Received Lamivudine Treatment Research Articles

Evaluation of chronic hepatitis B patients receiving lamivudine: Single center experience

Background/Aim: Lamivudine (LAM), which has been used for the treatment of Chronic Hepatitis (CHB) infection for many years, is now provided for short-time use to immunosuppressive patients due to resistance. We aimed to evaluate the current state and pandemic period routine follow-ups in patients who still used LAM today due to treatment or prophylaxis in terms of virologic or serologic treatment response. Methods: In this retrospective cohort study, we included 33 patients who received LAM treatment or prophylaxis due to CHB. Evaluations included patients’ serologic results for Hepatitis B, platelet counts, comprehensive metabolic panel, HBV DNA levels, ultrasonographic (USG) evaluation of the liver, and the number and duration of outpatient visits between 01.01.2020 and 31.12.2021. Results: Of all the patients, 51.5% (n=17) were males, and the average age was 57.3 (12.3) years. The median LAM treatment duration was found 10 (2.58) years. The ratio of receiving LAM due to immunosuppressive therapy was 27.27% (n=9). Except for HBV DNA-negative patients or patients with no accessed results, the virologic response rate of patients was found 60.7% (n=20). Within the study period, while Anti-Hbe seroconversion was found 3.2% (n=1), Anti-Hbs seroconversion was found 6.5% (n=2). One patient whose virologic response was not obtained, received the treatment without any alterations in the regimens. While the number of outpatient follow-ups in the study period was found 1.94 (0.24) on average, the duration between follow-ups was found 13.82 (12.8) months. Conclusion: It is pleasing to obtain virologic response and Anti-HBs, Anti-HBe seroconversion in patients with low resistance profile who receive the LAM treatment. While watchful waiting is recommended for patients receiving long-term LAM treatment, our retrospective analysis showed that planned outpatient follow-ups for every three months was done in longer intervals. The treatment is not altered in one patient whose virologic response was not obtained because of inadequate number of follow-ups within the study period. Since monitoring without having prolonged follow-up durations due to the pandemic is of importance in terms of preventing complications, we believe that there is a need for further studies on this issue.

The use of Chinese herbal medicines associated with reduced mortality in chronic hepatitis B patients receiving lamivudine treatment

Ethnopharmacological relevanceLamivudine associated mutation and resistance reduces the effect of anti-hepatitis B virus. Pharmacological studies in cell and animal model suggest that Chinese herbal medicines (CHMs) have anti-hepatitis B virus effect. Observational studies offer mixed results. The aim of this study was to evaluate the relation between the use of CHMs and outcome in patients with chronic hepatitis B receiving lamivudine treatment and further estimate the association of Jia-Wei-Xiao-Yao-Sang (JWXYS) use with mortality of those patients. Materials and methodsWe conducted a cohort study among patients age 20–90 years within a National Health Insurance Healthcare system. Information on the use of CHMs and covariates were obtained from Taiwan National Health Insurance Research Database. We used Cox proportional hazards models to estimate the hazard ratio and 95% confidence intervals (95% CI) for all-cause mortality among CHMs users compared to nonusers. ResultsAmong 1037 patients studied from 2004 to 2011, median follow-up time 5.3 years and 88 deaths were identified. During the study period, 49% of patients used CHMs and the median duration of use was 2.4 years. We found that significant difference on all-cause mortality among CHMs users (aHR=0.45, 95% CI: 0.27–0.76) compared to CHMs nonusers. All-cause mortality also differed by JWXYS use (aHR=0.26, 95% CI: 0.08–0.83). ConclusionsThis study reveals that the use of CHMs may lower the risk of death in patients with chronic hepatitis B receiving lamivudine treatment. Further randomized-controlled trials are required to validate these findings.

Circulating full-length cytokeratin 18 for predicting prognosis of hepatitis B virus-related acute-on-chronic liver failure patients with lamivudine treatment.

The predictive value of circulating full-length cytokeratin 18 (M65) on prognosis of hepatitis B virus-related liver failure is still not well investigated. The aim of this study was to reveal the association between serum M65 levels and outcomes of hepatitis B virus-related acute-on-chronic liver failure, and to further clarify clinical significance of M65 in lamivudine treatment. Ninety-six patients with hepatitis B virus-related acute-on-chronic liver failure were recruited between January 2011 and December 2013, and 52 of them received lamivudine treatment. Blood were obtained from participants at admission, and M65 were determined by enzyme-linked immunosorbent assay. Other necessary data were collected from medical records. The liver failure patients were divided into high and low level groups according to the serum M65 levels. After 24-week follow up, survival incidences were significantly higher in the low level group than that in the high level group (odds ratio [OR] = 0.3, 95% confidence interval = 0.1-0.7). In addition, the survival incidences and albumin levels improved in the patients with lamivudine treatment compared with the patients without lamivudine treatment in the low level group (OR = 5.4, 95% CI = 1.1-26.0 and OR = 4.2, 95% CI = 1.3-13.2). A similar improvement was not observed in the high level group. The study suggested that the circulating M65 may serve as a relatively independent prognostic parameter for liver failure. If prospectively validated in further studies, M65 measurement may also be a useful method for optimizing antiviral therapy.

Telbivudin May Cause Increased Polineuropathy/Myopathy in Liver Transplant Recipients

Purpose: Liver transplantation (LT) is often complicated by chronic renal disease with multifactorial causes. Some recent studies have suggested that telbivudine treatment can contribute to provide an improvement on renal functions, compared with lamivudine in patients with hepatitis B virus (HBV)-related cirrhosis. This study was initiated to examine the effects of switching to telbivudine treatment on renal functions in LT recipients receiving lamivudine treatment for prophylaxis of HBV recurrence. Because of the high percentage of polyneuropathy and myopathy that we observed in the study group, we did an interim analysis, and report our preliminary 6-month results. Methods: Forty patients (35 men) with an average age of 57 years (SD ± 9.38), who had been transplanted for HBV-related cirrhosis were enrolled. All patients had a serum creatinine concentration more than the upper limit of the normal range. Creatinine clearance (CrCl) and modification of diet in renal disease (MDRD) formulation were used to estimate glomerular filtration rate. Serum creatinine kinase (CK) and myoglobin levels were monitored. Electrophysiological tests were performed if the patient had elevated CK and muscle pain and/or weakness. All patients continued their regular immunosuppressive medications. Results: Six-month data were available in 25 of 40 patients. Mean (± SD) of CrCl at baseline (CrCl0), 3-month (CrCl3), and 6-month (CrCl6) were: 53.42±21.19, 51.52±23.08, and 57.81±19.53, respectively. Mean (± SD) of MDRD at baseline (MDRD0), 3-month (MDRD3), and 6-month (MDRD6) were: 47.18±10.59, 48.06±12.89, and 51.67±12.99, respectively. No statistical difference was found between CrCl0 vs. CrCl3, CrCl0 vs. CrCl6, and MDRD0 vs. MDRD3, but the difference was significant between MDRD0 vs. MDRD6 (p=0.017). Of 10 patients who had elevated CK levels underwent electrophysiological tests, seven patients (18%) diagnosed polyneuropathy (n=5) or myopathy (n=2), with a median duration of 6 (range, 2-9) months after switching to telbivudine. Conclusion: Although telbivudine may provide a promising beneficial effect on renal functions in LT recipients, high polyneuropathy/myopathy rates observed in our study group indicate that it is necessary to be very careful with its use in LT settings.

Current Role of Lamivudine Regarding Therapeutic Response and Resistance in Children with Chronic Hepatitis B

PurposeTo identify the predictive factors of long-term therapeutic response or resistance to lamivudine treatment in children and adolescents with chronic hepatitis B.MethodsEighty one children and adolescents with chronic hepatitis B were included, who received lamivudine treatment for at least 6 months. Their condition was monitored for at least 12 months (12-88 months) thereafter. Twenty one (25.9%) were preschool children (age≤6). For patients who had developed HBeAg seroconversion or breakthrough, univariate and multivariate analyses were used to identify the effects of age, gender, pretreatment alanine aminotransferase (ALT) and hepatitis B virus DNA levels.ResultsHBeAg seroconversion occurred in 49 (60.5%) of the 81 patients after the initiation of the lamivudine therapy. In 65 patients whom were monitored for over 24 months, the seroconversion rate was significantly higher in younger patients (p=0.040), especially in those patients of preschool age (age≤6, p=0.031). The seroconversion rate was significantly higher in higher pretreatment ALT (p=0.003). The breakthrough occurred in 21 (25.9%) of the 81. The breakthrough rate was lower in younger aged patients (age≤6), and with higher pretreatment ALT levels, but no significant difference.ConclusionYounger age is a good predictor of HBeAg seroconversion in children with long-term lamivudine treatment as well as high pretreatment ALT levels.

High-Resolution Melting and Real-Time Pcr for Quantification and Detection of Drug-Resistant HBV Mutants in a Single Amplicon

Antiviral therapy by nucleoside/nucleotide analogues (NAs) effectively reduces HBV replication in chronic hepatitis B (CHB) patients. Because long-term NA treatments will eventually select for drug-resistant mutants, early detection of mutants and frequent monitoring of viral loads is crucial for successful NA therapy. Because no efficient test for one-tube quantification and qualification of various HBV-resistant mutants exists, we propose to use high-resolution melting (HRM) analysis in combination with real-time PCR to achieve this unmet need. We developed a single amplicon for detecting HBV mutants resistant to lamivudine (LMV), adefovir (ADV) and entecavir (ETV), which are commonly used for CHB treatment. Our design consists of two steps: real-time PCR for viral quantification, and hybridization probe HRM analysis for detection of specific drug-resistant mutants. Assay quantification was accurate (R=0.98) for viral loads from 10(3) to 10(9) copies/ml. HRM analysis produced distinct melting temperatures that clearly distinguished the mutants, rtM204V/I (LMV), rtA181V and rtN236T (ADV), and rtT184G and rtM250V (ETV), from their respective wild types. The assay detected mutants at only 10-25% of the HBV population. The clinical applicability of this assay was tested in a pilot study with serial samples from patients receiving LMV treatment. Flexibility, speed and cost-efficiency are additional benefits unique to our assay. The clinical sample results further support the feasibility of applying our design to frequent and long-term monitoring of CHB patients receiving NA treatments in the clinical setting.

Safety of lamivudine treatment for chronic hepatitis B in early pregnancy

To evaluate the safety of lamivudine (LAM) treatment for chronic hepatitis B in early pregnancy. A total of 92 pregnant women who received LAM treatment either before pregnancy or in early pregnancy were enrolled in this study. All of the pregnant women volunteered to take lamivudine during pregnancy and were not co-infected with hepatitis C virus, human immunodeficiency virus, cytomegalovirus, or other viruses. All infants received passive-active immunoprophylaxis with 200 IU hepatitis B immunoglobulin and three doses of 10 μg hepatitis B vaccines (0-1-6 mo) according to the guidelines for the prevention and treatment of chronic hepatitis B. Adverse events were observed throughout the entire pregnancy and perinatal period, and the effectiveness of lamivudine treatment for blocking mother-to-infant transmission of hepatitis B virus (HBV) was evaluated. All adverse events in mothers and infants during pregnancy and the perinatal period and the HBV mother-to-infant transmission blocking rate were compared with the literature. Among the 92 pregnant women, spontaneous abortions occurred in 11 cases, while 3 mothers had a second pregnancy after the initial abortion; 72 mothers delivered 73 live infants, of whom 68 infants were followed up for no less than 6 mo, and 12 mothers were still pregnant. During pregnancy, the main maternal adverse events were vaginitis (12/72, 16.7%), spontaneous abortion (11/95, 11.6%), and gestational diabetes (6/72, 8.3%); only one case had 1-2 degree elevation of the creatine kinase level (195 U/L). During the perinatal period, the main maternal adverse events were premature rupture of the membranes (8/72, 11.1%), preterm delivery (5/72, 6.9%), and meconium staining of the amniotic fluid (4/72, 5.6%). In addition, 2 infants were found to have congenital abnormalities; 1 had a scalp hemangioma that did not change in size until 7 mo, and the other had early cerebral palsy, but with rehabilitation training, the infant's motor functions became totally normal at 2 years of age. The incidence of adverse events among the mothers or abnormalities in the infants was not higher than that of normal mothers or HBV-infected mothers who did not receive lamivudine treatment. In only 2 cases, mother-to-infant transmission blocking failed; the blocking rate was 97.1% (66/68), which was higher than has been previously reported. Lamivudine treatment is safe for chronic HBV-infected pregnant mothers and their fetuses with a gestational age of less than 12 wk or throughout the entire pregnancy.

Molecular characterization of a novel entecavir mutation pattern isolated from a multi-drug refractory patient with chronic hepatitis B infection

Background Prolonged antiviral treatment results in selection and accumulation of resistant strains in quasispecies pool in hepatitis B virus (HBV) infection. Objectives The aim of this study was to characterise a novel HBV pattern which shows resistance to lamivudine, adefovir dipivoxil and entecavir using in vitro phenoyping assay. Study design A male 36 years old patient diagnosed with anti HBe-positive chronic hepatitis B (CHB) had received lamivudine treatment for 7 years following an initial unsuccessfull interferon treatment. The therapy had been switched to adefovir and then to entecavir when breakthrough occcured during each treatment. This led only to a temporary HBV DNA decline which soon was followed by viral breakthrough despite the lack of known entecavir resistance mutations. Patient died after 9 months of entecavir treatment from liver failure. A total of 434 clones from 6 different serum samples were analysed retrospectively. HBV genomes bearing mutation patterns suggestive of antiviral resistance were analysed by in vitro phenotyping assay. Results Dominance of a clone carrying L80LV, L91I, M204I, S219A, N238D, Y245H changes was detected in the last serum sample of the patient just before his death. This pattern displayed 30.4 fold resistance to entecavir when compared with the wild type HBV by in vitro phenotyping assay. Conclusion A novel mutation pattern showing a high degree of resistance to entecavir was documented. In this pattern, the S219A and Y245H mutations mainly seem to contribute to the emergence of ETV resistance.

The therapeutic response of antiviral therapy in HBsAg-positive renal transplant recipients and a long-term follow-up

Early prediction of lamivudine (LAM) response by individualized monitoring of serum HBV DNA like roadmap concept, and investigation of the outcome after LAM discontinuation in renal transplant recipients (RTRs) with chronic hepatitis B (CHB). We conducted a study on 19 RTRs with HBV infection receiving LAM treatment for 2years from 2004 to 2007. HBV DNA level was assessed at baseline, 12, 24, 52, and 104weeks after treatment. Risk factors of tyrosine-methionine-aspartate-aspartate (YMDD) mutation on treatment and relapse rate of HBV after LAM discontinuation were analyzed. HBV DNA levels became undetectable in 32, 37, 63, and 53% of patients after 12, 24, 52, and 104weeks of LAM treatment, respectively. Overall, three (16%) and five (33%) patients were detected with YMDD mutations at week 52 and 104, respectively. In the concept of roadmap, of the seven patients with inadequate virologic response (IAVR) at week 24, five had YMDD mutations. There was no significant association of YMDD mutations with age, gender, genotype, cirrhosis, HBeAg status, baseline HBV DNA, precore/core promoter mutations, and primary response, except IAVR at week 24 (P=0.001). The relapse rate of HBV after LAM discontinuation was high (75%) during a median follow-up of 65weeks. The rate of LAM resistance in RTRs is similar to immunocompetent CHB patients in a 2-year therapy. By roadmap concept, RTRs with IAVR require a change in therapy to prevent viral resistance. Relapse after LAM withdrawal is frequent. Long-term antiviral therapy is crucial for immunosuppressed patients.

Lamivudine treatment is associated with improved survival in fulminant hepatitis B

Fulminant hepatitis B is a clinical syndrome that results from massive necrosis of liver cells leading to the development of hepatic encephalopathy. The aim of this study was to evaluate the efficacy of lamivudine in patients with fulminant hepatitis B and study the prognostic factors. A matched retrospective cohort study using data on fulminant hepatitis B patients derived from our hospital database was conducted. Forty patients receiving lamivudine treatment were selected into the lamivudine treatment group with another 40 without lamivudine treatment studied as control. They were matched for sex, age and HBeAg status with lamivudine treatment group. The mortality of patients in two groups was compared. The influential factors on the mortality were studied by Cox proportional hazards model. The mortality of patients in the lamivudine group (n=38) was significantly lower than that of the control group (n=39) (63.2 vs. 84.6%; χ(2) =4.609, P=0.032). For patients without systemic inflammatory response syndrome (SIRS), the mortality of patients in the lamivudine group (n=25) was significantly lower than that of the control group (n=26) (52.0 vs. 80.8%; χ(2) =4.747, P=0.029). In multivariate Cox proportional hazards analyses, for patients without SIRS, age (P=0.037), ratio of total to direct bilirubin (P=0.008), treatment method (P=0.005) and the decline of hepatitis B virus (HBV) DNA load during therapy (P=0.019) were independent predictors of prognosis. Treatment with lamivudine significantly decreases the mortality of fulminant hepatitis B patients without SIRS, and a rapid decline of HBV DNA load is one of the good predictors for the treatment outcome.

Higher pretherapy and significant decrease during the first 12 months of therapy in serum laminin levels may associate with hepatitis B e antigen seroconversion in chronic hepatitis B patients treated with lamivudine

Laminin participates in regulating immune response in addition to being a biomarker of liver fibrosis. Lamivudine has been shown to be able to restore cytotoxic T-cell response in chronic hepatitis B. In this study, fifty-two patients with HBeAg-positive chronic hepatitis B received lamivudine treatment for more than 12 months. Serum laminin levels were determined at baseline and during treatment and analyzed regarding treatment responses at the end of 12 months of therapy. The results showed that laminin levels at 12 months of treatment in patients who lost HBeAg were significantly lower compared with baseline (P = 0.001). The baseline laminin levels were higher in HBeAg seroconversion group than those without seroconversion (P = 0.037). Compared with baseline, the levels of serum laminin in HBeAg seroconversion group showed significant decrease (P = 0.001). It is concluded that higher pretherapy and significant decrease during the first 12 months of therapy in laminin levels may associate with HBeAg seroconversion in chronic hepatitis B patients treated with lamivudine, indicating the possible novel information of laminin for clinical reference.

Identification of factors associated with YMDD mutation in patients with chronic hepatitis B receiving lamivudine treatment

To identify factors associated with YMDD mutation in patients with chronic hepatitis B before and after lamivudine treatment in Zunyi region. 53 patients with chronic hepatitis B were enrolled in this study, HBV DNA,HBV markers, ALT, AST, TBil, albumin in the serum were examined at 0, 3, 6, 12, 18 and 24 months after lamivudine treatment. HBV genotype and YMDD mutation were determined by sequencing before lamivudine treatment. YMDD mutation was checked again if serum HBV DNA rebound to more than 1 x 10(4) copies/ml after the initial decrease. HBV genotype in Zunyi region is constitute of B, C and B+C genotype. YMDD mutation occurred in 18 cases after lamivudine treatment, the rate of YMDD mutation was 15.1%, and 34.0% after 1 year and 2 years treatment. There are four types of mutation: rtL180M/M204V, rtL180M/M204I, rtM204I, rtL180M. rtM204V mutation in C gene was always accompanied by rtL180M mutation (100%). The rate of rtL180M/M204V mutation in genotype C group was significantly higher than that in genotype B group (77.8% to 25.0%), the same was true for the rtL180M/ M204I mutation (22.2% to 12.5%). There was no point mutation in genotype C group. The point mutation of rtM204I and rtL180M appeared only in genotype B group. Gender, nation, family history of hepatitis B and HBeAg were not associated with YMDD mutation (P more than 0.05), while the mutation rate was associated with the disease course and severity of disease. YMDD mutation did not occur in patients with low HBV DNA level (less than 10(5) copies/ml). YMDD mutation after lamivudine therapy is associated with HBV genotype and P gene mutation type, and prolonged treatment increases the the mutation rate. In order to reduce the incidence of YMDD mutation, patients with shorter disease course, lower HBV DNA level, more serious liver damage should be treated with lamivudine.

Early changes of hepatitis B virus quasispecies during lamivudine treatment and the correlation with antiviral efficacy

To investigate dynamic changes of hepatitis B virus (HBV) quasispecies within the reverse transcriptase (RT) region during the early stage of lamivudine treatment and the correlation with antiviral efficacy. Twenty-five chronic hepatitis B patients received lamivudine treatment for 48 weeks. Fourteen patients responded to lamivudine, while eleven patients were non-responders. HBV DNA was extracted from serum samples at baseline and week 4. The RT region of HBV was amplified, then cloned and sequenced. Quasispecies complexity and diversity within the RT region were analyzed at baseline and week 4, and viral nucleotide substitution rates during the first 4 weeks were calculated. The quasispecies complexity and diversity were not different between responders and non-responders at baseline (p>0.05). However, the quasispecies complexity and diversity of responders were significantly lower than those of non-responders at week 4 (p<0.01). Furthermore, the viral nucleotide substitution rate of responders was significantly higher than that of non-responders (p<0.05). The dynamic changes of HBV quasispecies within the RT region showed distinct patterns between responders and non-responders during early stage of lamivudine treatment. The dynamic changes of quasispecies complexity and diversity during the first 4 weeks were correlated with lamivudine antiviral efficacy and antiviral resistance.

Management of hepatitis B reactivation in patients with lupus nephritis

Hepatitis B is endemic in many Asian countries and immunosuppression may precipitate hepatitic flare. There is little data on the treatment of hepatitis B in patients with systemic lupus erythematosus. We monitored serial transaminase and HBV DNA levels in our HBsAg-positive patients with a history of lupus nephritis and instituted anti-viral treatment in patients who showed virological reactivation. This retrospective pilot study reports the data with this pre-emptive management strategy. Amongst 228 patients with lupus nephritis, eight (3.51%) were HBsAg-positive and five had received Lamivudine treatment for hepatitis B. In two patients the virological flares were preceded by lupus flares that necessitated an increase in immunosuppressive treatment. Median HBV DNA level was 1.9 x 10(7) copies/mL (range 1.2 x 10(4)-1.0 x 10(9) copies/mL) at baseline, and it decreased by 2-5 logs after treatment. Four patients had abnormal transaminase levels at baseline, with mean alanine aminotransferase at 125.0 +/- 67.4 U/L, and all achieved normalisation after 3-24 months (median 13 months) of treatment. Discontinuation of Lamivudine treatment was attempted in three patients after 9-15 months. In one patient treatment was recommenced because of virological flare. For the remaining two patients in whom treatment was not interrupted, one showed sustained viral suppression and one developed drug resistance. All antiviral treatments were well-tolerated. These results indicate the importance of serial monitoring of HBV DNA and transaminase levels, and prompt anti-viral therapy, in the management of HBsAg-positive lupus patients. Also, it may be feasible to discontinue treatment in stable patients to avoid the selection of drug-resistant variants.

Short-term overlap lamivudine treatment with adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B

To evaluate the efficacy of short-term overlap lamivudine therapy with adefovir in patients with lamivudine-resistant and naive chronic hepatitis B, we compared patients receiving overlap therapy with those receiving adefovir alone. Eighty patients who had received lamivudine treatment for various periods and had a lamivudine-resistant liver function abnormality were enrolled. Forty of these patients received adefovir treatment combined with lamivudine treatment for > or = 2 mo, while the other 40 received adefovir alone. We assessed the levels of hepatitis B virus (HBV) DNA at 0, 12 and 48 wk and serum alanine aminotransferase (ALT) levels after 0, 12, 24 and 48 wk of adefovir treatment in each group. We found serum ALT became normalized in 72 (87.5%) of the 80 patients, and HBV DNA decreased by > or = 2 log10 copies/mL in 60 (75%) of the 80 patients at the end of a 48-wk treatment. HBV DNA levels were not significantly different between the groups. The improvements in serum ALT were also not significantly different between the two groups. These findings suggest short-term overlap lamivudine treatment results in no better virological and biological outcomes than non-overlap adefovir monotherapy.

The Incidence and Clinical Outcome of YMDD Mutants in Hepatitis B Surface Antigen-Positive Renal Allograft Recipients After Prolonged Lamivudine Therapy

Although lamivudine (LAM) is a potent inhibitor of hepatitis B virus (HBV), prolonged therapy may induce the development of LAM-resistant strains, YMDD mutants. Although YMDD mutants have impaired replication that leads to a benign clinical course compared with wild-type virus, some immunosuppressive agents may enhance replication of YMDD mutants, causing a severe hepatitis flare. We retrospectively investigated the incidence and clinical outcomes of YMDD mutants in renal allograft recipients on immunosuppressive treatment. Clinical records of 25 renal allograft recipients, who underwent renal transplantation between December 1997 and February 2006 were hepatitis B surface antigen positive at the time of transplantation, were reviewed. All patients received LAM treatment after renal transplantation. Over 9 to 98 months of follow-up, 16 patients (64.0%) maintained undetectable HBV DNA levels; however, 9 patients (36.0%) showed persistent or increased levels of HBV DNA. Seven were identified as having developed YMDD mutants. Although genotypic analysis was not performed, YMDD mutants were strongly suspected in another two patients, who developed severe hepatic dysfunction combined with high levels of HBV viremia at close to 2 years of LAM therapy. One patient recovered after hepatic transplantation and another patient died of hepatic failure. In conclusion, the incidence of YMDD mutants was similar to that of nonimmunosuppressed individuals; however, the presence of these mutants made it more likely for severe liver disease to develop in renal transplant recipients. Therefore, close monitoring for the development of YMDD mutants should be performed during LAM treatment, especially in this group of patients.

Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response

The best time and hepatitis B virus (HBV) DNA level during an early lamivudine treatment period for predicting the long-term outcome are unknown. We aimed to determine the optimal time and HBV DNA level during an early treatment period for the prediction of the response after a 5-year lamivudine treatment. The HBV DNA levels at the baseline, at weeks 2, 4, 8, 12, 16, 24, and 32, and at yearly intervals until year 5 were measured in 74 hepatitis B e antigen (HBeAg)-positive chronic HBV patients receiving lamivudine treatment. Seventeen patients achieved an ideal response [HBV DNA level < 2000 copies/mL (400 IU/mL), HBeAg seroconversion, normal alanine aminotransferase levels, and absence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations] at year 5. Receiver operating characteristic curves showed good predictions as early as week 4. The areas under the curve for weeks 4 and 16 were 0.89 and 0.94, respectively. Predictive indices revealed 4 and 3.6 log copies/mL (2000 and 800 IU/mL, respectively) to be the best cutoff HBV DNA levels for these 2 times, respectively. All patients with HBV DNA levels lower than these respective cutoff levels at the 2 times achieved an ideal response at year 5. Patients with HBV DNA levels above these cutoff values had 83.8% and 87.7% chances of not achieving an ideal response at year 5, respectively. The measurement of the HBV DNA levels at week 4 of lamivudine treatment should be performed in all patients to predict the long-term outcome. The treatment can be continued for those with HBV DNA levels of less than 4 log copies/mL (2000 IU/mL). The addition of or switch to alternative antiviral agents should be considered for patients who fail to achieve this early target.

Hepatitis B Reverse Seroconversion in Long Term Survivors of Allogeneic Hematopoietic Stem Cell Transplantation.

Reverse seroconversion (RS) known as reactivation of resolved hepatitis B virus (HBV) infection is a complication after allogeneic hematopoietic stem cell transplantation (SCT) in patients exposed to hepatitis B virus. Four hundred thirty six (436) patients with hematological disorder received SCT from an HLA identical sibling in our institute between September 1993 and June 2004. Of these, 103 patients who are 3 or more years post-transplantation have been enrolled in a long-term evaluation protocol. Sixteen had pre-transplant resolved HBV infection (negative HBsAg, positive anti-HBs and anti-HBc antibodies). We investigated the serologic markers of HBV infection in this cohort (median follow-up 59.5 months, range 40–113). Diagnoses included chronic or acute myelogenous leukemia and myelodysplastic syndrome (14), acute lymphoblastic leukemia (1), and severe aplastic anemia (1). Median age at SCT was 32 years (range 10–56). Thirteen patients were positive for anti-HBc and anti-HBs. One had anti-HBc, one had anti-HBs alone, and 1 had no antibodies to hepatitis B. None had detectible HBsAg (HBV surface antigen) at transplant. Twelve patients (median age 39.5 years) received a 12–13.6 Gy total body irradiation (TBI)-based myeloablative SCT followed by a T-cell depleted peripheral blood stem cell transplantation (PBSCT). Four patients (median age 31 years) received a reduced-intensity regimen of fludarabine 125 mg/m2 and cyclophosphamide 60 mg/kg, followed by a PBSCT. All received cyclosporine as graft-verse-host disease (GVHD) prophylaxis. Nine developed acute GVHD, and 13 developed chronic GVHD. Nine (56%) patients received immunosuppressive therapy (IST) for chronic GVHD beyond 3 years from SCT. Fifteen (94%) patients were alive with a median follow-up of 59.5 months. One patient with RS of HBV died at 59 months after SCT. Six (38%) patients developed RS of hepatitis B with reappearance of HBsAg, 21–101 (median 29.5) months after SCT. Four (67%) of the 6 developed clinical hepatitis and received Lamivudine treatment with a decrease of HBV viral load. There was no significant difference in median age of 6 patients with, and 10 patients without RS (38 vs 32 years). RS of hepatitis B was associated with prolonged immunosuppressive therapy for cGVHD. Theses results show that RS of HBV post SCT is a significant long-term complication of patients with pre-transplant resolved HBV infection. This emphasizes the importance of long-term hepatitis B serologic monitoring, post-transplant prophylaxis with Lamivudine, HBV vaccine, and prompt initiation of Lamivudine treatment if RS of HBV occurs.VariableWith RS of HBVWithout RS of HBVCases6 (38%)10 (62%)Age in years (median, range)38 (10–46)32(13–56)Myeloablative48Reduced intensity22aGVHD2/6 (33%)7/10 (70%)cGVHD5/6 (83%)8/10 (80%)IST for cGVHD >3 years4/6 (67%)5/10 (50%)Lamivudine Treatment4/6 (67%)Lamivudine Prophylaxis5/10 (50%)HBV Vaccine after HSCT5/10 (50%)RS of HBV in months (median, range)29.5 (21–101)Follow-up in months (median, range)71(55–107)57.5 (40–113)

Evolution of Primary and Compensatory Lamivudine Resistance Mutations in Chronic Hepatitis B Virus-Infected Patients during Long-Term Lamivudine Treatment, Assessed by a Line Probe Assay

With the availability of more potent nucleotide/nucleoside analogues, the early detection of drug-resistant mutants of hepatitis B virus (HBV) is important for the strategic treatment of chronic hepatitis B. We studied 336 serum samples from 80 patients chronically infected with HBV who were receiving lamivudine treatment for the presence of lamivudine resistance mutations at codons 80, 173, 180, and 204 of the HBV polymerase. The sequencing data were compared with the results generated with the INNO-LiPA HBV DR (drug resistance) v2 strip, a line probe assay (LiPA) covering wild-type and mutant motifs, for resistance mutations to lamivudine and adefovir dipivoxil. This method provided at least the same information as sequencing for 99.1% of all codons analyzed. On the basis of the LiPA results, 20 of 80 patients developed a lamivudine resistance mutation after 1 year. In all 20 patients, the mutation occurred in the YMDD motif at reverse transcriptase position 204 (rt204; M204V/I) either with or without the compensatory mutation at position rt180 (L180M). A compensatory mutation at position rt80 (L80V/I) was detected in half of these patients. After 36 months, a compensatory mutation was seen at position rt173 (V173L) in 3/15 patients. Time-to-event survival analysis indicated a 2.8 times greater chance for LiPA to detect a given mutation than sequencing at any moment in time (hazard ratio, 2.8, 95% confidence interval, 1.79, 4.41; P < 0.0001). These results demonstrate that a highly sensitive and specific assay such as the INNO-LiPA HBV DR v2 can precociously detect and monitor the emergence of primary and compensatory lamivudine resistance mutations in patients chronically infected with HBV and is more sensitive than sequencing.

Clinical study on YMDD mutation and pre-core C region and core promotor region mutation of the patients with chronic hepatitis B virus receiving lamivudine therapy

目的 探讨慢性乙型肝炎患者中拉米夫定诱导的YMDD变异和前C区1896位核苷酸以及C区启动子1762和1764位核苷酸变异的检出率及其临床意义.方法 采用基因芯片技术检测拉米夫定治疗6个月以上的122例慢性乙型肝炎患者血清中前C区1896位以及C区启动子1762和1764位核苷酸变异发生率.结果 122例慢性乙型肝炎患者中检出40例YMDD变异阳性患者,检出率为32.8%.发生YMDD变异后,HBV DNA反跳,ALT和AST增高,差异有统计学意义(P＜0.01).YMDD变异阳性患者前C区1896位和C区启动子1762和1764位核苷酸变异检出率显著高于无YMDD变异的慢性乙型肝炎患者,差异有统计学意义(P＜0.01).YMDD变异阳性伴前C区1896位以及C区启动子1762和1764位核苷酸变异患者与无前C区1896位以及C区启动子1762和1764位核苷酸变异的YMDD变异阳性患者比较,病情容易加重.易发展为重型肝炎或肝硬化,但差异无统计学意义(P＞0.05).结论 拉米夫定诱导的YMDD变异患者容易发生前C区1896位/C区启动子1762和1764位核苷酸变异,但与病情加重和预后无相关性。