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Kristen Chalmet, Kenny Dauwe, Lander Foquet, Bea Van Der Gucht, Dirk Vogelaers, Jean Plum, Linos Vandekerckhove and Chris Verhofstede AIDS Reference Laboratory and AIDS Reference Centre, Ghent University, Belgium Arevir Meeting, Bonn, Germany,

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SLIDE 1

Kristen Chalmet, Kenny Dauwe, Lander Foquet, Bea Van Der Gucht, Dirk Vogelaers, Jean Plum, Linos Vandekerckhove and Chris Verhofstede AIDS Reference Laboratory and AIDS Reference Centre, Ghent University, Belgium

Arevir Meeting, Bonn, Germany, May 2011

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SLIDE 2

ž

University Hospital Ghent, Belgium

ž

Patients newly diagnosed between 2001 and March 2009

ž

No follow-up elsewhere, treatment naïve

ž

Willing to participate Part 1 à 519 patients selected

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SLIDE 3

ž Demographics: age, gender, race ž Infection: route, timing, source ž Laboratory data: viral load, CD4 count, baseline drug resistance, history of

STI infection (Syphilis, HBV, HCV, Chlamydia)

¤ PR-RT sequences contain sufficient information for phylogenetic analysis and

localization of transmission events (Hue et al. AIDS 2004; 18: 719-728) à 506 successfully sequenced pol sequences (97.5%) Transmission Cluster ⇔ at least 2 out of 3 criteria are fulfilled:

  • 1. Bootstrap value ≥ 90
  • 2. Mean genetic distance ≤ 0.015
  • 3. Posterior probability = 1

NJ analysis Bayesian analysis

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SLIDE 4

ž Subtype:

B: 60% non-B: 40%

Chalmet et al. 2010, BMC Infectious Diseases, 10, 262.

B Non B

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SLIDE 5

Chalmet et al. 2010, BMC Infectious Diseases, 10, 262.

B Non B

26 transmission clusters (n≥3) containing 169 individuals

  • Subtype B: 18 clusters (av. Number of patients 4.7 [3-10]) + 1 cluster of 57 patients
  • Non B subtypes: 7 clusters (av. Number of patients 3.7 [3-6])
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SLIDE 6

Predictors for being a member of a cluster

ž Homosexual transmission ž Caucasian origin ž Slightly younger of age cluster cluster Count Count p-value ODDS ratio 95% CI p-value 169 (33.4%) 337 (66.6%) Subtype B 84.6% 47.2% <0.001

  • Homosexual transmission

83.3% 45.3% <0.001 3.1 1.8 - 5.4 <0.001 HBV+ 33.5% 40.7% 0.12

  • HCV+

8.4% 6.2% 0.356 Syphilis+ 40.2% 21.8% <0.001

  • Chlamydia+

40.4% 28.2% 0.013

  • Gender (male)

91.1% 64.4% <0.001

  • Caucasian origin

95.2% 58.2% <0.001 14.5 4.2 - 49.9 <0.001 DRM 7,10% 6,20% 0,709 PHI 21.0% 12.6% 0.017

  • Median (IQR)

Median(IQR) p-value CD4+ T cells (cells/µl) 419.5 (311-580) 351 (192-550) 0.002

  • Age (years)

36 (31-42) 38 (32-45) 0.067 0.9 0.92 - 0.97 <0.001 Multivariate Bin. Log. Regression ž Subtype B infection - Homosexual transmission – Male – Caucasian origin ž More STI à Risk behavior? ž Higher CD4+ T cell counts and more PHI à Earlier presentation? cluster cluster Count Count p-value ODDS ratio 95% CI p-value 169 (33.4%) 337 (66.6%) Subtype B 84.6% 47.2% <0.001

  • Homosexual transmission

83.3% 45.3% <0.001 3.1 1.8 - 5.4 <0.001 HBV+ 33.5% 40.7% 0.12

  • HCV+

8.4% 6.2% 0.356 Syphilis+ 40.2% 21.8% <0.001

  • Chlamydia+

40.4% 28.2% 0.013

  • Gender (male)

91.1% 64.4% <0.001

  • Caucasian origin

95.2% 58.2% <0.001 14.5 4.2 - 49.9 <0.001 DRM 7,10% 6,20% 0,709 PHI 21.0% 12.6% 0.017

  • Median (IQR)

Median(IQR) p-value CD4+ T cells (cells/µl) 419.5 (311-580) 351 (192-550) 0.002

  • Age (years)

36 (31-42) 38 (32-45) 0.067 0.9 0.92 - 0.97 <0.001 Multivariate Bin. Log. Regression cluster cluster Count Count p-value ODDS ratio 95% CI p-value 169 (33.4%) 337 (66.6%) Subtype B 84.6% 47.2% <0.001

  • Homosexual transmission

83.3% 45.3% <0.001 3.1 1.8 - 5.4 <0.001 HBV+ 33.5% 40.7% 0.12

  • HCV+

8.4% 6.2% 0.356 Syphilis+ 40.2% 21.8% <0.001

  • Chlamydia+

40.4% 28.2% 0.013

  • Gender (male)

91.1% 64.4% <0.001

  • Caucasian origin

95.2% 58.2% <0.001 14.5 4.2 - 49.9 <0.001 DRM 7,10% 6,20% 0,709 PHI 21.0% 12.6% 0.017

  • Median (IQR)

Median(IQR) p-value CD4+ T cells (cells/µl) 419.5 (311-580) 351 (192-550) 0.002

  • Age (years)

36 (31-42) 38 (32-45) 0.067 0.9 0.92 - 0.97 <0.001 Multivariate Bin. Log. Regression

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SLIDE 7

Combination of genetic variability with patients demographics and laboratory data provides a more in depth understanding of the local epidemic

ž

More and larger transmission clusters are seen in Subtype B infected patients compared to non B infected

ž

Association between phylogenetic clustering, homosexual transmission and presence of other STI à high risk-taking MSM are the most important source for local onward HIV transmission.

ž

Tendency for earlier presentation of MSM à Higher awareness of risk-taking?

Continuous efforts to sustain prevention programs targeting MSM are needed!

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SLIDE 8

ž

University Hospital Ghent, Belgium

ž

Patients newly diagnosed between 2001 and 2009

ž

No follow-up elsewhere, treatment naïve

ž

Willing to participate à 594 patients selected

¤

PR-RT sequences contain sufficient information for phylogenetic analysis and localization of transmission events (Hue et al. AIDS 2004; 18: 719-728) à Succesful pol sequencing for 576 patients (97%)

Transmission Cluster ⇔ at least 2 out of 3 criteria are fulfilled:

  • 1. Bootstrap value ≥ 90
  • 2. Mean genetic distance ≤ 0.015
  • 3. Posterior probability = 1

NJ analysis Bayesian analysis

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SLIDE 9

ž

University Hospital Ghent, Belgium

ž

Patients newly diagnosed between 2001 and December 2009

ž

No follow-up elsewhere, treatment naïve

ž

Baseline plasma sample available and qualified for sequencing of pol region

ž

Willing to participate Part 2 à 576 patients selected (=part 1 + 70 patients)

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SLIDE 10

ž Demographics: age, gender, race ž Infection: route, timing, source ž Laboratory data: viral load, CD4 count, baseline drug resistance ž Subtype:

B: 60% non-B: 40%

ž CCR5 genotype:

wt/wt: 414 (87.5%) wt/Δ32: 59 (12.5%) Δ32/Δ32: 0

ž Co-receptor tropism: population V3 sequencing, Geno2pheno (5.75% and

10% FPR cut off) Successful for 539 individuals: 11.9% X4/DM (5.75%) 19.1% X4/DM (10%)

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SLIDE 11

Infection status Acute 56% 63%

(n=144; X4/DM: n=25; R5: n=119)

Chronic 44% 37% Transmission route Homosexual 62% 59% 0,65 Heterosexual 33% 38% 0,42 IVDU 5% 1% 0,05 Other 0% 1% 0,59 Transmitted drug resistance Yes (n=38) 13% 6% No 87% 94% 0,51 0,01

Correlates for tropism X4/DM R5

103 436 19,1% 80,9% p-value Age 38 (31-43) 37 (31-44) 0,67 Gender Male 76% 73% Female 24% 27% Origin Caucasian 73% 71% 0,70 African 19% 25% 0,26 Other 8% 4% 0,16 CCR5 genotype wt-wt 89% 87% wt-D32 11% 13% Patients (total n=539) 0,63 0,63*

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SLIDE 12

Viral load

X4/DM R5

Patient n 539 103 436 19,1% 80,9% p-value Baseline viral load Median (IQR) 4,6 (4,0-5,0) 4,5 (3,9-5,0) 0,27 VL > 100 000 c/ml 29% 27% 0,59

X4/DM R5

Patient n 539 103 436 19,1% 80,9% p-value Baseline CD4 count Median (IQR) 360 (160-521) 385 (256-581) 0,012 CD4 <200 (n=108) 33% 17% <0,001

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SLIDE 13

X4/DM R5

Patient n=539 103 436 19,1% 80,9% p-value Subtype B 323 55% 61% non-B 216 45% 39% 0,29

X4/DM R5

Patient n=539 103 436 19,1% 80,9% p-value Subtype B 323 55% 61% C 31 5% 6% 0,66 A 34 7% 6% 0,83 01_AE 43 17% 6% <0,001 02_AG 58 8% 11% 0,30 Other 50 9% 9% 0,83

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SLIDE 14

ž 103/539 (19.1%) of newly diagnosed patients were infected with X4/

DM viruses (G2P 10%FPR).

ž Presence of X4/DM virus was associated with lower CD4 counts but

not with higher viral load.

ž Presence of X4/DM virus was not associated with the wt/∆32 CCR5

genotype

ž Significant higher prevalence of X4/DM viruses in patients infected

with the 01_AE subtype, through IVDU or with a resistant strain.

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SLIDE 15

B Non B

Blue branches: transmission cluster (n≥2) Red stars: X4/DM virus

B Non B

Chalmet et al. 2010, BMC Infectious Diseases, 10, 262.

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SLIDE 16

X4/DM viruses only 7/63 (11.1%) of all clusters

X4/DM R5 X4/DM + R5 n (pts) n (pts) n (pts) n (pts) Transmission clusters 63 (261) 7 (20) 38 (167) 18 (74) Clusters (=2) 36 (72) 5 (10) 25 (50) 6 (12) Clusters (>=3) 27 (189) 2 (10) 13 (117) 12 (62)

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SLIDE 17

¤ MSM ¤ Almost identical PR-RT and V3 sequences ¤ Epidemiological link (n=3) ¤ Acute infection (n=3) ¤ Phenotype: DM (n=1); MT2 positive virus (n=2)

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SLIDE 18

X4/DM + R5 2 HoS 2 HeS 7 HoS 2 HeS 2 B 2 non B 7 B 2 non B Transmission route Subtype X4/DM 4 (31%) R5 9 (69%) Source-receptor pairs 13

Selection of transmission pairs

¤ Epidemiologically linked as source and

receptor

¤ Phylogenetically confirmed à 38 transmission pairs ¤ Genetic distance in pol ≤ 0.001 à 13 transmission pairs

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SLIDE 19

ž Viruses reported as X4/DM (FPR <10%) can be readily transmitted: Ø

Overall X4/DM incidence in newly diagnosed individuals: 19.1%

Ø

X4/DM in transmission clusters: 11.1%

Ø

X4/DM in transmission pairs: 31%

ž This observation DOES NOT exclude the use of the CCR5 receptor at transmission

but warrants a rethinking of the dogma that mainly R5 strains are transmitted.

ž Patients infected with X4/DM strains are at risk for

Ø

Faster immune deterioration

Ø

Intrinsic resistance to CCR5 inhibitors.  Baseline tropism determination and early treatment of those infected with X4/DM ?

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SLIDE 20

ARL

Chris Verhofstede Kenny Dauwe Jacqueline Reynaerts Els Demecheleer Delfien Staelens Marlies Schauvliege Jean Plum

ARC

Dirk Vogelaers Linos Vandekerckhove Bea Vandergucht Jolanda Pelgrom Filip Van Wanzeele Steven Callens Erica Sermyn

Ghent University