Treatment optimisation for hepatitis C in the era of combination direct-acting antiviral therapy: a systematic review and meta-analysis.

Background: Prior to direct-acting antiviral (DAA) therapy, personalised medicine played an important role in the treatment of hepatitis C virus (HCV). Whilst simplified treatment strategies are central to treatment scale-up, some patients will benefit from treatment optimisation. This systematic review and meta-analysis explores treatment optimisation strategies in the DAA era. Methods: We systematically searched Medline, Embase, and Web of Science for studies that adopted a stratified or personalised strategy using a licensed combination DAA regimen, alone or with additional agents. We performed a thematic analysis to classify optimisation strategies and a meta-analysis of sustained virologic response rates (SVR), exploring heterogeneity with subgroup analyses and meta-regression. Results: We included 64 studies (9450 participants). Thematic analysis found evidence of three approaches: duration, combination, and/or dose optimisation. We separated strategies into those aiming to maintain SVR in the absence of predictors of failure, and those aiming to improve SVR in the presence of predictors of failure. Shortened duration regimens achieve pooled SVR rates of 94.2% (92.3-95.9%) for 8 weeks, 81.1% (75.1-86.6%) for 6 weeks, and 63.1% (39.9-83.7%) for ≤4 weeks. Personalised strategies (100% vs 87.6%; p<0.001) and therapy shortened according to ≥3 host/viral factors (92.9% vs 81.4% or 87.2% for 1 or 2 host/viral factors, respectively; p=0.008) offer higher SVR rates when shortening therapy. Hard-to-treat HCV genotype 3 patients suffer lower SVR rates despite treatment optimisation (92.6% vs 98.2%; p=0.001). Conclusions: Treatment optimisation for individuals with multiple predictors of treatment failure can offer high SVR rates. More evidence is needed to identify with confidence those individuals in whom SVR can be achieved with shortened duration treatment.

Is technetium-99 (Tc-99) radiologically significant?

According to radiological protection authorities the radioisotope technetium-99 (Tc-99) is not 'radiologically significant' to humans or other species. The Sellafield plutonium reprocessing plant discharges large amounts of Tc-99 into the Irish Sea; by the year 2015 a total of about 3,000 tera-becquerels of Tc-99, weighing about 5 tonnes, will have been discharged. This article considers the effects of Tc-99 on the environment. After discharge, Tc-99 travels large distances in the ocean. Levels of Tc-99 in Norwegian coastal waters increased by ten times between 1991 and 1996. Tc-99 becomes concentrated offshore in seaweed, winkles and mussels. A concentration factor of 120,000 has been reported in seaweed and one of 650,000 has been measured in the green gland of lobster. It may be necessary to reassess the risk to human health following the ingestion of the relevant isotopes, including Tc-99, because of the possibility of radiation induced genomic instability, as well as the cancer risk. The committed effective doses used to determine permitted levels of intake of these isotopes should be increased and the authorized limits for the discharge of radioactive wastes from Sellafield reduced. Authorized limits of the discharge of radioactivity should be based on Contaminated Food Intervention Levels rather than Generalized Derived Limits as they are now.

The nuclear arsenals and nuclear disarmament.

Current world stockpiles of nuclear weapons and the status of treaties for nuclear disarmament and the ultimate elimination of nuclear weapons are summarised. The need for including stockpiles of civil plutonium in a programme for ending production and disposing of fissile materials is emphasized, and the ultimate difficulty of disposing of the last few nuclear weapons discussed.

The plutonium problem: the Royal Society sits on the fence.

A recent Royal Society report, Management of Separated Plutonium, considers the production and disposal of plutonium from the spent fuel from civil and nuclear power reactors. It accepts the need for dealing with plutonium stocks because of the toxicity of the element and as it can be used to fabricate nuclear weapons, and expresses concern that it might be illicitly acquired by terrorists. It recommends an independent Government commission on the management of plutonium, and considers the various options for this. However, it does not analyse the arguments against plutonium as a reactor fuel, and underestimates the risks of diversion to nuclear weapons and nuclear terrorism. This paper reviews the options, and concludes that separated plutonium should be added to high-level waste, vitrified, and eventually buried in a deep geological repository.

The radiological hazards of plutonium.

About 1,500 tonnes of plutonium, 1,200 tonnes civilian, are now in world stockpiles, of which 200 tonnes have been separated from spent fuel in reprocessing plants. This will rise to 300 tonnes by the year 2000. Such reactor-grade plutonium contains a higher proportion of isotopes other than Pu-239, which progressively increases with longer burn-up. These isotopes have an increased risk of causing cancer, particularly if inhaled. Possible cancer rates from scattering of such plutonium in a city centre (e.g. by terrorist activity) are considered, and the implications of these calculations for the wisdom of continued reprocessing of spent nuclear reactor fuel are discussed.