HIV and Pregnancy

A/Prof Michelle Giles

HIV Congress 2014

Hotel Taj Lands End, Mumbai

21st-23rd March 2014

Overview

Antiretroviral therapy

Recent guideline changes

When to start?

What to start?

When to stop?

Safety data (efavirenz, tenofovir)

New drugs

Pharmacokinetic considerations

Preferred/Recommended Regimens:

DHHS, IAS-USA, BHIVA

EFV*† ATV/RTV*ǂ

DRV/RTV§ RAL§

TDF/FTC +

NNRTI 3rd agent PI 3rd agent

PI 3rd agent Integrase 3rd agent

WHO 2013: FDC tenofovir/emtricitabine/efavirenz

When to start recommendations: other than

pregnancy no sex differences

Guideline Recommendation

DHHS For all individuals (strength of

recommendation varies according

to CD4 count)

BHIVA Start before CD4 falls below 350

(higher in specific groups eg HBV)

IAS For all individuals regardless of

CD4 count

WHO CD4 <500 (lifelong

pregnant/breastfeeding women)

Summary of Adult Guidelines- when to start

Topic 2002 2003 2006 2010 2013

When to

start

CD4 ≤200 CD4 ≤ 200 CD4 ≤ 200 Consider 350

- CD4 ≤ 350 for TB

CD4 ≤ 350 -Irrespective CD4 for

TB and HBV

CD4 ≤ 500

-Irrespective CD4 for

TB, HBV, PW and

SDC

- CD4 ≤ 350 as

priority

1st Line

8 options - AZT preferred

4 options - AZT preferred

8 options - AZT or

TDFpreferred

- d4T dose reduction

6 options &FDCs - AZT or TDF preferred

- d4T phase out

1 preferred option &

FDCs

TDF and EFV

preferred across all

populations

2nd Line Boosted and

non-boosted

PIs

Boosted PIs -IDV/r LPV/r,

SQV/r

Boosted PI - ATV/r, DRV/r, FPV/r

LPV/r, SQV/r

Boosted PI - Heat stable FDC:

ATV/r, LPV/r

Boosted PIs

Heat stable FDC:

ATV/r, LPV/r

3rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV

Viral Load

Testing

No No (Desirable)

Yes (Tertiary centers)

Yes (Phase in approach)

Yes

(preferred for

monitoring,

use of PoC, DBS)

Earlier initiation

Simpler treatment

Less toxic, more robust regimens

Better monitoring

Rationale: One Regimen For All

Simplicity: regimen is very effective, well tolerated and available as a

single, once-daily FDC

Harmonizes regimens across range of populations (Adults, Pregnant

Women (1st trimester), Children >3 years, TB and hepatitis B)

Simplifies drug procurement

Safety in pregnancy

Efficacy against hepatitis B

Affordability (cost has declined significantly since 2010)

Preferred 1st line regimen:

TDF + 3TC (or FTC) + EFV

Efavirenz safety data

Efavirenz: historical data

Anencephaly, anophthalmia, cleft palate observed in 3/20 (15%) monkeys who received EFV 1TM similar to human doses

6 retrospective/2 prospective

human case reports; anophthalmia with facial clefts and myelomeningocoele

Previously “not recommended in 1TM”

Neural tube closes 6 weeks

Antiretroviral Pregnancy Registry: Birth

Defects With First Trimester Exposure

Prospective registry fetal ARV exposure

Provides mechanism for detecting teratogenicity

Does not measure toxicity

Rate of birth defects compared with background population rate (2.7%)

With exception of nelfinavir and didanosine no increased rate of birth defects

www.apregistry.com Data through to 31 July 2013

Lamivudine 136/4360 3.1%

Zidovudine 129/4000 3.2%

Ritonavir 52/2260 2.3%

Tenofovir 46/1982 2.3%

Nelfinavir 47/1211 3.9%

Emtricitabine 34/1400 2.4%

Nevirapine 31/1061 2.9%

Lopinavir 26/1125 2.3%

Abacavir 27/905 3.0%

Stavudine 21/805 2.6%

Atazanavir 19/878 2.2%

Efavirenz 18/766 2.3%

Darunavir 5/212 2.4%

Didanosine 20/416 4.8%

Only 2X NTDs

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Paper #81 Birth Defects and ART in the French Perinatal Cohort, a Prospective Exhaustive Study among 13,124 Live Births from 1994 to 2010 Jeanne Sibiude*1, L Mandelbrot1,2,3, S Blanche4, J Le Chenadec3,5, N Boullag-Bonnet3, A Faye2,6, C Dollfus7, R Tubiana8, B Khoshnood9, J Warszawski3,5,10, and ANRS CO1/CO10/CO11 1Hosp Louis Mourier, Colombes, France; 2Univ Diderot Paris 7, Paris, France; 3CESP, INSERM U1018, Le Kremlin-Bicetre, France; 4Hosp Necker, EA 3620, Univ Paris Descartes 5, Paris, France; 5INED, Paris, France; 6Hosp Robert Debre, Paris, France; 7Hosp Trousseau, Paris, France; 8Hosp Pitie Salpetriere, INSERM U943, Paris, France; 9INSERM, UMR S953, Univ Paris-6, Paris, France; and 10Univ Paris Sud, Le Kremlin-Bicetre, France

Background: The use of ARV regimens during pregnancy has led to a spectacular decrease in MTCT, now on the order of 1% in industrialized countries. Potential adverse effects including teratogenic risk have to be evaluated. We aimed to estimate the prevalence of birth defects in children born to HIV+ women receiving ARV during pregnancy, and to assess the association with each in utero ARV drug. Methods: Since 1986, the French Perinatal Cohort (EPF) prospectively enrolls pregnant HIV+ women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 years of age. All live births between 1994 and 2010 were included. We excluded patients not treated during pregnancy. Birth defects were studied using both the EUROCAT and the MACDP classifications, and associations with ARV were evaluated using univariate and multivariate logistic regressions. Results: We included 13,124 livebirths. The prevalence of birth defects was 4.4% % (95% confidence interval [CI] 4.0-4.7; n = 575), according to EUROCAT and 7.0% (6.5-7.4; n = 914), according to the MACDP classification, which included minor defects when 2 were present in the same child. A significant association was found between exposure to efavirenz in the first trimester and neurological defects (adjusted odds ratio [aOR] = 3.15 [1.09-9.09]). Zidovudine in the first trimester was associated with congenital heart defects (aOR = 2.34 [1.39-3.94]), and didanosine with head and neck birth defects (aOR = 2.89 [1.03-8.11]). Lamivudine and indinavir in the first trimester were also associated with birth defects, but the association with lamivudine concerned mostly minor musculo-skeletal and head and neck defects, while indinavir was not associated with any specific defects in the multivariate analysis adjusting for potential confounding variables and concomittant medications. Conclusions: This study, which is the largest prospective study of birth defects in ARV-exposed infants, shows a specific association between in utero exposure to efavirenz and neurological defects. As in other cohort studies, the rate of birth defects may be underestimated by including only live births. Recently, WHO and US Department of Health and Human Services guidelines have been changed to authorize the use of efavirenz even in the first trimester in women already treated with this drug. The association we observed between efavirenz and neurological defects has been previously described and calls for caution and continued follow-up.

Tenofovir: safe in pregnancy?

Osteomalacia, reversible upon dose reduction

or cessation (↓ BMD dogs and rats) and ↓weight

and crown rump length

Male and female fertility unaffected,

Excreted in breast milk

Renal toxicity in 4 animal species

Tenofovir toxicity: paediatric

growth data

Prospective study in utero exposure n=449

Endpoints

• SGA

• LBW (<2.5kg)

• Weight for age Z score

• Length for age Z score (birth and 1 year)

• Head circumference for age Z score (birth and 1 year)

Slightly lower LAZ and HCAZ at one year

Significance uncertain Siberry GK AIDS 2012

The Development of AntiRetroviral

Therapy in Africa (DART) study

1867 women <45 years ART initiation

382 pregnancies; 226 live births

182 enrolled in infant follow up study

120/182 in utero TDF exposure

No evidence of reduced growth at 2 years

No evidence of fracture

No evidence of increased renal abnormalities

No evidence of increased congenital abnormalities

80% power to detect a difference of 20% between

TDF exposed and unexposed groups Gibb DM PLoS 2012

Newborns exposed to TDF in utero may have

lower bone mineral content (BMC)

HUE infants exposed for >8 weeks to TDF and

>36 weeks gestation (n=74) were compared

with infants with no TDF exposure (n=69)

DEXA scan between 0-4 weeks after birth

Boosted PI 86% and 64% respectively

Whole body BMC 6.4gm lower in TDF exposed

group (CI 2.1, 10.7 p=0.004)

Clinical significance and whether this persists

unclear

Siberry GK Conference on Retroviruses and Opportunistic Infections 2014 Abstract 71

No increased risk of birth defects with

EFV when compared with other ARVs

Safety of EFV and TDF in Pregnancy

o Systematic review (including Antiretroviral Pregnancy Registry), reported outcomes for 1502 live births to women receiving EFV in the first trimester and found no increase in overall birth defects

o Excludes > 3 fold increased risk in overall birth defects

Source: Ford N et al. AIDS, 2011. Ford N et al. AIDS, 2013. Ekouevi DK et al.J AIDS, 2011. WHO, Geneva Use of EFV during pregnancy. 2012.

http://www.who.int/hiv/pub/treatment2/efavirenz/en

Nightingale SL. JAMA, 1998. British HIV Association. Guidelines for the management of HIV infection in pregnant women. HIV Medicine. 2012. De Santis M et al. Arch of Int Medicine, 2002.

Source: Antiretroviral Pregnancy Registry Steering Committee http://www.APRegistry.com Siberry GK et al. AIDS, 2012

EFV

o Potential concerns include renal toxicity, adverse birth outcomes, growth and effects on bone density

o Systematic review assessed the toxicity of fetal exposure to TDF in pregnancy

• In Antiretroviral Pregnancy Registry, prevalence of all birth defects with TDF exposure in 1st trimester was 2.4% (same as background)

o Limited studies, conflicting data on growth, reduced BMC, significance uncertain

o No studies of TDF among lactating women, who normally have bone loss during breastfeeding

o Current data reassuring o More extensive studies ongoing

TDF

Insufficient safety data in

pregnancy

Etravirine (0/39)

Rilpivirine* (0/31)

Food requirements 3rd TM

“blips” vs failure 3rd TM (volume of distribution)

PK study underway

Fosamprenavir (2/102)

Tipranavir (0/4)

Enfuvirtide (0/20)

Maraviroc (0/13)

Raltegravir* (3/141)

Raltegravir

Favourable PK profile in pregnancy and

capacity to rapidly reduce viral load

Mean VL reduction 1.7-2.2 log copies/mL by

day 10

Consider

Late presentation

HIV seroconversion

Added to standard ART

Case report transaminitis (23X ULN)

Adeyemo Int J STD & AIDS 2013; Westling AIDS Patient Care and STDs 2012; Markowitz J Acquir Immune Defic Syndr 2006; Renet J Obstet Gynaecol Can 2013

Raltegravir: a role in preterm

neonates?

2 case reports raltegravir started <24 hours prior to delivery

RGV plasma concentration (>15ng/ml) achieved in mother and baby but lower than women on established therapy

RPC remained therapeutic for up to 5 days in preterm neonate

Consider “preloading” in pregnancy for PMTCT in preterm neonates who cannot take or absorb oral drugs poorly and for whom parenteral options are limited (?800mg)

Hegazi AIDS 2012

PROMOTE study

New global guidelines recommend EFV

based cART for all pregnant women

The current gaps in evidence

Maternal and infant outcomes

ART toxicity

Alternative regimens

Cohan D CROI 2014 Abstract 69

PROMOTE study

Aim: to compare efficacy and safety of EFV vs

LPV/r based ART during pregnancy and

breastfeeding

Outcomes

Perinatal HIV transmission

Adverse events

HIV free infant survival

Women enrolled between 12-28 weeks cART

naïve, open labelled randomised

LPV/r increased to 600/150mg BD from 30 weeks

PROMOTE study results

Virological efficacy (<400 copies); a non

inferiority comparison (11% margin)

Any grade 1/2 D/N/V higher in LPV/r arm

(p<0.05)

Rate of HIV transmission 0.5%

EFV LPV/r

Week 8 on

ART

Antepartum 89% 87%

Delivery 98% 86%*

Week 24 Post partum 92% 89%

Week 48 Post partum 91% 88%

Why?

Adherence?

Drug Exposure?

PK studies suggest LPV/r exposure

reduced 3rd TM

Pharmacokinetic

changes with pregnancy

Lopinavir PK data in pregnancy Parameter Reference 3rd TM PP Key finding

400/100mg

Calza L 2012 n=21 n=20

Std dose

recommended

400/100 soft gel

capsule vs

tablet

Else L 2012 n=6 vs n=11 n=5 Reduction in LPV

exposure 3rd TM. Std

dose suitable treatment

naïve, consider TDM

treatment experienced

400/100 tablet Fayet-Mello A

2013

n=36 n=30 Reduction in LPV

exposure 3rd TM. Std

dose suitable treatment

naïve, consider TDM

treatment experienced

400/100 tablet

vs 500/125

Patterson KB

2013

n=12 n=12 LPV exposure

significantly decreased.

Predose unbound LPV

not affected. Std

dosing suitable

400/100 tablet

vs 600/150

Best B 2010 n=33 n-=27 Higher dose should be

used 2nd and 3rd TM

Best J Acquir Immune Def Syndr 2010

2nd TM 300mg

3rd TM 400mg

Recommended dosing during pregnancy for

lopinavir/ritonavir and atazanavir/ritonavir

Options for lopinavir

Standard dosing throughout and monitor virologic response

TDM (especially if PI experienced or adherence issues)

Empirically increase the dose to 3 tablets twice daily

Considerations

Adherence (pill burden)

Side effects of lopinavir/ritonavir

Pregnancy related symptoms 3rd trimester N/V

Availability of TDM

Atazanavir

Consider increase to 400mg daily 3rd TM

When to stop?

Lifelong versus stopping if woman doesn’t meet

eligibility criteria

“Conditional” based on setting and

programme (eg generalised epidemic,

minimal access to CD4 testing, long duration

breastfeeding, high rates of fertility, limited

partner testing)

Lack of conclusive evidence regarding

impact of lifelong treatment

Estimated 60% women meet eligibility

criteria (CD4 <500) with a further 10-20% in

1-2 years after birth

A sobering thought….

CROI 2014: Maternal deaths due to HIV not

declining despite PMTCT successes in South Africa

15 year review

Perinatal transmission 1.5% 2012

No change in proportion of maternal deaths

caused by HIV since 2007

37% deaths non pregnancy related

Over 75% of women with HIV who died had

never started antiretroviral therapy

PMTCT of HIV is of limited value for the child if its

mother dies in the early years of life

Mnyani et al CROI 2014 Abstract 67

Thank you