HIV-1 co-receptor tropism in recently diagnosed patients: correlates of CXCR4-use, impact of subtype and indications for X4/DM virus transmission

Transcription

1 Poster nr. O_26 HIV-1 co-receptor tropism in recently diagnosed patients: correlates of CXCR4-use, impact of subtype and indications for X4/DM virus transmission 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

2 Patient selection University Hospital Ghent, Belgium Patients newly diagnosed between 2001 to 2009 No follow-up elsewhere, treatment naïve Baseline plasma sample available Willing to participate 579 patients selected

3 Patient information (n=579) Demographics: age, gender, race Infection: route, timing, source Laboratory data: viral load, CD4 count, baseline drug resistance Subtype: B: 60% non-b: 40% CCR5 genotype: wt/wt: 414 (87.5%) wt/ 32: 59 (12.5%) 32/ 32: 0 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%)

4 Correlates for tropism X4/DM R5 Patient (total n=539) ,1% 80,9% p-value Age 38 (31-43) 37 (31-44) 0,67 Gender Male 76% 73% Female 24% 27% 0,63 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% 0,63* Transmission route Homosexual 62% 59% 0,65 Heterosexual 33% 38% 0,42 IVDU (n=8) 5% 1% 0,05 Other 0% 1% 0,59 Transmitted drug resistance Yes (n=38) 13% 6% No 87% 94% 0,01 * p=0,57 when analyzing Caucasians only

5 Baseline CD4 count Patient n=539 X4/DM R ,1% 80,9% p-value Baseline CD4 count Median (IQR) 360 ( ) 385 ( ) 0,012 CD4 <200 (n=108) 33% 17% <0,001 Viral load Patient n=539 X4/DM R ,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

6 HIV-1 subtype Patient n=539 X4/DM R ,1% 80,9% p-value Subtype B (n=323) 55% 61% non-b (n=216) 45% 39% Patient n=539 X4/DM R ,1% 80,9% 0,29 p-value Subtype B % 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

7 Conclusions (part 1) 103/539 (19.1%) of newly diagnosed patients were infected with X4/DM viruses (G2P 10%FPR). Presence of X4/DM virus was associated with lower CD4 counts but not with higher viral load. Presence of X4/DM virus was not associated with the wt/ 32 CCR5 genotype Significant higher prevalence of X4/DM viruses in patients infected with the 01_AE subtype

8 Phylogenetic analysis based on baseline PR/RT sequences B PR-RT sequences contain sufficient information for phylogenetic analysis and localization of transmission events (Hue Non-B et al. AIDS 2004; 18: ) NJ & Bayesian analysis - construction of phylogenetic tree 0.1 Chalmet et al. 2010, BMC Infectious Diseases, 10, 262.

9 Transmission events 2 out of 3 criteria fullfilled: B bootstrap value 90, mean genetic distance Non-B 0.015, posterior probability = 1 Identification of 63 transmission clusters (261 individuals) Chalmet et al. 2010, BMC Infectious Diseases, 10, 262.

10 Distribution of X4/DM and R5 in the phylogenetic trees Non-B B Blue branches: transmission cluster Red stars: X4/DM virus

11 Localization of X4/DM and R5 viruses in the phylogenetic tree X4/DM R5 n Patients Patients Patients Separate branches (19,9%) 225 (80,9%) Clustered branches (18,4%) 213 (81,6%) 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) 5 Clusters (>=3) 2 (5) X4/DM viruses only in 7/63 (11.1%) of all clusters

12 X4/DM cluster -MSM - Not IVDU - Almost identical PR-RT and V3 sequences - Epidemiological link (n=3) - Acute infection (n=3) - Phenotype: DM (n=1); MT2 positive virus (n=2)

13 Tropism in transmission pairs 38 transmission pairs localized in the phylogenetic tree Selection of transmission pairs also identified as most probable source and receptor with a genetic distance in pol of <= n X4/DM R5 Both Source-receptor couples 13 4 (31%) 9 (69%) 0 2 HoS/ 2 HeS 2 B/ 2 non-b 7 HoS/ 2 HeS 7 B/ 2 non-b

14 Conclusions (part 2) Viruses reported as X4/DM (FPR <10%) can be readily transmitted. Overall X4/DM incidence in newly diagnosed individuals: 19.1% X4/DM in transmission clusters: 11.1% X4/DM in transmission pairs: 31% 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. Patients can become infected with viral strains known to be associated with a faster immune deterioration and an intrinsic resistance to CCR5 inhibitors.

15 Acknowledgements ARL ARC Kristen Chalmet Kenny Dauwe Jacqueline Reynaerts Els Demecheleer Delfien Staelens Marlies Schauvliege Jean Plum Dirk Vogelaers Linos Vandekerckhove Bea Vandergucht Jolanda Pelgrom Filip Van Wanzeele Steven Callens Erica Sermyn Ghent University The patients