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Page 1: Increase in HIV Plasma Viral Load Set-Point Among … · 1015 Increase in HIV Plasma Viral Load Set-Point Among UK MSM Victoria Parsons 1, Andrew ... North Cumbria Acute Hospitals

Increase in HIV Plasma Viral Load Set-Point Among UK MSM1015

Victoria Parsons1, Andrew Phillips1, Richard Gilson1, Sarah Fidler2, Martin Fisher3, Anne Johnson1, David Hawkins4, Ken McLean5, Margaret Johnson6, Kholoud Porter1

for the UK Register of HIV Seroconverters1University College London, London, UNITED KINGDOM, 2Imperial College London, London, UNITED KINGDOM, 3Brighton & Sussex Medical School, Brighton, UNITED KINGDOM, 4Chelsea & Westminster NHS Foundation Trust, London, UNITED KINGDOM, 5West London Centre for Sexual Health, London, UNITED KINGDOM,

6Royal Free London NHS Foundation Trust, London, UNITED KINGDOM.

• High viral loads (VL) during Primary HIV Infection (PHI)may disproportionately contribute to the propagation ofthe epidemic.

• Whether there has been a temporal increase in viral loadset point (VLSP) is debateable as findings are conflicting.

• We sought to describe temporal trends in VL at initialpresentation and VLSP in MSM HIV seroconverters (SC)from the UK.

We would like to thank all the UK Register participants for allowing their routine clinical data to be included. We gratefully acknowledge the work of the members of the Steering Committee and colleagues at the clinical centres. Special thanks go to the following colleagues: Kristin Kuldanek, Scott Mullaney (St Mary’s Hospital, London), Carmel Young (Mortimer Market Centre, London), Antonella Zucchetti, Margaret-Ann Bevan (St Thomas’ Hospital, London), Sinead McKernan (Royal Victoria Hospital, Belfast), Emily Wandolo (King’s College Hospital, London), Celia Richardson, Elaney Youssef (Bri ghton and Sussex University Hospital), Pippa Green (Withington Hospital, Manchester), Sue Faulkner (Gloucester Royal Hospital),Rebecca Faville (Whittall Street Clinic, Birmingham), Sandra Herman, Christine Care (Royal Hallamshire Hospital, Sheffield), Helen Blackman (St Mary’s Hospital, Portsmouth), and Katharine Bellenger, Keith Fairbrother, Ashley Olson, and Louise Walker-Nathenda (Medical Research Council Clinical Trials Unit, London). Members of the UK Register Steering Committee: Andrew Phillips (Chair), University College London (UCL), London ; Abdel Babiker, UCL , London; Valerie Delpech, Public Health England, London; Sarah Fidler, St. Mary’s Hospital, London; Martin Fisher, Brighton & Sussex University Hospitals NHS Trust, Brighton; Julie Fox, Guys and St Thomas’ NHS Trust/Kings College, London; Richard Gilson, UCL, London ; DavidGoldberg, Health Protection Scotland, Glasgow; David Hawkins, Chelsea & Westminster NHS Trust, London; Anne Johnson, UCL, London; Margaret Johnson, UCL and Royal Free NHS Trust, London; Ken McLean, West London Centre for Sexual Health, London; Deenan Pillay, UCL, London; Frank Post, King’s College, London. UK Register of HIV Seroconverters collaborators are: N Kennedy, Monklands Hospital, Airdrie; J Pritchard, Ashford Hospital, Ashford; U Andrady, Ysbyty Gwynedd, Bangor; N Rajda, North Hampshire Hospital, Basingstoke; C Donnelly, S McKernan, Royal Victoria Hospital, Belfast; S Drake, G Gilleran, D White, Birmingham Heartlands Hospital, Birmingham; J Ross, J Harding, R Faville, Whittall Street Clinic,Birmingham; J Sweeney, P Flegg, S Toomer, Blackpool Victoria Hospital, Blackpool; H Wilding, R Woodward, Royal Bournemouth Hospital, Bournemouth; G Dean, C Richardson, N Perry, Royal Sussex County Hospital, Brighton; M Gompels, L Jennings, Southmead Hospital, Bristol; D Bansaal, Queen’s Hospital, Burton-Upon-Trent; M Browing, L Connolly, Cardiff Royal Infirmary, Cardiff; B Stanley, North Cumbria Acute Hospitals NHS Trust, Carlisle; S Estreich, A Magdy, St. Helier Hospital, Carshalton; C O’Mahony, Countess of Chester Hospital, Chester; P Fraser, Chesterfield & North Derbyshire Royal Hospital, Chesterfield; SPR Jebakumar, Essex County Hospital, Colchester; L David, Coventry & WarwickshireHospital, Coventry; R Mette,Mayday University Hospital, Croydon; H Summerfield, Weymouth Community Hospital, Dorset; M Evans, Ninewells Hospital, Dundee; C White, University Hospital of North Durham, Durham; R Robertson, Muirhouse Medical Group, Edinburgh; C Lean, S Morris, Western General Hospital, Edinburgh; A Winter, Gartnavel General Hospital & Glasgow Royal Infirmary, Glasgow; S Faulkner, Gloucestershire Royal Hospital, Gloucester; B Goorney, Salford Hope Hospital, Greater Manchester; L Howard, Farnham Road Hospital, Guildford; I Fairley, C Stemp, Harrogate Hospital, Harrogate; L Short, Huddersfield Royal In firmary, Huddersfield; M gomez, F young, St Mary’s Hospital Isle of Wi ght; M Roberts, S Green, Kidderminster GeneralHospital, Kidderminster; K Sivakumar, the Queen Elizabeth Hospital, King’s Lynn; J Minton, A Siminoni, Leeds General Infirmary, Leeds; J Calderwood, D Greenhough, J Minton, St. James’ Hospital, Leeds; C DeSouza, Lisa Muthern, C Orkin, Barts & the London NHS Trust, London; S Murphy, M Truvedi, Central Middlesex Hospital, London; K McLean, Charing Cross Hospital, London; D Hawkins, C Higgs, A Moyes, Chelsea & Westminster Hospital, London; S Antonucci, S McCormack, Dean Street Clinic, London; W Lynn, Ealing Hospital, London; M Bevan, J Fox, A Teague, Guy’s & St. Thomas NHS Trust, London; J Anderson, S Mguni, Homerton Hospital, London; F Post, L Campbell, E Wandolo King’s College Hospital, London; C Mazhude,H Russell, Lewisham University Hospital, London; R Gilson, D Morris, O Otiko, Mortimer Market Centre, London; J Ainsworth, A Waters, North Middlesex Hospital, London; P Byrne, M Johnson, Royal Free Hospital, London; London; S Fidler, K Kuldanek, S Mullaney, St. Mary’s Hospital, London; V Lawlor, R Melville, Whipps Cross Hospital, London; A Sukthankar, S Thorpe, Manchester Royal Infirmary, Manchester; C Murphy, E Wilkins, North Manchester General Hospital, Manchester; S Ahmad, P Green, Withington Hospital, Manchester; S Tayal, James Cook Hospital, Middlesbrough; E Ong, Newcastle General Hospital, Newcastle; J Meaden, Norfolk & Norwich University Hospital, Norwich; L Riddell, City Hospital, Nottingham; DLoay, K Peacock, George Eliot Hospital, Nunneaton; H Blackman, V Harindra, St. Mary’s Hospital, Portsmouth; AM Saeed, Royal Preston Hospital, Preston; S Allen, U Natarajan, East Surrey Hospital, Redhill; O Williams, Glan Clwyd District General, Rhyl; H Lacey, Baillie Street Health Centre, Rochdale; C Care, C Bowman, S Herman, Royal Hallamshire Hospital, Sheffield; SV Devendra, J Wither, Royal Shrewsbury Hospital, Shrewsbury; A Bridgwood, G Singh, North Staffordshire Hospital, Stoke-on-Trent; S Bushby, Sunderland Royal Hospital, Sunderland; D Kellock, S Young, King’s Mill Centre, Sutton-in-Ashfield; G Rooney, B Snart, the Great Western Hospital, Swindon; J Currie, M. Fitzgerald, Taunton & Somerset Hospital, Taunton; JArumainayyagam, S Chandramani, Manor Hospital, Walsall; S Rajamanoharan, T Robinson, Watford General Hospital, Watford; M Roberts, Worcester Royal Infirmary, Worcester; O Williams, Maelor Hospital, Wrexham; B Taylor, Wycombe General Hospital, Wycombe; C Brewer, I Fairley, Monkgate Health Centre, York Hospital NHS Trust, York.

UK Register of HIV SeroconvertersIs an observational study of HIV positive persons in the UK for whomthe time of HIV seroconversion is well estimated. The originalobjectives of the study, to investigate the natural history of HIVinfection and its determinants, have been modified with the advent ofeffective therapy for HIV, to monitoring temporal changes in the time toAIDS and death (i.e. the population effectiveness of therapy) andexamining the effect of time since infection and presence oftransmitted drug resistant HIV on virological and immunologicalresponse to therapy

• Analysis restricted to MSM aged 16 years or over,diagnosed between 1st January 1997 & 31st December2012 and with 1 or more ART-naïve VL measure availablewithin 3-12 months of SC.

• All had SC interval (time between negative & positive HIVAb tests) of 1 year or less, or laboratory evidence of acuteinfection, or an “incident” result using a RITA (recentincident testing algorithm) assay.

• Initial VL was defined as the first VL on or after the dateof HIV diagnosis and within 12 months of SC.

• VLSP defined as the mean of ART-naïve VLmeasurements taken between 3 and 12 months after dateof SC.

• Multiple regression used to examine whether initial VL &VLSP had changed by calendar year of SC (1997-99,2000-01, 2002-03, 2004-05, 2006-07, 2008-09, 2010-12)after adjusting for potential confounders.

• Year of SC modelled as a 5 knot restricted cubic spline toallow for non-linear trends.

• The following sensitivity analyses were performed:• restricting the dataset to white ethnicity MSM• restricting to MSM with a SC interval ≤180 days• right truncating the data at 5.0 log10 copies/ml, in

line with the upper limit of linear range in the earlierassay types

• We found evidence of an overall increase in both VL at first presentation and VLSP between 1997 and 2012,with evidence of non-linearity in the trends.

• This overall increase remained after sensitivity analyses accounting for changes over time to assay type andupper range of detection.

• A bias towards earlier recruitment of the more symptomatic men to the UK Register may be responsible forparticularly high measures observed in most recent years, although the calendar year effect remainedsignificant, albeit weakened, when excluding MSM seroconverting in 2012 from the analysis.

• As VL is known to be correlated with risk of transmission, these findings may translate to increased virulenceover time and, potentially, increased incidence.

• However, interpretation of the reasons for increased VLSP over time is not straightforward because analyses ofthe viral genotype do not suggest an effect of increased virulence (see poster 288, Hodcroft et al). Otherfactors, many of which have changed over time, could be responsible for the increase observed.

Initial Viral Load• Median (IQR) initial VL overall was 4.99 log10

copies/ml (4.34, 5.62).• Initial VL was lowest at 4.71 log10 copies/ml (4.05,

5.21) in 1997-99 and highest at 5.05 (4.46, 5.70) in2010-12 (p=0.005), but there was some evidence ofdeparture from linearity (p=0.050).

• Initial VL remained associated with calendar year ofSC in adjusted models (see table 2) and all sensitivityanalyses.

Viral Load Set-Point• Median (IQR) VLSP overall was 4.64 log10 copies/ml

(4.05, 5.08).• VLSP increased from 4.51 log10 copies/ml (4.10, 4.89)

in 1997-99 to 4.76 (4.15, 5.16) in 2010-12 (p=0.013),but there was evidence of departure from linearity(p=0.028).

• Table 3 shows the overall effect of SC year on VLSPremained significant in the adjusted model.

• Findings held in all sensitivity analyses apart fromrestricting to white ethnicity MSM (p=0.060).

• 1,194 of the 3,626 individualsenrolled in the UK Register meteligibility criteria.

• The majority were of white ethnicity(90.1%), the median age was 32.6years, and large proportion hadmissing HIV subtype data (60.8%).

• As expected, VL assay type andupper range of detection werestrongly associated with calendartime, with increasing use of PCRassays (49.6% in 1997-99 to 93.0%in 2010-12) and an increase in theupper linear range of assays.

Table 1: Demographic & clinical characteristics for MSM in the UK Register of HIVSeroconverters

Table 3: Factors associated with viral load set point

Table 2: Factors associated with initial viral load at first clinic presentation

ContactVictoria Parsons: [email protected] website: http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=42

Unadjusted coefficient 95% CI p-value

Adjusted coefficient* 95% CI p-value

Year of seroconversion1997-99 0.00 - 0.005 0.00 - 0.0182000-01 0.33 0.03, 0.62 0.24 -0.04, 0.532002-03 0.26 0.00, 0.53 0.23 -0.03, 0.492004-05 0.37 0.11, 0.62 0.21 -0.04, 0.462006-07 0.36 0.11, 0.62 0.29 0.04, 0.542008-09 0.16 -0.10, 0.42 0.05 -0.20, 0.302010-12 0.44 0.21, 0.66 0.35 0.12, 0.57

Acute infection (acute vs. not acute) 0.73 0.56, 0.91 <0.001 0.60 0.40, 0.80 <0.001Seroconversion interval (per month) -0.05 -0.07, -0.04 <0.001 -0.02 -0.04, 0.00 0.026Time diagnosis to initial VL (per day) -0.10 -0.15, -0.05 <0.001 -0.09 -0.14, -0.04 <0.001Age at seroconversion (per decade) 0.07 0.01, 0.14 0.025 0.05 -0.02, 0.11 0.153*Adjusted for all other variables in table

ResultsBackground

Methods

Conclusions

OverallN 1194Median (IQR) year of SC 2006 (2003, 2010)Median (IQR) age at SC (years) 32.6 (26.8, 40.1)Median (IQR) SC interval (months) 4.8 (1.6, 8.1)Median (IQR) days from diagnosis to first VL measure 7 (1, 15)Median (IQR) months from diagnosis to first VLSP measure 4.5 (3.7, 5.5)Median (IQR) months from diagnosis to last VLSP measure 9.4 (6.7, 10.8)Median (IQR) number VL measures included in VLSP 2 (2, 3)Acute infection* (N) 166Ethnicity (N) White 1087

Non-white 90Missing 17

HIV Subtype (N) B 437Non-B 31

Missing 726VL assay upper range of detection copies/ml (N)

>100,000 137>500,000 139>750,000 289

>6,000,000 45>10,000,000 513

Missing 71* Defined as SC interval ≤30 days or laboratory evidence of acute infection

Unadjusted coefficient 95% CI p-value

Adjusted coefficient* 95% CI p-value

Year of seroconversion1997-99 0.00 - 0.013 0.00 - 0.0102000-01 0.14 -0.10, 0.37 0.16 -0.08, 0.392002-03 0.08 -0.14, 0.29 0.08 -0.13, 0.302004-05 0.07 -0.14, 0.28 0.10 -0.11, 0.312006-07 0.09 -0.12, 0.30 0.13 -0.08, 0.332008-09 -0.10 -0.30, 0.11 -0.04 -0.25, 0.172010-12 0.21 0.03, 0.40 0.26 0.07, 0.44

Age at seroconversion (per 10 years) 0.06 0.00, 0.11 0.033 0.06 0.01, 0.11 0.021Seroconversion interval (per month) 0.02 0.00, 0.03 0.010 0.03 0.01, 0.05 0.011Time from diagnosis to first VLSP measure (per month)

-0.01 -0.03, 0.01 0.331 0.06 0.02, 0.10 0.008

Time from diagnosis to last VLSP measure (per month)

-0.02 -0.03, 0.00 0.055 -0.04 -0.07, -0.01 0.019

Number of VL measures contributing to VLSP calculation (continuous)

0.00 -0.04, 0.04 0.980 0.12 0.03, 0.20 0.007

Acute infection (acute vs. not acute) -0.08 -0.22, 0.07 0.290 0.04 -0.13, 0.20 0.673* Adjusted for all other variables in table

Figure 1: Estimated (95% CI) temporal trends in initial viral load atfirst clinic presentation in UK MSM after adjusting for all variablesin table 2

Figure 2: Estimated (95% CI) temporal trends in viral load set-point amongst UK MSM after adjusting for all variables in table 3