Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Assessment and Management of Eyelid Injury

Background and aim: Among all sites of injury, eyelid laceration seems to be neglected in terms of sufficient epidemiological investigations. With a thorough understanding of the causes of eye lid lacerations, it is possible to develop a better preventive strategy and hence improve the public health policy in this respect. Hence the aim of the study was to understand the type of eyelid injury and study management of the injuries.&#x0D; Materials and methods: A total of 100 cases that were reported to the hospital department opd with the chief complain of blunt as well as penetrating eye lid injuries were included in the study. Evaluation by a physician was done for all cases to note the presence of any systemic diseases and for opinion regarding fitness for surgery. In cases where General Anaesthesia (GA) was used, Anaesthetist examined the patient and opined regarding status of the patient towards                           GA.&#x0D; Results: The results of the present study showed that 3rd and 4th decade were more prone to the eyelid injuries. Majority of the 58 cases showed involvement of left eye whereas the involvement of right eye was seen in 42 cases. In the present study, Minimonoka stent was used for 8 cases of canalicular lacerations and 8 cases of canalicular tear that were not affordable were repaired with 24G Venflon tube.&#x0D; Conclusion: As the injuries occur more commonly due to road traffic accidents showing 54 cases in our study, preventive measures are to be taken while riding such as controlling speed. Domestic injuries are more common in females. This study showed that Minimonoka stent is an effective and easy tool in reconstructing canalicular tear, with successful anatomical and functional integrity.</jats:p

Gaps in the patient journey through the diagnosis and management of primary biliary cholangitis

Introduction: Primary biliary cirrhosis cholangitis (PBC) is a chronic, inflammatory, autoimmune disease primarily targeting the hepatic bile duct cholangiocytes that is associated with systemic manifestations. Longterm management is essential. Published guidance on both diagnosis and management are expected to give guidance to practitioners regarding their patients with PBC. The aim of our study was to identify potential gaps in both the diagnosis and management of PBC amongst providers Methods: Patients ≥ 18yo diagnosed with PBC from 7 institutions were included. Participating providers were GI/Hepatology. Diagnosis of PBC was based on current AASLD criteria. Patients were included if they had ≥ 4 documented PBC laboratory assessments within 3 years or 5 prior office visits. Both prospective and retrospective chart analysis was performed. Data was collected and analyzed centrally via RedCap with support of the Chronic Liver Disease Foundation, a non-profit educational organization dedicated to increasing awareness of the effects of chronic liver disease in the US Results: 118 patients were included (87% F, 13% M, average age 63). 32% of patients were diagnosed by the participating provider with the remaining 68% of patients being previously referred. Of those referred, the majority were diagnosed by a specialist (GI 64%, Hepatology 21%, IM 3%, unknown 10%). 70% underwent liver biopsy(bx) at diagnosis or referral. Initial bx stage 1 (27%), 2 (28%), 3 (9%) 4 (6%). Of the remaining 30%, fibroscan was used infrequently (6%) at diagnosis or following. Symptoms were common (fatigue 32%, pruritus 30%). Pruritus management included antihistamines 61%, cholestyramine 28%, Rifampicin 7%, SSRI 4%. Providers reported patient monitoring as follows: biannual visits 79% and labs 41%. 93% were receiving or planned to receive ursodeoxycholic acid (UDCA). 47% of patient lab results met criteria for OCA treatment defined as ALP \u3e160 with only 19% receiving or planned to receive. Over the study period, ALP decreased in 75% of patients with 45% falling into the normal range (Figure 1). 77% of patients on OCA (n=22) had a decrease of ALP on treatment as compared with 60% of patients on UDCA alone Conclusion: These data suggest opportunity for staging, follow up and medical management of patients with PBC. Institution of planned educational efforts toward providers around current published guidelines for PBC are necessary to close these gaps

Complementary and alternative Medicine (CAM) for the Treatment of Chronic Hepatitis B and C: A Review

Complementary and alternative medicine (CAM) has been used for centuries in China and Japan to treat various illnesses, including viral hepatitis. Several therapeutic approaches constitute CAM, the most relevant for this review being the use of herbals. However, profound disagreements exist between conventional and alternative medicine practitioners regarding their value. Western medical advocates cite deep concerns about the purity of most herbals because of lack of standardized production, the paucity of pharmacokinetic data, the fact that few well-designed randomized, controlled trials of these products have been performed and the evidence that some herbals have been responsible for severe adverse effects. Nevertheless, many in the public, even in western countries, turn to the use of herbals, believing that they must be safe and effective because they are ‘natural’ and have been used for centuries, and because of dissatisfaction with conventional medicine. Accordingly, their use in western countries and the costs incurred have increased each year. While there is evidence that some herbals have physiological effects, there still is insufficient evidence to recommend their use. This paper reviews the classification, epidemiology and philosophy of CAM, and the reasons advanced for herbal use to treat viral hepatitis. The criteria necessary to develop a potential pharmacological agent are presented, as well as the requirements for conducting a scientifically valid treatment trial of herbals. Five herbals used in the past to treat viral hepatitis are reviewed and evaluated for the quality of their studies and mention is made of herbals known to have adverse effects. </jats:p

Effect of Low Positive End of Treatment Viral Load with Direct-Acting Antiviral Therapy on Sustained Virologic Response

Background. Direct-acting antivirals (DAAs) are highly effective treatments against hepatitis C virus (HCV), with sustained virologic response (SVR) rates of 93–100% against all genotypes. In most patients, viral load (VL) becomes undetectable four weeks into treatment, but rarely a low positive VL may be observed at the end of treatment (EOT). This study was conducted to determine the effect of low positive EOT VLs with DAA therapies on SVR at 12 and 24 weeks. Methods. A retrospective chart review was conducted from January 2014 to December 2018 on 1256 HCV patients of all genotypes (1–6) who had received DAA therapy at two large hepatology referral centers. Baseline demographic data, along with VL at week four, EOT, and SVR12/24 time points were collected for patients that had positive EOT VL. Treatment outcome for any patient with positive EOT VL was noted. Results. Eight out of 1256 patients treated with varying DAA therapies were observed to have low positive EOT VLs ranging from &lt;15 to 235 IU/mL. One patient had a negative EOT VL, but 23 IU/mL at week four after EOT. All eight patients who had low positive EOT VLs and one patient who had a low positive VL at four weeks after EOT achieved SVR at weeks 12 and 24. One of the eight patients had cirrhosis. The majority of patients were genotype 1a. Conclusion. In the DAA treatment era, low levels of detectable HCV RNA at EOT does not predict treatment failure.</jats:p

Effect of Low Positive End of Treatment Viral Load with Direct-Acting Antiviral Therapy on Sustained Virologic Response

Background. Direct-acting antivirals (DAAs) are highly effective treatments against hepatitis C virus (HCV), with sustained virologic response (SVR) rates of 93–100% against all genotypes. In most patients, viral load (VL) becomes undetectable four weeks into treatment, but rarely a low positive VL may be observed at the end of treatment (EOT). This study was conducted to determine the effect of low positive EOT VLs with DAA therapies on SVR at 12 and 24 weeks. Methods. A retrospective chart review was conducted from January 2014 to December 2018 on 1256 HCV patients of all genotypes (1–6) who had received DAA therapy at two large hepatology referral centers. Baseline demographic data, along with VL at week four, EOT, and SVR12/24 time points were collected for patients that had positive EOT VL. Treatment outcome for any patient with positive EOT VL was noted. Results. Eight out of 1256 patients treated with varying DAA therapies were observed to have low positive EOT VLs ranging from <15 to 235 IU/mL. One patient had a negative EOT VL, but 23 IU/mL at week four after EOT. All eight patients who had low positive EOT VLs and one patient who had a low positive VL at four weeks after EOT achieved SVR at weeks 12 and 24. One of the eight patients had cirrhosis. The majority of patients were genotype 1a. Conclusion. In the DAA treatment era, low levels of detectable HCV RNA at EOT does not predict treatment failure