Antiretroviral therapy in pregnancy: Is there cause for concern?

Graham P Taylor

Professor of Human Retrovirology

new Paediatric HIV infections declining

Global update on the Health Sector Response 2014

Is there cause for concern?

Carcinogenesis in mice exposed to zidovudine in utero

Fundam Appl Toxicol 1996;32:148-158

Anaemia in infants NEJM 1994;331:1173-1180

1st trimester exposure to ART + PCP prophylaxis associated with increased risk congenital malformations?

STI 2001;77:403-407

VSDs with Delavirdine in rodents, CNS with Efavirenz in macaques Antiretroviral Pregnancy Register July 2004

Neutropenia in infants STI 2003;79:448-52

Neural tube defect scare

Cynomolgus macaques exposed to efavirenz3/22 (13.7%) malformations

�Efavirenz reclassified D following 3 cases meningo-myelocoele and one Dandy-Walker Syndrome retrospectivelyreported�SPC still states that Efavirenz should not be used in pregnancy55.

Date of download: 11/23/2015Copyright © 2015 American Medical

Association. All rights reserved.

From: Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus–Exposed

Uninfected Infants

JAMA Pediatr. 2015;169(1):48-55. doi:10.1001/jamapediatrics.2014.1889

1.39 (1.00 – 1.92)Protease inhibitors

8.19 (1.53 – 43.3)DDI + D4T

1.95 (1.24 – 3.05)Atazanavir

Data from the SMARTT study

Date of download: 11/23/2015Copyright © 2015 American Medical

Association. All rights reserved.

From: Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus–Exposed

Uninfected Infants

JAMA Pediatr. 2015;169(1):48-55. doi:10.1001/jamapediatrics.2014.1889

Hypospadias

and

Cryptorchidism

The Antiretroviral Pregnancy RegisterJan 1989 – Jan 2015

16,428 Prospective reports

Trimester of Earliest Exposure

Any regimen 1st 2nd/3rd

containing % %

any PI 122/4224 (2.9) 168/5703 (2.9)

any nRTI 213/7198 (3.0) 252/8917 (2.8)

any NNRTI 52/1970 (2.6) 52/1737 (3.0)

Any NtRTI 58/2500 (2.3) 25/1188 (2.1)

Any integrase 6/201 (3.0) 7 /190 (3.6)

Individual drugs with sufficient numbers to identifya > 1.5 fold increase in risk (Jan 2015)

Lamivudine 142/4527 3.1% 2.6 – 3.7

Zidovudine 133/4092 3.3% 2.7 – 3.9

Ritonavir 62/2628 2.4% 1.8 – 3.0

Tenofovir 58/2452 2.4% 1.8 – 3.0

Emtricitabine 46/1834 2.5% 1.8 – 3.3

Lopinavir 29/1242 2.3% 1.6 – 3.3

Nelfinavir 47/1214 3.9% 2.8 – 5.1

Nevirapine 32/1096 2.9% 2.0 – 4.1

Atazanavir 23/1037 2.2% 1.4 - 3.3

Efavirenz 20/852 2.3% 1.4 - 3.6

sufficient numbers to identify a > 2.0 fold increase (Jan 15)

Antiretroviral Pregnancy Register Jan 1989 -

CDC Population All 2.72% (2.68 – 2.76)

based survey Early (<24hrs) 2.09% (2.07 – 2.12)

1989 – 2003

Abacavir 29/976 3.0% 2.0 - 4.2

Efavirenz 20/852 2.3% 1.4 - 3.6

Stavudine 21/810 2.6% 1.6 - 4.0

Didanosine 20/423 4.7% 2.9 - 7.2

Darunavir 9/314 2.9% 1.3 – 5.4

Indinavir 7/289 2.4% 1.0 – 4.9

Individual drugs with sufficient numbers to identify a > 2.0 fold increase (Jan 15)

Registrations to the APR

0

5000

10000

15000

20000

25000

Total

0

500

1000

1500

2000

2500

3000

3500

4000

4500

New Prospective Registrations per annum

Of the ~24000 reports 1/3 relate to compounds no longer or rarely prescribed

Reports to APR

1. USA 77.3%

2. UK 4.2%

3. Brazil 4.0%

4. Uganda 3.1%

5. Argentina 2.4%

6. South Africa 1.5%

7. France 1.1%

8. Germany 0.5%

9. Ivory Coast 0.5%

10.Kenya 0.5%

Europe & N America 85%

Summary of current situation

1.Antiretroviral Pregnancy Register has

excluded significant compound risk

2.Small increase in compound risk/specific

defects not excluded

3.Published studies continue to identify

potential risk

4.Few data from low and middle income

countries

5.Lack of data on co-medications

Preterm birth and HAART

Regional Year Monotherapy HAART OR a Ref

Switzerland 1996 -1998 19/112

(16.7%)

10/30 (33%) 2.0 1

Europe (ECS) 1986 -2000 93/555 (17%) 41/188 (22%) no PI

29/101 (29%) with PI

1.49 b

2.15b

2

Europe (ECS) 1986 -2004 118/704

(16.8%)

274/1075 (25.5%)

Started antenatally

Started pre-pregnancy

2.03

2.19

3

Germany/Austria c 1995 -2001 20/76 (26%) 29/75 (39%)

No PI

With PI

1.15

4.47

4

London UK 1995 -2006 3/52 (6%) 27/159 (16.9%) 5

UK National 1990 -2005 107/1061

(10.1%)

(incl dual)

476/3384 (14.1%) 1.5 6

USA (WITS) 1990 -1998 254/1590

(16%)

55/396 (14%)CART no PI

25/137 (18%) HAART with PI0.95

1.45

7

USA (PSD) 1989 -2004 457/2601

(17%)

329/ 1781 (18%) no PI

132 782 (17%) with PI

d 8

Impact of PTB on babies of HIV treated mothers

Brussels – Single Centre 1985 – 2006

537 neonates: 82 born Pre-ART era

455 born during ART era

11.6% born pre-term

77 infants had 81 episodes of severe infection during 1st year of life.

21 episode during the neonatal period

Severe infection in infancy associated with

Birth during ART era 2.9 (1.1 – 8.1)

Severe infection post neonatal period was associated with:

PTB 3.0 (1.5 – 5.9) p 0.001

Severe neonatal infection was associated with

PTB aHR 21.3 (7.1 – 63.9)

Adler C Plos One 2015 DOI:10.1271 18th August 2015

Risk of severe infection in HEU infants

Adler C Plos One 2015 DOI:10.1271 18th August 2015

High risk – ART

available not taken

Pre-ART era

ART taken

PTB and HAART in a Resource Poor setting

Mma Bana Study (HAART and Excl BF RCT)

PTD Rates <32 weeks

Combivir/Kaletra 61/270 (23%) 8 (3%)

Trizivir 42/283 (15%) 4 (1%)

Combivir/Nevirapine 16/156 (10%) 2 (1%)

Shapiro et al NEJM 2010;362:2282 - 94

The PROMISE study

3 Randomisations

1. Antenatal and Delivery therapy

2. Post-partum therapy

3. Post Breast-Feeding

Triple ART

Infant Nevirapine

Triple ART

Stop ART

Triple ART

Zidovudine Add sd NVP +

Tenofovir/emtricitabineARM A

ZDV/3TC/Lopinavir/r

TDF/FTC/Lopinavir/r

ARM B

ARM C

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

Maternal Baseline Characteristics:Young Pregnant African Women with High CD4 Count

Entry Characteristics (N=3,523) Value

Age (median) 26 years

Race – Black African 97%

Gestational age (median) 26 weeks

CD4 cell count (median) 530 cells/uL

WHO Clinical Stage 1 97%

Hepatitis B Surface Antigen + 4%

No ARV for prior PMTCT or no prior

pregnancy

94%

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

MTCT rates at age 14 days

1.8%

Difference in MTCT Risk:

-1.28% (95% CI -2.11%, -0.44%)

25 /

1,326

9/1,710

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

Moderate Adverse

Pregnancy Outcome

Severe Adverse

Pregnancy Outcome

Birth weight Birth weightGest. Age Gest. Age

% w

ith E

vent

B vs C

P=0.02B vs C

P=0.04

Moderate Adverse Pregnancy Outcomes

Higher with FTC/TDF Triple ARV then ZDV monotherapy

A vs C

P=0.004

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

Moderate Adverse

Pregnancy Outcome

Severe Adverse

Pregnancy Outcome

Birth weight Birth weightGest. Age Gest. Age

% w

ith E

vent

B vs C

P=0.02B vs C

P=0.04

Comparing Triple therapy arms

Severe Adverse Pregnancy Outcomes

greater with TDF/FTC than ZDV/3TC

A vs C

P=0.004

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

Infant Deaths No difference between ZDV and ZDV/3TC/Lop/r arms

All Versions

(Arm A v B)

Version 3 only

(Arm A v C, B v C)

% w

ith E

vent

28/1432 17/1419 11/349 2/346 15/341

Any Grade 3+ AE Death Any Grade 3+ AE Death

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

Infant Deaths Higher in TDF/FTC Arm than in ZDV/3TC arm (V3)

All Versions

(Arm A v B)

Version 3 only

(Arm A v C, B v C)

% w

ith E

vent

28/1432 17/1419 11/349 2/346 15/341

Any Grade 3+ AE Death Any Grade 3+ AE Death

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

Summary of 1077BF/FF Antepartum

Component Infant Safety Results

There were no significant differences in infant

signs/symptoms and lab AEs by study arm for all infants and

for version 3.0 only infants.

There were 60 early infant deaths in all versions by 14 days;

including 28 deaths in version 3.0.

In Version 3.0 there was a significantly lower risk of infant

death for ZDV/3TC vs TDF/FTC:

• 0.6%(2/346) vs. 4.4% (15/341) p=0.001

• The difference was primarily seen in deaths among

infants <34 weeks gestation.

MG Fowler et al. CROI 2015. February 23-26, | Seattle, Washington #LB31

Summary of current situation

1.There is a signal linking combination ART

with PTB

2.PTB is associated with adverse outcomes

3.The mechanism of this association is

unknown

4.Not all regimen are equally linked

No cause for alarm, some cause for concern

Target:

The goal of antiretroviral therapy in pregnancy is the safe delivery

of a healthy HIV uninfected baby to a healthy mother.

Mostly Achieved:

HIV mother-to-child transmission can be eradicated with current

therapies

Remaining Tasks:

Ensuring that the safest regimens are identified and made

available

Thanks to Mary Glenn Fowler who kindly shared

the PROMISE slides from her CROI presentation