Single-Dose Perinatal Nevirapine Single-Dose Perinatal Nevirapine plus Standard Zidovudine to Prevent plus Standard Zidovudine to Prevent

Mother to Child Transmission of Mother to Child Transmission of HIV-1 in ThailandHIV-1 in Thailand

NEJM

July 15, 2004

Lallemant et al.

UNAIDS & WHO Update Dec 2004UNAIDS & WHO Update Dec 2004

Geographical Distribution of People Geographical Distribution of People Living with HIV/AIDSLiving with HIV/AIDS

Factors determining Maternal to Child Factors determining Maternal to Child Transmission of HIV-1Transmission of HIV-1

• High maternal viral load• Low maternal CD4 cell count• Illicit drug use• Birth weight < 2500 grams• Rupture of membranes > 4 hours• Virulence factors of HIV strain• Host susceptibility factors

Mother to Child Transmission of HIV-1Mother to Child Transmission of HIV-1

• In utero

• Perinatally

• Breastfeeding

The “When” of MTCT of HIV-1The “When” of MTCT of HIV-1

• Risk of transmission in those receiving no antiretroviral therapy ~25% overall

Antenatal Period : 30%

*Moment of Birth(Perinatal): 70%

Some History: PACTG 076 TRIALSome History: PACTG 076 TRIAL

• Multi-centered, double blind, placebo controlled

• Women with HIV (not AIDS)– CD4 count > 200– No clinical symptoms of AIDS

• ZDV during 2nd and 3rd trimesters• IV ZDV during labor & delivery• ZDV to infant 0 - 6 weeks

Connor EM et al N Engl J Med 1994, 331:1173-80.

Results of PACTG 076 trialResults of PACTG 076 trial

• Mother - Infant dyads:– 23% transmission in controls– 8% transmission in treated

• Overall 67.5% relative reduction in risk of HIV transmission during labor!

This is HUGE!This is HUGE!

• Why?

- The study that showed that transmission of HIV could be prevented by antiretroviral therapy…

Applies to:

1. MTCT

2. Needlestick accidents

Perinatal Infections in the USPerinatal Infections in the US

The “Thai Regimen”The “Thai Regimen”

• 1999, MPH provides short course AZT to HIV-infected women in 3rd trimester

• Transmission rates >6%

STUDY IDEA:• Add single dose nevirapine (sdNVP) perinatally

to lower transmission rates

*hypothesis: the addition of sdNVP to a 3rd trimester regimen of AZT is superior to short-course AZT alone for preventing MCTC of HIV-1

Study designStudy design

• Multicenter

• Phase 3 (safety and efficacy evaluation)

• Double-blind

• Randomized

• Placebo-controlled

PatientsPatients

• Inclusion criteria- AZT received at 28

weeks gestation or asap after (at least for 2 weeks)

- “health” screen before randomization

- Written consent- Agreement not to

breastfeed

• Exclusion criteria

- maternal/fetal condition or treatment that contraindicated treatment with NVP or AZT

Experimental TreatmentsExperimental Treatments

• Patients were randomized to 3 groups:

1. NVP-NVP (NVP dose to mom and baby)2. NVP-placebo (NVP to mom, placebo to baby)3. Placebo-placebo (placebo to both)

*Study powered to evaluate the superiority of the NVP-NVP arm over the placebo-placebo arm

EvaluationEvaluation

• Follow-up: - mother: every 2 weeks predelivery, postdelivery at 10

days, 6 weeks, 4 months- Infant: 10 days, 6 weeks, 4,6,8,12 months

• Evaluation of infant for HIV-infection:- Peripheral blood/Amplicor Assay- + if 2 positive PCR on 2 different occasions- - if 2 negative PCR on 2 different occasions after age of

1 month

Results – Part 1Results – Part 1

First interim (40% women enrolled)- NVP-NVP: 1.1% transmission- NVP-placebo: 2.1% transmission- placebo-placebo: 6.3% transmission

*Placebo-placebo group discontinued; study restructured to show noninferiority of NVP-placebo to NVP-NVP

Results – Part 2Results – Part 2

• Final analysis

- NVP-placebo: 2.8 % transmission

- NVP-NVP: 1.9% transmission

* difference not statistically significant

http://content.nejm.org/content/vol351/issue3/images/large/07t2.jpeg

http://content.nejm.org/content/vol351/issue3/images/large/07t4.jpeg

DiscussionDiscussion

• NVP-placebo noninferior to NVP-NVP for lowering risk of transmission

Problems:

1. True transmission rates: stratification by viral load (NVP-placebo had lower median viral load) and T cell counts

2. Ethical concerns: exposing mothers to NVP

More about EthicsMore about Ethics

• The problem with NVP:

- long t1/2 - levels detectable 21 days later- single mutation confers resistance to NNRTI class of antiretrovirals

• Women from the same study – those exposed to NVP had higher rates of virologic failure at 6 months of treatment with an NVP-containing regimen than those that were not exposed to NVP

Jourdain G et al N Engl J Med 2004, 351: 229-238.

What about breastfeeding?What about breastfeeding?

• Meta-analysis estimates 14-24% transmission• Critical for parts of the world where safe

alternatives not available

• Recommendations:– 1985 CDC: against breastfeeding– 1987-92 WHO: regions where infections and

malnutrition profound – continue breastfeeding– 1996 UNAIDS- allow mothers to make informed

choice

Thanks to:Thanks to:

• Dr. Marian Michaels

• Krista Pfaendler

• Dr. John Mellors