A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antiviral effect was observed. Binding was demonstrated via a solid state structure of the isolated p15-Ec domain of HIV-1 RT showing inhibitor and two Mn(II) ions bound to the RNase H active site.

We need to develop systems wide understanding of what supports a healthy environment and the art and science of making change.

No abstract

ObjectiveTo assess the cost–effectiveness of community-based practitioner programmes in Ethiopia, Indonesia and Kenya.MethodsIncremental cost–effectiveness ratios for the three programmes were estimated from a government perspective. Cost data were collected for 2012. Life years gained were estimated based on coverage of reproductive, maternal, neonatal and child health services. For Ethiopia and Kenya, estimates of coverage before and after the implementation of the programme were obtained from empirical studies. For Indonesia, coverage of health service interventions was estimated from routine data. We used the Lives Saved Tool to estimate the number of lives saved from changes in reproductive, maternal, neonatal and child health-service coverage. Gross domestic product per capita was used as the reference willingness-to-pay threshold value.FindingsThe estimated incremental cost per life year gained was 82 international dollars ($)in Kenya, $999 in Ethiopia and $3396 in Indonesia. The results were most sensitive to uncertainty in the estimates of life-years gained. Based on the results of probabilistic sensitivity analysis, there was greater than 80% certainty that each programme was cost-effective.ConclusionCommunity-based approaches are likely to be cost-effective for delivery of some essential health interventions where community-based practitioners operate within an integrated team supported by the health system. Community-based practitioners may be most appropriate in rural poor communities that have limited access to more qualified health professionals. Further research is required to understand which programmatic design features are critical to effectiveness.