A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir.

Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs.

Investigating equalisation of health inequalities during adolescence in four low-income and middle-income countries: an analysis of the Young Lives cohort study.

OBJECTIVE: To investigate if socioeconomic gradients in health reduce during adolescence (the equalisation hypothesis) in four low-income and middle-income countries (LMIC). SETTING: Analysis of the Young Lives Study cohorts in Ethiopia, Peru, Vietnam and India. PARTICIPANTS: A total of 3395 participants (across the four cohorts) aged 6-10 years at enrolment and followed up for 11 years. OUTCOMES MEASURED: Change in income-related health inequalities from mid-childhood to late adolescence. Socioeconomic status was determined by wealth index quartile. The health indicators included were self-reported health, injuries in the previous 4 years, presence of long-term health problems, low mood, alcohol use, overweight/obesity, thinness and stunting. The relative risk of each adverse health outcome between highest and lowest wealth index quartile were compared across four waves of the study within each country. RESULTS: We found steep socioeconomic gradients across multiple health indicators in all four countries. Socioeconomic gradients remained similar across all waves of the study, with no significant decrease during adolescence. CONCLUSION: We found no consistent evidence of equalisation for income-related health inequalities in youth in these LMIC. Socioeconomic gradients for health in these cohorts appear to persist and be equally damaging across the early life course and during adolescence.

Adolescent cohorts assessing growth, cardiovascular and cognitive outcomes in low and middle-income countries.

INTRODUCTION: Life-course studies are needed to explore how exposures during adolescence, particularly puberty, contribute to later cardiovascular risk and cognitive health in low and middle-income countries (LMIC), where 90% of the world's young people live. The extent of any existing cohorts investigating these outcomes in LMIC has not previously been described. METHODS: We performed a systematic literature review to identify population cohort studies of adolescents in LMIC that assessed anthropometry and any of cardiovascular risk (blood pressure, physical activity, plasma glucose/lipid profile and substance misuse), puberty (age at menarche, Tanner staging, or other form of pubertal staging) or cognitive outcomes. Studies that recruited participants on the basis of a pre-existing condition or involved less than 500 young people were excluded. FINDINGS: 1829 studies were identified, and 24 cohorts fulfilled inclusion criteria based in Asia (10), Africa (6) and South / Central America (8). 14 (58%) of cohorts identified were based in one of four countries; India, Brazil, Vietnam or Ethiopia. Only 2 cohorts included a comprehensive cardiovascular assessment, tanner pubertal staging, and cognitive outcomes. CONCLUSION: Improved utilisation of existing datasets and additional cohort studies of adolescents in LMIC that collect contemporaneous measures of growth, cognition, cardiovascular risk and pubertal development are needed to better understand how this period of the life course influences future non-communicable disease morbidity and cognitive outcomes.