JAC Advance Access originally published online on January 25, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):705-713; doi:10.1093/jac/dkm522
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Original research |
What is the risk of mortality following diagnosis of multidrug-resistant HIV-1?
1 Centre of Sexual Health and HIV Research, Department of Primary Care and Population Sciences, Mortimer Market Centre, London, UK 2 HIV and Infectious Diseases Group, Medical Research Council Clinical Trials Unit, London, UK 3 The Mortimer Market Centre, Department of Genitourinary Medicine, Camden PCT, London, UK 4 Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, UK 5 Centre of Virology, Department of Infection, Royal Free and University College Medical School, London, UK 6 Centre for Infections, Health Protection Agency, London, UK
* Correspondence address. HIV/Genitourinary Medicine, St Stephen’s Centre, Chelsea and Westminster Hospital, London SW10 9TH, UK. Tel: +44-20-8846-6148; Fax: +44-20-8846-6198; E-mail: deepa.grover{at}chelwest.nhs.uk
Received 1 October 2007; returned 6 December 2007; revised 26 October 2007; accepted 9 December 2007
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Abstract |
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Objectives: To estimate the risk of death and examine the predictors of death and virological/immunological response, following diagnosis of multidrug-resistant (MDR) HIV-1 in a UK multicentre cohort of HIV-infected individuals.
Methods: Five hundred and seventy-two patients were identified with MDR HIV-1 between 1997 and 2004. Factors associated with survival and virological/immunological response 24–48 weeks after MDR diagnosis were determined by the Poisson and linear regression, respectively.
Results: Patient characteristics: 86% males; median age 39 years; median CD4 and viral load (VL) at MDR diagnosis 230 cells/mm3 and 4.2 log10copies/mL; median number of antiretroviral drugs previously exposed to 8. Sixty patients died over a median follow-up of 31 months (IQR: 17–50), giving an estimated mortality rate of 3.7 deaths per 100 person-years (95% CI 2.9–4.7) following MDR diagnosis. In adjusted analysis, higher CD4 count, lower VL, more recent calendar year, lower number of antiretroviral drugs previously exposed to and greater age at MDR diagnosis were associated with an increased chance of survival. There was some evidence of a better virological response at 24–48 weeks after MDR diagnosis in patients who changed regimen compared with patients who did not change regimen.
Conclusions: The risk of death following MDR diagnosis may be at least 3-fold the risk observed overall in HIV-infected individuals. Changing antiretroviral therapy following emergence of MDR HIV-1 may be associated with improved short-term virological response.
Keywords: MDR HIV-1 , genotypic sensitivity score , antiretroviral therapy
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Introduction |
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Highly active antiretroviral therapy (HAART) has had a significant impact on HIV-related morbidity and mortality. Within a large seroconverter cohort study (CASCADE), compared with pre-1997 data (pre-HAART), the hazard ratio (HR) for death fell sharply to 0.47 (95% CI 0.39–0.56) in 1997, dropping further to 0.16 (0.12–0.22) in 2001.1 More recently, an analysis of the Swiss HIV Cohort also described the benefit of treatment, with overall HRs for death being 0.14 (95% CI 0.07–0.29) for HAART-treated patients compared with no treatment and 0.49 (0.31–0.79) compared with dual therapy.2 Nevertheless, some patients receiving therapy experience viral rebound (virological failure), associated with development of drug resistance and require therapy change. Such drug resistance may compromise subsequent therapy options. Within the UK, it is estimated that about one-quarter of all antiretroviral-treated individuals have virological failure after experiencing all three commonly utilized classes of drugs.3 In the EuroSIDA study, which includes over 11 000 patients across Europe, treatment failure to all three main classes of antiretrovirals occurred in 16% of all treatment-experienced patients who started HAART since 2002, and these patients had a higher incidence of newly diagnosed AIDS or death than patients who did not experience triple class failure.4
One consequence of multiple therapies is the emergence of viruses that have reduced susceptibility to drugs within all three classes, termed multidrug-resistant (MDR) HIV-1. We have recently described the changing pattern of such viruses within the UK,5 with minimal estimates of the actual number of patients infected with such viruses exceeding 1000.
The optimal clinical management of patients with extensive prior drug therapy is still unknown. Many salvage studies have been of short duration with little follow-up data, making it difficult to judge whether or not any viral suppression will be maintained over the long term. The Pursuing Later Treatment Options collaboration concluded that in patients for whom viral load (VL) suppression to below the level of detection is not possible, maintaining a CD4 count above 200 cells/mm3 was associated with a better clinical outcome.6 Other strategies include selective cessation of some components of drug therapy, in order to reduce toxicity while maintaining antiviral effects.7 A further approach, involving structured treatment interruptions,8–11 is now thought to be detrimental to most heavily treatment-experienced patients.12–15
A recent study has described a relationship between emergence of non-nucleoside reverse transcriptase inhibitor resistance and mortality, in comparison to protease inhibitor (PI) resistance, in those initiating HAART.16 However, there remains a paucity of data on the risk of death following laboratory diagnosis of MDR HIV-1. Such information is essential in order to quantify the impact of MDR viruses for the infected population and therefore to predict the potential benefit conferred by newly available antiretroviral drugs on morbidity and mortality. We have utilized a large, linked clinical cohort and drug resistance data set from the UK to address these issues.
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Methods |
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Patients with MDR HIV were identified from the UK HIV Drug Resistance Database. The database was established in 2001 as a central repository of resistance tests performed as part of routine clinical care in the UK and is estimated to have achieved at least 85% coverage.5 Clinical data were obtained from the UK Collaborative HIV Cohort Study (UK CHIC—demographic and clinical data from six major UK HIV centres) and other local databases.17 All patients followed through UK CHIC are linked to the Office of National Statistics for England and Wales and the General Register Office for Scotland death registers.17 The risk of death in HIV-1-infected patients in the UK in general was estimated from patients being followed in UK CHIC between 1997 and 2004 (patients were censored at the date of their last laboratory measurement or their last visit).
MDR was defined as major resistance mutations to all three main classes of antiretroviral drugs based on the International AIDS Society list 2005,18 accumulated over all tests undertaken for each patient. The level of resistance to individual antiretroviral drugs prescribed was assessed by the Stanford HIVdb algorithm 4.1.8 (31 January 2006). Based on all previous resistance tests in a patient, each drug was scored as 0 if the virus had ever been reported as ‘resistant’ to it (Stanford categories 4 and 5), 0.5 for an ‘intermediate susceptibility’ (category 3) and 1 if all the reports had shown the virus to be fully susceptible to the drug in question (categories 1 and 2). The genotypic sensitivity score (GSS) for a drug regimen was defined as the sum of the scores across all drugs in the regimen. A total regimen score of 0 implies that none of the drugs in the regimen had activity as defined by resistance test results.
The principal analyses are based on those patients who were on HAART at MDR diagnosis and who are subsequently followed-up for at least 24 weeks. The latter restriction is introduced to allow treatment strategies in response to MDR diagnosis to be established. All resistance tests were performed as part of routine clinical care and the results would have been available to the clinician at the time of treatment choices. The outcome measures of the study were survival beyond 24 weeks (patients were censored at the date of their last laboratory measurement or their last visit) and the virological/immunological response 24–48 weeks after MDR diagnosis (the measurement taken closest to 36 weeks). The probability of death over time was estimated using Kaplan–Meier analysis. The factors associated with survival and virological/immunological response 24–48 weeks after MDR diagnosis were determined by the Poisson and linear regression, respectively. For virological response interval censored regression was used as some values were recorded as below a limit of detection and some above.
We define treatment strategies from regimen data for the period of 24 weeks following MDR diagnosis. We define a major change in therapy to occur when two or more drugs are added to the regimen at one time or where two or more drugs are removed, and this new regimen is maintained for at least 12 weeks. Stopping therapy is defined where all drugs are removed for a period of at least 12 weeks. A minor change is defined for all other patients unless their regimen was unchanged through the 24 week period (which includes changing one drug for toxicity reasons). Treatment strategy following MDR diagnosis was defined by one of the following five categories: (i) continued on current regimen; (ii) stopped therapy; (iii) a major change to a new regimen with the same or lower GSS; (iv) a major change to a new regimen with a higher GSS; and (v) a minor change.
Other factors considered included CD4 count (per 100 cells/mm3), log10 VL and age at time of MDR diagnosis, calendar year of MDR diagnosis, the number of resistance tests the MDR diagnosis was based on, the number of antiretroviral drugs previously exposed to, number of years on antiretroviral therapy (ART), the GSS of the new regimen, the number of inactive drugs in the regimen at time of MDR diagnosis, the change in number of inactive drugs in the regimen (after MDR diagnosis) and whether a boosted PI was included in a new regimen. The latter two factors are only defined for those patients experiencing a major change in treatment strategy; other patients are considered to have a change of zero in inactive drugs and no boosted PI in new regimen. In multiple regression analyses, these factors indicate their additional effect beyond experiencing a major change with increasing or non-increasing GSS.
Statistical comparisons of factors at MDR diagnosis between groups defined by subsequent treatment strategy were performed based on the Kruskal–Wallis test for continuous or ordinal factors and the 
2 test for unordered categorical factors. Survival in the MDR patient group and the CHIC cohort overall were compared using simple Poisson regression. All analysis was performed in Stata 9.
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Results |
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Overall, 692 patients first identified with MDR between 1997 and 2004 were available for analysis. Of these, 643 were identified as on HAART at MDR diagnosis; of which 71 did not have 24 weeks follow-up data (1 due to death). Therefore, 572 patients were available for further analysis. These patients overall were 86% male, median age of 39 years and had been exposed to a median of 8 ART drugs over a median of 4.6 years. Median CD4 count and VL at MDR diagnosis were 230 cells/mm3 and 4.2 log10copies/mL, respectively. Forty-six per cent of the patients had had more than one previous resistance test. The most common treatment strategies were to maintain the regimen at MDR diagnosis (25%), or make a minor change (30%). Twenty-two per cent of patients experienced a major change to a regimen with higher GSS, 13% a change to a regimen with the same or lower GSS, and for 10% therapy was stopped. The median (IQR) time from MDR diagnosis to a major treatment strategy change identified for our study was 9 (6–15) weeks. Of the characteristics of patients at MDR diagnosis considered (Table 1), only the VL and the number of inactive drugs (reflecting breadth of resistance) differed significantly according to the subsequent treatment strategy. In particular, we note that the number of inactive drugs was lowest for those who experienced a major change with an increase in GSS. Those for whom GSS did not increase had highest VL and the highest number of inactive drugs.
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Survival
There were 60 deaths (beyond 24 weeks from MDR diagnosis) over a median follow-up period of 31 months (IQR: 17–50), giving an overall estimated mortality rate of 3.7 deaths per 100 person-years (95% CI 2.9–4.7) following an MDR diagnosis between 1997 and 2004; the rate in UK CHIC in general over the same time period was 1.2 deaths per 100 person-years (95% CI 1.1–1.3) (P < 0.001). The overall estimated probability of death was 4% (95% CI 3–6), 8% (6–11) and 12% (9–15) by 12, 24 and 36 months (beyond 24 weeks from MDR diagnosis), respectively. The numbers of deaths and death rates in each treatment strategy are shown in Table 2, and Figure 1 shows the estimated probabilities of survival over time.
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Table 3 shows analyses of the factors associated with survival in HIV patients with MDR. In the unadjusted and multiple regression analyses, higher CD4 cell count and lower VL at time of MDR diagnosis were significantly associated with an increased chance of survival, with the risk of death decreasing by 44% per 100 CD4 cells/mm3 higher and increasing
2-fold per 1 log10 copy/mL higher in VL. More recent calendar year of MDR diagnosis, greater age at MDR diagnosis and lower number of ART previously exposed to were also significantly associated with an increased chance of survival. There was some evidence that treatment strategy was associated with survival (P = 0.04), with a decreased risk of death in patients who changed regimen with a minor change, compared with patients who did not change regimen. However, the number of inactive drugs in the regimen at time of MDR diagnosis and the number of resistance tests both lost significance on adjustment for other factors.
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CD4 and VL at 24–48 weeks
Four hundred and ninety-nine patients included in this analysis provided information on HIV VL 24–48 weeks after diagnosis, and 511 provided information on CD4. Tables 4 and 5 show unadjusted and multiple regression analyses of the factors associated with these outcomes. In the unadjusted analyses, higher CD4 cell count and lower VL at time of MDR diagnosis, more recent calendar year of MDR diagnosis and lower number of ART previously exposed to were significantly associated with an increased CD4 count and a lower VL at 24–48 weeks after MDR diagnosis. In addition, a lower number of inactive drugs in the regimen at time of MDR diagnosis, a reduction in the number of inactive drugs, a boosted PI in the new regimen, a greater number of resistance tests and fewer years of ART were all associated with a lower VL at 24–48 weeks. Treatment strategy was significantly associated with VL at 24–48 weeks, but not CD4 count, with patients who experienced a minor change in regimen or a major change to a new regimen with a higher GSS experiencing the lowest VLs at 24–48 weeks.
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In adjusted analyses, VL at time of MDR diagnosis, a boosted PI in the new regimen, calendar year, years on ART and treatment strategy remained significant for the outcome VL 24–48 weeks after MDR diagnosis. CD4 count, VL and calendar year at MDR diagnosis remained significant for the outcome CD4 count 24–48 weeks after MDR diagnosis, and treatment strategy became significant. The impact of change in GSS among those experiencing a major regimen change was small, but stopping therapy was clearly associated with lower CD4 and a minor change was linked to higher CD4 at 24–48 weeks.
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Discussion |
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We have previously found that the prevalence of MDR HIV-1 infections is around 4% of the treated population in the UK, representing more than 1000 individuals.5 The impact of this phenomenon on the morbidity and mortality of the epidemic requires study. We estimated an overall mortality rate of 3.7 deaths per 100 person-years following an MDR diagnosis between 1997 and 2004. This is over three times the rate for a large UK cohort (UK CHIC) over the same time period incorporating individuals at all stages of infection, and demonstrates the detrimental impact of such resistant viruses, as well as identifying resistance as a likely cause for the mortality excess previously described in triple drug experienced patients with virological failure.4 We acknowledge that the relatively small number of deaths during study follow-up has limited our ability to detect associations with survival, particularly in adjusted analysis.
Furthermore, the population we have identified in our analysis is unlikely to include all the patients in the UK with MDR as we know resistance testing was not routinely undertaken for all patients with possible resistance. Indeed, during 1999–2002, only 30% of treatment switches in patients in UK CHIC were preceded by a resistance test within 6 months; this percentage did not vary by calendar year.5 The frequency of resistance testing also has an impact on the timing of the diagnosis of MDR, i.e. we know a patient had developed MDR at some time between two resistance tests, but the exact time is unknown. In our analysis, we defined the diagnosis of MDR to be the date of the resistance test at the end of this interval, and therefore our figures estimate the mortality rate in this cohort once MDR has been established clinically but may overestimate the mortality rate from the time of underlying MDR.
We must also be wary of the confounding influences inherent in such comparisons, such as CD4 cell count and other indices of disease progression. Indeed, within our study, factors associated with an increased chance of survival included higher CD4 count and lower VL at MDR diagnosis, demonstrating that individuals with MDR viruses are highly heterogeneous. Also, clinical data on new AIDS-defining events have not been examined in this study, which could again have an added impact on morbidity and mortality.
Further, we recognize the importance of treatment adherence and the development of drug resistance. Poor adherence with ART can lead to suboptimal circulating drug levels, with resistant virus more likely to develop. This can ultimately lead to virological failure, disease progression and poor clinical outcome.
The definition of HIV drug resistance is complex. Specific mutations or sets of mutations within the viral genome may confer reduced susceptibility to one or more drugs within a class, and resistance is a continuum rather than all or none. Thus, the term MDR, meaning at least one key mutation conferring resistance to at least one drug within each of the three major classes, may encompass a large range of different viruses rather than a homogeneous population. However, in a sensitivity analysis conducted on the subset of patients meeting a broader definition of MDR including reduced susceptibility to two drugs from each class rather than one major mutation (accumulated over all tests undertaken in a patient), our key findings were little affected.
It follows that MDR HIV-1 may still be susceptible to specific drugs. Indeed, we demonstrated that the fewer number of antiretrovirals previously exposed to prior to MDR was associated with improved survival, a reflection of the degree of cross-resistance conferred by the precise MDR pattern. The improvement in survival in those diagnosed with MDR HIV-1 in latter years may also reflect the better use of resistance test results to optimize therapy and the availability of new drugs. This analysis was limited to diagnoses of MDR prior to 2004, and as new classes of drugs are used more widely to treat MDR patients, the additional risk of mortality from MDR may decrease. Interestingly, the use of boosted PIs was not associated with improved survival, although accompanied by short-term virological response.
A number of trials of new drugs in highly treatment-experienced patients, such as for enfuvirtide,19 tipranavir20 and more recently darunavir,21 integrase inhibitors22,23 and CCR5 inhibitors,24,25 all demonstrate that virological suppression is favoured by the use of the new investigational drug with at least one other active drug. Consistent with this concept, our findings suggest that change of therapy following MDR diagnosis may confer improvement in short-term virological response, with those patients changing to a more ‘active’ regimen possibly doing the best in terms of clinical outcome. Whether changing therapy translates to an increased chance of survival is unclear from our study, and larger studies are needed to determine whether a true survival benefit exists. Stopping treatment as expected was associated with the poorest outcome virologically, immunologically and in terms of survival, although this group had the smallest number of patients.
Our results have highlighted the possible value of changing therapy following MDR diagnosis but clearly several factors are involved in achieving sustained clinical benefit. Clinicians may have selected patients for a therapy change who were more motivated and therefore most likely to adhere to a new regimen, or may have chosen a particular regimen based on the ability of these patients to tolerate and adhere to a new drug regimen, e.g. a regimen with a reduced pill burden and better toxicity profile.
Patients who changed therapy to a regimen with a higher GSS had more treatment options (smaller total number of inactive drugs) at MDR diagnosis compared with patients who changed therapy to a regimen with lower or same GSS, who had more advanced HIV infection with lower CD4 counts and higher VL, and this may have influenced subsequent choice of therapy. Nevertheless, this observation supports the assertion that maintaining highly drug-experienced patients on a failing regimen, despite presence of MDR virus, may further compromise outcome through accumulation of more mutations, and thus extensive cross-resistance.
Finally, in this study, we used the GSS and number of inactive drugs, according to the Standford HIVdb algorithm, as a measure of the level of drug activity in a patient. While the GSS has been shown to predict virological response according to different interpretation systems, findings are inconclusive regarding its ability to predict the response for different classes of drugs,26–28 and other measures may have better captured the potential effectiveness of a regimen. We have not evaluated the role of individual drugs included in each regimen and it may be that our current definitions of drug resistance, which underpin the GSS, are inadequate to capture the full benefits of specific drugs, particularly in patients with high levels of existing resistance. For instance, some drugs, such as lamivudine, may have residual activity despite presumed high-level resistance.29 In addition, the maintenance of specific resistance mutations by use of selected drugs may confer a fitness deficit on the virus, making it less pathogenic.30
In summary, we describe mortality following diagnosis of MDR HIV-1, which may be at least 3-fold the risk observed in non-selected HIV-infected individuals. Our data suggest that active management of such individuals may still confer clinical benefit and it appears that changing therapy may be associated with better short-term virological response. Over the next few years, new drugs within existing drug classes and new classes of drugs will become available. We suggest that their judicious use in patients with MDR HIV-1 will further improve clinical outcome in this growing difficult-to-treat group of patients.
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The UK HIV Drug Resistance Database is partly funded by the Department of Health; the views expressed in the publication are those of the authors and not necessarily those of the Department of Health. Additional financial support is provided by Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Tibotec (a division of Janssen-Cilag Ltd) and Roche. UK CHIC is funded by the Medical Research Council, UK (Grant G0000199).
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Transparency declarations |
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None to declare.
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Footnotes |
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See the Acknowledgements section for membership of Steering Committees. 
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Acknowledgements |
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We would like to thank all the clinicians, virologists, data managers and research nurses in participating centres who have assisted with the provision of data. Full lists available at www.hivrdb.org.uk and www.chic.org.uk.
UK Collaborative Group on HIV Drug Resistance Steering Committee: Jane Anderson, Homerton University Hospital, Sheila Burns, Royal Infirmary of Edinburgh; Sheila Cameron, Gartnavel General Hospital, Glasgow; Patricia Cane, Health Protection Agency, Porton Down; Ian Chrystie, Guy’s and St Thomas’ NHS Foundation Trust, London; Duncan Churchill, Brighton and Sussex University Hospitals NHS Trust; Dr Duncan Clark, St Bartholemews and The London NHS Trust; Valerie Delpech, Deenan Pillay, Health Protection Agency—Centre for Infections London; David Dunn, Esther Fearnhill, Hannah Green, Kholoud Porter, MRC Clinical Trials Unit, London (Coordinating Centre); Philippa Easterbrook, Mark Zuckerman, King’s College Hospital, London; Anna Maria Geretti, Royal Free NHS Trust, London; Paul Kellam, Deenan Pillay, Andrew Phillips, Caroline Sabin, Royal Free and University College Medical School, London; David Goldberg, Health Protection Scotland, Glasgow; Mark Gompels, Southmead Hospital, Bristol; Antony Hale, Leeds Teaching Hospitals NHS Trust; Steve Kaye, St Mary’s Hospital, London; Svilen Konov, Community Advisory Board; Linda Lazarus, Department of Health; Andrew Leigh-Brown, University of Edinburgh; Chloe Orkin, St Bartholemews Hospital, London; Anton Pozniak, Chelsea and Westminster Hospital, London; Erasmus Smit, Health Protection Agency, Birmingham Heartlands Hospital; Peter Tilston, Manchester Royal Infirmary; Ian Williams, Mortimer Market Centre, London; and Hongyi Zhang, Addenbrooke’s Hospital, Cambridge.
Participating Laboratories: Addenbooke’s Hospital, Cambridge (Hongyi Zhang), Department of Virology, St Bartholemews and The London NHS Trust (Duncan Clark, Ines Ushiro-Lumb, Tony Oliver), Belfast Health and Social Care Trust (Suzanne Mitchell), HPA Birmingham Public Health Laboratory (Erasmus Smit), Chelsea and Westminster Hospital, London (Adrian Wildfire), East Dulwich Hospital (Melvyn Smith), Royal Infirmary of Edinburgh (Jill Shepherd), West of Scotland Specialist Virology Lab, Gartnavel, Glasgow (Alasdair MacLean), Guy’s and St Thomas’ NHS Foundation Trust, London (Ian Chrystie), Leeds Teaching Hospitals NHS Trust (Diane Bennett), Specialist Virology Centre, Liverpool (Mark Hopkins), Manchester (Peter Tilston), Department of Virology, Royal Free Hospital (Clare Booth, Ana Garcia-Diaz), St Mary’s Hospital, London (Steve Kaye) and University College London Hospitals (Stuart Kirk).
UK CHIC Steering Committee: Jonathan Ainsworth, North Middlesex University Hospital NHS Trust; Jane Anderson, Homerton University Hospital NHS Trust, Abdel Babiker, MRC Clinical Trials Unit, London; David Dunn, MRC Clinical Trials Unit; London, Philippa Easterbrook, King’s College Hospital, London; Esther Fearnhill, MRC Clinical Trials Unit, London; Martin Fisher, Brighton and Sussex University Hospitals NHS Trust; Brian Gazzard (Chair), Chelsea and Westminster NHS Trust, London; Richard Gilson, Mortimer Market Centre, Royal Free and University College Medical School (RFUCMS), London; Mark Gompels, North Bristol NHS Trust; Teresa Hill, RFUCMS, London; Margaret Johnson, Royal Free NHS Trust and RFUCMS, London; Chloe Orkin, Barts and The London NHS Trust; Barry Peters, St Thomas’ Hospital, London; Andrew Phillips, RFUCMS, London; Deenan Pillay, RFUCMS, London; Kholoud Porter, MRC Clinical Trials Unit, London; Caroline Sabin, RFUCMS, London; Achim Schwenk, North Middlesex University Hospital NHS Trust; John Walsh, St Mary’s Hospital, London; and Katy Sinka, Health Protection Agency-Communicable Disease Surveillance Centre (HPA-CDSC) London.
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References |
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