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.
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
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
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
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