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Nucleos(t)ide analogues (NAs) are a mainstay of therapy for chronic hepatitis B (CHB) infections and have a profound effect on hepatitis B virus (HBV) suppression. We report a rare case of HBV reactivation in a CHB patient without cirrhosis following cessation of NA therapy that resulted in acute liver failure requiring liver transplantation. Investigation of the viral genetics and host immune responses suggest that viral mutations known to promote virus replication are associated with reactivation, whereas adaptive immunity to HBV remained defective in this patient. Viral sequencing may be useful for identifying mutations that are unfavorable for therapy withdrawal.

Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir.

Introduction:The addition of protease inhibitors such as telaprevir and boceprevir with PEGylated interferon and ribavirin has significantly improved cure rates for genotype 1 hepatitis C virus (HCV) infection. Simeprevir(TMC435) is a second-generation protease inhibitor that is in development for the treatment of genotype 1 HCV infection.Areas covered:The authors present: i) an overview of Phases I – III clinical trials of simeprevir for HCV infection based on peer-reviewed literature and congress presentations and ii) an evaluation of the efficacy and safety of simeprevir in the treatment of HCV infection.Expert opinion:Simeprevir is a once-daily oral medication that combined with PEGylated interferon and ribavirin appears to be a potent and safe agent to treat genotype 1 HCV infection for patients who are treatment-naïve and prior treatment-failures. Compared to telaprevir and boceprevir, simeprevir will likely be the protease inhibitor of choice for genotype 1 HCV infection based on ease of use, lower rates of adverse events, including rash and anemia, and no significant reported drug–drug interactions. Associated side effects inherent with interferon-based regimens may be problematic for patients. As HCV therapies evolve into interferon-free regimens, simeprevir may potentially be combined with other oral direct-acting agents without interferon to treat HCV infection.

ABSTRACTChronic Hepatitis C virus (HCV) infection has been linked with B cell lymphoproliferative disorders and several autoimmune-related diseases. The mechanisms of how chronic viral infection affects B cell development and predisposes the patients to autoimmune manifestations are poorly understood. In this study, we established an experimental system to probe the B cell responses and characterize the antibodies from chronic-HCV-infected individuals. We identified an unusual polyclonal expansion of the IgM memory B cell subset in some patients. This B cell subset is known to be tightly regulated, and autoreactive cells are eliminated by tolerance mechanisms. Genetic analysis of the immunoglobulin (Ig) heavy chain variable gene (VH) sequences of the expanded cell population showed that the levels of somatic hypermutation (SHM) correlate with the extent of cell expansion in the patients and that the VHgenes exhibit signs of antigen-mediated selection. Functional analysis of the cloned B cell receptors demonstrated autoreactivity in some of the expanded IgM memory B cells in the patients which is not found in healthy donors. In summary, this study demonstrated that, in some patients, chronic HCV infection disrupts the tolerance mechanism that normally deletes autoreactive B cells, therefore increasing the risk of developing autoimmune antibodies. Long-term follow-up of this expanded B cell subset within the infected individuals will help determine whether these cells are predictors of more-serious clinical manifestations.

Introduction: The approval of the first direct-acting antiviral (DAA) drugs for treatment of HCV in 2011 has lead to improved sustained viral response rates of up to 79% in treatment-naïve or relapse genotype 1 patients.Areas covered: Clinical trial data, the clinical skills required for the use of DAA drugs, the use of genetic tests and HCV RNA assays, new small molecules, resistance-associated variants, combinations of two or more DAAs, treatment of special populations, and future directions. The results of the pivotal Phase III trials with telaprevir and boceprevir, including the efficacy, safety and tolerability, drug–drug interactions and management of the most common side-effects. Resistance-associated variant data and treatment strategies implemented to minimize the development of resistance with these first-generation protease inhibitors.Expert opinion: Combination therapies of protease inhibitors with nucleoside or non-nucleoside polymerase inhibitors, non-structural protein 5A (NS5A) inhibitors and cyclophylin inhibitors are currently underway in regimens that use pegylated interferon and ribavirin or are interferon-free. The explosion of new drug development will probably move the field forward and offer both improved efficacy and tolerability to patients with hepatitis C infections. The use of these drugs ushers in a new era for the treatment of HCV but must be done with care and caution.

No new therapy has been approved for the treatment of chronic hepatitis C in the last 5 years in the USA since the approval of pegylated interferon (IFN)-α2aand ribavirin. Multiple new drugs are currently in development and are expected to be approved for use in the USA and/or the EU by 2011–2013. Although the mechanism of action of pegylated IFN and ribavirin are not completely known, it is likely that they will continue to be used in combination regimens for a number of years. Direct antivirals are likely to be the first new drugs to be used in combination with pegylated IFN and ribavirin. Viral resistance will prove to be a significant barrier and require that consolidation therapy with at least 24 weeks of pegylated IFN and ribavirin be used to successfully prevent the selection or emergence of resistant variants. Numerous other compounds, such as ribavirin analogs, long-acting IFNs, hepatoprotectants and immunomodulators, are in development and may replace the drugs that are used currently. The combination of direct antivirals, such as protease and polymerase inhibitors, may rapidly follow in development, as has occurred in HIV drug therapy.

Background Measuring hepatitis C virus (HCV) RNA in serum or plasma may underestimate the true HCV burden. Extracting viral RNA from whole blood (WB) with a cationic surfactant (Catrimox-14) has resulted in HCV RNA concentrations up to 1000-fold higher than from serum or plasma in some studies, but not others. We compared the Catrimox-14 WB assay with a standard serum assay.Methods Seventy-two chronic HCV patients received 48 weeks of standard or pegylated interferon alpha-2b and ribavirin therapy. Catrimox-14-treated WB and corresponding serum samples were obtained at baseline and weeks 12, 24, 48 and 72. HCV RNA concentrations from WB and serum were quantified by a previously validated RT-PCR assay.Results Overall mean (±SD) baseline serum log10HCV RNA concentration was 6.5 ((±0.58) copies/ml. Out of 72 patients, 33 had no detectable virus at 72 weeks. Neither assay detected virus in these patients at 12 weeks and neither WB nor serum assays detected virus at end-of-treatment in the 10 patients who subsequently relapsed at 72 weeks. HCV RNA concentrations from WB and serum assays were linearly correlated (R2=0.73; P<0.001), although mean serum HCV RNA concentrations were 0.5 log10copies/ml higher in serum than in WB [6.0 (±0.82) vs 5.5 ((±0.84), respectively, P=0.12].Conclusions Catrimox-14-treated WB assays detect changes in HCV RNA, but do not offer clinical advantage over a conventional serum RT-PCR based assay.

SUMMARYRecipients of solid-organ transplantation are at risk of severe infections due to their life-long immunosuppression. Despite emerging evidence that vaccinations are safe and effective among immunosuppressed patients, most vaccines are still underutilized in these patients. The efficacy, safety, and protocols of several vaccines in this patient population are poorly understood. Timing of vaccination appears to be critical because response to vaccinations is decreased in patients with end-stage organ disease and in the first 6 months after transplantation. For these reasons, the primary immunizations should be given before transplantation, as early as possible during the course of disease. Vaccination strategy should include vaccination of household contacts and health care workers at transplant centers unless contraindicated. No conclusive data are available on the use of immunoadjuvants and screening for protective titers. Most vaccines appear to be safe in solid-organ transplantation recipients, but live vaccines should be avoided until further studies are available. The risk of rejection appears minimal. Recommended vaccines include pneumovax, hepatitis A and B, influenza, and tetanus-diphtheria. We outline specific protocols and recommendations in this particular patient population. Specific contraindications exist for other vaccines, such as yellow fever, oral polio vaccine, bacillus Calmette-Guerin, and vaccinia. We conclude that solid-organ recipients will benefit from consistent immunization practices. Further studies are recommended to improve established protocols in this patient population.

Hepatitis C virus is the most common chronic, blood-bourne infection, affecting 170 million people worldwide, approximately 3% of the global population. Of those infected with hepatitis C virus, 50 – 85% will develop chronic hepatitis C. Although hepatitis C is primarily a disease of the liver, a diagnosis is currently defined by the presence of the hepatitis C virus and treatment success is defined by the clearance of the virus. IFN-α is currently the mainstay of chronic hepatitis C therapy; the antiviral and anti-inflammatory components of IFN target both the infectious and the hepatic manifestations of the disease. However, even in combination with ribavirin, interferon therapy is not fully efficacious. Recently, the search for a more effective treatment has led investigators to optimise interferon therapy by developing pegylated interferons. Challenges facing our current treatment of hepatitis C virus include lack of efficacy in patients with difficult-to-treat disease, such as patients with cirrhosis or infected with hepatitis C virus genotype 1 (who represent a majority of US hepatitis C virus infections), the toxicity of combination therapy, the expense and difficulty of therapy and the poor reception of these treatments by many patients. The development of new hepatitis C antiviral agents is critical to our management of this disease. A number of approaches are under investigation, including long-acting interferons, immunomodulators, antifibrotics, specific hepatitis C virus-derived enzyme inhibitors, drugs that either block hepatitis C virus antigen production from RNA or prevent normal processing of hepatitis C virus proteins and other molecular approaches to treating hepatitis C virus, such as ribozymes and antisense oligonucleotides.

Serial ascites and plasma volumes were measured during diuresis in nine patients with ascites caused by peritoneal carcinomatosis, four patients with chylous malignant ascites, and three patients with portal hypertension-related ascites caused by massive hepatic metastases. Oral diuretics were given to achieve an adequate natriuresis on a sodium-restricted diet. During the study period (7.8 ± 3.2 days), patients with peritoneal carcinomatosis and chylous ascites lost 0.49 ± 0.31 and 0.51 ± 0.42 kg/ day in weight, respectively, with negligible change in ascites volumes (−0.03 ± 0.11 and 0.02 ± 0.09 L/day). Patients with ascites caused by massive hepatic metastasis lost 1.06 ± 0.15 kg/day in weight (P= 0.01 for massive hepatic metastasis vs. peritoneal carcinomatosis) and 0.23 ± 0.13 L/day of ascites (P< 0.05 vs. other groups). Plasma volume changes were not significantly different among the three groups. Patients with edema (9/16) had a greater natriuresis and daily weight loss. Three patients with peritoneal carcinomatosis and one with chylous ascites developed renal dysfunction or symptomatic hypotension. No patient with massive hepatic metastasis developed these complications. In patients with ascites caused by peritoneal carcinomatosis or chylous malignant ascites there is no mobilization of ascites, whereas in patients with massive hepatic metastasis, ascites may be mobilized with diuretics.

We prospectively studied the changes of colonic mucosa in patients receiving two different preparations for colonoscopic examination. Eighteen consecutive patients undergoing colonoscopy for polyps or mass lesions, properly age- and sex-matched, were randomized to receive Golytely lavage (3–4 L) or a standard preparation (48-h clear liquid diet, 240 ml of magnesium citrate and “X-Prep” senna derivative). Patients with diarrhea or inflammatory bowel disease, or both, were excluded. Biopsy specimens were obtained from normal-appearing mucosa of the right and left side of the colon (none in the distal 10 cm of rectum). Blind review of coded slides was performed with 0–3 scoring for artifact, edema and hemorrhage of the lamina propria, surface epithelial and goblet cells, crypts, and cells in the lamina propria including eosinophils and polymorphonuclear leukocytes. Statistically significant differences were found for preservation of surface epithelial and goblet cells and less edema in favor of patients receiving Golytely. We conclude that the standard form of colon preparation flattens the surface epithelial cells and depletes the goblet cells as well as causes an increase in lamina propria edema, whereas colon lavage preserves normal mucosal histology.

Serial measurements of plasma volume and ascites volume were made during treatment with large doses of oral diuretics in 14 patients with stable chronic liver disease. Eight patients had pitting edema in addition to ascites. Reproducibility of ascites and plasma volume measurements was verified in 10 control subjects not receiving diuretics. Six patients without edema undergoing rapid diuresis lost a mean of 1.2 ± 0.2 L of ascites and an equivalent amount of weight (1.3 ± 0.4 kg) per day. All had a rise in blood urea nitrogen or creatinine, or both, and a fall in creatinine clearance. Eight patients with edema undergoing rapid diuresis lost more weight (1.8 ± 0.5 kg/day, p = 0.06) but less ascites (0.7 ± 0.35 L/day, p < 0.05) than those without edema, and none developed renal insufficiency. After edema disappeared, ascites mobilization increased (1.4 ± 0.7 L/day) and renal dysfunction occurred. Plasma volume fell an average of 24% ± 9% in patients without edema but did not change in patients with edema (−0.4% ± 3%). When edema disappeared, plasma volume fell significantly (28% ± 8%, p < 0.001). Electrolyte changes including hyponatremia, hyperkalemia, and hypochloremia were seen only in the group without edema. Patients with ascites and no edema are able to mobilize more than 1 L/day during rapid diuresis, but at the expense of plasma volume contraction and renal insufficiency. Patients with peripheral edema appear to be protected from these effects because of the preferential mobilization of edema and may safely undergo diuresis at a rapid rate (> 2 kg/day) until edema disappears.