Initial Virological Response and Viral Mutation with Adefovir Dipivoxil Added to Ongoing Lamivudine Therapy in Lamivudine-Resistant Chronic Hepatitis B

Background  

Although adefovir dipivoxil (ADV) has been used for antiviral treatment of lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients, the long-term efficacy of this treatment is not well understood. Initial virological response (IVR) has been reported to be an important factor in relation to the development of ADV-resistance.     

The Efficacy of Adefovir Plus Entecavir Combination Therapy in Patients with Chronic Hepatitis B Refractory to Both Lamivudine and Adefovir

Background

The efficacy of adefovir (ADV) plus entecavir (ETV) combination in patients with chronic hepatitis B (CHB) who developed multidrug refractoriness had not been fully evaluated. We aimed to evaluate the efficacy of ADV plus ETV as compared to that of lamivudine (LAM) plus ADV in the patients with antiviral refractoriness to sequential LAM monotherapy and then ADV monotherapy.

Methods

Twenty-seven patients were treated with a combination of ADV plus ETV and 63 patients were treated with a combination of LAM plus ADV. The virological and biochemical parameters were compared between the two groups, retrospectively.

Results

Treatment with a combination of ADV plus ETV produced significantly superior virological response than that of a combination of LAM plus ADV. At 12 months, the HBV DNA declined more in the ADV plus ETV group than in the LAM plus ADV (?4.52 ± 1.956 vs. ?2.65 ± 1.723 log₁₀IU/mL; p = 0.001). The rate of a complete response at 12 months was greater in the ADV plus ETV group than that in the LAM plus ADV group (63.16 vs. 14.81 %, p < 0.001).

Conclusion

In the patients with CHB refractory to both LAM and ADV, the response to ADV plus ETV was significantly superior compared to that of the LAM plus ADV in suppressing HBV DNA. The result indicates that ADV plus ETV can be used as a bridging therapy in the patients with refractoriness to both LAM and ADV, especially in the areas where tenofovir is not yet available.     

Efficacy and safety of transbronchial lung biopsy for the diagnosis of lymphangioleiomyomatosis: A report of 24 consecutive patients

Background and objective

Lymphangioleiomyomatosis (LAM) is a diffuse cystic lung disease that occurs in women of childbearing age. LAM can be diagnosed on a clinical basis in patients with typical high‐resolution computed tomography (HRCT) patterns and at least one other corroborating disease feature, such as chylothorax, angiomyolipoma, tuberous sclerosis complex or elevated serum vascular endothelial growth factor (VEGF)‐D. However, patients who do not meet these criteria require tissue confirmation for a definitive diagnosis, and the utility of methods that are less invasive than surgical lung biopsy, such as transbronchial lung biopsy (TBLB), are not well studied. We retrospectively studied the efficacy and safety of TBLB for the diagnosis of LAM.

Methods

From January 1991 to August 2015, 131 consecutive LAM patients were prospectively registered in our study, and a TBLB was conducted for 24 patients. We retrospectively studied the yield and safety of TBLB in this cohort.

Results

All 24 patients were women; the median age was 42 years. HRCT showed multiple round thin‐walled cysts diffusely scattered throughout the lungs. The median level of serum VEGF‐D was 2109 pg/mL. Characteristic pathological findings for LAM were identified in 17 patients (70.8%) by two expert pathologists. The %predicted value for diffusing capacity of carbon monoxide was significantly lower in the 17 TBLB‐positive LAM patients compared to the seven TBLB‐negative LAM patients (P = 0.046). There were no serious adverse events such as pneumothorax or uncontrollable bleeding due to TBLB.

Conclusion

TBLB is a safe and effective method for the pathological diagnosis of LAM.

     

Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations

OBJECTIVE:

Lymphangioleiomyomatosis (LAM) is a rare disease that is currently considered a low-grade neoplasm with metastatic potential and variable progression. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have recently become a treatment option for LAM patients, especially those with extrapulmonary manifestations. The objective of the present study was to describe a case series of four patients with LAM in Brazil who showed significant improvement, particularly in their extrapulmonary manifestations, after treatment with sirolimus (at 1-4 mg/day).

METHODS:

We describe four cases of LAM patients with different extrapulmonary manifestations who were treated with sirolimus.

RESULTS:

After treatment with sirolimus for 12 months, one patient presented resolution of severe chylothorax; one had a significant reduction in renal angiomyolipoma volume; and one showed significant regression of retroperitoneal lymphangioleiomyomas and abdominal lymph node enlargement. After treatment with sirolimus for 6 months, the remaining patient had a significant reduction in the volume of a massive retroperitoneal lymphangioleiomyoma.

CONCLUSIONS:

Our findings confirm that mTOR inhibitors are beneficial for patients with LAM, especially those with extrapulmonary manifestations, such as renal angiomyolipoma, lymphangioleiomyomas, and chylous effusions. However, certain aspects, such as the optimal dose, duration of treatment, and long-term adverse effects, have yet to be sufficiently clarified for mTOR inhibitors to be incorporated into LAM management protocols.     

Quasispecies and Pre-Existing Drug-Resistant Mutations of Hepatitis B Virus in Patients with Chronic Hepatitis B

Background/Aims

To investigate pre-existing hepatitis B virus (HBV) quasispecies and the genotypic evolution of several variants.

Methods

From six patients with lamivudine (LAM) failure, serum samples at pretreatment, 6 months of LAM therapy, and virologic breakthrough were obtained. One hundred clones with HBV inserts in each patient were sequenced at each time point. Pretreatment serum samples were also analyzed from six patients who achieved good responses to LAM therapy.

Results

Among the six patients with LAM failure, the analysis of 100 clones from patient 1 revealed the substitutions L180M in 1% of clones and V173L in 2% of clones. Patient 2 had substitutions of L80V, W153Q, and L180M. In patient 3, mutations conferring resistance to adefovir at V84I (5%), I169L (1%), and N236H (7%) and entecavir at S202G (2%) were detected. Patient 4 had mutations at T128N (1%), I169L (1%), V173L (2%), A181V (1%), and Q215H (1%). In patient 5, M204V/I was detected in 1% and 2% of clones, respectively. L80I and V173L were also identified in patient 6. In the six patients who responded to LAM, the degree of overall quasispecies was less than those with LAM failure.

Conclusions

Various HBV quasispecies associated with drug resistance existed before treatment, and the quasispecies dynamically changed through LAM therapy.     

The optimal threshold: Baseline serum hepatitis B virus DNA and alanine transaminase levels can predict the 2-Year on-treatment virological response to lamivudine

Background

HBV is still a worldwide health problem. Annually about 0.5-1.2 million patients die of HBV-related diseases such as liver cirrhosis and hepatocellular carcinoma. Lamivudine (LAM) is the first nucleoside analog used in the treatment of chronic hepatitis B. As LAM has been clinically used for a long time, increasing clinical experience has been achieved showing that the resistance mutation rate is relatively high. Numerous studies have also focused on the predictive factors of long-term efficacy of LAM treatment.

Objectives

To determine the optimal cutoff values of baseline hepatitis B virus (HBV) DNA and alanine transaminase (ALT) levels as predictors for the long-term efficacy of LAM treatment in patients with chronic hepatitis B.

Patients and Methods

A total of 163 HBeAg-positive chronic hepatitis B patients receiving LAM treatment were recruited into the present study. Logistic regression analysis was performed to find out the independent predictors of 2-year on-treatment virological response among the baseline parameters. The receiver operating characteristic (ROC) curve was used to evaluate the optimal cutoff values of these independent predictors. The accuracy of the prediction was assessed using the area under curve (AUC) and optimal cutoff values were determined through maximizing the Youden''s index.

Results

After 2 years of LAM treatment, undetectable HBV DNA was maintained in 114 (69.9%) patients. LAM-related resistance mutation (YMDD mutation) was detected in 45 (27.6%) patients. Logistic regression analysis indicated that the baseline ALT and HBV DNA levels were the independent predictors of the efficacy. ROC curve analysis suggested the integration parameter derived from the baseline ALT and HBV DNA levels had the maximal predictive value for a 2-year on-treatment virological response. The optimal cutoff values of ALT and HBV DNA were 220 IU/L and 8.2 log10 copies/mL, respectively.

Conclusions

The incidence of LAM-resistant mutations in HBeAg-positive chronic hepatitis B patients may be significantly reduced and long-term efficacy improved when the baseline ALT was greater than 220 IU/L and HBV DNA was less than 8.2 log10 copies/mL.     

YMDD Motif Mutation Profile Among Patients Receiving Liver Transplant Due to Hepatitis B Virus Infection With Long Term Lamivudine/Immunoglobulin Therapy

Background:

Recurrence of Hepatitis B Virus infection in patients undergoing liver transplanted (LT) is a serious and often fatal problem. Lamivudine (LAM) and Hepatitis B Immunoglobulin (HBIG) are widely used to manage hepatitis B recurrence after liver transplantation. However, the outcomes in patients are less elucidated.

Objectives:

The current study aimed to evaluate the YMDD motif mutations profile among the patients undergoing LT infected with HBV and treated with LAM/HBIG at least for one year.

Patients and Methods:

Thirty patients with liver transplantation due to HBV were enrolled, while DNA level remained under detection limit of 50 IU/mL before transplantation and abnormal higher levels of liver enzymes after LT. The HBV genome detection was performed by two different Polymerase Chain Reaction methods following viral quantification by commercial Real-Time PCR. HbsAg detection, besides liver function tests were conducted as complementary assays. To assess nucleotide analogue mutations, the major part of polymerase gene (aa 80 - 240) was amplified by Nested-PCR, introduced to sequencing and subjected to phylogenetic analysis.

Results:

Totally, according to the laboratory criteria there were 13 cases with detectable HBV genome, while the mean liver enzyme levels were higher in recurrent patients and HBsAg was detected only in four out of the 13 cases. Phylogenetic analysis demonstrated that all isolated genomes belonged to genotype D. Critical M204I mutation, as a proof for resistance to LAM, was detected among 46% of the subjects and natural entecavir resistance (S202I) was also distinguished in one subject. Viral quantification showed higher titer in LAM resistant group in comparison to the group with undetectable drug resistance mutant (P > 0.05).

Conclusions:

Although the patients carrying M204I mutation were more likely to show lack of responses to LAM therapy, LAM replacing by other nucleoside/tide analogs plus HBIG maybe still effective in decreasing hepatitis B recurrence after liver transplantation. However, it is suggested that drug resistance test should be considered by clinicians during therapeutic management to avoid the following viral breakthrough.     

Entecavir Versus Lamivudine Therapy for Patients With Chronic Hepatitis B-Associated Liver Failure: A Meta-Analysis

Background:

Nucleoside analogues are recommended as antiviral treatments for patients with hepatitis B virus (HBV)-associated liver failure. Clinical data comparing entecavir (ETV) and lamivudine (LAM) are inconsistent in this setting.

Objectives:

To compare the efficacy and safety of ETV and LAM in patients with chronic hepatitis B (CHB)-associated liver failure.

Patients and Methods:

A literature search was performed on articles published until January 2014 on therapy with ETV and LAM for patients with CHB-associated liver failure. Risk ratio (RR) and mean difference (MD) were used to measure the effects. Survival rate was the primary efficacy measure, while total bilirubin (TBIL), prothrombin activity (PTA) changes and HBV DNA negative change rates were secondary efficacy measures. A quantitative meta-analysis was performed to compare the efficacy of the two drugs. Safety of ETV and LAM was observed.

Results:

Four randomized controlled trials and nine retrospective cohort studies comprising a total of 1549 patients were selected. Overall analysis revealed comparable survival rates between patients received ETV and those received LAM (4 weeks: RR = 1.03, 95%CI [0.89, 1.18], P = 0.73; 8 weeks: RR = 0.98, 95% CI [0.85, 1.14], P = 0.84; 12 weeks: RR = 0.98, 95% CI [0.90, 1.08], P = 0.70; 24 weeks: RR = 1.02, 95% CI [0.94, 1.10], P = 0.66). After 24 weeks of treatment, patients treated with ETV had a significantly lower TBIL levels (MD = -37.34, 95% CI [-63.57, -11.11], P = 0.005), higher PTA levels (MD = 11.10, 95% CI [2.47, 19.73], P = 0.01) and higher HBV DNA negative rates (RR = 2.76, 95% CI [1.69, 4.51], P < 0.0001) than those treated with LAM. In addition, no drug related adverse effects were observed in the two treatment groups.

Conclusions:

ETV and LAM treatments had similar effects to improve 24 weeks survival rate of patients with CHB-associated liver failure, but ETV was associated with greater clinical improvement. Both drugs were tolerated well during the treatment. It is suggested to perform further studies to verify the results.     

Metabolic Impact of Rapamycin (Sirolimus) and B-Estradiol Using Mouse Embryonic Fibroblasts as a Model for Lymphangioleiomyomatosis

Introduction

Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease that predominantly affects women of childbearing age. Exogenous rapamycin (sirolimus) has been shown to improve clinical outcomes and was recently approved to treat LAM, whereas estrogen (E₂) is implicated in disease progression. No consistent metabolic model currently exists for LAM, therefore wild-type mouse embryonic fibroblasts (MEF +/+) and TSC2 knockout cells (MEF ?/?) were used in this study as a model for LAM.

Methods

Oxygen consumption rates (OCR) and redox potential were measured to determine metabolic state across control cells, MEF +/+ and ?/? cells treated with rapamycin (Rapa), and MEF +/+ and ?/? cells treated with E₂. An XF96 extracellular flux analyzer from Seahorse Bioscience^® was used to measure OCR, and a RedoxSYS? ORP was used to measure redox potential.

Results

OCR of MEF ?/? cells treated with rapamycin (MEF ?/? Rapa) versus MEF ?/? control were significantly lower across all conditions. The static oxidation reduction potential of the MEF ?/? Rapa group was also lower, approaching significance. The coupling efficiency and ratio of ATP-linked respiration to maximum respiration were statistically lower in MEF ?/? Rapa compared to MEF +/+ Rapa. There were no significant metabolic findings across any of the MEF cells treated with E₂. MEF ?/? control cells versus MEF +/+ control cells were not found to significantly differ.

Conclusion

MEF cells are thought to be a feasible metabolic model for LAM, which has implications for future pharmacologic and biologic testing.

     

Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus infection

Background

Nucleotide analogues have recently been approved for the treatment of patients with hepatitis B virus (HBV) infection. However, it is still controversial whether the decrease of HBV-DNA amount induced by treatment with nucleotide analogues can reduce the risk of hepatocellular carcinoma (HCC) development in HBV patients.

Methods

A total of 293 HBV patients without HCC who were treated with lamivudine (LAM) were enrolled in a multicenter trial. The incidence of HCC was examined after the start of LAM therapy, and the risk factors for liver carcinogenesis were analyzed. The mean follow-up period was 67.6?±?27.4?months.

Results

On multivariate analysis for HCC development in all patients, age ≥50?years, platelet count <14.0?×?10⁴/mm³, cirrhosis, and median HBV-DNA levels of ≥4.0?log copies/ml during LAM treatment were significant risk factors. The cumulative carcinogenesis rate at 5?years was 3% in patients with chronic hepatitis and 30% in those with cirrhosis. For the chronic hepatitis patients, the log-rank test showed the significant risk factors related to HCC development to be age ≥50?years, platelet count <14.0?×?10⁴/mm³, and hepatitis B e antigen negativity, but median HBV-DNA levels of <4.0?log copies/ml (maintained viral response, MVR) did not significantly suppress the development of HCC. In cirrhosis patients, however, the attainment of MVR during LAM treatment was revealed to reduce the risk of HCC development.

Conclusions

These results suggest that the incidence of HCC in HBV patients with cirrhosis can be reduced in those with an MVR induced by consecutive LAM treatment.     

Doxycycline use in patients with lymphangioleiomyomatosis: biomarkers and pulmonary function response ,

OBJECTIVE:

To assess blockade of matrix metalloproteinase (MMP)-2 and MMP-9, as well as the variation in FEV₁, in patients with lymphangioleiomyomatosis (LAM) treated with doxycycline (a known MMP inhibitor) for 12 months.

METHODS:

An open-label, single-arm, interventional clinical trial in which LAM patients received doxycycline (100 mg/day) for 12 months. Patients underwent full pulmonary function testing, a six-minute walk test, and quality of life assessment, as well as blood and urine sampling for quantification of MMP-2, MMP-9, and VEGF-D levels-at baseline, as well as at 6 and 12 months after the initiation of doxycycline.

RESULTS:

Thirty-one LAM patients received doxycycline for 12 months. Although there was effective blockade of urinary MMP-9 and serum MMP-2 after treatment, there were no significant differences between pre and post-doxycycline serum levels of MMP-9 and VEGF-D. On the basis of their response to doxycycline (as determined by the variation in FEV₁), the patients were divided into two groups: the doxycycline-responder (doxy-R) group (n = 13); and the doxycycline-nonresponder (doxy-NR) group (n = 18). The patients with mild spirometric abnormalities responded better to doxycycline. The most common side effects were mild epigastric pain, nausea, and diarrhea.

CONCLUSIONS:

In patients with LAM, doxycycline treatment results in effective MMP blockade, as well as in improved lung function and quality of life in those with less severe disease. However, these benefits do not seem to be related to the MMP blockade, raising the hypothesis that there is a different mechanism of action.     

A comparison of 4-year entecavir efficacy in nucleos(t)ide analog-naïve and -experienced adult Taiwanese chronic hepatitis B patients

Purpose

To compare the efficacy of entecavir (ETV) monotherapy up to 4 years in nucleos(t)ide analog (NA)-experienced and -naïve subjects.

Methods

One hundred sixty NA-experienced and 282 naïve chronic hepatitis B patients who were treated with ETV were enrolled. Of the 160 NA-experienced patients, 49 had prior lamivudine (LAM)-resistant mutants, 18 had resistant mutants to LAM followed by adefovir (ADV) after switching to ADV sequential therapy (LAM/ADV resistance), and 9 had prior ADV-resistant mutants. NA-resistant mutants were detected by line probe assay.

Results

Four years of ETV therapy resulted in virological response (VR, HBV DNA < 300 copies/ml), HBeAg seroconversion, and ETV-resistant mutants development in 98.2, 45.2, and <1 % of naïve patients, respectively. LAM- and ADV-experienced patients who never developed LAM-resistant mutants had similar VR and ETV-resistant mutant rates to NA-naïve patients. In contrast, prior LAM-resistant mutants were significantly associated with higher ETV-resistant mutants development and reduced VR rates. Patients with prior LAM-resistant mutants but not at baseline had a lower rate of ETV-resistant mutants compared to those with baseline LAM-resistant mutants [hazard ratio (HR): 0.58, 95 % confidence interval (CI): 0.35–0.95] and those who had LAM/ADV resistance (HR:0.16, 95 % CI:1.0.03–0.76). Early add-on ADV achieved VR in eight of nine patients with ETV-resistant mutants when HBV DNA was <2 × 10⁵ copies/ml.

Conclusions

Entecavir was highly efficacious and low resistance in NA-naïve, LAM-, or ADV-experienced patients without LAM-resistant mutants. Patients with prior LAM-resistant mutants but not at baseline had lower ETV-resistant mutant rates compared to those with baseline LAM-resistant mutants or LAM/ADV resistance.     

A low viral load predicts a higher initial virologic response to adefovir in patients with Lamivudine-resistant chronic hepatitis B

Background/Aims

Adefovir (ADV) is the preferred drug for treating lamivudine (LAM)-resistant hepatitis B. However, not all patients who face virologic breakthrough during LAM treatment respond to ADV. The aim of this study was to determine the factors associated with efficacy of ADV in LAM-resistant hepatitis B patients.

Methods

The medical records of 231 patients who received ADV due to LAM-resistance were reviewed. Efficacy was assessed by the initial virologic response (IVR), defined as hepatitis B virus (HBV) DNA not being undetectable by real-time PCR at 6 months of ADV treatment.

Results

Seventy patients (30%) achieved IVR. While ''add-on'' modality, hepatitis B e antigen (HBeAg) negativity, and low baseline HBV DNA levels were associated with IVR in univariate analysis, multivariate analysis revealed HBeAg status and the DNA level to be the significant factors. The probability of IVR achievement increased sharply per each log₁₀ copies/mL decrement in the baseline viral load, which was 133 times in patients who had HBV DNA <10⁵ copies/mL compared with those who had ≥10⁸ copies/mL.

Conclusions

Factors associated with the IVR were HBeAg negativity and a low baseline viral load. Therefore, when virologic breakthrough with genotypic resistance emerges during LAM therapy, ADV treatment should be considered immediately before further increases in viral load. Additional long-term follow-up data are warranted.     

COPD assessment test as a possible tool for evaluating health-related quality of life in lymphangioleiomyomatosis

Background

Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease that causes an obstructive ventilatory impairment similar to chronic obstructive pulmonary disease (COPD) and impairs the health-related quality of life (HRQoL). Here, we extended the use of the COPD assessment test (CAT) to patients with chronic respiratory diseases other than COPD. Specifically, the CAT was administered to patients with LAM for the first time.

Tenofovir rescue therapy in chronic hepatitis B patients who failed previous nucleoside analogue treatment

Background

Tenofovir (TDF) is considered as the first line therapy for chronic hepatitis B. This study presents the results of TDF monotherapy in patients who failed previous nucleoside analogue treatment.

Methods

The study included 29 patients treated with TDF 245 mg once daily for 18 months after lamivudine monotherapy (LAM arm: n = 15) or sequential therapy with lamivudine and entecavir (LAM → ETV arm: n = 14). The previous antiviral therapy was discontinued due to lack of efficacy. All patients had HBV DNA between 2.1 and 8.23 log₁₀ IU/ml and 15 were HBeAg-positive, while 45 % of patients had increased ALT activity. Undetectable HBV DNA (<20 IU/ml) at months 3, 6, 12 and 18 was the primary endpoint in the study, while HBeAg/HBsAg loss/seroconversion and ALT normalisation were secondary endpoints.

Results

Primary nonresponse to TDF was not observed. HBV DNA was undetectable in 80, 80, 80 and 93 % in LAM arm and 50, 71, 86 and 86 % in LAM → ETV arm patients, at 3, 6, 12 and 18 months of TDF therapy, respectively. One patient achieved anti-HBeAg seroconversion. 86.5 % of patients had normal ALT activity at the end of the study. The baseline HBV DNA load, HBeAg status and the length of the duration of TDF therapy appeared significantly associated with the response to the therapy. HBV DNA clearance occurred faster in HBeAg-negative patients than in those positive for HBeAg.

Conclusions

TDF is an effective antiviral medication in patients with previous exposure to LAM or LAM and ETV. Final proportion of patients who achieved undetectable HBV DNA and had normal ALT activity in both arms, was similar.

     

Clinical Predictors of Mortality and Cause of Death in Lymphangioleiomyomatosis: A Population-based Registry

Purpose

Lymphangioleiomyomatosis (LAM) is a rare, progressive, frequently lethal cystic lung disease that almost exclusively affects women. Prognostic information in LAM has been limited by small numbers and heterogeneous study methodology. Early retrospective cohorts cited 5- and 10-year mortality of 40 and 80 %, respectively. More recently, mortality at 10 years has been estimated to be approximately 10–20 % from the onset of symptoms and 30 % at 10 years from the time of lung biopsy but varies widely in individual patients. Given the heterogeneous disease course, it would be useful to establish which clinical characteristics are associated with survival to develop prediction models for disease outcome.

Methods

The LAM Foundation maintains a population-based registry of 1,149 registered self-identified LAM patients. Of these, 590 have completed a “General Information/Clinical History Questionnaire” with limited demographic and clinical data, 410 of whom were identified as U.S. residents and provided date of birth. Vital status was obtained on all 410 participants through December 31, 2007 by linking patient identifiers and the National Death Index. Survival time was calculated as the time since first lung-related symptom or physician diagnosis until censoring (still alive, received lung transplant, or died). Cox proportional hazard analysis evaluated the association of demographic and clinical features with survival.

Results

Among the 410 subjects, there were 50 deaths and 55 lung transplantations during a median of 10.4 years of observation time. The estimated median transplant-free survival time for LAM patients in the United States is 29 years from symptom onset and 23 years from diagnosis. The estimated 10-year survival transplant-free was 86 %. Age at disease onset, smoking status, race, presence of tuberous sclerosis, occurrence of pneumothorax, and pregnancy did not demonstrate an association with survival or transplant. Greater age at presentation and presence of angiomyolipoma were associated with less risk of mortality. Treatment with hormonal therapy was associated with an increased risk of death/transplant (hazard ratio (HR) 2.93; 95 % confidence interval (CI), 1.54–5.58; p = 0.001), particularly progesterone therapy (HR 2.17; 95 % CI 1.26–3.75, p = 0.005), and may represent confounding by indication. Patients who required oxygen therapy had a worse outcome (HR 4.53; 95 % CI 2.76–7.42; p < 0.001).

Conclusions

Our population-based study showed that the median survival in patients with LAM from the onset of symptoms or diagnosis is much longer than previously described. This has important implications for life choices and treatment decisions regarding medication use and lung transplantation for patients with LAM.     

Renal dysfunction and hypophosphatemia during long-term lamivudine plus adefovir dipivoxil therapy in patients with chronic hepatitis B

Background

Renal dysfunction and Fanconi’s syndrome associated with hypophosphatemia caused by long-term administration of low-dose adefovir dipivoxil (ADV) has been reported in recent years. The aim of this retrospective study was to determine the incidence and factors associated with renal dysfunction and hypophosphatemia in patients with hepatitis B infection on long-term treatment with ADV and lamivudine (LAM).

Methods

The study subjects were 292 patients treated with 10 mg/day ADV and 100 mg/day LAM for more than 6 months. We evaluated estimated glomerular filtration rate (eGFR), serum creatinine and serum phosphate level at the start of ADV and every 6 months.

Result

During a median treatment duration of 64 months, 28 (9.6 %) patients developed renal impairment (defined as eGFR < 50 ml/min/1.73 m²), and 73 (27.1 %) developed hypophosphatemia, including 14 with persistent hypophosphatemia. The cumulative incidences of renal impairment at 1, 3, and 5 years were 1.4, 7.5, 10.5 %, respectively, and those of hypophosphatemia were 6.8, 20.6, 26.7 %, respectively. Multivariate analysis identified old age, liver cirrhosis and hypertension as determinants of renal impairment, and male sex, HCC, low baseline serum phosphate as determinants of hypophosphatemia. Three of the 14 patients with persistent hypophosphatemia developed Fanconi’s syndrome; their serum creatinine level remained normal, but eGFR was lower than at baseline.

Conclusion

Long-term treatment of hepatitis B with low-dose (10 mg/day) ADV and LAM can potentially cause renal impairment and hypophosphatemia. We advocate regular monitoring of serum phosphate and evaluation of eGFR, in addition to serum creatinine, in such patients.     

Frequency and mutation patterns of resistance in patients with chronic hepatitis B infection treated with nucleos(t)ide analogs in add-on and switch strategies

Background

Treatment for chronic hepatitis B (CHB) has improved over the last 10 years mainly due to the development of effective oral antiviral agents [nucleoside/nucleotide analogs (NUCs)].

Objectives

The aim of the present study is to identify the frequency and major patterns of resistance to the hepatitis B virus (HBV) in a Turkish population of CHB patients treated with NUCs using add-on and switch therapy strategies. Patients and Methods: The investigation involved a total of 194 patients (88 were treated using add-on therapy, and 106 were treated using switch therapy). We analyzed the HBV polymerase gene by amplification and direct sequencing procedures.

Results

Primary drug-resistance mutations were detected in 84 patients (43%; 42 in add-on therapy, and 42 in switch therapy) taking lamivudine (LAM), 10 patients (5%; 6 in add-on therapy, and 4 in switch therapy) taking entecavir (ETV), and 16 patients (8%; 8 in add-on therapy, and 8 in switch therapy) taking adefovir (ADV). The most common LAM and ETV resistance mutations were rtM204I/V, rtL180M and rtT184A/I/S, respectively, while rtA181T/V and rtN236T substitutions were the most frequently observed ADV resistance mutations.

Conclusions

Patients with CHB who developed NUC resistance were managed using 2 different rescue strategies. The frequency and mutation pattern of resistance were similar in patients treated with add-on and switch strategies. These findings may be helpful in the management of rescue strategies in LAM-resistant patients.     

Entecavir therapy in Turkish adult patients with chronic hepatitis B: one-year results from Izmir province, Turkey

Background

In the present study, we aimed to present the initial results of chronic hepatitis B patients who received entecavir (ETV) therapy in our hospital in Izmir, Turkey.

Methods

A total of 52 patients were enrolled in the study. ETV was given in a dosage of 0.5 mg/day and 1 mg/day to 50 patients without Lamivudine/Adefovir (LAM/ADV) resistance and to 2 patients with LAM resistance, respectively. ETV was given in a dose of 0.5mg/day every three days to one patient with a renal transplant. The treatment duration was 48 weeks.

Results

Out of a total of 52 patients, 23 (44.23%) were hepatitis B e antigen (HBeAg)-positive, and 29 (55.77%) of them were HBeAg-negative. In 29 HBeAg-negative patients, early biochemical and virological responses were 82.6% and 100%, respectively. These responses were 97% and 79.3% in the 12th month. In HBeAg-positive patients, early biochemical and virological responses were found to be 78.3% and 82.6%, respectively. They were 100% and 52.2% in the 12th month. HBeAg s oconversion developed in 4.5% of HBeAg-positive patients.

Conclusions

According to our one-year ETV treatment results, both HBeAg-negative and -positive patients had high biochemical and virological response rates. Their HBeAg seroconversion rate was 4.5%. In conclusion, more studies of longer duration are needed to understand the required duration of treatment, to assess its long-term effectiveness, and to check the resistance and side effects of ETV. There is also a need to have late-phase results after treatment.     

Successful treatment with lamivudine may correlate with reduction of serum ferritin levels in the patients with chronic hepatitis and liver cirrhosis type B

Purpose  To study the changes in serum ferritin levels in lamivudine (LAM)-treated patients with chronic hepatitis and liver cirrhosis type B and determine whether successful treatment with LAM results in a reduction of serum ferritin levels. Methods  Thirty patients with chronic hepatitis B virus (HBV) infection were followed prospectively during their treatment with LAM for 12 months. Serum HBV DNA, ferritin levels, and emergence of YMDD mutants were monitored. A case of severe liver cirrhosis with hepatic hemosiderosis that was treated successfully with LAM also is shown as a representative case. Results  Serum alanine aminotransferase and ferritin levels decreased significantly more in the patients treated with LAM without YMDD mutants (n = 23) than those with mutants (n = 7). Hepatic hemosiderosis along with serum iron markers improved greatly in the representative patient. Conclusion  Successful treatment with LAM may reduce serum ferritin levels and improve hepatic siderosis in a subset of patients with chronic HBV infection. A study of Niigata-Zeffix investigation meeting.