register interest

Professor Brian J Angus FRCP

Research Area: Global Health
Technology Exchange: Vaccine production and evaluation
Scientific Themes: Tropical Medicine & Global Health and Immunology & Infectious Disease
Keywords: Malaria, HIV and Melioidosis

Prof Brian Angus is the Director of the Oxford Centre for Clinical Tropical Medicine. He joined the Nuffield Department of Clinical Medicine in 1993 and originally worked in Thailand and Ghana studying pharmacokinetics in severe malaria and melioidosis. His research focus is now on clinical trials in influenza, HIV, Chronic Fatigue Syndrome, C. difficile-Associated Diarrhoea and typhoid. He is Clinical Tutor in Medicine and Associate Professor and Reader in Infectious Diseases at the University of Oxford. He holds an honorary Senior Clinical Scientist tltle at the MRC CTU.

Name Department Institution Country
Professor Abdel Babiker MRC United Kingdom
Professor Adrian VS Hill Jenner Institute Oxford University, Old Road Campus Research Building United Kingdom
Professor Sarah C Gilbert Jenner Institute Oxford University, Old Road Campus Research Building United Kingdom
Professor Lucy Dorrell NDM Research Building Oxford University, NDM Research Building United Kingdom
Professor Susanna J Dunachie FRCP FRCPath Tropical Medicine Oxford University, Peter Medawar Building United Kingdom
Professor Simon Cutting Royal Holloway University of London United Kingdom
Professor Andrew Pollard Jenner Institute Oxford University, Centre for Clinical Vaccinology and Tropical Medicine United Kingdom
Hancock G, Morón-López S, Kopycinski J, Puertas MC, Giannoulatou E, Rose A, Salgado M, Hayton EJ, Crook A, Morgan C et al. 2017. Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects. J Int AIDS Soc, 20 (1), pp. 21171. | Show Abstract | Read more

INTRODUCTION: Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). METHODS: Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 10(7) plaque-forming units, pfu, n = 8; 2.2 × 10(8) pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination. RESULTS: 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos in ex vivo Elispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group. CONCLUSIONS: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent. CLINICAL TRIALS REGISTRATION: NCT01024842.

Salerno-Goncalves R, Luo D, Fresnay S, Magder L, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM et al. 2017. Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells. Front Immunol, 8 (APR), pp. 398. | Show Abstract | Read more

Gastrointestinal infections by Salmonella enterica serovar Typhi (S. Typhi) are rare in industrialized countries. However, they remain a major public health problem in the developing world with an estimated 26.9 million new cases annually and significant mortality when untreated. Recently, we provided the first direct evidence that CD8(+) MAIT cells are activated and have the potential to kill cells exposed to S. Typhi, and that these responses are dependent on bacterial load. However, MAIT cell kinetics and function during bacterial infections in humans remain largely unknown. In this study, we characterize the human CD8(+) MAIT cell immune response to S. Typhi infection in subjects participating in a challenge clinical trial who received a low- or high dose of wild-type S. Typhi. We define the kinetics of CD8(+) MAIT cells as well as their levels of activation, proliferation, exhaustion/apoptosis, and homing potential. Regardless of the dose, in volunteers resistant to infection (NoTD), the levels of CD8(+) MAIT cells after S. Typhi challenge fluctuated around their baseline values (day 0). In contrast, volunteers susceptible to the development of typhoid disease (TD) exhibited a sharp decline in circulating MAIT cells during the development of typhoid fever. Interestingly, MAIT cells from low-dose TD volunteers had higher levels of CD38 coexpressing CCR9, CCR6, and Ki67 during the development of typhoid fever than high-dose TD volunteers. No substantial perturbations on the levels of these markers were observed in NoTD volunteers irrespective of the dose. In sum, we describe, for the first time, that exposure to an enteric bacterium, in this case S. Typhi, results in changes in MAIT cell activation, proliferation, and homing characteristics, suggesting that MAIT cells are an important component of the human host response to bacterial infection.

Fresnay S, McArthur MA, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM, Pollard AJ, Sztein MB. 2017. Importance of Salmonella Typhi-Responsive CD8+ T Cell Immunity in a Human Typhoid Fever Challenge Model. Front Immunol, 8 (MAR), pp. 208. | Show Abstract | Read more

Typhoid fever, caused by the human-restricted organism Salmonella enterica serovar Typhi (S. Typhi), constitutes a major global health problem. The development of improved attenuated vaccines is pressing, but delayed by the lack of appropriate preclinical models. Herein, we report that high levels of S. Typhi-responsive CD8+ T cells at baseline significantly correlate with an increased risk of disease in humans challenged with a high dose (~10(4) CFU) wild-type S. Typhi. Typhoid fever development was associated with higher multifunctional S. Typhi-responsive CD8+ T effector memory cells at baseline. Early decreases of these cells in circulation following challenge were observed in both S. Typhi-responsive integrin α4β7- and integrin α4β7+ CD8+ T effector memory (TEM) cells, suggesting their potential to home to both mucosal and extra-intestinal sites. Participants with higher baseline levels of S. Typhi-responsive CD8+ T memory cells had a higher risk of acquiring disease, but among those who acquired disease, those with a higher baseline responses took longer to develop disease. In contrast, protection against disease was associated with low or absent S. Typhi-responsive T cells at baseline and no changes in circulation following challenge. These data highlight the importance of pre-existing S. Typhi-responsive immunity in predicting clinical outcome following infection with wild-type S. Typhi and provide novel insights into the complex mechanisms involved in protective immunity to natural infection in a stringent human model with a high challenge dose. They also contribute important information on the immunological responses to be assessed in the appraisal and selection of new generation typhoid vaccines.

Dobinson HC, Gibani MM, Jones C, Thomaides-Brears HB, Voysey M, Darton TC, Waddington CS, Campbell D, Milligan I, Zhou L et al. 2017. Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model. Clin Infect Dis, 64 (8), pp. 1066-1073. | Show Abstract | Read more

Background: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge. Results: The primary study objective was achieved following challenge with 1-5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24-85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia. Conclusions: Challenge with S. Paratyphi A at a dose of 1-5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology. Clinical Trials Registration: NCT02100397.

White PD, Chalder T, Sharpe M, Angus BJ, Baber HL, Bavinton J, Burgess M, Clark LV, Cox DL, DeCesare JC et al. 2017. Response to the editorial by Dr Geraghty. J Health Psychol, 22 (9), pp. 1113-1117. | Show Abstract | Read more

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

O'Connor J, Vjecha MJ, Phillips AN, Angus B, Cooper D, Grinsztejn B, Lopardo G, Das S, Wood R, Wilkin A et al. 2017. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial. Lancet HIV, 4 (3), pp. e105-e112. | Show Abstract | Read more

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71-0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50-1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.

Darton TC, Jones C, Blohmke CJ, Waddington CS, Zhou L, Peters A, Haworth K, Sie R, Green CA, Jeppesen CA et al. 2016. Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a. PLoS Negl Trop Dis, 10 (8), pp. e0004926. | Show Abstract | Read more

BACKGROUND: Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. METHODS AND FINDINGS: We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. CONCLUSIONS: Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).

Churchill D, Waters L, Ahmed N, Angus B, Boffito M, Bower M, Dunn D, Edwards S, Emerson C, Fidler S et al. 2016. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. HIV Med, 17 Suppl 4 pp. s2-s104. | Read more

Toapanta FR, Bernal PJ, Fresnay S, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM et al. 2016. Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis, 10 (6), pp. e0004766. | Show Abstract | Read more

A novel human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently established by the Oxford Vaccine Group. In this model, 104 CFU of Salmonella resulted in 65% of participants developing typhoid fever (referred here as typhoid diagnosis -TD-) 6-9 days post-challenge. TD was diagnosed in participants meeting clinical (oral temperature ≥38°C for ≥12h) and/or microbiological (S. Typhi bacteremia) endpoints. Changes in B cell subpopulations following S. Typhi challenge remain undefined. To address this issue, a subset of volunteers (6 TD and 4 who did not develop TD -NoTD-) was evaluated. Notable changes included reduction in the frequency of B cells (cells/ml) of TD volunteers during disease days and increase in plasmablasts (PB) during the recovery phase (>day 14). Additionally, a portion of PB of TD volunteers showed a significant increase in activation (CD40, CD21) and gut homing (integrin α4β7) molecules. Furthermore, all BM subsets of TD volunteers showed changes induced by S. Typhi infections such as a decrease in CD21 in switched memory (Sm) CD27+ and Sm CD27- cells as well as upregulation of CD40 in unswitched memory (Um) and Naïve cells. Furthermore, changes in the signaling profile of some BM subsets were identified after S. Typhi-LPS stimulation around time of disease. Notably, naïve cells of TD (compared to NoTD) volunteers showed a higher percentage of cells phosphorylating Akt suggesting enhanced survival of these cells. Interestingly, most these changes were temporally associated with disease onset. This is the first study to describe differences in B cell subsets directly related to clinical outcome following oral challenge with wild-type S. Typhi in humans.

Blohmke CJ, Darton TC, Jones C, Suarez NM, Waddington CS, Angus B, Zhou L, Hill J, Clare S, Kane L et al. 2016. Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med, 213 (6), pp. 1061-1077. | Show Abstract | Read more

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever.

Milligan ID, Gibani MM, Sewell R, Clutterbuck EA, Campbell D, Plested E, Nuthall E, Voysey M, Silva-Reyes L, McElrath MJ et al. 2016. Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized Clinical Trial. JAMA, 315 (15), pp. 1610-1623. | Show Abstract | Read more

IMPORTANCE: Developing effective vaccines against Ebola virus is a global priority. OBJECTIVE: To evaluate an adenovirus type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein (MVA-BN-Filo). DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18- to 50-year-olds from December 2014; 8-month follow-up was completed October 2015. INTERVENTIONS: Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 10(10) viral particles) or MVA-BN-Filo (1 × 10(8) median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later. MAIN OUTCOMES AND MEASURES: The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7 days after each immunization until 8 months after priming immunizations. RESULTS: Among 87 study participants (median age, 38.5 years; 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%- 99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses. CONCLUSIONS AND RELEVANCE: In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02313077.

Hodgson SH, Angus BJ. 2016. Malaria: fluid therapy in severe disease. BMJ Clin Evid, 2016 | Show Abstract

INTRODUCTION: Severe malaria mainly affects children aged under 5 years, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria. Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and may lead to neurological sequelae in survivors. Severe malarial anaemia may have a mortality rate of over 13%. The role of fluid resuscitation in severe malaria is complex and controversial. Volume expansion could help to improve impaired organ perfusion and correct metabolic acidosis. However, rapid volume expansion could aggravate intracranial hypertension associated with cerebral malaria, leading to an increased risk of cerebral herniation. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What is the optimal method of fluid resuscitation in patients with severe malaria? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 187 studies. After deduplication and removal of conference abstracts, 93 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 82 studies and the further review of 11 full publications. Of the 11 full articles evaluated, two systematic reviews and three RCTs were added at this update. We performed a GRADE evaluation for seven PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for three interventions based on information about the effectiveness and safety of human albumin, intravenous fluids, and whole blood or plasma.

Fresnay S, McArthur MA, Magder L, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM, Pollard AJ, Sztein MB. 2016. Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans. J Transl Med, 14 (1), pp. 62. | Show Abstract | Read more

BACKGROUND: Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. METHODS: Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). RESULTS: Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM. CONCLUSIONS: These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates.

Li HK, Scarborough M, Zambellas R, Cooper C, Rombach I, Walker AS, Lipsky BA, Briggs A, Seaton A, Atkins B et al. 2015. Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomised controlled trial. Trials, 16 (1), pp. 583. | Show Abstract | Read more

BACKGROUND: Bone and joint infection in adults arises most commonly as a complication of joint replacement surgery, fracture fixation and diabetic foot infection. The associated morbidity can be devastating to patients and costs the National Health Service an estimated £20,000 to £40,000 per patient. Current standard of care in most UK centres includes a prolonged course (4-6 weeks) of intravenous antibiotics supported, if available, by an outpatient parenteral antibiotic therapy service. Intravenous therapy carries with it substantial risks and inconvenience to patients, and the antibiotic-related costs are approximately ten times that of oral therapy. Despite this, there is no evidence to suggest that oral therapy results in inferior outcomes. We hypothesise that, by selecting oral agents with high bioavailability, good tissue penetration and activity against the known or likely pathogens, key outcomes in patients managed primarily with oral therapy are non-inferior to those in patients treated by intravenous therapy. METHODS: The OVIVA trial is a parallel group, randomised (1:1), un-blinded, non-inferiority trial conducted in thirty hospitals across the UK. Eligible participants are adults (>18 years) with a clinical syndrome consistent with a bone, joint or metalware-associated infection who have received ≤7 days of intravenous antibiotic therapy from the date of definitive surgery (or the start of planned curative therapy in patients treated without surgical intervention). Participants are randomised to receive either oral or intravenous antibiotics, selected by a specialist infection physician, for the first 6 weeks of therapy. The primary outcome measure is definite treatment failure within one year of randomisation, as assessed by a blinded endpoint committee, according to pre-defined microbiological, histological and clinical criteria. Enrolling 1,050 subjects will provide 90 % power to demonstrate non-inferiority, defined as less than 7.5 % absolute increase in treatment failure rate in patients randomised to oral therapy as compared to intravenous therapy (one-sided alpha of 0.05). DISCUSSION: If our results demonstrate non-inferiority of orally administered antibiotic therapy, this trial is likely to facilitate a dramatically improved patient experience and alleviate a substantial financial burden on healthcare services. TRIAL REGISTRATION: ISRCTN91566927 - 14/02/2013.

Darton T, Jones C, Waddington C, Blohmke C, Peters A, Haworth K, Green C, Jeppesen C, Moore M, Thompson B et al. 2015. LIVE ATTENUATED ORAL VACCINE, AGE AND ANTI-VI ANTIBODY STATUS AT BASELINE SIGNIFICANTLY AFFECT ATTACK RATE IN A HUMAN SALMONELLA TYPHI CHALLENGE MODEL JOURNAL OF INFECTION, 71 (6), pp. 689-689. | Read more

Green CA, Scarselli E, Sande CJ, Thompson AJ, de Lara CM, Taylor KS, Haworth K, Del Sorbo M, Angus B, Siani L et al. 2015. Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults. Sci Transl Med, 7 (300), pp. 300ra126. | Show Abstract | Read more

Respiratory syncytial virus (RSV) causes respiratory infection in annual epidemics, with infants and the elderly at particular risk of developing severe disease and death. However, despite its importance, no vaccine exists. The chimpanzee adenovirus, PanAd3-RSV, and modified vaccinia virus Ankara, MVA-RSV, are replication-defective viral vectors encoding the RSV fusion (F), nucleocapsid (N), and matrix (M2-1) proteins for the induction of humoral and cellular responses. We performed an open-label, dose escalation, phase 1 clinical trial in 42 healthy adults in which four different combinations of prime/boost vaccinations were investigated for safety and immunogenicity, including both intramuscular (IM) and intranasal (IN) administration of the adenovirus-vectored vaccine. The vaccines were safe and well tolerated, with the most common reported adverse events being mild injection site reactions. No vaccine-related serious adverse events occurred. RSV neutralizing antibody titers rose in response to IM prime with PanAd3-RSV and after IM boost for individuals primed by the IN route. Circulating anti-F immunoglobulin G (IgG) and IgA antibody-secreting cells (ASCs) were observed after the IM prime and IM boost. RSV-specific T cell responses were increased after the IM PanAd3-RSV prime and were most efficiently boosted by IM MVA-RSV. Interferon-γ (IFN-γ) secretion after boost was from both CD4(+) and CD8(+) T cells, without detectable T helper cell 2 (TH2) cytokines that have been previously associated with immune pathogenesis following exposure to RSV after the formalin-inactivated RSV vaccine. In conclusion, PanAd3-RSV and MVA-RSV are safe and immunogenic in healthy adults. These vaccine candidates warrant further clinical evaluation of efficacy to assess their potential to reduce the burden of RSV disease.

Toapanta FR, Bernal PJ, Fresnay S, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM et al. 2015. Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis, 9 (6), pp. e0003837. | Show Abstract | Read more

A new human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently developed. In this model, ingestion of 104 CFU of Salmonella resulted in 65% of subjects developing typhoid fever (referred here as typhoid diagnosis -TD-) 5-10 days post-challenge. TD criteria included meeting clinical (oral temperature ≥38°C for ≥12 h) and/or microbiological (S. Typhi bacteremia) endpoints. One of the first lines of defense against pathogens are the cells of the innate immune system (e.g., monocytes, dendritic cells -DCs-). Various changes in circulating monocytes and DCs have been described in the murine S. Typhimurium model; however, whether similar changes are present in humans remains to be explored. To address these questions, a subset of volunteers (5 TD and 3 who did not develop typhoid despite oral challenge -NoTD-) were evaluated for changes in circulating monocytes and DCs. Expression of CD38 and CD40 were upregulated in monocytes and DCs in TD volunteers during the disease days (TD-0h to TD-96h). Moreover, integrin α4β7, a gut homing molecule, was upregulated on monocytes but not DCs. CD21 upregulation was only identified in DCs. These changes were not observed among NoTD volunteers despite the same oral challenge. Moreover, monocytes and DCs from NoTD volunteers showed increased binding to S. Typhi one day after challenge. These monocytes showed phosphorylation of p38MAPK, NFkB and Erk1/2 upon stimulation with S. Typhi-LPS-QDot micelles. In contrast, monocytes from TD volunteers showed only a moderate increase in S. Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation. This is the first study to describe different activation and migration profiles, as well as differential signaling patterns, in monocytes and DCs which relate directly to the clinical outcome following oral challenge with wild type S. Typhi.

McArthur MA, Fresnay S, Magder LS, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM et al. 2015. Activation of Salmonella Typhi-specific regulatory T cells in typhoid disease in a wild-type S. Typhi challenge model. PLoS Pathog, 11 (5), pp. e1004914. | Show Abstract | Read more

Salmonella Typhi (S. Typhi), the causative agent of typhoid fever, causes significant morbidity and mortality worldwide. Currently available vaccines are moderately efficacious, and identification of immunological responses associated with protection or disease will facilitate the development of improved vaccines. We investigated S. Typhi-specific modulation of activation and homing potential of circulating regulatory T cells (Treg) by flow and mass cytometry using specimens obtained from a human challenge study. Peripheral blood mononuclear cells were obtained from volunteers pre- and at multiple time-points post-challenge with wild-type S. Typhi. We identified differing patterns of S. Typhi-specific modulation of the homing potential of circulating Treg between volunteers diagnosed with typhoid (TD) and those who were not (No TD). TD volunteers demonstrated up-regulation of the gut homing molecule integrin α4ß7 pre-challenge, followed by a significant down-regulation post-challenge consistent with Treg homing to the gut. Additionally, S. Typhi-specific Treg from TD volunteers exhibited up-regulation of activation molecules post-challenge (e.g., HLA-DR, LFA-1). We further demonstrate that depletion of Treg results in increased S. Typhi-specific cytokine production by CD8+ TEM in vitro. These results suggest that the tissue distribution of activated Treg, their characteristics and activation status may play a pivotal role in typhoid fever, possibly through suppression of S. Typhi-specific effector T cell responses. These studies provide important novel insights into the regulation of immune responses that are likely to be critical in protection against typhoid and other enteric infectious diseases.

McCullagh D, Dobinson HC, Darton T, Campbell D, Jones C, Snape M, Stevens Z, Plested E, Voysey M, Kerridge S et al. 2015. Understanding paratyphoid infection: study protocol for the development of a human model of Salmonella enterica serovar Paratyphi A challenge in healthy adult volunteers. BMJ Open, 5 (6), pp. e007481. | Show Abstract | Read more

INTRODUCTION: This study will develop the first human challenge model of paratyphoid infection which may then be taken forward to evaluate paratyphoid vaccine candidates. Salmonella Paratyphi A is believed to cause a quarter of the estimated 20 million cases of enteric fever annually. Epidemiological evidence also suggests that an increasing proportion of the enteric fever burden is attributable to S. Paratyphi infection meriting further attention and interest in vaccine development. Assessment of paratyphoid vaccine efficacy in preclinical studies is complicated by the lack of a small animal model and the human-restricted nature of the infection. The use of experimental human infection in healthy volunteers provides an opportunity to address these problems in a cost-effective manner. METHODS AND ANALYSIS: Volunteers will ingest virulent S. Paratyphi A bacteria (NVGH308 strain) with a bicarbonate buffer solution to establish the infectious dose resulting in an 'attack rate' of 60-75%. Using an a priori decision-making algorithm, the challenge dose will be escalated or de-escalated to achieve the target attack rate, with the aim of reaching the study end point while exposing as few individuals as possible to infection. The attack rate will be determined by the proportion of paratyphoid infection in groups of 20 healthy adult volunteers, with infection being defined by one or more positive blood cultures (microbiological end point) and/or fever, defined as an oral temperature exceeding 38 °C sustained for at least 12 h (clinical end point); 20-80 participants will be required. Challenge participants will start a 2-week course of an oral antibiotic on diagnosis of infection, or after 14 days follow-up. ETHICS AND DISSEMINATION: The strict eligibility criterion aims to minimise risk to participants and their close contacts. Ethical approval has been obtained. The results will be disseminated in a peer-reviewed journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT02100397.

Waddington CS, Darton TC, Angus B, Pollard AJ. 2014. Reply to Farmakiotis et al. Clin Infect Dis, 59 (8), pp. 1198-1199. | Read more

Waddington CS, Darton TC, Woodward WE, Angus B, Levine MM, Pollard AJ. 2014. Advancing the management and control of typhoid fever: A review of the historical role of human challenge studies Journal of Infection, 68 (5), pp. 405-418. | Show Abstract | Read more

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design. © 2014.

Angus B. 2014. Novel anti-malarial combinations and their toxicity. Expert Rev Clin Pharmacol, 7 (3), pp. 299-316. | Show Abstract | Read more

Artemisinin combination therapy for the treatment of uncomplicated malaria includes artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, artesunate plus sulfadoxine-pyrimethamine and dihydroartemisinin plus piperaquine. These drugs are safe and efficacious at present. The emergence of artemisinin resistant parasites in SE Asia means that there is a need to optimise drug dosing and investigate novel therapies to maintain the impressive reduction in malaria mortality which has been seen in the past decade.

Waddington CS, Darton TC, Jones C, Haworth K, Peters A, John T, Thompson BA, Kerridge SA, Kingsley RA, Zhou L et al. 2014. An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin Infect Dis, 58 (9), pp. 1230-1240. | Show Abstract | Read more

BACKGROUND: Typhoid fever is a major global health problem, the control of which is hindered by lack of a suitable animal model in which to study Salmonella Typhi infection. Until 1974, a human challenge model advanced understanding of typhoid and was used in vaccine development. We set out to establish a new human challenge model and ascertain the S. Typhi (Quailes strain) inoculum required for an attack rate of 60%-75% in typhoid-naive volunteers when ingested with sodium bicarbonate solution. METHODS: Groups of healthy consenting adults ingested escalating dose levels of S. Typhi and were closely monitored in an outpatient setting for 2 weeks. Antibiotic treatment was initiated if typhoid diagnosis occurred (temperature ≥38°C sustained ≥12 hours or bacteremia) or at day 14 in those remaining untreated. RESULTS: Two dose levels (10(3) or 10(4) colony-forming units) were required to achieve the primary objective, resulting in attack rates of 55% (11/20) or 65% (13/20), respectively. Challenge was well tolerated; 4 of 40 participants fulfilled prespecified criteria for severe infection. Most diagnoses (87.5%) were confirmed by blood culture, and asymptomatic bacteremia and stool shedding of S. Typhi was also observed. Participants who developed typhoid infection demonstrated serological responses to flagellin and lipopolysaccharide antigens by day 14; however, no anti-Vi antibody responses were detected. CONCLUSIONS: Human challenge with a small inoculum of virulent S. Typhi administered in bicarbonate solution can be performed safely using an ambulant-model design to advance understanding of host-pathogen interactions and immunity. This model should expedite development of diagnostics, vaccines, and therapeutics for typhoid control.

Waddington CS, Darton TC, Woodward WE, Angus B, Levine MM, Pollard AJ. 2014. Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. J Infect, 68 (5), pp. 405-418. | Show Abstract | Read more

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design.

Dougall D, Johnson A, Goldsmith K, Sharpe M, Angus B, Chalder T, White P. 2014. Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome. J Psychosom Res, 77 (1), pp. 20-26. | Show Abstract | Read more

OBJECTIVE: Adverse events (AEs) are health related events, reported by participants in clinical trials. We describe AEs in the PACE trial of treatments for chronic fatigue syndrome (CFS) and baseline characteristics associated with them. METHODS: AEs were recorded on three occasions over one year in 641 participants. We compared the numbers and nature of AEs between treatment arms of specialist medical care (SMC) alone, or SMC supplemented by adaptive pacing therapy (APT), cognitive behaviour therapy (CBT) or graded exercise therapy (GET). We examined associations with baseline measures by binary logistic regression analyses, and compared the proportions of participants who deteriorated by clinically important amounts. RESULTS: Serious adverse events and reactions were infrequent. Non-serious adverse events were common; the median (quartiles) number was 4 (2, 8) per participant, with no significant differences between treatments (P=.47). A greater number of NSAEs were associated with recruitment centre, and baseline physical symptom count, body mass index, and depressive disorder. Physical function deteriorated in 39 (25%) participants after APT, 15 (9%) after CBT, 18 (11%) after GET, and 28 (18%) after SMC (P<.001), with no significant differences in worsening fatigue. CONCLUSIONS: The numbers of adverse events did not differ significantly between trial treatments, but physical deterioration occurred most often after APT. The reporting of non-serious adverse events may reflect the nature of the illness rather than the effect of treatments. Differences between centres suggest that both standardisation of ascertainment methods and training are important when collecting adverse event data.

Brown ST, Tate JP, Kyriakides TC, Kirkwood KA, Holodniy M, Goulet JL, Angus BJ, Cameron DW, Justice AC, OPTIMA Team. 2014. The VACS index accurately predicts mortality and treatment response among multi-drug resistant HIV infected patients participating in the options in management with antiretrovirals (OPTIMA) study. PLoS One, 9 (3), pp. e92606. | Show Abstract | Read more

OBJECTIVES: The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. METHODS: Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel's C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. RESULTS: Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14-0.49) and 0.39(95% CI 0.22-0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27-3.38) and 1.51 (95%CI 0.90-2.53) for the 25% least improved scores. CONCLUSIONS: The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research.

Franzen SRP, Chandler C, Atashili J, Angus B, Lang T. 2013. Barriers and enablers of locally led clinical trials in Ethiopia and Cameroon: a prospective, qualitative study LANCET, 382 pp. 14-14.

Bayoumi AM, Barnett PG, Joyce VR, Griffin SC, Sun H, Bansback NJ, Holodniy M, Sanders G, Brown ST, Kyriakides TC et al. 2013. Cost-effectiveness of newer antiretroviral drugs in treatment-experienced patients with multidrug-resistant HIV disease. J Acquir Immune Defic Syndr, 64 (4), pp. 382-391. | Show Abstract | Read more

OBJECTIVE: Newer antiretroviral drugs provide substantial benefits but are expensive. The cost-effectiveness of using antiretroviral drugs in combination for patients with multidrug-resistant HIV disease was determined. DESIGN: A cohort state-transition model was built representing treatment-experienced patients with low CD4 counts, high viral load levels, and multidrug-resistant virus. The effectiveness of newer drugs (those approved in 2005 or later) was estimated from published randomized trials. Other parameters were estimated from a randomized trial and from the literature. The model had a lifetime time horizon and used the perspective of an ideal insurer in the United States. The interventions were combination antiretroviral therapy, consisting of 2 newer drugs and 1 conventional drug, compared with 3 conventional drugs. Outcome measures were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness. RESULTS: Substituting newer antiretroviral drugs increased expected survival by 3.9 years in advanced HIV disease. The incremental cost-effectiveness ratio of newer, compared with conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity analyses showed that substituting only one newer antiretroviral drug cost $54,559 to $68,732/QALY, depending on assumptions about efficacy. Substituting 3 newer drugs cost $105,956 to $117,477/QALY. Cost-effectiveness ratios were higher if conventional drugs were not discontinued. CONCLUSIONS: In treatment-experienced patients with advanced HIV disease, use of newer antiretroviral agents can be cost-effective, given a cost-effectiveness threshold in the range of $50,000 to $75,000 per QALY gained. Newer antiretroviral agents should be used in carefully selected patients for whom less expensive options are clearly inferior.

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Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P, Tajar A, Piechnik SK et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients Circulation, 128 (8), pp. 814-822. | Show Abstract | Read more

BACKGROUND - : HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS - : Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P < 0.003) and 74% higher median plasma triglyceride levels (both P < 0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P < 0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS - : Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV. © 2013 American Heart Association, Inc.

Clutton G, Yang H, Hancock G, Sande N, Holloway C, Angus B, von Delft A, Barnes E, Borrow P, Pellegrino P et al. 2013. Emergence of a distinct HIV-specific IL-10-producing CD8+ T-cell subset with immunomodulatory functions during chronic HIV-1 infection. Eur J Immunol, 43 (11), pp. 2875-2885. | Show Abstract | Read more

Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.

Newton PN, Stepniewska K, Dondorp A, Silamut K, Chierakul W, Krishna S, Davis TM, Suputtamongkol Y, Angus B, Pukrittayakamee S et al. 2013. Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand. Malar J, 12 (1), pp. 229. | Show Abstract | Read more

BACKGROUND: Severe malaria remains a major cause of death and morbidity amongst adults in the Asiatic tropics. METHODS: A retrospective analysis of the clinical and laboratory data of 988 adult patients, hospitalized with Plasmodium falciparum malaria and prospectively recruited to malaria studies in western Thailand between 1986 and 2002, was performed to assess the factors associated with a fatal outcome. Different severity scores and classifications for defining severe malaria were compared and, using multiple logistic regression, simple models for predicting mortality developed. RESULTS: The proportion of patients fulfilling the WHO 2000 definition of severe malaria was 78.1%, and their mortality was 10%. Mortality in patients given parenteral artesunate or artemether (16/317, 5%) was lower than in those given parenteral quinine (59/442, 13%) (P < 0.001). Models using parameter sets based on WHO 1990, 2000 and Adapted AQ criteria plus blood smear parasite-stage assessment gave the best mortality prediction. A malaria prognostic index (MPI), derived from the dataset using five clinical or laboratory variables gave similar prognostic accuracy. CONCLUSIONS: The mortality of severe malaria in adults has fallen and the switch from quinine to artesunate has probably been an important contributor. Prognostic indices based on WHO 2000 definitions, and other simpler indices based on fewer variables, provide clinically useful predictions of outcome in Asian adults with severe malaria.

Saira K, Lin X, DePasse JV, Halpin R, Twaddle A, Stockwell T, Angus B, Cozzi-Lepri A, Delfino M, Dugan V et al. 2013. Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus. J Virol, 87 (14), pp. 8064-8074. | Show Abstract | Read more

Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established.

Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P, Tajar A, Piechnik SK et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients. Circulation, 128 (8), pp. 814-822. | Show Abstract | Read more

BACKGROUND: HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS: Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS: Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV.

Yang H, Yorke E, Hancock G, Clutton G, Sande N, Angus B, Smyth R, Mak J, Dorrell L. 2013. Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection Journal of Immunological Methods, 391 (1-2), pp. 174-178. | Show Abstract | Read more

The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10 -2 to 8×10 -5 , and by nearly two-fold (p < 0.001) at the optimal MOI tested (10 -2 ). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs. © 2013 Elsevier B.V.

Yang H, Yorke E, Hancock G, Clutton G, Sande N, Angus B, Smyth R, Mak J, Dorrell L. 2013. Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection. J Immunol Methods, 391 (1-2), pp. 174-178. | Show Abstract | Read more

The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10(-2) to 8×10(-5), and by nearly two-fold (p<0.001) at the optimal MOI tested (10(-2)). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs.

Franzen SR, Chandler C, Enquselassie F, Siribaddana S, Atashili J, Angus B, Lang T. 2013. Understanding the investigators: a qualitative study investigating the barriers and enablers to the implementation of local investigator-initiated clinical trials in Ethiopia. BMJ Open, 3 (11), pp. e003616. | Show Abstract | Read more

OBJECTIVES: Clinical trials provide 'gold standard' evidence for policy, but insufficient locally relevant trials are conducted in low-income and middle-income countries. Local investigator-initiated trials could generate highly relevant data for national governments, but information is lacking on how to facilitate them. We aimed to identify barriers and enablers to investigator-initiated trials in Ethiopia to inform and direct capacity strengthening initiatives. DESIGN: Exploratory, qualitative study comprising of in-depth interviews (n=7) and focus group discussions (n=3). SETTING: Fieldwork took place in Ethiopia during March 2011. PARTICIPANTS: Local health researchers with previous experiences of clinical trials or stakeholders with an interest in trials were recruited through snowball sampling (n=20). OUTCOME MEASURES: Detailed discussion notes were analysed using thematic coding analysis and key themes were identified. RESULTS: All participants perceived investigator-initiated trials as important for generating local evidence. System and organisational barriers included: limited funding allocation, weak regulatory and administrative systems, few learning opportunities, limited human and material capacity and poor incentives for conducting research. Operational hurdles were symptomatic of these barriers. Lack of awareness, confidence and motivation to undertake trials were important individual barriers. Training, knowledge sharing and experience exchange were key enablers to trial conduct and collaboration was unanimously regarded as important for improving capacity. CONCLUSIONS: Barriers to trial conduct were found at individual, operational, organisational and system levels. These findings indicate that to increase locally led trial conduct in Ethiopia, system wide changes are needed to create a more receptive and enabling research environment. Crucially, the creation of research networks between potential trial groups could provide much needed practical collaborative support through sharing of financial and project management burdens, knowledge and resources. These findings could have important implications for capacity-strengthening initiatives but further research is needed before the results can be generalised more widely.

Davey RT, Lynfield R, Dwyer DE, Losso MH, Cozzi-Lepri A, Wentworth D, Lane HC, Dewar R, Rupert A, Metcalf JA et al. 2013. The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: results of two international observational cohort studies. PLoS One, 8 (2), pp. e57121. | Show Abstract | Read more

BACKGROUND: Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies. METHODS: Among patients with RT-PCR-confirmed influenza A(H1N1)pdm09 virus infection, odds ratios (ORs) estimated by logistic regression were used to summarize the associations of biomarkers measured at enrollment with worsened disease outcome or death after 14 days of follow-up for those seeking outpatient care (FLU 002) or after 60 days for those hospitalized with influenza complications (FLU 003). Biomarkers that were significantly associated with progression in both studies (p<0.05) or only in one (p<0.002 after Bonferroni correction) were identified. RESULTS: In FLU 002 28/528 (5.3%) outpatients had influenza A(H1N1)pdm09 virus infection that progressed to a study endpoint of complications, hospitalization or death, whereas in FLU 003 28/170 (16.5%) inpatients enrolled from the general ward and 21/39 (53.8%) inpatients enrolled directly from the ICU experienced disease progression. Higher levels of 12 of the 25 markers were significantly associated with subsequent disease progression. Of these, 7 markers (IL-6, CD163, IL-10, LBP, IL-2, MCP-1, and IP-10), all with ORs for the 3(rd) versus 1(st) tertile of 2.5 or greater, were significant (p<0.05) in both outpatients and inpatients. In contrast, five markers (sICAM-1, IL-8, TNF-α, D-dimer, and sVCAM-1), all with ORs for the 3(rd) versus 1(st) tertile greater than 3.2, were significantly (p≤.002) associated with disease progression among hospitalized patients only. CONCLUSIONS: In patients presenting with varying severities of influenza A(H1N1)pdm09 virus infection, a baseline elevation in several biomarkers associated with inflammation, coagulation, or immune function strongly predicted a higher risk of disease progression. It is conceivable that interventions designed to abrogate these baseline elevations might affect disease outcome.

Bjerk SM, Baker JV, Emery S, Neuhaus J, Angus B, Gordin FM, Pett SL, Stephan C, Kunisaki KM, INSIGHT SMART Study Group. 2013. Biomarkers and bacterial pneumonia risk in patients with treated HIV infection: a case-control study. PLoS One, 8 (2), pp. e56249. | Show Abstract | Read more

BACKGROUND: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist. METHODS: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. RESULTS: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). CONCLUSIONS: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Yang H, Wu H, Hancock G, Clutton G, Sande N, Xu X, Yan H, Huang X, Angus B, Kuldanek K et al. 2012. Antiviral inhibitory capacity of CD8+ T cells predicts the rate of CD4+ T-cell decline in HIV-1 infection. J Infect Dis, 206 (4), pp. 552-561. | Show Abstract | Read more

BACKGROUND: Rare human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain control of viremia without therapy show potent CD8+ T-cell-mediated suppression of viral replication in vitro. Whether this is a determinant of the rate of disease progression in viremic individuals is unknown. METHODS: We measured CD8+ T-cell-mediated inhibition of a heterologous HIV-1 isolate in 50 HIV-1-seropositive adults with diverse progression rates. Linear mixed models were used to determine whether CD8+ T-cell function could explain variation in the rate of CD4+ T-cell decline. RESULTS: There was a significant interaction between CD8+ T-cell antiviral activity in vitro and the rate of CD4+ T-cell decline in chronically infected individuals (P < .0001). In a second prospective analysis of recently infected subjects followed for up to 3 years, CD8+ T-cell antiviral activity strongly predicted subsequent CD4+ T-cell decline (P < .0001) and explained up to 73% of the interindividual variation in the CD4+ T-cell slope. In addition, it was inversely associated with viral load set point (r = -0.68 and P = .002). CONCLUSIONS: The antiviral inhibitory capacity of CD8+ T cells is highly predictive of CD4+ T-cell loss in early HIV-1 infection. It has potential as a benchmark of effective immunity in vaccine evaluation.

Darton T, Jones C, Waddington C, Dougan G, Sztein M, Levine M, Angus B, Farrar J, Lockhart S, Crook D et al. 2012. Demonstration of primary and asymptomatic DNAaemia in participants challenged with Salmonella Typhi (Quailes strain) during the development of a human model of typhoid infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E215-E215. | Read more

Jones C, Waddington C, Darton T, Bowman J, Farrar J, Dougan G, Levine M, Lockhart S, Sztein M, Crook D et al. 2012. Quantification of antibody secreting cell responses in a human challenge model of Salmonella Typhi infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E224-E224. | Read more

Waddington C, Darton T, Jones C, Haworth K, Peters A, Kerridge S, Crook D, Lockhart S, Farrar J, Dougan G et al. 2012. Variations in attack rate in a single-blind, dose escalation challenge study of Salmonella Typhi in healthy adult volunteers INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E244-E244. | Read more

Holloway C, Ntusi N, Suttie J, Mahmod M, Clutton G, Hancock G, Wainwright E, Angus B, Asaad M, Beak P et al. 2012. Comprehensive Cardiac Magnetic Resonance Reveals HIV is Associated with High Burden of Myocardial Disease HIV MEDICINE, 13 pp. 3-3.

Clutterbuck EA, Lazarus R, Yu LM, Bowman J, Bateman EA, Diggle L, Angus B, Peto TE, Beverley PC, Mant D, Pollard AJ. 2012. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J Infect Dis, 205 (9), pp. 1408-1416. | Show Abstract | Read more

BACKGROUND: A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults. METHODS: We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved. RESULTS: A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans. CONCLUSIONS: This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP. Clinical Trials Registration. ISRCTN: 78768849.

Crook DW, Walker AS, Kean Y, Weiss K, Cornely OA, Miller MA, Esposito R, Louie TJ, Stoesser NE, Young BC et al. 2012. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis, 55 Suppl 2 (suppl 2), pp. S93-103. | Show Abstract | Read more

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

Newton PN, Green MD, Mildenhall DC, Plançon A, Nettey H, Nyadong L, Hostetler DM, Swamidoss I, Harris GA, Powell K et al. 2011. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority. Malar J, 10 (1), pp. 352. | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. METHODS: Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. RESULTS: Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. CONCLUSIONS: Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

Angus B, Schmid M, Dockrell D, Grant A. 2011. 10 Travel-related opportunistic infections. HIV Med, 12 Suppl 2 pp. 88-101. | Read more

Pett SL, Carey C, Lin E, Wentworth D, Lazovski J, Miró JM, Gordin F, Angus B, Rodriguez-Barradas M, Rubio R et al. 2011. Predictors of bacterial pneumonia in Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT). HIV Med, 12 (4), pp. 219-227. | Show Abstract | Read more

BACKGROUND AND OBJECTIVES: Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin-2 (rIL-2) with cART vs. cART alone (control arm) in HIV-infected adults with CD4 counts ≥300cells/μL, offered the opportunity to explore associations between bacterial pneumonia and rIL-2, a cytokine that increases the risk of some bacterial infections. METHODS: Baseline and time-updated factors associated with first-episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected. RESULTS: IL-2 cycling was most intense in years 1-2. Over ≈7 years, 93 IL-2 [rate 0.67/100 person-years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P=0.68]. Median CD4 counts prior to pneumonia were 570cells/μL (IL-2 arm) and 463cells/μL (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log(10) higher VL 1.28; 95% CI 1.11, 1.47; P<0.001) was associated with increased risk; higher CD4 count prior to the event (HR per 100 cells/μL higher 0.94; 95% CI 0.89, 1.0; P=0.04) decreased risk. Compared with controls, the hazard for a pneumonia event was higher if rIL-2 was received <180 days previously (HR 1.66; 95% CI 1.07, 2.60; P=0.02) vs.≥180 days previously (HR 0.98; 95% CI 0.70, 1.37; P=0.9). Compared with the control group, pneumonia risk in the IL-2 arm decreased over time, with HRs of 1.41, 1.71, 1.16, 0.62 and 0.84 in years 1, 2, 3-4, 5-6 and 7, respectively. CONCLUSIONS: Bacterial pneumonia rates in cART-treated adults with moderate immunodeficiency are high. The mechanism of the association between bacterial pneumonia and recent IL-2 receipt and/or detectable HIV viraemia warrants further exploration.

Holodniy M, Brown ST, Cameron DW, Kyriakides TC, Angus B, Babiker A, Singer J, Owens DK, Anis A, Goodall R et al. 2011. Results of antiretroviral treatment interruption and intensification in advanced multi-drug resistant HIV infection from the OPTIMA trial. PLoS One, 6 (3), pp. e14764. | Show Abstract | Read more

BACKGROUND: Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. METHODS AND FINDINGS: We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. CONCLUSIONS: We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options. TRIAL REGISTRATION: Clinicaltrials.gov NCT00050089.

Lazarus R, Clutterbuck E, Yu LM, Bowman J, Bateman EA, Diggle L, Angus B, Peto TE, Beverley PC, Mant D, Pollard AJ. 2011. A randomized study comparing combined pneumococcal conjugate and polysaccharide vaccination schedules in adults. Clin Infect Dis, 52 (6), pp. 736-742. | Show Abstract | Read more

BACKGROUND: The widely used 23-valent plain polysaccharide vaccine (23vP) has limited effectiveness, produces short-lived immune responses, and induces attenuated antibody production after subsequent challenge with pneumococcal vaccines. Our goal was to examine whether priming with the 7-valent pneumococcal conjugate vaccine (PCV7) could enhance the immunogenicity of 23vP for the PCV7 serotypes and to investigate whether 23vP induced hyporesponsiveness could be overcome using PCV7. METHODS: We conducted an open-label randomized study that compared 3 vaccine schedules, each of which consisted of 2 doses of PCV7 and 1 dose of 23vP (23vP-PCV7-PCV7, PCV7-23vP-PCV7, PCV7-PCV7-23vP) administered over a 1-year period in a cohort of 348 adults 50-70 years of age. All vaccines were administered intramuscularly and were given 6 months apart. Blood samples were obtained prior to and 1 month after each vaccination. RESULTS: 23vP administered after priming with 2 doses of PCV7 produced significantly higher antibody concentrations for 3 of the 7 PCV7 serotypes, compared with vaccination with a single dose of 23vP; however, the same immunogenicity could be achieved with a single dose of PCV7. Prior vaccination with 23vP attenuated the antibody response to subsequent PCV7, which was not restored by additional doses of PCV7. CONCLUSION: In adults, vaccination schedules combining PCV7 and 23vP do not provide improved immunogenicity over the use of a single dose of 23vP for most of the serotypes contained in PCV7.

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White PD, Goldsmith K, Johnson AL, Potts L, Walwyn R, Decesare JC, Baber HL, Burgess M, Clark LV, Cox DL et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): A randomised trial The Lancet, 377 (9768), pp. 823-836. | Show Abstract | Read more

Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments. In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094. We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95 CI 1·8 to 5·0) points lower for CBT (p=0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p=0·0003), but did not differ for APT (0·7 [-0·9 to 2·3] points lower; p=0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p=0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p=0·0005), but did not differ for APT (3·4 [-1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p=0·0027; GET p=0·0059) and better physical function (CBT p=0·0002; GET p < 0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1) of 159 participants in the APT group, three (2) of 161 in the CBT group, two (1) of 160 in the GET group, and two (1) of 160 in the SMC-alone group. CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition. UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions. © 2011 Elsevier Ltd.

Sheehy SH, Angus BJ. 2011. Malaria: severe, life-threatening. BMJ Clin Evid, 2011 | Show Abstract

INTRODUCTION: Severe malaria mainly affects children under 5 years old, non-immune travellers, migrants to malarial areas, and people living in areas with unstable or seasonal malaria. Cerebral malaria, causing encephalopathy and coma, is fatal in around 20% of children and adults, and neurological sequelae may occur in some survivors. Severe malarial anaemia may have a mortality rate of over 13%. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antimalarial treatments and adjunctive treatment for complicated falciparum malaria in non-pregnant people? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: dexamethasone, exchange blood transfusion, initial blood transfusion, intramuscular artemether, intravenous and intramuscular artesunate, intravenous and intramuscular dihydroartemisinin, quinine, and rectal/intravenous/intramuscular artemisinin and its derivatives.

White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet, 377 (9768), pp. 823-836. | Show Abstract | Read more

BACKGROUND: Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments. METHODS: In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094. FINDINGS: We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p = 0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p = 0·0003), but did not differ for APT (0·7 [-0·9 to 2·3] points lower; p = 0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p = 0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p = 0·0005), but did not differ for APT (3·4 [-1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p = 0·0027; GET p = 0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group. INTERPRETATION: CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition. FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.

Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN. 2010. Artemisinin combination therapy for vivax malaria. Lancet Infect Dis, 10 (6), pp. 405-416. | Show Abstract | Read more

Early parasitological diagnosis and treatment with artemisinin-based combination therapies (ACTs) are key components of worldwide malaria elimination programmes. In general, use of ACTs has been limited to patients with falciparum malaria whereas blood-stage infections with Plasmodium vivax are mostly still treated with chloroquine. We review the evidence for the relative benefits and disadvantages of the existing separate treatment approach versus a unified ACT-based strategy for treating Plasmodium falciparum and P vivax infections in regions where both species are endemic (co-endemic). The separate treatment scenario is justifiable if P vivax remains sensitive to chloroquine and diagnostic tests reliably distinguish P vivax from P falciparum. However, with the high number of misdiagnoses in routine practice and the rise and spread of chloroquine-resistant P vivax, there might be a compelling rationale for a unified ACT-based strategy for vivax and falciparum malaria in all co-endemic regions. Analyses of the cost-effectiveness of ACTs for both Plasmodium species are needed to assess the role of these drugs in the control and elimination of vivax malaria.

Dau B, Ayers D, Singer J, Harrigan PR, Brown S, Kyriakides T, Cameron DW, Angus B, Holodniy M. 2010. Connection domain mutations in treatment-experienced patients in the OPTIMA trial. J Acquir Immune Defic Syndr, 54 (2), pp. 160-166. | Show Abstract | Read more

OBJECTIVES: To determine the frequency of mutations in the connection domain (CD) of HIV reverse transcriptase in treatment-experienced patients in the Options in Management with Antiretrovirals trial, their impact on susceptibility to antiretroviral (ARV) drugs, and their impact on virologic outcomes. METHODS: Baseline plasma ARV genotypes and inferred resistance phenotypes were obtained. Frequencies of E312Q, Y318F, G333D, G333E, G335C, G335D, N348I, A360I, A360V, V365I, A371V, A376S, and E399G were compared with a treatment-naive population. The association of CD mutations with inferred IC50 fold changes to nucleos(t)ide reverse transcriptase inhibitors was evaluated. Univariate and multivariate analyses examined the association of CD mutations with a >1 log10 per milliliter decrease in HIV viral load after 24 weeks on a new ARV regimen. RESULTS: Higher CD mutation rates were seen in Options in Management with Antiretrovirals patients (n = 345) compared with a treatment-naive population. CD mutations were associated with increased inferred IC50 fold changes to abacavir, stavudine, tenofovir, and zidovudine. On univariate analysis, A371V was associated with lack of virologic response, as was having any CD mutation on multivariate analysis. CONCLUSIONS: CD mutations are frequent in treatment-experienced populations. They are associated with reduced susceptibility to some nucleos(t)ide reverse transcriptase inhibitors and with a diminished response to ARV therapy.

Neuhaus J, Angus B, Kowalska JD, La Rosa A, Sampson J, Wentworth D, Mocroft A, INSIGHT SMART and ESPRIT study groups. 2010. Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV. AIDS, 24 (5), pp. 697-706. | Show Abstract | Read more

OBJECTIVES: Among patients with HIV, the risk of death associated with different AIDS events has been quantified, but the risk of death associated with non-AIDS events has not been examined. We compared the risk of all-cause mortality following AIDS versus serious non-AIDS (SNA) events in the Strategies for Management of Antiretroviral Therapy (SMART) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). DESIGN: Data from 9583 HIV-infected participants, 5472 with a CD4 cell count more than 350 cells/microl enrolled in SMART and 4111 with a CD4 cell count 300 cells/microl or more enrolled in ESPRIT, were analyzed. METHODS: Cumulative mortality 6 months after AIDS and SNA events (cardiovascular, renal, hepatic disease, and malignancies) was estimated using the Kaplan-Meier method. Cox models were used to estimate hazard ratios associated with AIDS and SNA events on the risk of death overall and by treatment group within study. RESULTS: AIDS and SNA events occurred in 286 and 435 participants with 47 (16%) and 115 (26%) subsequent deaths, respectively. Six-month cumulative mortality was 4.7% [95% confidence interval (CI) 2.8-8.0] after experiencing an AIDS event and 13.4% (95% CI 10.5-17.0) after experiencing an SNA event. The adjusted hazard ratio for all-cause mortality for those who experienced AIDS versus those who did not was 4.9 (95% CI 3.6-6.8). The corresponding hazard ratio for SNA was 11.4 (95% CI 9.0-14.5) (P < 0.001 for difference in hazard ratios). Findings were similar for both treatment groups in SMART and both treatment groups in ESPRIT. CONCLUSION: Among HIV-infected persons with higher CD4 cell counts, SNA events occur more frequently and are associated with a greater risk of death than AIDS events. Future research should be aimed at comparing strategies to reduce morbidity and mortality associated with SNA events for HIV-infected persons.

Lang TA, White NJ, Tran HT, Farrar JJ, Day NP, Fitzpatrick R, Angus BJ, Denis E, Merson L, Cheah PY et al. 2010. Clinical research in resource-limited settings: enhancing research capacity and working together to make trials less complicated. PLoS Negl Trop Dis, 4 (6), pp. e619. | Read more

Gupta RK, Angus BJ. 2009. Human Immunodeficiency Virus pp. 177-205. | Read more

Byren I, Bejon P, Atkins BL, Angus B, Masters S, McLardy-Smith P, Gundle R, Berendt A. 2009. One hundred and twelve infected arthroplasties treated with 'DAIR' (debridement, antibiotics and implant retention): antibiotic duration and outcome. J Antimicrob Chemother, 63 (6), pp. 1264-1271. | Show Abstract | Read more

OBJECTIVES: We describe treatment failure rates by antibiotic duration for prosthetic joint infection (PJI) managed with debridement, antibiotics and implant retention (DAIR). METHODS: We retrospectively collected data from all the cases of PJI that were managed with DAIR over a 5 year period. Surgical debridement, microbiological sampling, early intravenous antibiotics and prolonged oral follow-on antibiotics were used. RESULTS: One hundred and twelve cases of PJI were identified. Twenty infections (18%) recurred during a mean follow-up of 2.3 years. The mean duration of antibiotic use was 1.5 years. Failure was more common after arthroscopic debridement, for previously revised joints and for Staphylococcus aureus infection. There were 12 failures after stopping antibiotics and 8 while on antibiotics [hazard ratio (HR) = 4.3, 95% confidence interval (CI) 1.4-12.8, P = 0.01]. However, during the first 3 months of follow-up, there were eight failures after stopping antibiotics and two while on antibiotics (HR = 7.0, 95% CI 1.5-33, P = 0.015). The duration of antibiotic therapy prior to stopping did not predict outcome. CONCLUSIONS: PJI may be managed by DAIR. The risk of failure with this strategy rises after stopping oral antibiotics, but lengthening antibiotic therapy may simply postpone, rather than prevent, failure.

Mocroft A, Wyatt C, Szczech L, Neuhaus J, El-Sadr W, Tracy R, Kuller L, Shlipak M, Angus B, Klinker H et al. 2009. Interruption of antiretroviral therapy is associated with increased plasma cystatin C. AIDS, 23 (1), pp. 71-82. | Show Abstract | Read more

BACKGROUND: Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4 cell count (drug conservation) had altered cystatin C levels compared with those randomized to continuous antiretroviral therapy (viral suppression) in the Strategies for Management of Antiretroviral Therapy trial, and to identify factors associated with increased cystatin C. METHODS: Cystatin C was measured in plasma collected at randomization, 1, 2, 4, 8 and 12 months after randomization in a random sample of 249 and 250 participants in the drug conservation and viral suppression groups, respectively. Logistic regression was used to model the odds of at least 0.15 mg/dl increase in cystatin C (1 SD) in the first month after randomization, adjusting for demographic and clinical characteristics. RESULTS: At randomization, mean (SD) cystatin C level was 0.99 (0.26 mg/dl) and 1.01 (0.28 mg/dl) in the drug conservation and viral suppression arms, respectively (P = 0.29). In the first month after randomization, 21.8 and 10.6% had at least 0.15 mg/dl increase in cystatin C in the drug conservation and viral suppression arms, respectively (P = 0.0008). The difference in cystatin C between the treatment arms was maintained through 1 year after randomization. After adjustment, participants in the viral suppression arm had significantly reduced odds of at least 0.15 mg/dl increase in cystatin C in the first month (odds ratio 0.42; 95% confidence interval 0.23-0.74, P = 0.0023). CONCLUSION: These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function.

Jones ME, Walker E, Chiodini PL, Angus B, Boyne L, Grieve A. 2009. Travel medicine has come of age and a new examination marks the 21st birthday. Travel Med Infect Dis, 7 (4), pp. 179-180. | Read more

Angus B, Lampe F, Tambussi G, Duvivier C, Katlama C, Youle M, Williams I, Clotet B, Fisher M, Post FA et al. 2008. TILT: a randomized controlled trial of interruption of antiretroviral therapy with or without interleukin-2 in HIV-1 infected individuals. AIDS, 22 (6), pp. 737-740. | Show Abstract | Read more

OBJECTIVE: We aimed to see if structured treatment interruption (STI) could be supported safely with the use of two cycles of IL-2 (4.5 MIU q12h subcutaneously 5 days) before STI to prolong the time before therapy restarted. METHODS: Subjects were randomly allocated to either A - continuous ART; B - continue for 9 weeks, then STI; restart with the same ART when the CD4 count falls below 200 cells; or C - two cycles of IL-2, 8 weeks apart, while still on ART; at week 9 stop ART and use a new cycle of IL-2 alone whenever the CD4 count falls < 300 cells. Patients were followed until week 105. RESULTS: 86 mostly white middle aged homosexual men with a baseline median CD4 count of 754 cells/ml (range 240-1400) and a nadir CD4 count of 268 cells/ml (range 62-822) enrolled. By 96 weeks there was a 66% probability of having restarted ART in arm B compared with 34% in arm C (p = 0.002; log rank test). New drugs were used in 60% in arm A, 57% in arm B and 45% in arm C. 4 subjects had a dose modification in the first cycle due to toxicity with 2 interrupting. There were 39 SAEs with 21 in arm C. There were no deaths. CONCLUSIONS: The primary aim of the trial was to gain experience in using IL-2. IL-2 delayed restarting drugs and fewer new drugs were used.

Brent AJ, Angus BJ. 2008. Not all that is malaria is falciparum. Lancet Infect Dis, 8 (3), pp. 208. | Read more

Brent AJ, Angus B. 2008. Not all that is malaria is falciparum LANCET INFECTIOUS DISEASES, 8 (3), pp. 208-208. | Read more

Angus B, ESPRIT, STALWART, SILCAAT trial steering committees. 2006. Interleukin 2 treatment in HIV-1 infection. Lancet, 367 (9516), pp. 1054-1055. | Read more

Newton PN, Ward S, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. 2006. Early treatment failure in severe malaria resulting from abnormally low plasma quinine concentrations. Trans R Soc Trop Med Hyg, 100 (2), pp. 184-186. | Show Abstract | Read more

A patient admitted with severe Plasmodium falciparum malaria in western Thailand had an early treatment failure with quinine, despite full dosing. Plasma quinine concentrations were subtherapeutic. Abnormal quinine pharmacokinetics may explain sporadic reports of quinine treatment failures in severe malaria.

Lo S, Noble J, Bowler I, Angus B. 2004. Dysuria and a headache. Lancet, 364 (9444), pp. 1554. | Read more

Lo S, Noble J, Bowler I, Angus B. 2004. Dysuria and a headache LANCET, 364 (9444), pp. 1554-1554. | Read more

Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. 2003. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis, 37 (1), pp. 7-16. | Show Abstract | Read more

A randomized, open-label comparison of artesunate and quinine was conducted in 113 adults with clinically severe falciparum malaria in western Thailand. Mortality was 12% with artesunate and 22% with quinine treatment (relative risk, 0.53; 95% confidence interval, 0.23-1.26; P=.22). Multiple logistic regression analysis found admission plasma lactate level, Glasgow Coma Scale score, and total serum bilirubin level to be independent risk factors for death. Coma recovery and times to normalize plasma lactate levels were similar, but the parasite clearance time was much shorter among artesunate-treated patients (P=.019). Fewer patients became hypoglycemic during artesunate therapy (10%) than during quinine therapy (28%) (P=.03). Artesunate is at least as effective as quinine in the treatment of adults with severe malaria. Larger trials are required to determine whether mortality is reduced among patients treated with artesunate.

Angus B. 2002. Topics in international health: Malaria CD-Rom TROPICAL DOCTOR, 32 (2), pp. 126-126.

Angus BJ, Thaiaporn I, Chanthapadith K, Suputtamongkol Y, White NJ. 2002. Oral artesunate dose-response relationship in acute falciparum malaria. Antimicrob Agents Chemother, 46 (3), pp. 778-782. | Show Abstract | Read more

The combination of an oral artemisinin derivative (usually artesunate) and mefloquine has become standard treatment for multidrug-resistant falciparum malaria in several parts of Southeast Asia. The doses of artesunate used in monotherapy and combination treatment have largely been derived empirically. In order to characterize the in vivo dose-response relationship for artesunate and thus rationalize dosing, 47 adult patients with acute uncomplicated falciparum malaria and parasitemia > or = 1% were randomized to receive a single oral dose of artesunate varying between 0 and 250 mg together with a curative dose of oral mefloquine. Acceleration of parasite clearance was used as the pharmacodynamic variable. An inhibitory sigmoidal maximum effect (Emax) pharmacodynamic model typical of a dose-response curve was fitted to the relationship between dose and shortening of parasite clearance time (PCT). The Emax was estimated as 28.6 oral h, and the 50% effective concentration was 1.6 mg/kg of body weight. These results imply that there is no reduction in PCTs with the use of single doses of artesunate higher than 2 mg/kg, and this therefore reflects the average lower limit of the maximally effective dose.

Suputtamongkol Y, Newton PN, Angus B, Teja-Isavadharm P, Keeratithakul D, Rasameesoraj M, Pukrittayakamee S, White NJ. 2001. A comparison of oral artesunate and artemether antimalarial bioactivities in acute falciparum malaria. Br J Clin Pharmacol, 52 (6), pp. 655-661. | Show Abstract | Read more

AIMS: Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives. METHODS: The pharmacokinetic properties of oral artesunate and artemether (4 mg kg(-1)) were compared in a randomized cross-over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay. RESULTS: Despite a 29% lower molar dose, oral artesunate administration resulted in significantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether (P <or= 0.02). The mean (95% CI) oral antimalarial bioavailability of artemether, relative to oral artesunate, corrected for molar dose was 58 (40-76)%. The mean (95% CI) relative antimalarial bioavailability of artemether was lower on the first day of treatment, 31 (17-100)%, compared to the second day, 72 (44-118)% (P = 0.018). In vivo parasite clearance and time above the in vitro IC90 were similar for the two drugs, despite considerable differences in Cmax and AUC. CONCLUSIONS: The oral antimalarial bioavailability following artemether was significantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.

Angus BJ, Yates M, Conlon C, Byren I. 2001. Cutaneous tuberculosis of the penis and sexual transmission of tuberculosis confirmed by molecular typing. Clin Infect Dis, 33 (11), pp. E132-E134. | Show Abstract | Read more

A case of culture-positive primary cutaneous Mycobacterium tuberculosis infection of the penis was diagnosed in a male patient; 1 year later, endometrial tuberculosis was diagnosed in the patient's wife. These organisms were confirmed to be indistinguishable by use of molecular techniques.

Angus BJ. 2001. Malaria on the World Wide Web. Clin Infect Dis, 33 (5), pp. 651-661. | Show Abstract | Read more

The Internet is enabling scientists and clinicians in areas with endemic malaria to transfer information to scientists and clinicians in other countries. This should allow changes in therapy to follow the rapid changes in the disease that have posed such difficulties in the past. This article reviews Internet resources that focus on malaria. This includes 90 Web sites in 12 sections. Authoritative multinational organizational sites and regional sites, such as those in Africa, Asia (including Thailand and India), and South America (in Venezuela and Brazil), are described. Basic research-oriented databases, such as those that deal with plasmodia genomics, biochemistry, and vaccine development, as well as vector information and geographic satellite information systems, are reviewed. There is a section about malaria research-funding organizations that offer online applications. Useful teaching resources and journals, including those with full online access, are detailed.

Paton NI, Angus B, Chaowagul W, Simpson AJ, Suputtamongkol Y, Elia M, Calder G, Milne E, White NJ, Griffin GE. 2001. Protein and energy metabolism in chronic bacterial infection: studies in melioidosis. Clin Sci (Lond), 100 (1), pp. 101-110. | Show Abstract | Read more

Chronic infection is often accompanied by a wasting process, the metabolic basis of which is not fully understood. The aims of the present study were to measure protein and energy metabolism in patients with melioidosis (a serious and antibiotic-refractory Gram-negative bacterial infection which is endemic in South-East Asia) in order to define the metabolic abnormalities that might contribute to wasting. Whole-body protein turnover was measured using the [(13)C]leucine technique, both in the fasted state and while consuming a high-energy meal. Resting energy expenditure was measured by indirect calorimetry, and total energy expenditure by the bicarbonate/urea method. Results were normalized for fat-free mass, as estimated from skinfold thickness. Protein turnover was increased in melioidosis patients compared with healthy controls during fasting (170.9 compared with 124.1 micromol x kg(-1) x h(-1); P=0.04), but the net rate of catabolism (22.2 compared with 20.5 micromol x kg(-1) x h(-1); P=0.77) and the anabolic response to feeding were similar in the two groups. Resting energy expenditure was higher in melioidosis patients compared with controls (191.4 and 157.3 kJ x kg(-1) x day(-1) respectively; P=0.04), but total energy expenditure (measured in a separate group of eight patients with melioidosis) was low (192.1 kJ x kg(-1) x day(-1)). In conclusion, this study found no evidence of metabolic causative factors, such as accelerated net protein catabolism during fasting, a blunted anabolic response to feeding or increased daily energy expenditure, and therefore suggests that reduced energy intake is the prime cause of wasting. The observed normal response to feeding should encourage nutritional approaches to prevent wasting.

Angus BJ, Smith MD, Suputtamongkol Y, Mattic H, Walsh AL, Wuthiekanun V, Chaowagul W, White NJ. 2000. Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis (vol 49, pg 445, 2000) BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 50 (2), pp. 183-191.

Angus BJ, Smith MD, Suputtamongkol Y, Mattie H, Walsh AL, Wuthiekanun V, Chaowagul W, White NJ. 2000. Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis. Br J Clin Pharmacol, 49 (5), pp. 445-452. | Show Abstract | Read more

AIMS: Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta-lactam antibiotics for serious Gram-negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality of 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis. METHODS: Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg-1 8 hourly by bolus injection or 4 mg kg-1 h-1 by constant infusion following a 12 mg kg-1 priming dose to perform estimation of pharmacokinetic and pharmacodynamic parameters. RESULTS: Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l-1, giving a target concentration CT, of 8 mg l-1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half-lives of ceftazidime were 0.468 (0.241-0.573) l kg-1, 0.058 (0.005-0.159) l kg-1 h-1 and 7.74 (1.95-44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0. 71; P < 0.001) and there was no evidence of significant nonrenal clearance. CONCLUSIONS: Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure which is common in these patients is Clearance = k * creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg-1 (1. 9-4.6) and infusion rate I = 0.46 mg kg h-1 (0.04-1.3) (which equals 14.8 mg kg-1 day-1). A nomogram for adjustment in renal failure is given.

Agbenyega T, Angus BJ, Bedu-Addo G, Baffoe-Bonnie B, Guyton T, Stacpoole PW, Krishna S. 2000. Glucose and lactate kinetics in children with severe malaria. J Clin Endocrinol Metab, 85 (4), pp. 1569-1576. | Show Abstract | Read more

Children with severe malaria often present with lactic acidosis and hypoglycemia. Although both complications independently predict mortality, mechanisms underlying their development are poorly understood. To study these metabolic derangements we sequentially allocated 21 children with falciparum malaria and capillary lactate concentrations of 5 mmol/L or more to receive either quinine or artesunate as antimalarial therapy, and dichloroacetate or saline placebo for lactic acidosis. We then administered a primed infusion (90 min) of L-[3-13C1]sodium lactate and D-[6,6-D2]glucose to determine the kinetics of these substrates. The mean (SD) glucose disposal rate in all patients was 56 (16) micromol/kg x min, and the geometric mean (range) lactate disposal rate was 100 (66-177) micromol/kg x min. Glucose and lactate disposal rates were positively correlated (r = 0.62; P = 0.005). Artesunate was associated with faster parasite clearance, lower insulin/glucose ratios, and higher glucose disposal rates than quinine. Lactate disposal was positively correlated with plasma lactate concentrations (r = 0.66; P = 0.002) and time to recovery from coma (r = 0.82; P < 0.001; n = 15). Basal lactate disposal rates increased with dichloroacetate treatment. Elevated glucose turnover in severe malaria mainly results from enhanced anaerobic glycolysis. Quinine differs from artesunate in its effects on glucose kinetics. Increased lactate production is the most important determinant of lactic acidosis.

Suputtamongkol Y, Intaranongpai S, Smith MD, Angus B, Chaowagul W, Permpikul C, Simpson JA, Leelarasamee A, Curtis L, White NJ. 2000. A double-blind placebo-controlled study of an infusion of lexipafant (Platelet-activating factor receptor antagonist) in patients with severe sepsis. Antimicrob Agents Chemother, 44 (3), pp. 693-696. | Show Abstract | Read more

Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock. A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures). Detailed serial clinical, biochemical, and cytokine measurements were performed. Lexipafant treatment was well tolerated. The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%). There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels. PAF may not have an important role in the pathogenesis of severe sepsis.

Van Vugt M, Angus BJ, Price RN, Mann C, Simpson JA, Poletto C, Htoo SE, Looareesuwan S, White NJ, Nosten F. 2000. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg, 62 (1), pp. 65-69. | Show Abstract | Read more

The artemisinin derivatives are now used widely in areas with multidrug-resistant Plasmodium falciparum malaria such as Southeast Asia, but concerns remain over their potential for neurotoxicity. Mice, rats, dogs, and monkeys treated with high doses of intramuscular artemether or arteether develop an unusual pattern of focal damage to brain stem nuclei (particularly those involved in auditory processing). To investigate whether a similar toxic effect occurs in patients treated with these compounds, clinical neurologic evaluation, audiometry and early latency auditory evoked responses were measured in a single-blind comparison of 79 patients who had been treated with > or =2 courses of oral artemether or artesunate within the previous 3 years, and 79 age- and sex-matched controls living in a malaria-endemic area on the northwestern border of Thailand. There were no consistent differences in any of these test results between the cases and controls. This study failed to detect any evidence of significant neurotoxicity in patients treated previously with oral artemether or artesunate for acute malaria.

Chaowagul W, Simpson AJ, Suputtamongkol Y, Smith MD, Angus BJ, White NJ. 1999. A comparison of chloramphenicol, trimethoprim-sulfamethoxazole, and doxycycline with doxycycline alone as maintenance therapy for melioidosis. Clin Infect Dis, 29 (2), pp. 375-380. | Show Abstract | Read more

A prospective, open, randomized, comparative treatment trial was conducted to compare the therapeutic efficacy of the conventional four-drug combination (chloramphenicol, trimethoprim-sulfamethoxazole, and doxycycline) with that of doxycycline alone in oral maintenance treatment of melioidosis. Adult Thai patients with culture-confirmed melioidosis were randomized to receive treatment with either regimen for a minimum of 12 weeks, usually following intravenous treatment of severe disease. The main outcome measure was culture-confirmed relapse. One hundred sixteen patients were enrolled; 109 had culture-confirmed melioidosis, and 87 were considered evaluable (43 had received doxycycline). Culture-confirmed relapse occurred in one patient randomized to the conventional regimen and in 11 (25.6%) randomized to the doxycycline regimen (P = .009), and treatment failed for 8 (18.2%) versus 20 (46.5%), respectively (P = .009). Adverse effects occurred in 26% of patients overall. Doxycycline alone cannot be recommended for a first-line regimen of oral maintenance treatment of melioidosis.

Simpson AJ, Suputtamongkol Y, Smith MD, Angus BJ, Rajanuwong A, Wuthiekanun V, Howe PA, Walsh AL, Chaowagul W, White NJ. 1999. Comparison of imipenem and ceftazidime as therapy for severe melioidosis. Clin Infect Dis, 29 (2), pp. 381-387. | Show Abstract | Read more

An open, prospective, randomized, comparative treatment trial was conducted to compare the therapeutic efficacy of high-dose intravenous imipenem and ceftazidime for acute severe melioidosis. Adult Thai patients with suspected acute, severe melioidosis were randomized to receive either imipenem, at a dosage of 50 mg/(kg x d), or ceftazidime, at a dosage of 120 mg/(kg x d), for a minimum of 10 days. The main outcome measures were death or treatment failure. Of the 296 patients enrolled, 214 had culture-confirmed melioidosis, and 132 (61.7%) of them had positive blood cultures. Mortality among patients with melioidosis was 36.9% overall. There were no differences in survival overall (P = .96) or after 48 hours (P = .3). Treatment failure after 48 hours was more common among patients treated with ceftazidime (P = .011). Both treatments were well tolerated. Imipenem is a safe and effective treatment for acute severe melioidosis and may be considered an alternative to ceftazidime.

Dondorp AM, Angus BJ, Chotivanich K, Silamut K, Ruangveerayuth R, Hardeman MR, Kager PA, Vreeken J, White NJ. 1999. Red blood cell deformability as a predictor of anemia in severe falciparum malaria. Am J Trop Med Hyg, 60 (5), pp. 733-737. | Show Abstract | Read more

Decreased erythropoiesis and increased clearance of both parasitized and noninfected erythrocytes both contribute to the pathogenesis of anemia in falciparum malaria. Erythrocytes with reduced deformability are more likely to be cleared from the circulation by the spleen, a process that is augmented in acute malaria. Using a laser diffraction technique, we measured red blood cell (RBC) deformability over a range of shear stresses and related this to the severity of anemia in 36 adults with severe falciparum malaria. The RBC deformability at a high shear stress of 30 Pa, similar to that encountered in the splenic sinusoids, showed a significant positive correlation with the nadir in hemoglobin concentration during hospitalization (r = 0.49, P < 0.002). Exclusion of five patients with microcytic anemia strengthened this relationship (r = 0.64, P < 0.001). Reduction in RBC deformability resulted mainly from changes in unparasitized erythrocytes. Reduced deformability of uninfected erythrocytes at high shear stresses and subsequent splenic removal of these cells may be an important contributor to the anemia of severe malaria.

Desakorn V, Smith MD, Walsh AL, Simpson AJ, Sahassananda D, Rajanuwong A, Wuthiekanun V, Howe P, Angus BJ, Suntharasamai P, White NJ. 1999. Diagnosis of Penicillium marneffei infection by quantitation of urinary antigen by using an enzyme immunoassay. J Clin Microbiol, 37 (1), pp. 117-121. | Show Abstract

Penicillium marneffei is a major cause of opportunistic infection in patients with AIDS in north and northeastern Thailand. A method for the quantitation of P. marneffei antigen in urine was developed by using fluorescein isothiocyanate-labelled purified rabbit hyperimmune immunoglobulin G in an enzyme-linked immunosorbent assay. This method was evaluated with 33 patients with culture-proven penicilliosis and 300 controls (52 healthy subjects, 248 hospitalized patients without penicilliosis) from the same area in which penicilliosis is endemic. Urinary antigen was found in all 33 (100%) patients with penicilliosis, with a median titer of 1:20,480. With undiluted samples, 67 (27%) of 248 hospital patients and 3 (6%) of 52 healthy controls were reactive. At a cutoff titer of 1:40, the urine antigen detection assay had a diagnostic sensitivity of 97% and specificity of 98% (positive predictive value, 84%; negative predictive value, 99.7%). This test offers a valuable and rapid method for the diagnosis of penicilliosis in patients with AIDS and could be a useful addition to conventional diagnostic methods in areas in which penicilliosis is endemic.

Wuthiekanun V, Howe PA, Simpson AJ, Smith MD, Walsh AL, Angus BJ, Rajchanuwong A, White NJ. 1999. Antifungal susceptibilities of Cryptococcus neoformans in north-east Thailand. Trans R Soc Trop Med Hyg, 93 (1), pp. 96-97. | Read more

Nontprasert A, Nosten-Bertrand M, Pukrittayakamee S, Vanijanonta S, Angus BJ, White NJ. 1998. Assessment of the neurotoxicity of parenteral artemisinin derivatives in mice. Am J Trop Med Hyg, 59 (4), pp. 519-522. | Show Abstract | Read more

In all experimental mammals tested (rats, dogs, primates), intramuscular injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stem centers predominantly involved in auditory processing and vestibular reflexes. Artesunate, the most widely used of these compounds, is a water soluble hemisuccinate derivative given parenterally either by intravenous or intramuscular injection. The neurotoxic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-day regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detected with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. These were reversible in all but one (artemether) mouse. At 100 mg/kg/day, eight of 36 artemether recipients, two of 36 artesunate recipients, and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnormalities of balance and equilibrium, whereas only four artesunate recipients (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence interval) for death or disability was 5.3 (2.6-11.2) for artemether recipients. Intramuscular artemether is significantly more neurotoxic than intramuscular artesunate in this murine model.

Dondorp AM, Planche T, de Bel EE, Angus BJ, Chotivanich KT, Silamut K, Romijn JA, Ruangveerayuth R, Hoek FJ, Kager PA et al. 1998. Nitric oxides in plasma, urine, and cerebrospinal fluid in patients with severe falciparum malaria. Am J Trop Med Hyg, 59 (3), pp. 497-502. | Show Abstract | Read more

It has been suggested that nitric oxide (NO) plays an important role in the pathogenesis of severe falciparum malaria. Since NO has a very short half-life, nitrate and nitrite (NOx) levels, stable metabolites of NO, are used as measures of NO production. We measured plasma NOx levels in 24 adults with severe falciparum malaria on the Thai-Burmese border. After correction for renal function, there was no correlation between plasma NOx levels, or the total amount of NOx excreted in the urine, and disease severity. Plasma NOx levels decreased after the first 48 hr in all patients (P = 0.007), suggesting decreased NO production. The NOx levels in cerebrospinal fluid (CSF) correlated well with plasma NOx levels, but these did not show a correlation with coma depth, and were not significantly different from those in a healthy control group. These findings do not support the hypothesis that excessive NO production contributes to the pathogenesis of severe falciparum malaria. However, local changes in NO production, e.g., in the central nervous system, might not be reflected in the total NOx production or NOx levels in the CSF.

Chotivanich KT, Udomsangpetch R, Pipitaporn B, Angus B, Suputtamongkol Y, Pukrittayakamee S, White NJ. 1998. Rosetting characteristics of uninfected erythrocytes from healthy individuals and malaria patients. Ann Trop Med Parasitol, 92 (1), pp. 45-56. | Show Abstract | Read more

Rosetting, defined as the binding of two or more uninfected red blood cells (rbc) to an infected rbc, occurs when malarial parasites mature, to trophozoites and schizonts, in the second half of their asexual development. Rosetting is believed to be an important factor in the development of cerebral malaria. In a series of studies to examine the characteristics of the uninfected rbc which contribute to rosetting, the ability of rbc from healthy donors to form rosettes was found to be greater in the cells of group A and B than in those of group O (P = 0.05), and to decrease during storage under blood-blank conditions. Normal rbc exposed for > or = 30 min to quinine, artesunate or artemether (each at 0.25 microgram/ml) in vitro showed significantly decreased rosetting. This effect could not be reversed by extensive washing followed by cultivation for another 24 h in drug-free medium. Mefloquine and pyrimethamine had no effect. Uninfected rbc from patients with uncomplicated or severe falciparum malaria exhibited a lower rosetting ability than rbc from healthy donors (P = 0.01). The rosetting of uninfected rbc of all blood groups from patients with uncomplicated malaria decreased significantly within 2 h of the patients starting treatment with qinghaosu derivatives (artesunate or artemether) and within 8 h of them starting quinine treatment. Similar effects were observed with uninfected rbc from patients with severe malaria after treatment with artesunate but not after quinine. The mechanisms underlying this potentially beneficial effect on rbc adherence are not known.

Dondorp AM, Angus BJ, Hardeman MR, Chotivanich KT, Silamut K, Ruangveerayuth R, Kager PA, White NJ, Vreeken J. 1997. Prognostic significance of reduced red blood cell deformability in severe falciparum malaria. Am J Trop Med Hyg, 57 (5), pp. 507-511. | Show Abstract | Read more

Severe falciparum malaria is associated with microvascular obstruction resulting from sequestration of erythrocytes containing mature stages of the parasite. Since reduced red blood cell deformability (RBC-D) can contribute to impaired microcirculatory flow, RBC-D was measured in 23 patients with severe falciparum malaria (seven of whom subsequently died), 30 patients with uncomplicated malaria, and 17 healthy controls. The RBC-D, measured by ektacytometry, was significantly reduced in severe malaria and was particularly low in all fatal cases. At a low shear stress of 1.7 Pascal (Pa), a red blood cell elongation index less than 0.21 on admission to the hospital predicted fatal outcome with a sensitivity of 100% (confidence interval [CI] = 59-100%) and a specificity of 88% (CI = 61-98%). The reduction in the RBC-D appeared to result mainly from changes in unparasitized erythrocytes. Reduced deformability of unparasitized red blood cells in severe malaria may contribute to impaired microcirculatory flow and a fatal outcome in severe falciparum malaria.

Smith MD, Angus BJ, Wuthiekanun V, White NJ. 1997. Arabinose assimilation defines a nonvirulent biotype of Burkholderia pseudomallei. Infect Immun, 65 (10), pp. 4319-4321. | Show Abstract

Two distinct types of Burkholderia pseudomallei, differentiated by the ability to assimilate L-arabinose but with similar morphologies and antigenicities, can be isolated from soil in Thailand. Approximately 25% of soil isolates from northeast Thailand were arabinose assimilators (Ara+), but in 1,200 sequentially studied patients, only arabinose "nonassimilators" (Ara-) caused melioidosis (P < 0.0001). In a murine model, there was a striking difference in virulence between Ara- and Ara+ B. pseudomallei. The mean (standard deviation) 50% lethal dose (LD[50]) inoculum for Ara- isolates was 182 (111) CFU/mouse compared with approximately 10(9) CFU/mouse for Ara+ soil isolates. There was no significant difference between the LD(50)s for clinical and soil Ara- isolates. All attempts to convert the biochemical phenotype by selective culture failed, which suggests that the biotype is stable.

Angus BJ, Chotivanich K, Udomsangpetch R, White NJ. 1997. In vivo removal of malaria parasites from red blood cells without their destruction in acute falciparum malaria. Blood, 90 (5), pp. 2037-2040. | Show Abstract

During acute falciparum malaria infection, red blood cells (RBC) containing abundant ring-infected erythrocyte surface antigen (Pf 155 or RESA), but no intracellular parasites, are present in the circulation. These RESA-positive parasite negative RBC are not seen in parasite cultures in vitro. This indicates that in acute falciparum malaria there is active removal of intraerythrocytic parasites by a host mechanism in vivo (probably the spleen) without destruction of the parasitized RBC. This may explain the observed disparity between the drop in hematocrit and decrease in parasite count in some hyperparasitemic patients. The fate of these "once-parasitized" RBC in vivo is not known.

Desakorn V, Silamut K, Angus B, Sahassananda D, Chotivanich K, Suntharasamai P, Simpson J, White NJ. 1997. Semi-quantitative measurement of Plasmodium falciparum antigen PfHRP2 in blood and plasma. Trans R Soc Trop Med Hyg, 91 (4), pp. 479-483. | Show Abstract | Read more

Plasmodium falciparum histidine rich protein 2 (PfHRP2) antigen was measured semi-quantitatively in whole blood, plasma, and supernatants and red blood cells of cultures in vitro using the dipstick ParaSight-F test and also by a quantitative antigen-capture enzyme-linked immunosorbent assay (ELISA). In vitro, PfHRP2 was secreted mainly during the second half of the asexual cycle with a marked rise during schizont development and rupture. The total PfHRP2 secreted before schizogony corresponded to approximately 4% of that contained in the red blood cells. In samples from 55 patients with acute falciparum malaria, the level of detection by ELISA corresponded to parasitaemias of 100/microL for whole blood and 1600/microL for separated plasma. Whole blood PfHRP2 levels were correlated significantly with admission parasitaemia (r = 0.76, P < 0.0001) and the stage of parasite development (r = 0.43, P < 0.01). Although whole blood PfHRP2 concentrations were higher in severe malaria, plasma concentrations of PfHRP2 were considerably higher in severe malaria (median titre 1:320, range zero to 1:1280) than in uncomplicated malaria (median titre 1:5, range zero to 1:80; P < 0.0001). The ratio of whole blood to plasma PfHRP2 was lower in severe than in uncomplicated malaria (median 4, range 0.25 to 256, versus 64, range 4 to 1280; P < 0.0001). With plasma samples the intensity of colour change on the dipstick correlated well with more precise measurement of optical density in the ELISA (r = 0.88, P < 0.0001). These results suggest that measurement of PfHRP2 in plasma could provide an alternative approach to the assessment of the parasite biomass, and thus prognosis, in severe malaria, and that this could be done simply by using the currently available dipsticks.

Agbenyega T, Angus B, Bedu-Addo G, Baffoe-Bonnie B, Griffin G, Vallance P, Krishna S. 1997. Plasma nitrogen oxides and blood lactate concentrations in Ghanaian children with malaria. Trans R Soc Trop Med Hyg, 91 (3), pp. 298-302. | Show Abstract | Read more

Nitric oxide is an important host defence molecule as well as being a mediator in many pathophysiological processes. To investigate its role in severe malaria, we measured plasma nitrate and nitrite concentrations in 70 children with malaria (54 with severe malaria) and 48 control subjects (33 with medical conditions and 15 surgical patients). We related these measurements to plasma lactate concentrations, an established marker of disease severity in malaria. Plasma lactate levels were significantly elevated in patients with deep coma (P = 0.0007) and those with a fatal outcome, but mean nitrogen oxide concentrations were not significantly different in the 2 outcome categories and were not related to depth of coma (P > 0.5). In patients whose cerebrospinal fluid (CSF) was examined, lactate concentrations were elevated in fatal cases (geometric mean 8.2 mmol/L, n = 5) compared with survivors (3.4 mmol/L, n = 13; P = 0.032); corresponding CSF nitrogen oxide concentrations were 10.7 microM in fatal cases compared with 12.5 microM in survivors (P = 0.5). Plasma nitrogen oxide concentrations were negatively correlated with admission parasitaemia (r = -0.41, n = 70; P < 0.0001). In our population, elevations of plasma lactate, but not nitrite or nitrate, reflected disease severity in malaria.

Angus BJ, Thanikkul K, Silamut K, White NJ, Udomsangpetch R. 1996. Short report: Rosette formation in Plasmodium ovale infection. Am J Trop Med Hyg, 55 (5), pp. 560-561. | Show Abstract | Read more

Red blood cells infected by mature stages of Plasmodium ovale obtained from a 56-year-old Thai patient formed rosettes readily with uninfected erythrocytes. Ex vivo, the ring stage-infected erythrocytes matured well under the in vitro conditions used for P. falciparum culture, and the infected erythrocytes formed rosettes when the parasites became mature trophozoites. These rosettes were stable and remained intact until completion of schizogony. Plasmodium ovale rosettes were similar to those formed by P. falciparum- and P. vivax-infected erythrocytes. Rosette formation appears to be a common property of three species of human plasmodia.

Udomsangpetch R, Pipitaporn B, Krishna S, Angus B, Pukrittayakamee S, Bates I, Suputtamongkol Y, Kyle DE, White NJ. 1996. Antimalarial drugs reduce cytoadherence and rosetting Plasmodium falciparum. J Infect Dis, 173 (3), pp. 691-698. | Show Abstract | Read more

The in vivo and in vitro effects of antimalarials on cytoadherence and rosette formation were studied in 17 patients with severe and 46 with uncomplicated falciparum malaria. Cytoadherence was increased in severe malaria (P<.001). Artesunate and artemether were more potent than quinine in inhibiting both adherence properties. Artesunate was the most rapidly acting drug tested, producing >50% inhibition of both cytoadherence and rosetting in vivo and in vitro within 2 hr of drug exposure. Exposure to quinine for > or = to 4 h in vivo reduced rosetting by >50%, but not cytoadherence. Quinine did not reduce cytoadherence or rosetting significantly in vitro with exposure times of < or = to 8 h. These results suggest that artemisinin derivatives are more effective than quinine in preventing pathologic processes in parasitized erythrocytes that contribute to microvascular obstruction in severe malaria.

Viravan C, Dance DA, Ariyarit C, Looareesuwan S, Wattanagoon Y, Davis TM, Wuthiekanun V, Tantivanich S, Angus BJ, White NJ. 1996. A prospective clinical and bacteriologic study of inguinal buboes in Thai men. Clin Infect Dis, 22 (2), pp. 233-239. | Show Abstract | Read more

One-hundred thirteen men (mean age, 23 years) who presented with inguinal buboes to a government-operated hospital for sexually transmitted diseases (STDs) in Bangkok were studied between February 1987 and February 1989. The median duration of preceding symptoms was 7 days (range, 1-62 days). The majority of patients (74; 65%) had received treatment previously; 31 (27%) were febrile, 13 (12%) had extrainguinal lymphadenopathy, and 31 (27%) had concurrent active genital ulcers. There was no history of genital ulceration in 66 (58%) of the patients. Pus was obtained from 51 of the 110 buboes aspirated for culture; 21 (41%) of these cultures yielded Haemophilus ducreyi, and 2 (3.9%) were positive for Chlamydia trachomatis on immunofluorescence microscopy. Saline (1 mL) was injected and reaspirated from the buboes of 35 of the other 59 patients; 3 buboes yielded H. ducreyi and 9 were positive for C. trachomatis. All cultures for other aerobic and anaerobic bacteria and viruses in intact buboes were negative. Syphilis serology was positive in only one case. Patients attending STD clinics in this region who have large, fluctuant, edematous inguinal buboes containing pus should receive presumptive treatment for chancroid. If there is no pus, then the bubo is more likely to be caused by lymphogranuloma venereum.

Walsh AL, Smith MD, Wuthiekanun V, Suputtamongkol Y, Chaowagul W, Dance DA, Angus B, White NJ. 1995. Prognostic significance of quantitative bacteremia in septicemic melioidosis. Clin Infect Dis, 21 (6), pp. 1498-1500. | Show Abstract | Read more

Pour-plate blood cultures were performed for 418 adult patients with suspected septicemic melioidosis in order to determine the relationship between quantitative bacterial counts in blood and mortality. Of 108 patients whose hemocultures yielded Burkholderia pseudomallei, 53% had < 10 cfu/mL and 24% had > 100 cfu/mL. High blood bacterial counts were more common than reported previously with regard to other gram-negative septicemias and were significantly associated with the development of hypotension (P = .008) and a fatal outcome (P = .0001). The overall mortality was 63% (95% CI, 53%-72%); however, counts of < or = 1 cfu/mL were associated with a mortality of 42% (95% CI, 28%-58%), compared with 96% (95% CI, 80%-100%) with counts of > 100 cfu/mL. Heavy bacteremia (> 50 cfu/mL) is common in septicemic melioidosis and is usually fatal.

Silamut K, Hough R, Eggelte T, Pukrittayakamee S, Angus B, White NJ. 1995. A simple method for assessing quinine pre-treatment in acute malaria. Trans R Soc Trop Med Hyg, 89 (6), pp. 665-667. | Show Abstract | Read more

Administration of a loading dose of quinine in severe malaria may be dangerous if therapeutic blood concentrations are already present because of previous treatment. To assess the reliability of the history of pretreatment we conducted a prospective study of 379 adult patients with acute falciparum malaria admitted to a hospital in western Thailand. Admission plasma concentrations of quinine were measured by high performance liquid chromatography (HPLC), and compared with the patients' history of previous quinine treatment. The sensitivity of the history was 59% (95%) confidence interval [CI] 49-69%), the specificity was 79% (95% CI 74-84%), the positive predictive value was 53%, and the negative predictive value 82%. A rapid (10 min semi-quantitative estimate of plasma quinine concentrations, based on simple 'dipstick' method using a quinine-specific monoclonal antibody, proved considerably more sensitive and specific. The correlation between the dipstick estimate and the subsequent HPLC measurement of plasma quinine concentration was 0.85 (n = 404; P < 0.0001). In 404 admission samples, the negative predictive value of the dipstick estimate for plasma quinine concentrations > 1 microgram/mL was 100%. In Thailand the history of previous quinine treatment given by the patients or their relatives was unreliable but the quinine dipstick provided a simple and rapid means of assessment of quinine pre-treatment in acute falciparum malaria.

Krishna S, Agbenyega T, Angus BJ, Bedu-Addo G, Ofori-Amanfo G, Henderson G, Szwandt IS, O'Brien R, Stacpoole PW. 1995. Pharmacokinetics and pharmacodynamics of dichloroacetate in children with lactic acidosis due to severe malaria. QJM, 88 (5), pp. 341-349. | Show Abstract

Lactic acidosis frequently complicates severe malaria in African children, and is a strong independent predictor of mortality. We tested the hypothesis that sodium dichloroacetate (DCA), an activator of pyruvate dehydrogenase, rapidly reduces hyperlactataemia in this patient population. Eighteen children with severe malaria and capillary plasma lactate > or = 5 mM were randomized to receive either intramuscular quinine plus a single 50 mg/kg intravenous infusion of DCA in saline, or quinine plus intravenous saline alone. Two patients in each treatment group died following randomization. Thirty minutes after treatment, the mean plasma lactate was 28% below pretreatment baseline values in the DCA group, but was unchanged in the placebo group. Throughout the first 4 h after treatment, mean plasma lactate in the DCA-treated patients was significantly less than that in controls (p = 0.003). Thereafter, mean plasma lactate declined in both groups and was < 2 mM 10 h after treatment. DCA was well tolerated and did not alter quinine pharmacokinetics. A single intravenous dose of DCA rapidly improved lactic acidosis in African children with severe malaria, suggesting that DCA may be a useful adjunct in the initial treatment of these patients, and may increase their chance of survival by improving a major complication of their illness.

Newton PN, Ward S, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. 2006. Early treatment failure in severe malaria resulting from abnormally low plasma quinine concentrations. Trans R Soc Trop Med Hyg, 100 (2), pp. 184-186. | Show Abstract | Read more

A patient admitted with severe Plasmodium falciparum malaria in western Thailand had an early treatment failure with quinine, despite full dosing. Plasma quinine concentrations were subtherapeutic. Abnormal quinine pharmacokinetics may explain sporadic reports of quinine treatment failures in severe malaria.

Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. 2003. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis, 37 (1), pp. 7-16. | Show Abstract | Read more

A randomized, open-label comparison of artesunate and quinine was conducted in 113 adults with clinically severe falciparum malaria in western Thailand. Mortality was 12% with artesunate and 22% with quinine treatment (relative risk, 0.53; 95% confidence interval, 0.23-1.26; P=.22). Multiple logistic regression analysis found admission plasma lactate level, Glasgow Coma Scale score, and total serum bilirubin level to be independent risk factors for death. Coma recovery and times to normalize plasma lactate levels were similar, but the parasite clearance time was much shorter among artesunate-treated patients (P=.019). Fewer patients became hypoglycemic during artesunate therapy (10%) than during quinine therapy (28%) (P=.03). Artesunate is at least as effective as quinine in the treatment of adults with severe malaria. Larger trials are required to determine whether mortality is reduced among patients treated with artesunate.

Angus BJ, Thaiaporn I, Chanthapadith K, Suputtamongkol Y, White NJ. 2002. Oral artesunate dose-response relationship in acute falciparum malaria. Antimicrob Agents Chemother, 46 (3), pp. 778-782. | Show Abstract | Read more

The combination of an oral artemisinin derivative (usually artesunate) and mefloquine has become standard treatment for multidrug-resistant falciparum malaria in several parts of Southeast Asia. The doses of artesunate used in monotherapy and combination treatment have largely been derived empirically. In order to characterize the in vivo dose-response relationship for artesunate and thus rationalize dosing, 47 adult patients with acute uncomplicated falciparum malaria and parasitemia > or = 1% were randomized to receive a single oral dose of artesunate varying between 0 and 250 mg together with a curative dose of oral mefloquine. Acceleration of parasite clearance was used as the pharmacodynamic variable. An inhibitory sigmoidal maximum effect (Emax) pharmacodynamic model typical of a dose-response curve was fitted to the relationship between dose and shortening of parasite clearance time (PCT). The Emax was estimated as 28.6 oral h, and the 50% effective concentration was 1.6 mg/kg of body weight. These results imply that there is no reduction in PCTs with the use of single doses of artesunate higher than 2 mg/kg, and this therefore reflects the average lower limit of the maximally effective dose.

Angus BJ, Yates M, Conlon C, Byren I. 2001. Cutaneous tuberculosis of the penis and sexual transmission of tuberculosis confirmed by molecular typing. Clin Infect Dis, 33 (11), pp. E132-E134. | Show Abstract | Read more

A case of culture-positive primary cutaneous Mycobacterium tuberculosis infection of the penis was diagnosed in a male patient; 1 year later, endometrial tuberculosis was diagnosed in the patient's wife. These organisms were confirmed to be indistinguishable by use of molecular techniques.

Angus BJ. 2001. Malaria on the World Wide Web. Clin Infect Dis, 33 (5), pp. 651-661. | Show Abstract | Read more

The Internet is enabling scientists and clinicians in areas with endemic malaria to transfer information to scientists and clinicians in other countries. This should allow changes in therapy to follow the rapid changes in the disease that have posed such difficulties in the past. This article reviews Internet resources that focus on malaria. This includes 90 Web sites in 12 sections. Authoritative multinational organizational sites and regional sites, such as those in Africa, Asia (including Thailand and India), and South America (in Venezuela and Brazil), are described. Basic research-oriented databases, such as those that deal with plasmodia genomics, biochemistry, and vaccine development, as well as vector information and geographic satellite information systems, are reviewed. There is a section about malaria research-funding organizations that offer online applications. Useful teaching resources and journals, including those with full online access, are detailed.

Paton NI, Angus B, Chaowagul W, Simpson AJ, Suputtamongkol Y, Elia M, Calder G, Milne E, White NJ, Griffin GE. 2001. Protein and energy metabolism in chronic bacterial infection: studies in melioidosis. Clin Sci (Lond), 100 (1), pp. 101-110. | Show Abstract | Read more

Chronic infection is often accompanied by a wasting process, the metabolic basis of which is not fully understood. The aims of the present study were to measure protein and energy metabolism in patients with melioidosis (a serious and antibiotic-refractory Gram-negative bacterial infection which is endemic in South-East Asia) in order to define the metabolic abnormalities that might contribute to wasting. Whole-body protein turnover was measured using the [(13)C]leucine technique, both in the fasted state and while consuming a high-energy meal. Resting energy expenditure was measured by indirect calorimetry, and total energy expenditure by the bicarbonate/urea method. Results were normalized for fat-free mass, as estimated from skinfold thickness. Protein turnover was increased in melioidosis patients compared with healthy controls during fasting (170.9 compared with 124.1 micromol x kg(-1) x h(-1); P=0.04), but the net rate of catabolism (22.2 compared with 20.5 micromol x kg(-1) x h(-1); P=0.77) and the anabolic response to feeding were similar in the two groups. Resting energy expenditure was higher in melioidosis patients compared with controls (191.4 and 157.3 kJ x kg(-1) x day(-1) respectively; P=0.04), but total energy expenditure (measured in a separate group of eight patients with melioidosis) was low (192.1 kJ x kg(-1) x day(-1)). In conclusion, this study found no evidence of metabolic causative factors, such as accelerated net protein catabolism during fasting, a blunted anabolic response to feeding or increased daily energy expenditure, and therefore suggests that reduced energy intake is the prime cause of wasting. The observed normal response to feeding should encourage nutritional approaches to prevent wasting.

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