Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients.METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome.RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria.CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.     

Hyperreactio luteinalis associated with fetal hyperandrogenism and cystic hygroma

A 23‐year‐old woman with a gestational age of 17 weeks presented with abdominal pain. The ultrasound showed maternal hyperreactio luteinalis with fetal cystic hygroma. After termination of pregnancy, the female fetus showed masculinization features with muscular hypertrophy. The hyperreactio luteinalis regressed under hormonal suppression therapy.     

Characterization of alkaline and acid phosphatases from skeletal muscles of young and old rats

Alkaline phosphatase (ALP) and acid phosphatase (ACP) specific activities were measured in gastrocnemius muscles of female Wistar rats ranging in age from 2 to 30 months. ALP activity reached a peak at 12 months, with a subsequent slow decline with age. ACP activity increased sharply up to 12 months of age, followed by a slower elevation up to the age of 30 months. Using histochemical staining techniques and electron microscopy, the presence of ALP was demonstrated in the sarcolemma of gastrocnemius muscles, as well as in some capillaries around muscle fibers. ALP and ACP were isolated further from muscles of young (12 months) and old (30 months) animals by applying ion-exchange chromatography and separation on a Sephadex G-200 column. The purity of ALP was shown on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). From a calibrated Sephadex G-200 column and SDS-PAGE, the molecular mass of ALP was determined as 116 kilodaltons (kDa), a dimer of two 56-kDa monomers. The ACP major peak of the Sephadex G-200 column revealed a molecular mass of 40 kDa. No differences in molecular mass or in amino acid analysis were detected between ALP(s) from young and old animals, indicating that most probably the decline of activity with age is due to some post-translational events, as has been shown in the past for many other enzymes and proteins.     

Effect of Laparoscopic fundoplication on gastroesophageal reflux disease-induced respiratory symptoms

Laparoscopic fundoplication controls heartburn and regurgitation, but the effects on the respiratory symptoms of gastroesophageal reflux disease (GERD) are unclear. Confusion stems from difficulty preoperatively in determining whether cough or wheezing is actually caused by reflux when reflux is found on pH monitoring. To date, there is no proven way to pinpoint a cause-and-effect relationship. The goals of this study were to assess the following: (1) the value of pH monitoring in establishing a correlation between respiratory symptoms and reflux; (2) the predictive value of pH monitoring on the results of surgical treatment; and (3) the outcome of laparoscopic fundoplication on GERD-induced respiratory symptoms. Between October 1992 and October 1998, a total of 340 patients underwent laparoscopic fundoplication for GERD. From the clinical findings alone, respiratory symptoms were thought possibly to be caused by GERD in 39 patients (11 %). These 39 patients had been symptomatic for an average of 134 months. They were all taking H-blocking agents (21 %) or proton pump inhibitors (79%). Seven patients (18%) were also being treated with bronchodilators, alone (3 patients) or in combination with prednisonc (4 patients). Median length of postoperative follow-up was 28 months. In 23 patients (59%) a temporal correlation was found during 24-hour pH monitoring between respiratory symptoms and episodes of reflux. Postoperatively heartburn resolved in 91% of patients, regurgitation in 90% of patients, wheezing in 64% of patients, and cough in 74% of patients. Cough resolved in 19 (83%) of 23 patients in whom a correlation between cough and reflux was found during pH monitoring, but in only 8 (57%) of 14 of patients when this correlation was absent. Cough persisted postoperatively in the two patients who did not cough during the study. These data show that pH monitoring helped to establish a correlation between respiratory symptoms and reflux, and it helped to identify the patients most likely to benefit from antircflux surgery. Following laparoscopic surgery, respiratory symptoms resolved in 83% of patients when a temporal correlation between cough and reflux was found on pH monitoring; heartburn and regurgitation resolved in 90%. Presented at the Fortieth Annual Meeting ot The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999.     

Influence of estrogen deficiency and replacement on T-cell populations in rat lymphoid tissues and organs

Estrogen deficiency following ovariectomy or menopause results in bone loss. Although evidence strongly suggests that the immune system is involved in the pathogenesis of estrogen-deficient osteoporosis, it is not clear what role, if any, the T-lymphocyte plays in this process. Therefore, we examined the distribution of T-cell subsets in lymphoid organs and tissues, under varying estrogenic states in the rat. Six-month-old female Sprague-Dawley rats, ovariectomized (Ovx) and sham-operated, were randomized 5 d post-surgery into six groups to receive the following treatments: (A) sham/placebo; (B) sham/low-dose E₂; (C) sham/high-dose E₂; (D) Ovx/placebo; (E) Ovx/low-dose E₂; (F) Ovx/high-dose E₂. Half of the treated rats (groups A–F) were sacrificed on d 14; the remainder on d 28. Following euthanasia, mononuclear cells were isolated from the thymus, peripheral blood, spleen, lymph node and bone marrow, and were labeled for flow cytometric analysis using mouse anti-rat monoclonal antibodies directed against CD5, CD4, and CD8 antigenic markers. In the thymus, ovariectomy caused a dramatic increase and E₂ treatment caused a dose-dependent decrease in weight that was proportional to the number of thymocytes. In the bone marrow, ovariectomy caused a significant reduction in the percentage of all T-cell subsets examined and this effect persisted throughout the duration of the study. Estrogen replacement therapy at the low-dose reversed the effects of ovariectomy and high-dose E₂ treatment caused an increase in T-cell subsets in both the sham and Ovx groups, an effect that was more pronounced at d 14 compared with d 28. Although the percentages of some T-cell subsets in the other lymphoid organs/tissues were altered by ovariectomy or E₂ treatment at d 0 and 14, all these changes had normalized by d 28 except for CD5 and CD4 cells in peripheral blood. In summary, with the exception of T-lymphocytes in the bone marrow, the effects of varying estrogenic states on T-cells were variable and transient. The influence of estrogen status on bone marrow T-lymphocytes suggests that these cells may play a role in mediating the effects of estrogen on bone turnover and warrant additional studies focusing on the functional role of T-cells in the bone marrow compartment.     

Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: safety and antiviral properties

Treatment of chronic hepatitis B virus (HBV) infection with interferon alfa and lamivudine is characterized by lack of viral clearance, loss of response, or emergence of drug-resistant mutants. Thus, new and multiple drug approaches are needed. We have developed two fully human monoclonal antibodies, directed against different epitopes of hepatitis B surface antigen (HBsAg) that bind to all major HBV subtypes. A phase I clinical study was conducted to evaluate the safety, tolerability, and efficacy of a mixture of these two monoclonal antibodies, HBV-AB(XTL). A total of 27 chronic HBV patients were enrolled. In part A of the study 15 patients in 5 cohorts received a single intravenous infusion of antibodies with doses ranging from 0.26 mg (260 IU) to 40 mg (40,000 IU). All patients completed 16 weeks of follow-up. In the second part of the study (part B), 12 patients in 4 cohorts received 4 weekly infusions of 10, 20, 40, or 80 mg each of HBV-AB(XTL) and were followed for 4 additional weeks. Administration of antibodies was well tolerated. Patients administered doses at an Ab:Ag molar ratio of 1:2 to 1:20 showed a rapid and significant decrease in HBsAg to undetectable levels, with a corresponding reduction of HBV-DNA levels. In part B, HBV-AB(XTL) induced a significant reduction in both HBsAg and HBV-DNA levels repeatedly after administration. In conclusion, these data suggest that HBV-AB(XTL) binds HBV particles and reduces serum viral titers and HBsAg levels. HBV-AB(XTL) could be combined with other monotherapies that are currently used to treat HBV carriers.