# Presentation: 376152

## Perinatal HIV Prevention: Successes and Challenges in the U.S. and Internationally

- Mary Glenn Fowler, MD, MPH
- Divisions of HIV/AIDS Prevention
- National Center for HIV, STD, and TB Prevention
- November 9, 2004

## Overview: Perinatal HIV Prevention in U.S. and Internationally

- U.S. Successes and Remaining Challenges
- International Situation
- Epidemiology
- Current and Planned Research Efforts
- Program Activities
- Next Steps and Conclusions

## Update on U.S. Perinatal HIV Epidemic and Prevention

- Major progress since 1994 in decreasing perinatal HIV in the U.S.
- Before 1994 in the U.S. perinatal transmission rates were 20%-25%
- Now rates of 2% or less can be achieved
- Current estimates are that 6,000-7,000 HIV-infected women deliver each year
- Status of most are known by delivery
- 10%-12% receive little or no prenatal care
- CDC estimates that 280-370 babies continue to be infected each year in the U.S.

## Perinatal HIV Transmission Ratesin U.S. Studies from 1993-2002

## Transmission Rates by Type of ARV and OB Interventions

- AZT alone given prenatally, intrapartum and to newborn: about 8%
- Dual ARV’s
- Prenatal AZT/SD NVP: 2% non BF; 6% BF
- Prenatal/ Intrapartum/Post AZT/3TC: 2%
- Triple ARV’s: 2% or less non BF settings
- Scheduled c-section prior to labor onset decreases transmission by about 50%

## Perinatally Acquired AIDS Cases by Year of Diagnosis, 1981 – 2002, United States

- 0

- 200

- 400

- 600

- 800

- 1000

## Current CDC Perinatal HIV Prevention Strategies in the U.S.

- Increase awareness among pregnant women of the importance of HIV screening
- Reduce barriers to universal prenatal HIV screening — support opt out approach
- Promote rapid HIV testing at L&D for women whose status is still unknown
- Integrate HIV prenatal screening with other MCH programs and services that screen for and prevent other congenital infections (syphilis, Group B Strep, Hep B)

## Specific CDC Perinatal HIV Prevention Projects in U.S.

- Since 1999, $10M in Congressional funding per year for Perinatal Prevention goes to
-  16 high-prevalence states to support perinatal prevention programs
-  10 states for  Perinatal HIV Surveillance Activities and assessment of states prenatal testing rates
- 5 national organizations for development of  training and education materials
** **The MIRIAD study of rapid testing at L&D

## General Types of Perinatal Prevention Programs in High-Prevalence States

- Social marketing
- Outreach
- Case management high-risk women
- Training of health care workers
- Rapid testing at labor/delivery

## MIRIAD Study: Mother-Infant Rapid Intervention at Delivery

- CDC supported research in 5 university sites with 15 related hospitals -- began 1999
- Objectives:
- Assess feasibility of offering rapid testing at labor/delivery and intervention
- Assess use of rapid test kits for sensitivity and specificity
- Assess rates of seroprevalence and transmission among late presenting women of unknown HIV status
- Provide linkages to comprehensive care and treatment for those women identified by rapid testing as HIV-infected, and for their infants

## MIRIAD Demonstrates Feasibility of Rapid Testing and Intervening at Labor/Delivery   

**Between November 2001 – June 2003,  ****69,094 ****women were evaluated at 15 hospital L&D units**
**Of these, ****5,374 (7.8%)**** women were eligible based on undocumented HIV status late in pregnancy or at labor**
**Uptake of  rapid testing was ****85% **
**Two thirds of  HIV infected women in labor received antiretrovirals as did all  their newborns**
**To date 52 HIV+ women have been detected by rapid testing and 4 infants are infected**

- (Bulterys, et al. JAMA July 2004)

## Follow-up Translation Efforts to Support Rapid Testing at Labor/Delivery

- Recent FDA licensing of rapid tests — Oraquick and Reveal
- CDC Model Protocol  for implementing rapid testing at L/D
- Regional trainings on rapid testing in L&D settings

## Conclusions: U.S. Progress in Perinatal HIV Prevention

- Dramatic progress in U.S. related to
- Increased uptake of prenatal testing and access to rapid testing at L&D
- Availability of potent combination ARV’s and obstetrical interventions including C-section
- Generally adequate public and private health care infrastructure
- Feasibility of not breastfeeding in U.S. — safe water, availability of formula for low income women, lack of stigma
- Elimination of any new infant infections is the current DHHS/CDC goal

##  Remaining Challenges in the U.S.

- Achieve universal prenatal HIV testing
- Implement rapid HIV testing in labor/delivery settings for women whose status is still unknown
- Ensure adequate follow up, comprehensive treatment for HIV-infected women
- Develop mechanisms to monitor possible late adverse events among ARV-exposed infants
- 70,000+ infants have now been exposed to perinatal antiretrovirals
- How best to follow up these infants into adulthood for potential rare late effects of perinatal ARV exposures?

## International Perinatal HIV Prevention:EpidemiologyPEPFAR ActivitiesResearch Success and Plans   

## Epidemiology of Perinatal HIV in International Settings  

- >95% of HIV-infected children are born in resource limited breastfeeding settings
- WHO estimates >700,000 new infant infections each year
- Most all due to mother-to-child transmission
- Transmission rates are generally in 25%-40% range without antiretroviral interventions
- With antiretroviral interventions, late transmission rates at 18-24 months are currently 15%-25%
- Maternal HIV seroprevalence up to 35-40% in some settings
- Adolescent females are at high risk of infection
- Breastfeeding accounts for 1/3 to 1/2 of all transmissions

## Baseline Assessment: High Antenatal Clinic HIV Prevalence*

*** 14 countries in the President’s Mother and Child HIV Prevention Initiative**

## The President’s International Mother and Child Prevention Initiative

- Announced in June 2002
- $500 million Initiative jointly implemented by HHS (CDC and HRSA) and USAID
- Objectives for the Initiative
- Reach up to 1 million women annually
- Reduce mother-to-child HIV transmission by up to 40% among women treated

## The President’s Emergency Plan for AIDS Relief

-  Announced January 28, 2003
-  Targets 15 countries
-  Goals:
- Treat 2 million HIV-infected people
- Prevent 7 million new HIV infections
- Provide care for 10 million HIV-infected people and AIDS orphans
- Builds upon earlier efforts including the President’s Mother and Child HIV Prevention Initiative

## Key Partners

- Led by the Department of State Global AIDS Coordinator
- Ministries of Health
- Nongovermental organizations, faith-based  and community-based organizations
- Elizabeth Glaser Pediatric AIDS Foundation,  Columbia MTCT-plus, Family Health International, et al
- University partners
- UNICEF/ UNAIDS/ WHO/ World Bank/ Global Fund
- US government agencies:  Health and Human Services, USAID, State Dept, Department of Defense, et al

##      PMTCT: Core Strategies 

- Routine ANC C&T
- Simplified pre-test, rapid same-day results
- ARV prophylaxis (2004 WHO guidelines)
- AZT + SD NVP
- HAART treatment where feasible and eligible
- SD NVP or short-course AZT
- Screening and prophylaxis in labor
- Infant feeding counseling
- Program support for safe, feasible alternatives
- Family planning, prevention
- Links to care and treatment (e.g., PMTCT+)

## Key CDC Support Roles for PMTCT 

- Funding and support for national plans
- Policy and program guidelines
- Strategies / support for scale-up and link to care
- PMTCT curriculum and training
- WHO/CDC generic PMTCT curriculum
- PMTCT monitoring system (generic, facility-based, local and national monitoring)
- Training guide for routine counseling and testing
- Applied infant diagnosis, program effectiveness
- Program evaluation / operational research

## Operational Research & Program Evaluation in PMTCT

- Integration with MCH programs
- National scale-up and decentralization
- Early infant diagnosis/ program effectiveness
- Use of combination regimens
- Interventions at labor for women of unknown status
- NVP resistance – implications for treatment
- Linkages to care and treatment (PMTCT+)

## Research Addressing Breastfeeding Transmission 

##  Breastfeeding Postnatal Transmission:Accounts for at Least one-third of all Transmissions Among Breastfeeding Women

## Transmission Rates by Feeding Method: Nairobi Randomized Trial 

- (Nduati et al, JAMA 2000; 283: 1167-74)

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

- Birth

- 6 wks

- 14 wks

- 6 mos

- 12 mos

- 24 mos

## Timing of Breastfeeding Transmission

- Several studies suggest a large proportion of breast milk transmission occurs quite early, before 1-2 month of age – as high as an absolute risk of 6% by age 2 months or 3% in months 1 and 2.
- However, there is then a low continuous risk throughout lactation, — 0.6-0.8%/mo — into the 2nd year of breastfeeding.

## Summary: Estimates of Monthly Risk of HIV Transmission While Breastfeeding

- Early BF Transmission

- Late BF Transmission

## Risk Factors Associated with Transmission Through Breastfeeding

- HIV viral load in breast milk
- “Breast pathology” – mastitis, abscess
- Type of breastfeeding: mixed vs. predominant or exclusive breastfeeding (BF)
- Other factors (innate immune factors, vitamin A, possibly subtype, HLA etc.)

## South Africa Vitamin A Trial, Transmission by Feeding Practice 

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 40

- 1 day

- 6 mos

- 15 mos

- Infant Age

- Never BF

- Excl BF

- Mixed

## Early BF Cessation Could Prevent a Sizeable Fraction of Postnatal HIV Infections

-    68% of all infant postnatal HIV infections occurred after 6 months: ZVITAMBO Study *(N=2060)*

- Source: Piwoz, Iliff, et al, Bangkok 2004

**Notes:**
Note – have not rerun this using age at 6 wks as starting time

## Prevention of HIV Transmission 

- Through Breastfeeding

**WHO Guidelines for resource-limited settings: **
- Balances risk of HIV transmission through BF with potential increased morbidity and mortality associated with not breastfeeding
- Individual counseling
- When acceptable, feasible, affordable, sustainable and safe, formula should be used;
- Otherwise, exclusive BF with early weaning is recommended
- Individual decisions are up to mother

## Issues Regarding Breastfeeding and HIV in Resource Limited Settings

- Breast feeding improves overall infant survival in resource limited settings
- Safe, feasible and sustainable alternatives to breast feeding are not available to most HIV-infected women in international resource limited settings
- To not breast feed goes against cultural norms and may stigmatize a mother or lead to disclosure of HIV status
- Decisions on infant feeding are often influenced by  the father and other family members
- Research is being conducted to determine effective strategies that reduce transmission risk for HIV+ women in resource limited settings who choose to breastfeed

## Recent International Perinatal HIV Trial Results

## International Perinatal HIV Research Trials Following PACTG 076

- Initial focus on deliverable, prenatal short course ARV’s in resource-limited settings
- Short course (begun at 36 wks) maternal ZDV regimens-Thailand and West Africa
- Combination short course ZDV/3TC—PETRA multi-site trial in East Africa and South Africa
- SD NVP to mother and newborn--Uganda
- Current and planned trials are now addressing transmission during breast feeding
- ARV’s to mother or infant during BF
- Immune strategies—vaccines, HIVIG

##  Trial Regimens Shown to Prevent MTCT

- 3d to
- 1 wk

-  36
- wks

-  14
- wks

-   6
- wks

- _IP_

- 076

- Thai (Harvard)

- Thai (Harvard)

- IvC (ANRS), PETRA, Thai (Harvard)

- Thai (CDC), IvC (CDC)

- PETRA, 012, SAINT

- _AP_

- _PP_ (baby, mother or both)

- Thai (Harvard)

- 28
- wks

- NVAZ

- Regimens:
- AZT; AZT+3TC; single dose (SD) NVP; AZT+ SD NVP

## International Perinatal HIV Trial Results:  Early Efficacy  at 6 Weeks-4 Mos

| 1998 Thai Bangkok short AP/IP AZT (no BF) reduction in transmission | 50% |
| --- | --- |
| 1998 Ivory Coast short AP/IP AZT (BF) reduction in transmission | 37% |
| 1999 PETRA AZT/3TC trial (BF)
 reduction with longest (AP/IP/PP) arm
reduction with the IP/PP arm 	 | 
63%
42% |
| 1999 Uganda 2-dose IP/PP nevirapine (BF)	       reduction in transmission | 42% |
| 2003 Malawi infant NVP vs NVP/AZT (BF)	 | 32% |
| 2004 Thailand AZT from 28 weeks plus SD NVP at labor and to newborn | 73%
 |

##  Effects of Breastfeeding on Late Perinatal Transmission Rates

-  Effects of Breastfeeding on Late Perinatal Transmission Rates

**14.9%  ****AZT/3TC AP-IP-PP**

**15.7%  ****NVP IP-PP**

**18.1%  ****AZT/3TC IP-PP**

**22.5%  ****AZT AP-IP**

**37%  ****No ARV, BF**

**20%**

**16.5%**

**11.8%**

**8.9%**

**5.7%**

**Infant Age**

**Notes:**
Factors associated with breast milk postnatal transmission risk included:
Mean antenatal viral load (adjusted OR 3.3 per 1 log increase)
Mean antenatal CD4 count (adjusted OR 1.6 per 100 cell decrease)
Short-course ZDV did not affect postnatal breast milk transmission risk (adjusted OR 1.1)

Thus, more advanced maternal HIV disease associated with increased risk of postnatal transmission.

While short-course ZDV efficacy was retained at 24 months demonstrating significant lasting benefit even in breastfeeding population, the risk of postnatal transmission was ~9% and further interventions to decrease breast milk transmission needed.

## Latest Successful Short-Course International Trial Results 

- Combining  ZDV in the last trimester + SD NVP at labor and to newborn appears highly efficacious
- Thai CDC/TUC results— 4.6% if ZDV begun at 34 weeks + SD NVP to mother/newborn
- Thai NIH results— 2% if begin ZDV at 28 weeks + SD NVP
- Ditrame Plus results in BF W. Africa— 5.9% with combining ZDV from 34 wks + SD NVP
- Feb 2004, WHO recommends  Short Course ZDV as early as possible in  the 3rd trimester followed by SD NVP regimen at labor onset

## Strategies of New Trials to Address Breastfeeding Transmission

- Maternal HAART in last trimester and during 4-6 months of breast feeding to lower maternal viral load
- Infant ARV prophylaxis during first 4-6 months of breast feeding
- Exclusive breast feeding  followed by  early weaning at 4-6 months

## Challenges to Perinatal HIV Prevention: U.S. and Internationally

- Increasing uptake of HIV testing among pregnant women, both prenatally and at labor/delivery
- Safety monitoring of ARVs among pregnant women and  ARV - exposed infants
- Translating perinatal research into deliverable sustainable PMTCT programs
- Integrating with other MCH programs
- Using PMTCT as an opportunity  gateway for ARV treatment and care for HIV affected families
- Assessment of  ARVs for PMTCT and their potential impact on later treatment options

## Summary and Conclusions

- There has been major progress in perinatal HIV prevention in U.S; and international PMTCT research, but challenges remain
- PMTCT activities provide a gateway for families to access HIV treatment/care

## Summary and Conclusions 

- International issues include breastfeeding transmission and health care infrastructure
- Current  international research focuses on reducing breast milk transmission, resistance
- Primary prevention of HIV infection among adolescents and women of child-bearing age is key to reducing the perinatal HIV pandemic