Drug Resistance Mutations to Antiretrovirals in HIV ... · Increases PMTCT in Africa up to 65% in High Burden Countries – simplifies ART eligibility – Protection in Future Pregnancies

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

And: 50% are women!

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

Baddell M et al, Infect Dis Obstet Gynecol 2013

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

Questions?