Danoprevir for the Treatment of Hepatitis C Virus Infection: Design, Development, and Place in Therapy.

On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b - the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.

Impact of HCV genotype on treatment regimens and drug resistance: a snapshot in time.

The introduction of highly potent direct-acting antivirals (DAAs) has revolutionized hepatitis C virus treatment. Nevertheless, viral eradication worldwide remains a challenge also in the era of DAA treatment, because of the high associated costs, high numbers of undiagnosed patients, high re-infection rates in some risk groups and suboptimal drug efficacies associated with host and viral factors as well as advanced stages of liver disease. A correct determination of the HCV genotype allows administration of the most appropriate antiviral regimen. Additionally, HCV genetic sequencing improves our understanding of resistance-associated variants, either naturally occurring before treatment, acquired by transmission at HCV infection, or emerging after virological failure. Because treatment response rates, and the prevalence and development of drug resistance variants differ for each DAA regimen and HCV genotype, this review summarizes treatment opportunities per HCV genotype, and focuses on viral genetic sequencing to guide clinical decision making. Although approval of the first pan-genotypic DAA-only regimen is expected soon, HCV genetic sequencing will remain important because when DAA therapies fail, genotyping and resistance testing to select a new active DAA combination will be essential. Copyright © 2016 John Wiley & Sons, Ltd.

The relative importance of pre- and post-germination determinants for recruitment of an annual plant community on moving sandy land.

BACKGROUND AND AIMS: The relative importance of pre- and post-germination determinants for recruitment of natural plant communities is rarely explored. An annual plant community on moving sandy land was chosen for a case study. Answers to the following questions were sought: (a) Does recruitment of new individuals within the community of annual plants differ in time and space? (b) Is there spatial concordance between seed deposition, seedling emergence, survival and recruitment? (c) What are the direct and indirect effects of pre- and post-germination determinants on plant recruitment. METHODS: An integrative approach combining investigation of natural recruitment processes with regression, correlation and path analyses was adopted. Data on seed deposition and seedling recruitment were collected by monitoring the number of seeds deposited in the top 5 cm of the soil and the numbers of seedlings emerged and recruited from all annual plants at sites to a range of distances from the existing shrub Artemisia halodendron (Asteraceae) in eight compass directions for two consecutive growing seasons. KEY RESULTS: Community-level recruitment was strongly affected by inter-annual rainfall variation and was highly site- and density-dependent. Low recruitment rate in this system was due to low emergence rate and low post-emergence survival rate. Of the pre- and post-germination determinants studied, it was the number of seedlings which emerged and the post-emergence survival rate that had the greatest direct effects on recruitment, with a combination of both variables explaining the majority of the variance (97 %) in recruitment. CONCLUSIONS: This study suggests that post-germination determinants (emergence and survival) rather than pre-germination determinants (seed deposition) substantially determined the final pattern of recruitment. Although the density of seeds deposited did not have a significant direct effect on recruitment, it contributed to observed variation in recruitment indirectly through density-dependent emergence of seedlings.