Imperial College London

ProfessorGrahamCooke

Faculty of MedicineDepartment of Infectious Disease

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

170 results found

Joshi M, Ashrafian H, Arora S, Khan S, Cooke G, Darzi Aet al., A Systematic Review and Meta-Analysis of digital alerting and outcomes in patients with sepsis, JMIR mHealth and uHealth, ISSN: 2291-5222

Journal article

Cole M, Saeed Z, Shaw A, Guo Y, Hoschler K, Winston A, Cooke G, Fidler S, Taylor G, Pollock Ket al., RESPONSES TO QUADRIVALENT INFLUENZA VACCINE REVEAL DISTINCT CIRCULATING CD4+CXCR5+ T CELL SUBSETS IN MEN LIVING WITH HIV, Scientific Reports, ISSN: 2045-2322

Journal article

Manalan K, Green N, Arnold A, Cooke GS, Dedicoat M, Lipman M, Loyse A, Harrison TS, Kon OMet al., 2019, A cost comparison of amikacin therapy with bedaquiline, for drug-resistant tuberculosis in the UK., J Infect

OBJECTIVES: Prioritisation of oral bedaquiline over the injectable agents in the treatment of multidrug-resistant Tuberculosis (MDR-TB) in the World Health Organisations (WHO) 2019 guidelines prompted this UK analysis of cost implications. The objective was to estimate the costs of amikacin versus bedaquiline in MDR TB treatment regimens using a historical cohort where the injectable agents were the standard of care. METHODS: This was a retrospective study using a known cohort of UK patients treated with an injectable agent, with data available on resource use, costs for the use of amikacin were compared with those for bedaquiline, based on recommended monitoring for bedaquiline. RESULTS: The estimated cost of treatment per patient had mean (sd) of £27,236 (4952) for the observed injectable group, £30,264 (3392) and 36,309 (3901) for the 6 and 8 month amikacin groups, and £31,760 (2092) for the bedaquiline group. The cost in the bedaquiline group was £30,772 (1855) with a 10% reduction and £27,079 (1234) with a 33% reduction in-patient stay. CONCLUSIONS: In most scenarios, bedaquiline is close to cost neutral compared with injectable therapy, especially if, as expected, some reduction in duration of admission is possible as a result of bedaquiline's more rapid culture conversion.

Journal article

Ansari MA, Aranday-Cortes E, Ip CLC, Filipe ADS, Lau SH, Bamford C, Bonsall D, Trebes A, Piazza P, Sreenu V, Cowton VM, Ball J, Barnes E, Burgess G, Cooke G, Dillon J, Foster G, Gore C, Guha N, Halford R, Holmes C, Hudson E, Hutchinson S, Irving W, Khakoo S, Klenerman P, Martin N, Mbisa T, McKeating J, McLauchlan J, Miners A, Murray A, Shaw P, Simmonds P, Smith S, Spencer C, Thomson E, Troke P, Vickerman P, Zitzmann N, Hudson E, Bowden R, Patel AH, Foster GR, Irving WL, Agarwal K, Thomson EC, Simmonds P, Klenerman P, Holmes C, Barnes E, Spencer CCA, McLauchlan J, Pedergnana Vet al., 2019, Interferon lambda 4 impacts the genetic diversity of hepatitis C virus, eLife, Vol: 8, ISSN: 2050-084X

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establisheschronic infection. This genetic variability is affected by the adaptive immune response but thecontribution of other host factors is unclear. Here, we examined the role played by interferonlambda-4 (IFN-l4) on HCV diversity; IFN-l4 plays a crucial role in spontaneous clearance orestablishment of chronicity following acute infection. We performed viral genome-wide associationstudies using human and viral data from 485 patients of white ancestry infected with HCVgenotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-l4protein production and activity, influence amino acid variation across the viral polyprotein - notrestricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We alsoobserved an association with viral di-nucleotide proportions. These results support a direct role forIFN-l4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.

Journal article

Szubert A, Bailey SL, Cooke GS, Peto T, Llewelyn MJ, Edgeworth JD, Walker AS, Thwaites GEet al., 2019, Predictors of recurrence, early treatment failure and death from Staphylococcus aureus bacteraemia: Observational analyses within the ARREST trial, Journal of Infection, ISSN: 0163-4453

Predictors of recurrence, early treatment failure and death from Staphylococcus aureus bacteraemia: Observational analyses within the ARREST trial

Journal article

Scarborough M, Li HK, Rombach I, Zambellas R, Walker AS, McNally M, Atkins B, Kumin M, Lipsky BA, Hughes H, Bose D, Warren S, Mack D, Folb J, Moore E, Jenkins N, Hopkins S, Seaton RA, Hemsley C, Sandoe J, Aggarwal I, Ellis S, Sutherland R, Geue C, McMeekin N, Scarburough C, Paul J, Cooke G, Bostock J, Khatamzas E, Wong N, Brent A, Lomas J, Matthews P, Wangrangsimakul T, Gundle R, Rogers M, Taylor A, Thwaites GE, Bejon Pet al., 2019, Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT, Health Technology Assessment, Vol: 23, Pages: 1-94, ISSN: 1366-5278

BackgroundManagement of bone and joint infection commonly includes 4–6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes.ObjectiveTo determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection.DesignParallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%.SettingTwenty-six NHS hospitals.ParticipantsAdults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively).InterventionsParticipants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm.Main outcome measureThe primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data.ResultsOut of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was –1.38% (90% confidence interval –4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm v

Journal article

Safreed-Harmon K, Blach S, Aleman S, Boe Kielland K, Bollerup S, Cooke G, Dalgard O, Dillon JF, Dore GJ, Duberg A-S, Grebely J, Midgard H, Porter K, Razavi H, Tyndall M, Weis N, Lazarus JVet al., The consensus hepatitis C cascade of care: standardized reporting to monitor progress toward elimination, Clinical Infectious Diseases, ISSN: 1058-4838

Cascade-of-care (CoC) monitoring is an important component of the response to the global hepatitis C virus (HCV) epidemic. CoC metrics can be used to communicate in simple terms the extent to which national and subnational governments are advancing on key targets, and CoC findings can inform strategic decision-making regarding how to maximize the progression of HCV-infected individuals to diagnosis, treatment and cure. The value of reporting would be enhanced if reporting entities utilized a standardized approach for generating their CoCs. We have described the Consensus HCV CoC that we developed to address this need and have presented findings from Denmark, Norway and Sweden, where it was piloted. We encourage the uptake of the Consensus HCV CoC as a global instrument for facilitating clear and consistent reporting via the World Health Organization (WHO) viral hepatitis monitoring platform and ensuring the accurate monitoring of progress toward WHO’s 2030 hepatitis C elimination targets.</jats:p>

Journal article

Simmons B, Cooke GS, Miraldo M, 2019, Effect of voluntary licences for hepatitis C medicines on access to treatment: a difference-in-differences analysis, The Lancet Global Health, ISSN: 2214-109X

BackgroundVoluntary licences are increasingly being used to expand access to patented essential medicines in low-income and middle-income countries (LMICs). Since 2014, non-exclusive voluntary licences have been issued by Gilead and Bristol-Myers Squibb for key drugs for hepatitis C virus (HCV) infection. We aimed to evaluate the effect of these licences on access to HCV treatment.MethodsWe conducted a difference-in-differences analysis, exploiting the staggered and selective introduction of voluntary licensing in different countries, to identify the effect of voluntary licensing agreements on treatment uptake. We extracted Polaris Observatory data on the total number of people infected with HCV, diagnosed with HCV, and treated for HCV, and constructed a longitudinal panel of LMICs over a 13-year period (2004–16). Countries were included if they were classified as LMICs by the World Bank in 2014, and had available data on HCV outcomes. The exposure was defined as inclusion in any voluntary licence agreement for HCV drugs. Treatment uptake was calculated as the number of people treated for HCV in a given year per 1000 living people ever diagnosed with HCV. We fit difference-in-differences linear regression models controlling for different confounders that could influence treatment access and uptake, including country and year fixed effects and a range of country-level factors. We additionally assessed the dynamics of the effect and the robustness of our findings.Findings35 countries were included in the panel: 19 in the intervention group and 16 in the control group. In the simplest model, adjusting only for country and year fixed effects, voluntary licences were associated with an increase in the annual number of people accessing HCV treatment of 69·3 per 1000 diagnosed (95% CI 46·7–91·9; p=0·0060). After adjusting for country-level covariates, this increase was 53·6 per 1000 diagnosed (25·8–81·5; p=

Journal article

Cooke GS, Hallett TB, 2019, Pricing viral hepatitis as part of universal health coverage, The Lancet Global Health, ISSN: 2214-109X

Journal article

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

Smith D, Magri A, Bonsall D, Ip CLC, Trebes A, Brown A, Piazza P, Bowden R, Nguyen D, Ansari MA, Simmonds P, Barnes E, STOP-HCV Consortiumet al., 2019, Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors, Hepatology, Vol: 69, Pages: 1861-1872, ISSN: 0270-9139

Hepatitis C virus (HCV) genotype (gt) 3 is highly prevalent globally, with non-gt3a subtypes common in Southeast Asia. Resistance-associated substitutions (RASs) have been shown to play a role in treatment failure. However, the role of RASs in gt3 is not well understood. We report the prevalence of RASs in a cohort of direct-acting antiviral treatment-naive, gt3-infected patients, including those with rarer subtypes, and evaluate the effect of these RASs on direct-acting antivirals in vitro. Baseline samples from 496 gt3 patients enrolled in the BOSON clinical trial were analyzed by next-generation sequencing after probe-based enrichment for HCV. Whole viral genomes were analyzed for the presence of RASs to approved direct-acting antivirals. The resistance phenotype of RASs in combination with daclatasvir, velpatasvir, pibrentasvir, elbasvir, and sofosbuvir was measured using the S52 ΔN gt3a replicon model. The nonstructural protein 5A A30K and Y93H substitutions were the most common at 8.9% (n = 44) and 12.3% (n = 61), respectively, and showed a 10-fold and 11-fold increase in 50% effect concentration for daclatasvir compared to the unmodified replicon. Paired RASs (A30K + L31M and A30K + Y93H) were identified in 18 patients (9 of each pair); these combinations were shown to be highly resistant to daclatasvir, velpatasvir, elbasvir, and pibrentasvir. The A30K + L31M combination was found in all gt3b and gt3g samples. Conclusion: Our study reveals high frequencies of RASs to nonstructural protein 5A inhibitors in gt3 HCV; the paired A30K + L31M substitutions occur in all patients with gt3b and gt3g virus, and in vitro analysis suggests that these subtypes may be inherently resistant to all approved nonstructural protein 5A inhibitors for gt3 HCV. (Hepatology 2018).

Journal article

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

Journal article

Pristera P, Bruton J, Cooke G, Day S, Ward Het al., Perspectives on transmission, treatment and elimination of hepatitis C in HIV-positive MSM in London: a qualitative study, AIDS IMPACT 2019

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

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

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

Journal article

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.

Journal article

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

Journal article

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.

Journal article

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 Rep, Vol: 12

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.

Journal article

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

Journal article

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.

Journal article

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.

Journal article

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.

Journal article

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

Journal article

Cacoub P, Buggisch P, Carrión JA, Cooke GS, Zignego AL, Beckerman R, Younossi Zet al., 2018, Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe, Journal of Viral Hepatitis, Vol: 25, Pages: 811-817, 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

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.

Journal article

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