HIV co-receptor tropism in treatment-na

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 Stephens Centre,
• Chelsea Westminster Hospital,
• London, UK

2
CCR5- CXCR4-tropic HIV
R5 viruses (M-tropic, NSI) Transmitted
variants Prevalent in early disease

• X4 viruses (T-tropic, SI)
• Late disease associated with CD4 decline, HIV
  RNA increase and clinical progression

Dual-tropic viruses use CCR5 or CXCR4 (in vitro)
3
Prevalence of Co-receptor Usage
Study/Source Population R5 X4 X4/R5
Maraviroc Phase 2a Naive 94 0 6
Homer cohortb (n979) Naive 83 lt1 17
C W cohortc (n563) Naïve/ Experienced 85 lt1 15
GSKd (n299) Naive 88 0 12
TORO 1/2e Experienced 62 4 34
ViroLogicf Experienced 50 2 48
a Data on file d Demarest et al. ICAAC
2004. Abstract H-1136 b Brumme ZL et al. JID
2005192(3)466-74. e Whitcomb et al. CROI
2003. Abstract 557 c Moyle GJ et al. JID
2005191(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 ()
Mean R5 Tropic R5/ X4 Tropic
CD4 (cells/mm3) 307 231
HIV RNA (copies/mL) 35,800 66,228
lt100 101-300 gt300 (n81)
(n185) (n248)
CD4 (cells/mm3)
P0.007 Plt0.001.
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 ()
lt5K
gt5-50K
gt50-100K
lt100 101-300
gt300
gt100K
Baseline CD4 (cells/mm3)
Baseline HIV RNA (copies/mL)
n563.
Moyle GJ, et al. JID 2005
6
Clinical Progression Response to HAART

• Swiss HIV Cohort
• 96 progressors vs. 84 matched non-progressors

R5 at baseline (n84) X4/R5 at baseline (n84) Significance
CD4 rise at 6 months 82 40 p 0.012
HIV RNA lt 500 at 6 months 57 (68) 27 (32) p 0.33
Hazard ratio for clinical progression 1.00 4.00 95 CI 1.83 8.72
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 lt 50 c/mL
• - Proportion with HIV RNA lt 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 lt 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
• - lt 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 lt 50 c/mL ?2 test
• Time to HIV RNA lt 50 c/mL survival analysis
  Coxs proportional hazards regression to adj. for
  baseline HIV RNA and HAART

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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

lt 6/12 follow-up (n28) non-HAART (n23)
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Baseline Demographics
R5-tropic (n326) R5-tropic (n326) X4/R5 (n76) p-value
Male 288 (88.3) 288 (88.3) 72 (94.7) 0.101
White Black Other 236 (72.4) 44 (13.5) 46 (14.1) 236 (72.4) 44 (13.5) 46 (14.1) 50 (65.8) 9 (11.8) 17 (22.4) 0.203
CD4 (IQR) 325 (207-458) 325 (207-458) 203 (58-375) lt0.001
HIV RNA (IQR) 39385 (13358-120818) 39385 (13358-120818) 142568 (47186-275726) lt0.001
Mutations NRTI NNRTI PI - - - - - - - - - 0.826 0.893 0.550
Clade B Clade Other Untested Clade B Clade Other Untested 252 (77.3) 57 (17.5) 17 (5.2) 64 (84.2) 11 (14.5) 1 (1.3) 0.242
14
Baseline Genotypic Resistance
R5-tropic (n326) X4-tropic (n76) p-value
NRTI mutations 0 1 2 3 4 untested 286 (87.7) 19 (5.8) 4 (1.2) 2 (0.6) 1 (0.4) 14 (4.3) 66 (86.8) 5 (6.6) 1 (1.3) 1 (1.3) 1 (1.3) 2 (2.7) 0.826
PI mutations 0 1 2 3 4 untested 304 (93.3) 3 (0.8) 2 (0.6) 1 (0.4) 2 (0.6) 14 (4.3) 69 (90.8) 2 (2.7) 1 (1.3) 1 (1.3) 1 (1.3) 2 (2.7) 0.550
NNRTI mutations 0 1 2 untested 302 (92.6) 6 (1.8) 4 (1.2) 14 (4.3) 71 (93.4) 1 (1.3) 2 (2.7) 2 (2.7) 0.893
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CD4 decline before HAART
R5 n 187 119 127 100
107 76 74 72
93 X4 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
16
CD4 rise on HAART
R5 n 229 197 190 188
194 172 161 151
182 X4 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
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CD4 rise on HAART
R5 X4/R5 p-value
12 months mean (95 CI) 185 (166-204) 182 (145-219) 0.812
24 months mean (95 CI) 247 (227-267) 292 (254-330) 0.482
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Rates of Viral Suppression

• 289 subjects (229 R5, 60 X4/R5) started HAART

R5 tropic (n229) X4/R5 tropic (n60) p-value
N () with HIV RNA lt 50 at 6 months 163 (71.2) 45 (75.0) 0.637
N () with HIV RNA lt 50 at 12 months 168 (73.4) 47 (78.3) 0.509
N () with HIV RNA lt 50 at 24 months 166 (72.5) 41 (68.3) 0.670
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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 VLlt50 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 Coxs proportional hazards
regression to adjust for baseline HIV RNA and
HAART
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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

21
Acknowledgements

• Dr Marta Boffito
• All the St Stephens Centre patients
• Pfizer for funding of tropism testing
• Monogram Biosciences