Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial

BACKGROUND: In Japan, glycyrrhizin therapy is widely used for chronic hepatitis C and reportedly reduces the progression of liver disease to hepatocellular carcinoma. The aims of this study were to evaluate the effect of glycyrrhizin on serum alanine aminotransferase (ALT), hepatitis C virus (HCV)-RNA and its safety in European patients. METHODS: Fifty-seven patients with chronic hepatitis C, non-responders or unlikely to respond (genotype 1/cirrhosis) to interferon therapy, were randomized to one of the four dose groups: 240, 160 or 80 mg glycyrrhizin or placebo (0 mg glycyrrhizin). Medication was administered intravenously thrice weekly for 4 weeks; follow up also lasted for 4 weeks. RESULTS: Within 2 days of start of therapy, serum ALT had dropped 15% below baseline in the three dosage groups (P < 0.02). The mean ALT decrease at the end of active treatment was 26%, significantly higher than the placebo group (6%). A clear dose-response effect was not observed (29, 26, 23% ALT decrease for 240, 160 and 80 mg, respectively). Normalization of ALT at the end of treatment occurred in 10% (four of 41). The effect on ALT disappeared after cessation of therapy. During treatment, viral clearance was not observed: the mean decrease in plasma HCV-RNA after active treatment was 4.1 x 10(6) genome equivalents/mL (95% confidence interval, 0-8.2 x 10(6); P > 0.1). No major side-effects were noted. None of the patients withdrew from the study because of intolerance. CONCLUSIONS: Glycyrrhizin up to 240 mg, thrice weekly, lowers serum ALT during treatment, but has no effect on HCV-RNA levels. The drug appears to be safe and is well tolerated. In view of the reported long-term effect of glycyrrhizin, further controlled investigation of the Japanese mode of administration (six times weekly) for induction appears of interest.     

Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study

BACKGROUND AND AIMS: Hepatitis C virus (HCV) reinfection after liver transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use of antiviral therapy in this situation remains controversial. This study aimed to assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent hepatitis C following liver transplantation. METHODS: Transplant recipients with recurrent chronic hepatitis C were randomized to receive either no treatment or therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day ribavirin for 1 year. Patients were followed up for 6 months after the end of treatment. The primary end point was loss of HCV RNA 6 months after the end of treatment. RESULTS: Fifty-two patients were randomized (treatment, 28; placebo, 24). Sixteen patients were withdrawn from the study; 12 (43%) were from the treated group (mainly for anemia [7 patients]) and 4 (17%) from the control group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point (P = 0.036 at the end of follow-up). However, there was no significant histologic improvement. CONCLUSIONS: The combination of interferon alfa-2b plus ribavirin induced a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. However, 43% discontinued therapy due to adverse events (primarily severe anemia). Strategies to enable treatment with lower doses of ribavirin need to be explored.     

Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naïve patients with chronic hepatitis C

BACKGROUND AND AIM: In this study, we compared the efficacy of triple therapy (interferon alfa, ribavirin, and amantadine) with standard therapy (interferon alfa and ribavirin) in treatment na?ve patients with chronic hepatitis C virus (HCV). METHODS: In this prospective, randomised, double blind, placebo controlled, multicentre study, 85 patients (amantadine group) received a three drug regimen of interferon alfa-2b 3 million units three times per week, ribavirin 1000-1200 mg daily in divided doses, and amantadine 100 mg twice daily, and 86 patients (placebo group) received interferon alfa-2b, ribavirin, and identical placebo. Treatment was discontinued at 24 weeks if patients had detectable HCV RNA by polymerase chain reaction (PCR). All patients were followed for 24 weeks after completion of treatment. The primary end point was undetectable HCV-RNA by PCR at 24 weeks (sustained viral clearance) after completion of treatment. RESULTS: At the end of treatment, HCV RNA clearance was seen in 32.9% of the amantadine group and 38.4% of the placebo group (p=0.3). Sustained virological response was seen in 24.7% of the amantadine group and in 27.9% of the placebo group by intention to treat analysis; response rate was 30.4% and 34.8%, respectively, in those who completed 24 weeks of treatment. Poor response was seen in both groups among cirrhotics, African-Americans, genotype 1, and those with a higher viral load. By multivariate analysis, genotype 1, high viral load, and low serum albumin were the only predictors of poor response. Addition of amantadine to the standard regimen did not result in any unexpected side effects. CONCLUSION: Response to triple therapy of interferon alfa, ribavirin, and amantadine was similar to standard therapy of interferon alfa and ribavirin. Our results suggest that amantadine has no role in the management of HCV.     

Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C

OBJECTIVE: In Japan, ALT normalization induced by long-term i.v. glycyrrhizin treatment reportedly reduces the progression of liver disease to hepatocellular carcinoma in chronic hepatitis C patients. The aim of this study was to evaluate the short-term (4-wk) feasibility and efficacy on serum ALT of three or six times per week i.v. glycyrrhizin therapy in European patients. METHODS: Patients with chronic hepatitis C, nonresponders, or unlikely to respond (genotype 1/cirrhosis) to interferon therapy were included in this study. Medication was administered i.v. three or six times per week for 4 wk; follow-up also lasted 4 wk. RESULTS: Sixty-nine out of 72 treatment courses were completed according to protocol. There were no significant changes in ALT levels within the placebo group (n = 13). The mean percentage ALT decrease from baseline at the end of treatment was 26% and 47% for the three times per week and six times per week treatment group, respectively (both p < 0.001 vs placebo). At the end of active treatment, 10% (four of 41) and 20% (three of 15) of the patients reached normal ALT levels for the three times per week and six times per week treatment group, respectively. The ALT lowering effect disappeared after cessation of treatment. No major side effects were observed. CONCLUSION: It appeared feasible to treat European outpatients with chronic hepatitis C three or six times per week with i.v. glycyrrhizin. Glycyrrhizin treatment induces a significant ALT decrease in patients with chronic hepatitis C. Six times per week treatment appears more effective than three times per week.     

A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance

We examined the feasibility of hepatitis C treatment in patients on opioid maintenance. One hundred patients with chronic hepatitis C, 50 on methadone maintenance, and 50 with no intravenous drug use or opioid maintenance for at least 5 years were prospectively matched for sex, age, hepatitis C virus (HCV) genotype and HCV RNA. The primary end point was undetectable HCV RNA at 24 weeks posttreatment. Treatment with peginterferon alfa-2b (1.5 microg/kg per week) and ribavirin (1000-1200 mg /day) was initiated for 24 weeks (HCV genotype 2, 3) or 48 weeks (HCV genotype 1, 4). Within the first 8 weeks of therapy, discontinuation due to noncompliance or patient request was observed in 22% (11/50) in the methadone group versus 4% (2/50) in the control group (P =.02). After 8 weeks, there was no significant difference in discontinuation due to noncompliance or patient request (4/39 [10%] vs. 4/48 [8%]). There was no difference in discontinuation of therapy because of viral failure or adverse events (10/50 methadone vs. 6/50 control, P =.41). At the end of treatment, 50% (25/50) in the methadone group and 76% (38/50) in the control group had undetectable HCV RNA (P =.01). Sustained viral response was 42% (21/50) in the methadone group and 56% (28/50) in the control group (P =.16). No serious psychiatric event occurred in either group. In conclusion, peginterferon and ribavirin seem reasonably safe and sufficiently effective in patients on methadone maintenance. Patients discontinuing therapy due to noncompliance or request did so early, thereby limiting the cost of an unsuccessful approach to treatment.     

Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial

BACKGROUND/AIMS: Phase I/II studies of 4 weeks duration have confirmed the ALT lowering effect of glycyrrhizin in Western chronic hepatitis C patients. Our aim was to determine the dose frequency of glycyrrhizin required to maintain the ALT response beyond 4 weeks and evaluate its effect on liver histology and quality of life. METHODS: HCV-RNA-positive patients with elevated ALT and marked fibrosis or necro-inflammation who were not eligible for interferon therapy were treated for 4 weeks with six infusions weekly of glycyrrhizin. Patients with an ALT response at week 4 were randomized to continue treatment for 22 weeks in three dose frequency groups: 6x, 3x or once weekly. RESULTS: 72/121 (60%) patients were randomized. At the end of treatment the ALT response was maintained in 60%, 24% and 9% of patients in the 6x, 3x, and once weekly groups, respectively (p<0.001). In ALT responders the necro-inflammation score improved non-significantly compared to ALT non-responders. Quality of life assessed by SF-36 increased in patients treated with the study drug, albeit unrelated to the occurrence of ALT response. CONCLUSIONS: ALT responses induced by 4 weeks glycyrrhizin therapy can be maintained in a subset of chronic hepatitis C patients receiving at least three injections weekly. The observed ALT response did not translate in a significant histological improvement after 6 months treatment.     

Interferon Beta 1a versus Interferon Beta 1a plus Ribavirin for the Treatment of Chronic Hepatitis C in Chinese Patients: A Randomized, Placebo-Controlled Trial

For chronic hepatitis C virus (HCV) infection, the effects of current therapies are limited. To evaluate the efficacy and safety of the interferon beta-1a (IFN β-1a) versus IFN β-1a plus ribavirin (RBV) combination on Chinese treatment-naïve patients with chronic hepatitis C, a randomized, placebo-controlled study was performed. A total of 26 naïve patients histologically confirmed to have chronic hepatitis C were double-blindly and randomly assigned to receive either IFN β-1a 44 μg (12 MIU) (IFN β-1a group) or placebo (placebo group) three times per week for 12 weeks. At the end of the 12 weeks of treatment, the patients who received IFN β-1a continued to complete 24 weeks of treatment. Placebo non-responders were crossed over to IFN β-1a plus RBV (1,000–1,200 mg/day) combination therapy (IFN β-1a plus RBV group) for 24 weeks after 4 weeks washout. All patients were followed up for 24 weeks after the end of treatment. Sustained virological response (SVR) was defined as the absence of detectable HCV RNA in the serum both at the end of 24 weeks of treatment and at the end of 24 weeks of untreated follow-up. There were no differences in the clinical background between the groups before the initiation of treatment. At the end of the 12 weeks of double-blind therapy, HCV RNA was negative and undetectable in 10/11 patients (90.9%) in the IFN β-1a group and none in the placebo group. The virological response rate (14/15, 93.3%) of the IFN β-1a plus RBV group at week 12 after the initiation of therapy was similar to that of the IFN β-1a group. SVR was observed in 5/11 (45.5%) of the IFN β-1a group and 11/15 (73.3%) of the IFN β-1a plus RBV group (P = 0.23). At the end of follow-up, a biochemical response was found in 5/11 patients in the IFN β-1a group (45.5%) and 8/15 patients in the IFN β-1a plus RBV group (53.3%, P = 1.00). Multiple logistic regression analysis confirmed that an HCV RNA load lower than 1.0×10⁶ copies/ml was independently associated with SVR (OR 11.00; 95% CI 1.81–66.97; P = 0.003). The side effects were mild and similar in the two therapy groups. We conclude that IFN β-1a alone or in combination with RBV provided considerable benefit in Chinese naïve patients with chronic hepatitis C. Treatments with IFN β-1a alone or IFN β-1a plus RBV are safe and well tolerated, and may represent an alternative for chronic hepatitis C patients who are unable to tolerate pegylated interferon α.     

Efficacy of an angiotensin II receptor antagonist in managing hyperaldosteronism

OBJECTIVE: To determine whether an angiotensin II receptor antagonist decreases blood pressure in patients with hyperaldosteronism and hypertension who are taking other antihypertensive agents. DESIGN: A double-blind randomized placebo-controlled crossover study. PATIENTS AND METHODS: Blood pressure and hormonal responses to 2-week courses of placebo/irbesartan (150 mg/day given by mouth at 08.05 h) were assessed in 10 patients with hyperaldosteronism. Clinic blood pressure was measured by sphygmomanometer, and plasma concentrations of aldosterone, cortisol, angiotensin II, electrolytes and renin activity (PRA) were determined weekly. Automated 24 h ambulatory blood pressure recordings were made at the end of the active and placebo phases. RESULTS: Irbesartan caused a post-dose decrease in ambulatory blood pressure (systolic, P = 0.02; diastolic, P = 0.05) in the period from 10.00 h to 20.00 h. Clinic blood pressure, measured at trough, was not significantly decreased. Plasma aldosterone decreased (P < 0.03) and PRA increased (P < 0.04) in the first week of active treatment with irbesartan, but differences between the placebo and active-treatment groups were not significant in the second week. There were no significant changes in plasma concentrations of angiotensin II, cortisol or potassium in either week. In the second week of irbesartan treatment, there were associations between change in plasma aldosterone and maximal change in ambulatory blood pressure (systolic and diastolic). CONCLUSION: Irbesartan has a role in combination antihypertensive treatment of patients with hyperaldosteronism.     

Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C

Background/Aims: Silybum marianum is a herbal preparation commonly used by subjects with chronic hepatitis C (CHC). The aims of this pilot study were to assess the efficacy and safety of S. marianum on serum hepatitis C virus (HCV) RNA, alanine aminotransferase levels and well‐being in patients with CHC. Methods: Twenty‐four subjects with CHC were enrolled into a randomized, double‐blind, placebo‐controlled, crossover study. Subjects received 12 weeks of S. marianum (either 600 mg or 1200 mg/day) and placebo separated by a 4‐week washout interval. Baseline biochemical, virological, psychological and quality‐of‐life tests were performed, with biochemical tests repeated monthly, and HCV RNA titer and quality‐of‐life and psychological assessments repeated at the end of both treatment periods. Results: Seventeen patients completed the trial. Mean changes in HCV RNA titers, serum ALT levels and Short Form‐36 scores were not significantly different for subjects on S. marianum compared to those on placebo. There was no significant change in mean State‐Trait Anxiety Inventory State‐Anxiety scores on S. marianum from baseline. Adverse events were similar with S. marianum and placebo. Conclusions: S. marianum is well tolerated in subjects with CHC, but does significantly affect serum HCV RNA, alanine aminotransferase levels, quality of life or psychological well‐being in subjects with this condition.     

索磷布韦/维帕他韦联合或不联合利巴韦林治疗基因3型慢性丙型肝炎病毒感染者的疗效及安全性:一项真实世界研究

目的评估索磷布韦/维帕他韦(sofosbuvir/velpatasvir,SOF/VEL)联合或不联合利巴韦林(ribavirin,RBV)治疗基因3型慢性丙型肝炎病毒(hepatitis c virus,HCV)感染者的有效性及安全性。方法以2018年12月至2020年1月至成都市公共卫生临床医疗中心就诊的84例基因3型慢性HCV感染者为研究对象,其中慢性丙型肝炎56例,代偿期肝硬化17例,失代偿期肝硬化11例。根据患者病情予以SOF/VEL联合或不联合RBV抗病毒治疗12~24周,检测患者基线、治疗4周、治疗结束时以及治疗结束后12周肝功能[丙氨酸氨基转移酶(alanine transaminase,ALT)、天门冬氨酸氨基转移酶(aspartate transaminase,AST)、总胆红素(total bilirubin,TBil)、白蛋白(albumin,ALB)]、肾功能[尿素、肌酐(creatinine,Cr)]和血常规[白细胞(white blood cell,WBC)、血红蛋白(hemoglobin,HGB)和血小板(platelet,PLT)]等指标,检测基线和治疗结束后12周的肝硬度值。同时详细记录患者在治疗期间的不良事件。主要结局指标为治疗结束后12周的持续病毒学应答(sustained virological response,SVR)和治疗中不良事件的发生情况。结果共80例患者(95.2%)达到SVR12,其中慢性丙型肝炎、代偿期肝硬化及失代偿期肝硬化患者的SVR12分别为100%(56/56)、94.1%(16/17)和72.7%(8/11),差异有统计学意义(P=0.003)。慢性丙型肝炎组、代偿期肝硬化及失代偿期肝硬化患者治疗结束后12周肝硬度值均较基线显著降低[(6.7±0.7)kPa vs(7.4±1.1)kPa,(17.8±3.1)kPa vs(25.9±3.4)kPa,(23.0±4.5)kPa vs(31.0±4.9)kPa;P均<0.001]。3组患者治疗后ALT和AST均较基线显著降低(P均<0.05),尿素、Cr、WBC和PLT差异无统计学意义(P均>0.05)。代偿期肝硬化和失代偿期肝硬化患者治疗后ALB较基线显著升高,HGB较基线显著降低(P均<0.05)。84例患者总体不良事件发生率为13.1%(11/84),其中慢性丙型肝炎、代偿期肝硬化和失代偿期肝硬化患者不良事件发生率分别为8.9%(5/56)、11.8%(2/17)和36.4%(4/11),差异无统计学意义(P=0.055),常见的不良事件包括疲劳、头痛和贫血等,无严重不良事件发生,无因不良事件导致的治疗中止。结论应用SOF/VEL联合或不联合RBV方案治疗基因3型慢性HCV感染者具有较高的SVR12,不良事件发生率较低,疗效显著,安全性良好。     

Combined ursodeoxycholic acid and glycyrrhizin therapy for chronic hepatitis C virus infection: a randomized controlled trial in 170 patients.

OBJECTIVE AND DESIGN: To assess the efficacy and safety of combination therapy using ursodeoxycholic acid with glycyrrhizin for chronic hepatitis C virus infection, we conducted a prospective randomized controlled trial of glycyrrhizin (group G) compared with glycyrrhizin plus ursodeoxycholic acid (group G+U) in 170 patients. METHODS: All patients had elevated serum aminotransferase levels over 6 months before entry into the trial. Glycyrrhizin was administered to both groups for 24 weeks, and in group G+U, ursodeoxycholic acid (600 mg/day) was administered orally as well. RESULTS: Serum aspartate transaminase and alanine transaminase concentrations significantly decreased during treatment in both groups, but serum gamma-glutamyl transpeptidase concentrations fell significantly only in group G+U. Concentrations of all three enzymes fell significantly more in group G+U than in group G, and had normalized in more cases when the trial ended at 24 weeks. However, levels of HCV viraemia did not change during the trial in either group. Multiple regression analysis linked only the treatment regimen, not HCV-related factors or liver histology, to the degree of serum enzyme reduction. No adverse effects were noted in either group. CONCLUSIONS: The combined therapy with ursodeoxycholic acid and glycyrrhizin is safe and effective in improving liver-specific enzyme abnormalities, and may be an alternative to interferon in chronic hepatitis C virus infection, especially for interferon-resistant or unstable patients.     

Daily induction combination treatment with alpha 2b interferon and ribavirin or standard combination treatment in naive chronic hepatitis C patients. A multicentre randomized controlled trial

The standard treatment for patients with chronic hepatitis C is a 6-12-month combination therapy with interferon alpha and ribavirin. Induction treatment could result in a faster early decline of the hepatitis C virus (HCV) load and a better response rate. Naive chronically infected HCV patients (n = 454) were randomized into two arms to receive either induction treatment with interferon alpha 2b 5 million units (MU) subcutaneously (s.c.) daily during a period of 8 weeks (arm A); or treatment with interferon alpha 2b 5 MU s.c. three times a week (TIW) for a period of 8 weeks (arm B). After week 8, interferon treatment in both arms was 3 MU s.c. TIW for a total period of 12 months. In both arms, ribavirin (1000-1200 mg orally per day) was added at week 4. Induction treatment resulted in a higher virological response at week 8 of treatment (66%vs 47%; P < 0.01). However, response at the end of treatment and at 6 months follow-up was not different (53%vs 50%, 41%vs 33%). The occurrence of adverse events and the drop-out rate were similar in both arms. Although an early virological response is observed more frequently in the induction treatment, end of treatment response and sustained responses did not differ.     

Comparative Effects of Different Doses of Ribavirin Plus Interferon-α2b for Therapy of Chronic Hepatitis C: Results of a Controlled, Randomized Trial

Compared to either drug alone, therapy with the combination of ribavirin and interferon- leads to improved rates of response in patients with chronic hepatitis C. Side effects often mandate downward dose adjustment or cessation of therapy, and the optimal dose of ribavirin has not been established. The aim of this study was to learn whether 600 mg ribavirin per day would prove as efficacious as 1000–1200 mg/day when combined with interferon (3 million units thrice weekly) for therapy of patients previously treated with standard interferon who had failed to respond or who had relapsed. We enrolled 69 patients with chronic hepatitis C and compensated liver disease: 45 were men, 65 were Caucasian, 48 were infected with genotype 1 hepatitis C virus. By random assignment, 35 received 600 mg ribavirin/day (group A), whereas the other 34 received 1000 mg (75 kg body wt) or 1200 mg/day (>75 kg body wt) (group B). At baseline, the two groups were well matched for demographic and laboratory features. In both groups, mean serum levels of alanine aminotransferase (ALT) and hepatitis C viral (HCV) RNA levels fell promptly and remained significantly lower than baseline throughout 24 weeks of therapy. There was no significant difference in mean levels of ALT or HCV RNA during therapy or at the end of follow-up (24 weeks after cessation of therapy). At the end of 24 weeks of posttherapy follow-up, 12 patients in each group had undetectable HCV RNA in serum, whereas 11 (31%) in group A and 9 (26.5%) in group B had normal serum ALT levels. The lower doses of ribavirin (group A) were tolerated better. %In conclusion, in previous nonresponders or relapsers to interferon done, combination therapy with interferon-_2b (3 MU thrice weekly) + 600 mg ribavirin/day is tolerated better and is as effective as interferon plus higher (standard) doses of ribavirin (1000–1200 mg/day).     

Triple therapy with amantadine in treatment-naive patients with chronic hepatitis C: a placebo-controlled trial

The antiviral efficacy of amantadine in patients with chronic hepatitis C is controversial. In this randomized, prospective, placebo-controlled, multicenter trial, triple therapy with interferon alfa (IFN-alpha)-2a plus ribavirin and amantadine (amantadine group) was compared with combination therapy IFN-alpha plus ribavirin (control group). Four hundred previously untreated patients with histologically proven chronic hepatitis C were randomly allocated to treatment with amantadine sulphate (100 mg twice daily orally) or a matched placebo together with IFN-alpha induction plus ribavirin (1,000-1,200 mg/day orally) for 48 weeks. The primary end point was sustained virologic response (SVR) defined as undetectable serum hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment. SVR was observed in 52% of the amantadine group and in 43.5% of the control group (P =.11). Among patients with HCV genotype 1 infection, the corresponding SVR rates were 39% and 31%, respectively. The virologic on-treatment response rate in week 24 was significantly higher in the amantadine group as compared with the control group (70% vs. 59%, respectively, P =.016). This beneficial effect was mainly related to HCV type 1-infected patients (63% vs. 47%, respectively, P =.012). Independent factors associated with SVR, according to multiple logistic regression analysis, were amantadine treatment, low baseline HCV RNA, platelet counts (>/=250/nL), pretreatment ALT quotient >/=3, and GGT level (<28 U/L) as well as HCV genotypes other than 1. In conclusion, although we could not demonstrate a significant advantage of the triple regimen in univariate analysis, multivariate analysis offers arguments that amantadine should be considered as a potential anti-HCV drug in future studies.     

Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks

Chronic hepatitis C patients often fail to respond to interferon-based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin-based therapy non-responders. A randomised, double-blind, placebo-controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with ≥50% ALT (alanine aminotransferase) reduction after 12 weeks double-blind phase, and (2) the proportion of patients with improvement of necro-inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction ≥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro-inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro-inflammation and fibrosis after 52-weeks treatment. Generally, glycyrrhizin treatment was well tolerated.     

Effects of combination therapy with interferon and ofloxacin on chronic type C hepatitis: A pilot study

Interferon is effective in only a limited number of patients with the 1b type of hepatitis C virus (HCV), indicating that a combination therapy with other antiviral drugs may be essential to obtain better results. In the present pilot study, the effects of a combination therapy with interferon (IFN) and an antibacterial drug, ofloxacin, were analysed. Ten patients with chronic type C hepatitis received the combination therapy (combination group). Six million units of natural IFN-α were administered daily for 3 weeks and then three times a week for 21 weeks. The combination therapy was initiated at the beginning of the eighth week of IFN treatment and 600 mg ofloxacin per day was administered for 12 weeks. As a control, changes in HCV-RNA were also analysed in patients who were treated with only IFN for the same period (IFN-alone group). In the combination group, serum transaminase levels and the titres of HCV decreased significantly with ofloxacin administration. Such changes were not observed in the IFN-alone group. The incidence of HCV-negativity at the end of ofloxacin administration of the combination group was significantly higher than in the IFN-alone group. The complete response rate was twice as high in the combination group as in the IFN-alone group. In two patients who did not respond well to the IFN-alone treatment, ofloxacin administration was commenced after the 24th week. Serum transaminase levels were normalized and HCV-RNA became negative in these two patients after the administration of ofloxacin. These results suggest that combination therapy with IFN and ofloxacin may be an effective treatment for chronic type C hepatitis.     

Efficacy and safety of 6 or 8 weeks of simeprevir,daclatasvir, sofosbuvir for HCV genotype 1 infection

The phase 2, open‐label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6‐ or 8‐week regimen of simeprevir, daclatasvir and sofosbuvir in treatment‐naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early‐stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early‐stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty‐eight patients were treated (6‐week group: n = 59; 8‐week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early‐stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6‐week group was viral relapse (11.9%; 7/59). One patient had on‐treatment failure due to an early withdrawal (lost to follow‐up due to incarceration). One patient with SVR12 in the 6‐week group had a late viral relapse at post‐treatment week 24. No clinically significant drug‐drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct‐acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment‐naïve, HCV GT1‐infected patients with early‐stage fibrosis or compensated cirrhosis.     

Enalapril versus combined enalapril and nadolol treatment: Effects on blood pressure,heart rate,humoral variables,and plasma potassium at rest and during exercise in hypertensive patients

Summary The effect of enalapril alone and in combination with nadolol on resting and exercising blood pressure, heart rate, plasma renin activity, aldosterone, noradrenaline, and potassium levels was studied in 10 hypertensive patients (diastolic blood pressure between 95 and 114 mmHg). Patients received placebo for 4 weeks, enalapril (mean daily dose 24.5 mg) for 8 weeks, and nadolol, 40 mg once daily, was added for the remaining 8 weeks of the study. Exercise testing (modified Bruce, treadmill) was conducted at the end of the placebo run-in phase and at the end of each treatment period. Enalapril reduced resting and exercising blood pressure independent of any change in heart rate: This effect was increased with combination treatment. Plasma renin activity at rest and during exercise was increased by enalapril. Combination treatment attenuated this response and significantly reduced plasma aldosterone. Neither treatment had any effect on plasma noradrenaline levels. Resting plasma potassium levels were increased with combination treatment, whereas both treatment regimens increased plasma potassium levels during exercise. There were no clinically relevant episodes of hyperkalemia. Further investigation is required to qualify the nature of the blood pressure and plasma potassium response with combination treatment.     

Outcomes of peginterferon alpha-2a and ribavirin hepatitis C therapy in Aboriginal Canadians

BACKGROUND: There is little published information on baseline characteristics and therapeutic outcomes in hepatitis C virus (HCV)-infected Aboriginal Canadians. It is unclear what proportion of HCV-infected Aboriginal people receive therapy relative to other populations. METHODS: Adults with chronic HCV infection, quantifiable serum HCV-RNA levels and compensated liver disease were assigned, at the physician's discretion, to either 24 or 48 weeks of treatment with peginterferon alpha-2a 180 mug/week plus ribavirin at a dose of 800 mg/day, or 1000 mg/day or 1200 mg/day in an open-label, expanded access program. The primary outcome was sustained virological response, defined as undetectable HCV-RNA by qualitative polymerase chain reaction (less than 50 IU/mL) at the end of 24 weeks of untreated follow-up. Baseline characteristics and outcomes in Aboriginal and non-Aboriginal patients were compared. RESULTS: A total of 2614 patients were eligible for the analysis; 44 individuals (1.7%) self-identified as being of Aboriginal heritage. The baseline characteristics of these two groups were similar. An overall sustained virological response was achieved in 47.7% and 46.5% of Aboriginal and non-Aboriginal patients, respectively. The overall frequencies of adverse events and laboratory abnormalities were similar between the two groups, although cytopenias occurred less frequently in Aboriginal patients. INTERPRETATION: Aboriginal patients were greatly under-represented in the present 'community'-based treatment program, yet viral responses were similar to those of a non-Aboriginal cohort. To increase the uptake of HCV therapy in the Aboriginal population, clarification of the obstacles to treatment is warranted.