Elijah Paintsil, MD, FAAP - PDF Free Download

Roadmap to elimination of mother-to-child transmission of HIV in Ghana by 2015 Towards HIV Free Generation Elijah Paintsil, MD, FAAP Assistant Professor of Pediatrics & Pharmacology Yale School of Medicine, New Haven, USA Ghana College of Physicians & Surgeons CME Conference - August 6 11, 2011, Accra, Ghana

Objectives To be familiar with issues surrounding motherto-child transmission (MTCT) of HIV To be an advocate for elimination of mother-tochild transmission of HIV

Elimination of MTCT by 2015 1.) Reduction of MTCT to under 5% Earlier ART initiation & protection during breastfeeding. 2.) 90% reduction in new pediatric HIV infections Reduce incident infections among women of reproductive age. Increase access to family planning methods.

The Unholy Trinity of MTCT Unintended Pregnancy HIV- Infected Infant Unknown HIV Status in Pregnancy Lack of Antenatal Care

Lecture outline Overview of Global HIV statistics The science of Mother-to-child transmission of HIV The practice of Mother-to-child transmission of HIV Elimination of mother-to-child transmission of HIV in Ghana

14000 new infections in a day Global HIV Statistics Almost 2000 are in children under 15 years of age About 1600 MTCT events each day 2.5 Million infected women give birth annually Sub-Saharan Africa accounts for more than 2/3s of HIV infected persons 1. 80% of the World s HIV infected women 2. 90% HIV infected Children reside in sub-saharan Africa

Mother-to-Child HIV Transmission Puzzle Breast Feeding Viral Characteristics Maternal Health Antiretroviral Prematurity Co-infections Mode of Delivery PROM > 4 h About 1600 MTCT events each day

MTCT: Risks, Mechanisms and Timing of transmission Risk factor Mechanism of transmission Timing of transmission HIV RNA load Increased viral burden In utero/ intrapartum/ postpartum HIV subtypes Increased viral burden In utero/intrapartum/postpartum Resistant Viral strains Increased viral burden In utero/intrapartum/postpartum Replication fitness Increased viral burden In utero/intrapartum/postpartum Facilitator Pathogens (HBV, HCV, HSV,malaria, etc.) Increased viral burden/placental disruption In utero/ intrapartum/postpartum Paintsil. Current HIV Research 2012

Maternal Factors Mechanism of Transmission Timing of Transmission Maternal Neutralizing Antibodies Increased and/or decreased viral In utero/intrapartum burden Race/ethnicity Unknown Intrapartum /postpartum Advanced HIV disease -Low CD4 and low hemoglobin Increased viral burden/placental disruption/maternal-fetal microtransfusions/mucosal exposure In utero/ Intrapartum/ postpartum Maternal Age <30 Placental disruption/maternal-fetal microtransfusions/mucosal exposure In utero/ Intrapartum/ postpartum Poor health-seeking behavior Increased viral burden/placental disruption/maternal-fetal microtransfusions/mucosal exposure In utero/intrapartum Non-compliance with HAART Illicit drug use/cigarette smoking Increased viral burden/mucosal exposure/placental disruption/ascending infection In utero/ Intrapartum/ postpartum Obstetric- Diagnostics/Interventions Placental disruption/maternal-fetal microtransfusions In utero/intrapartum Chorioamnionitis and genital infections Prolonged rupture of membranes Mode of delivery Ascending infections Maternal-fetal microtransfusions/ placental disruption Mucosal exposure/placental disruption In utero/intrapartum In utero/intrapartum Intrapartum/Postpartum

MTCT: Risks, Mechanisms and Timing of transmission III Fetal/Infant Mechanism of Transmission Timing of Transmission Low Birth Weight Premature delivery/birth order Innate immunity /β-defensin polymorphism Feeding practices (Breast feeding and mixed feeding) Increased viral burden/maternal-fetal microtransfusion/placental disruption Placental disruption/maternalfetal microtransfusions Increased viral burden/maternal-fetal microtransfusions/placental disruptions Mucosal exposure In utero In utero/intrapartum In utero Postpartum Paintsil. Current HIV Research 2012

Significant Milestone in Pediatric HIV 1994, US PHS recommended use of AZT for pmtct based on 076 study showing up to 70% reduction in transmission

Because Knowledge of Timing of MTCT Was Limited in 1992, the AZT Regimen in PACTG 076 Was Designed to Target Multiple Potential Time Points of Transmission Pregnancy Labor/Delivery Infant AZT 100 mg 5 times daily AZT IV 2 mg/kg 1 mg/kg/hr AZT 2 mg/kg q 6 hr x 6 weeks TARGET: In Utero (after 1 st trimester) TARGET: Intrapartum TARGET: Postpartum

67% Reduction in Perinatal Transmission with PACTG 076 AZT Regimen Placebo 25.5% Zidovudine 8.3%

Research to Implementation: MTCT in Resource-Rich Countries Over Time AZT Era Combination ARV Era 1993: 1994: 1997: 1999: 2001: 2002: 2003: 2006: WITS PACTG PACTG WITS PACTG PACTG WITS UK 076 185 247 316

Timing of Mother to Child HIV Transmission in Formula-Fed Populations In Formula-Fed Infants, Most HIV Transmission Occurs Around Delivery Antenatal Early Late Pregnancy 25-35% Labor and Delivery 65-75% Overall cumulative risk perinatal HIV transmission (without antiretroviral drugs): 20-25% <28 wks >28 wks

Antenatal Early Timing of Mother to Child HIV Transmission Doubling of Transmission Risk with Prolonged Breastfeeding Late Overall cumulative risk MTCT (without antiretroviral drugs): 40-45% Postpartum 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 Since breastfeeding is the cornerstone of infant survival in many resource-limited countries but is associated with high rates of HIV transmission, development of interventions to allow safe breastfeeding was critical

How Do Antiretroviral Drugs Reduce Mother to Child HIV Transmission? Lowering maternal blood/genital viral load This mechanism likely most important in women with high viral load. However, ARV drugs reduce transmission with low viral load and are effective even when antenatal drugs are not given. Two other important mechanisms through which ARVs reduce transmission: Pre-exposure prophylaxis of infant (through transplacental drug passage). Post-exposure prophylaxis of infant (through continued drug after birth).

Post-076 Clinical Trials of PMTCT in Resource-Limited Countries Evolution of PMTCT Regimens for Resource-Limited Countries 1994 2004 1994 US Ante IP PACTG 076: AZT (formula) Post 1999 Thailand Bangkok CDC: Short AZT (formula) Only 4 wks maternal AZT and no infant AZT had 50% efficacy Efficacy of same short regimen diminished with breastfeeding to 37% at age 3 mos AP 1999 Cote d Ivoire Wiktor CDC: Short AZT (breastfed) IP AP IP In formula-fed population, AZT + sdnvp results in transmission of 1-2% 2002 Cote d Ivorie 2004 Thailand PHPT-2: Short AZT + SD NVP (formula) DITRAME+: Short AZT + SD NVP (partially [46%] breastfed) Adding sdnvp to short AZT increased efficacy over AZT alone in breastfeeding population 1999 Uganda IP PP HIVNET 012: Single-Dose (sd) maternal/infant NVP (breastfed) Single dose NVP to mother at onset labor and to infant in breastfeeding population without antenatal ARV had 47% efficacy at 3 mos AP IP PP AP IP PP

2010 WHO Antiretroviral Drugs Use for Treating Pregnant Women and Preventing MTCT Two Key Approaches 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 Maternal Lifelong ARV Treatment (ART) for Maternal Health if CD4 <350 or WHO Stage 3/4 Time-Limited Provision of ARV Prophylaxis if CD4 >350 and WHO Stage 1/2 to Prevent MTCT

2010 WHO Guidelines: Women Not Requiring ART Two Options for PMTCT Prophylaxis (Both with Extended Coverage Breastfeeding) 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 A Starting 14 wks AZT + sdnvp (+ tail) Daily Infant NVP x12 mos Option B Maternal Triple Drug Prophylaxis through 12 mos Infant ZDV or NVP for 4-6 wks

New WHO Guidelines

Percent (%) women/infants PMTCT in Low-Resource Countries Has Significantly Improved -- But is Still Below What is Needed 70 60 59% 50 40 30 20 38% 42% 2004 2005 2006 2007 10 2008 0 % pregnant women receiving HIV test % HIV+ women receiving ARV prophylaxis % HIV-exposed infants receiving ARV prophylaxis 2009 2010 PEPFAR Targets: 80% 85% 85% Adapted from WHO 2011 Global HIV/AIDS Update

Roadmap: Effective strategies need be comprehensive along the full cascade of service touch points. <14 weeks before birth Thru full breastfeeding period Early Identification/ Testing Prenatal Care Safe Delivery Postpartum/ Early Infant Care All PW attending ANC All PW attending ANC are testing for HIV All HIV+ PW are staged (clinically and thru CD4) for ART eligibility in a timely manner Those eligible are started on ART treatment asap; those not eligible are started on prophylaxis Support skill birth attendance; ensure intraand post - partum ARVs; Infant prophylaxis/maternal prophylaxis thru end of breastfeeding; EID testing at 2 mos; serology 9 12 mos and post weaning. Referral/link to long term care and treatment

22 Countries with highest estimated Pregnant women living with HIV Angola, Botswana, Burundi, Cameroon, Chad, Côte d Ivoire, Democratic Republic of the Congo, Ethiopia, Ghana India, Kenya, Lesotho, Malawi, Mozambique, Namibia, Nigeria, South Africa, Swaziland, Uganda, United Republic of Tanzania, Zambia and Zimbabwe.

HIV PREVALENCE 2011 Median ANC HIV prevalence for 2011 was 2.1% (Confidence limits: 1.48-2.72) The median syphilis prevalence was 1.7%. Prevalence of HIV among STI clients was 7.9%. NACP@ Dec 2010

ARV-Treatment Options recommended for HIV-infected pregnant women who need treatment for their own health Mother All HIV-infected pregnant women with CD4 cell count <350 cells/mm3, irrespective of WHO clinical staging; and All HIV-infected pregnant women in WHO clinical stage 3 or 4, irrespective ofcd4 cell count. Treatment Options The preferred first-line ART regimen should include an AZT + 3TC backbone: AZT + 3TC + NVP or AZT + 3TC + EFV. (EFV is contraindicated in 1 st Trimester) Alternative regimens that are recommended include TDF + 3TC (or FTC) + NVP or TDF + 3TC (or FTC) + EFV*. ( TDF recommended in cases of anaemia) Infant All HIV exposed infants Irrespective of feeding option: Provide AZT daily for six weeks. NB: NVP daily for six weeks should be given if baby has anemia.

ARV-prophylaxis options recommended for HIV-infected pregnant women who do not need treatment for their own health Maternal triple ARV prophylaxis Mother Triple ARV from 14 weeks until one week after all infant exposure to breast milk has ended* AZT + 3TC + EFV TDF + 3TC (or FTC) + EFV Infant All infants irrespective of feeding option should receive Daily AZT from birth to 6 weeks (For infants with severe anaemia or haemorrhagic disease: Use NVP) * Breast feeding must be up to 12months only

Ghana service uptake: Limited Progress on PMTCT Service Uptake NACP 2009 UA 2011 95% 53% 74% 68% 53% 48% 30% 35% 30% 19% 1% 1% ANC 1 PW: tested for HIV PW: efficacious ARV regimens* PW: ART tx Infants: ARV prophylaxis Infants: DNA PCR by 2 months

2011-2015 PMTCT Objectives for Ghana The national scale-up plan for PMTCT of HIV strives towards achieving a generation free of HIV and AIDS in Ghana through the following goal and objectives: Goal: Virtual elimination of HIV transmission from mother-to-child and improvement of the health of the family, especially maternal, newborn and child health, within the context of the HIV and AIDS response in Ghana. Virtual elimination refers to 90% reduction in estimated number of new infant infections; and an HIV transmission rate of <5%, which is associated with at least 90% of all the HIV-exposed infants being alive and uninfected with the virus at the age of 2 years.

Challenges and Obstacles to emtct identified at the Summit Operational challenges and barriers to implementation of PMTCT programs in Ghana Low-cost Point of Care laboratory technology to enhance identification of HIV-infected pregnant women and early infant diagnosis Community-based strategies for increasing PMTCT uptake Family centered-approach to PMTCT - integrating delivery of PMTCT, pediatric HIV and Maternal, Neonatal and Child Health services

Operational challenges and barriers to implementation of PMTCT programs in Ghana: Policy and management at national and sub-national is fragmented and verticalized, as a result: Lack of integration policy/communication across health platforms Poor dissemination of policy changes Funding shortages for scale up of emtct Human Resources: Inadequate and siloed training Stigma/discrimination from the staff to patients Management of personnel staff chose to not treat patients or perform newly acquired training Significant percentage of current midwives are due to retire Service delivery: infrastructure: access to power; access to lab diagnostics/systems and space SCM of commodities: not unusual to have stock out of all commodities In the lower level facilities, where large percentage of the population have access to ANC and HIV testing only; all else needs referral and travel to District hospitals

4 Key Lessons from the Summit The health of the woman should be paramount Country ownership Leveraging synergies, linkages and integration of care Shared responsibility: Public-Private Partnership Not only money; infrastructure, service delivery

Learn from other sub-saharan Africa countries - Clinton Foundation Experience Key lessons include: 1. Earlier initiation & protection during breastfeeding is necessary to reduce MTCT and improve health outcomes for mothers and infants. Efficient and effective roll-out of the 2010 WHO guidelines is paramount. 2. Need better information to improve service delivery, reduce turn-around-times, and make the best use of limited resources. Strategic mapping exercise and situation analyses are a critical first step towards achieving emtct goals. 3. Rational sample transport systems, complemented by POC technology, will decrease time to ARV initiation. 4. Utilizing community cadres will help address persistent HR challenges & bring services closer to the end users. 5. Loss to follow-up is one of the most important challenges facing most PMTCT programs; in order to ensure high levels of service uptake throughout pregnancy and the postnatal period, proactive client outreach is necessary. 6. Careful monitoring and rapid, narrowly focused evaluations of key program components allow to identify, intensify & replicate the most effective program elements.

Acknowledgements Lynne Mofenson Sostena Romano Dr. Nii Addo Funding NIAID NIH USAID-HED: UG-Brown Partnership