Cost-effectiveness analysis of lamivudine and adefovir dipivoxil in the treatment of patients with HBeAg-negative chronic hepatitis B

AIM: To estimate the cost-effectiveness over a 4-year duration of lamivudine and adefovir dipivoxil for patients with hepatitis B 'e' antigen-negative chronic hepatitis B. METHODS: A decision analysis model has been used to perform a cost-effectiveness analysis of lamivudine and adefovir dipivoxil from the perspective of the Spanish Public Health System. Data were obtained from clinical trials. RESULTS: For the base-case, the total estimated cost per patient treated with lamivudine or adefovir dipivoxil for 4 years was 11,457 and 21,939 respectively. Virological response at year 4 for the lamivudine arm was 40.4% and 78.0% for the adefovir dipivoxil arm. The average cost-effectiveness ratio (cost per responding patient at year 4) was 28,375 for the lamivudine arm and 28,132 for the adefovir dipivoxil arm. The incremental cost-effectiveness ratio of adefovir dipivoxil vs. lamivudine (cost per additional responding patient with adefovir dipivoxil) was 27,872, demonstrating that this cost was slightly lower than the average cost-effectiveness ratios of adefovir dipivoxil or lamivudine. The sensitivity analysis demonstrated that the factors that most influence the cost-effectiveness were the response to adefovir dipivoxil and lamivudine at year 4. CONCLUSION: Long-term treatment with adefovir dipivoxil is a cost-effective strategy in patients with chronic hepatitis B 'e' antigen-negative hepatitis.     

Mutations in the conserved woodchuck hepatitis virus polymerase FLLA and YMDD regions conferring resistance to lamivudine

During more than 104 weeks of treatment with lamivudine (3TC) in chronic woodchuck hepatitis virus (WHV) carrier woodchucks, viral recrudescence occurred. Analysis of WHV DNA polymerase from woodchuck serum samples by PCR followed by DNA sequencing demonstrated that all samples were wild type at the conserved YMDD motif in domain C. Four of the six 3TC-treated woodchucks showed a mixture of the wild-type Ala (GCT) and the mutant Thr (ACT) at the conserved amino acid residue 566 (FLLA) in domain B of the WHV polymerase region. The appearance of the A566T mutation was temporally associated with viral recrudescence. This change is analogous with the amino acid 181 (FLLA) in HBV where 3TC selects for a change from Ala to Thr in humans. In the woodchuck, the Ala to Thr change in the polymerase gene results in a mutation of the WHV surface protein (amino acid 377) from Trp (TGG) to an opal codon (TGA), which may prematurely terminates the polypeptide. Three WHV molecular infectious clones were constructed to study this mutation in greater detail in vitro: A566T, analogous to A181T in HBV; M589V, analogous to the M204V in HBV; and the double mutant A566T/M589V, analogous to A181T/M204V in HBV. These mutants exhibited drug-sensitivity and replication profiles that paralleled those reported for analogous HBV variants. In transfected Huh7 cells, WHV containing the M589V mutation conferred at least 100-fold increased resistance to 3TC, but replicated approximately 5-fold less efficiently than wild-type virus as judged by both extracellular virus production and intracellular DNA replicative forms. In contrast, A566T mutant was approximately 10-fold more resistant to 3TC, replicated intracellularly as well as wild type, but produced 10-fold lower levels of virions than wild type. These findings are consistent with the observation that the A566T mutation alters the overlapping WHV surface antigen reading frame. WHV carrying mutations in the conserved YMDD motif, while not directly selected during lamivudine therapy in WHV carrier woodchucks, are replication competent in cell culture indicating the potential for their emergence in treated animals. These results further illustrate the utility of the WHV/woodchuck model to studies of HBV-drug resistance.     

Clinical reactivation during lamivudine treatment correlates with mutations in the precore/core promoter and polymerase regions of hepatitis B virus in patients with anti-hepatitis B e-positive chronic hepatitis

BACKGROUND: Drug-resistant mutants may emerge in patients with chronic hepatitis B receiving lamivudine therapy. AIM: To evaluate whether different viral mutational patterns may be associated with clinical reactivation during lamivudine treatment in patients with chronic B hepatitis. METHODS: Eight anti-hepatitis B e-positive patients with (group A) and 14 patients without clinical exacerbation (five anti-hepatitis B e-positive, group B1; nine hepatitis B e antigen-positive, group B2) during lamivudine treatment were investigated. RESULTS: 'Polymerase region': M204V/I variants were found in all group A patients, but in none of group B1 (P=0.0007) and in four of nine of group B2 (44%; P=0.02) patients. The L180M substitution was detected in four of eight (50%) of group A and in none of groups B1 and B2. 'Core promoter': the double basic core promoter (A1762T/G1764A) variant was detected in seven of eight (87%) of group A and in one of five (20%; P=0.03) of group B1 and one of nine (11%; P=0.002) of group B2 patients. 'Precore': the G1896A stop codon mutation was present in seven of eight (87%) of group A and in zero of five (P=0.004) of group B1 and one of nine (11%; P=0.002) of group B2. CONCLUSIONS: Different mutational patterns were observed in the lamivudine-treated patients with and without exacerbation. There was an association of the basic core promoter and stop codon mutations with lamivudine resistance in patients with disease exacerbation.     

Adefovir dipivoxil added to ongoing lamivudine therapy in patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B

BACKGROUND: Long-term treatment with lamivudine is required to control viral replication in patients with hepatitis B e antigen-negative chronic hepatitis B, but is associated with a high rate of viral resistance. The role of adefovir dipivoxil in these patients has not been definitively evaluated. AIM: To address the role of adefovir in the management of patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B. METHODS: Patients were assigned to receive adefovir 10 mg once daily plus ongoing lamivudine 100 mg once daily for 52 weeks. The primary end point was reduction in serum hepatitis B virus DNA level (hepatitis B virus DNA response). Secondary end points included the proportion of patients with undetectable hepatitis B virus DNA at week 52 (complete virological response) and the percentage of patients with normalization of alanine transferase level at week 52 (biochemical response). RESULTS: A total of 49 consecutive patients were enrolled in this study. After 52 weeks of treatment, all patients had an hepatitis B virus DNA response and 57.1% had complete virological response. Biochemical response occurred in 75.6% of patients. CONCLUSIONS: Administration of adefovir in patients with lamivudine-resistant chronic hepatitis B results in significant suppression of viral replication. Nevertheless, continuous therapy will probably be needed in order to maintain remission in these patients.     

Viral nucleotide changes in asymptomatic hepatitis B carriers undergoing interferon treatment

Background: Interferon might induce mutation in regions of hepatitis B virus DNA that encode for immunologic target of cytotoxic T lymphocytes.
Aim: To investigate the short-term effect of steroid priming and interferon therapy on hepatitis B virus, we followed the nucleotide changes in the precore and core region of hepatitis B virus DNA in seven healthy asymptomatic carriers who underwent steroid priming followed by recombinant alpha interferon for 3 months.
Methods: Hepatitis B virus DNA from serial sera of the patients were polymerase chain reaction-amplified, and the precore and core region directly sequenced and analysed.
Results: Analysis revealed no serial changes in the hepatitis B virus nucleotide sequence in any of the patients.
Conclusions: Steroid priming and short-term treatment with interferon in healthy asymptomatic patients does not select for hepatitis B virus with mutations in the precore and core region.     

Liver histology of Asian patients with chronic hepatitis B on prolonged lamivudine therapy

BACKGROUND: Long-term effect of YMDD mutations on liver histology in Chinese hepatitis B patients is unknown. AIM: To examine the effect of prolonged lamivudine treatment on liver histology in Chinese patients with and without YMDD mutations. METHODS: Liver histology was assessed in 85 patients on long-term lamivudine at baseline and year 1, and at year 3 for 25 patients. RESULTS: Comparing patients with and without YMDD mutations at year 1, the former had higher baseline median necroinflammatory (11 vs. six respectively, P = 0.014) and fibrosis scores (three vs. one respectively, P = 0.001). The proportion of patients with improvement in necroinflammation and worsening of fibrosis was comparable for patients with and without YMDD mutations at year 1 (57.1%, 14.3% vs. 55%, 15% respectively) and year 3 (57.9%, 26.3% vs. 50%, 16.7% respectively). Comparing the histology at year 1 and 3, more patients with YMDD mutations developing after year 1 had worsening of necroinflammation than patients with persistent YMDD wild type (53.8% vs. 25% respectively). CONCLUSIONS: Patients who developed YMDD mutations had higher baseline histological scores. With YMDD mutations, the liver histology became less favourable after 3 years than at the first year, although there was still improvement when compared with that at baseline.     

HBV-前C区基因变异与乙肝病毒复制的相关性

目的 研究乙型肝炎病毒(HBV)前C区G1896A变异与乙肝病毒复制的相关性.方法 选取38例慢性轻度,57例慢性中度,29例慢性重度的乙型肝炎患者为研究对象.采用突变特异PCR技术检测HBV前C基因nt1896位点突变情况,并对血清中HBVDNA进行测序.同时检测乙型肝炎病毒HBeAg/抗-Hbe、HBVDNA定量、肝纤维化指标.结果 (1)抗Hbe阳性者在单纯变异株感染的慢性乙型肝炎患者中所占的比例(84.61%)高于单纯野生株感染者(24.32%).(2)随着变异株感染率的增加,HBVDNA的含量增高.(3)随着变异株感染率增加,肝脏纤维化分期的逐渐加重.结论 前C区G1896A变异与乙肝病毒的复制程度相关.     

慢性重型乙型肝炎患者的乙型肝炎病毒C基因启动子和前C基因变异及与e抗原系统的关系

目的 研究慢性重型乙型肝炎患血清的HBV C基因启动子(CP)和前C基因变异情况。方法 通过DNA扩增、基因序列分析检测75例慢性乙型肝炎(CHB)和14例慢性重型乙肝(CSH)患血清的EIBV CP和前C基因序列，通过微粒子发光法定量检测血清中HBeAg的含量及通过荧光定量PCR技术定量检测血清中的HBV DNA。结果 (1)前C终止变异(nt1896G→A)在CASH组中的发生率显高于CHB组(71．4％和26．7％)；CP双变异(nt1762A→T和1764G→A)则在CASH组和CHB组的发生率无显差异(42．9％和48．0％)。(2)CSH组的HBeAg含量显低于CHB组；CSH组的HBeAb阳性率则显高于CHB组(71．4％和32．0％)。(3)CSH组和CHB组的HBV DNA定量则无明显差异。结论 前C终止变异，对e系统有明显影响，与CSH的发病有关。     

乙型肝炎病毒基因突变及耐药的研究

目的　研究拉咪呋啶在治疗乙型肝炎过程中乙型肝炎病毒基因突变与耐药的关系。方法　选择 1 4 9例服用拉咪呋啶用药 1年后 ,且 HBV DNA含量持续维持在较高水平或 DNA含量有反跳现象的乙型肝炎患者 ,留取服药前和服药 1年后的两份血清 ,分别作 YVDD、YIDD、HBV M的检测 ,同时设置 2 0例未服用拉咪呋啶乙型肝炎患者为对照组。结果　在实验组 1 4 9例中有 70 % YVDD或 YIDD阳性 ,对照组无 1例阳性。HBV M,在 1 4 9例中有 1 2 %发生了三种模式的转化。结论　乙型肝炎病毒 P基因 C区 YMDD的突变与耐拉咪呋啶有直接关系     

Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 – 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in ～ 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-α. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 – 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.     

乙型肝炎病毒前C区及基本核心启动子区变异的临床研究

目的 研究慢性乙型肝炎病毒(HBV)前C区G1896A变异、基本核心启动子(BCP)A 1762T/G1764A变异及二者联合变异在HBeAg阴性和HBeAg阳性慢性乙型肝炎(CHB)患者中的变异特点及与病情进展的关系.方法 将120例HBV DNA阳性CHB患者分为A、B两组,A组为HBeAg阴性CHB患者60例,B组为HBeAg阳性CHB患者60例,用荧光定量PCR检测A、B两组HBV DNA水平,用直接测序法检测A、B两组前C区G1896A及BCP区A1762T/G1764A变异的发生率.根据前C区及BCP区测序结果又分为变异组和无变异组,分析前C区及BCP区变异发生与病情进展的关系.结果 120例HBV DNA阳性CHB患者中A组检出变异株47例,B组检出变异株15例,A组和B组CHB患者中G1896A变异检出率分别为40.0％和10.0％ (x2=14.40,P=0.000);A1762T/G 1764A变异检出率分别为38.3％和15.0％(x2=8.35,P=0.003);联合变异的检出率分别为21.7％和0％(x2=14.58,P=0.000).120例CHB患者中G1896A、A1762/G1764A、联合变异的变异组HBV DNA含量明显高于无变异组HBV DNA含量,P＜0.05,差异有统计学意义.HBeAg阴性CHB患者轻、中、重度不同病情中,G1896A变异、A1762T/G1764A变异及联合变异的变异组与无变异组比较,差异有统计学意义(P＜0.05).结论 (1 )HBV前C区G1896A变异和BCP区A1762T/G 1764A变异是导致HBeAg阴性、HBV DNA持续阳性的主要机制之一.(2) HBV前C区G1896A变异和BCP区A1762T/G 1764A变异可能加重HBeAg阴性CHB患者病情的发展.     

慢性乙肝患者HBV DNA载量与YMDD自然变异之间的相关性

目的探讨未经任何抗病毒药物治疗的慢性乙肝患者HBV DNA载量与YMDD自然变异之间的关系。方法筛选51例未经任何抗病毒药物治疗的慢性乙肝患者,检测HBV DNA载量与YMDD变异情况。结果 51例标本中检出YMDD变异株13例（25.5%）,其中YIDD变异1例,YVDD变异7例,共生变异（YIDD＋YVDD）5例;未检出YMDD变异株38例（74.5%）。结论未经任何抗病毒药物治疗的慢性乙肝患者存在YMDD自然变异,其自然变异的发生率与HBV DNA载量呈正相关。     

Four years of treatment with lamivudine: clinical and virological evaluations in HBe antigen-negative chronic hepatitis B

AIM: To evaluate the clinical and virological impact of the prolonged use of lamivudine in 94 patients with HBe antigen-negative chronic hepatitis B. METHODS: Initial virological and biochemical responses were obtained in 84 (89%) and in 83 (88%) patients respectively. RESULTS: The virological response peaked within the first 12 months, but diminished to 39% at 48 months because of drug resistance. Overall a virological breakthrough developed in 44 patients (52.4%). After virological breakthrough, the actuarial probability of maintaining biochemical remission diminished to 15% at 24 months and 0% at 29 months. There was no response in 10.6%. Polymerase gene mutations were observed in 82.5% of virological breakthroughs but also in 75% of the non-responders. Overall 7.4% of patients developed a hepatocellular carcinoma. CONCLUSION: Almost 90% of patients responded initially to lamivudine but the emergence of drug resistance progressively reduced the rate of virological remission to 39% at the fourth year of therapy. YMDD mutants explained the 75% of lamivudine resistances and were also selected very early in non-responders. Although the biochemical response is invariably lost within 29 months of the YMDD mutant's duration, the clinical outcome was benign despite severe postvirological breakthrough hepatitic flares in about 12% of cases.     

乙型肝炎病毒X蛋白截断变异对HBeAg含量和HBV DNA定量的影响

目的研究乙型肝炎病毒(HBV)X蛋白截断变异对HBeAg含量和HBV DNA定量的影响。方法通过DNA扩增、基因序列分析检测75例慢性乙肝和14例慢性重型乙肝和34例肝硬化病人血清的HBV X基因和前C基因序列,通过微粒子发光法定量检测血清中HBeAg的含量,以及通过荧光定量PCR技术定量检测血清中的HBVDNA。结果(1)9例检出X蛋白截断变异。(2)同无变异组比较,X蛋白截断变异组、CP双变异(nt 1762A→T,1764G→A)组和前C基因终止变异(nt 1896G→A)组的HBeAg含量均显著下降,其中前C终止变异组HBeAg血清转换最为明显。(3)同无变异组比较,X蛋白截断变异组的HBV DNA含量无明显差异。结论X蛋白截断变异影响HBeAg表达,但影响程度不及前C基因终止变异;X蛋白截断变异对HBV DNA定量无明显影响。     

Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 - 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in approximately 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-alpha. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 - 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.     

Clinical course after stopping lamivudine in chronic hepatitis B patients with lamivudine-resistant mutants

BACKGROUND: The efficacy of lamivudine therapy in chronic hepatitis B is well established. However, drug-resistant YMDD mutants emerge with extended therapy. This may result in the resurgence of viral replication, the return of hepatitis and histological deterioration. AIM: To study the safety of stopping lamivudine when the drug is no longer effective. METHODS: In the 5-year Asian Lamivudine Study, 34 patients from a single centre were included in this study. They had harboured YMDD mutants for at least 2 years. Lamivudine was discontinued and they were followed up at regular intervals. Clinical symptoms, liver biochemistry and viral serology were monitored. RESULTS: In a median follow-up of 20 months after stopping lamivudine (range, 7-39 months), 20 of the 34 patients (58.8%) had elevated alanine aminotransferase (ALT), 13 patients (38.2%) had elevated ALT one to five times the upper limit of normal and seven patients (20.6%) had an ALT flare (ALT more than five times the upper limit of normal with detectable hepatitis B virus DNA). There was no liver decompensation. ALT flare could be predicted by ALT over twice the upper limit of normal at the time of stopping lamivudine (P = 0.037). CONCLUSIONS: It is relatively safe to stop lamivudine after YMDD mutants have emerged. ALT levels greater than or equal to twice the upper limit of normal at the time of stopping lamivudine have a higher risk for ALT flare.     

Impact of precore and core promoter mutations on hepatic histology in patients with chronic hepatitis B

BACKGROUND: The details of liver histology of patients with precore and core promoter mutations are still not clear. AIM: To determine the role of precore and core promoter mutations in liver histology in Chinese patients with chronic hepatitis B. PATIENTS AND METHODS: Intrahepatic hepatitis B virus DNA (by COBAS Amplicor hepatitis B virus Monitor test) and precore and core promoter mutations (by a line probe assay) were measured in 54 chronic hepatitis B patients. Expression of hepatitis B core antigen, hepatitis B e antigen and hepatitis B surface antigen was determined by immunohistological staining. Histological activity index was scored according to Knodell's criteria. RESULTS: Compared with patients without core promoter mutations, patients with core promoter mutations had more severe intrahepatic inflammation and fibrosis, and more cytoplasmic expression of hepatitis B core antigen (P = 0.028). No such differences were found in patients with and without precore mutations. Logistic regression showed that core promoter mutations were independently associated with cytoplasmic expression of hepatitis B core antigen (P = 0.026). Intrahepatic hepatitis B virus DNA levels correlated with serum hepatitis B virus DNA levels (r = 0.71, P < 0.001) and the percentage of hepatitis B core antigen-positive hepatocytes (r = 0.37, P = 0.047), but had no correlation with serum alanine aminotransferase levels nor the degree of inflammation and fibrosis. CONCLUSIONS: Patients with core promoter mutations had more severe inflammation and fibrosis, and more frequent cytoplasmic expression of hepatitis B core antigen. This suggested that core promoter mutations might cause more serious liver disease.