing hepatitis B surface antigen (HBsAg) alone has shown complete clearance or reduction of HBV DNA, clearance of hepatitis B e antigen (HBeAg), and development of antibodies to hepatitis B e antigen (anti-HBe) in more than one third of chronic HBV carriers.[3] Thus, vaccination could be the therapeutic option with the lowest cost and potentially the greatest benefit,[4] because boosting immune system response to HBV vaccine may offer an advantage to some patients who are infected with the virus and receive lamivudine treatment for it. For this purpose, we aimed to evaluate the efficacy of therapeutic immunostimulation in a chronic hepatitis B patient who received 18 monthly intramuscular vaccinations with HBsAg/pre-S2 in combination with daily lamivudine.

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Case Report
A 28-year-old female was admitted to our department with complaints of fatigue and malaise. She was known to have been a chronic HBsAg carrier for 6 years and had never received any antiviral treatment. At her first admission, she presented with elevated levels of amin otransferases, with detectable serum HBsAg, HBeAg, and HBV DNA. She had no detectable antibodies to hepatitis C virus, hepatitis D virus, or human immunodeficiency virus. After a 6-month period of screening, a liver biopsy was performed. Histologic diagnosis of chronic hepatitis B was made according to the Knodell scoring system with a histologic activity index of grade 7/18 and Stage 0/4.

The patient was treated with synchronous combination of recombinant hepatitis B vaccine and lamivudine (100 mg/d administered PO) for 12 months. Twelve standard injections of Genhevac-B vaccine (Pasteur Merieux, Lyon, France) were given in the deltoid muscle at 1-month intervals. Each 0.5-mL dose of vaccine contains 20 µg of HBsAg and pre-S2 protein, with aluminum hydroxide as adjuvant. At baseline, alanine aminotransferase (ALT) was 74 IU/L, aspartate aminotransferase was 58 IU/L, and serum HBV DNA level was 5,241 pg/mL as determined by liquid hybridization assay (Digene Hybride Capture System, Beltsville, MD). The efficacy of combination treatment with specific anti-HBV vaccine and lamivudine was defined by loss of serum HBV DNA, HBeAg seroconversion, and ALT normalization. The secondary endpoint of combination therapy was prevention of viral breakthrough and emergence of resistant-type HBV. Postvaccination follow-up lasted 24 months after the first dose.

Although the serum HBV DNA level showed a sharp decrease in the first month of treatment, the patient had detectable HBV DNA until the ninth month of therapy. At Months 9 and 10 of therapy, the patient became seronegative for serum HBV DNA by polymerase chain reaction (Techne [Cambridge], Ltd., Duxford, UK), with the lower sensitivity of approximately 103 to 104 copies/mL. Unfor-tunately, serum HBV DNA reappeared at month 11 of therapy. It was considered that the patient had viral breakthrough due to the newly occurring resistant-type HBV. At month 12, sequence analysis of HBV DNA polymerase gene (ABI 310 Genetic Analyser; Applied Biosystems, Foster City, CA) revealed an emergence of mutant virus with a methionine-to-valine substitution in the YMDD amino acid motif (M204V) and a change from leucine to methionine in the B domain of viral reverse transcriptase (L180M). After the occurrence of the YMDD mutation, the serum HBV DNA level increased, up to the level of 4,473 pg/mL at month 15.

The therapy was not discontinued, due to the emergence of the resistant strain and the patient received an additional second vaccination cycle, consisting of the intramuscular administration of six 20-µg doses of vaccine given monthly for 6 months in combination with lamivudine (100 mg/d). The patient again failed to respond to the second vaccination cycle according to the aforementioned definition (Fig. 1).

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[upload=gif]uploadImages/20048/2004891523112807.gif[/upload]

Figure 1. (click image to zoom) The 24-month course of the patient with the changes in serum HBV DNA and ALT levels. Diamonds indicate ALT (IU/L) and circles indicate HBV DNA (pg/ml).

Moreover, the patient achieved neither HBeAg seroconversion to anti-HBe nor normalization of ALT during the entire period of treatment, except for month 12, when her ALT concentration decreased to 33 IU/L (the upper limit of normal was 35 IU/L). At the end of treatment, at month 18, ALT was 136 IU/L, aspartate aminotransferase was 72 IU/L, and HBV DNA was 2,963 pg/mL. At the 6-month follow-up, there were no changes in the virologic and biochemical status of the patient. A second biopsy, performed at month 19, revealed a four-point decrease in histologic necroinflammatory score compared with the initial biopsy. No serious adverse events with signs of disease related to immune complex formation were observed.

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Discussion
Lamivudine can overcome cytotoxic T-lymphocyte hyporesponsiveness,[5,6] and this may serve as a bridge to subsequent HBV-specific immune therapies, which may cause changes in the balance between viral replication and the host's immune response in favor of eradication of chronic HBV infection. In contrast, therapeutic vaccination may act better and more safely under conditions of low viremia. It was shown that therapeutic vaccination of chronically infected woodchucks under conditions of low viremia shifts the cytokine profile against viral antigens toward Th0/Th1.[7] In an open-labeled trial, it was also reported that inoculating those patients with vaccine containing HBsAg creates a situation where immune system cells secrete beneficial cytokines, augmenting the effects of lamivudine therapy.[8] For this purpose, we aimed to evaluate therapeutic immunostimulation in a chronic hepatitis B patient who received 18 monthly intramuscular vaccinations with HBsAg/pre-S2 in combination with daily lamivudine, and it was hoped that the immune cytotoxic restoration associated with lamivudine therapy would be synergistically added to the specific proliferative responses associated with vaccination.[9]

Usually, serum HBV DNA levels become undetectable within a few months of lamivudine therapy.[10] In the present case, HBV DNA levels were persistently detectable until the ninth month of therapy, and the patient did not normalize ALT activity during the entire period of therapy. In contrast to other studies, we failed to show any synergism between lamivudine therapy and vaccination.[7,8] In the European trial, two groups of chronic hepatitis B patients received combination HBV vaccine/lamivudine therapy or combination HBV vaccine/lamivudine/interleukin-2 therapy. After the therapy was stopped, seven of nine vaccine/lamivudine and two of five vaccine/lamivudine/interleukin-2 recipients had undetectable HBV DNA. Ultimately, four patients demonstrated viral clearance, although one experienced viral reactivation, with spontaneous clearance shortly thereafter.[8] In another uncontrolled trial, it was reported that simultaneous administration of interferon α and HBsAg vaccination in patients previously not responding to interferon alone appears to be a safe and well-tolerated procedure, and response rates are similar to or even higher than to interferon in naive patients.[11]

In the current case, there was a viral breakthrough at month 11, and sequence analysis of the reverse-transcriptase domain of the resistant viral strain revealed the selection of mutant virus (L180M). Thus, combination of lamivudine and anti-HBV vaccine therapy did not have any effect on preventing viral resistance, which is one of the main problems during lamivudine therapy that limits the efficacy of the drug. In addition, HBV vaccination administered after negativation of serum HBV DNA on treatment with lamivudine did not prevent viral multiplication relapse and did not induce HBeAg seroconversion. The clinical course of chronic hepatitis B in patients with lamivudine-resistant mutants is variable.[2] HBeAg seroconversion has been reported in approximately 25% of the patients who continued treatment after the detection of lamivudine-resistant mutants.[1] In the presented case, the additional 6-month course of combination therapy again did not have any beneficial effect on the prevention of the occurrence of breakthrough during therapy or on relapse after the emergence of the drug-resistant mutant. The patient did not experience any side effects-neither evidence for immune complex-mediated disease nor severe worsening of liver disease-during the period of vaccination or during the follow-up period, indicating the safety of therapeutic vaccinations.

Although it appears to be a safe and well-tolerated regimen, the data from the present case demonstrated that combination of anti-HBV vaccine and lamivudine did not eliminate viral DNA despite prolonged treatment and did not have any effect on preventing resistant-type HBV. However, due to the single-patient experience, no firm conclusions can be drawn concerning the combined effect of lamivudine administration and vaccination. Whether combination of reinforced specific vaccination and lamivudine might have an effect in limiting the occurrence of breakthrough during therapy and relapse after lamivudine discontinuation needs to be analyzed in further randomized trials.


Reprint Address

Reprint requests to Kendal Yalcin, MD, Division of Hepatology, Dicle University School of Medicine, 21280 Diyarbakir, Turkey. Email: [email protected]


  

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到底是只有一例失败还是都失败了呢，请告诉我。