Fatal liver failure caused by reactivation of lamivudine-resistant hepatitis B virus： A case report

We present a case of fetal liver failure caused by the activation of lamivudine-resistant hepatitis B virus (HBV) nine months after lamivudine treatment. A 57-year old man visited our hospital for the treatment of decompensated chronic hepatitis B. Lamivudine was started in December 2001. Subsequently, serum HBV was negative for HBV DNA with seroconversion from HBeAg to anti-HBe and improvement of liver function. However, HBV DNA and HBeAg were again detected in September 2002. He was complicated by breakthrough hepatitis and admitted to our hospital in November for severely impaired liver function. Vidarabine treatment was started and serum HBV DNA and alanine aminotransferase (ALT) decreased transiently. However, after the start of α-interferon treatment, HBV DNA level increased and liver function deteriorated. He died 1 mo after admission. An analysis of amino acid sequences in the polymerase region revealed that rtM204I/V with rtL80I/V occurred at the time of viral breakthrough. After the start of antiviral treatment, rtL180M was detected in addition to rtM204I/V and rtL80I/V, and became predominant in the terminal stage of the disease. HBV clone with a high replication capacity may be produced by antiviral treatment leading to the worsening of liver function. Antiviral therapy for patients with breakthrough hepatitis in advanced liver disease should be carefully performed.     

Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation

AIM: To analyze the effectiveness and safety of lamivudine treatment in patients with chronic HBV infection undergoing hemodialysis or after kidney transplantation, and to study the frequency of tyrosine - methionine - aspartate - aspartate (YMDD) mutation occurrence after lamivudine treatment. METHODS: We analyzed 91 patients with chronic hepatitis B, among whom, 16 patients underwent hemodialysis, 7 patients had kidney transplantation and 68 patients had normal function of kidney. The hemodialysis patients were treated by lamivudine 300 mg/wk. patients after kidney transplantation and patiente with normal function of kidney were treated with lamivudine 100 mg/d. Therapy lasted for 12 mo. HBV-DNA, HBsAg, HBeAg and anti-HBe, and anti-HCV antibodies were assessed in sera of patients. The analysis was performed before and 6 mo after the end of lamivudine treatment. Before, during and after the lamivudine therapy, the number of erythrocytes, leukocytes, platelets and hemoglobin concentration, ALT and AST activity, as well as bilirubin, urea and creatinine concentrations were analyzed in sera from patients. RESULTS: After the 12-mo lamivudine treatment, elimination of HBV - DNA was observed in 56% patients undergoing hemodialysis and in 53% patients with normal kidney function. Only 1 from 7 (14%) kidney-transplanted patients eliminated HBV-DNA. Furthermore, HBeAg elimination was observed in 36% hemodialysis patients, in 51% patients with normal function of kidneys and in 43% kidney transplanted patients. Among the patients undergoing dialysis, no YMDD mutation was found after 12 mo of therapy, while it was detected in 9 patients (13%) with normal function of kidney and in 2 kidney-transplanted patients (29%, P<0.006). We did not observe significant side effecte of lamivudine treatment in studied patiente. CONCLUSION: Effectiveness of lamivudine therapy in dialysis patients is comparable with that in patiente with normal function of kidney. Lamivudine treatment is well tolerated and safe in patiente with renal insufficiency undergoing hemodialysis and kidney-transplantation. However, in the latter group, high incidence of YMDD mutation after lamivudine treatment was observed.     

Rapid re-emergence of YMDD mutation of hepatitis B virus with hepatic decompensation after lamivudine retreatment

Lamivudine has a high rate of antiviral resistance. Sequential treatment of anti-hepatitis B virus （HBV） is commonly used for lamivudine resistance. We report 4 cases of patients with rapid redetection of HBV mutants during the lamivudine retreatment. The four patients received lamivudine as an initial treatment of HBV and adefovir and lamivudine as a rescue therapy consecutively. HBV-DNA level, YMDD mutations and adefovir -resistant mutations （RFMP） were tested every 3 mo during the sequential treatment. All the patients showed YMDD mutations during the initial lamivudine therapy. After adefovir therapy for lamivudine resistance, they showed viral breakthrough. Adefovir was switched to lamivudine, however, it did not induce viral suppression at all, rather increased HBV-DNA with rapid reemergence of the YMDD mutations. All the patients had ALT flares, and hepatic decompensation occurred in two patients. After switching to adefovir combined with entecavir or lamivudine for a rescue therapy, the patients had reduction in HBV-DNA and ALT improvement. These cases demonstrated that lamivudine retreatment of patients with preexposed lamivudine resistance leads to rapid reemergence of YMDD mutation with significant viral rebounds and subsequent hepatic decompensation. Sequential administration of lamivudine in patients with a prior history of YMDD mutation should be abandoned.     

Effect of SEN virus coinfection on outcome of lamivudine therapy in patients with hepatitis B

AIM:Interactions between hepatitis B virus (HBV) and otherviral hepatitis infections are well known,whether the newlydiscovered SEN virus (SENV) has any effect on lamivudineantiHBV activity is unclear.Our aim was to clarify the effecton treatment outcome of coinfection with SEN virus inpatients with hepatitis B during lamivudine therapy.METHODS:Nested polymerase chain reaction (PCR)amplification was used to detect SENV-D and SENV-Hstrains in serum from 45 patients with chronic hepatitis Btreated with lamivudine 100 mg daily for 12 mo.HBV DNAload was detected with fluorescence quantitative PCR (FQ-PCR) and YMDD (tyrosine,methionine,aspartate,aspartate)motif mutation of HBV DNA was investigated with cDNAmicroarray.RESULTS:SENV DNA was detected in 5 of 45(11.1%) casesafter 12 mo they received lamivudine treatment.SENV-Dand SENV-H were 4.4% and 6.7% respectively.HBV DNAfailed to respond to lamivudine therapy in 4 of 5 SENVcoinfected patients while only 10 of 40 patients becameSENV positive and the difference was statistically significant.Response of ALT and HBeAg to lamivudine had no significantdifference between coinfection patients and single HBVinfection ones.CONCLUSION:Coinfection with SEN virus in chronichepatitis B patients may adversely affect the outcome oflamivudine treatment.     

Treatment of chronic hepatitis B patients with tyrosinemethionine-aspartate-aspartate mutations

Lamivudine is an antiviral used for the treatment of chronic hepatitis B. Several studies have reported various mutations that are induced by lamivudine therapy. These mutations in the tyrosine-methionineaspartate-aspartate(YMDD) motif are necessary and sufficient to confer high-level lamivudine resistance. During treatment with lamivudine, mutations develop in the YMDD motif of the hepatitis B virus(HBV) polymerase gene and lamivudine cannot prevent the replication of the mutant form. The virulence strain of developed mutation in the polymerase gene is lower than the original virus and they are susceptible to treatment with some other nucleoside analogs except lamivudine. Entecavir and tenofovir are potent HBV inhibitors and they can be confidently used as first line monotherapies. We read the article written by Tan et al that lamivudine therapy improved the clinical course in HBV patients with natural YMDD mutations. We think that lamivudine use for this patient group is not appropriate. These patients should use YMDD mutant form-effective drugs such as adefovir, tenofovir.     

Dynamic changes of HBV DNA in serum and peripheral blood mononuclear cells of chronic hepatitis patients after lamivudine treatment

AIM: To study the dynamic changes of hepatits B virus (HBV) DNA in serum and peripheral blood mononuclear cells (PBMCs) of patients after lamivudine therapy. METHODS: A total of 72 patients with chronic HBV infection were included in this study. All patients were confirmed to have the following conditions: above 16 years of age, elevated serum alanine amonotransferase (ALT), positive hepatitis B e antigen (HBeAg), positive HBV DNA in serum and PBMCs, negative antibodies against HAV, HCV, HDV, HEV. Other possible causes of chronic liver damages, such as drugs, alcohol and autoimmune diseases were excluded. Seventy-two cases were randomly divided into lamivudine treatment group (n=42) and control group (n=30). HBV DNA was detected both in serum and in PBMCs by fluorescence quantitative polymerase chain reaction (PCR), during and after lamivudine treatment. RESULTS: In the treatment group, HBV DNA became negative both in serum and in PBNIC, of 38 and 25 out of 42 cases respectively during the 48 wk oflamivudine treatment, the negative rate was 90.5% and 59.5% respectively. In the control group, the negative rate was 23.3% and 16.7% respectively. It was statistically significant at 12, 24 and 48 wk as compared with the control group (P < 0.005). The average conversion period of HBV DNA was 6 wk (2-8 wk) in serum and 16 wk (8-24 wk) in PBMC. CONCLUSION: Lamivudine has remarkable inhibitory effects on HBV replication both in serum and in PBMCs. The inhibitory effect on HBV DNA in PBMCs is weaker than that in serum.     

YMDD mutations in patients with chronic hepatitis B untreated with antiviral medicines

AIM: To polymerase P region (YMDD) mutations of hepatitis B virus gene (HBV DNA) in patients with chronic hepatitis B (CHB) untreated with antiviral medicines and to explore its correlation with pre-c-zone mutations, HBV genotypes and HBV DNA level, and to observe its curative effect. METHODS: A total of 104 cases (38 cases in group of familial aggregation and 66 cases in group of non-familial aggregation) were randomly chosen from 226 patients with CHB who did not receive the treatment of lamivudine (LAM) and any other antivirus drugs within the last one year. Their serum YMDD mutations were detected by microcosmic nucleic acid and cross-nucleic acid quantitative determination, HBV genotypes by PCR-microcosmic nucleic acid crossELISA, HBV DNA quantitative determination and fluorescence ration PCR analysis, hepatitis B virus markers (HBVM) by ELISA. LAM was taken by 10 patients with YMDD mutations and its curative effect was observed. RESULTS: Twenty-eight cases (26.9%) had YMDD mutations, of them 11 cases (28.9%) were in familial aggregation group (38 cases) and 17 cases (25.8%) in nonfamilial aggregation group (66 cases) with no significant difference between the two groups. Twenty-seven point one percent (16/59) cases were positive for HBeAg YMDD mutations, and 26.7% (12/45) cases were negative for HBeAg and positive for anti-HBe. There was also no significant difference between the two groups. Different YMDD incidence rate existed in different HBV genotypes. HBV DNA level did not have a positive correlation with the incidence of YMDD mutations. LAM was effective for all patients with mutations. CONCLUSION: Wild mutant strains in HBV and their incidence rate have no significant difference between familial aggregation and non-familial aggregation. It may have no significant relationship between YMDD mutations and pre-c-zone mutations. HBV DNA level may not have a positive correlation with YMDD mutations. LAM is clinically effective for CHB patients with YMDD mutations.     

Treatment of chronic viral hepatitis with nitazoxanideand second generation thiazolides

Nitazoxanide, the first thiazolide, was originally developed for the treatment of Cryptosporidium parvum. More recently, antiviral activity of nitazoxanide against hepatitis B virus （HBV） and hepatitis C virus was recognized in in vitro systems. These basic studies led to phase Ⅱ clinical trials that demonstrated the safety and efficacy of nitazoxanide in combination with peginterferon, with or without ribavirin, in the treatment of chronic hepatitis C genotype 4. The sustained virologic response rate was 79% and 80% in two studies, which was higher than the response rate of 50% with the standard of care with peginterferon plus ribavirin. In very preliminary studies of patients with chronic hepatitis B, nitazoxanide suppressed serum HBV DNA and led to loss of hepatitis B e antigen in the majority of patients and hepatitis B surface antigen in approximately a quarter of patients. Randomized controlled studies of naive and nonresponder patients with chronic hepatitis C genotype 1 are underway, new second generation and controlled release thiazolides are being developed, and future studies of patients with chronic hepatitis B are planned.     

Natural YMDD-motif mutants affect clinical course of lamivudine in chronic hepatitis B

AIM:To investigate the prevalence of nature tyrosinemethionine-aspartic acid-aspartic acid motif mutations in chronic hepatitis B(CHB)patients and to evaluate the efficacy of lamivudine.METHODS:A total of 1268 CHB patients were recruited from the outpatient and inpatient departments of six centers.Tyrosine-methionine-aspartic acid-aspartic acid(YMDD)mutations were analyzed using the hepatitis B virus(HBV)drug resistance line probe assay.Forty voluntary patients were selected from those with positive or negative natural YMDD mutations to undergo treatment with lamivudine.RESULTS:YMDD mutations were detected in 288(22.71%)of the 1268 CHB patients.Multivariate analysis revealed that the patients’HBV DNA level(P=0.0282)and hepatitis B e antigen status(P=0.0133)were also associated with natural YMDD mutations.The rates of normalization of alanine aminotransferase levels and HBV DNA nondetection at 6,24,36,and 48 wk were compared between the patients with natural YMDD mutations and those without,and the differences were not significant.However,there was a significant difference in the cumulative emergence rates of virological breakthrough at 48 wk in the patients with natural YMDD mutations and those without(32.5%vs 12.5%,P=0.032).CONCLUSION:Naturally occurring YMDD mutationsare detectable in a large proportion of CHB patients;breakthrough hepatitis tended to occur in patients with natural YMDD mutations.     

Serum concentration of sFas and sFasL in healthy HBsAg carriers, chronic viral hepatitis B and C patients

AIM: To estimate the amount of apoptosis among healthy HBsAg carriers, patients with chronic HBV infection treated with lamivudine and patients with chronic HCV infedJon treated with interferon alpha and ribavirin. Activity of apoptosis was evaluated by serum sFas/sFasL concentration measurement.Moreover dependence between apoptosis and HBV-DNA or HCV-RNA levels was studied.METHODS: Eighty-six persons were included into study: 34 healthy HBsAg carriers, 33 patients with chronic HBV infection and 19 patients with chronic HCV infection. Serum levels of sFas/sFasL were measured by ELISA assay. HBV-DNA and HCV-RNA were measured by RT-PCR assay. Levels of sFas/sFasL were determined before and 2 and 12 wk after therapy in patients with chronic hepatitis B and C infection.HBV-DNA or HCV-RNA was detected before treatment and 6 mo after treatment.RFSULTS: Twenty-four (71%) healthy HBsAg carriers showed HBV-DNA over 10^5/mL, which was comparable to the patients with chronic hepatitis B. Independently from HBV-DNA levels,the concentration of sFas among healthy HBsAg carriers was comparable to healthy persons. Among patients with chronic hepatitis B and C, the concentration of sFas was significantly higher in comparison to healthy HBsAg carriers and healthy persons. In chronic hepatitis B patients the concentration of sFas was decreased during lamivudine treatment. Among chronic hepatitis C patients the concentration of sFas was increased during IFN alpha and ribavirin treatment, sFasL was not detected in control group. Furthermore sFasL oo:urred more frequently in chronic hepatitis C patients in comparison to chronic hepatitis B patients.CONCLUSION: There are no correlations between apoptosis and HBV-DNA levels. However ther is an association between apoptosis and activity of inflammation in patients with chronic HBV infection. Apoptosis can be increased in patients with chronic hepatitis C by effective treatment which may be a result of apoptosis stimulation by IFN-α.     

肿瘤病人弓形虫感染分析

在肿瘤的发生和发展进程中 ,多伴有免疫功能低下或缺陷 ,从而极易遭受各种感染。弓形虫是机会感染因子 ,当患者免疫功能受损时 ,易于感染 ,还会使隐性感染激活 ,引起低热不退、淋巴结肿和脑神经系统的反应 ,此现象尚未引起临床医师的重视。近年来 ,我们对 4 0 9例肿瘤病人进行了弓形虫感染及弓形虫病的分析观察 ,报告如下 :1　材料与方法1 1　材料　 30 4例病人血清取自江西省肿瘤医院住院或门诊病人 ,随机抽样后低温保存待检 ,10 5例取自其他医院送检样品 ,有急性症状者随到随检 ,以便及时做病原学检测。1 2　弓形虫病诊断方法1 2 1　免疫…     

A patient with rectal ulcer with severe stenosis presenting with perforated peritonitis

We report a patient with rectal ulcer with severe stenosis, who underwent urgent surgical treatment for perforated peritonitis. The 54-year-old man suddenly developed cramping abdominal pain and fever while hospitalized, with signs of peritoneal irritation. An emergency laparotomy was performed, and severe stenosis of the rectum and a perforated lesion on the oral side approximately 10 cm distant from the stenosis were found, with massive abdominal purulent fluid. He was treated by rectosigmoid colon resection with transverse colon loop colostomy. Histopathologically, the stenosis was caused by ulceration extending to all muscular layers of the rectum, with inflammatory changes. Benign rectal stenosis is so rare that differential diagnosis from malignancy may be difficult when there are inflammatory changes in the surrounding tissues. However, it is necessary to keep in mind the likelihood of this disease in differentiation from rectal cancer. Received: December 21, 1998 / Accepted: May 28, 1999     

Infection with Rhodococcus equi in a patient with sarcoidosis treated with corticosteroids

A 51-year-old female farmer was diagnosed as having sarcoidosis. During 4 years of observation, slow radiological progression was observed. Cough then developed, necessitating treatment with corticosteroids. After 28 months of continuous treatment with prednisolone in low doses (5-7.5 mg daily), she suffered fever episodes, recurrent haemoptyses, general malaise and loss of weight. A chest roentgenogram showed a left upper lobe infiltrate, which progressed and finally cavitated, and rib destruction. Despite efforts, including a thoracotomy, 22 months passed before a diagnosis could be made. Blood and sputum cultures and cultures from the destroyed rib showed growth of Rhodococcus equi, a common soil organism which can cause infections in foals and other animals. Treatment with rifampicin and erythromycin was successful. R. equi has been reported to cause infection in patients with neoplastic disease and/or immunosuppression, but the disease might be more common than is suggested by the sparse case reports in the literature, owing to lack of familiarity with the organism, which will tend to be overlooked as a contaminant.     

Evaluation of atrial vulnerability with transoesophageal stimulation in patients with atrioventricular junctional: Comparison with patients with ventricular pre-excitation and with normal subjects

The aim of our work was to evaluate the inducibility of atrialfibrillation in a group of patients with atrioventricular junctionalreentrant tachycardia and to compare it with that of patientswith a Kent-type ventricular pre-excitation (Wolff-Parkinson-Whitesyndrome) and a control group. One hundred and twenty-five subjects were separated into groups.Group 1 comprised 49 Wolff-Parkinson-White patients, with amean age of 26.4, range 10.66 years; group 2, 51 patients withatrioventricular junctional reentrant tachycardia inducibleby transoesophageal atrial stimulation andlor clinically documented,with a mean age of 43.4, range 16–78 years; group 3, 25control subjects with a mean age of2.64, range 13–76 years. Each subject underwent atrial transoesophageal stimulation withthe following protocol: programmed atrial stimulation with 1and 2 stimuli during atrial pacing of 100. min^–1 and 150.min^–1; atrial stimulation for 10 s at a rate of 200–300–400–500–600.min^–1 with intervals of 10 s between stimulations, fivesuccessive ‘ramp-up’ atrial stimulations for 9 swith the rate increasing from 100 to 800. min^–1 with intervalsof 10 s between stimulations. The end point was the completionof the protocol or induction of sustained atrial fibrillation(>1 min). The chi-square test was used for statistical analysis. Our resultsshowed that in group 1 atrial fibrillation was induced in 27149patients (55.1%); this was sustained in 13149 (26.5%) and non-sustainedin 14149 (28.5%); in group 2, atrial fibrillation was inducedin 22151 patients (43.0%); it was sustained in 7151 (13.7%)and non-sustained in 15151 (29.4%); in group 3, sustained atrialfibrillation was not induced in any subject and in only onesubject was a non-sustained atrial fibrillation (4 s) induced. The chi-square test showed that group 2 vs group 1 were non-significant,while group 2 vs group 3 and group 1 vs group 3 were significant(P<0.003 and P<0.0007, respectively). Therefore group 2 patients showed a greater atrial vulnerabilityin comparison to the control subjects and a similar vulnerabilityto group 1 patients. It is possible that the greater atrialvulnerability in the patients of group 2 was due to the doublenodal pathway.     

Treating patients with lupus with B-cell depletion

A new era in the treatment of systemic lupus erythematosus has dawned with the increasing introduction of monoclonal antibodies and other approaches, that target the key molecules involved in the pathogenesis of the disease. At present the ability to block the CD20 molecule on those B cells that carry this marker has proved the most effective way to treat patients resistant to conventional immunosuppressive drugs. However, these studies have all been open label and the results of double blind controlled studies are eagerly awaited.