The number of HIV-1 infections diagnosed among MSM increased prior to 2007 and has remained high since then in all ethnic groups. This has been accompanied by an increase in the total number of non-B non-C subtypes diagnosed during this period. Substantial differences in the subtype make-up of diagnosed MSM by ethnicity are evident. White MSM and other MSM were chiefly diagnosed with subtype B, whereas black African MSM were estimated to have a mixture of subtype B (250; 48.9%), C (85; 16.7%) and non-B, non-C (177; 34.6%). However, the number and proportion of non-B, non-C subtypes for white MSM increased markedly from 80 (4.8%) in 2002 to 272 (12.4%) in 2010. This increase was largely driven by novel recombinant viruses, accounting for 8.0% of diagnoses among white MSM in 2010. Trends cannot be discerned for other ethnicities due to the small numbers diagnosed.
This study found broad representation of HIV-1 subtypes within the UK, both overall and within specific demographic subgroups. Subtype should no longer be used as a proxy for transmission group when this is unknown, as has been the case historically, as heterosexual infections now account for 22% of all subtype B infections. The increase in non-B non-C subtypes, particularly novel recombinants among MSM of white and other ethnicity, demonstrates that there is ongoing emergence of new novel recombinant forms in the UK or that these variants are more transmissible. The number of patients diagnosed with subtype B virus has remained stable and is the most prevalent subtype in the UK, whereas the annual number of subtype C HIV-1 diagnoses, has fallen since 2004, reflecting a decline in new HIV-1 diagnoses in the black African population. However, it remains the second most prevalent subtype overall and remains the most common subtype in the black African population.
Previous UK studies  have also found ‘an increasingly broad range of genetic diversity’ and using phylogenetic surveillance showed that subtypes typically associated with infections acquired in East Africa were spreading among MSM in the UK. Gifford et al.  used 10 537 sequences collected between 1996 and 2004, so our study represents a significant update on the changes in the prevalence of subtypes that have occurred since then, while also focusing on temporal trends within probable exposure groups in greater detail. Another UK study  examined the prevalence of non-B subtypes among MSM diagnosed from 1980 to 2007, and also found that nonsubtype B infections were increasing in the UK and suggested that the association of subtypes to sociodemographic groups was weakening.
A recent meta-analysis  of global data, with 65 913 samples, has concluded that there has been an increase in the proportion of the subtypes A, F, G, H, CRF01 AE and CRF02 AG and that the global proportion of all CRFs has also grown, but did not describe this by demographic subgroup. However, URFs decreased as a proportion of infections by 3.1% between 2000–2003 and 2004–2007. Abecasis et al.  used data from the SPREAD European surveillance programme in 2002–2005 and found that subtype was highly determined by demographic subgroups and suggested highly compartmentalized, parallel, epidemics but only CRF02_AG and subtype F had significant time trends. Our more recent data suggest that the effect of increased migration to the UK has led to a very different epidemic to the rest of Europe, although the compartmentalization found in SPREAD may have also broken down since 2005. Other studies [21–23] have also observed increasing genetic diversity demonstrating that this is not a phenomenon unique to the UK.
Our study population comprises patients who received a drug resistance test and may not therefore be representative of the entire HIV-1-positive population in the UK. We tried to minimize this bias by only using tests conducted after 2001 and by accounting for differential use of resistance testing by ethnicity and exposure group. However, we could not adjust for the 24% of the HIV-1-positive population estimated to not yet be aware of their infection . As a consequence, we may be underreporting some non-B subtypes as previous research has shown that non-African born heterosexuals have a higher undiagnosed rate of infection compared with MSM (31 compared with 20% ). For our temporal trend analyses, we used the year of sampling for the resistance test, which might not reflect the date of seroconversion, although this should not change our main conclusions. It would have been interesting to have conducted further analyses comparing UK acquired infections to those acquired abroad. An indirect method for estimating country of infection, based on year of migration and CD4+ cell count at diagnosis, was recently published  and showed that 33% of heterosexuals born abroad acquired their infection in the UK. However, a similar analysis was not possible in this study due to incomplete data on these two variables.
The choice of SCUEAL as the automated subtyping tool could have influenced our findings compared to other studies, which have generally used the REGA v2 algorithm. A comparison between the subtype assigned by SCUEAL and REGA v2 to sequences in this study is shown in Table 6 (Supplementary Digital Content, http://links.lww.com/QAD/A440). Consistent with another analysis , there was strong concordance between the pure subtypes; the main difference between the algorithms is that viruses classified as CRF02_AG by REGA are usually classified as either G, A/G recombinants with alternate breakpoints, or as a complex subtype, by SCUEAL. The estimated prevalence of these subtypes would, therefore, have been affected accordingly. Our analysis uses partial sequences of the pol gene, comprising approximately 10% of the viral genome, as this is the region typically sequenced for resistance testing. This results in underestimates of the prevalence of novel recombinant forms as mosaic viruses may have breakpoints outside of this region. This bias cannot currently be quantified, but the increasing availability of full length sequences from next generation sequencing platforms will allow future quantification of this effect.
The increasing diversity of HIV-1 could be viewed as evidence that any fitness differences between subtypes are likely to be small. The fact that distinct demographic subgroups have overlapping subtypes suggests sexual linkage between different subgroups, although this can only be confirmed by conducting further phylogenetic analyses. The increase in novel recombinants is further evidence that sexual linkage between demographic subgroups is occurring for individuals to be simultaneously infected with genetically distinct viruses. The impact this increase in novel recombinants will have on disease progression, treatment and the development of drug resistance is not yet known.
The UK Collaborative Group on HIV Drug Resistance is a collaboration between the UK HIV Drug Resistance Database; UK CHIC; Public Health England HARS; and participating academic centres, clinics, and laboratories.
Members of Analysis/Writing Group are as follows: David Dolling, Stéphane Hué, Valerie Delpech, Esther Fearnhill, Andrew Leigh Brown, Anna Maria Geretti, Deenan Pillay, David Dunn.
Members of Steering Committee are as follows: Celia Aitken, Gartnavel General Hospital, Glasgow; David Asboe, Anton Pozniak, Chelsea & Westminster Hospital, London; Daniel Webster, Royal Free NHS Trust, London; Patricia Cane, Health Protection Agency, Porton Down; Hannah Castro, David Dunn (Co-Chair), David Dolling, Esther Fearnhill, Anna Tostevin, Kholoud Porter, MRC Clinical Trials Unit, London; David Chadwick, South Tees Hospitals NHS Trust, Middlesbrough; Duncan Churchill, Brighton and Sussex University Hospitals NHS Trust; Duncan Clark, St Bartholomew's and The London NHS Trust; Simon Collins, HIV i-Base, London; Valerie Delpech, Health Protection Agency, Centre for Infections, London; Anna Maria Geretti, Institute of Infection and Global Health, University of Liverpool; David Goldberg, Health Protection Scotland, Glasgow; Antony Hale, Leeds Teaching Hospitals NHS Trust; Stéphane Hué, University College London; Steve Kaye, Imperial College London; Paul Kellam, Wellcome Trust Sanger Institute & UCL Medical School; Linda Lazarus, Expert Advisory Group on AIDS Secretariat, Health Protection Agency, London; Andrew Leigh-Brown, University of Edinburgh; Nicola Mackie, Imperial NHS Trust; Chloe Orkin, St. Bartholomew's Hospital, London; Philip Rice, St George's Healthcare Trust, London; Deenan Pillay (Co-Chair), Andrew Phillips, Caroline Sabin, University College London Medical School; Erasmus Smit, Health Protection Agency, Birmingham Heartlands Hospital; Kate Templeton, Royal Infirmary of Edinburgh; Peter Tilston, Manchester Royal Infirmary; William Tong, Guy's and St. Thomas’ NHS Foundation Trust, London; Ian Williams, Mortimer Market Centre, London; Hongyi Zhang, Addenbrooke's Hospital, Cambridge; Mark Zuckerman, King's College Hospital, London.
Centres contributing data: Clinical Microbiology and Public Health Laboratory, Addenbrooke's Hospital, Cambridge (Jane Greatorex); HIV/GUM Research Laboratory, Chelsea and Westminster Hospital, London (Adrian Wildfire); Guy's and St. Thomas’ NHS Foundation Trust, London (Siobhan O'Shea, Jane Mullen); HPA – Public Health Laboratory, Birmingham Heartlands Hospital, Birmingham (Erasmus Smit); HPA London (Tamyo Mbisa); Imperial College Health NHS Trust, London (Alison Cox); King's College Hospital, London (Richard Tandy); Medical Microbiology Laboratory, Leeds Teaching Hospitals NHS Trust (Tony Hale, Tracy Fawcett); Specialist Virology Centre, Liverpool (Mark Hopkins, Lynn Ashton); Department of Clinical Virology, Manchester Royal Infirmary, Manchester (Peter Tilston); Department of Virology, Royal Free Hospital, London (Claire Booth, Ana Garcia-Diaz); Edinburgh Specialist Virology Centre, Royal Infirmary of Edinburgh (Jill Shepherd); Department of Infection & Tropical Medicine, Royal Victoria Infirmary, Newcastle (Matthias L Schmid, Brendan Payne); South Tees Hospitals NHS Trust, Middlesbrough (David Chadwick); St George's Hospital, London (Phillip Hay, Phillip Rice, Mary Paynter); Department of Virology, St Bartholomew's and The London NHS Trust (Duncan Clark, David Bibby); Molecular Diagnostic Unit, Imperial College, London (Steve Kaye); University College London Hospitals (Stuart Kirk); West of Scotland Specialist Virology Lab Gartnavel, Glasgow (Alasdair MacLean, Celia Aitken, Rory Gunson).
Coordinating Centre: Medical Research Council Clinical Trials Unit (MRC CTU), London (Kate Coughlin, David Dolling, David Dunn, Esther Fearnhill, Anna Tostevin, Lorraine Fradette, Kholoud Porter).
This work was supported by the UK Medical Research Council (grant G0900274) and the European Community's 7th framework programme (FP7/2007–2013) under the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; project 223131).
Conflicts of interest
None of the authors have an association that might pose a conflict of interest for this piece of work.
1. Robertson DL, Anderson JP, Bradac JA, Carr JK, Foley B, Funkhouser RK, et al. HIV-1 nomenclature proposal
3. Geretti AM, Harrison L, Green H, Sabin C, Hill T, Fearnhill E, et al. Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy
. Clin Infect Dis
4. Holguin A, Ramirez de Arellano E, Rivas P, Soriano V. Efficacy of antiretroviral therapy in individuals infected with HIV-1 non-B subtypes
. AIDS Rev
5. Pai NP, Shivkumar S, Cajas JM. Does genetic diversity of HIV-1 non-B subtypes differentially impact disease progression in treatment-naive HIV-1-infected individuals? A systematic review of evidence: 1996–2010
6. Klein M, Odueyungbo A, Scherrer A, Ledergerber B, Fearnhill E, Sabin C, et al. Impact of viral subtype on immunologic and clinical disease progression in antiretroviral-naïve HIV-infected adults. 18th Conference on Retroviruses and Opportunistic Infections. Boston, USA; 2011.
7. Lodi S, Phillips A, Touloumi G, Geskus R, Meyer L, Thiebaut R, et al. Time from human immunodeficiency virus seroconversion to reaching CD4+ cell count thresholds < 200, <350, and <500 cells/mm(3): assessment of need following changes in treatment guidelines
. Clin Infect Dis
8. Thomson MM, Najera R. Increasing HIV-1 genetic diversity in Europe
. J Infect Dis
9. Gifford R, de Oliveira T, Rambaut A, Myers RE, Gale CV, Dunn D, et al. Assessment of automated genotyping protocols as tools for surveillance of HIV-1 genetic diversity
10. Fox J, Castro H, Kaye S, McClure M, Weber JN, Fidler S. Epidemiology of non-B clade forms of HIV-1 in men who have sex with men in the UK
11. Tatt ID, Barlow KL, Clewley JP, Gill ON, Parry JV. Surveillance of HIV-1 subtypes among heterosexuals in England and Wales, 1997–2000
. J Acquir Immune Defic Syndr
12. Gazzard B, Comm BW. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005)
. HIV Med
13. Kosakovsky Pond SL, Posada D, Stawiski E, Chappey C, Poon AF, Hughes G, et al. An evolutionary model-based algorithm for accurate phylogenetic breakpoint mapping and subtype prediction in HIV-1
. PLoS Comput Biol
14. de Oliveira T, Deforche K, Cassol S, Salminen M, Paraskevis D, Seebregts C, et al. An automated genotyping system for analysis of HIV-1 and other microbial sequences
15. The UK Collaborative HIV Cohort Steering CommitteeThe creation of a large UK-based multicentre cohort of HIV-infected individuals: the UK Collaborative HIV Cohort (UK CHIC) Study
. HIV Med
18. Gifford RJ, de Oliveira T, Rambaut A, Pybus OG, Dunn D, Vandamme AM, et al. Phylogenetic surveillance of viral genetic diversity and the evolving molecular epidemiology of human immunodeficiency virus type 1
. J Virol
19. Hemelaar J, Gouws E, Ghys PD, Osmanov S. Global trends in molecular epidemiology of HIV-1 during 2000–2007
20. Abecasis AB, Wensing AM, Paraskevis D, Vercauteren J, Theys K, Van de Vijver DA, et al. HIV-1 subtype distribution and its demographic determinants in newly diagnosed patients in Europe suggest highly compartmentalized epidemics
21. Chibo D, Birch C. Increasing diversity of human immunodeficiency virus type 1 subtypes circulating in Australia
. AIDS Res Hum Retroviruses
22. Chen JH, Wong KH, Chen Z, Chan K, Lam HY, To SW, et al. Increased genetic diversity of HIV-1 circulating in Hong Kong
. Plos One
23. Torimiro JN, D’Arrigo R, Takou D, Nanfack A, Pizzi D, Ngong I, et al. Human immunodeficiency virus type 1 intersubtype recombinants predominate in the AIDS epidemic in Cameroon
. New Microbiol
24. Health Protection Agency. HIV in the United Kingdom: 2012 Report
. Edited by Health Protection Agency; 2012.
25. Rice BD, Elford J, Yin Z, Delpech VC. A new method to assign country of HIV infection among heterosexuals born abroad and diagnosed with HIV
26. Pineda-Peña AC, Faria NR, Imbrechts S, Libin P, Abecasis AB, Deforche K, et al. Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: performance evaluation of the new REGA version 3 and seven other tools
. Infect Genet Evol
Keywords:© 2014 Lippincott Williams & Wilkins, Inc.
epidemiology; genetic diversity; HIV-1; subtype; subtyping; UK