Haematological acclimation and re-acclimation to hypoxia in the mouse

Haematological responses throughout 4 w of initial acclimation (IA) and three paradigms of re-acclimation (RA) to hypoxia (FI_O2=0.12${\text{FI}}_{{\text{O}}_2}=0.12$) were examined in female mice. We hypothesised that (i) haematological responses would be increased during re-exposure, resulting in greater O₂-carrying capacity in RA compared to IA; and (ii) further improvements would occur when abbreviating the de-acclimation period to 1 w (RA_↓DA) or extending the IA period to 8 w (RA_↑IA). The serum [EPO] response was blunted in all RA groups compared to IA but the resulting reticulocyte response was similar in all experimental groups. The [Hb] response was the same in RA and RA_↓DA as in IA but was blunted in RA_↑IA due to a reduction in mean corpuscular Hb. The sensitivity of EPO-producing cells appears blunted but the sensitivity of erythroid precursors to EPO is enhanced by recent hypoxic exposure. Erythropoietic regulation is altered during RA in a manner that is dependent on the paradigm of initial exposure.     

Health utilities and psychometric quality of life in patients with early- and late-stage hepatitis C virus infection

Background and Aim: Hepatitis C virus (HCV) infection is associated with impairment in health‐related quality of life (HRQOL). The purpose of this study was to evaluate HRQOL across the HCV disease spectrum using preference‐based (utility) and non‐preference‐based (psychometric) methods, adjusting for sociodemographic factors and co‐morbidity. Methods: Hepatitis C virus patients (n = 751) were recruited from several tertiary care settings in Vancouver, Canada for this observational, cross‐sectional cohort study. Patients completed the Health Utilities Index Mark 2/3, a self‐administered time trade‐off utility instrument, and the Hepatitis Quality of Life Questionnaire (SF‐36 with HCV‐specific items). We examined the association between HRQOL and disease stage using linear regression adjusting for age, education, marital status, income, and co‐morbidities. Results: Utility scores were low across disease stage and instrument, ranging from 0.51 to 0.80. On the SF‐36, the mean Physical Component Summary score ranged from 37.2 to 49.2 across disease stage, and the Mental Component Summary score ranged from 39.7 to 45.7 (United States norms = 50). In general, patients with viral clearance had the highest scores, and those with late‐stage disease (cirrhosis, liver cancer) had the lowest. Multivariable linear regression showed that the effect of disease stage was modest overall. Increasing age, lower income, unattached marital status, and high comorbidity were strongly associated with impairment in HRQOL. Conclusions: The effect of stage of disease on HRQOL is modest, although viral clearance is associated with higher HRQOL. HCV patients' HRQOL is strongly associated with concomitant illness and sociodemographic factors.     

Optimal follow-up time to determine the sustained virological response in patients with chronic hepatitis C receiving pegylated-interferon and ribavirin

Background and Aim: This study evaluated whether the assessment of hepatitis C virus (HCV)‐RNA at 12 weeks (FW+12) post‐treatment follow‐up was as applicable as FW+24 to evaluate sustained virological response (SVR) using the highly sensitive real‐time polymerase chain reaction (PCR) HCV assay. Methods and Results: Two hundred and twenty‐two patients with chronic hepatitis C were included in this study. Pegylated interferon (Peg‐IFN) and ribavirin were administered for 24–72 weeks based on the genotype and viral load. Serum HCV‐RNA was measured using real‐time PCR at pretreatment, the end of treatment, FW+4, FW+8, FW+12, FW+16, FW+20 and FW+24. Two hundred patients had a virological response at the end of treatment. One hundred and forty‐eight of 200 (74.0%) patients with a virological response at the end of treatment had an SVR at the FW+24. The positive predictive value (PPV) to identify patients with SVR at FW+4, FW+8, FW+12 was 87.1, 96.1, 98.0%, respectively. The viral load showed a reversion to the basal level as early as 8 weeks in relapse patients. There were only three patients who relapsed after FW+12 and all three of these patients were females with genotype Ib and a high viral load. Conclusion: The assessment of serum HCV‐RNA FW+12, using the highly sensitive real‐time PCR assay, is almost as effective as FW+24 to predict SVR. However, there are false negatives in female patients with a high viral load of genotype Ib when the SVR is predicted by FW+12. The current standard with FW+24 is reasonable, but the assessment of serum HCV‐RNA FW+12 may be effective in most patients.     

Longitudinal changes of the laboratory data of chronic hepatitis C patients with sustained virological response on long-term follow-up

There is no study that follows up longitudinal changes in laboratory data of patients with C-viral chronic liver disease (C-CLD) who achieved sustained virological esponse (SVR) with interferon treatment in a long-term study. We investigated the laboratory data in a long-term retrospective cohort study of 581 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005. 467 were treated with interferon and 207 of these patients achieved SVR with follow-up periods of 8.36 ± 5.13 years. Alanine aminotransferase (ALT) levels, albumin levels, platelet counts, and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values were serially examined during the follow-up period. None of the 207 patients with SVR exhibited hepatitis C virus (HCV) RNA positivity more than 6 months after the end of IFN treatment. Platelet counts and albumin levels increased only in those with eradication of HCV. APRI values decreased more in patients with SVR than in those with nonsustained virological responses (non-SVR). Patients who achieved SVR and had fibrosis stage 0-1 and 2-4 at enrolment had platelet counts that longitudinally increased by 2.81 ± 3.95 and 5.49 ± 4.53 × 10(3) /μL during the 10-year follow-up period, respectively. Albumin levels continuously increased during the first 2 years by 0.15 ± 0.31 and 0.33 ± 0.37 in fibrosis stage 0-1 and 2-4, respectively and then plateaued. ALT levels decreased rapidly one year after the start of treatment by 110.3 ± 140.0 and 100.5 ± 123.4 in fibrosis 0-1 and 2-4, respectively. HCV RNA negativity persisted in all patients with SVR, and laboratory data including APRI longitudinally improved during the long-term follow-up period.     

Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C

The aims of this phase III study were to assess the efficacy and safety of telaprevir in combination with peginterferon alfa-2b (PEG-IFN) and ribavirin (RBV) for difficult-to-treat patients who had not achieved sustained virological response (SVR) to prior regimens in Japan. The subjects were 109 relapsers (median age of 57.0 years) and 32 nonresponders (median age of 57.5 years) with hepatitis C virus genotype 1. Patients received telaprevir (750 mg every 8 h) for 12 weeks and PEG-IFN/RBV for 24 weeks. The SVR rates for relapsers and nonresponders were 88.1% (96/109) and 34.4% (11/32), respectively. Specified dose modifications of RBV that differed from that for the standard of care were introduced to alleviate anaemia. RBV dose reductions were used for 139 of the 141 patients. The SVR rates for relapsers did not depend on RBV dose reduction for 20-100% of the planned dose (SVR rates 87.5-100%, P < 0.05). Skin disorders were observed in 82.3% (116/141). Most of the skin disorders were controllable by anti-histamine and/or steroid ointments. The ratios of discontinuation of telaprevir only or of all the study drugs because of adverse events were 21.3% (30/141) and 16.3% (23/141), respectively. A frequent adverse event leading to discontinuation was anaemia. Telaprevir in combination with PEG-IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period.     

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

Summary. It is unclear whether the current threshold for ‘high’ hepatitis C virus (HCV) RNA level (800 000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono‐infected and 176 HIV–HCV co‐infected patients treated with peginterferon alfa‐2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono‐infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400 000 IU/mL was used and 16% (59%vs 43%) when 800 000 IU/mL was used. In HIV–HCV genotype 1 co‐infected patients, the difference was 51% (71%vs 20%) when 400 000 IU/mL was used and 43% (61%vs 18%) when 800 000 IU/mL was used. A lower threshold (200 000 IU/mL) was identified for genotype 1 mono‐infected patients with ‘normal’ alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400 000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1‐infected individuals with elevated ALT.     

载三联抗结核药硫酸钙/氨基酸聚合物人工骨体内缓释实验研究

目的:观察载异烟肼、利福平、吡嗪酰胺三联抗结核药硫酸钙/氨基酸聚合物人工骨在大鼠体内的缓释效果.方法:取6～7周龄SD大鼠80只,随机分为实验组与对照组,实验组载三联抗结核药人工骨植入大鼠骶脊肌内,40只;对照组植入空白未载药人工骨于大鼠骶脊肌内,40只;术后1d、3d、1周、2周、4周、6周、8周、12周处死大鼠,每次处死实验组、对照组大鼠各5只,应用高效液相色谱法检测大鼠植入人工骨局部周边组织及血液中三种药物浓度,2周及6周时HE染色观察大鼠肝、肾病理组织学变化.结果:植入载三联抗痨药人工骨局部周边1cm肌肉组织中,术后1d、3d、1周、2周、4周、6周、8周、12周时,高效液相色谱法检测异烟肼为4.09 ±0.56μg/ml、2.45 ±1.33μg/ml、2.12±1.56μg/ml、1.58 ±4.12μg/ml、2.09 ±2.35μg/ml、2.31 ±1.44μg/ml、4.26±2.17 μg/ml、3.79 ±0.49 μg/ml;利福平为4.02±1.14 μg/ml、1.90±0.11 μg/ml、1.88±0.90μg/ml、0.79±1.08 μg/ml、0.86±0.44μ g/ml、0.89±0.98μg/ml、3.92± 1.09μ g/ml、3.57±0.22μg/ml;吡嗪酰胺为460.87±1.41 μg/ml、440.91±1.69 μg/ml、430.21 ±0.86μg/ml、340.73± 1.45μg/ml 、320.85±2.0μg/ml、270.61±1.0μg/ml、230.38±0.48μg/ml;12周时植骨块局部组织,周边1cm肌肉组织异烟肼、利福平、吡嗪酰胺能达到10倍最低抑菌浓度,静脉血三种药物平均浓度为2.79μg/ml、2.02μg/ml、4.38 μg/ml低于植骨块局部周边浓度;肝、肾组织组织病理学检查未见损伤.结论:载三联抗结核药硫酸钙/氨基酸聚合物人工骨体内释放平稳,可实现体内局部用药缓释;其可直接植入体内,对肝、肾组织无明显药物损伤.     

Virological response for recurrent hepatitis C improves long‐term survival in liver transplant recipients

Recurrent hepatitis C virus (HCV) infection occurs universally and is regarded as a major cause of mortality after liver transplantation (LT) for HCV‐related end‐stage liver disease. We conducted this large, single‐center, retrospective study to ascertain the long‐term impact of virological response to treatment of recurrent hepatitis C on survival of LT recipients. From August 1987 to October 2011, 285 patients have received interferon‐based antiviral therapy for recurrent hepatitis C. Of these 285, 245 patients were enrolled in this study. One hundred and twenty‐six patients (51.4%) achieved sustained virological response (SVR). Relapsers (undetectable HCV‐RNA at end of treatment, becoming positive afterward) comprised 9.0% (22/245), and nonresponse (NR; never achieving undetectable HCV‐RNA) 39.6% (97/245). The median follow‐up after completion of antiviral treatment was 2081 days. Using Kaplan–Meier method, patients who achieved SVR were shown to have significantly better 5‐year patient survival (95.2%) than the NR group (49.9%) (P < 0.001), and a trend toward better 5‐year survival than relapsers (87.5%) (P = 0.14); relapsers had a significantly longer survival than NR group (P = 0.005). When compared with NR, SVR and relapse appeared to be significant predictors of better survival, independent of underlying characteristics. In conclusion, virological response, especially SVR, translates into markedly improved long‐term patient outcomes in patients transplanted for hepatitis C.