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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. - PowerPoint PPT Presentation
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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
R5 viruses (M-tropic, NSI)Transmitted variantsPrevalent 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)
CCR5
Q
LSD
TF
F
LR
A
PI
A
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ETYNDS T Y I S I GEM- NH2
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*
*
N39-
-65 75-
-97 110-
-133 154-
-176 -202
224- -239
-262-282
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352
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CCR5- & CXCR4-tropic HIV
Prevalence of Co-receptor UsageStudy/Source Population R5 X4 X4/R5
Maraviroc Phase 2a Naive 94 0 6
Homer cohortb
(n=979)Naive 83 <1 17
C & W cohortc
(n=563)Naïve/
Experienced85 <1 15
GSKd
(n=299)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-1136b Brumme ZL et al. JID 2005;192(3):466-74. e Whitcomb et al. CROI 2003. Abstract 557c Moyle GJ et al. JID 2005;191(6):866-72 f Huang et al. ICAAC 2002. Abstract 2040
Prevalence and Predictive Factors for R5 and X4 Coreceptor Usage
0
20
40
60
80
100
Prev
alen
ce (%
)Pr
eval
ence
(%)
CD4 (cells/mmCD4 (cells/mm33))
84.3%84.3%
59.3%59.3%
<<100 101-300 >300100 101-300 >300 (n=81) (n=185) (n=248)(n=81) (n=185) (n=248)
83.5%83.5%
R5 PrevalenceR5 Prevalence 563 HIV patients– 85% male– 66% Caucasian– Mean age: 44 years– Clade B: 76%– R5 tropic: 85%– R5/X4 dual tropic: 15%
Moyle GJ, et al. JID 2005
MeanR5
TropicR5/ X4 Tropic
CD4 (cells/mm3)
307* 231
HIV RNA (copies/mL)
35,800† 66,228
**PP=0.007; =0.007; ††PP<0.001.<0.001.
Prevalence of R5 Use by BaselineCD4 and HIV RNA Levels
71
92 89
60
85 84
67
80 81
58
8278
Prev
alen
ce o
f R5
Use
(%)
Prev
alen
ce o
f R5
Use
(%)
100100
8080
6060
4040
2020
00 <<100 101-300 >300100 101-300 >300Baseline CD4Baseline CD4
(cells/mm(cells/mm33))
>100K>100KBaseline HIV RNABaseline HIV RNA
(copies/mL)(copies/mL)
>5-50K>5-50K >50-100K>50-100K
<5K<5K
n=563.n=563.
Moyle GJ, et al. JID 2005
Clinical Progression & Response to HAART
• Swiss HIV Cohort• 96 progressors vs. 84 matched non-progressors
R5 at baseline(n=84)
X4/R5 at baseline(n=84)
Significance
CD4 rise at 6 months
82 40 p = 0.012
HIV RNA < 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
Determination of R5/X4 Tropism
Two potential roles for tropism testing:
• Guiding therapy decisions
• Predicting disease progression
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
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
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
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
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)
Baseline DemographicsR5-tropic(n=326)
X4/R5(n=76)
p-value
Male 288 (88.3%) 72 (94.7%) 0.101
WhiteBlackOther
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) 203 (58-375) <0.001
HIV RNA (IQR) 39385 (13358-120818) 142568 (47186-275726) <0.001
Mutations NRTI NNRTI PI
---
---
0.8260.893 0.550
Clade BClade Other Untested
252 (77.3%)57 (17.5%)17 (5.2%)
64 (84.2%)11 (14.5%)
1 (1.3%)0.242
-600
-500
-400
-300
-200
-100
0
100
200
300
400
3 6 9 12 15 18 21 24
Duration since sample result (months)
CD
4 co
unt f
rom
tim
e w
hen
sam
ple
take
n
Naïve : R5 Naïve : X4/R5
DAVG analysis (time weighted differences in average.Censored at HAART; Error bars are 95% CI
p = 0.562
p = 0.026
R5 n= 187 119 127 100 107 76 74 72 93 X4 n= 23 18 13 9 11 6 5 2 2
CD4 decline before HAART
R5 n= 229 197 190 188 194 172 161 151 182 X4 n= 60 51 26 50 56 44 47 50 50
CD4 rise on HAART
-600
-500
-400
-300
-200
-100
0
100
200
300
400
0 3 6 9 12 15 18 21 24
Duration since sample result (months)
CD
4 co
unt f
rom
tim
e w
hen
sam
ple
take
n
Naïve: R5 Naïve: X4/R5
Time weighted differences in averages (DAVG) from baseline estimated using linear MIXED model
CD4 rise on HAART
R5 X4/R5 p-value
12 monthsmean (95% CI)
185(166-204)
182(145-219)
0.812
24 months mean (95% CI)
247(227-267)
292(254-330)
0.482
Rates of Viral Suppression289 subjects (229 R5, 60 X4/R5) started HAART
R5 tropic(n=229)
X4/R5 tropic(n=60)
p-value
N (%) with HIV RNA< 50 at 6 months
163(71.2%)
45(75.0%)
0.637
N (%) with HIV RNA< 50 at 12 months
168(73.4%)
47(78.3%)
0.509
N (%) with HIV RNA< 50 at 24 months
166(72.5%)
41(68.3%)
0.670
Time to Viral Suppression
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 6 9 15 18 21
Duration since sample result (months)
Pro
porti
on a
chie
ving
VL<
50 c
opie
s/m
l
R5 X4/R5
R5 n= 229 197 190 188 194 172 161 151 X4 n= 60 51 26 50 56 44 47 50
3 12
Survival analysis; Cox’s proportional hazards regression to adjust for baseline HIV RNA and HAART
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
Acknowledgements
• Dr Marta Boffito• All the St Stephen’s Centre patients• Pfizer for funding of tropism testing• Monogram Biosciences
