Treatment of hepatitis C monoinfection in adults--Dutch national guidelines.

In this new Dutch guideline for hepatitis C virus infection we provide recommendations for the management of hepatitis C infection. Until 2012 the standard for treatment consisted of pegylated interferon alpha (peg-IFNa) and ribavirin. The advent of first-generation direct antiviral agents such as boceprevir and telaprevir has changed the concept of treatment of adult chronic hepatitis C genotype 1 infected patients. There are three benefits of boceprevir and telaprevir. They increase the likelihood of cure in 1) naive genotype 1 patients and 2) in patients who did not respond to earlier treatment with peg-IFNa and ribavirin, while 3) allowing shortening of treatment duration from 48 weeks to 24 or 28 weeks, which is possible in 40-60% of non-cirrhotic naive (boceprevir and telaprevir) and relapsing patients (telaprevir). The use of boceprevir and telaprevir is associated with multiple side effects and awareness of these side effects is needed to guide the patient through the treatment process. This guideline, formulated on behalf of The Netherlands Association of Hepato-gastroenterologists, The Netherlands Association of Internal Medicine, and The Dutch Association for the Study of Liver Disease, serves as a manual for physicians for the management and treatment of acute and chronic hepatitis C virus monoinfection in adults.

Hepatitis C virus infection management in 2012.

Hepatitis C virus (HCV) is the most common infectious cause of chronic liver disease in Europe. With the introduction of interferon based therapy in combination with ribavirin treatment of chronic HCV has become feasible. This therapy has become the standard of care for patients with HCV and depending on the HCV genotype treatment is successful in 40-70% of patients. In the recent years a new class of drugs have emerged that changed the landscape of HCV treatment. These direct antiviral agents inhibit the NS3/N4A serine protease of HCV. Prototypes are telaprevir and boceprevir and they specifically exert antiviral activity against genotype 1 HCV. A series of landmark trials has paved the way for introduction of these agents, and they have documented a great improvement in the care of genotype 1 HCV patients. Telaprevir and boceprevir are given in combination with pegylated interferon and ribavirin and are useful for treatment naive as well as treatment experienced patients. The clinician should be aware of these developments as they have implications for side effect management, and drug-drug interactions. Finally, strategic use of these agents comes with stopping rules and require close monitoring of the HCV viral load.

Current clinical care compared with new Dutch guidelines for hepatitis C treatment.

BACKGROUND: Recently, the Dutch Association of Gastroenterology and Hepatology issued new guidelines for the treatment of chronic hepatitis C virus (HCV). These guidelines reflect the current standard of care. Before these guidelines were published and implemented we (1) studied the current clinical care of HCV patients among Dutch physicians, and (2) identified areas for future refinement in the current treatment. METHODS: We conducted a non-targeted survey among Dutch medical specialists in Gastroenterology, Hepatology and Internal Medicine who actively treat HCV patients. The questionnaire contained items about facility, duration and dosing of treatment, and side effect management using clinical vignettes followed by short questions. RESULTS: We received 49 questionnaires from treating HCV specialists. The majority (65%) of respondents treat HCV patients during regular outpatient clinics, while 35% treat these patients in a separate setting dedicated to the care of HCV patients. The majority of physicians follow the stipulated dosage regimens of pegylated interferon (88%) and ribavirin (83%). A minority (13%) exceed the advised dosage of ribavirin. Side effects such as neutropenia are mostly managed by decreasing the interferon dosage (42%). Some 35% of physicians reduce ribavirin if haemoglobin levels drop below 5.4 mmol/l, and 41% initiate erythropoietin treatment. CONCLUSION: Dutch clinical practice reflects the recently issued HCV guidelines. An important area of refinement in treatment of HCV is the management of side effects.

The crystal structure of DNA mismatch repair protein MutS binding to a G x T mismatch.

DNA mismatch repair ensures genomic integrity on DNA replication. Recognition of a DNA mismatch by a dimeric MutS protein initiates a cascade of reactions and results in repair of the newly synthesized strand; however, details of the molecular mechanism remain controversial. Here we present the crystal structure at 2.2 A of MutS from Escherichia coli bound to a G x T mismatch. The two MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual base pairing and kinking of the DNA. Nonspecific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutS alpha (MSH2/MSH6) that lead to hereditary predisposition for cancer, such as hereditary non-polyposis colorectal cancer, can be mapped to this crystal structure.