Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

Decline in pulmonary function during chronic hepatitis C virus therapy with modified interferon alfa and ribavirin.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 µg q4wk or Peg-IFNα-2a 180 µg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 µg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B.

In the phase-III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2-year treatment in HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine-treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2-year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per-protocol population. Amongst 293 HBeAg-positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg-negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off-treatment follow-up). The cumulative 4-year resistance rate was 10.6% for HBeAg-positive and 10.0% for HBeAg-negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m(2) (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg-positive and HBeAg-negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg-positive patients.

Randomized trial of albinterferon alfa-2b every 4 weeks for chronic hepatitis C virus genotype 2/3.

Albinterferon alfa-2b (albIFN) is a fusion protein of recombinant human albumin/recombinant interferon (IFN)-α-2b, with ∼200-h half-life. Safety/efficacy of albIFN q4wk was evaluated in 391 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2/3. Patients were randomized 3:4:4:4 to one of four open-label treatment groups: pegylated IFN (Peg-IFN)-α-2a 180 µg qwk or albIFN 900, 1200 or 1500 µg q4wk, plus oral ribavirin 800 mg/day, for 24 weeks. Primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <20 IU/mL 24 weeks post-treatment). SVR rates were as follows: 85%, 76%, 76% and 78% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 µg, respectively (P = NS); corresponding rapid virologic response rates (HCV RNA <43 IU/mL at week 4) were as follows: 78%, 49% (P < 0.001), 60% (P = 0.01) and 71%. SVR rates were not influenced by interleukin 28B genotype, although rapid virologic response rates were greater with interleukin 28B CC (P = NS). Serious adverse event rates were as follows: 4%, 11%, 3% and 3% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 µg, respectively. No increase in serious/severe respiratory events was noted with albIFN. Fewer absolute neutrophil count reductions <750/mm(3) occurred with albIFN (P = 0.03), leading to fewer IFN dose reductions. Haemoglobin reductions <10 g/dL were less frequent with albIFN 900 and 1200 µg vs 1500 µg and Peg-IFNα-2a (P = 0.02), leading to fewer ribavirin dose reductions. albIFN administered q4wk produced fewer haematologic reductions than Peg-IFNα-2a, but had numerically lower SVR rates (P = NS) in patients with chronic HCV genotype 2/3.

Correlation between mutations in the core and NS5A genes of hepatitis C virus genotypes 1a, 1b, 3a, 3b, 6f and the response to pegylated interferon and ribavirin combination therapy.

Several studies have reported correlation between mutations in core and NS5A proteins of hepatitis C virus (HCV) and response to interferon (IFN) therapy. In particular, mutations in NS5A protein have been shown to correlate with responsiveness to IFN treatment of HCV-1b in Japanese patients. This study investigated whether amino acid (aa) mutations in the core and NS5A proteins of HCV-1a, 1b, 3a, 3b and 6f correlated with the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy in Thai patients. The entire sequences of core and NS5A of HCV from 76 HCV-infected patients were analysed in comparison with corresponding reference sequences. The data revealed that the number of aa mutations in full-length NS5A, its C-terminus, IFN sensitivity-determining region, variable region 3 (V3) and V3 plus flanking region of HCV-1b NS5A protein were significantly higher in responders than in the treatment failure group (P = 0.010, 0.031, 0.046, 0.020 and 0.006, respectively). Similar results were found in a putative protein kinase R binding domain region in HCV-6f NS5A protein (P = 0.022). Moreover, specific aa substitutions in NS5A that appeared to be associated with responders or the treatment failure group were observed at positions 78 and 305 for HCV-1b (P = 0.028), 64 and 52 for HCV-1a (P = 0.033) and 6f (P = 0.045). Nevertheless, analysis of aa sequences of core protein revealed highly conserved sequences among HCV genotypes and no significant differences between the viruses from responders and the treatment failure group. Our findings indicate that mutations in aa residues of NS5A of HCV-1a, 1b and 6f correlated well with responsiveness to Peg-IFN and RBV combination therapy.

An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome.

BACKGROUND: Tegaserod has been shown to be an effective therapy for the multiple symptoms of irritable bowel syndrome (IBS) in Western populations. However, little information is available regarding the use of tegaserod in the Asia-Pacific population. AIMS: To evaluate the efficacy, safety, and tolerability of tegaserod versus placebo in patients with IBS from the Asia-Pacific region. PATIENTS: A total of 520 patients from the Asia-Pacific region with IBS, excluding those with diarrhoea predominant IBS. METHODS: Patients were randomised to receive either tegaserod 6 mg twice daily (n=259) or placebo (n=261) for a 12 week treatment period. The primary efficacy variable (over weeks 1-4) was the response to the question: "Over the past week do you consider that you have had satisfactory relief from your IBS symptoms?" Secondary efficacy variables assessed overall satisfactory relief over 12 weeks and individual symptoms of IBS. RESULTS: The mean proportion of patients with overall satisfactory relief was greater in the tegaserod group than in the placebo group over weeks 1-4 (56% v 35%, respectively; p<0.0001) and weeks 1-12 (62% v 44%, respectively; p<0.0001). A clinically relevant effect was observed as early as week 1 and was maintained throughout the treatment period. Reductions in the number of days with at least moderate abdominal pain/discomfort, bloating, no bowel movements, and hard/lumpy stools were greater in the tegaserod group compared with the placebo group. Headache was the most commonly reported adverse event (12.0% tegaserod v 11.1% placebo). Diarrhoea led to discontinuation in 2.3% of tegaserod patients. Serious adverse events were infrequent (1.5% tegaserod v 3.4% placebo). CONCLUSIONS: Tegaserod 6 mg twice daily is an effective, safe, and well tolerated treatment for patients in the Asia-Pacific region suffering from IBS and whose main bowel symptom is not diarrhoea.

Effect of acute hyperglycemia on jejunal compliance and peristaltic reflex in healthy humans.

Acute hyperglycemia has been shown to affect gastric motor function and colonic peristaltic reflex, but little is known about its effects on the small bowel. Our aim was to determine the effect of experimentally induced acute hyperglycemia on small bowel compliance and peristaltic reflex. Ten healthy subjects were studied during euglycemia and induced hyperglycemia. Sequential balloon inflation in the jejunum was used to determine pressure-volume relationships. The frequency of jejunal contractions and motility index proximal and distal to a distending balloon were measured for assessment of the peristaltic reflex. The intestinal pressure-volume relationship was not affected by hyperglycemia (In pressure/volume 0.084+/-0.006 vs 0.096+/-0.006, P = 0.19). During hyperglycemia, there was significantly more distal inhibition of frequency of contractions (51.0+/-26.6% vs 26.7+/-22.3%, P < 0.05) and of motility index (18.8+/-10.8% and 10+/-6.4, P < 0.05) in response to balloon inflation. We conclude that in the small bowel of healthy subjects, experimentally induced acute hyperglycemia has no effect on compliance and little effect on enteric nerve function.

Prolonged ambulatory duodeno-jejunal manometry in humans: normal values and gender effect.

OBJECTIVE: The aim of this study was to provide a detailed comparison of motor activity in the duodenum and jejunum and between men and women studied by prolonged ambulatory manometry. METHODS: Thirty healthy volunteers (17 males) underwent prolonged ambulatory recording of duodeno-jejunal motility using a catheter with five built-in strain-gauge transducers (two duodenal and three jejunal). Manometric data was obtained during an extended period of fasting, the postprandial period and during sleep. RESULTS: There was a wide range of durations of the migrating motor complex (MMC), but at least one phase III was detected during 6 h of fasting, or 6 h of sleep in each subject (0.52+/-0.04 phase III/hour during fasting vs 0.59+/-0.04 during sleep, p=0.1). There was marked variation in the duration and pattern of phase III. Postprandially, frequency of contractions and motility index were maximal in the first 2 h after the meal, in both the duodenum and jejunum. There were no substantive differences between males and females or between the duodenum and jejunum. CONCLUSION: We conclude that upper small bowel motility is little affected by gender or segment.

Small bowel manometry: short or long recording sessions?

The study of small bowel motility in humans is commonly done by one of two techniques: short-term recording in a stationary patient or long-term recording in an ambulatory patient. To compare the diagnostic yield of short- and long-term manometric studies of small intestinal motility, we reviewed all prolonged records performed in our center over the years. Long-term studies that included less than 6 hr of recording during fasting or less than 5 hr during sleep and short-term studies using the perfused tube technique were excluded, leaving 91/121 tracings suitable for review. We analyzed the first 3 hr of the fasting period and the first 2 hr of the postprandial period on one occasion and the whole tracing on another; the fasting, postprandial and sleep period were analyzed separately. This allowed us to compare short and long recording sessions in the same patient. The two analyses agreed in 81/91 of the cases. In 7/10 patients a study was diagnosed as abnormal in the short recording but was considered normal after review of the long recording, while the opposite occurred in the remaining three. Periods of sleep and fasting contributed similarly to the change in diagnosis. In another 6 patients with equivocal abnormalities during the short period, the long period helped to establish the diagnosis of normality with confidence. Most of the improvement in the long-term study came from extension of the studies during fasting to 6-7 hr from 3 hr. Long-term records of small bowel motility, including study during sleep enhance the diagnostic accuracy of the test. Accuracy can be improved also simply by prolonging the recording during fasting.

Clinical value of duodenojejunal manometry. Its usefulness in diagnosis and management of patients with gastrointestinal symptoms.

The records of all patients who had duodenojejunal manometry (DJM) from 1989 to 1995 were retrospectively reviewed. We evaluated the main symptoms of the patients, the indication for the study, its result, and the impact on therapy and management. One hundred sixteen patients out of 154 were included in the study, of whom 96 were women and 20 were men, with a mean age of 41.2 years. Twenty-five had perfused tube studies, and 91 had prolonged ambulatory recordings. Forty-one patients were referred for evaluation of abdominal pain, 34 for chronic constipation, 24 for nausea and vomiting, 8 for pseudoobstruction, and the remaining 9 for other reasons. All patients had appropriate endoscopic, radiographic, or scintigraphic studies prior to manometry. Forty-seven (40.5%) had abnormal manometry: 20 of 41 (48.8%) for abdominal pain, 7 of 34 (20.6%) for chronic constipation, 10 of 24 (41.7%) for nausea and vomiting, 5 of 8 (62.5%) for pseudoobstruction, and 5 of 9 (55.6%) for the miscellaneous group. The various subgroups did not have specific patterns of motor abnormalities. In 22 patients (18.9%) manometry helped in the choice of therapy: in 15 patients by affecting surgical approach, particularly in the constipation group, and in 7 patients by affecting feeding options and prokinetic agents. Detection of motor abnormalities was helpful in patients with severe symptoms thought to have functional disease even when no specific therapy was rendered. Thus, DJM was abnormal in 2/5 patients referred for evaluation of suspected motility disorders. It directly affected therapy in approximately 1/5 patients, particularly in those with constipation. It is helpful in the management of patients even when specific therapy is not rendered, particularly in those with abdominal pain. The modest impact on specific therapy is related to limited availability of effective prokinetic drugs and the limited specificity and predictive value of tests results.