Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor.

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients.

A molecular epidemiological perspective of rhinovirus types circulating in Amsterdam from 2007 to 2012.

Rhinoviruses (RVs) are frequently detected respiratory viruses that cause mild common cold symptoms, but may also lead to more severe respiratory tract infections. The large number of RV types, classified into species A, B and C, hampers clear insights into the epidemiology and clinical significance of each RV type. The aim of this study was to map the circulation of RV types in the Amsterdam area. RV-positive nasopharyngeal and oropharyngeal samples, collected from 2007 to 2012 in the Academic Medical Centre (Amsterdam, the Netherlands), were typed based on the sequence of the region coding for capsid proteins VP4 and VP2. RV-A, RV-B and RV-C were found in proportions of of 52.4% (334/637), 11.3% (72/637), and 36.2% (231/637), respectively. We detected 129 of the 167 currently classified types. RVs circulated throughout the entire year with a peak in the autumn and a decline in the summer. Some RV types were observed throughout the entire sampling period and others had a more seasonal pattern. Nine RV-A and four RV-B novel provisionally assigned types were identified. This study provides an insight into the molecular epidemiology of RVs in the Amsterdam area. The RVs circulating are diverse and include several provisionally new types.