Imperial College London

ProfessorGrahamCooke

Faculty of MedicineDepartment of Medicine

Professor of Infectious Diseases
 
 
 
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Contact

 

+44 (0)20 7594 3903g.cooke

 
 
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Location

 

Infectious Diseases SectionWinston Churchill WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

159 results found

Fawsitt CG, Vickerman P, Cooke G, Welton NJ, STOP-HCV Consortiumet al., 2019, A cost-effectiveness analysis of shortened direct-acting antiviral treatment in genotype 1 noncirrhotic treatment-naive patients with chronic Hepatitis C virus, Value in Health, Vol: 22, Pages: 693-703, ISSN: 1098-3015

BACKGROUND: Direct-acting antivirals are successful in curing hepatitis C virus infection in more than 95% of patients treated for 12 weeks, but they are expensive. Shortened treatment durations, which may have lower cure rates, have been proposed to reduce costs. OBJECTIVES: To evaluate the lifetime cost-effectiveness of different shortened treatment durations for genotype 1 noncirrhotic treatment-naive patients. METHODS: Assuming a UK National Health Service perspective, we used a probabilistic decision tree and Markov model to compare 3 unstratified shortened treatment durations (8, 6, and 4 weeks) against a standard 12-week treatment duration. Patients failing shortened first-line treatment were re-treated with a 12-week treatment regimen. Parameter inputs were taken from published studies. RESULTS: The 8-week treatment duration had an expected incremental net monetary benefit of £7737 (95% confidence interval £3242-£11 819) versus the standard 12-week treatment, per 1000 patients. The 6-week treatment had a positive incremental net monetary benefit, although some uncertainty was observed. The probability that the 8- and 6-week treatments were the most cost-effective was 56% and 25%, respectively, whereas that for the 4-week treatment was 17%. Results were generally robust to sensitivity analyses, including a threshold analysis that showed that the 8-week treatment was the most cost-effective at all drug prices lower than £40 000 per 12-week course. CONCLUSIONS: Shortening treatments licensed for 12 weeks to 8 weeks is cost-effective in genotype 1 noncirrhotic treatment-naive patients. There was considerable uncertainty in the estimates for 6- and 4-week treatments, with some indication that the 6-week treatment may be cost-effective.

JOURNAL ARTICLE

Simmons B, Cooke G, Miraldo M, The impact of voluntary licences for hepatitis C on access to treatment: a difference-in-differences analysis, The Lancet Global Health, ISSN: 2214-109X

Background. Voluntary licences are increasingly being utilised as a mechanism to increase access to patented essential medicines in low- and middle-income countries (LMICs). Since 2014, non-exclusive voluntary licences have been issued for key medicines for the treatment of hepatitis C (HCV), an important challenge to global health for which elimination targets have recently been set. We utilized HCV treatment rate data to carry out the first evaluation of the impact of these licences on access to treatment.Methods. We exploit the staggered and selective introduction of voluntary licensing in different countries to identify the impact of voluntary licensing agreements on access to treatment measured as the HCV treatment rate. We do so with difference-in-differences methods applied to a panel of 35 LMICs over a 13-year period (2004-2016). The analyses control for country and year fixed effects and a range of country-level factors that may influence access and treatment uptake. Findings. The intervention group consisted of 19 countries; the remaining 16 countries formed the control group. In the simplest model adjusting only for country and year fixed effects, voluntary licences were associated with an increase in annual treatment rate of 69·3 per 1,000 diagnosed with HCV (95%CI 46·7,91·9; p=0·006). After adjusting for country-level covariates, the impact of licences was 53·6 per 1,000 diagnosed with HCV (95%CI 25·8,81·5; 0·035). The effect of licensing increased over time and was largest in the second year after implementation. Results were robust to alternative specifications.Interpretation. Voluntary licensing initiatives appear to have had a significant impact on increasing HCV treatment rate in eligible countries. This evidence provides support for expansion of licensing strategies to include more countries and more treatments. The results suggest voluntary licensing may be an effective mechanism for increas

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Takwoingi Y, Whitworth H, Rees-Roberts M, Badhan A, Partlett C, Green N, Boakye A, Lambie H, Marongiu L, Jit M, White P, Deeks JJ, Kon OM, Lalvani A, Abdoyeku D, Branley H, Chua F, Conlon C, Cooke G, Davison R, Dedicoat M, Kunst H, Lipman M, Loebingher M, Lynn W, Macallan D, Menzies S, Nathani N, O'Connell R, Post F, Pozniak A, Wiselka M, Woltmann Get al., 2019, Interferon gamma release assays for diagnostic evaluation of active tuberculosis (IDEA): test accuracy study and economic evaluation, Health Technology Assessment, Vol: 23, ISSN: 1366-5278

BackgroundInterferon gamma release assays (IGRAs) are blood tests recommended for the diagnosis of tuberculosis (TB) infection. There is currently uncertainty about the role and clinical utility of IGRAs in the diagnostic workup of suspected active TB in routine NHS clinical practice.ObjectivesTo compare the diagnostic accuracy and cost-effectiveness of T-SPOT.TB® (Oxford Immunotec, Abingdon, UK) and QuantiFERON® TB GOLD In-Tube (Cellestis, Carnegie, VIC, Australia) for diagnosis of suspected active TB and to estimate the diagnostic accuracy of second-generation IGRAs.DesignProspective within-patient comparative diagnostic accuracy study.SettingSecondary care.ParticipantsAdults (aged ≥ 16 years) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB.InterventionsThe index tests [T-SPOT.TB and QuantiFERON GOLD In-Tube (QFT-GIT)] and new enzyme-linked immunospot assays utilising novel Mycobacterium tuberculosis antigens (Rv3615c, Rv2654, Rv3879c and Rv3873) were verified against a composite reference standard applied by a panel of clinical experts blinded to IGRA results.Main outcome measuresSensitivity, specificity, predictive values and likelihood ratios were calculated to determine diagnostic accuracy. A decision tree model was developed to calculate the incremental costs and incremental health utilities [quality-adjusted life-years (QALYs)] of changing from current practice to using an IGRA as an initial rule-out test.ResultsA total of 363 patients had active TB (culture-confirmed and highly probable TB cases), 439 had no active TB and 43 had an indeterminate final diagnosis. Comparing T-SPOT.TB and QFT-GIT, the sensitivities [95% confidence interval (CI)] were 82.3% (95% CI 77.7% to 85.9%) and 67.3% (95% CI 62.1% to 72.2%), respectively, whereas specificities were 82.6% (95% CI 78.6% to 86.1%) and 80.4% (95% CI 76.1% to 84.1%), respectively. T-SPOT.TB was mor

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Jones CR, Ortega-Prieto AM, Cooke G, Dorner Met al., 2019, A phenotypic resistance assay for clinical HCV isolates could help rationalise DAA therapy in individuals experiencing recurrent virologic failure, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E704-E704, ISSN: 0168-8278

CONFERENCE PAPER

Garvey L, Smith C, Stingone C, Ghosh I, Rodger A, Jain L, Sood C, Mahungu T, Freeman C, Dakshina S, Ferro F, Waters L, Brown A, Cooke G, Bhagani Set al., 2019, Fall in HCV incidence in HIV plus MSM in London following expansion of access to DAA therapy, Publisher: WILEY, Pages: 12-12, ISSN: 1464-2662

CONFERENCE PAPER

Cole M, Saeed Z, Shaw AT, Guo Y, Hoschler K, Winston A, Cooke G, Fidler S, Taylor G, Pollock Ket al., 2019, Equivalent responses to quadrivalent influenza vaccine are detectable in blood and oral fluid in healthcare workers and men living with HIV on ART, Publisher: WILEY, Pages: 10-10, ISSN: 1464-2662

CONFERENCE PAPER

Heffernan A, Cooke G, Nayagam S, Hallett TB, Thursz Met al., 2019, Scaling up prevention and treatment towards the elimination of hepatitis C: a global mathematical model, Lancet, Vol: 393, Pages: 1319-1329, ISSN: 0140-6736

BackgroundThe revolution in hepatitis C virus (HCV) treatment through the development of direct-acting antivirals (DAAs) has generated international interest in the global elimination of the disease as a public health threat. In 2017, this led WHO to establish elimination targets for 2030. We evaluated the impact of public health interventions on the global HCV epidemic and investigated whether WHO's elimination targets could be met.MethodsWe developed a dynamic transmission model of the global HCV epidemic, calibrated to 190 countries, which incorporates data on demography, people who inject drugs (PWID), current coverage of treatment and prevention programmes, natural history of the disease, HCV prevalence, and HCV-attributable mortality. We estimated the worldwide impact of scaling up interventions that reduce risk of transmission, improve access to treatment, and increase screening for HCV infection by considering six scenarios: no change made to existing levels of diagnosis or treatment; sequentially adding the following interventions: blood safety and infection control, PWID harm reduction, offering of DAAs at diagnosis, and outreach screening to increase the number diagnosed; and a scenario in which DAAs are not introduced (ie, treatment is only with pegylated interferon and oral ribavirin) to investigate the effect of DAA use. We explored the effect of varying the coverage or impact of these interventions in sensitivity analyses and also assessed the impact on the global epidemic of removing certain key countries from the package of interventions.FindingsBy 2030, interventions that reduce risk of transmission in the non-PWID population by 80% and increase coverage of harm reduction services to 40% of PWID could avert 14·1 million (95% credible interval 13·0–15·2) new infections. Offering DAAs at time of diagnosis in all countries could prevent 640 000 deaths (620 000–670 000) from cirrhosis and liver cancer. A comprehensive p

JOURNAL ARTICLE

Le Ngoc C, Tran Thi Thanh T, Tran Thi Lan P, Nguyen Mai T, Nguyen Hoa T, Nghiem My N, Le Van T, Le Manh H, Le Thanh P, Nguyen Van Vinh C, Thwaites G, Cooke G, Heilek GM, Shikuma C, Le T, Baker S, Rahman Met al., Differential prevalence and geographic distribution of hepatitis C virus genotypes in acute and chronic hepatitis C patients in Vietnam, PLoS ONE, Vol: 14, ISSN: 1932-6203

BackgroundThe highest burden of disease from hepatitis C virus (HCV) is found in Southeast Asia, but our understanding of the epidemiology of infection in many heavily burdened countries is still limited. In particular, there is relatively little data on acute HCV infection, the outcome of which can be influenced by both viral and host genetics which differ within the region. We studied HCV genotype and IL28B gene polymorphism in a cohort of acute HCV-infected patients in Southern Vietnam alongside two other cohorts of chronic HCV-infected patients to better understand the epidemiology of HCV infection locally and inform the development of programs for therapy with the increasing availability of directly acting antiviral therapy (DAAs).MethodsWe analysed plasma samples from patients with acute and chronic HCV infection, including chronic HCV mono-infection and chronic Human Immunodeficiency Virus (HIV)-HCV coinfection, who enrolled in four epidemiological or clinical research studies. HCV infection was confirmed with RNA testing. The 5’ UTR, core and NSB5 regions of HCV RNA positive samples were sequenced, and the genotype and subtype of the viral strains were determined. Host DNA from all HCV positive patients and age- and sex-matched non-HCV-infected control individuals were analysed for IL28B single nucleotide polymorphism (SNP) (rs12979860 and rs8099917). Geolocation of the patients were mapped using QGIS.Results355 HCV antibody positive patients were analysed; 54.6% (194/355) and 46.4% (161/355) were acute and chronic infections, respectively. 50.4% (81/161) and 49.6.4% (80/161) of chronic infections had HCV mono-infection and HIV-HCV coinfection, respectively. 88.7% (315/355) and 10.1% (36/355) of the patients were from southern and central regions of Vietnam, respectively. 92.4% (328/355) of patients were HCV RNA positive, including 86.1% (167/194) acute and 100% (161/161) chronic infections. Genotype could be determined in 98.4% (322/328) patients. Gen

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Cockbain BC, Mora Peris B, Abbara A, So CW, Cooke Get al., 2019, Disseminated CMV infection and HLH in a patient with well-controlled HIV and ulcerative colitis, BMJ Case Reports, Vol: 12, ISSN: 1757-790X

We present a case of haemophagocytic lymphohistiocytosis (HLH) in the context of disseminated cytomegalovirus (CMV) viraemia in a 50-year-old man with well-controlled HIV infection and ulcerative colitis (UC), for which he was receiving azathioprine. Peak CMV viral load was 371 000 copies/ml with evidence of end-organ CMV in the lungs and colon. A bone marrow biopsy showed evidence of haemophagocytosis of platelets, neutrophils and erythrocytes. The azathioprine was stopped, and he received intravenous ganciclovir and corticosteroids with suppression of the CMV viral load and resolution of the HLH.

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Whitworth HS, Badhan A, Boakye AA, Takwoingi Y, Rees-Roberts M, Partlett C, Lambie H, Innes J, Cooke G, Lipman M, Conlon C, Macallan D, Chua F, Post FA, Wiselka M, Woltmann G, Deeks JJ, Kon OM, Lalvani A, Interferon-γ Release Assays for Diagnostic Evaluation of Active Tuberculosis study groupet al., 2019, Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study, Lancet Infectious Diseases, Vol: 19, Pages: 193-202, ISSN: 1473-3099

BACKGROUND: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. METHODS: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. FINDINGS: Of the 1060 adults enrolled in the study, 845 were eligible and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs. INTERPRETATION: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negati

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Cooke GS, Andrieux-Meyer I, Applegate TL, Atun R, Burry JR, Cheinquer H, Dusheiko G, Feld JJ, Gore C, Griswold MG, Hamid S, Hellard ME, Hou JL, Howell J, Jia J, Kravchenko N, Lazarus JV, Lemoine M, Lesi OA, Maistat L, McMahon BJ, Razavi H, Roberts TR, Simmons B, Sonderup MW, Spearman CW, Taylor BE, Thomas DL, Waked I, Ward JW, Wiktor SZ, Abdo A, Aggarwal R, Aghemo A, Al-Judaibi B, Al Mahtab M, Altaf A, Ameen Z, Asselah T, Baatarkkhuu O, Barber E, Barnes E, Boulet P, Burrows L, Butsashvili M, Chan E, Chow C, Cowie B, Cunningham C, de Araujo A, Diap G, Dore G, Doyle J, Elsayed M, Fajardo E, Gane E, Getehun A, Goldberg D, Got T, Hickman M, Hill A, Hutchinson S, Jones C, Kamili S, Khan A, Lee A, Lee TY, Malani J, Morris TM, Nayagam S, Njouom R, Ocama P, Pedrana A, Peeling R, Reddy A, Roberts T, Sacks J, Sarin S, Shimakawa Y, Silva M, Skala P, Taylor-Robinson S, Thompson A, Thursz M, Tonganibeia A, Wallace J, Ward J, Wolff F, Vickerman P, Yau Jet al., 2019, Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission, The Lancet Gastroenterology and Hepatology, Vol: 4, Pages: 135-184, ISSN: 2468-1253

Viral hepatitis is a major public health threat and a leading cause of death worldwide. Annual mortality from viral hepatitis is similar to that of other major infectious diseases such as HIV and tuberculosis. Highly effective prevention measures and treatments have made the global elimination of viral hepatitis a realistic goal, endorsed by all WHO member states. Ambitious targets call for a global reduction in hepatitis-related mortality of 65% and a 90% reduction in new infections by 2030. This Commission draws together a wide range of expertise to appraise the current global situation and to identify priorities globally, regionally, and nationally needed to accelerate progress. We identify 20 heavily burdened countries that account for over 75% of the global burden of viral hepatitis. Key recommendations include a greater focus on national progress towards elimination with support given, if necessary, through innovative financing measures to ensure elimination programmes are fully funded by 2020. In addition to further measures to improve access to vaccination and treatment, greater attention needs to be paid to access to affordable, high-quality diagnostics if testing is to reach the levels needed to achieve elimination goals. Simplified, decentralised models of care removing requirements for specialised prescribing will be required to reach those in need, together with sustained efforts to tackle stigma and discrimination. We identify key examples of the progress that has already been made in many countries throughout the world, demonstrating that sustained and coordinated efforts can be successful in achieving the WHO elimination goals.

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Li H-K, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, Lipsky BA, Hughes HC, Bose D, Kümin M, Scarborough C, Matthews PC, Brent AJ, Lomas J, Gundle R, Rogers M, Taylor A, Angus B, Byren I, Berendt AR, Warren S, Fitzgerald FE, Mack DJF, Hopkins S, Folb J, Reynolds HE, Moore E, Marshall J, Jenkins N, Moran CE, Woodhouse AF, Stafford S, Seaton RA, Vallance C, Hemsley CJ, Bisnauthsing K, Sandoe JAT, Aggarwal I, Ellis SC, Bunn DJ, Sutherland RK, Barlow G, Cooper C, Geue C, McMeekin N, Briggs AH, Sendi P, Khatamzas E, Wangrangsimakul T, Wong THN, Barrett LK, Alvand A, Old CF, Bostock J, Paul J, Cooke G, Thwaites GE, Bejon P, Scarborough Met al., 2019, Oral versus intravenous antibiotics for bone and joint infection, New England Journal of Medicine, Vol: 380, Pages: 425-436, ISSN: 0028-4793

BackgroundThe management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication.MethodsWe enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points.ResultsAmong the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of −1.4 percentage points (90% confidence interval [CI], −4.9 to 2.2; 95% CI, −5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%).ConclusionsOral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed b

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Maurice JB, Garvey L, Tsochatzis EA, Wiltshire M, Cooke G, Guppy N, McDonald J, Marchesi J, Nelson M, Kelleher P, Goldin R, Thursz M, Lemoine Met al., 2019, Monocyte-Macrophage activation is associated with NAFLD and liver fibrosis in HIV mono-infection independently of the gut microbiome and bacterial translocation, AIDS, Vol: 33, Pages: 805-814, ISSN: 0269-9370

Background: Non-alcoholic fatty liver disease (NAFLD) is common among people living with HIV. There is limited data available on the pathophysiology of NAFLD and the development of fibrosis in this population.Objectives: to investigate the association of bacterial translocation, adipose tissue dysfunction, monocyte activation and gut dysbiosis in patients with HIV mono-infection and NAFLD.Methods: Cases with biopsy-proven NAFLD and HIV mono-infection were age and sex-matched to HIV+ and HIV- controls. Markers of bacterial translocation (lipopolysaccharide-binding protein (LBP), bacterial DNA and lipopolysaccharide (LPS)), adipose tissue dysfunction (leptin, adiponectin) and monocyte activation (sCD14 and sCD163) were measured by ELISA. Hepatic patterns of macrophage activation were explored with immunohistochemistry. 16 s rRNA sequencing was performed with stool.Results: Thirty-three cases were included (≥F2 fibrosis n = 16), matched to HIV+ (n = 29) and HIV- (n = 17) controls. Cases with NAFLD were more obese (BMI 31.0 ± 4.4 kg/m2 vs 24.1 ± 2.8 kg/m2 p < 0.001) and had significantly increased levels of sCD14, sCD163 and higher leptin to adiponectin ratio versus HIV+ controls. Cases with ≥F2 verses < F2 fibrosis had increased sCD14 (1.4 ± 0.4 vs 1.1 ± 0.3 μg/ml, p = 0.023) and sCD163 (1.0 ± 0.3 vs 0.8 ± 0.3 μg/ml, p = 0.060) which correlated with waist circumference (sCD14 p = 0.022, sCD163 p = 0.011). Immunohistochemistry showed increased hepatic portal macrophage clusters in patients with fibrosis. No markers of bacterial translocation or changes to the microbiome were associated with NAFLD or fibrosis.Conclusion: NAFLD fibrosis stage in HIV mono-infected patients is associated with monocyte activation in the context of obesity, which may be independent of bacterial translocation and gut microbiome.

JOURNAL ARTICLE

Joshi M, Ashrafian H, Aufegger L, Khan S, Arora S, Cooke G, Darzi Aet al., 2019, Wearable sensors to improve detection of patient deterioration, Expert Review of Medical Devices, Vol: 16, Pages: 145-154, ISSN: 1743-4440

INTRODUCTION: Monitoring a patient's vital signs forms a basic component of care, enabling the identification of deteriorating patients and increasing the likelihood of improving patient outcomes. Several paper-based track and trigger warning scores have been developed to allow clinical evaluation of a patient and guidance on escalation protocols and frequency of monitoring. However, evidence suggests that patient deterioration on hospital wards is still missed, and that patients are still falling through the safety net. Wearable sensor technology is currently undergoing huge growth, and the development of new light-weight wireless wearable sensors has enabled multiple vital signs monitoring of ward patients continuously and in real time. Areas covered: In this paper, we aim to closely examine the benefits of wearable monitoring applications that measure multiple vital signs; in the context of improving healthcare and delivery. A review of the literature was performed. Expert commentary: Findings suggest that several sensor designs are available with the potential to improve patient safety for both hospital patients and those at home. Larger clinical trials are required to ensure both diagnostic accuracy and usability.

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Rampling T, Ewer KJ, Bowyer G, Edwards NJ, Wright D, Sridhar S, Payne R, Powlson J, Bliss C, Venkatraman N, Poulton ID, de Graaf H, Gbesemete D, Grobbelaar A, Davies H, Roberts R, Angus B, Ivinson K, Weltzin R, Rajkumar B-Y, Wille-Reece U, Lee C, Ockenhouse C, Sinden R, Gerry SC, Lawrie A, Vekemans J, Morelle D, Lievens M, Ballou RW, Lewis DJM, Cooke GS, Faust SN, Hill AVet al., 2018, Safety and efficacy of novel malaria vaccine regimens of RTS, S/AS01B alone, or with concomitant ChAd63-MVA-vectored vaccines expressing ME-TRAP, npj Vaccines, Vol: 3, ISSN: 2059-0105

We assessed a combination multi-stage malaria vaccine schedule in which RTS,S/AS01B was given concomitantly with viral vectors expressing multiple-epitope thrombospondin-related adhesion protein (ME-TRAP) in a 0-month, 1-month, and 2-month schedule. RTS,S/AS01B was given as either three full doses or with a fractional (1/5th) third dose. Efficacy was assessed by controlled human malaria infection (CHMI). Safety and immunogenicity of the vaccine regimen was also assessed. Forty-one malaria-naive adults received RTS,S/AS01B at 0, 4 and 8 weeks, either alone (Groups 1 and 2) or with ChAd63 ME-TRAP at week 0, and modified vaccinia Ankara (MVA) ME-TRAP at weeks 4 and 8 (Groups 3 and 4). Groups 2 and 4 received a fractional (1/5th) dose of RTS,S/AS01B at week 8. CHMI was delivered by mosquito bite 11 weeks after first vaccination. Vaccine efficacy was 6/8 (75%), 8/9 (88.9%), 6/10 (60%), and 5/9 (55.6%) of subjects in Groups 1, 2, 3, and 4, respectively. Immunological analysis indicated significant reductions in anti-circumsporozoite protein antibodies and TRAP-specific T cells at CHMI in the combination vaccine groups. This reduced immunogenicity was only observed after concomitant administration of the third dose of RTS,S/AS01B with the second dose of MVA ME-TRAP. The second dose of the MVA vector with a four-week interval caused significantly higher anti-vector immunity than the first and may have been the cause of immunological interference. Co-administration of ChAd63/MVA ME-TRAP with RTS,S/AS01B led to reduced immunogenicity and efficacy, indicating the need for evaluation of alternative schedules or immunization sites in attempts to generate optimal efficacy.

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Ramamurthy N, Marchi E, Ansari MA, Pedergnana V, Mclean A, Hudson E, Bowden R, Spencer CCA, Barnes E, Klenerman Pet al., 2018, Impact of interferon lambda 4 genotype on interferon-stimulated gene expression during direct-acting antiviral therapy for hepatitis C, Hepatology, Vol: 68, Pages: 859-871, ISSN: 0270-9139

New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat, including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, patients with cirrhosis receiving a 16‐week course of sofosbuvir and ribavirin had a sustained virological response (SVR) rate of around 50%. In patients with cirrhosis, interferon lambda 4 (IFNL4) CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon‐stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, whereas the reverse was true for non‐CC patients. Conclusion: These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection.

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Shallcross L, Mentzer A, Rahman S, Cooke G, Sriskandan S, Noursadeghi Met al., 2018, Cohort study protocol: Bioresource in Adult Infectious Diseases (BioAID), Wellcome Open Research, Vol: 3, ISSN: 2398-502X

Introduction: Infectious diseases have a major impact on morbidity and mortality in hospital. Microbial diagnosis remains elusive for most cases of suspected infection which impacts on the use of antibiotics. Rapid advances in genomic technologies combined with high-quality phenotypic data have great potential to improve the diagnosis, management and clinical outcomes of infectious diseases. The aim of the Bioresource in Adult Infectious Diseases (BioAID) is to provide a platform for biomarker discovery, trials and clinical service developments in the field of infectious diseases, by establishing a registry linking clinical phenotype to microbial and biological samples in adult patients who attend hospital with suspected infection.Methods and analysis: BioAID is a cohort study which employs deferred consent to obtain an additional 2.5mL RNA blood sample from patients who attend the Emergency Department (ED) with suspected infection when they undergo peripheral blood culture sampling. Clinical data and additional biological samples including DNA, serum and microbial isolates are obtained from BioAID participants during hospital admission. Participants are also asked to consent to be recalled for future studies. BioAID aims to recruit 10,000 patients from 5-8 sites across England. Since February 2014 >4000 individuals have been recruited to the study. The final cohort will be characterised using descriptive statistics including information on the number of cases that can be linked to biological and microbial samples to support future research studies. Ethical approval and section 251 exemption have been obtained for BioAID researchers to seek deferred consent from patients from whom a RNA specimen has been collected. Samples and meta-data obtained through BioAID will be made available to researchers worldwide following submission of an application form and research protocol. Conclusions: BioAID will support a range of study designs spanning discovery science

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Walker AJ, Peacock CJ, Pedergnana V, Irving WLet al., 2018, Host genetic factors associated with hepatocellular carcinoma in patients with hepatitis C virus infection: A systematic review, Journal of Viral Hepatitis, Vol: 25, Pages: 442-456, ISSN: 1352-0504

Hepatitis C virus (HCV)‐infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened risk could be targeted by intensive follow‐up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV‐infected patients. A comprehensive search of Medline and Embase databases was performed, and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. Seventeen genes were classified as having “good” evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF‐α and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardized approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in HCV‐infected patients.

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Martinello M, Bhagani S, Gane E, Orkin C, Cooke G, Dore GJ, Petoumenos K, Applegate TL, Tu E, Marks P, Pagani N, Grebely J, Nelson M, Matthews GVet al., 2018, Shortened therapy of eight weeks with paritaprevir/ritonavir/ombitasvir and dasabuvir is highly effective in people with recent HCV genotype 1 infection., J Viral Hepat

Paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 12 weeks is approved for treatment of chronic HCV genotype 1 infection. This study assessed the efficacy of shortened duration paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for eight weeks among people with recent HCV infection. In this open-label single-arm trial conducted in Australia, England and New Zealand, adults with recent HCV (duration of infection <12 months) received paritaprevir/ritonavir/ombitasvir and dasabuvir (with weight-based ribavirin for genotype 1a and 1, no subtype) for eight weeks. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12) in the intention-to treat (ITT) population. Thirty people (median age 38 years, male 93%) commenced treatment (with ribavirin, 97%), of whom 77% (n=23) were HIV-positive, 93% (n=28) had genotype 1a infection and 53% (n=16) had ever injected drugs. Median maximum ALT in the preceding 12 months was 433 IU/L (IQR 321, 1012). Acute clinical hepatitis with ALT>10xULN was documented in 83% (n=25); one participant (3%) had jaundice. At baseline, median estimated duration of infection was 30 weeks (range 11, 51) and median HCV RNA was 5.7 log10 IU/mL (range 2.7, 7.3). SVR12 was achieved in 97% (29/30; early discontinuation at week 2, n=1; per-protocol 100%, 29/29). No relapse or reinfection was observed. In conclusion, Paritaprevir/ritonavir/ombitasvir and dasabuvir (with ribavirin) for eight weeks was highly effective among HIV-positive and HIV-negative individuals with recent HCV infection. This data supports the use of this shortened duration direct-acting antiviral regimen in this population. This article is protected by copyright. All rights reserved.

JOURNAL ARTICLE

Fawsitt C, Vickerman P, Cooke G, Welton NJet al., 2018, Cost-effectiveness analysis of baseline testing for resistance-associated polymorphisms to optimise treatment duration in genotype 1 non-cirrhotic treatment-naive patients with chronic hepatitis C virus, International Liver Congress (ILC), Publisher: ELSEVIER SCIENCE BV, Pages: S300-S301, ISSN: 0168-8278

CONFERENCE PAPER

Martinello M, Cerrone M, Bhagani S, Gane E, Orkin C, Cooke G, Dore GJ, Petoumenos K, Applegate TL, Tu E, Marks P, Pagani N, Schoolmeesters A, Grebely J, Nelson M, Matthews GVet al., 2018, TARGET3D: high efficacy of 8 weeks paritaprevir/ritonavir/ombitasvir and dasabuvir among people with recent genotype 1 HCV infection, Publisher: WILEY, Pages: S151-S152, ISSN: 1464-2662

CONFERENCE PAPER

Sood C, Jones C, Thompson E, Cooke G, Garvey Let al., 2018, Acute hepatitis C infection in HIV-positive men: which treatment pathways are being selected in 2017?, Publisher: WILEY, Pages: S147-S147, ISSN: 1464-2662

CONFERENCE PAPER

Ross S, Hatcher J, Dosekun O, Cooke G, Bailey Aet al., 2018, Strongyloides stercoralis infection in HIV-positive men who have sex with men (MSM): a case series of seven patients, Publisher: WILEY, Pages: S142-S142, ISSN: 1464-2662

CONFERENCE PAPER

Lemoine M, Cooke GS, 2018, The Egyptian hepatitis C programme: a model of HCV treatment intervention?, Journal of Hepatology, Vol: 68, Pages: 638-639, ISSN: 0168-8278

JOURNAL ARTICLE

Garvey L, Atzori S, Williamson M, Maurice J, Main J, Lemoine M, Cooke G, Taylor-Robinson Set al., 2018, A cross-sectional study to investigate spleen stiffness via acoustic radiation force impulse (arfi) elastography in HIV-infected patients with non cirrhotic portal hypertension, Publisher: WILEY, Pages: S71-S72, ISSN: 1464-2662

CONFERENCE PAPER

Cacoub P, Buggisch P, Carrión JA, Cooke GS, Zignego AL, Beckerman R, Younossi Zet al., Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe, Journal of Viral Hepatitis, ISSN: 1352-0504

Hepatitis C virus (HCV) infection is a systemic disease associated with both hepatic and extrahepatic manifestations. The burden associated with the hepatic manifestation of HCV infection has been well documented in Europe, although that of HCV extrahepatic manifestations remains unknown. In this study, we estimated the annual direct medical costs associated with HCV extrahepatic manifestations in five European countries. A previously validated economic model was used to estimate the annual direct medical cost associated with HCV extrahepatic manifestations. Global excess prevalence of extrahepatic manifestations in HCV patients relative to that in non-HCV patients was obtained from a recent meta-analysis. Per-patient per-year inpatient, outpatient and medication costs to treat each extrahepatic manifestation were from the literature, national databases or expert opinion if unavailable otherwise. All costs were adjusted to 2016 euros (€). The overall direct medical costs associated with HCV extrahepatic manifestations were calculated by multiplying the total per-patient per-year costs of each by the respective excess prevalence rates and then by the size of the HCV-infected population in each country. Treatment impact with direct-acting antivirals (DAAs) was explored using HCV extrahepatic manifestations excess prevalence rates among cured patients compared to untreated HCV patients, as sourced from a meta-analysis. The total annual direct medical cost associated with HCV extrahepatic manifestations was estimated to be 2.17 billion euro (€), with a per-HCV-patient cost ranging from €899 to €1647 annually. DAA treatment was projected to result in cost savings of €316 million per year. We find that the annual economic burden of extrahepatic manifestations is significant and may be partly mitigated by treatment with DAAs.

JOURNAL ARTICLE

Efsen AMW, Schultze A, Miller RF, Panteleev A, Skrahin A, Podlekareva DN, Miro JM, Girardi E, Furrer H, Losso MH, Toibaro J, Caylà JA, Mocroft A, Lundgren JD, Post FA, Kirk O, Karpov I, Vassilenko A, Skrahina A, Klimuk D, Skrahin A, Kondratenko O, Zalutskaya A, Bondarenko V, Mitsura V, Kozorez E, Tumash O, Suetnov O, Paduto D, Iljina V, Kummik T, Bolokadze N, Mshvidobadze K, Lanchava N, Goginashvili L, Mikiashvili L, Bablishvili N, Rozentale B, Zeltina I, Janushkevich I, Caplinskiene I, Caplinskas S, Kancauskiene Z, Podlasin R, Wiercinska-Drapalo A, Thompson M, Kozlowska J, Grezesczuk A, Bura M, Knysz B, Inglot M, Garlicki A, Loster J, Tetradov S, Duiculescu D, Rakhmanova A, Panteleeva O, Yakovlev A, Kozlov A, Tyukalova A, Vlasova Y, Panteleev A, Trofimov T, Kyselyova G, Andersen AB, Thorsteinsson K, Payen MC, Kabeya K, Necsoi C, Dabis F, Bruyand M, Morlat P, Dupont A, Gerard Y, Bonnal F, Ceccaldi J, De Witte S, Monlun E, Lataste P, Chossat I, Miller R, Vora N, Cooke G, Mullaney S, Wilkins E, George V, Collini P, Dockrell D, Post F, Campbell L, Brum R, Mabonga E, Saigal P, Kegg S, Ainsworth J, Waters A, Dhar J, Mashonganyika L, Girardi E, Rianda A, Galati V, Pinnetti C, Tommasi C, Lapadula G, Di Biagio A, Parisini A, Carbonara S, Angarano G, Purgatorio M, Matteelli A, Apostoli A, Toibaro J, Macias LM, Warley E, Tavella S, Garcia Messina O, Gear O, Laplume H, Marson C, Contarelia J, Michaan M, Scapellato P, Alessandro DD, Bartoletti B, Palmero D, Elias C, Cortes C, Crabtree B, Mosqueda Gomez JL, Villanueva A, Gonzalez Hernandez LAet al., 2018, Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study, Journal of Infection, Vol: 76, Pages: 44-54, ISSN: 0163-4453

JOURNAL ARTICLE

Uden L, Barber E, Ford N, Cooke GSet al., 2017, Risk of TB infection and disease for health care workers: An updated meta-analysis, Open Forum Infectious Diseases, Vol: 4, ISSN: 2328-8957

BackgroundTuberculosis (TB) remains a major challenge to global health. Healthcare workers (HCWs) appear to be at increased risk of TB compared with the general population, despite efforts to scale up infection control and reduce nosocomial TB transmission. This review aims to provide an updated estimate of the occupational risk of latent TB infection (LTBI) and active TB among HCWs compared with the general population.MethodsA systematic review was performed to identify studies published over the last 10 years reporting TB prevalence or incidence among HCWs and a control group. Pooled effect estimates were calculated to determine the risk of infection.ResultsTwenty-one studies met the inclusion criteria, providing data on 30961 HCWs across 16 countries. Prevalence of LTBI among HCWs was 37%, and mean incidence rate of active TB was 97/100000 per year. Compared with the general population, the risk of LTBI was greater for HCWs (odds ratio [OR], 2.27; 95% confidence interval [CI], 1.61–3.20), and the incidence rate ratio for active TB was 2.94 (95% CI, 1.67–5.19). Comparing tuberculin skin test and interferon-gamma release assay, OR for LTBI was found to be 1.72 and 5.61, respectively.ConclusionsThe overall risk of both LTBI and TB to HCWs continues to be significantly higher than that of the general population, consistent with previous findings. This study highlights the continuing need for improvements in infection control and HCW screening programs.

JOURNAL ARTICLE

Lessells RJ, Cooke GS, Nicol M, McGrath N, Newell ML, Godfrey-Faussett Pet al., 2017, Impact of point-of-care Xpert MTB/RIF on tuberculosis treatment initiation: a cluster randomised trial, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 9010-910, ISSN: 1535-4970

Rationale: Point-of-care (POC) diagnostics have potential to reduce pre-treatment loss to follow-up and delays to initiation of appropriate TB treatment. Objective: To evaluate the effect of a POC diagnostic strategy on initiation of appropriate TB treatment. Methods: A cluster randomised trial of adults with cough who were HIV positive and/or at high risk of drug-resistant TB. Two-week time blocks were randomised to two strategies (i) Xpert performed at district hospital laboratory (ii) POC Xpert performed at primary health care clinic. All participants provided two sputum specimens: one for Xpert and the other for culture as reference standard. The primary outcome was the proportion of culture-positive pulmonary TB (PTB) cases initiated on appropriate TB treatment within 30 days. Measurements and Main Results: Between August 22, 2011 and March 1, 2013, 36 two-week blocks were randomised and 1297 individuals were enrolled (646 in the laboratory arm, 651 in the POC arm); 159 (12.4%) had culture-positive PTB. The proportion of culture-positive PTB cases initiated on appropriate TB treatment within 30 days was 76.5% in the laboratory arm and 79·5% in the POC arm (odds ratio 1·13, 95% confidence interval [CI] 0·51-2.53, p = 0·76; risk difference 3.1%, 95% CI -16.2, 10.1). The median time to initiation of appropriate treatment was 7 days (laboratory) vs. 1 day (POC). Conclusions: POC positioning of Xpert led to more rapid initiation of appropriate TB treatment. Achieving one-stop diagnosis and treatment for all people with TB will require simpler, more sensitive diagnostics and broader strengthening of health systems. Clinical trial registration available at www.isrctn.com, ID ISRCTN18642314

JOURNAL ARTICLE

Arnold A, Cooke GS, Kon OM, Dedicoat M, Lipman M, Loyse A, Ster IC, Harrison TSet al., 2017, Adverse Effects and Choice between the Injectable Agents Amikacin and Capreomycin in Multidrug-Resistant Tuberculosis, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 61, ISSN: 0066-4804

The prolonged use of injectable agents in a regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) is recommended by the World Health Organization, despite its association with ototoxicity and nephrotoxicity. We undertook this study to look at the relative adverse effects of capreomycin and amikacin. We reviewed the case notes of 100 consecutive patients treated at four MDR-TB treatment centers in the United Kingdom. The median total duration of treatment with an injectable agent was 178 days (interquartile range [IQR], 109 to 192 days; n = 73) for those with MDR-TB, 179 days (IQR, 104 to 192 days; n = 12) for those with MDR-TB plus fluoroquinolone resistance, and 558 days (IQR, 324 to 735 days; n = 8) for those with extensively drug-resistant tuberculosis (XDR-TB). Injectable use was longer for those started with capreomycin (183 days; IQR, 123 to 197 days) than those started with amikacin (119 days; IQR, 83 to 177 days) (P = 0.002). Excluding patients with XDR-TB, 51 of 85 (60%) patients were treated with an injectable for over 6 months and 12 of 85 (14%) were treated with an injectable for over 8 months. Forty percent of all patients discontinued the injectable due to hearing loss. Fifty-five percent of patients experienced ototoxicity, which was 5 times (hazard ratio [HR], 5.2; 95% confidence interval [CI], 1.2 to 22.6; P = 0.03) more likely to occur in those started on amikacin than in those treated with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (odds ratio, 0.28; 95% CI, 0.11 to 0.72), with 5 of 37 (14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number of patients experiencing a rise in the creatinine level of >1.5 times the baseline level. Hearing loss is frequent in this cohort, though its incidence is significantly lower in those starting capreomycin, which should be given greater consideration as a first-line agent.

JOURNAL ARTICLE

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