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Gaps in hepatitis C virus (HCV) testing, diagnosis, liver disease assessment and treatment uptake among people who inject drugs (PWID) persist. We aimed to describe the cascade of HCV care among PWID in Australia, prior to and following unrestricted access to direct-acting antiviral (DAA) treatment. Participants enrolled in an observational cohort study between 2014 and 2018 provided fingerstick whole-blood samples for dried blood spot, Xpert HCV Viral Load and venepuncture samples. Participants underwent transient elastography and clinical assessment by a nurse or general practitioner. Among 839 participants (mean age 43 years), 66% were male (n = 550), 64% (n = 537) injected drugs in the previous month, and 67% (n = 560) reported currently receiving opioid substitution therapy. Overall, 45% (n = 380) had detectable HCV RNA, of whom 23% (n = 86) received HCV treatment within 12 months of enrolment. HCV treatment uptake increased from 2% in the pre-DAA era to 38% in the DAA era. Significant liver fibrosis (F2-F4) was more common in participants with HCV infection (38%) than those without (19%). Age 50 years or older (aOR, 2.88; 95% CI, 1.18-7.04) and attending a clinical follow-up with nurse (aOR, 3.19; 95% CI, 1.61-6.32) or physician (aOR, 11.83; 95% CI, 4.89-28.59) were associated with HCV treatment uptake. Recent injection drug use and unstable housing were not associated with HCV treatment uptake. HCV treatment uptake among PWID has increased markedly in the DAA era. Evaluation of innovative and simplified models of care is required to further enhance treatment uptake.

Objectives: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. Methods: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < −12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. Results: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. Conclusions: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.

ObjectivesThe Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. MethodsMARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. ResultsEighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. ConclusionsMVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.

Objectives: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. Method(s): MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. Result(s): Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. Conclusion(s): MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.Copyright © 2017 British H

Background. Alternative combination antiretroviral therapies in virologically suppressed human immunodeficiency virus (HIV)-infected patients experiencing side effects and/or at ongoing risk of important comorbidities from current therapy are needed. Maraviroc (MVC), a chemokine receptor 5 antagonist, is a potential alternative component of therapy in those with R5-tropic virus. Methods. The Maraviroc Switch Study is a randomized, multicenter, 96-week, open-label switch study in HIV type 1-infected adults with R5-tropic virus, virologically suppressed on a ritonavir-boosted protease inhibitor (PI/r) plus double nucleoside/nucleotide reverse transcriptase inhibitor (2 N(t)RTI) backbone. Participants were randomized 1:2:2 to current combination antiretroviral therapy (control), or replacing the protease inhibitor (MVC + 2 N(t)RTI arm) or the nucleoside reverse transcriptase inhibitor backbone (MVC + PI/r arm) with twice-daily MVC. The primary endpoint was the difference (switch minus control) in proportion with plasma viral load (VL) <200 copies/mL at 48 weeks. The switch arms were judged noninferior if the lower limit of the 95% confidence interval (CI) for the difference in the primary endpoint was < -12% in the intention-to-treat (ITT) population. Results. The ITT population comprised 395 participants (control, n = 82; MVC + 2 N(t)RTI, n = 156; MVC + PI/r, n = 157). Baseline characteristics were well matched. At week 48, noninferior rates of virological suppression were observed in those switching away from a PI/r (93.6% [95% CI, -9.0% to 2.2%] and 91.7% [95% CI, -9.6% to 3.8%] with VL <200 and <50 copies/mL, respectively) compared to the control arm (97.6% and 95.1% with VL <200 and <50 copies/mL, respectively). In contrast, MVC + PI/r did not meet noninferiority bounds and was significantly inferior (84.1% [95% CI, -19.8% to -5.8%] and 77.7% [95% CI, -24.9% to -8.4%] with VL <200 and <50 copies/mL, respectively) to the control arm in the ITT analysis. Conclusions

Background. Alternative combination antiretroviral therapies in virologically suppressed human immunodeficiency virus (HIV)-infected patients experiencing side effects and/or at ongoing risk of important comorbidities from current therapy are needed. Maraviroc (MVC), a chemokine receptor 5 antagonist, is a potential alternative component of therapy in those with R5-tropic virus. Methods. The Maraviroc Switch Study is a randomized, multicenter, 96-week, open-label switch study in HIV type 1-infected adults with R5-tropic virus, virologically suppressed on a ritonavir-boosted protease inhibitor (PI/r) plus double nucleoside/nucleotide reverse transcriptase inhibitor (2 N(t)RTI) backbone. Participants were randomized 1:2:2 to current combination antiretroviral therapy (control), or replacing the protease inhibitor (MVC + 2 N(t)RTI arm) or the nucleoside reverse transcriptase inhibitor backbone (MVC + PI/r arm) with twice-daily MVC. The primary endpoint was the difference (switch minus control) in proportion with plasma viral load (VL) <200 copies/mL at 48 weeks. The switch arms were judged noninferior if the lower limit of the 95% confidence interval (CI) for the difference in the primary endpoint was < -12% in the intention-to-treat (ITT) population. Results. The ITT population comprised 395 participants (control, n = 82; MVC + 2 N(t)RTI, n = 156; MVC + PI/r, n = 157). Baseline characteristics were well matched. At week 48, noninferior rates of virological suppression were observed in those switching away from a PI/r (93.6% [95% CI, -9.0% to 2.2%] and 91.7% [95% CI, -9.6% to 3.8%] with VL <200 and <50 copies/mL, respectively) compared to the control arm (97.6% and 95.1% with VL <200 and <50 copies/mL, respectively). In contrast, MVC + PI/r did not meet noninferiority bounds and was significantly inferior (84.1% [95% CI, -19.8% to -5.8%] and 77.7% [95% CI, -24.9% to -8.4%] with VL <200 and <50 copies/mL, respectively) to the control arm in the ITT analysis. Conclusions

Experimental design attempts to maximise the information available for modelling tasks. An optimal experiment allows the inferred models or parameters to be chosen with the highest expected degree of confidence. If the true system is faithfully reproduced by one of the models, the merit of this approach is clear - we simply wish to identify it and the true parameters with the most certainty. However, in the more realistic situation where all models are incorrect or incomplete, the interpretation of model selection outcomes and the role of experimental design needs to be examined more carefully. Using a novel experimental design and model selection framework for stochastic state-space models, we perform high-throughput in-silico analyses on families of gene regulatory cascade models, to show that the selected model can depend on the experiment performed. We observe that experimental design thus makes confidence a criterion for model choice, but that this does not necessarily correlate with a model's predictive power or correctness. Finally, in the special case of linear ordinary differential equation (ODE) models, we explore how wrong a model has to be before it influences the conclusions of a model selection analysis.

Pathogenic microbes exist in dynamic niches and have evolved robust adaptive responses to promote survival in their hosts. The major fungal pathogens of humans, Candida albicans and Candida glabrata, are exposed to a range of environmental stresses in their hosts including osmotic, oxidative and nitrosative stresses. Significant efforts have been devoted to the characterization of the adaptive responses to each of these stresses. In the wild, cells are frequently exposed simultaneously to combinations of these stresses and yet the effects of such combinatorial stresses have not been explored. We have developed a common experimental platform to facilitate the comparison of combinatorial stress responses in C. glabrata and C. albicans. This platform is based on the growth of cells in buffered rich medium at 30°C, and was used to define relatively low, medium and high doses of osmotic (NaCl), oxidative (H(2)O(2)) and nitrosative stresses (e.g., dipropylenetriamine (DPTA)-NONOate). The effects of combinatorial stresses were compared with the corresponding individual stresses under these growth conditions. We show for the first time that certain combinations of combinatorial stress are especially potent in terms of their ability to kill C. albicans and C. glabrata and/or inhibit their growth. This was the case for combinations of osmotic plus oxidative stress and for oxidative plus nitrosative stress. We predict that combinatorial stresses may be highly significant in host defences against these pathogenic yeasts.

Chaos and oscillations continue to capture the interest of both the scientific and public domains. Yet despite the importance of these qualitative features, most attempts at constructing mathematical models of such phenomena have taken an indirect, quantitative approach, for example, by fitting models to a finite number of data points. Here we develop a qualitative inference framework that allows us to both reverse-engineer and design systems exhibiting these and other dynamical behaviours by directly specifying the desired characteristics of the underlying dynamical attractor. This change in perspective from quantitative to qualitative dynamics, provides fundamental and new insights into the properties of dynamical systems.