SLIDE 1
AREVIR May 2012
Chris Verhofstede, Aids Reference Laboratory, Ghent University, Belgium
SLIDE 2
- Maraviroc initiated in only a limited number of patients for whom
tropism testing is requested (25.1% of the R5 predictions)
- Repeated requests for the same patient can be expected
Validity in time of an R5 prediction? Mechanisms responsible for co‐receptor switch
- Presence of X4/DM virus is associated with a faster CD4 decline,
faster disease progression, poorer response to ART
- X4/DM viruses can be transmitted – infection with X4/DM virus is
associated with faster progression
Added value of baseline tropism testing? Predict the chance for early tropism shift?
SLIDE 3
- 244 individuals newly diagnosed with HIV‐1
between 2001 and 2009 in Ghent that had follow‐ up samples available and remained treatment naive for at least 3 months (maximum 9 years).
SLIDE 4
- Genotypic tropism testing on plasma RNA
- Prediction using Geno2pheno; FPR of 10%
- Singleton testing (repeated in triplicate in switching
patients)
SLIDE 5
- Results of X4/DM prevalence studies suggest a
low prevalence of tropism switch 0.8% ‐ 15.9% X4/DM in recent infections 10% ‐ 18.9% X4/DM in chronic infections 31.4% ‐ 52% X4/DM in late stage disease
SLIDE 6
225 (92.2%) succesfully sequences 225 (92.2%) succesfully sequences 1st sample R5 189 (84.0%) 1st sample R5 189 (84.0%) 1st sample X4 36 (16.0%) 1st sample X4 36 (16.0%) 2nd sample R5 3 (8.3%) 2nd sample R5 3 (8.3%) 2nd sample X4 14 (7.4%) 2nd sample X4 14 (7.4%) 2nd sample R5 175 (92.6%) 2nd sample R5 175 (92.6%)
244 patients 244 patients
Technical failures 19 (7.8%) Technical failures 19 (7.8%) 2nd sample X4 33 (91.7%) 2nd sample X4 33 (91.7%)
SLIDE 7
- Patient 1: infection with X4 strain, super‐infection
with R5 virus
Patient Date FPR CD4 Viral load V3
2
6/04/2005 C T R P N N N T R R S I G I G P G K T F Y A T G D V I G D I R K A H C
6,8 658 61600 12/08/2005 - - - -
- - - - -
- - - -/Q
- - - - - -
- -
- 11,5
466 65300 22/02/2006 - - - -
Q
Y
407 10900 29/05/2007 - - - -
Q
X
242 12303 3
18/06/2009 C T R P N N N T G K S I H L G P G R A F F V T G R I I G N I R Q A H C
7,4 711 37863
19/10/2009 - - - -
- - - - -
- - -
- - - - - -
- -
- 7,4
1080 91209
1/02/2010 - - - -
- - - - -
- - -
- - - - - -
- -
- 7,4
764 19768
31/05/2010 - - - -
- - - - -
- - -
- - - - - - -/D - - -/E - -/Y -
8,1 728 / 27/09/2010 - - - - -/S -
- - - - -
- - -
- -/A - - - - - -
D
538 8686 18/04/2011 - - - -
D
E
533 12939
Patient Date FPR CD4 Viral load
1
21/11/2008 C T R P G N N T R K S I H L G P G R A W Y T T G E V I G N P R K A H C
3,8 609 600
26/01/2009 -
403 507
27/03/2009 -
378 1418 19/01/2010 -
X
298 67799
V3
SLIDE 8
R5/R5 R5/X4 p‐value n = 189 175 14 Age (yr) (n = 189) 175 14 Median (IQR) 40 (34‐46) 41 (31‐51) 0,788 Gender (n = 189) 175 14 Male 144 (82%) 11 (79%) 0,720 Female 31 (18%) 3 (21%) Race or ethnicity (n = 189) 175 14 Caucasian 145 (84%) 14 (100%) 0,228 Other 27 (16%) 0 (0%) Transmission route (n = 170) 158 12 Homosexual contact 109 (69%) 10 (84%) 0,514 Heterosexual contact 43 (27%) 1 (8%) 0,190 Other 6 (4%) 1 (8%) 0,407 Transmitted drug resistance (n = 189) 175 14 Yes 9 (5%) 0 (0%) 1,000 No 166 (95%) 14 (100%) Virus subtype (n = 189) 175 14 B 128 (75%) 11 (79%) 0,411 non B 43 (25%) 3 (21%) Follow‐up period, Mean (IQR), months (n = 189) 35 (19‐46) 31 (21‐38) 0,703
SLIDE 9
R5/R5 R5/X4 p‐value n = 189 175 14 CCR5 genotype (n = 184) 170 14 wt/wt 144 (85%) 13 (93%) 0,697 wt/Δ32 26 (15%) 1 (7%) Baseline CD4+ T cell count (cells/mm+) (n = 178) 164 14 Median (IQR) 498 (365‐653) 491 (339‐590) 0,457 CD4 <350 36 (22%) 4 (29%) 0,496 CD4 between 350 and 500 47 (29%) 3 (21%) 0,520 CD4 >500 81 (49%) 7 (50%) 0,781 Baseline viral load (log cp/ml) (n = 186) 172 14 Median (IQR) 4,46 (3,95‐4,96) 4,43 (3,96‐4,77) 0,867 Therapy initiation (n = 189) 175 14 Yes 137 (78%) 14 (100%) 0,077 No 38 (22%) 0 (0%) Drug free period, Mean (IQR), months (n = 152) 32 (15‐44) 31 (21‐38) 0,947 Treatment initiation CD4+ T cell count (cells/mm+) (n = 178) 164 14 Median (IQR) 360 (274‐482) 227 (159‐409) 0,015 Treatment initiation viral load (log cp/ml) (n = 183) 170 13 Median (IQR) 4,55 (3,84‐4,98) 4,81 (4,24‐5,07) 0,297 FPR at diagnosis (%) (n = 189) 175 14 Median (IQR) 59 (31‐81) 27 (15‐48) 0,001 FPR < 50 73 (42%) 12 (86%) 0,001 FPR > 50 102 (58%) 2 (14%)
SLIDE 10
SLIDE 11
Switch after 4y
FPR 10%‐25%: 28%
FPR 25%‐50%: 9.7%
FPR 50%‐75%: 7.1%
FPR 75%‐100%: 3.2%
SLIDE 12
- Overall low rate of co‐receptor switch in ART‐naive
individuals (17/225 )
- Tropism shift is associated with need to initiate treatment
during the study period and with a lower CD4 count at treatment initiation
- FPR of the baseline sample is highly predictive for R5 to
X4/DM switch. Additional study needed to understand the mechanisms behind this
- No tropism shift in the first 2 years in naive patients with a
baseline FPR >50% suggesting that in these patients the tropism result might remain valid for at least 2 years
SLIDE 13
ARL
Virginie Mortier, Jacqueline Reynaerts Els Demecheleer, Delfien Staelens Marlies Schauvliege, Kenny Dauwe Leen Vancoillie, Kristen Chalmet Jean Plum
ARC
Dirk Vogelaers, Linos Vandekerckhove Bea Vandergucht, Jolanda Pelgrom Filip Van Wanzeele, Steven Callens Erica Sermyn, Filip Moerman
