ShortTerm Antiretroviral Prophylaxis to Prevent MTCT of HIV

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Short-Term Antiretroviral Prophylaxis to Prevent
MTCT of HIV
Taha E Taha MD PhD Bloomberg School of Public
Health Johns Hopkins University Baltimore,
Maryland
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Background

• In Sub-Saharan Africa, most women present late
  for delivery with unknown HIV status.
• The efficacy of a baby-only post-exposure
  prophylaxis is not known.
• In situations where antenatal ARV or standard
  intrapartum NVP can be administered, it is not
  known if a combined regimen of NVP plus ZDV can
  lead to additional reduction in MTCT of HIV.
• Three studies, conducted in Malawi, South Africa
  and Ivory Coast are reviewed.

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Malawi (NVAZ) Study
Objective To determine the efficacy of a
short neonatal-only, post-exposure prophylaxis
(PEP) regimen of NVP and ZDV compared with NVP
alone, administered immediately after birth in
reducing MTCT of HIV. Babies born to women
arriving very late to the labor ward (late
presenters) with unknown HIV status therefore
HIV counseling, testing and administration of
intrapartum NVP prior to delivery was not
possible.
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Malawi - Study Design

• Randomized, open-label, phase III clinical trial.
  
• Babies born to late presenters were randomized to
  receive either single dose NVP alone or NVP plus
  ZDV for 1 week. Babies received prophylaxis
  immediately after birth.
• Follow-up visits at 6-8 weeks, 3 months and every
  3 months thereafter to 24 months.
• Sample Size
• Late Presenters 1180 (590/arm)

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Primary End Points

• Overall HIV infection at 6-8 weeks.
• HIV infection at 6-8 weeks among babies not
  infected at birth.
• Safety of these short-term regimens.

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Babies Born to Late Presenters
Proportion HIV Infected by Randomization Status
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Malawi

• Babies Born to Early Presenters
• Objective If adding ZDV to a standard neonatal
  NVP single dose reduces transmission further.
• Study Design
• Women presenting early were given a standard
  intrapartum NVP dose
• Babies randomized to receive either NVP alone or
  NVP ZDV
• Open-label clinical trial (890 445/arm)
• Study in progress.

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Malawi

• Babies Born to Early Presenters
• Preliminary Data
• Comparable overall MTCT rates at 6-8 weeks among
  babies who received a standard dose of NVP and
  those who received ZDV in addition to NVP. Rates
  also comparable to the HIVNET 012 study results
• NVAZ NVP alone 15.7 (95 CI 11.6-19.9)
• NVAZ NVPZDV 16.8 (95 CI 12.9-20.7)
• HIVNET 012 NVP 11.9 (95 CI 8.2-15.7)

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South Africa (ZDV/NVP) Study
Objective To investigate the role of PEP in
reducing risk of MTCT of HIV comparing two
drug regimens given to HIV exposed infants.
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South Africa - Study Design

• Randomized, open-label trial.
• Babies randomized to receive either NVP single
  dose only or ZDV for 6 weeks (medications given
  within 24 hours post-delivery).
• Babies born to women who had no prior
  anti-retroviral therapy were enrolled.
• Infants followed for 6 weeks to ascertain their
  HIV infection. Breast fed infants followed up to
  3 months post breastfeeding.

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South Africa Progress of the Study

• Preliminary analysis based on 781 infants.
• 773 (98.9) infants evaluable on Day 1
• 589 infants evaluable at Week 6.
• Proportion formula-fed at 6 weeks was similar in
  both groups 82 in NVP arm and 83 in ZDV arm.
• Babies PCR positive at Day 1 were 6.2 (23/381)
  in the NVP arm and 5.6 (22/378) in the ZDV arm.

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South Africa - Progress of the Study (Cont.)

• Babies PCR positive at 6 weeks (excluding those
  positive at Day 1) were 7.0 (20/285) in the NVP
  arm and 11.0 (33/304) in the ZDV arm.
• Lower maternal viral load and formula feeding
  were associated with significantly lower
  transmission while low CD4 was associated with
  higher transmission.
• Conclusion Single dose NVP administered within
  24 hours of birth was no different to 6 weeks ZDV
  in reducing post-partum MTCT.

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Ivory Coast (Ditrame Plus) Study
Objective To determine efficacy and
tolerance of a short course regimen of ZDV and
NVP in reducing peripartum transmission of
HIV below 10 in Africa.
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Ditrame Plus - Study Design

• No-randomized, open-label, intervention study.
• HIV-1 infected women were enrolled at gt 36 wks
  prepartum, and started on ZDV (300mg bid orally).
• These women received ZDV (600 mg) and NVP (200
  mg) tablets intraprtum.
• Newborns received ZDV orally during the first 7
  days plus a single oral standard dose of NVP.

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Ditrame Plus Study Design (Cont.)

• Diagnosis of HIV infection at 4-6 weeks.
• Ditrame Plus cohort MTCT rates compared with that
  of Ditrame (2 reference groups treated in the
  same population with a short ZDV regimen).
• In Ditrame, women received ZDV prepartum,
  intrapartum and postpartum.

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Ditrame Plus Study Progress

• Children assessed at 6 weeks
• Ditrame Plus 240
• Ditrame 331
• Rate of MTCT
• Ditrame Plus 7.1
• Ditrame 12.8
• p0.032

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Overall Conclusions

• Difficult to compare these studies there
• are some similarities and differences
• Similarities
• - Short-term prophylaxis (1-6 wks).
• - Regimens of 2 drugs with similar doses.
• - Open-label interventions.
• - No untreated arm cannot know true effect.
• Differences
• - Methodological differences in design, length
• of prophylaxis type of prophylaxis.

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Conclusions (Cont.)

• These studies agree on two important parameters
• Safety
• There were no major safety concerns.
• Efficacy
• The 3 studies demonstrated that it is possible
  to reduce MTCT of HIV using short-term
  antiretroviral prophylaxis either to the baby
  alone (Malawi and S. Africa studies), or baby and
  mother (Ivory Coast Study).

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Conclusions (Cont.)

• Advantages of these regimens
• Simplicity and ease of implementation.
• Less expensive.
• Comparable efficacy to other regimens involving
  administration of multiple ARVs to mother, or
  both mother and baby.
• Could avoid development of maternal drug
  resistance by using PEP regimens only the baby.

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Conclusions (Cont.)

• Future research
• The long-term benefits of these regimens are not
  known transmission through breastmilk remains a
  concern.
• Long-term prophylaxis to cover extended periods
  of breastfeeding should be evaluated.
• Long-term safety evaluations should continue.
• More effective (long-acting) ARVs should be
  explored.