Single-Dose Perinatal Nevirapine plus Standard Zidovudine to Prevent Mother to Child Transmission of HIV-1 in Thailand NEJM July 15, 2004 Lallemant et al.

UNAIDS & WHO Update Dec 2004

Geographical Distribution of People Living with HIV/AIDS

Factors determining Maternal to Child Transmission 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-1 In utero Perinatally Breastfeeding

The “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 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 weeks Connor EM et al N Engl J Med 1994, 331:

Results 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! 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 US

The “Thai Regimen” 1999, MPH provides short course AZT to HIV- infected women in 3 rd trimester Transmission rates >6% STUDY IDEA: Add single dose nevirapine (sdNVP) perinatally to lower transmission rates *hypothesis: the addition of sdNVP to a 3 rd trimester regimen of AZT is superior to short-course AZT alone for preventing MCTC of HIV-1

Study design Multicenter Phase 3 (safety and efficacy evaluation) Double-blind Randomized Placebo-controlled

Patients 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 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

Evaluation 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 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 2 Final analysis - NVP-placebo: 2.8 % transmission - NVP-NVP: 1.9% transmission * difference not statistically significant

Discussion 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 Ethics The problem with NVP: - long t 1/2 - 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:

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 – WHO: regions where infections and malnutrition profound – continue breastfeeding –1996 UNAIDS- allow mothers to make informed choice

Thanks to: Dr. Marian Michaels Krista Pfaendler Dr. John Mellors