Transmission of resistant HIV in patients with a known date of - PowerPoint PPT Presentation

Transmission of resistant HIV in patients with a known date of infection Data from the HIV-1 Seroconverter Cohort Bartmeyer B., Kuecherer C., Werning J., Hamouda O. for the German Seroconverter Study Group 1 Robert Koch-Institute, Berlin, Germany

Aim s � Monitoring the spread of resistant HIV - trends of transmission, classes of resistance - resistance mutations � Persistence and viral fitness of resistant HIV � Impact of resistant HIV - progression of disease 2 - treatment success

Study design Prospective multi-centre national study (1997) � - Recruitment of patients by private physicians and clinics - written informed consent of the patients Documented Seroconverters � - last negative and first positive HIV-test ≤ 3 years Acute Seroconverters � - HIV RNA+, EIA– or EIA+ and indeterminate WB 3 HIV-positive patients with reliably estimated date of infection

Genotypic Resistance Analysis pol -population sequences � Direct sequencing Identification of resistance mutations : � (IAS-List 2007, Johnson et al; Shafer et al, 2007 ) Prediction of resistant phenotype � - Stanford algorithm (http://hivdb.stanford.edu, Version 4.3.1,September 2007) - Level of resistance to each drug: sensitive: sensitiv + potentially resistant intermediate: low + intermediate high resistance 4 Statistics � Fisher's Exact test, comparison of proportions and proportions for trend (Epicalc 2000) �

Patient characteristics � Study Population 1563 (12/ 2007) � Sex 92% men; 7% women � MSM 82% � IVDU 4% � Heterosexuals 8% � HPL 3% � Subtype nonB 8% � Genotyped (N) 1043 67% � Primary mutations 143 (13.7% , CI 11.7-15.9) � Sex 139 men, 4 women � Age 33 (IQR, 18-61) � CDC classification 96% A, 3% B, 0,7% C � CD4 cell count (cells/ µl, median) 428 cells/ µl 5 � HIV RNA (copies/ ml, median) 102500 copies/ ml � Duration first line regimen 140 d 479 patients with first line therapy

Risk of transmission 250 200 patients 150 100 50 0 1987 1988 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2005 2006 2007 1984 1985 1986 1989 2003 2004 6 year of seroconversion IVDA occupational heterosexual high prevalence countries MSM & bisexual N=1563

Time of observation 1996 - 2007 1000 800 600 patients N 400 200 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 7 year of recruitment

Transmission of resistant HIV N=1563 (genotyped: 1043) 50,0 40,0 Percent % 30,0 20,0 10,0 0,0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Date of infection 8 Prevalence 13,7% (CI 11,7 – 15,9); p=0.05

Risk of infection with resistant HIV - Age - 100 90 Deviation measure is percent of patients (%) the 95% confidence 80 interval according to Wilson 70 60 50 >40 yrs. of age 40 18 -40 yrs. of age * 30 20 10 0 9 resistant susceptible *p=0.03 (95%CI 1,05-2,38; OR 1,58)

Resistance - Drug classes 10,00 8,00 6,00 Percent 4,00 2,00 0,00 NRTI NNRTI PI Dual Multi 1 0 Drug classes Genotyped: N=1043

Trend – Drug classes NRTI - Resistance 20 NRTI 15 10 p=0.02 5 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 NNRTI - Resistance 15 10 NNRTI 5 p=0.18 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 PI - Resistance 10 8 PI 1 1 6 4 p=0.007 2 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Resistance to single drug classes dominates 90 84 80 % mono resistant HIV 70 63,1 58,5 55 60 50 45 41,5 40 30 19,4 15,5 20 15,7 10 0 I I I I I I I I I T T T T T T P P P R R R R R R 1 1 N N N N N > N N N N 1 1 > 1 1 > 1 2 • 88% single class resistance (103/117) • 53% caused by singletons (54/103) • PI- and NNRTI-singletons >NRTI

Seroconverter-(HA)ART (HA)ART-regimen with > 1% of total runtime, treatment-interruptions and time-gaps 778 Patients – 923.307 days of (HA)ART-lifetime 100% Interruption Gap 80% Other 2NRTI/1NNRTI/1PIr 3NRTI/1NNRTI 60% 2NRTI/1NNRTI 3NRTI/1PIr 2NRTI/1PIr 40% 2NRTI/2PI 2NRTI/1PI 20% 1NRTI/1PI 3NRTI 2NRTI 0% 1 3 1 4 3 2 1 4 3 2 1 4 3 2 1 4 3 2 6 6 7 8 9 9 0 1 2 2 3 4 5 5 6 7 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 quarter of runtime

Seroconverter-(HA)ART (HA)ART-regimen with > 1% of total runtime 777 Patients – 691.069 days of (HA)ART 100% Other 80% 2NRTI/1NNRTI/1PIr 3NRTI/1NNRTI 2NRTI/1NNRTI 60% 3NRTI/1PIr 2NRTI/1PIr 2NRTI/2PI 40% 2NRTI/1PI 1NRTI/1PI 20% 3NRTI 2NRTI 1 4 0% 1 1 1 1 1 1 1 1 1 1 1 1 6 7 8 9 0 1 2 3 4 5 6 7 9 9 9 9 0 0 0 0 0 0 0 0 9 9 9 9 0 0 0 0 0 0 0 0 1 1 1 1 2 2 2 2 2 2 2 2 quarter of runtime

Seroconverter-(HA)ART Firstline-regimen 628 patients – 193.164 days of (HA)ART-time 3NRTI/1NNRTI/1PIr 100% 2NRTI/1NNRTI/1PIr 1NRTI/1NNRTI/1PIr 2NRTI/1NNRTI/1PI 80% 1NRTI/1NNRTI/1PI 3NRTI/1NNRTI 2NRTI/1NNRTI 60% 1NRTI/1NNRTI 2PIr 40% 3NRTI/1PIr 2NRTI/1PIr 1NRTI/1PIr 20% 2NRTI/2PI 1NRTI/2PI 3NRTI/1PI 0% 2NRTI/1PI 1 5 1NRTI/1PI 1 4 3 2 1 4 3 2 1 4 3 2 1 4 3 2 6 6 7 8 9 9 0 1 2 2 3 4 5 5 6 7 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 3NRTI 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2NRTI quarter of runtime 1NRTI

Seroconverter-(HA)ART Only PI containing firstline-regimen 353 patients – 97.630 days of (HA)ART-time 100% TPV/r FPV/r APV/r 80% APV LPV/ATV/r ATV/r 60% ATV SQV/LPV/r 40% LPV/r RTV IDV/r 20% IDV/RTV IDV IDV/NFV 0% 1 6 NFV 19961 19964 19973 19982 19991 19994 20003 20012 20021 20024 20033 20042 20051 20054 20063 20072 SQV/NFV SQV/r SQV/RTV quarter of runtime SQV

Seroconverter-(HA)ART Only NNRTI containing firstline-regimen 192 patients – 72.773 days of (HA)ART-time 100% 80% DLV 60% EFV 40% NVP 20% 0% 1 7 1 4 3 2 1 4 3 1 4 2 3 2 1 4 3 2 6 6 7 8 9 9 0 1 2 2 3 4 5 5 6 7 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 quarter of runtime

First-line Therapy-Preferences 50 50 ** p < 0.01 ** p < 0.01 percentage of patients (%) percentage of patients (%) ** p < 0.01 ** p < 0.01 40 40 30 30 2 NRTI/1 NNRTI 2 NRTI/1 NNRTI 2 NRTI/ 1 P 2 NRTI/ 1 Pir 20 20 10 10 0 0 1 8 Acute Acute Documented Documented Documented: n=1086 Acute: n=435

First line therapy Characteristics susceptible resistant N 247 47 Sex 236 male; 11 female 45 male, 2 female Age 32 (IQR: 18-63) 31(IQR: 18-61) First line therapy 92/247 (37%) 19/47 (40%) NRTI/NNRTI First line therapy 160/247 (65%) 25/47 (53%) NRTI/PIr CD4 cells/µl (median) 420 cells/µl 425 cells/µl initial (IQR:8-1319) (IQR:96-705) VL copies/ml (median) 275 000 copies/ml 130 000 copies/ml 1 9 Initial (IQR: 500-10 000000) IQR: 120-10 000000) Duration of first line 162 d 142 therapy (median) (IQR: 0-1774) (IQR: 5-1639)

Prediction of Phenotype NVP ETV EFV TDF FTC DDI D4T AZT Susceptible ABC Intermediate 3TC Resistant TPV SQV NFV LPV IDV FPV DRV 2 0 ATV 0% 20% 40% 60% 80% 100%

First-line Therapy - NNRTI - 90 80 70 Percent % 60 50 40 30 20 10 0 Susceptible Resistant Nevirapin Efavirenz Delavirdin 2 1 Susceptible: N=92 Resistant: N=19

First-line Therapy - Proteaseinhibitors - 60 50 Percent % 40 30 20 10 0 Susceptible Resistant Atazanavir Fosamprenavir Fortovase Indinavir 2 2 Invirase Nelfinavir Lopinavir/r Tipranavir Susceptible: N=160 Resistant: N=25

CD4 cell count 6 months after ART initiation Susceptible: n=139 1250 CD4 cells/µl: 524 (median) 1000 l µ Resistant: n=26 / s l CD4 cells/µl: 618 (median) l e 750 c 4 D Mann-Whitney-U-Test C 500 p=0.6 250 2 3 susceptible resistant

VL 6 months after ART initiation 75000,0 Susceptible: n=117 VL copies/ml: 250 (median) l m / 50000,0 s e Resistant: n=21 i p o VL copies/ml: 545 (median) c L V Mann-Whitney-U-Test 25000,0 p=0.8 0,0 2 4 susceptible resistant

Conclusion Resistance 1/7 newly HIV infected patients with resistant HIV � Decrease of NRTI and PI resistance � Increase of NNRTI resistance � Resistance to single drug classes predominant � - mainly singleton resistance mutations HAART Reduction of STI since 2006 � Increase of NRTI/PIr-regimen (Second generation PI) � 2 5 - more drug-combinations Longer run-time of NRTI/NNRTI regimen �