Women refusing 3 medications should be offered zidovudine prophylaxis, never Combivir alone.

1. Principles of care of the HIV-1 infected pregnant motherProtection of mothers from mono- and dual- therapies likely to induce resistance: • Women refusing 3 medications should be offered zidovudine prophylaxis, never Combivir alone. Combivir Alone

2. Priniciples of care of the HIV-1 infected pregnant motherAggressive use of combination antiretroviral therapy to achieve durable suppression of maternal HIV replication and to protect mother from induction of antiretroviral resistance: • Offer 3 or more medications • Twice daily dosing

3. Principles of care of the HIV-1 infected pregnant mother Cytochrome p4503A reductase activity: • AUC8 for indinavir is markedly suppressed late in pregnancy • p450 3A activity is significantly increased in the third trimester(Homma et al., 2001; Hayashi et al. 2001) • Increased p450 3A activity in late pregnancy is reversed by ritonavir, allowing twice daily dosing, for example, RTV200mg/IDV800mg q 12 h

4. Principles of care of the HIV-1 infected pregnant mother Aggressive use of combination antiretroviral therapy to achieve durable suppression of maternal HIV replication and to protect mother from induction of antiretroviral resistance: • When likelihood of non-adherence is high, do not offer nevirapine • If mother does not need therapy for her own health, HAART can be safely stopped post-partum

5. Priniciples of care of the HIV-1 infected pregnant motherAggressive use of combination antiretroviral therapy to achieve durable suppression of maternal HIV replication and to protect mother from induction of antiretroviral resistance: • Offer 3 or more medications • Twice daily dosing

6. Priniciples of care of the HIV-1 infected pregnant motherAntiretrovirals that should be avoided if possible:EFAVIRENZ: • Unpublished primate data show high incidence of neural tube defects. • 88 prospective cases in APR: no NTDs. • No indication, per se, to abort pregnancy. • Multiple ultrasound and blood tests can rule out neural tube defects. • Consider a switch to nevirapine.

7. Priniciples of care of the HIV-1 infected pregnant motherAntiretrovirals that should be avoided if possible:AMPRENAVIR: • Unpublished reports of abnormal calcification of bones. • Human data are lacking. • Consider a switch to another highly potent agent or combination, such as lopinavir/ritonavir.

8. Priniciples of care of the HIV-1 infected pregnant motherAntiretrovirals that should be avoided if possible:STAVUDINE/DIDANOSINE (D4T/ddI): • High potency nRTI combination. • Particularly effective in the setting of pan-resistance and virologic breakthrough. • Given alone short term in South Africa, was highly effective at preventing MCT, without lactic acidosis. • Reports of lactic acidosis during pregnancy. • If needed, requires very frequent monitoring of liver transaminases.

9. Vertical TransmissionMaternal risk factors: • Maternal immune status:maternal CD4 • Disease activity: maternal viral load (Garcia et al., NEJM 341:394) • Antiretroviral prophylaxis • Antiretroviral therapy • Prior infected child • Weight loss, Tb, OIs

10. Vertical TransmissionMechanisms: • Unknown! • Exposure to maternal secretions? • Exposure to maternal blood at delivery? Via the placenta?

11. Length of ruptured membranes(hours)

12. Vertical TransmissionObstetrical risk factors: • Length of ruptured membranes • Prematurity, low birth weight • Immune activation during pregnancy or at delivery? • Evidence of chorioamnionitis:infection or inflammation of membranes/placenta

13. Route of deliveryInformed maternal choice: • Retrospective evidence of prevention of vertical transmission by elective cesarean deliveryin absenceof treatment Hours of membrane rupture

16. Route of deliveryInformed maternal choice: No data exist that demonstrate a benefit of elective cesarean to mother or baby when mother is receiving potent combination therapy.

17. San Francisco, 1994-1999

18. Shaffer et al., Viral Load and Transmission Length of rupture of membranes,(hours)

19. Control of maternal viral load appears to be highly protective even in the setting of prolonged rupture of membranes

20. How impossible is HIV treatment for infected mothers in the developing world? • Today, although the challenges are enormous, we are closer than ever before. • Ten years ago we could not even imagine HIV therapy as it is today. • Availability of generic antiretrovirals, especially in single pill formulations, holds great promise. • R&D for practical treatment strategies in the developing world is ongoing.

21. How possible is mother to child transmission prophylaxis? • Theoretically, MTCT prevention with one or two drugs is both possible and practical. • However,uptake of counseling and testing is low in most settings where treatment is not available. • Uptake of prophylaxis is low (˜20%) even among women who consent to testing in pilot projects. • Despite widespread assumption that induction of ART resistance in mothers and infected infants will be inconsequential, this remains to be proven. • Implementation of these strategies could result in the induction of ART resistance on a massive scale.

22. Short-term RTI prophylaxis strategies in Africa • PETRA Arm A: Not significant at 18 months • HIVNET 012: 18 month data not published • Short term prophylaxis makes no significant difference when: maternal CD4<350 or >499 cells/ul maternal plHIVRNA <50,000 copies/ml • High rates of repeat pregnancies after HIVNET 012 regimens noted in Harare • At best, regimens still result in transmission rates >10%, a figure that is now unacceptable in the West.

24. “…the question is no longer whether Asia will have a major epidemic, but rather how massive it will be.” - P. Piot