ANTIRETROVIRAL DRUGS FOR PREVENTING MOTHER-TO- CHILD TRANSMISSION (OPTION B):
Pharmaceutical considerations for a public health approach
Mohammed Lamorde1, Jonathan M. Schapiro2, David Burge3, David J. Back4
1Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda
2National Hemophilia Center in Tel Aviv, Israel
3Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
4Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom
WHO/HIV/2013.63 © World Health Organization 2013
Background
• Antiretroviral drugs critical for preventing mother-to- child transmission of HIV (PMTCT)
• Antiretroviral therapy (cART) preferred strategy
• Option B: discontinue cART at the end of
breastfeeding or at childbirth (if not breastfeeding)1
• WHO 2010 guidelines recommend discontinuation of NNRTI-based ART with an NRTI tail of at least 7 days
1WHO (2010). Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants.
Background
• Efavirenz (EFV) preferred for first-line treatment of HIV-1 infection, including among pregnant women1
• However, concern about discontinuing EFV-based cART because EFV has:
– Low genetic barrier to resistance – Prolonged elimination half-life
• Increased risk of emergence of NNRTI-associated resistance
1WHO (2012) Technical update on treatment optimization. Use of efavirenz during pregnancy: a public health perspective.
WHO/HIV/2013.63 © World Health Organization 2013
Proposed nucleoside backbones for EFV-based cART:
– zidovudine, lamivudine (ZDV, 3TC)
– tenofovir disoproxil fumarate, lamivudine (TDF, 3TC)
Background
7 h
22 h
91 h
22 h
91 h 150 h
ZDV-TP 3TC-TP EFV TFV-DP 3TC-TP EFV
Half-life
3TC-TP, lamivudine triphosphate; EFV, efavirenz (plasma); TFV-DP, tenofovir diphosphate; ZDV-TP, zidovudine triphosphate.
FTC=39 h
WHO/HIV/2013.63 © World Health Organization 2013
Key questions
Assuming viral suppression, what is the risk of
selecting NNRTI resistance among women stopping ZDV, 3TC, EFV versus TDF, 3TC, EFV?
Is a tail required?
If a tail is required, what should the recommended duration be?
Search strategy
Aim: Identify studies reporting resistance following EFV- discontinuation
– Pubmed.gov – Clinicaltrials.gov – Reviews & Reports
Fifteen (15) reports met criteria
SEARCH TERMS
•(("HIV"[Mesh]) AND "efavirenz" [Supplementary Concept]) AND "Drug Resistance, Microbial"[Mesh]).
•“Drug Resistance, Viral"[Mesh] AND "Infectious Disease Transmission, Vertical"[Mesh] AND
"lamivudine"[Supplementary Concept]
•"Drug Resistance, Viral"[Mesh] AND "Infectious Disease Transmission, Vertical"[Mesh] AND
"zidovudine"[Supplementary Concept]
• ("Pregnancy"[Mesh] OR "Infectious Disease Transmission, Vertical"[Mesh]) AND
"tenofovir"[Supplementary Concept]
WHO/HIV/2013.63 © World Health Organization 2013
Findings
• No head-to-head comparison between
ZDV, 3TC, EFV versus TDF, 3TC, EFV.
ZDV,3TC, EFV
• SMART study1: ≥ 1 NNRTI mutation (EFV patients only)
– Without tail: 20.7%
– With tail*: 15.6%
• Darwich et al.2
– Without tail: 14% (nevirapine and EFV combined)
• STACCATO3
– Without tail: 12.5%
• TRIVACAN4 : ≥ 1 NNRTI mutation
– With tail: 10%
1. Fox Z et al. (2008); 2. Darwich et al .(2008); 3. Ananworanich (2003); 4. Danel (2009)
*7 days NRTI or replace with PI. Note: study tails ranged 5 days to 7 days.
WHO/HIV/2013.63 © World Health Organization 2013
TDF, 3TC, EFV
• Scarce data
• Case report1: TDF, 3TC, EFV, ddI
– Without tail: 1 NNRTI mutation
• STOP22 :Simultaneous stop followed by lopinavir/r * 4 weeks
– No NNRTI mutations (4 subjects)
1. Sadiq (2005); 2. Taylor et al. (2012).
Other considerations
• Different study designs and suboptimal timing for resistance testing
• Limited knowledge on EFV variability due to genetics, sex, postpartum state
• EFV true elimination half-life known to be nearly twice what was previously reported1
• Resistance test measurements: population testing versus more sensitive techniques
1. Jackson et al. (2012).
WHO/HIV/2013.63 © World Health Organization 2013
Resistance risk:
ZDV, 3TC, EFV versus TDF, 3TC, EFV
No data
Tail required?
ZDV, 3TC, EFV Yes
TDF, 3TC, EFV Probably not*
Duration of tail ? 2 weeks* NA
Recommendation
* Suggested based on PK characteristics; clinical studies required.
