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Pmtct
1. UPDATE PMTCT GUIDELINES 2010
Nittaya Phanuphak, MD
Thai Red Cross AIDS Research Centre (TRC-ARC)
and South East Asia Research Collaboration with Hawaii (SEARCH)
The 9th TAS HIV/AIDS Treatment and Care Workshop
27 August 2010
2. Outline
Changes in the most recent PMTCT Guidelines
Rationale behind these changes
2010 Thai National PMTCT Guidelines
Challenges in implementing the new guidelines in
Thailand
3. Estimated number of children (<15 years)
newly infected with HIV, 2008
Western & Eastern Europe
Central Europe & Central Asia
North America <100 3700
<100 [<100 – <200]
] [1700 – 6000] East Asia
[<100 – <200] Middle East & North 3200
Caribbean Africa [2100 – 4500]
2300 4600 South & South-East
Asia
[1400 – 3400] [2300 – 7500]
Sub-Saharan Africa
18 000
Latin America
390 000 [11Oceania
6900 [210 000 – 570 000]
000 – 25 000]
<500
[4200 – 9700]
[<500 – <1000]
Total: 430 000 (240 000 – 610 000)
= >1000 new infections in children each day
December 2009
4. Coverage of ARVs for PMTCT, 2008
An estimated 45% of HIV-infected pregnant
women received some ARVs for PMTCT in
2008, up from 35% in 2007 and 10% in 2004
5. WHO PMTCT Guidelines
2006 Guidelines
ART eligible if CD4 <200
or <350 cells/mm3 with
WHO stage 3 or 4
AZT + sd-NVP as the most
advanced PMTCT regimen
recommended
Start at 28 wk GA
AZT syrup 1 week or 4
weeks depends on the
length of maternal ARV
No recommendation for
maternal and infant’s ARV
if breastfeeds
6. WHO PMTCT Guidelines
2006 Guidelines Nov 2009 Rapid Advice
ART eligible if CD4 <200 ART eligible if CD4 <350
or <350 cells/mm3 with cells/mm3 or WHO stage 3
WHO stage 3 or 4 or 4
AZT + sd-NVP as the most Maternal 3-drug regimen
advanced PMTCT regimen as an equal option to AZT
recommended (+ sd-NVP)
Start at 28 wk GA Start earlier at 14 wk GA
AZT syrup 1 week or 4 AZT (or NVP) syrup 4-6
weeks depends on the weeks for all
length of maternal ARV
No recommendation for Maternal and infant’s ARV
maternal and infant’s ARV if breastfeeds
if breastfeeds
7. WHO eligibility criteria for ART in
pregnant women
Start as soon as Preferred
possible irrespective AZT+3TC+NVP or
of GA AZT+3TC+EFV (not during
the 1st trimester)
Alternative
TDF+3TC(FTC)+NVP or
TDF+3TC(FTC)+EFV
8. When HAART is not yet indicated
WHO ANTIRETROVIRAL DRUGS FOR TREATING PREGNANT WOMEN
AND PREVENTING HIV INFECTION IN INFANTS – 2010 VERSION
9. DHHS PMTCT Guidelines
29 April 2009
AZT+3TC+NVP (if CD4 <250), +EFV
(if after 1st trimester), +LPV/r
(preferred PI)
ART not yet eligible: start after the 1st
trimester and no later than 28 wk GA
Breastfeeding is not recommended in
the US (maternal or infant’s ARV
reduce risk during breastfeeding)
Ongoing PK study of LPV/r tablet
Conflicting data on PI and preterm
delivery
Majority of data did not show
increased hyperglycemia from PI
during pregnancy
10. DHHS PMTCT Guidelines
29 April 2009 24 May 2010
AZT+3TC+NVP (if CD4 <250), +EFV Breastfeeding is not recommended in
(if after 1st trimester), +LPV/r the US (risk of resistance in infants
(preferred PI) exposed to maternal or infant’s ARV
during breastfeeding)
ART not yet eligible: start after the 1st
trimester and no later than 28 wk GA No new info on LPV/r tablet PK
Breastfeeding is not recommended in Data on PI use and preterm delivery
the US (maternal or infant’s ARV continued to be conflicting
reduce risk during breastfeeding)
No new info on PI and hyperglycemia
Ongoing PK study of LPV/r tablet
Common M184V/I and NNRTI
Conflicting data on PI and preterm resistance after triple-drug prophylaxis
delivery (rare PI mutation)
Majority of data did not show Results from OCTANE
increased hyperglycemia from PI
during pregnancy NRTI tail (+PI) for 30 d esp. after
stopping EFV
11. Rationale behind these changes
Earlier CD4 count threshold for the initiation of HAART in
non-pregnant adults
Timing of transmission (with and without breastfeeding) and
benefits of starting ARV earlier during pregnancy
Importance of ARV regimens used during pregnancy to
reduce transmission and prevent postpartum resistance
Safety of 3-drug regimens (LPV/r, EFV) for use during
pregnancy
More countries ready to expand more effective PMTCT
services
12. Rationale behind these changes
Earlier CD4 count threshold for the initiation of HAART in
non-pregnant adults
Timing of transmission (with and without breastfeeding) and
benefits of starting ARV earlier during pregnancy
Importance of ARV regimens used during pregnancy to
reduce transmission and prevent postpartum resistance
Safety of 3-drug regimens (LPV/r, EFV) for use during
pregnancy
More countries ready to expand more effective PMTCT
services
13. Timing of transmission to infant:
Non-breastfeeding population
Athens PK, et al. Lancet Infect Dis 2006; 6:726–32.
14. Timing of transmission to infant:
Breastfeeding population
Athens PK, et al. Lancet Infect Dis 2006; 6:726–32.
15. Risk factors for perinatal HIV transmission
High maternal viral load
Low maternal CD4 count
Vaginal delivery
Premature rupture of membrane
Preterm delivery, low birth weight
Newell ML, et al. AIDS 1996; 10:1675-1681.
Magder LS, et al. JAIDS 2005; 38:87-95.
Joao E, et al. CROI 2010, abstract 897.
16. PMTCT during antepartum period
Antepartum
Antepartum ARV for pregnant women
To reduce maternal HIV RNA level to the lowest level as quick as possible
To increase maternal CD4 count to the highest level
To improve maternal health and reduce pre-term and LBW delivery
17. When should HAART be initiated in
pregnancy to achieve undetectable VL?
Read P, et al. CROI 2010, Abstract 896.
19. Rationale behind these changes
Earlier CD4 count threshold for the initiation of HAART in
non-pregnant adults
Timing of transmission (with and without breastfeeding) and
benefits of starting ARV earlier during pregnancy
Importance of ARV regimens used during pregnancy to
reduce transmission and prevent postpartum resistance
Safety of 3-drug regimens (LPV/r, EFV) for use during
pregnancy
More countries ready to expand more effective PMTCT
services
20. Perinatal HIV transmission in the UK and Ireland when
HAART is recommended for all pregnant women,
2000-2006 (N = 5131)
TR % •Overall transmission rate = 1.2%
30 •TR reduced 1% for every additional
25
25 week of HAART
•TR 0.1% if HAART and VL < 50
20 16.7 Elective C/S
N=637 N=143
Emergency C/S
15
11.1 Planned VD
Unplanned VD
10
N=4107 N=125 5.85.9
5
3.3 2.7
0.71.70.7 1.4
0 0 0 0 0
0
HAART DualRx MonoRx Untreated
Townsend CL, et al. AIDS 2008;22:973-981.
21. Efficacy in reducing perinatal HIV
transmission
AZT from 28 wk GA plus single-dose NVP (when maternal
therapy is not indicated)
2% from PHPT-2
5.8% from Dept. of Health report 2007 (Thailand)
HAART for PMTCT
<1-2% in developed and developing countries
2.4% from Thai Red Cross cohort (women with CD4>200 80%, CD4
<200 20%)
Kesho Bora study
Women with CD4 200−500, randomized between 28-36 weeks GA
1.8% with HAART versus 2.2% with AZT plus sd-NVP (not significant)
Lallemant M, et al. N Engl J Med 2004;351:217-228.
Cooper ER, et al. JAIDS 2002;29:484-494.
European Collaborative Study. CID 2005;40:458-465.
De Vincenzi I, et al. 5th IAS 2009, Abstract LBPEC0.
22. Efficacy in reducing perinatal HIV
transmission
AZT from 28 wk GA plus single-dose NVP (when maternal
therapy is not indicated)
2% from PHPT-2
5.8% from Dept. of Healthmust aim to reduce
Thailand report 2007 (Thailand)
HAART for PMTCT pediatric
“new HIV cases” from
<1-2% in developed and developing countries
500 (5.8%) to <100 cases/year (1%)
2.4% from Thai Red Cross cohort (women with CD4>200 80%, CD4
= 80% reduction in the whole country’s
<200 20%)
Kesho Bora studypediatric HIV burden.
Women with CD4 200−500, randomized between 28-36 weeks GA
1.8% with HAART versus 2.2% with AZT plus sd-NVP (not significant)
Lallemant M, et al. N Engl J Med 2004;351:217-228.
Cooper ER, et al. JAIDS 2002;29:484-494.
European Collaborative Study. CID 2005;40:458-465.
De Vincenzi I, et al. 5th IAS 2009, Abstract LBPEC0.
23. NVP resistance after sd-NVP
NVP has long half-life and has low genetic barrier
NNRTI resistance after exposure to sd-NVP has varied from 15%
to 75%, especially when virus is not fully suppresible
NVP resistance in plasma and cellular provirus can still be
detected at 12 months after exposure
1-week AZT/3TC after delivery decreased NVP resistance (from
60% to 10%) but did not eliminate the risk
Treatment outcome with NNRTI-based HAART in postpartum
women exposed to sd-NVP is impaired and associated with
NNRTI resistance (both standard and allele-specific genotype)
Loubser S, et al. AIDS 2006;20:995-1002.
McIntyre JA, et al. 3rd IAS Conference 2005.
McIntyre JA, et al. CROI 2010, Abstract 153LB.
Boltz V, et al. CROI 2010, Abstract 154.
24. OCTANE/A5208
OCTANE 1: Women exposed to sd-NVP
TDF/FTC/NVP (n=120): VF or death 26%
TDF/FTC/LPV/r (n=120): VF or death 8% (p=0.0004)
DSMB recommended in Oct 08 to release data as soon as possible
OCTANE 2: Women without sd-NVP exposure
TDF/FTC/NVP (n=249): VF or death 17%
TDF/FTC/LPV/r (n=251): VF or death 20% (ITT HR 0.85, 0.56-1.29)
25. Women and Infants Transmission Study
(WITS): postpartum resistance substudy
Postpartum samples from women exposed antepartum to
AZT+3TC+NVP (n=8)
AZT+3TC+NFV (n=87)
AZT+3TC (n=20)
Dual therapy (VS triple-drug therapy)
Significantly higher rate of M184V/I (19/20, 95%)
Risk factor for M184 V/I and NNRTI resistance
Triple-drug therapy
High rate of M184V/I (47/94, 51.6%
High rate of NNRTI resistance (3/8, 37.5%)
Rare PI resistance (1/87, 1.1%)
Paredes R, et al. AIDS 2010;24:45-53.
26. Rationale behind these changes
Earlier CD4 count threshold for the initiation of HAART in
non-pregnant adults
Timing of transmission (with and without breastfeeding) and
benefits of starting ARV earlier during pregnancy
Importance of ARV regimens used during pregnancy to
reduce transmission and prevent postpartum resistance
Safety of 3-drug regimens (LPV/r, EFV) for use during
pregnancy
More countries ready to expand more effective PMTCT
services
27. Use in pregnant women with high CD4 count (>250 or
>350) to avoid serious hepatotoxicity from NVP-based
regimen
LPV/rtv is the preferred PI
Overall side effects: dyslipidemia, nausea, vomiting, loose
stools, hyperglycemia and hepatitis
Inconclusive data on preterm delivery and hyperglycemia
associated with PI
No concern regarding drug resistance if discontinue after
delivery
LPV/rtv exposure during the third trimester is reduced but
dose modification is not needed in Thai pregnant women
Hitti J, et al. Am J Obstet Gynecol 2007;196:331–337.
Kourtis AP, et al. AIDS 2007;21:607–615.
28. Aluvia® tablet
Cressey T, et al. CROI 2010, Abstract 906.
GPO LPV/r (200/50) tablet
Ramautarsing R, et al. The 11th Workshop on Clinical
Pharmacology of HIV Therapy, Poster#9.
29. Hepatitis and rash can occur
5 retrospective cases and 1 prospective case of neural tube defects
in human exposed to EFV during the first trimester
Neural tube closes by around day 28 of gestation
Meta-analysis of 11 prospective cohorts and 5 retrospective
reviews of 1st trimester exposure to EFV
1132 exposed to EFV vs 7163 exposed to non-EFV RR 0.87 (0.61-1.24,
p=0.45)
2.9% overall birth defects
0.08% neural tube defects (1/1256)
Discontinue EFV before the other drugs in the regimen due to long
half-life (probably longer than NVP)
Ford N, et al. AIDS 2010;24:1461-1470.
30. Rationale behind these changes
Earlier CD4 count threshold for the initiation of HAART in
non-pregnant adults
Timing of transmission (with and without breastfeeding) and
benefits of starting ARV earlier during pregnancy
Importance of ARV regimens used during pregnancy to
reduce transmission and prevent postpartum resistance
Safety of 3-drug regimens (LPV/r, EFV) for use during
pregnancy
More countries ready to expand more effective PMTCT
services
34. PMTCT during intrapartum and
delivery period
Intrapartum and
delivery
Intrapartum ARV or ARV before delivery
To prepare adequate plasma ARV level in the infant for
“pre-exposure prophylaxis”
Elective Caesarian Section
Avoid invasive procedure and prolonged rupture of membrane
36. Mode of delivery in the HAART era
Overall transmission rate among women with VL<1,000
copies/mL is low (but can occur even at very low VL)
From UK and Ireland
0.1% if <50 copies/mL (3/2,309)
1.2% if 50-999 copies/mL (12/1,023)
Unclear if cesarean delivery confers any additional benefit
C/S reduced risk (aOR 0.3, p=0.022) among women with
VL<1,000 copies/mL (when AZT was primarily used)
Not clear if there is any benefit among women receiving triple-
drug therapy for several weeks (TR 0.8% if >14 days)
Townsend CL, et al. AIDS 2008;22:973-981.
Ioannidis JP, et al. J Infect Dis 2001;183:539-545.
37. 2010 Thai National PMTCT Guidelines
การคลอดทางชองคลอด
การผาทองคลอดกอนการเจ็บครรภ
38. PMTCT after delivery
After delivery
ARV for infant after delivery
As post-exposure prophylaxis for the infant
Formula feeding
To prevent HIV acquisition through breast
feeding
43. Management of HIV-exposed infants
AZT syrup 4mg/kg every 12 hrs for 4-6 weeks (as post-exposure
prophylaxis), start as soon as possible after delivery
Do not give single-dose NVP except high risk mother (does not
receive 3 drugs or no ANC)
Start cotrimoxazole syrup (after discontinue AZT) 10mg/kg/d,
divided into 2 doses, 3 days/wk until 6 months of age or earlier if
HIV-negative status can be assured from blood tests
Breast feeding is not recommended, do not use mixed feeding
Vaccination can be given for healthy infants
44. Laboratory tests to determine
infant’s HIV status
DNA-PCR x 2
First DNA-PCR at 1(-2) months of age
If 1st DNA-PCR is positive, repeat immediately, if 2nd DNA-
PCR is positive “HIV-positive”
If 1st DNA-PCR is negative, repeat at 4 months of age, if 2nd
DNA-PCR is negative “HIV-negative”, can discontinue
cotrimoxazole syrup
If 2 DNA-PCR give inconsistent results, repeat 3rd DNA-PCR
immediately and interpret the result according to the 3rd test
result
45. Laboratory tests to determine
infant’s HIV status
Anti-HIV at 12 months of age
If anti-HIV negative “HIV-negative”
If anti-HIV positive, could still be maternal antibody
repeat anti-HIV at 18 months of age
If anti-HIV positive at 18 months and does not go along
with 2 DNA-PCR test results repeat anti-HIV using
non-Ag-Ab test or repeat at 24 months of age
46. Challenges in implementing the new
Thai National PMTCT guidelines
Pilot implementation in Regional Health Center 7 (7
provinces, 97 hospitals) during March – May 2010
Meetings with regional/provincial/hospital
administrators
Trainings for health care workers in the field,
“nurse” in particular
Guidelines/policy documentation
Necessary for doctors in short-term rotation
47. Challenges in implementing the new
Thai National PMTCT guidelines
VMI system for PMTCT drugs regardless of
treatment access programs
Stock on-hand in each hospital/Regional Health Center
Needs for real-time consultation by phone/email
Manuals/IEC materials for health care workers,
peer educators, pregnant women
CD, pocket book, leaflet
Frequently asked questions
48. Summary
Significant changes in PMTCT guidelines were made in the
past year with trend towards triple-drug regimen for all
HIV-positive pregnant women
Regimen selection depends on gestational age, CD4 count,
HIV-related symptoms (and viral load) at an individual
level but greatly depends on practical purposes at the
country level
For breastfeeding population, maternal and/or infant’s
ARV greatly reduce, although not eliminate, transmission
risk during breastfeeding
Challenges are expected during the transitional period but
supports are ready both technically and logistically in
Thailand
