# Presentation: 481877

## What’s New in Perinatal Research?U.S. and International Update

*Marc Bulterys, MD, PhD*
*Centers for Disease Control and Prevention, Atlanta, GA*

## Incidence of Perinatally-Acquired AIDS United States, 1985-June 2000*

***Reported through December 2000**

**Notes:**
Remaining at risk groups in the US are those who do not access prenatal care, those who do come for care but are not offered HIV testing or do not receive the results, and those women who despite having received ARV prophylaxis, do  transmit HIV to their infant

## Antenatal Antiretroviral Treatment and Perinatal Transmission in WITS, 1990-1999Blattner W.  XIII AIDS Conf, July 2000, Durban S Africa (LBOr4)

**Notes:**
Maternal antenatal antiretroviral treatment was associated with risk of perinatal transmission.  Transmission was highest, 21% in women without therapy and also ZDV monotherapy when administered for maternal HIV disease (prior to 4/94); these rates were not significantly different.  Transmission was significantly lower with 076 ZDV monotherapy (8%), non-HAART multi-antiretroviral (4%), and lowest with HAART (1%).
In univariate analysis, significant factors associated with transmission was maternal delivery RNA, low maternal CD4 count,  type of antiretroviral therapy, maternal AIDS-defining illness, duration of membrane rupture, elective cesarean delivery, maternal antenatal hard drug use, gestational age of infant, low infant birthweight.
In multivariate analysis, independent risk factors for transmission were higher antenatal delivery RNA, increasing complexity of  maternal antiretroviral therapy, duration of membrane rupture over 4 hours, infant birthweight <2500 grams, and elective cesarean delivery (the latter borderline significance).

## PACTG 316 by Treatment Arm Dorenbaum A.  8th Retrovirus Conf, Feb 2001, Chicago, IL (Abs LB7)

## U.S. Trends in C-Section Among HIV-infected Women 1994-2000Pediatric Spectrum of Disease

**N=6467**

**Notes:**
6 sites around the country: MA, NYC, DC, LA, Puerto Rico, Texas
Summer 98, Geneva presentation of the meta-analyses and the European C-S trial
Now up to about 44%. Wed Poster 702
Still undercutting compared toy Europe; poster 697 presentation Wed

## Remaining U.S. Groups at Risk for Perinatal HIV Transmission

- Late presenters without prenatal care
- Women seen in antenatal care but not offered voluntary counseling/testing due to perceived low risk
- HIV infected pregnant women who were prescribed but did not take antiretrovirals
- Unexplained “failures”

## Understanding the Timing of HIV Transmission from Mother to Infant

- Determining the timing of perinatal HIV infection is of great clinical relevance for implementing cost-effective prophylaxis
- We propose a model for the approximate temporal distribution of mother-to-infant transmission (in non-breastfeeding populations) based on findings from recent studies, arguing that most HIV infections occur very late in gestation *(Kourtis, Bulterys, Nesheim, Lee. JAMA 2001; 285:709-712)*

## Slide 8

## Summary of Current Knowledge on Factors Affecting  Mother-to-Child HIV-1 Transmission 

**Known risk factors**
- High maternal viral load
- Viral genotype/phenotype
- Advanced maternal HIV disease
- Low CD4 count or percent
- Vaginal delivery
- Duration of membrane rupture > 4 hours
- Premature delivery (< 37 weeks)
- Breastfeeding

**Factors for which evidence is suggestive but not conclusive**
- Genetic factors
- Immature immune system in infant
- Increased viral strain diversity
- Maternal neutralizing antibody
- Illicit drug use during pregnancy
- Frequency of unprotected sexual intercourse
- Multiple sex partners during pregnancy
- Maternal nutritional status
- Anemia during pregnancy
- Cigarette smoking
- Chorioamnionitis
- Abruptio placentae
- Placental *P. falciparum *infestation
- Syphilis and other STD
- Fetal scalp electrodes
- Episiotomy and vaginal tears

## How Important is Maternal Viral Load? 

- Maternal HIV-1 RNA level is strongly correlated with risk of transmission
- RNA level near the time of delivery is an important predictor of transmission even among ARV-treated women
- Most studies do not find a threshold below which no transmission occurs
- The 076 zidovudine regimen appears to be protective at all levels of maternal RNA  (ACTG 076 findings)

## Bangkok:  Transmission Rates by Delivery Plasma Viral Load

## Perinatal Transmission from Pregnant Women with HIV RNA <1000 copies/ml (J Infect Dis 2001;183:539-45)

**Study**

**ART**

**RR (95% CI)**

- French

- PACTS

- 1/346

- 2/154

- ACTG076

- ACTG185

- 1/62

- 1/135

- -----

- Ariel

- ECS

- 3/44

- 0/56

- MICS

- WITS

- -----

- 0/22

- -----

- Fang

- Melvin

- -----

- 0/5

- -----

- Dickover

**TOTAL**

**Weighted**

*Heterogeneity*

- 0/10

**8/834 (1.0%)**

*p>0.3*

*p=0.13*

## Predictors of Perinatal Transmission in Women with RNA<1000 copies/ml

**Predictor**

- Maternal ART*

- Birthweight (per 100 g)

- Cesarean section

- CD4 count (per 100 cells)

- Gestational age (per wk)

- ROM (per hr)

- Neonatal ART

- *

**Multivariate model**

**OR (p**

**-**

**value)**

- 0.10 (<.001)

- 0.92 (.003)

- 0.30 (0.022)

- 0.86 (0.039)

- NS

- NS

- NS

- * usually ZDV mo

- notherapy

## Conclusions of Maternal RNA<1000 Meta-Analysis (J Infect Dis 2001;183:539-45) 

- Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/ml at delivery
- Antiretroviral treatment reduces the risk of transmission even in women with RNA < 1,000 copies/ml at delivery and when adjusting for potential confounders.  This protective effect seems to operate above and beyond the lowering of maternal viral load

## What do we know about host genetic factors and perinatal HIV transmission?

- Immunogenetic mechanisms facilitating protection of ~75% of HIV-exposed infants are still poorly understood
- Data from Kenya suggest that Class I HLA mother-infant concordance is associated with increased risk of transmission *(McDonald, JID, 1998)*; also independent effect of HLA supertype A2/6802 *(McDonald, JID, 2000)*
- Association of Class II HLA homozygocity with transmission as well as disease progression in PACTS case-control study
- Polymorphisms in the regulatory regions of CCR5 may also influence transmission* **(Kostrikis, J Virology 1999)*

## Class I HLA Concordance and Risk of Perinatal HIV-1 Infection

**Class I HLA Concordance and Risk of Perinatal HIV-1 Infection**

- Number of mother-infant matches at A, B, and C loci

***MacDonald et al. J Infect Dis 1998***

- Percent

## Sexual Behavior and Mother-to-Child HIV-1 Transmission 

- In two African cohort studies, investigators reported a higher risk of HIV-1 MTCT related to unprotected sexual intercourse with multiple partners *(Bulterys, AIDS 1993; Lallemant, AIDS, 1994)*
- In Italy, MTCT was more frequent among concordant HIV+ mother-father couples                   *(Galli, Pediatr AIDS HIV Inf 1993) *
- In New York, frequency of unprotected intercourse during pregnancy was strongly associated with HIV MTCT *(Matheson, AIDS, 1996)*

## From Biology to Sexual Behavior – Towards the Prevention of HIV-1 MTCT [AIDS 1996; 10:1287-9]

**Promotion of safer sexual practices and improved treatment of STD may be widely applicable public health strategies to also reduce MTCT**
**3 plausible pathophysiological mechanisms:   ****	**
**HIV-1 concentration or strain diversity;  **
**Inflammation of the cervix or vagina by****	****	****	****     microabrasions or STI;**
**Chorioamnionitis or reduced placental integrity**

## Are Mother-to-Child HIV-1 Transmission Rates Decreasing over Time? 

- Even in the absence of antiretroviral prophylaxis, HIV-1 MTCT rates appear to decrease over time in many locations (e.g., Bangkok, Kampala, Miami, Nairobi, New York City)
- Why do the highest MTCT rates occur during the early years of epidemic HIV-1 spread?
- Possible explanations: 1) Bias due to differential infant follow-up; 2) Changes in obstetric practice; 3) Changes in the proportion of women with advanced HIV disease or incident HIV infection; 4) Host genetics - women at highest risk for MTCT become infected first; 5) Viral attenuation over time?

## What is the Role of Neonatal Antiretroviral Prophylaxis in Reducing the Risk of Perinatal HIV Transmission?

## Neonatal Prophylaxis in Breast Feeding Settings HIVNET 012 Nevirapine and PETRA ZDV/3TC

- Neonatal Prophylaxis in Breast Feeding Settings HIVNET 012 Nevirapine and PETRA ZDV/3TC

- Percent Efficacy NPV vs ZDV and ZDV/3TC vs Placebo

## Neonatal Prophylaxis: Proportion of HIV Infected Infants by Timing of ZDV Receipt

**%Infected Infants **

- Wade et al., NEJM, 1998

## Vertical HIV Transmission by ZDV Treatment Regimen, PACTS, 1990-98

**                    ****	****	****                         ****Transmission****	****  **
**Perinatal ZDV****	****                        N                  Risk                RR (95% CI) **
**None (pre-076)*****	****         747                20.5%              1.00 (ref)**
**PPEP only****#****	****                        48                10.5%              0.51 (0.22-1.18)**
**PPEP **_**+**_** Intrapartum (IP)****#****        92                  8.7%              0.43 (0.22-0.84)**
**Prenatal + IP + PPEP****#****           559                  7.7%              0.38 (0.27-0.52)**
- *   Pre-PACTG-076 (January 1990 - February 1994)
- #   Post-PACTG-076 (March 1994-September 1998)

## Conclusions Regarding Neonatal Prophylaxis

- Neonatal prophylaxis starting in labor thru 1st week of life reduces transmission in BF settings
- Intrapartum ZDV/3TC alone is not sufficient
- 2 neonatal doses of PMPA can protect newborn macaques against SIV infection
- 6 weeks of neonatal ZDV can be effective in non-BF settings, if started within 12-24 hours after birth
- Optimal duration of prophylaxis for breastfed and non-breastfed infants remains unclear

## Slide 25

## Update: International Perinatal HIV Research Progress

_**Short-course ARV trials**__**	**_
-       Peripartum ZDV and NVP regimens remain
-          efficacious despite ongoing BF transmission
-       Resistance
_**Breastfeeding**__** transmission**_
-       Risk factors
-       Timing

## Ivory Coast Short-Course ZDV Trials: Combined Analysis Through 24 MonthsWiktor S.  XIII AIDS Conf, July 2000, Durban S Africa (TuOrB354)

**Placebo (N=322)**

**ZDV (N=318)**

**Risk Difference:    6 Wks:  9.5%**
**                             ****24 Mos:  8.4% (95% CI 2.0% - 15.4%)**

**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.

## HIVNET 012, Intrapartum/Postpartum Nevirapine vs ZDV:  HIV TransmissionOwen M.  XIII AIDS Conf, July 2000, Durban S Africa (LbOr01)

**24.1%**

**20.0%**

**10.4%**

**15.7%**

**11.8%**

**8.2%**

**0**

**10**

**20**

**30**

**1-3 Days**

**6-8 Weeks**

**12 Months**

**% Transmission**

**ZDV (N=308)**

**NVP (N=311)**

**12 Month Efficacy NVP vs ZDV: p = 0.003**

**Notes:**
Owen M.  Abstract LbOr01.  HIVNET 012
12 month efficacy analysis of HIVNET 012 (single dose IP/PP infant NVP vs IP/PP infant x1 wk ZDV).  Data available on 96% infants at 12 months.  Almost all infants breastfed, with encouragement to wean at age 6 months, with rates similar both groups; after age 6 months, women in ZDV compared to NVP arm more likely to stop breastfeeding. 

Efficacy of NVP in reducing transmission retained at age 12 months.  Absolute reduction transmission NVP vs ZDV was 8.2% at 6-8 wks and 8.4% at 12 months.  

12 month efficacy remains even when control for breastfeeding.  Cox proportional hazard: univariate, NVP vs ZDV 0.58 (95% CI, 0.4-0.8%); controlling for breastfeeding in time-dependent model, NVP vs ZDV 0.58 (95% CI 0.4-0.9).

No significant difference in any serious adverse events between groups for mothers or infants including rash, anemia, liver function (minor adverse events more common in infant ZDV arm during first 6 wks).

## Short Course NRTI Prophylaxis:  BMS 094ddI, d4T, ddI/d4T or ZDV: AP 36 wks, IP, PP x6 wk Gray G.  XIII AIDS Conf, July 2000, Durban S Africa (TuOrB355)

**Percent**
**Transmission**

**RNA Baseline-**
**Delivery**

**Cord Blood/**
**Maternal Blood**
**Ratio**

**1.5**

**0.47**

**Notes:**
Gray G.  Abstract TuOrB355.  Bristol-Myers Squibb 094
Evaluated alternative antiretrovirals vs ZDV for reducing transmission in small phase II study in S. Africa.  Study arms:
- d4T (N=50):       AP 34-36 wks, IP oral, PP infant x 6 wk
- ddI (N=54):        AP 34-36 wks, IP oral, PP infant x 6 wks
- ddI/d4T(N=50):  AP 34-36 wks, IP oral, PP infant x 6 wks
- ZDV (N=50):       AP 34-36 wks, IP oral, PP infant x 6 wks

All infants formula fed, and infection rates at age 6 weeks presented.

Transmission rates were not statistically different in any of the study arms, with overall transmission rate of 3.6%.  Similar data if evaluate rates of HIV infection or mortality (d4T, 8.3%; ddI, 3.8%; d4T/ddI, 10.0%; ZDV 14.30%; overall 9.0%).

Change in maternal RNA from baseline to delivery was largest in combination arm (-1.6 log), followed by ddI (-1.2 log), with similar decrease in d4T and ZDV arms (-0.9 log).

Adverse events similar in groups: congenital abnormalities ~6% (similar general population), grade 1/2 anemia, 8-13%; grade 3/4 anemia 2-7%.

## Presence of Maternal Resistant Mutations to NVP and 3TC at 6 Weeks Post Partum

- K103N

- M184VL

**Notes:**
HIVNET data based on 95 women%0—17/95 or 18% had mutation  most common k103n.  9/20 (4 infants demonstrated resistant mutations and Y181C was most common in infants (slide presentation 516)
PACTG 316 data based on 104 women with >400copies at delivery

## Risk Factors for HIV-1 Transmission through Breastfeeding

- Primary HIV-1 infection during lactation
- High plasma and breast milk viral load
- Prolonged duration of breastfeeding (>15 months)
- Clinical and subclinical mastitis, breast abscesses
- Thrush in the infant

## Clinical  Risk Factors for Postnatal Transmission: Nairobi  N=410        Embree et al: AIDS 2000: 14:2535

## Correlates of Early vs Late Infant HIV-1 Infection(John et al. J Infect Dis 2001;183:206-12)

_**Early Infection (<2 months of age):**_
**Viral load (plasma RNA, cervical or vaginal DNA)**
**Cervical or vaginal ulcers**
**CD4 count <200**
**Prematurity**
**Breastfed**
**Bleeding nipples**
_**Late Infection (> 2 months of age):**_
**Maternal plasma RNA >43,000**
**Mastitis**
**Breast abscess**
** **

**Notes:**
92 infected and 187 uninfected in the randomized  clinical trial for which above data available
Emphasize the importance of mucosal transmission in MCT

## Planned Clinical Trials to Reduce Breastfeeding HIV-1 Transmission

- Infant ARV prophylaxis trials
- Vaccine and passive immune trials
- Exclusive breastfeeding
- Early and abrupt weaning

**Notes:**
12 trials planned in Africa, India and Thailand.  Focus on prophylaxis first week, first 6 weeks or first 6 mo; zidovudine, 3TC, NVP, HIVIG, Alvac

## Mortality in Breast- and Formula-Feeding HIV-Infected Women, Nairobi, KenyaNduati R.  XIII AIDS Conf, July 2000, Durban S Africa (WeOrC495)

**1.5%**

**0%**

**4.2%**

**0.5%**

**6.5%**

**1.7%**

**9.0%**

**2.3%**

**10.5%**

**3.8%**

**0**

**4**

**8**

**12**

**% Mortality**

**6 Wks**

**6 Mos**

**12 Mos**

**18 Mos**

**24 Mos**

**Breastfeeding**

**Formula Feeding**

**RR Death (Breast vs Formula): 3.2 (95% CI 1.3-8.1%), p=0.01**

**Notes:**
Nduati R.  Abstract WeOrC495.  Kenya Formula/BreastFeeding Study
Evaluated maternal mortality among breast (N=212) vs formula-feeding (N=213) women in trial.  

Maternal mortality was significantly higher in breast-feeding than formula-feeding arm, with overall  3-fold increased risk of mortality in breast-feeding arm.

22% of excess mortality seen by  6 wks, 55% by 6 months, 72% by 1 ear, and 100% by 18months.  Attributable risk of mortality from breastfeeding was 69%.

Breastfeeding women had more weight loss than formula feeding women.

Mortality was associated with maternal CD4 count, RNA, AIDS illness and weight during follow-up.

Infant mortality higher among women who died; among the 24 women who died, 11 of their infants also died; RR of infant death was 3.1 (95% CI, 1.6-5.9, p=0.001) if mother died.

## International Perinatal HIV Prevention: Implementation Challenges

- Sharp increases in seroprevalence during adolescent years particularly among female youth
- High HIV prevalence among pregnant women
- Inadequate antenatal VCT infrastructure
- Reversal in infant survival gains related to HIV
- Breastfeeding transmission
- Competing health priorities in face of scarce resources

## Estimated number of children newly infected with HIV during 1999

**Western Europe**
**< 500**

**North Africa**
**   ****& Middle East**
**2 000**

**sub-Saharan Africa**
**515 000**

**Eastern Europe &**
**Central Asia**
**500**

**East Asia & Pacific**
**2 400**

**South **
**& South-East Asia**
**86 000**

**Australia **
**& New Zealand**
**< 100**

**North America**
**< 500**

**Caribbean**
**4 000**

**Latin America**
**6 800**

**Total: 620 000**** **

**Notes:**
To put these results into a global context – Although the HIV pandemic continues to evolve,  the burden is still greatest in subsaharan Africa where more than half a million children are infected with HIV each year.  
The Thai achievements will directly result in the prevention of thousands of Thai pediatric HIV infections each year. However if they can be translated successfully to other contexts they could impact on hundreds of thousands of lives. 
CDC has begun to work in partnership with many national governments to contribute to these efforts through the new Global AIDS Program – something you may have previously heard referred to as the LIFE initiative. 
Also exemplifying the continuum from research to program implementation my discussant Dr Shaffer was the lead investigator on the AZT trial and now heads CDC’s international programmatic efforts to prevent mother-to-child HIV transmission.  

## HIV-1 prevalence among teenagers 

**in Kisumu, Kenya, by age**

**Source: *****National AIDS Programme, Kenya, and Population Council, 1999***

## Estimated impact of AIDS on under-5 child mortality rates – Selected African countries, 2010

*Source:* US Bureau of  the Census

**250**
**200**
**150**
**100**
**50**
**0**

**per 1000 live births**

**with**** ****AIDS**

**Botswana**

**Kenya**

**Malawi**

**Tanzania**

**Zambia**

**Zimbabwe**

**without AIDS**

**Notes:**
Countries that had achieved low infant mortality <50/1000 such as Zimbabwe and Botswana related to antenatal care services, oral rehydration, safe water and immunization programs are seeing the most negative impact with 4-7 fold increases in under 5 mortality ;
other countries with higher background child mortality due to other causes are seeing near doubling in under 5 mortality related to AIDS

## CDC Perinatal HIV Activities in Kenya

- Implementation of single dose NVP at Kisumu Provincial Hospital, Nyanza Province
- Planned expansion to local district health centers and traditional birth attendants in Asembo Bay, Nyanza
- Follow-up of mother-infant cohort to assess the impact of placental malaria on perinatal HIV transmission
- An integrated approach to improving child survival
- Technical assistance to the Ministry of Health (LIFE)

## LEARN HIV STATUS

- Group antenatal counseling
- Voluntary HIV testing
- Individual post-test counseling
- Partner & couple counseling

**Prevention of Mother-to-Child HIV Transmission**
**Program components  (Kisumu, Kenya)**

_**INTERVENTIONS**_
- Nevirapine to HIV+
- Infant feeding advice/support
- (Exclusive breastfeeding and early weaning at ~ 6 months)
- M & E

_**Strengthen MCH care:**_
- ANC: Prevention and treatment
- of STD, anemia & malaria
- Safe obstetric services
- Family planning services

_**Nevirapine**_
- NVP given ~ 34 weeks GA
- 1 capsule taken at labor onset
- 1 dose to baby in first 3 days

**Notes:**
The PMCT program package is essentially this:

To strengthen essential MCH services
To assist women & couples to learn their HIV status through group antenatal HIV counseling, rapid voluntary HIV testing and same-day post-test counseling  

And to provide two interventions: 
The antiretroviral intervention is 2 doses of NVP given during antenatal care with one taken by the woman at the onset of labor and a dose given to the baby in the 1st 3 days of life

The second is an infant feeding intervention which is to promote exclusive BF & early weaning in the absence of safe water

## A Successful Model:  Thailand

- Built on short-course ZDV trial results
- Government commitment
- Well-organized antenatal infrastructure including VCT
- Successful pilot projects being expanded to national level
- Next steps include identifying women needing treatment

## Short Course AZT to Reduce HIV Perinatal Transmission in Region 7, Thailand

**Short Course AZT to Reduce HIV Perinatal Transmission in Region 7, Thailand**

- Thai Ministry of Public Health
- Department of Health
- Department of Mental Health
- Department of Communicable Disease Control
- Department of Medical Sciences
- Office of the Permanent Secretary
- UNICEF
- The HIV/AIDS Collaboration

_**Collaboration of**_**:**

## Antenatal HIV Test Coverage 

**July 98 – June 2000   (N**** = 121,545)**

**Chi square for linear trend p < 0.00001**

**Notes:**
This graph shows the trend for antenatal HIV test coverage over the 2 year program period. 

The y axis shows the percent of women with an HIV test during antenatal care and the x axis shows the two year period of the program from July 98 to June 2000. 

You can see that there was a trend to increasing test uptake through the course of the program. In the first 6 months 75% of women were tested, this had increased to a very high uptake of 93% by the last 6 months of the program. 

## Mean AZT coverage = 69%

**July 98 – June 2000    (n = 918)**

**Chi square for linear trend p < 0.001**

- 1998
- 60%

- 1999
- 72%

- 2000
- 74%

**Mean AZT coverage** = **69%**

- 0

- 20

- 40

- 60

- 80

- 100

- Jul

- Jan

- Jul

- Jan

**%**

**Notes:**
This is a similar graph which shows the uptake of AZT among HIV infected women over time. This also shows a trend to improved AZT coverage through the course of the program. 

## Summary:  Research Challenges in Global Prevention of Perinatal HIV Infection

- Primary prevention of HIV among youth
- Decreasing transmission through breast milk
- Operational research on implementation of short-course ARV interventions

## Conclusion

- Two perinatal HIV-1 epidemics exist
- Dramatic progress in U.S./Europe in research and implementation
- International research progress but major implementation challenges in the developing world
- Integrated MCH approaches to improve child survival are urgently needed

## "The Best Time To Plant A Tree Is 20 Years Ago; 

**"The Best Time To Plant A Tree Is 20 Years Ago; **
**The Next Best Time Is Today."**** **