Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C virus infection in adults.

The fixed-dose combination of glecaprevir (GLE), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (PIB), an NS5A inhibitor, was recently approved for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1-6 (GT-1-6) without cirrhosis or with compensated cirrhosis, and for the treatment of HCV GT-1 patients who have failed treatment with either NS5A inhibitors or NS3/4A protease inhibitors, but not both. This combination, administered over 8 or 12 weeks, has resulted in high cure rates in all six HCV genotypes, including patients with HIV coinfection. GLE/PIB was well tolerated, with the most common adverse events being headache and fatigue. GLE/PIB is recommended to be taken as three tablets (total daily dose: GLE 300 mg and PIB 120 mg) orally once daily with food. No dose adjustment is required in patients with any degree of renal impairment or in patients undergoing hemodialysis. Dose adjustment is also not required in patients with Child-Pugh A liver disease. However, the use of GLE/PIB is not recommended in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Demonstration of acid and water recovery systems: Applicability and operational challenges in Indian metal finishing SMEs.

Diffusion dialysis, acid retardation and nanofiltration plants were acquired from Europe and demonstrated in several Indian metal finishing companies over a three year period. These companies are primarily small and medium enterprises (SMEs). Free acid recovery rate from spent pickling baths using diffusion dialysis and retardation was in the range of 78-86% and 30-70% respectively. With nanofiltration, 80% recovery rate of rinse water was obtained. The demonstrations created awareness among the metal finishing companies to reuse resources (acid/water) from the effluent streams. However, lack of efficient oil separators, reliable chemical analysis and trained personnel as well as high investment cost limit the application of these technologies. Local manufacturing, plant customization and centralized treatment are likely to encourage the uptake of such technologies in the Indian metal finishing sector.

Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice.

Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiota ß-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host.

Sofosbuvir/ledipasvir fixed-dose combination for treatment of chronic hepatitis C virus infection in children.

The United States Food and Drug Administration recently approved sofosbuvir and the fixed-dose combination of ledipasvir/sofosbuvir for the treatment of hepatitis C virus (HCV) infection in children ages 12 to 17. These are the first direct-acting antiviral treatments approved for children and adolescents with HCV. Pharmacokinetic data confirm equivalent drug exposure in this population as that found in adults during clinical trials. The efficacy and safety of these drugs has been shown in clinical trials.

Sofosbuvir/velpatasvir fixed-dose combination for the treatment of chronic hepatitis C virus infection.

The fixed-dose combination of sofosbuvir, a nucleotide analogue NS5B polymerase inhibitor, and velpatasvir, a second-generation NS5A inhibitor, has been approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection. This combination, administered over 12 weeks as a single-tablet regimen, has resulted in high cure rates in all 6 HCV genotypes and in a variety of patient populations, including patients without cirrhosis, patients with compensated cirrhosis and patients with HIV coinfection. In patients with decompensated cirrhosis, high cure rates were also achieved over 12 weeks with sofosbuvir/velpatasvir plus ribavirin. Patients who had failed prior treatment with an NS5A-containing regimen were able to achieve high cure rates following 24 weeks of treatment with sofosbuvir/velpatasvir plus ribavirin. Sofosbuvir/velpatasvir was well tolerated, the most common adverse events being headache, fatigue and nausea.

Ledipasvir/sofosbuvir fixed-dose combination for treatment of hepatitis C virus genotype 4 infection.

Hepatitis C virus (HCV) genotype 4 accounts for 8-13% of all chronic HCV infections worldwide. Patients with HCV genotype 4 have been reported to have poor treatment responses to PEGylated interferon and ribavirin regimens. Recently a single tablet, fixed-dose combination of sofosbuvir, an RNA-directed RNA polymerase (NS5B) inhibitor, and ledipasvir, a nonstructural protein 5A (NS5A) inhibitor, has been approved for treatment of chronic HCV infection. Two studies using the fixed-dose combination in chronic HCV genotype 4 for 12 weeks reported sustained virologic response rates at 12 weeks (SVR12) of 93-95%. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 and HIV co-infection. Administered as a single once-daily oral regimen, this ribavirin- and interferon-free regimen is well tolerated, with low potential for adverse effects and represents a significant advancement in the treatment of chronic HCV genotype 4 infection.

Current status of treatment for chronic hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is responsible for substantial mortality and morbidity worldwide. Until recently, the standard of care for the treatment of chronic HCV infection had been a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). The recent availability of two directly acting agents, telaprevir and boceprevir, has led to significantly improved outcomes for those patients with HCV genotype 1. Unfortunately, each of these agents must be combined with peg-IFN and RBV for optimal efficacy, and substantial treatment-related toxicity continues to challenge clinicians. However, the drug development pipeline for chronic HCV infection is very robust and the emergence of new therapies and therapeutic strategies in the near future for managing chronic HCV infection is eagerly anticipated.

Telaprevir: looking for a sustained virologic response in hepatitis C virus infection.

Telaprevir, a hepatitis C virus (HCV) NS3/NS4A protease inhibitor, was recently approved by the U.S. Food and Drug Administration for the treatment of chronic HCV genotype 1 infection. When given in combination with pegylated interferon and ribavirin, it demonstrated improved efficacy over conventional pegylated interferon and ribavirin therapy. Improvement in efficacy was also noted in African American patients who traditionally respond less well to conventional anti-HCV treatment. While the role of telaprevir in the management of chronic HCV infection remains to be fully defined, its development and licensure represents an important milestone in anti-HCV therapeutics.

Boceprevir.

Boceprevir is a hepatitis C virus (HCV) serine protease NS3 inhibitor that has recently been approved by the U.S. Food and Drug Administration, the European Medicines Agency and Health Canada for the treatment of chronic genotype 1 HCV infection. It has potent in vitro antiviral activity against HCV genotypes 1a and 1b and is primarily metabolized via the aldoketoreductase pathway with minor cytochrome P450 3A4 metabolism. Boceprevir is well tolerated with few drug-drug interactions which are easy to manage; no dose adjustment is required in patients with hepatic or renal impairment. Phase I trials of boceprevir demonstrated favorable pharmacokinetic, metabolic and safety profiles. Phase II and III trials of boceprevir confirmed the antiviral activity of the drug and its use at a dose of 800 mg three times daily. Clinical trials in treatment-naive and previously treated HCV-infected patients demonstrated a 26% and 45% (respectively) improvement in sustained viral response when boceprevir was added to standard pegylated interferon and ribavirin anti-HCV therapy. Boceprevir is the first-in-class of an exciting new phase of HCV treatment.

Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.

The aim of this study was to determine if a relationship exists between nonalcoholic steatohepatitis (NASH) and serum levels of free fatty acids, choline deficiency, or celiac disease. Forty-seven patients with liver biopsy proven NASH were enrolled. Total serum free fatty acids and anti-endomysial antibodies were determined in all patients, while plasma free and phospholipid-bound choline were determined in 29 patients. Total serum free fatty acid concentration correlated significantly with female gender and serum albumin concentration. Patients with severe fibrosis on liver biopsy had significantly greater serum concentration of free fatty acids than patients without severe fibrosis. Plasma free and phospholipid-bound choline levels were normal and no significant correlation was found between the concentration of plasma free or phospholipid bound choline, and the severity of liver damage. Only one of the 47 patients with NASH had a positive titer for the anti-endomysial antibody. In conclusion, increased serum concentrations of free fatty acids were found in NASH and were associated with development of more severe liver disease. Neither choline deficiency nor celiac sprue by anti-endomysial antibody testing was associated with NASH.

Bleeding from cavernous angiomatosis of the rectum in Klippel-Trenaunay syndrome: report of three cases and literature review.

Klippel-Trenaunay syndrome (KTS) is a congenital vascular anomaly characterized by limb hypertrophy, cutaneous hemangiomas, and varicosities. GI hemorrhage is a potentially serious complication secondary to diffuse hemangiomatous involvement of the gut. We report on three patients with KTS who presented with transfusion-dependent anemia and life-threatening bleeding due to extensive cavernous hemangiomas involving the rectum. Two patients were treated by proctocolectomy and coloanal anastomosis, which preserved anal function while controlling bleeding. The third patient required an abdominoperineal resection because of extensive rectal, perianal, and perineal angiomatosis. The literature on the evaluation and management of GI hemorrhage in KTS, particularly of colorectal origin, is reviewed.

An open trial of octreotide long-acting release in the management of short bowel syndrome.

OBJECTIVES: The aim of this study was to assess the effects of the long-acting release (LAR) depot octreotide preparation Sandostatin LAR Depot on stool water and electrolyte losses, fecal fat excretion, and GI transit in patients with short bowel syndrome. METHODS: We performed a 15-wk, prospective, open-label study of intramuscular (i.m.) Sandostatin LAR Depot, 20 mg, at 0, 3, 7, and 11 wk. Balance studies were performed before and at the end of the 15-wk study. Baseline and posttreatment measurements of body weight, stool fat, sodium and potassium, and gastric and small bowel transit of a radiolabeled egg meal were compared by paired analysis. RESULTS: We studied eight patients with short bowel syndrome (five women and three men; mean age 52 yr, range 37-72 yr) who had been TPN dependent for a mean of 11.8 yr (range 1.5-22 yr). The underlying diagnoses were Crohn's disease (n = 6), intestinal ischemia (n = 1), and resection for carcinoid tumor (n = 1). Treatment with Sandostatin LAR Depot significantly increased small bowel transit time (p = 0.03). Changes in body weight, urine volume, stool weight, fecal fat excretion, stool sodium and potassium excretion, or gastric emptying rate were highly variable, and no overall significance was observed. CONCLUSIONS: Sandostatin LAR Depot for 15 wk significantly prolonged small bowel transit time. Body weight and stool parameters in response to Sandostatin LAR Depot treatment needs to be assessed further in multicenter studies assessing dose, frequency of administration, and a larger sample size.

Psychological disorders in patients with evacuation disorders and constipation in a tertiary practice.

OBJECTIVE: We aimed to evaluate the prevalence of psychological impairment in patients with rectal evacuation disorders and the influence of psychological disorder on the early outcome of behavioral treatment. METHODS: We retrospectively reviewed the medical records of patients with rectal evacuation disorders referred for biofeedback retraining at a tertiary referral center. The psychological disorder was classified using the DSM IV criteria. Outcome of biofeedback treatment of evacuation at 2 wk was based on symptoms or on the ability to spontaneously expel a balloon placed in the rectum. Improvements in the groups without versus with a psychological disorder or an eating disorder were compared by Fisher's exact test. RESULTS: In the 60 patients (55 women; 5 men; mean age, 38 yr), psychological disorders were identified in 39 (65%); also noted were eating disorder (n = 5), rumination syndrome (n = 3), pain disorder (n = 6), anxiety-depression (n = 10), a combination of depression and pain disorder (n = 3), and a combination of eating disorder with anxiety-depression and pain disorder (n = 12). There was an association between psychological status and outcome at 2 wk of behavioral treatment for evacuation disorder (p = 0.03). The coexistence of eating disorder and psychological disorder resulted in an unfavorable outcome (p = 0.02), compared with those without psychological disorder. CONCLUSION: Psychological impairment was identified in 65% of the patients with evacuation disorder and constipation in a tertiary care practice, and has a significant negative impact on the outcome of behavioral treatment. These data reinforce the importance of a multidisciplinary approach in the management of these patients.

Essential fatty acid deficiencies in patients with chronic liver disease are not reversed by short-term intravenous lipid supplementation.

The purpose of this study was to determine the plasma triglyceride and phospholipid fatty acid (FA) composition of severely malnourished patients with chronic liver disease and to examine the effects of parenteral nutrition with a total nutrient admixture (TNA) on these profiles. Nine consecutive patients with end-stage chronic liver disease were compared with 35 patients admitted for elective surgery of upper gastrointestinal malignancy. Baseline laboratory values and the FA profiles of the plasma triglyceride and phospholipids were analyzed. FA profiles were also performed after infusion of a TNA including 33+/-7 g of lipid/24 hr for 7.9+/-4 days in the patients with chronic liver disease. Compared with control patients, the plasma phospholipid fatty acid analysis results (relative mole percentage) of patients with chronic liver disease were significantly lower in the two essential FA, linoleic acid (15.4+/-3.4% vs. 20.8+/-2.9%, P<0.001) and alpha-linolenic acid (0.02+/-0.05% vs. 0.08+/-0.10%, P<0.001). Similar changes were demonstrated in the FA composition of the triglyceride fraction. Short-term infusion of intravenous lipid resulted in a significant increase in linoleic acid in the triglyceride fraction (9.9+/-2.8% before supplementation vs. 20.7+/-9.4% after supplementation, P<0.01) and a decrease in oleic acid (38.7+/-5.2% before supplementation vs. 29.3+/-7.5 after supplementation, P<0.01). In conclusion, acute and chronic deficiencies of essential FA occurs in patients with chronic liver disease. The clinical significance of these deficiencies is unknown, but they potentially may impact on eicosanoid metabolism. Short-term supplementation with modest amounts of intravenous lipid has only a minimal effect on normalization of longer-chain fatty acids.

Indications for total parenteral nutrition in the hospitalized patient: a prospective review of evolving practice.

The indications for initiating total parenteral nutrition (TPN) were prospectively evaluated in 100 consecutive patients at a tertiary referral hospital with a long-standing Nutritional Support Service to illustrate the reasons why the parenteral route was chosen at this unique institution in terms of patient population. Sixty male and 40 female patients, average age 59 +/- 17 years (range 22-86 years), were classified a priori as to the underlying reasons for initiation of TPN. The study was conducted by a Nutrition Support Service at this hospital without pediatric, trauma, or burn services specializing in the care of patients with diabetes mellitus. Of the 100 patients, 63% were from the surgical service; 24% had diabetes mellitus. Their mean weight (118 +/- 29% of ideal), body mass index (25 +/- 6 kg/m(2)), and serum albumin (2.8 +/- 0.7 g/dL) indicated a reasonable body composition with a moderate systemic inflammatory response. Six patients received preoperative TPN for an average of 5 +/- 3 days with a variety of diagnoses including malignancy, Crohn's disease, bowel obstruction, and gastrointestinal bleeding. The underlying reasons for initiating nutritional support were related to three factors that largely determine the need for involuntary feeding: preexisting protein calorie malnutrition, actual or anticipated semistarvation for a prolonged period, and the presence of a systemic inflammatory response. The choice of TPN was based on anticipated or proven intolerance to full enteral feeding. The duration of time before initiation of TPN postoperatively was 6 +/- 5 days, which reflects our policy that initially well-nourished patients who are experiencing a systemic inflammatory response should not undergo more than 5 to 7 days of inadequate feeding. The duration of TPN overall was 11 +/- 10 days, which primarily illustrates the dramatic reduction in length of hospital stay that has occurred throughout the health care system and the willingness to provide TPN in alternative settings including transitional care units, rehabilitation hospitals, and for short-term care, the patient's home. The most common specific reasons identified for initiating TPN rather than enteral nutrition were ileus (25%), an underlying acid-base or electrolyte/mineral disorder (13%) requiring correction, and the convenience of TPN because a central venous catheter was in place (12%). The usual indication for nutritional support at this tertiary referral and specialty hospital was actual or impending protein calorie malnutrition. TPN was chosen for a variety of reasons related to actual or anticipated tolerance to enteral feeding. This audit demonstrates that our TPN practice has evolved in relation to time of initiation and duration of feeding, which reflect a clearer appreciation of the risks and benefits of TPN.

New clinical issues in celiac disease.

Celiac disease is a chronic disorder of gluten sensitivity associated with a spectrum of mucosal lesions termed preinfiltrative, infiltrative, hyperplastic, destructive, and atrophic. The symptoms are not related to the degree of mucosal pathology but to the extent of the mucosal lesion. Neoplasms constitute the major complication of celiac disease, and EATCL is the most common neoplasm in this category. There is evidence that a strict gluten-free diet is protective against the complications of celiac disease; hence it is important that even the subclinical forms be diagnosed early. Small bowel biopsy remains the gold standard for diagnosis of celiac disease; however, antibody tests are a useful adjunct in deciding whom to biopsy and for screening groups at high risk before initiating a lifelong gluten-free diet.

A double-blind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS.

OBJECTIVES: Up to 20% of patients with AIDS have abnormal intestinal permeability (IP). Glutamine seems to play an important role in preventing the increase in IP and loss of intestinal mucosal mass associated with total parenteral nutrition, and may be superior to glucose for oral rehydration in the setting of intestinal infection. This study was designed to see if supplemental glutamine could alter the abnormal IP of AIDS. METHODS: Randomly chosen patients with AIDS from the Jacobi Medical Center human immunodeficiency virus (HIV) clinic underwent IP testing using lactulose and mannitol. Those with abnormal IP were enrolled. Duodenal biopsies were performed with a Crosby capsule and the patients were randomized in a double-blind fashion to receive placebo or glutamine (4 g/day or 8 g/day) for 28 days, after which intestinal permeability tests and duodenal biopsies were repeated. Intestinal morphology was graded by ratio of villus height to crypt depth, and by degree of inflammation. RESULTS: All patients complied with the therapy and there were no dropouts or reported side effects. The results showed less worsening of IP with the 4 g/day dose, compared with placebo. At the 8 g/day dose, there was stabilization of IP and improved absorption of mannitol. Intestinal morphology and inflammation did not change in any group. CONCLUSIONS: These results, although not significant, suggest a trend towards improved IP and enhanced intestinal absorption with glutamine. Glutamine doses of at least 20 g/day may be necessary to improve IP. We recommend further studies at higher doses and for longer durations.

Appropriate nutritional support in acute and complicated Crohn's disease.

Crohn's disease is frequently complicated by protein-calorie malnutrition. Four common clinical presentations of Crohn's disease include acute exacerbations or flares of disease, intestinal obstruction, fistulizing disease, and perianal disease. In this review, we examine the role of nutritional support in these clinical scenarios. Nutritional support is important for maintaining functional status and preventing loss of lean tissue. Determinants of lean-tissue loss include severity of underlying injury, baseline nutritional status, and duration of inadequate nutrition. One of the clinically useful measures of nutritional status is the nutritional risk index (NRI) defined on the basis of the serum albumin and weight loss. Nutritional support is important in severely malnourished patients (NRI < 83). Enteral nutrition is the route of choice, provided there are no contraindications to using the gastrointestinal tract. In acute exacerbations of Crohn's disease, enteral nutrition also has a role in the primary management of disease although it is not as effective as corticosteroids in inducing remission. The mechanisms are poorly understood and the most effective enteral formulation needs to be determined. Total parenteral nutrition is justified in severely malnourished Crohn's disease patients who are unable to tolerate enteral feeding or in whom enteral feeding is contraindicated. More clinical studies are needed on the assessment of malnutrition in Crohn's disease, the effects of nutritional management on functional status, and the timing of nutritional intervention.