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Antiretroviral Therapies to Prevent MTCT of HIV in Resource-Limited Settings

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Jonathan Mosser

on 6 May 2011

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Transcript of Antiretroviral Therapies to Prevent MTCT of HIV in Resource-Limited Settings

What About Breastfeeding? 3 African Trials
Lessons:
ZDV effectiveness lasted up to 24 mo,
but effectiveness waned during breastfeeding 2/2 breastfeeding-related MTCT 1. Ivory Coast 2. Ivory Coast /
Burkina Faso Ante/ Intrapartum (like Thai trial, but in breastfeeding mothers) DITRAME: Same regimen, but with one week PP ZDV (prevent early breastfeeding transmission?) 1. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d'Ivoire. Lancet 1999; 353:781.
2. Dabis F, Msellati P, Meda N, et al. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Côte d'Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. DITRAME Study Group. DIminution de la Transmission Mère-Enfant. Lancet 1999; 353:786. 3. Botswana Thior I, Lockman S, Smeaton LM, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. JAMA 2006; 296:794. [Breastfeeding + 6mo PP ZDV] vs [formula + 1mo PP ZDV]
All pts: maternal ZDV +/- single dose nevirapine
Lessons:
Formula regimen better at preventing MTCT
Infant mortality higher with formula (diarrhea, PNA)
HIV-free survival equivalent in both groups @ 18 mo Estimated number of children (<15)
newly infected with HIV (2009) Total: 370,000 UNAIDS report on the global AIDS epidemic 2010 http://www.unaids.org/globalreport/ Coverage of antiretrovirals to prevent MTCT of HIV in low- and middle income countries (2009) WHO, Mother-to-child transmission of HIV http://www.who.int/hiv/topics/mtct/data/en/index4.html The Natural History of Mother-to-Child Transmission of HIV Fetal risk factors risk factors Breastfeeding risk factors risk factors Increased Risk
for MTCT Obstetric Maternal Viral:
Viral load (but MTCT can happen at any VL)
Viral subtype (C > A/D?) polymorphisms (only limited # quasispecies transmitted; macrophage-trophic CCR5-using variants predominate)
Primary HIV infection
Maternal neutralizing ab titers protective (?)

Maternal:
Coinfections (HSV / genital ulcers)
Systemic infections (?) Immunologic
Innate immunity: chemokine & MBL polymorphisms protective?
Adaptive immunity: Treg / other HIV-specific immune responses
Role of breast milk immune factors?
CCR5: delta32 polymorphism protects?
HLA discordance protective?

Gender: females > males (2x risk) Invasive monitoring
Vaginal delivery or laboring / ROM
PROM, PPROM
PTL
Chorioamnionitis Early breastfeeding (colostrum)
Mastitis
Oral candidiasis (infant), other GI tract infections ARVs to prevent MTCT: 1994 Pediatric Aids Clinical Trial Group Antepartum: ZDV 300 bid or 200 tid po, wk 14 until delivery
Intrapartum: ZDV IV 2 mg/kg over first hr then 1 mg/kg/hr until delivery
Postpartum: (Infant): ZDV syrup 2 mg/kg po q 6h (or 1.5 mg/kg q 6h IV) x 6 wks Approximately 2/3 reduction in MTCT History Short-term ZDV is somewhat effective when breastfeeding What about other drugs? 1. Antepartum / Intrapartum trial: no postpartum dose for infant
2. Ante / Intra / Post-partum: varied lengths of ante & post-partum regimens
Both in non-breastfeeding populations

Lessons:
Better than no prophylaxis
If > 36 weeks when begun, less benefit (significant transmission from 28-36 wks)
Longer, 3-part PACTG 076 regimen was superior if feasible Shorter ZDV Course? 2 Thai Trials 1. Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet 1999; 353:773.
2. Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV
Prevention Trial (Thailand) Investigators. N Engl J Med 2000; 343:982. Zidovudine (ZDV, AZT) NRTI
Good clinical trial evidence
Crosses placenta rapidly (good fetal serum drug levels)
Clinical experience in pregnancy
Prefered NRTI in combo regimens in pregnancy Koutris, AP and Bulterys, M. "Mother-to-Child Transmission of HIV: Pathogenesis, Mechanisms, and Pathways. Clin Perinatol 37 (2010) 721-737. (lamivudine) 3TC (nevirapine) NVP Lamiduvine (3TC) NRTI
Good safety profile & clinical experience in pregnancy
Often given with ZDV as Combivir Bottle-feeding France (ANRS 076 trial):
Adding 3TC from 32 wks to delivery to 3-part ZDV regimen reduced MTCT rate to 1.6% (from 6.8% in historical controls)

Thai trial:
Adding 3TC from 34 wks to delivery to short-course ZDV regimen reduced MTCT rate to 2.8% (from 11.7% in historical controls) Breast-feeding Africa (PETRA trial, 5 sites):

Reduction in MTCT when adding 3TC to ZDV in intrapartum/postpartum (42%) or 3-part regimen (63%), but not when 3TC added to ZDV intrapartum only
Started antenatal ARV late (at 36 wks)
Effect waned with breastfeeding (@ 18 mo, 63% to 33% decline for 3-part regimen, NS for 2-part) Nevirapine NNRTI
Very potent, long half-life, rapid oral absorption
Good placental transfer: within 30m, fetal levels = maternal levels
Generated interest in possibility of single-dose ppx

HIVNET 012 (Uganda) Single dose nevirapine 200 mg PO @ onset of labor superior to ultra-short ZDV regimen (47% MTCT reduction)

99% breastfed - and effect persisted @ 18 months

For pts without antenatal care, approximately equivalent to PETRA results (ZDV+3TC intra/postpartum group) SAINT (S. Africa) PETRA ZDV + 3TC intra/postpartum regimen compared to modified HIVNET 012 (second NVP dose to mother @ 24-48h)

Similar rates of MTCT and toxicity

NVP second dose didn't improve results vs HIVNET 012
Putting it all together Maternal indication: nevirapine-based HAART if possible
No maternal indication: short course ZDV/3TC and single dose nevirapine WHO recommendations for resource-limited settings Short course ZDV +/- 3TC along with single dose NVP Various trials: PHPT2 (Thailand), DITRAME Plus (Ivory Coast, Burkina Faso), Masha (Botswana), PATCG 316 (multiple countries), NVAZ (Malawi)

Lessons:
Adding NVP to ZDV/3TC regimens provides additional efficacy in MTCT prevention
Single-dose NVP provides unique benefit in preventing MTCT in early breastfeeding NEJM June 17, 2010 Methods Results Conclusions Methods Results Conclusions Women with CD4 > 200 (n=560) randomized to: Trizivir (abacavir +
zidovudine + lamiduvine) BID PI group Kaletra (lopinavir + ritonavir) &
Combivir (zidovudine + lamiduvine) BID NRTI group CD4 < 200 / AIDS (n=170): "observational group" Nevirapine, zidovudine, lamiduvine (standard of care for Botswana)
Started @ 18-34 wks, continued indefinitely HAART started @ 26-34 wks, continued through 6 mo PP All infants: 6mg nevirapine @ birth, zidovudine 4mg/kg BID x 4 wks
All women: breastfeed until 6mo, then wean. Free food / formula from 6-12 mo Breastfeeding:
71% for at least 5 mo, 93% exclusive before weaning

Compliance (self report):
21% missed 1+ days HAART
6% missed 3+ days HAART

Adverse event rates higher in observational group; not significantly different between randomized groups
Although higher rate prematurity in PI (23%) vs NRTI (15%)

No difference in maternal virologic suppresion @ delivery or while breastfeeding

Overall risk factors for lack of VL suppression
(no difference between groups):
Later gestational age @ enrollment
High VL at enrollment

Not powered to detect MTCT differences;
low absolute numbers (6/283 in NRTI, 1/270 in PI, NS) Viral suppression rates similar or better than in non-pregnant pts in Africa
Success of both regimens due to good adherence in all treatment groups & early HAART start
Overall 1.1% rate of MTCT compares well with rate achieved in developed countries
Adverse events similar, although PI group had more prematurity (seen in previous studies also)
Limitation: HIV RNA used as surrogate endpoint for MTCT (not powered to detect MTCT differences) HIV+ women* with CD4 > 250 (n=2369) *exclusion criteria: age < 14, gestation > 30wks, CD4 < 250, Hb < 7, ALT > 2.5x ULN, serious pregnancy complications, serious infection, previous ARV use in this or prior pregnancy All mothers and newborns: nevirapine PO x 1
All mothers: Combivir (zidovudine + lamiduvine) q12h from onset of labor to 7d PP
All newborns: zidovudine 2mg/kg q12h + lamiduvine 4mg/kg x 7d
Counseled to breastfeed exclusively then rapid weaning between 24-28wks PP For all subjects: Randomized to: Maternal regimen Combivir (zidovudine + lamiduvine)
+ [nevirapine, nelfinavir,
or lopinavir / ritonavir]
daily x 2 wks, then BID until 28 wks Infant regimen Nevirapine 10-30 mg
(dose escalated by age) Adherence (self report)
Maternal HAART: took doses 89% of time
Infant nevirapine: gave doses 91% of time

Breast-feeding: 96-97% exclusive @ 21 wks PP

Risk of MTCT at 2 weeks PP:
Similar rates of MTCT between control (5.4%), maternal regimen (5.5%), and infant regimen (4.4%; all differences NS)

Risk of MTCT at 28 wks PP in previously HIV-neg newborns
5.7% in control group
2.9% in maternal regimen group
1.7% in infant regimen group

Adverse events:
Higher risk neutropenia in maternal HAART (6.2%) than control (2.6%) or infant regimens (2.3%)
Nevirapine hypersensitivity in 6/39 women; SJS in 2/39- black box warning for mothers with CD4 > 250; reason for protocol change Control group No ARV intervention p < 0.05 NS p < 0.05 Both maternal & infant regimens were effective in lowering MTCT during breastfeeding
Delay noted for maternal HAART to reach significant effect could be 2/2 time taken to suppress viral load - antenatal regimen could prevent this lag time

Confirmed danger of nevirapine in mothers with CD4 > 250
Limitations: may be desirable to breastfeed x 12 mo

Longer course of daily infant nevirapine more effective than less frequent previously studied regimens & had good safety profile, but no advantage for maternal health.
Suggest if HAART not indicated for maternal health, infant nevirapine and maternal HAART may be equally effective - and nevirapine may be preferable (inexpensive & easy to give)


ARV Treatment Pregnancy detected Antenatal Care Awareness
Availability of care (funding, infrastructure)
Social / political barriers
Geography / transportation HIV testing Percentage of pregnant women who received a HIV test in low- and middle-income countries by region http://www.who.int/hiv/topics/mtct/data/en/index1.html Postnatal Care Breast vs bottle; clean water supplies, formula availability
Postnatal ARV availability
Follow up infant testing Proximity of L&D facility, geographic / transportation issues
Cultural factors surrounding childbirth
Availability of obstetric services Delivery References Anderson B, Cu-Uvin S. Antiretroviral therapy for the pregnant HIV-infected patient in resource-rich settings. In: Basow D, editor. UpToDate. Waltham, MA,: UpToDate; 2011.
Bell DM, Brewinski MM, Holmes CB. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. 2010 Nov 11;363(20):1969,70; author reply 1970.
John-Stewart G. Prevention of HIV transmission through breastfeeding in resource-limited settings. In: Basow D, editor. UpToDate. Waltham, MA,: UpToDate; 2011.
Kourtis AP, Bulterys M. Mother-to-child transmission of HIV: Pathogenesis, mechanisms and pathways. Clin Perinatol. 2010;37(4):721-37.
Mofenson L. Interventions to prevent mother to child HIV transmission: Antiretroviral prophylaxis trials in resource-limited settings. In: Basow D, editor. UpToDate. Waltham, MA,: UpToDate; 2011.
Shapiro R, Hughes M, Ogwu A, Kitch D, Lockman S, Moffat C, et al. Antiretroviral regimens in pregnancy and breast-feeding in botswana. N Engl J Med. 2010;362(24):2282-94.
UNAIDS report on the global AIDS epidemic, 2010 [Internet].: United Nations; 2010. Available from: http://www.unaids.org/globalreport/default.htm
Weidle PJ, Nesheim S. HIV drug resistance and mother-to-child transmission of HIV. Clin Perinatol. 2010;37(4):825-42.
World Health Organization: Mother-to-child transmission of HIV [Internet]. Available from: http://www.who.int/hiv/topics/mtct/en/. MTCT Without ARV Therapy: 14-42% Via direct hematogenous transplacental spread
or ascending infection of amniotic membranes / fluid ~ 1/3 to 1/2 In Labor Via contact with secretions in birth canal, ascending cervical infection after ROM, or maternal-fetal transfusion Hard to distinguish late antepartum / intrapartum / early postpartum routes of transmission ~ 1/3 In Utero < 4% MTCT happens
in first trimester < 20% MTCT happens
by 36 wks ~ 1/3 via Breastfeeding Possible higher rate immediately postpartum (colostrum has higher viral load)
Majority of transmission if antepartum / intrapartum ARVs used 8.9 transmissions / 100 child-years of breastfeeding
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