Background Network meta-analyses (NMAs) provide comparative treatment effects estimates in the absence of head-to-head randomized controlled trials (RCTs). This NMA compared the efficacy and safety of dolutegravir (DTG) with other recommended or commonly used core antiretroviral agents. Methods A systematic review identified phase 3/4 RCTs in treatment-naïve patients with HIV-1 receiving core agents: ritonavir-boosted protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand inhibitors (INSTIs). Efficacy (virologic suppression [VS], CD4 + cell count change from baseline) and safety (adverse events [AEs], discontinuations, discontinuation due to AEs, lipid changes) were analyzed at Week 48 using Bayesian NMA methodology, which allowed calculation of probabilistic results. Subgroup analyses were conducted for VS (baseline viral load [VL] ≤/> 100,000copies/mL, ≤/> 500,000copies/mL; baseline CD4 + ≤/>200cells/μL). Results were adjusted for the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) combined with the core agent (except subgroup analyses). Results The NMA included 36 studies; 2 additional studies were included in subgroup analyses only. Odds of achieving VS with DTG were statistically superior to PIs (odds ratios [ORs] 1.78–2.59) and NNRTIs (ORs 1.51–1.86), and similar but numerically higher than other INSTIs. CD4 + count increase was significantly greater with DTG than PIs (difference: 23.63–31.47 cells/μL) and efavirenz (difference: 34.54 cells/μL), and similar to other core agents. INSTIs were more likely to result in patients achieving VS versus PIs (probability: 76–100%) and NNRTIs (probability: 50–100%), and a greater CD4 + count increase versus PIs (probability: 72–100%) and NNRTIs (probability: 60–100%). DTG was more likely to result in patients achieving VS (probability: 94–100%), and a greater CD4 + count increase (probability: 53–100%) versus other core agents, including INSTIs (probability: 94–97% and 53–93%, respectively). Safety outcomes with DTG were generally similar to other core agents. In patients with baseline VL > 100,000copies/mL or ≤ 200 CD4 + cells/μL (18 studies), odds of achieving VS with DTG were superior or similar to other core agents. Conclusion INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious, including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4 + cells/μL, who can be difficult to treat. Electronic supplementary material The online version of this article (10.1186/s12879-019-3975-6) contains supplementary material, which is available to authorized users.

NaChBac from Bacillus halodurans is a bacterial homologue of mammalian voltage-gated sodium channels. It has been proposed that a NaChBac monomer corresponds to a single domain of the mammalian sodium channel and that, like potassium channels, four monomers form a tetrameric channel. However, to date, although NaChBac has been well-characterized for functional properties by electrophysiological measurements on protein expressed in tissue culture, little information about its structural properties exists because of the difficulties in expressing the protein in large quantities. In this study, we present studies on the overexpression of NaChBac in Escherichia coli, purification of the functional detergent-solubilized channel, its identification as a tetramer, and characterization of its secondary structure, drug binding, and thermal stability. These studies are correlated with a model produced for the protein and provide new insights into the structure-function relationships of this sodium channel.

PurposeFrequent exacerbations which are both costly and potentially life-threatening are a major concern to patients with chronic obstructive pulmonary disease (COPD), despite the availability of several treatment options. This study aimed to assess the lifetime costs and outcomes associated with alternative treatment regimens for patients with severe COPD in the UK setting.Patients and methodsA Markov cohort model was developed to predict lifetime costs, outcomes, and cost-effectiveness of various combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), an inhaled corticosteroid (ICS), and roflumilast in a fully incremental analysis. Patients willing and able to take ICS, and those refusing or intolerant to ICS were analyzed separately. Efficacy was expressed as relative rate ratios of COPD exacerbation associated with alternative treatment regimens, taken from a mixed treatment comparison. The analysis was conducted from the UK National Health Service (NHS) perspective. Parameter uncertainty was explored using one-way and probabilistic sensitivity analysis.ResultsBased on the results of the fully incremental analysis a cost-effectiveness frontier was determined, indicating those treatment regimens which represent the most cost-effective use of NHS resources. For ICS-tolerant patients the cost-effectiveness frontier suggested LAMA as initial treatment. Where patients continue to exacerbate and additional therapy is required, LAMA + LABA/ICS can be a cost-effective option, followed by LAMA + LABA/ICS + roflumilast (incremental cost-effectiveness ratio [ICER] versus LAMA + LABA/ICS: £16,566 per quality-adjusted life-year [QALY] gained). The ICER in ICS-intolerant patients, comparing LAMA + LABA + roflumilast versus LAMA + LABA, was £13,764/QALY gained. The relative rate ratio of exacerbations was identified as the primary driver of cost-effectiveness.ConclusionThe treatment algorithm recommended in UK clinical practice represents a costeffective approach for the management of COPD. The addition of roflumilast to the standard of care regimens is a clinical and cost-effective treatment option for patients with severe COPD, who continue to exacerbate despite existing bronchodilator therapy.

ObjectiveChronic obstructive pulmonary disease (COPD) represents a burden on patients and health systems. Roflumilast, an oral, selective phosphodiesterase-4-inhibitor reduces exacerbations and improves lung function in severe/very severe COPD patients with a history of exacerbations. This study aimed to estimate the lifetime cost and outcomes of roflumilast added-on to commonly used COPD regimens in Switzerland.MethodsA Markov cohort model was developed to simulate COPD progression in patients with disease states of severe, very severe COPD, and death. The exacerbation rate was assumed to be two per year in severe COPD. COPD progression rates were drawn from the published literature. Efficacy was expressed as relative ratios of exacerbation rates associated with roflumilast, derived from a mixed-treatment comparison. A cost-effectiveness analysis was conducted for roflumilast added to long-acting muscarinic antagonists (LAMA), long-acting β2-agonist/ inhaled corticosteroids (LABA/ICS), and LAMA + LABA/ICS. The analysis was conducted from the Swiss payer perspective, with costs and outcomes discounted at 2.5% annually. Parameter uncertainties were explored in one-way and probabilistic sensitivity analyses.ResultsIn each of the comparator regimens mean life expectancy was 9.28 years and quality-adjusted life years (QALYs) gained were 6.19. Mean estimated lifetime costs per patient in the comparator arms were CHF 83,364 (LAMA), CHF 88,161 (LABA/ICS), and CHF 95,564 (LAMA + LABA/ICS) respectively. Adding roflumilast resulted in a mean cost per patient per lifetime of CHF 86,754 (LAMA + roflumilast), CHF 91,470 (LABA/ICS + roflumilast), and CHF 99,364 (LAMA + LABA/ICS + roflumilast), respectively. Life-expectancy and quality-adjusted life-expectancy were 9.63 years and 6.47 QALYs (LAMA + roflumilast), 9.64 years and 6.48 QALYs (LABA/ICS + roflumilast), and 9.63 years and 6.47 QALYs (LAMA + LABA/ ICS + roflumilast). Incremental cost-effectiveness ratios were CHF 12,313, CHF 11,456, and CHF 13,671 per QALY when roflumilast was added to the three regimens.ConclusionTreatment with roflumilast is estimated to reduce the health and economic burden of COPD exacerbations and represent a cost-effective treatment option for patients with frequent exacerbations in Switzerland.

Dolutegravir (DTG) is widely recommended within three-drug regimens. However, similar efficacy and tolerability have also been achieved with DTG within two-drug regimens in clinical trials. This study evaluated the real-world effectiveness and discontinuations in people living with HIV-1 (PLHIV) switching to DTG with lamivudine (3TC) or rilpivirine (RPV). MethodsThis was a one-arm meta-analysis utilizing data from a systematic literature review. Data from real-world evidence studies of DTG + RPV and DTG + 3TC were extracted, pooled and analysed. The primary outcome was the proportion of patients with viral failure (VF; ≥ 50 copies/mL in two consecutive measurements and/or ≥ 1000 copies/mL in a single measurement) at week 48 (W48) and week 96 (W96). Other outcomes included virological suppression (VS; < 50 copies/mL) and discontinuations (W48 and W96). Estimates were calculated for VF, VS as per snapshot (VSS) and on treatment analysis (VSOT), and discontinuations. ResultsPooled mean estimates of VF for DTG + 3TC and DTG + RPV were 0.8% [95% confidence interval (CI): 0.4-1.3] and 0.6% (95% CI: 0.0-1.6), respectively, at W48. VSS rate at W48 was 85.0% (95% CI: 82.3-87.5) for DTG + 3TC regimen and 92.4% (95% CI: 85.0-97.7) in the DTG + RPV regimen. The DTG + 3TC and DTG + RPV regimens led to discontinuations in 13.6% (95% CI: 11.1-16.2) and 7.2% (95% CI: 2.1-14.4) of patients, respectively, at W48. Similar results were observed at W96. ConclusionsTreatment with DTG + 3TC or DTG + RPV in clinical practice provides a low rate of VF and a high rate of VS when initiated in virologically suppressed PLHIV with diverse backgrounds.