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PMTCT Research

Didier Koumavi EKOUEVI

INSERM U-897, Bordeaux, France, Programme PACCI, site ANRS, Abidjan, Côte d’Ivoire

FMMP, Université de Lomé

1

Mother-to-child transmission(MTCT) of HIV

• Without ARV interventions, MTCT rate is 15-40%

• Differences between populations are associated with maternal characteristics (HIV RNA viral load, CD4, clinical disease progression) and infant feeding

Infected children

Mother-to-child

transmission

HIV infection in women

2

Objectives of PMTCT research

• To increase the efficacy of the ARV regimens during labor and breastfeeding period

• To increase PMTCT coverage

3

Balancing act

Benefit ofMaternal Treatment

Risk ofAdverse Fetal Effects

Has direct benefit to maternal health plus prevention of MTCTThis outweighs any potential risks to fetus

Efficacy of antiretroviral drugs regimens

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1991-1993 : ACTG076/ANRS 024 trial

• First clinical trials of antiretroviral (ARV) drug prophylaxis for women and infants were conducted in Europe and the United States of America– 477 HIV-infected women – Treatment : Zidovudine >=14 weeks of gestation

• Results: rate of HIV transmission – Zidovudine arm : 8.3%– Placebo arm : 25.5% Reduction of 68%

Connor, New Engl J Med 19945

Three generations of PMTCT research in Sub-Saharan Africa

1st generation 1994-2002

Short-course ARV > 32 weeks

Replacement feeding or breastfeeding

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First generation (1994-2002): Short-course ARV regimen

0

5

10

15

20

25

Rate of HIV transmission < 5% 7

Three generations of PMTCT research in Sub-Saharan Africa

1st generation1994-2002

Short-course ARV>32-26 weeks

gestation

Replacement feeding or breastfeeding

2nd generation2002-2014

Short-course ARV / HAART*

>28 weeks gestationBreastfeeding

+ARV prophylaxis

8* Eligibility criteria for HAART 

Second generation (2003-2012) : Rate of HIV transmission < 2%

• HAART for the breastfeeding women– Mma Bana– MTCT-Plus – AMATA – KISUMU

• PEP for the breastfed infant– PEPI trial – SWEN– Promise-ANRS

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10

ARV Prophylaxis: Postnatal HIV Transmission Between Age 4-6 Weeks and 6-7 Months

0,9%0,6%

1,1%0,6%

1,2%0,8%

4,4% 4,4%

2,3%

0%

2%

4%

6%

8%

10%

% M

TCT

6 M

onth

s

MitraPlus

Amata KIBS DREAM Mitrainfant(3TC)

SIMBA(NVP)

Mashi(AZT)

SWEN(NVP)

PEPI-Malawi(NVP)

Maternal Postpartum HAART Infant Postpartum ARV

All also antepartum maternalARVs (Mashi only AZT)

No antepartum maternal ARV

Mom AZT/3TC

Mom AZT/ddI

Mom AZT

PMTCT research with ANRS

PROMISE-PEP study (ANRS 12174)1

Aim : efficacy of a treatment strategy to PMTCT of HIV-1 during 12 months of breastfeeding

Regimens : Lopinavir/Ritonavir vs. Lamivudine from day 7 until 4 weeks after cessation of to prevent postnatal HIV-1 acquisition (7 days and 50 weeks)

Next steps : comparative data on efficacy and tolerance of the two regimens will be available in September 2013

Transmission rate of MTCT

1.1% at 12 months

1. Towards Elimination of Breastfeeding Transmission by Infant Prep: Results of ANRS 12174 Trial Using Boosted Lopinavir or Lamivudine in Africa ; Thorkild Tylleskar, CROI 2013

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Current WHO PMTCT recommended interventions

2

Eligible women

Non-eligiblewomen

Published in 2010 and updated in 2012 12

Towards the 2013 WHO*

• All HIV+ pregnant and breastfeeding women should initiate triple ARVs as soon as possible (Option B+)

• All women not eligible for antiretroviral therapy for their own health, consideration can be given to discontinue the antiretroviral regimen after the period of MTCT risk has ceased (option B)

New Guidelines on PMTCT will release mid 201313

2013 WHO recommendations*

• Treatment eligibility criteria: – CD4 <500 cells/ml ??– CD4 <350 cells (current recommendation)

• Preferred regimen (adults & PMTCT):TDF / (3TC or FTC) / EFV

7New Guidelines on PMTCT will release mid 201314

Paradox of the PMTCT research

• The new WHO program update recommends use of tenofovir/lamivudine/efavirenz is not “formally evaluated” among pregnant women

– Tenofovir + Emtricitabine : resistance study1,2

– Efavirenz : Amata study (Rwanda)3

1 TeMAA team  AIDS  2009 & TEmAA, ANRS team, AIDS 2010, 2. CHI, B Lancet 20073. Peltier CA, AIDS 2009 15

Three generations of PMTCT research in Sub-Saharan Africa

1st generation1994-2002

Short-course ARV

> 32 weeks$

Replacement feeding or

breastfeeding

2nd generation2002-2014

Short-courseARV / HAART>28 weeks$

Breastfeeding+

ARV prophylaxis

3rd generation2012-2020

HAART> 14 weeks$

Breastfeeding

16$ Weeks of gestation 

Research related to option B/B+ : Acceptability

• To evaluate the acceptability of and adherence to triple ARV regimens for PMTCT in women not yet candidates for ART

• To evaluate the effectiveness of Option B/B+ on MTCT rates

• To evaluate the costs and cost-benefit of Option B/B+

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Research related to optionB/B+ Pharmacovigilance

• Need of more pregnancy outcome and later infant outcome data

• Urgent to implement pharmacovigilancesystem – Pregnancy outcomes: preterm birth1, low birth

weight 2 , stillbirth, congenital anomalies– Safety of long-term HAART exposure among

infants: growth, bone mineral density, neurodevelopment

181. Powis KM, J Infect Dis. 2011, 2. Ekouevi, AIDS 2008 

Is there any place for new antiretroviral drugs?

• Identify drugs that can be used safely among pregnant women– Physicians should be comfortable to prescribe

HAART – What will happen if congenital malformation is

confirmed with Efavirenz-based regimen?

• Possible candidates for pharmacokinetics studies – TMC125 : Etravirine– Inhibitor of integrase : Raltegravir

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PMTCT Future researchMore operational research

• Axis 1 : Evaluation of PMTCT program

• Axis 2 : Strategies to increase PMTCT coverage

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Evaluation of PMTCT program

Lack of clarity and consensus around how to monitor the effectiveness of PMTCT programmes

Need to validate a consensus model for PMTCT effectiveness monitoring

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Evaluation of PMTCT program in Africa

59%PMTCT coveragePearl Survey (2007)

60%PMTCT coverageUNAIDS (2011)

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Urgent need to find innovative strategies to increase HIV testing and PMTCT coverage

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1 000 000 pregnant women

Tested for HIV35%

(350,000)

Not Tested for HIV65%

(650,000)

HIV + (n=32, 500)

HIV+ (n=17,500)

HIV prevalence 5%

Pediatric HIV infection(n=13, 000)

40% of MTCT

Pediatric HIV infection(n=3, 500)

Pediatric HIV infection(n=175)

50% PMTCT

A B B+

Increase PMCT coverage• To identify best practices and barriers for

effective PMTCT services including HIV testing

• Evaluation of different strategies – Conditional cash transfers1

– Mobile phone or SMS reminder for adherence1

– Male partner involvment1

– Transport vouchers– Task-shifting from physicians to nurses /midwifes2

– Community implication

1. http://www.clinicaltrials.gov [PMTCT] 2. WHO 200724

Conclusions • End of the cycle of the clinical research on

PMTCT

• More operational research

• Research should focused more on PMTCT coverage

• Pharmacovigilance is urgent need to put in place

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Aknowlegements

• François Dabis, Bordeaux, France

• Xavier Anglaret, Bordeaux, France

• Patrick Coffie, Abidjan, Côte d’Ivoire

• Renaud Becquet, Bordeaux, France

• Serge Paul Eholie, Abidjan, Côte d’Ivoire

• Emmanuel Bissagnene, Abidjan, Côte d’Ivoire

• Serge Kanhon, Abidjan, Côte d’Ivoire

• Eugène Messou, Abidjan, Côte d’Ivoire

• Out team at the ANRS site in Abidjan Côte d’Ivoire

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