Trends in transmission of resistant HIV and HIV 1 subtypes Update - PowerPoint PPT Presentation

Trends in transmission of resistant HIV and HIV ‐ 1 subtypes Update German HIV ‐ 1 seroconverter study Kuecherer C, Meixenberger K, Scheufele R, Gunsenheimer- Bartmeyer B, Hamouda O in behalf of the seroconverter study group Kuecherer C AREVIR Meeting 5. Mai 2011, Köln

Transmission of resistant HIV  Resistant HIV are transmitted ‐ Patients with treatment failure ‐ Onward transmission by patients in the viremic phase  Impact on treatment options and success ‐ Persistence of resistance mutations ‐ Minor resistant variants not detected by bulksequencing

HIV ‐ 1 seroconverter study  Prospective longitudinal observational study since 1997 ‐ Open cohort ‐ Patients with known infection date ‐ Date of seroconversion as best approximation to the infection date  Laboratory diagnostic criteria - Documented seroconversion last negative and confirmed first positive antibody test (< 3 years apart) ‐ "Acute seroconversion“ first reactive test, before seroconversion is completed

AIMS  Monitoring the spread of resistant HIV and subtypes  Trend analyses  In vivo persistence of resistant HIV during drug ‐ naïve course  Impact on disease progression and treatment success  Identification of factors influencing progression of disease

Study partners in Germany 68 centers health services ‐ blue hospitals ‐ red medical practices ‐ green 2141 seroconverters enroled (end of 2010) Sample transport within 24 h to the RKI

Genotypic resistance testing of HIV 440 bp 718 1800 920 FI PI RTI INI EI  RT ‐ PCR ‐ > population sequences  Identification of resistance associated mutation  Surveillance drug resistance mutation list for drug ‐ naive patients (PI, RTI (Bennett et al. 2009)

Drug ‐ naive study population Year of seroconversion characteristics 1996-2009 % Patients 1639 100 drug-naïve at entry Age median (range) 33 14-76 Sex male 1553 94,6 female 84 5,4 unknown 2 0,1 Living in Berlin 946 59,0 Transmission route MSM. 1429 87,2 HET 137 8,4 HPL 13 0,8 IVD 21 1,3 Professional contacts 5 0,3 unknown 34 2,1 Genotyped* 1603 97,8 * 21 PCR neg

Stable Transmissionrate of resistant HIV no decrease 1996 ‐ 2009 60 50 N=1603 Resistant HIV (%) 40 30 20 10 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Year of seroconversion 15 27 29 31 33 60 71 155 192 227 206 195 196 166 Prevalence 12,2% 195/1603 [CI 95% 10,8 -13,7] p for trend 0,374

Trends drug classes NRTI NRTI decrease 18 Prevalence TDR 16 14 P for trend 0.04 Resistant HIV (%) 12 NRTI 6.2% 10 NRTI 8 6 NNRTI 2.4% 4 2 PI 2.1% 0 6 7 8 9 0 1 2 3 4 5 6 7 8 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 9 9 9 9 0 0 0 0 0 0 0 0 0 0 1 2 2 2 2 2 2 2 2 2 2 1 1 1 Dual- 1.5% Year of seroconversion NNRTI Multi- 0.3% NNRTI stable 18 16 14 P for trend 0.39 Resistant HIV (%) 12 10 NNRTI 8 6 4 2 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 1 1 1 1 1 Year of seroconversion PI PI stable 18 16 14 P for trend 0.29 Resistant HIV (%) 12 10 PI 8 6 4 2 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 1 1 1 1 1 Year of seroconversion

TDR by single resistance mutations 4,5 4 3,5 3 prevalence (%) 2,5 2 1,5 1 0,5 0 1 NRTI > 1 NRTI 1 NNRTI > 1NNRTI 1 PI > 1PI 1 TAM > 1 TAM NNRTI and PI resistance mainly caused by singletons

Risk for TDR: subtype B 18,0 16,0 14,0 Proportion TDR (%) 12,0 OR 4,41 10,0 p=0,00267 8,0 12,9 6,0 4,0 2,0 3,2 0,0 B non-B 4/124 191/1479 Subtype B strains 4,4 fold more likely to be resistant

Prevalence of non ‐ B subtypes 7,7 % non-B infections 124/1603 [CI 95% 6,3-9,1] 1,2 1,4 0,7 0,3 92,3 7,7 0,2 1,7 2,2 B CRF02_AG C A1 CRF01_AE nicht klassifizierbar, rekombinant G andere (A2, D, F2, CRF12_BF)

Origin of non ‐ B infections Origin N % Country % 124 of risk Germany 81 65,3 74 59,7 EU 5 4,0 3 2,4 Northafrica 2 1,6 0 0 Subsaharan Afr. 26 21,0 22 17,7 Latinamerica 4 3,2 0 0 Russia 3 2,4 2 1,6 Thail/Vietn/Phil 2 1,6 11 8,9 unknown 1 0,8 12 9,7 - 41 % 50/124 German, infected in Germany ‐ 25 % 31/124 German, infected in another country

Non ‐ B infections in all transmission groups 70 60 proportion of non-B (%) 50 40 30 20 10 0 MSM HET HPL IVD unkn 57% of the non-B infections in heterosexually acquired infections

Transmission routes and subtypes N=124 80 Anteil pro Subtyp (%) 70 MSM 60 HET 50 40 HPL 30 IVD 20 unbek 10 0 G 1 E . G e C k A r A A e e R _ _ d 2 1 n . 0 0 a f i F F s R R s a C C l k n u • All non ‐ B subypes identified also observed in MSM (G n=4) • No hint to preferential transmission of subtypes

Increase of non ‐ B infection (1996 ‐ 2009) 120 100 prevalence (%) 80 B 60 non-B 40 20 0 6 8 0 2 4 6 8 9 9 0 0 0 0 0 9 9 0 0 0 0 0 1 1 2 2 2 2 2 Non-B Infektionen: 124/1603 7,7% [KI 95 6,3 -9,1] P for trend =0,0168

Non ‐ B subtypes in different risk groups over time N=124 120 proportion nonB (%) 100 80 60 40 20 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 HET MSM HPL IVD unbek • Non ‐ B subtypes since 1998 (pol) in study cohort • Highest prevalences in HET during the epidemic • In MSM since 2001 ‐ > trend of increase?

Increase of non ‐ B infections in MSM 6 5 Proportion TDR (%) 4 3 2 1 0 6 7 8 9 0 1 2 3 4 5 6 7 8 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 9 9 9 9 0 0 0 0 0 0 0 0 0 0 1 1 1 1 2 2 2 2 2 2 2 2 2 2 P for trend =0.0129

Prevalence of non ‐ B infections parallels heterosexual HIV transmissions 18 16 14 relative proportion (%) 12 HET 10 non-B 8 HET_rep 6 4 2 0 6 8 0 2 4 6 8 9 9 0 0 0 0 0 9 9 0 0 0 0 0 1 1 2 2 2 2 2

pol -NJ Tree Evidence of transmission of non ‐ B strains among 1 2 3 MSM and IDU 4 5 6 8 Non ‐ B Transmis ‐ sion HET/ 7 clusters HET MSM MSM IDU 9 13 7 4 1 1 13 MSM cluster no. 2, 5, 6,10 11 12 IDU cluster no. 12 with 4 members 10 same city and treating center

Conclusions (1)  Study is representative for MSM in Germany  Stable rate of transmission of resistant HIV  Transmitted NRTI resistance declines ‐ improved regimens  NNRTI resistance: no clear cut evidence of increase  Persistance of resistance mutations (e.g. K103N and T215 revertants) in combination with onward transmission of TDR is likely to contribute to the stable transmission rate of TDR  TDR is correlated with HIV subtype B infections (OR 4.4)  Continued monitoring of TDR needed

Conclusions (2)  Low but increasing rate of HIV ‐ 1 subtype B infections  Parallels heterosexually transmitted HIV infections  Transmission of non ‐ B observed for all routes of infection, trend of increase in MSM  Evidence from closely related transmissicon clusters of Non ‐ B infections in MSM and IDU: Non ‐ B strains are endemically established in Germany  German Data are shared with European HIV collaborations SPREAD/EHR (in the past), CASCADE, CHAIN, EuroCoord ongoing.

Acknowledgement  All study doctors and their patients  National reference center  Former SPREAD laboratories  BMG and BMBF for funding

FIN

Proportion of study patients in comparison to registred newly diagnosed patients (2000 ‐ 2009) 5000 Meldedaten 2000-2009 Serokonverter 4000 3000 2000 36 % 1000 4 % 14 % 5 % 5 % 3 % 7 % 9 % 1 % 1 % 2 % 2 % 5 % 3 % 0 NRW Berlin Bayern Ba.-Wü. Hessen Hamburg Niedersachsen Rheinland-Pfalz Sachsen Schleswig-Holstein Sachsen-Anhalt Bremen Brandenburg Meck.-Vorpommern 9

Number of mutations causing resistance 1996 ‐ 2009 14 12 prevalence (%) 10 8 6 4 2 0 6 7 8 9 0 1 2 3 4 5 6 7 8 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 9 9 9 9 0 0 0 0 0 0 0 0 0 0 1 1 1 1 2 2 2 2 2 2 2 2 2 2 1 NRTI > 1NRTI 1 NNRTI > 1 NRTI 1 PI >1 PI • 1 NRTI decreases (not TAMs) • > 1 NRTI stable • > 1 NNRTI since 2002 • > 1PI decreases

Transmission groups and prevalence of TDR 45 40 35 proportion TDR (%) P=0,015 30 OR 2,67 25 20 12,9 5,3 8,3 5,0 11,8 15 10 5 0 MSM HET HPL IVD unkn others MSM more frequently infected with resistant HIV than HET