Mother to Child HIV Transmission

Transcription

1 Koff WC. NEJM 2010;363:e7 Mother to Child HIV Transmission Why We Still Need New Prevention Modalities Lynne M. Mofenson, M.D. Maternal and Pediatric Infectious Disease Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Department of Health and Human Services

2 Outline While there has been dramatic progress in development and implementation of effective interventions for PMTCT in the last 5 years, with current interventions we are unlikely to meet the goal of elimination by Briefly discuss PMTCT in US Current WHO guidelines Review progress on implementation Discuss why we still need new preventive interventions to reduce residual transmission and reach elimination goals

3 PMTCT Strategies in the US Universal prenatal HIV testing of all pregnant women Use of antiretroviral drugs during pregnancy to rapidly and durably suppress viral load Laboratory-guided, individualized patient management (HIV RNA, CD4) Infant antiretroviral prophylaxis Elective caesarean section (if RNA >1,000 c/ml) Replacement feeding

4 Number of HIV-Infected Infants and MTCT Rate in New York State by Year of Delivery, : N=475, MTCT ~25% Important to Note that in the US, Breastfeeding is NOT Recommended for HIV-Infected Women Source: AIDS Institute, New York State Department of Health, 2012

5 Effective Implementation Strategies in the US In addition to individualized care and not breastfeeding: 98% of women in US have antenatal care (90% HIVinfected women had antenatal care) 73% women in US start prenatal care in 1 st trimester, 21% 2 nd trimester 94% pregnant women receive HIV test 85% HIV-infected pregnant women received ARVs (pregnancy and/or IP) 96% HIV-exposed infants received ARV Enhanced Perinatal Surveillance System, US, Whitmore SK et al. Pediatrics 2012;129:e74-e Natality Public Use File CDC

6 2010 WHO Guidelines: Public Health Approach to PMTCT Shift to use of multi-drug efficacious regimens sd-nvp no longer recommended regimen Emphasized the importance of identifying and treating ART-eligible women Extended ARV coverage through duration of exposure Prophylaxis initiated at 14 wks ARV to mother or infant during breast feeding Endorsed breast feeding as preferred method with ARV coverage

7 Women Eligible for ART Are At Highest Risk for Mother to Child HIV Transmission and Mortality Kuhn L et al. AIDS 2010;24: Not Eligible 31.9% Eligible for ART Not eligible for ART MTCT by 6 wk 16.7% 5.0% Eligible 68.1% Proportion of MTCT by 6 wks 87.5% 12.5% MTCT after 6 wks 17.0% 4.2% 1,025 pregnant women and their infants in Zambia prior to HAART availability, followed for 24 mos Analyzed MTCT/mortality by eligibility for ART with current WHO criteria (CD4 <350 or WHO Stage 3 or 4) Proportion of MTCT after 6 wks Maternal mortality 24 mo post delivery 87.5% 12.5% 92% 8%

8 2010 WHO Guidelines Antenatal Early Late Postpartum Early Late Pregnancy 10-25% Full Option <28 wks A >28 vs wks B have not been compared 0-1 mo 1-6 in mos trial (there 6-24 mos is ~40-50% Option A Option B Starting 14 wks AZT + sdnvp (+ tail) Labor- Delivery 35-40% Breastfeeding 35-40% ongoing trial) Maternal but lifelong available ARV data Therapy indicate (CD4<350, both WHO Options 3, 4) have similar efficacy for PMTCT in women with high CD4: Time-Limited Provision of ARV Prophylaxis if CD4 >350 and WHO Stage 1/2 to Prevent MTCT In utero MTCT ~1.7% with maternal triple ARV vs AZT/sdNVP when maternal CD (Kesho Bora, devincenzi I et al. Lancet Inf Dis 2011;11:171-80) Daily Infant NVP x12 mos Postpartum MTCT ~2-3% with maternal triple ARV vs infant NVP when maternal CD4 >250 (BAN, Chasela C et al. NEJM 2010;362: ) Maternal Triple Drug Prophylaxis through 12 mos Infant ZDV or NVP for 4-6 wks

9 Lancet 2011;378:282-4 Proposed Option B+ : Life-Long ART for All Pregnant Women Antenatal Postpartum Early Late Early Late Pregnancy 10-25% Labor- Delivery 35-40% Breastfeeding 35-40% <28 wks >28 wks 0-1 mo 1-6 mos 6-24 mos Maternal Lifelong ARV Treatment (ART) for ALL HIV-Infected Pregnant Women

10 Benefits of Option B+ Antenatal Early Late Pregnancy 10-25% Labor- Delivery 35-40% Postpartum Early Late Breastfeeding 35-40% <28 wks >28 wks 0-1 mo 1-6 mos 6-24 mos OPTION B+ Maternal Lifelong ARV Treatment (ART) for ALL HIV-Infected Pregnant Women Easier to implement when CD4 availability limited and assures women who need ART get appropriate regimen Use of once daily TDF/3TC/EFV simplifies administration and harmonizes with adult recommendation Reduce MTCT Avoid stop-start with repeat pregnancies ( protection from conception for future pregnancies) Reduces sexual transmission in discordant partners, assuming good adherence and maintenance of viral suppression

11 Uncertainties of Option B+ Antenatal Postpartum Early Late Early Late Pregnancy 10-25% Labor- Delivery 35-40% Breastfeeding 35-40% <28 wks >28 wks 0-1 mo 1-6 mos 6-24 mos OPTION B+ Maternal Lifelong ARV Treatment (ART) for ALL HIV-Infected Pregnant Women Limited ARV safety data for TDF/EFV in pregnancy especially in populations with underlying malnutrition/comorbidities; conflicting data on triple ARV and preterm delivery Critical need to assure pharmacovigilance surveillance Acceptability and adherence Special attention needed - resistance if not adherent (and assumed benefits PMTCT and sexual tx will not accrue) Need for trained staff/task shifting from MDs to administer drugs Drug costs/equity

12 PMTCT Program Implementation in South Africa and Uganda

13 Cross-Sectional, Facility-Based Survey of National PMTCT Efficacy Using South Africa Immunization Clinics ( ) Dinh T-H et al th IAS Conference, Rome, Italy Abs.MoAC0206 Caregiver-infants wk old infant attending 1 st DPT (10,820) Caregiver-infants interviewed & infant-dbs* (9,915, 92%) Refused to participate, 84 (0.8%) No or insufficient infant-dbs 821 (7.6%) HIV not exposed, 6912 (69.7%) HIV-exposed (3,003; 30.3%) No PCR test result, 35 (1.2%) HIV-exposed infants with PCR test result (2,958; 98.5%) Inclusion: 4-8 wk/o attending clinic for 6 wk vaccine Exclusion: Severely ill infants needing emergency care

14 Weighted Perinatal (6 Week) MTCT, S Africa Dinh T-H et al th IAS Conference, Rome, Italy Abs.MoAC0206 Province Infant HIV Exposure % (95% CI) N= Wk Perinatal MTCT % (95% CI) Eastern Cape 30.0 ( ) 4.1 ( ) Free State 31.1 ( ) 6.0 ( ) Gauteng 30.2 ( ) 2.2 ( ) KwaZulu-Natal 43.9 ( ) 2.8 ( ) Limpopo 22.6 ( ) 3.5 ( ) Mpumalanga 36.2 ( ) 5.9 ( ) Northern Cape 15.6 ( ) 1.7 ( ) Northwest 30.9 ( ) 4.5 ( ) Western Cape 20.8 ( ) 3.3 ( ) National 31.4 ( ) 3.5% ( ) MTCT at age 6 wks without ARV 17-22%

15 PMTCT Implementation, Uganda HIV Prevalence In HIV-Exposed Infants <18 mos, Bannink-Mbazzi F et al. JAIDS 2013 (in press) CD4<200 ART CD4 >200 sdnvp CD4<200 ART CD4 >200 AZT+sdNVP+tail CD4<350 ART CD4 Option A infant NVP

16 Comparison 2008 and 2010 South Africa National PMTCT Guidelines Rundare A et al. 19 th CROI, Seattle, WA March 2012 (Abs 1003) In 2010, S. African guidelines implemented Option A (AZT/sdNVP + infant NVP) & ART with CD4 <350. 1,995 mother-infant pairs, June : 1147 (57.5%) in ANC before 2010 (AZT/sdNVP, no infant prophylaxis) 848 (42.5%) in ANC after 2010 (Option A) 6 week MTCT rates significantly lower with new guidelines: Historical MTCT at 6 weeks with no ARV: 17-22% Before new guidelines (AZT/sdNVP): 3.4% (95% CI %) After new guidelines (add infant NVP):1.5% (95% CI %)

17 Based on new PMTCT trials and implementation, WHO set a new goal to virtually eliminate new pediatric HIV infections and improve maternal survival by 2015

18 COUNTDOWN TO ZERO Global plan towards the elimination of new HIV infections among children and keeping their mothers alive. Global Target #1: Reduce the number of new HIV infections among children by 90% from 2009 baseline estimate By 2015, MTCT <5% in breastfeeding infants and new infections <40,000 by 2015 Global Target #2: Reduce the number of AIDS-related maternal deaths by 50%

19 If We Are Doing So Well, Why Do We Still Need New Prevention Modalities for PMTCT?

20 New Ped Infections Where are We in the Elimination Plan? Major Progress in PMTCT in Past Decade >100,000 HIV infections averted between (600,000 since 1995) 400, ,000 But we remain short of the goal of global elimination of MTCT 2011 In 2011, still 330,000 new pediatric HIV infections with ARV interventions 40, UNAIDS: World AIDS Day Report 2011

21 Virtual elimination is defined as MTCT <5% and 90% decrease in new infant infections to <40,000/year Even with optimal implementation, still anticipate residual transmission and significant numbers of new infections annually.

22 Elimination of MTCT Requires More than Just ARVs: New Perinatal HIV Infections, 25 Countries in the Year 2015: Virtual Elimination Goal <40,000 Perinatal Infections/Year and <5% MTCT , , ,000 MTCT 11% 95,000 MTCT 11% 72,000 MTCT 8% 0 No ARV for PMTCT 2009 ARV coverage (53% women reached) Mahy M et al. Sex Trans Infect 2010;86 Suppl 2:ii % ARV coverage 90% ARV coverage, AND HIV incidence women reduced by 50%, AND no unmet family planning 90% ARV coverage AND HIV incidence reduced by 50% AND no unmet family planning AND limit BF to 12 mos

23 Why Still Need New Prevention Modalities for PMTCT HIV testing still low; even if identified as HIV+, in 2011 only 63% of HIV+ women receive any ARV (57% effective ARV), 43% infants receive infant ARV prophylaxis % % % pregnant women receiving HIV test % HIV+ women receiving ARV prophylaxis 43% % HIV-exposed infants receiving ARV prophylaxis Adapted from WHO 2011 Global HIV/AIDS Update

24 ARV Coverage for PMTCT in Low- and Middle-Income Countries by Region, 2011 WHO 2012 Global HIV/AIDS Update

25 Continuing HIV Infections in Women of Childbearing Age HIV Prevalence (%) Among People15-24 Years Old, By Sex, Selected African Countries, Prevalence of HIV among young women in Sub- Saharan Africa is disproportionately higher than among young men than young women. In 2010, in sub-saharan Africa, 71% of people years old living with HIV were women. Together we will end AIDS. WHO 2012

26 New HIV Infections in Young Women WHO 2011 Global HIV/AIDS Update Among 24 high prevalence countries, since 2000, there is average 31% decline in HIV in pregnant women in antenatal clinics. The range, however, is wide from >50% increase to >70% decline. 7/24 had a >50% reduction. No decline in 5 others, including South Africa, with the largest HIV epidemic in the world. Botswana: , 46% decline

27 Women Continue to Be Infected In countries most affected by HIV, women of childbearing age continue to constitute 50% or more of HIV-infected individuals in Trends in Women Living with HIV Proportion of people age >15 years living with HIV who are female WHO 2011 Global HIV/AIDS Update

28 Why Still Need New Prevention Modalities for PMTCT Risk of HIV acquisition may be increased during pregnancy and HIV incidence in pregnancy in lowresource countries ranges between %. Country Reference Incidence per 100 Pt-Yrs Pregnancy Uganda Gray R et al. Lancet 2005;366: Botswana Lu L et al CROI Abs.94LB 1.3 ( ) Zimbabwe, Uganda South Africa Morrison CS et al. AIDS 2007;21:1027 Rehle T et al. S Afr Med J 2007;97: (0-12.9) South Africa Moodley D et al. AIDS 2009;23: ( )

29 Why Still Need New Prevention Modalities for PMTCT Risk of MTCT in infants of mothers with acute infection during pregnancy or lactation is increased ~3-fold over mothers with chronic HIV. Author Population Acute/recent HIV infection HIV Transmission to Infant Moodley D (JID 2011; 203:1231-4) 1,396 HIVwomen/48 3.4% seroconverted pregnancy or by 12 mo PP 2.3-fold higher risk of MTCT (Overall MTCT 20.5% acute vs 9.0% chronic HIV) Taha TE (AIDS 2011 May 21 epub) 2,561 HIV+ women (PP) 2.9% had recent infection 2.5-fold higher risk in utero MTCT (In utero MTCT 17.8% acute vs 6.7% chronic HIV) Humphrey (BMJ 2010;341: c6580) 11,240 HIVwomen 3.0% seroconverted postpartum 2.8-fold higher risk postnatal MTCT (Postnatal MTCT 23.6% acute vs 8.5% chronic HIV)

30 Antenatal Care Sub-Saharan Africa UNICEF: Antenatal care increasing in Sub-Saharan Africa, but less than half of women have minimum recommended 4 antenatal visits or have skilled birth attendant

31 Late Presentation for Antenatal Care Common While 75% of women in sub-saharan Africa have at least 1 antenatal visit, most are not seen until the 2 nd trimester (40%), and 32% not until 3 rd trimester. 4% 28% 40% 28% Sub-Saharan Africa

32 Time of Antenatal Care US vs Sub-Saharan Africa 73% of women in the US initiate care in 1 st trimester compared to 28% in Sub-Saharan Africa

33 For Maximal Efficacy, Early ARV Initiation Needed ARV Duration in Pregnancy and MTCT: - Johannesburg, S. Africa Hoffman R et al. JAIDS 2010;54:35-41 Group (873 pregnant women with advanced HIV infection; formula) % MTCT Overall group women all on HAART (N=873) (no sig. difference NVP vs LPV/r vs EFV regimen) 4.9% Duration of HAART during pregnancy: <4 weeks (N=151) 9.3% 4-16 weeks (N=422) 5.5% weeks (N=157) 3.5% In women starting HAART during pregnancy, each additional week of HAART reduced odds of transmission by 8% (adjusted OR 0.92, 95% CI )

34 No Maternal AP ARV Infants Why Not Give Infant HAART When the Mother Has Not Received Antepartum ARV: NICHD/HPTN 040 Study Birth <48h 2-4d 5-7d 2wk 6 wk 3 mo Arm 1 n=566 AZT x 6 wk Arm 2 n=562 AZT x 6 wk NVP NVP NVP Arm 3 n=556 AZT x 6 wk 3TC + Nefinavir x 2 wk 1684 Formula-Fed Infants from Brazil, S Africa, US infant HAART HIV Infection Status

35 % IP MTCT at 3 Mos NICHD/HPTN 040: IP MTCT Decreased by ~50% with Dual or Triple Infant ARV BUT Still Residual 2-3% Intrapartum Transmission Nielsen-Saines K et al. 18 th CROI, Boston, 2011 Abs 124LB Intrapartum Infection (HIV- at Birth, + after) K-M estimate 10.0% p=0.045 for comparison experimental arms to AZT control 8.0% 6.0% 4.9% More hematologic toxicity with 3 drug regimen 4.0% 2.2% 2.5% 2.0% 0.0% AZT AZT/NVP AZT/3TC/NFV # infants infected after birth with NVP resistance: 1 2 1

36 ART Adherence During Pregnancy and Postpartum Nachega J et al. AIDS 2012;26: Meta-analysis 51 studies in 20,153 pregnant women. Adequate adherence defined as >80% adherence to doses. Overall, only 73% reported >80% adherence. Antepartum 75.7 ( ) ( ) 9 Postpartum ZDV sdnvp cart % Adherence % Adherent (95% CI) No. Estimates 79.0 ( ) ( ) ( ) 28 Adherence was significantly worse in the postpartum period Adherence was also significantly worse in women receiving cart.

37 Survival Limiting Breastfeeding is Not An Option: Mortality and Weaning at 6 Months Kesho Bora Trial Cournil A et al. AIDS 2012 Dec (Epub ahead print) Within six months after birth, weaned or never breastfed children were at 7-fold higher risk of dying compared to children who were still breastfed - despite a context where interventions were provided to reduce risks associated with replacement feeding. Cause of Death by HIV & BF Status Uninfected HIV-Infected Wean/ no BF Still BF Wean/ no BF Still BF Gastro Pn Other Inf Malaria Other Total

38 Why Still Need New Prevention Modalities for PMTCT Breastfeeding needs to be prolonged even longer than 12 months to optimize infant health.. Diarrhea-Related Hospitalization or Death Among 618 HIV-Exposed Uninfected Infants by Actual Breastfeeding Practice and Age, ZEBS 3.2-fold increased risk (95% CI ) diarrhealhospitalizations or death between ages 4 and 24 months among infants who weaned vs those who continue to breastfeed Fawzy A et al. JID 2011;203:

39 Why Still Need New Prevention Modalities for PMTCT Even with maternal triple drug regimens, there is still residual postnatal transmission, particularly for infants of women presenting late in pregnancy or in labor (as in BAN). Overall HIV Transmission at 6 months Postnatal 2.9% 3.8% 3.1% 2.5% 1.0% 0.5% 0.5% MTCT (6wk-6mo)

40 Why Still Need New Prevention Modalities for PMTCT 12 month rates difficult to compare weaning varied; 99% weaned before 6 months in Mma Bana vs 68% BAN; lowest 12 mo rates (Mma Bana, Amata) are likely because infants not breastfeeding. Overall HIV Transmission at 12 months Note: Most stopped BF by 6 months Postnatal 4.5% 5.7% 3.9% 3.2% 1.8% 0.5% 0.5% MTCT (6wk-12mo)

41 Why Need New PMTCT Modalities? - Summary More than ARV are needed to reach virtual elimination goal (which is still 40,000 infections/year) Continuing infection in young women Acute HIV may be increased in pregnancy Increased infant transmission with acute infection Late presentation (common) reduces ARV efficacy for PMTCT Even if give infant HAART, still residual 2-3% intrapartum transmission in formula-fed infants (not accounting for BF) ART adherence particularly postpartum problematic For optimal infant survival need BF more than12 months Even with maternal ART, residual BM infection 1-4% at 6 months, 2-6% at 12 months

42 Conclusion: Why We Still Need New Prevention Modalities Women continue to become infected and even with optimized PMTCT interventions and achieving virtual elimination, still estimated to be 40,000 infected children born every year. Infants born to women with late HIV diagnosis at high transmission risk due to lack of antepartum drugs. Even with ARV prophylaxis, breast milk transmission occurs in a minimum 2-3% of infants by age 6-12 months. Yet for optimal infant survival need prolonged safe breastfeeding 18 months or more. Need intervention provides immediate protection and then provides prolonged protection through at least 2 years and does not rely on daily adherence to drugs.

43 Thanks For Your Attention