Drug Resistance Mutations to Antiretrovirals in HIV-infected
Pregnant Women
Arevir-GenaFor-Meeting Cologne 30.04.2016
Ulrike Haars Klinik für Dermatologie
Uniklinik Essen
Nadine Lübke Institut für Virologie Uniklinik Düsseldorf
Women with HIV: around the globe
• the HIV prevalence rate for young women (15-24
years) is twice that of young men
• for women in their reproductive years (15–49), HIV/AIDS is the leading cause of death
• women are at least twice more likely to acquire HIV
from men during sexual intercourse than vice versa
Why Option B+?
• Option B+ – Increases PMTCT in Africa up to 65% in High Burden
Countries – simplifies ART eligibility – Protection in Future Pregnancies – Prevention of Transmission in Serodiscordant Couples
• PMTCT prevented 800.000 Children from acquiring HIV
Infection between 2005 - 2012
• 3,5 Million more infections and 3 Million more deaths averted due to new WHO Guidelines by 2025
Which ART in Pregnancy?
NNRTIs
Efavirenz (EFV) Nevirapin (NVP) Etravirin (ETV) Rilpivirin (RPV)
PIs
Lopinavir/Ritonavir (LPV/RTV) Atazanavir (ATV) Saquinavir (SQV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Nelfinavir (NFV) Ritonavir (RTV) Tipranavir (TPV)
Zidovudin (ZDV) Abacavir (ABC) Stavudin (d4T) Didanosin (ddI) Emtricitabin (FTC) Lamivudin (3TC) Tenofovir (TDF)
NRTIs/NtRTIs
Fusions-Inhibitor
Enfuvirtide (ENF)
CCR5-Inhibitor
Integrase-Inhibitor
Maraviroc (MVC)
Raltegravir (RGV) Dolutegravir (DLG) Elvitegravir (EVG)
Deutsch-Österreichische Leitlinien 2014
Prevention of HIV Mother-to-Child Transmission (PMTCT) in Germany
• Starting ART during Pregnancy (2nd Trimester) or Maintain ART
• Delivery mode – Caesarean Section – Vaginal Delivery (HIV-VL < 50 c/ml)
• IV ZDV during Labour if HIV-VL > 50 c/ml
• PEP for the Newborn
• No Breastfeeding
• A survey of births to HIV-infected women in the UK and Ireland from 2000 to 2011 that examined 12,486 singleton infants who showed a decline in MTCT rates over time, reaching an all-time low of 5 per 1000 in 2010–20111
• Retrospective analysis of HIV-infected pregnant women in a Portuguese centre between 1999 and 20122
• 136 patients with 169 pregnancies had a total of 147 living newborns
• MTCT rate was 2% (3/147)
ART, antiretroviral therapy; cART, combination ART; CI, confidence interval; MTCT, mother-to-child transmission; NR, not reported; SD, standard deviation; VL, viral load. 1. Townsend CL, et al. AIDS 2014;28:1049–57. 2. Pineiro C, et al. JIAS 2014;17:19705 (Abstract P173).
Year Infected, n MTCT rate, %
95% CI p
2000–2010 17/816 2.1 NR –
2010–2011 9/1975 0.46 0.21–0.86 0.01
Characteristic Value
Median age at pregnancy, years (SD) 30 (5.7)
HIV diagnosis, n (%) During routine pregnancy screening During delivery Post-delivery
33 (24.2)
4 2
ART used in pregnancy, n (%) 157 (92.9)
Undetectable VL at the time of delivery, n (%)
86/144 (59.7)
ART successfully reduces MTCT
In the German Pregnancy Registry 2012-2014 MTCT rate was 0,75%
Deliveries MX-Outpatient Clinic University
Hospital Duesseldorf 01/2009-02/2016
Diagnosis
First Pregnancy n=29
Diagnosis independant from First Pregnancy
n=56
Deliveries MX-Outpatient Clinic
Düsseldorf 01/2009-02/2016
n=103 (Women n=85)
Resistance Testing of HIV-infected
pregnant women 01/2009-02/2016
25%
4%
16%
55%
not donenegativresistanceno resistance
In 25% (n=21) no resistance-testing was performed
HIV-Subtypes in Pregnant Women MX- Outpatient Clinic Düsseldorf
02_AG 28%
06_CPX 2% A
9% B
9% C
10% D 1%
F 3%
G 6%
J 1%
K 1%
n.d. 27%
neg. 3%
n=85
Elfenbeinküste
1% Gambia
1% Marokko
1% Namibia
1% Tansania 1%
Thailand 1%
Eritrea 1%
Angola 3% Guinea
3% Mosambik
3%
Kenia 6%
Kongo 6%
Togo 12%
Ghana 13% Deutschland
14%
Süd-/Osteuropa 14%
Nigeria 16%
Elfenbeinküste
Gambia
Marokko
Namibia
Tansania
Thailand
Eritrea
Angola
Guinea
Mosambik
Kenia
Kongo
Togo
Ghana
Deutschland
Süd-/Osteuropa
Nigeria
Origin of Pregnant Women MX- Outpatient Clinic Düsseldorf, n=85
ID VL subtype nucleic acid PR mutations RT mutations ART History
1 184546 G RNA M41LM (71,8%), K103N (98,8%), V108IV (78,4%), M184V (99,1%), T215FY (26,1%, 69,2%), M230L (99%)
AZT, 3TC, NVP, EFV, ATV/r, MVC
2 98549 C RNA K65KR (2,5%) naive
3 24532 C RNA M46LM (85,8%)
AZT, 3TC, NVP, LPV/r
4 not
known F RNA A98G, Y181CY
AZT, 3TC, FTC, TDF, NVP, LPV/r
5 2458 06_CPX RNA
D67N (92,6%), K70R (93%), K103N (97,5%), M184V (98,5%), T215F (92,8%), K219Q (93,3%), P225H (99,1%), K238T (93,3%)
AZT, 3TC, FTC, TDF, NVP, EFV, LPV/r
6 113 06_CPX RNA D67N (98,4%), K101E (99,5%), Y181C (99,2%), M184V (99,7%)
d4T, 3TC, FTC, NVP, AZT, TDF, DRV/r
7 8286 01_AE RNA+DNA K103KN (34,2%) naive
8 <40 G DNA M184IM (45,1%), M230I (44,9%), W42* (42,8%), W88* (47%), W152* (46,5%), W212* (43,1%), W252* (47,6%)
naive
9 1253 C RNA D67N (95,6%), K70R (96,9%), A98AG (60,5%), M184V (97,4%), K219EQ (38%, 58,5%)
AZT, 3TC, FTC, ABC, TDF, LPV/r, SQV/r
10 2350 02_AG RNA A98G, Y181C, M184V AZT, 3TC, NVP
11 93 K RNA M41L (92,8%), G190S (93%), L210W (94,1%), T215Y (93,7%)
AZT, 3TC, d4T, ABC, TDF, ddI, NVP, EFV
12 8099 B RNA+DNA T215N (99,3%) naive 13 54258 14_BG RNA+DNA D30N(4,6%) naive
14 <40 G RNA+DNA E138K (21%), M184I (22,1%) W42*, W71*, W88*, W153*, W212*, W229*, W239*, W252*, W266*
FTC, TDF, NVP
Drug Resistance Mutations to Antiretrovirals in HIV-infected
Pregnant Women
Mutation N= ARV
M41L 2 NRTI K65R 1 K70R 2 M184V 5 L210W 1 T215Y/F/N 4 K219Q 2
A98G 2 NNRTI K103N 3 G190A/E/Q/S 1 Y181C 3
M46I/L 1 PI L33F 1
Mutations associated with ARV resistance in 14 women
ID Affected drugs
NRTIs NNRTIs PIs
1 all all 2 all except AZT
3 IDV, NFV, LPV/r, FPV, ATV
4 all
5 all NVP, EFV
6 AZT, d4T, ddI, 3TC, FTC all
7 NVP, EFV
8 (FTC/3TC) (RPV, EFV)
9 all 10 3TC, FTC all
11 AZT, d4T, ddI, ABC, TDF NVP, EFV
12 AZT, d4T 13 NFV
14 (FTC/3TC) (RPV, ETR)
ID VL subtype nucleic acid PR mutations RT mutations ART History
1 184546 G RNA M41LM (71,8%), K103N (98,8%), V108IV (78,4%), M184V (99,1%), T215FY (26,1%, 69,2%), M230L (99%)
AZT, 3TC, NVP, EFV, ATV/r, MVC
2 98549 C RNA K65KR (2,5%) naive
3 24532 C RNA M46LM (85,8%) AZT, 3TC, NVP, LPV/r
4 not known F RNA A98G, Y181CY AZT, 3TC, FTC, TDF, NVP, LPV/r
5 2458 06_CPX RNA
D67N (92,6%), K70R (93%), K103N (97,5%), M184V (98,5%), T215F (92,8%), K219Q (93,3%), P225H (99,1%), K238T (93,3%)
AZT, 3TC, FTC, TDF, NVP, EFV, LPV/r
6 113 06_CPX RNA D67N (98,4%), K101E (99,5%), Y181C (99,2%), M184V (99,7%)
d4T, 3TC, FTC, NVP, AZT, TDF, DRV/r
7 8286 01_AE RNA+DNA K103KN (34,2%) naive
8 <40 G DNA M184IM (45,1%), M230I (44,9%), W42* (42,8%), W88* (47%), W152* (46,5%), W212* (43,1%), W252* (47,6%)
naive
9 1253 C RNA D67N (95,6%), K70R (96,9%), A98AG (60,5%), M184V (97,4%), K219EQ (38%, 58,5%)
AZT, 3TC, FTC, ABC, TDF, LPV/r, SQV/r
10 2350 02_AG RNA A98G, Y181C, M184V AZT, 3TC, NVP
11 93 K RNA M41L (92,8%), G190S (93%), L210W (94,1%), T215Y (93,7%)
AZT, 3TC, d4T, ABC, TDF, ddI, NVP, EFV
12 8099 B RNA+DNA T215N (99,3%) naive
13 54258 14_BG RNA+DNA D30N(4,6%) naive
14 <40 G RNA+DNA E138K (21%), M184I (22,1%) W42*, W71*, W88*, W153*, W212*, W229*, W239*, W252*, W266*
FTC, TDF, NVP
M41LM, T69ADNT, K103N, V108IV, M184V, M230L
HI-VL during pregnancy (c/ml)
0
100
200
300
400
500
600
700
800
Dez13
Dez13
Dez13
Jan 14Jan 14 Feb14
Feb14
Mrz14
Mrz14
Apr14
Apr14
Mai14
Mai14
Jun 14Jun 14Jun 14 Jul 14 Jul 14 Aug14
Aug14
Sep14
Sep14
Add-On Isentress
Dosis Adjustment LPVr regarding TDM
Birth
N=231 pregnant women •ARV naive: 7,4 % primary resistance •ARV experienced: 8,2% resistance •Most common resistant Mutations: M184V/I and K103N
Take Home Message
• In 14/85 of HIV-infected pregnant women in this study we detected drug resistance
• 4/14 pregnant women presented combined NRTI- and NNRTI-resistance
• Perinatally infected women getting pregnant in adolescence can be challenging with possible multi-resistant virus
• MTCT of resistant strains is possible, PEP of the newborn should be adapted
• Despite present resistance, there was no case of mother to child transmission
• HIV-resistance mutations reduce mainly the susceptibility of AZT, 3TC/FTC and NVP – therefore the usage of PI-containing regimes in pregnancy makes sense – also to be considered in children!
Institute of Virology, University of Cologne Rolf Kaiser
Thanks to…
Thomas Lengauer, MPI of Informatics, Saarbrücken
University of Düsseldorf Hepatology & Infectiology Björn Jensen Dieter Häussinger
Institute for Immunogenetics, Kaiserslautern Martin Däumer, Alex Thielen