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Laura Waters , Sundhiya Mandalia, Adrian Wildfire, Paul Randell, Brian Gazzard & Graeme Moyle.

HIV co-receptor tropism in treatment-naïve patients: impact on CD4 decline and subsequent response to HAART. Laura Waters , Sundhiya Mandalia, Adrian Wildfire, Paul Randell, Brian Gazzard & Graeme Moyle. St Stephen’s Centre , Chelsea & Westminster Hospital, London, UK. CCR5. I. Y. S.

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Laura Waters , Sundhiya Mandalia, Adrian Wildfire, Paul Randell, Brian Gazzard & Graeme Moyle.

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  1. HIV co-receptor tropism in treatment-naïve patients: impact on CD4 decline and subsequent response to HAART Laura Waters, Sundhiya Mandalia, Adrian Wildfire, Paul Randell, Brian Gazzard & Graeme Moyle. St Stephen’s Centre, Chelsea & Westminster Hospital, London, UK

  2. CCR5 I Y S CXCR4 T I M - NH S G E 2 D N Y D M Q - NH 2 V Y D S S M Y K S T D E G P E Y Y N K Q * T I S G E I I D P S G M Y C C I E F R E * D L E E N N W F N E L P C P V F Q Y Q Y F G L C S N E Q S W G Y V K W I Y F S N F L N A N V P K D N A D F F S A V W G F R I T F E F N N D Q V N H E V L Q K N F D S F G E R F N H A T Q * Q S L C A C F K R V S K Y Q K I -282 A M S Q I H Q F L I D K D 110- N -97 39- -176 -202 -262 A T F W D A C C P L A A H I I A Y S T F L Q T A V I S I S 277- F T Q V R Y R K N Y I W H F I V M G I T F 31- 102- -89 -168 -197 -258 A I L S P G I A G D L I I T L T Y I P I L Y Y L P L H T I L M Q F I V T L P F A P A L F V L V T L V L N L L G P W L F F Y L F W G T I I L I V L T S P L G G I T E G L Y L I C C H V I D L S S P A I V F A C L T V F Y L P L Y N L V V G A V L F N L F L S L P M G I I S G N I L V C S L A P V W F I F L G F A L P W A T F L L L G Y I L I G F F V L F C H I V L H F A Y I C I L Y V F D L G S A M V F L C V V L R I V I V F A G S I V Y N I V M V Y S I T T L L V M N A I F F T C I I V P W G A G L L I I Y M I I Y K K D K S -65 75- -133 154- 224- -239 I L N L I S V G S T I Y V K 308- Q L L T I F F A E R L Q K L A D H L I Y I T L L I F V V A A S Y I E G L A K T K T N I D K R L 67- 219- V L L -57 -125 146- -235 K K S K 303- L M R G T V T C D L L L V A R S G R F H R F S S F A Y S V Y L S K K T R N I K L S F T R K Q L L G H R R K M V K Q H L S G R V H P K A R K A A I R K T G I R K H Q F N S R L G S T C V C R H K N V R E K K S S S H E A S Q Q A K S C F E V F A L S F E A C I V S T S H P S -352 S E S R T R T Y A S V S G E Q E I S L V G - COOH 352 CCR5- & CXCR4-tropic HIV R5viruses (M-tropic,NSI) Transmitted variants Prevalent in early disease • X4viruses (T-tropic,SI) • Late disease; associated with CD4 decline, HIV RNA increase and clinical progression Dual-tropic viruses useCCR5orCXCR4(in vitro)

  3. Prevalence of Co-receptor Usage a Data on file d Demarest et al. ICAAC 2004. Abstract H-1136 b Brumme ZL et al. JID 2005;192(3):466-74. e Whitcomb et al. CROI 2003. Abstract 557 c Moyle GJ et al. JID 2005;191(6):866-72 f Huang et al. ICAAC 2002. Abstract 2040

  4. Prevalence and Predictive Factors for R5 and X4 Coreceptor Usage • 563 HIV patients • 85% male • 66% Caucasian • Mean age: 44 years • Clade B: 76% • R5 tropic: 85% • R5/X4 dual tropic: 15% R5 Prevalence 84.3% 83.5% 59.3% Prevalence (%) <100 101-300 >300 (n=81) (n=185) (n=248) CD4 (cells/mm3) *P=0.007; †P<0.001. Moyle GJ, et al. JID 2005

  5. Prevalence of R5 Use by BaselineCD4 and HIV RNA Levels 100 80 60 40 20 0 Prevalence of R5 Use (%) <5K >5-50K >50-100K <100 101-300 >300 >100K Baseline CD4 (cells/mm3) Baseline HIV RNA (copies/mL) n=563. Moyle GJ, et al. JID 2005

  6. Clinical Progression & Response to HAART • Swiss HIV Cohort • 96 progressors vs. 84 matched non-progressors Phillpott et al. IAS 2006. Abstract THAA0201

  7. Determination of R5/X4 Tropism Two potential roles for tropism testing: • Guiding therapy decisions • Predicting disease progression

  8. Aim To study the impact of R5/X4 tropism as determined by the ViroLogic Phenosense Assay on: • The rate of CD4 decline prior to commencing therapy • Response to therapy: - CD4 rise - Time to HIV RNA < 50 c/mL - Proportion with HIV RNA < 50 c/mL

  9. MethodsStudy Design • Subjects from epidemiology study: R5 tropic vs.X4/mixed/dual tropic • Prospective cohort database used to record: - Sequential CD4 counts from tropism test to HAART initiation (censored if < 3 months) - Sequential CD4 counts and HIV RNA after HAART - HAART regimen prescribed

  10. Methods Response to HAART • HAART defined as: - ≥ 2NRTI + NNRTI - ≥ 2NRTI + PI (unboosted) - ≥ 2NRTI + PI/r (boosted) • Exclusions: - Non-HAART regimens - < 6 months follow-up • Data censored at: - 96 weeks - End of follow-up - Therapy switch for virological failure

  11. MethodsStatistics • CD4 decline: DAVG using MIXED model adjusted for baseline HIV RNA • CD4 response to HAART: univariate + multivariate linear MIXED model (adj. for baseline HIV RNA and HAART) • Proportion with HIV RNA < 50 c/mL: 2 test • Time to HIV RNA < 50 c/mL: survival analysis; Cox’s proportional hazards regression to adj. for baseline HIV RNA and HAART

  12. Results • 402 naïve subjects tropism tested: - 326 R5 - 73 X4/R5 (mixed/dual) - 3 X4 • 340 commenced HAART by August 2006 - 51 excluded from analysis* - 229 R5 - 60 X4/mixed/dual • 62 remained off therapy *< 6/12 follow-up (n=28); non-HAART (n=23)

  13. Baseline Demographics

  14. CD4 decline before HAART R5 n= 187 119 127 100 107 76 74 72 93X4 n= 23 18 13 9 11 6 5 2 2 400 300 200 Duration since sample result (months) 100 3 6 9 12 15 18 21 24 0 CD4 count from time when sample taken -100 -200 -300 p = 0.026 -400 p = 0.562 Naïve : R5 Naïve : X4/R5 -500 -600 DAVG analysis (time weighted differences in average. Censored at HAART; Error bars are 95% CI

  15. CD4 rise on HAART R5 n= 229 197 190 188 194 172 161 151 182X4 n= 60 51 26 50 56 44 47 50 50 400 300 200 100 0 0 3 6 9 12 15 18 21 24 CD4 count from time when sample taken -100 Duration since sample result (months) -200 -300 Naïve: R5 Naïve: X4/R5 -400 -500 -600 Time weighted differences in averages (DAVG) from baseline estimated using linear MIXED model

  16. CD4 rise on HAART

  17. Rates of Viral Suppression 289 subjects (229 R5, 60 X4/R5) started HAART

  18. Time to Viral Suppression R5 n= 229 197 190 188 194 172 161 151 X4 n= 60 51 26 50 56 44 47 50 1 0.9 0.8 0.7 0.6 Proportion achieving VL<50 copies/ml 0.5 0.4 0.3 R5 X4/R5 0.2 0.1 0 0 6 9 15 18 21 3 12 Duration since sample result (months) Survival analysis; Cox’s proportional hazards regression to adjust for baseline HIV RNA and HAART

  19. Conclusions • Subjects with X4 HIV-1 experience more rapid CD4 decline than those with R5 patients (adjusted for baseline viral load) • Similar proportions achieve viral suppression at 1 year and 2 years • CD4 rise similar over 96 weeks of HAART • Time to viral suppression same for R5 and X4 virus when adjusted for baseline viral load

  20. Acknowledgements • Dr Marta Boffito • All the St Stephen’s Centre patients • Pfizer for funding of tropism testing • Monogram Biosciences

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