HIV transmission rates are 20-40% when no ante-/intra- or postnatal treatments are available and infected mothers breastfeed. This transmission rate can be cut to under 2% with effective PMTCT. Also PPTCT (Prevention of Parent to Child Transmission) - Fathers also responsible! Without treatment there is a 15-30% risk of HIV transmission. HIV rates can be reduced to 2-4% with effective ARV regimens. HIV transmission rates were 10.4% for women recieving AZT monotherapy, 3.8% for dual therapy and 1.2% for triple ARV regimens. Reduces HIV transmission rate ~40%. HIV tx ~8% with 68% efficacy (PACT076) Prevelance of birth defects in infants exposed to ARV drugs did not differ significantly from rates in the general population. - C-section delivery is often done in the developed world to further reduce the risk of transmission - Decreases the chance of blood contact during birth - Not often done in the developing world - The risk of complcations often too high - Increased risk of infection - Concern about sterility of tools/equipment - The infant should be tested for HIV at 6-8 weeks after birth (PCR test) as well as 18 months (Ab test) - Any infant (under 18 months) that tests positive should be immediately put on ART - HIV progression occurs very rapidy in children due to the fact that their immune system is not fully developed - Replacement feeding is reccomended in the developing world when AFASS (Acceptable, Feasible, Affordable, Safe, and Sustainable) - Mixed feeding refers to the practice of giving infants breatmilk as well as formula or other foods - If mixed feeding happens it usually happens early after birth and continues - Many women feel that they must BF at times to appease family/community - MF is not reccomened as it can actually increase HIV transmission - It is believed that mixed feeding may cause some degradation of the intestine allowing for easier HIV transmission - Parent should choose one feeding practice and try to stick to it - Replacement feeding is the number one way to prevent postnatal HIV transmission Breastfeeding by an infected mother increases the risk of transmission 5-20%. - Replacement feeding is the number one way to prevent postnatal HIV transmission - Replacement feeding is always done in the developed world - Replacement feeding is reccomended in the developing world when AFASS (Acceptable, Feasible, Affordable, Safe, and Sustainable) - Only South Africa (SA) and Botswana offer RF options - There can be significant stigma associated with bottle feeding - Mother is identified as being HIV+ - Can lead to abandonment by the husband or family - Loss of job or being ostracized by community - Most families cannot afford formula or fuel costs to prepare - Requires clean water and know how of how to properly prepare the formula - Poor quality formulas or diluted down forumla can lead to malnutrition and even death of the infant - RF is the option of choice and many countries are trying to make this standard practice but there are concerns - When RF is done right it can greatly reduce the HIV transmission rate without increasing morbidity - In some cases the mother will be unable to BF due to her condition and RF is the only option - When offered women will often choose RF regardless of stigma and other concerns (>90% - Kenya study - Victorio Torres) - Initial cost of providing RF may be out weighed by costs associated with ART for infants (Cost beneficial?) - HIV disclosure may not be a bad thing - Requires a shift in understanding - Once people/communities see that infants are surviving without becoming HIV+ others are likely to follow - Acknowledging that HIV is prevalant among mothers may help to decrease stigma and increase discussion and awareness - Support is needed at several levels - Clinics, funds and programs - Education about how RF can reduce HIV transmission - Teaching about how to properly prepare forumla to be safe and effective (Water filters, etc.) - Equipment to reduce mixed feeding (Thermos, etc.) - Many governments/organizations do not believe that RF is the best alternative - Concerns exist that mothers will not RF due to cultural/community issues - Mixed feeding will result and dimish the benefits of RF and possible casue more harm - Many mothers are unable to maintan AFASS standards - May result in increased risk of infection and malnutrition - Cost associated with RF is high and resources limited - ~550 USD/infant (Formula 80-90% of that) - Working with large multinational organizations/funding agencies can reduce that cost (clinton foundation) - Due to chronic food shortages mothers may share the milk with other children/family leading to malnutrition - Due to money shortages milk may be sold to provide income - Is there a difference in urban/rural settings? - Will there be spillover - Mothers who are HIV- wanting to RF because they see affluent people doing it - Replacement feeding is reccomended in the developing world when AFASS (Acceptable, Feasible, Affordable, Safe, and Sustainable) - Breastfeeding is reccomended for children in the developed world - % of children breastfeed (??) - Breastfeeding is the method of choice in the developed world in HIV- women - If child is diagnosed as HIV+, then BF is reccomended PROS - Many HIV+ women cannot RF for a varitey of reasons - BF is free and provides need nutrition, immunity and vitamens to the infant - BF acts as a natural contraception, which helps to space out children CONS - BF can result in an HIV transmission rate of up to 20% - Can negate the reduced risk provided by SD-NVP or AZT - - Certain practices can help reduce the risk of HIV transmission while BF - If BF is chosen it should be the exclusive feeding practice - The amount of time BF should be limited (ween earlier) - This is difficult as it is poorly defined when weening should occur (not too early, not too late) - Decrease the weening transition time (straigth from BF to RF if possible) - It should be made sure that if BF is stopped mothers can feed/support children with AFASS standards as to not revert bake to BF - ART (or HAART) can be taken while BF to reduce the rick of HIV transmission (PEPE study) - 5% HIV transmission (6 month study?) - Daily NVP for 14 weeks (what about after 14 weeks?) - Baby also needs to be on a protease inhibitor - Can lead to drug resistence for mother/child - Concern about mother/child being on drug treament for so long - What happens when ART is stopped - HIV levels may spike when treament stopped - Increased risk of transmitting HIV if BF continues (Must ensure that BF/weening is finished) - Mother may have HIV progression and become more sick and unable to take care of the infant - Mixed feeding refers to the practice of giving infants breatmilk as well as formula or other foods - If mixed feeding happens it usually happens early after birth and continues - Many women feel that they must BF at times to appease family/community - MF is not reccomened as it can actually increase HIV transmission - It is believed that mixed feeding may cause some degradation of the intestine allowing for easier HIV transmission - Parent should choose one feeding practice and try to stick to it - Cotrimoxazole (CTZ) prophylaxis can be given to decrease the chance of opportunistic infections in the infant - Shown to decrease motality - Can be difficult to administer HIV tx 36.7% (breastfeed) vs 20.5% (formula feed) (24 months) - 44% efficacy Infant mortality 24.4% (breastfeed) vs 20.0% (formula feed) (24 months) Maternal mortality 10.5% (breastfeed) vs 3.8% (formula feed) MTCT 4.0% (exclusive BF) vs 10.1% (mix feed) Median duration of BF 4 months (abrupt ween) vs 16 months (continued BF) Duration/quantity of HIV RNA in milk higher with abrupt weening (68%) vs continuing BF (42% detectable) Infants HIV- by month 4: No difference HIV-free survival 17% (abrupt ween) vs 19% (continued BF) (24 months) Infants HIV+ by month 4: Benefit to continue BF - Mortality 57% (ween) vs 29% (continue BF) (12 months) Uninfected infants at 4 months: Mother CD4>350, continue BF better survival; CD4<350 no difference (24 months) Substudy, NVP Resistance: 33% (first NVP exposure) vs 25% (repeat exposure, same pregnancy) vs 27% (repeat exposure, prior pregnancy) 83% exclusive BF at least 6 wks (159 ds median) MTCT 14.1% (6 wks), 18.1% (4 months), 18.6% (5 months), 19.5% (6 months) MTCT associated with maternal CD4<200 and birth weight <2500g Postnatal MTCT if unifected at 6 wks): 1.1% (after 1 month), 2.2% (2 months), 2.7% (3 months), 3.3% (4 months), 4.0% (5 months) MTCT per child days if unifected at 6 wks: 0.029 (exclusive BF) vs 0.044 (mixed feed) Mixed feed with solids 10.9 fold increase risk MTCT vs exclusive BF; 1.8 fold increase with mix feed vs formula feed Cumulative mortality: 6.1% (exclusive BF) vs 15.1% (replacement feed) (3 months) HR 2.06 for formula feed 52% formula feed vs 48% BF from birth (median 124 ds); by age 3 22% mix fed Breastfeeding longer than 6 months and mixed feeding in 1st month associated with increase tx. Mixed feeding in 2nd and 2rd month not assocatied with increased risk Pilot study to assess feasibility and effect of chloroquine on cell free virus in breast milk Overall HIV tx 23% Timing of tx: 58% early (birth to 4 wks) 42% late infection (HIV- @ 4wks but HIV+ after) Probability of late postnatal tx at 18 months 15.6% Overall maternal mortality 28.7/1000pt-yr (12 months) and 32.2/1000 pt-yr at (18 months) Infant feeding modality not associated maternal mortality Maternal mortality CD4 count associated with mortality risk HIV tx 18.4% (treatment) vs 20.8% (no treatment) (6 wks) Lowering material STDs assoicated with imporved pregnancy outcome (decreased - mortality, prematurity and low birth weight) HIV tx 16.0% (antibiotics) vs 15.7% (placebo) (4-6 wks) No signif difference in tx, chorio or preterm birth Participation: 64% (targeted - HIV+) vs 71% (universal - all) NVP adherence: 74% (targeted - HIV+) vs 61% (universal - all) Rapid testing for late presenters Compare feasibility, acceptability, and early infant tx btn rapid testing IntrP vs immediately PostP HIV tx 27% (chlorhexidine) vs 28% (no intervention)(12 wks) Reduced sepsis and hospitalizations for mom/baby with chlorhexidine treatment) Sub Group analysis (ROM > 4 hrs): HIV tx 25% (chlorhexidine) vs 39% (no intervention)(12 wks) HIV tx 20.5% (chlorhexidine) vs 21.7% (no intervention)(6-14 wks) HIV tx 17.2% (chlorhexidine) vs 15.9% (no intervention)(Intra tx) Sub Group analysis (lavage before ROM): Had lower tx HIV tx 23.5% (benzalkonium chloride) vs 24.8% (placebo) Benzalkonium chloride well tolerated Tolerance: 0.25% chlorhexidine - No complaints 1.00% chlorhexidine - 13% complaints (max tolerated concentration) 2.00% chlorhexidine - 31% complaints HIV tx 1.8% (18 months) vs 10.5% (vaginal delivery) 80% efficacy HIV tx 8.2% (elective cesarean) vs 16.7% (other mode of delivery)- 57% efficacy With 3 part ZDV treatment: HIV tx 2.0% (elective cesarean) vs 7.3% (other mode of delivery)- 87% efficacy Pharmokinetics: Maternal HIVIG half life 15 days after first injection, 32 days after third injection; Infant HIVIG half life 30 days No change in viral or immune paramaters with HIVIG infusion Overall low tx (HIVIG 4.1%, IVIG 6.1%) - enrollment stopped Maternal delivery HIV RNA most significant risk factor for tx Well tolerated No change in viral or immune parameters with infusions Median pharmokinetic half life 28 days (mother), 30 days (infant) Chose 400 mg/kg for phase III trial No change CD4, HIV RNA, neutralizing antibody, or binding antibody with vaccine No serious events Immunogenic in >50% (presist 104 wks) Need 2 immunizations to get response Accelerated schedule with 5ug Chiron vaccine had 100% response by 4 wks Genetech less response regardless dose/schedule LPA response >2 time, 44-56% vacciness vs 0% Placebo CTL response >1 time, 44-63% vacinees, only 1 placebo point Mucosal IgA response rare (11-33%); no Ab 3 infants with grade 3 reactions LPA response best with ALVAC/AIDSVAX; CTL less frequent Enrolling HIV tx 29% (no MultiVit) HIV tx 34% (VitA) - No effect of AnteP/IntraP tx or infant mortality but increased PostP tx - Infants had lower rate of pneumonia HIV tx 31% (MultiVit) - No signif difference on tx or infant mortality - Infants had lower diarrhea and higher CD4 (HIV positive and negtive) - Reduced development of AIDS in women PostP HIV tx 25% (No VitA) HIV tx 31% (MultiVit) HIV tx 34% (VitA) HIV tx 29% (No MultiVit) HIV tx 25% (No VitA) HIV tx 26.6% (VitA) vs 27.8% (Placebo) (6 wks), 27.3% vs 32.0% (12 wks), 27.7% vs 32.8% (6 months) VitA did not increase PostP tx ? VitA improved pregnancy outcome and reduced LBW Vit A less infant anemia and better growth at age 6 wks Insufficient follow up, no tx data MicroNut did not effect prevelence of subclinical mastitis in HIV negative women and boarderline decrease in HIV positive women HIV tx 20.3% (VitA+Carotene) vs 22.3% (Placebo) (3 months), 17.9% vs 33.8 % (3 months in preterm subgroup - decreased trend but not signif different) Preterm delivery 11.4% vs 17.4% (Placebo) Infant death 9.3% vs 10.0% (Placebo) (12 months) 1.9x increase morbidity never BF vs BF, 4x increase if infant HIV positive VitA supplementation did not reduce tx or infant mortality Postnatal tx 12.1% (6 wk - 18 months) 68% of Postnatal tx occured at age >6 months HIV tx 6.9% (elclusive BF) 8.5% (predom BF) 14.1% (mixed BF) CD4 count RNA Genital HIV shedding Mastitis AnteP and post P pharmokinetics similar Dose same as non-pregnant Pk higly variable in infant Same pharmokinetics as PACTG 250 recommed ZDV 600mg, then 300mg every 3 hrs Pharmokinietc half life increased, peak decreased in women infant NVP maintained >100mg/mL at day 7 Pharmokinetic similar in pregnant/non-pregnant 50% of infants NVP <100ng/mL at day 7 Recomendation ZDV 15.mg/kg oral every 12 hrs increase to every 8 hrs at 2 wks (>30 wks at birth), or 4 wks (<30 wks at birth) Pharmokinetics and dose similar to non-pregnant Prolonged pharmokinetc half life at day 6 vs day 42 in infants Pregnancy: 750 mg three times daily inadequate 1250 mg twice daily adequate Infant: NFV 10 mg/kg three times daily inadequate 40 mg/kg twice daily inadequate Pregnancy: RTV levels higher postP than anteP Infant: RTV levels too low, higher dose needed Pregnancy: IDV levels ~ 2 times as high postP than anteP RTV boost during pregnancy may be needed Pregnancy: 3TC pharmokinetics similar to non-pregnant 3TC clearence for ~ half of older children Pregnancy: No change in pharmokinetics with ZDV 3TC/ZDV levles similar mother/cord/infant Pregnancy: Clearence reduced by 50% in preg vs non-preg Infant: Pharmokinetic half life 11hr (1 wk) or 8 hr (2 wk) Pregnancy: SQV 12000 mg three time sdaily inadequate Low dose boost with RTV adequate RNA decrease -1.33 log HIV tx 10.6% (6 months) No resistance at 6-12 wks in infected babies RNA decrease -1.12 log HIV tx 12.1% (6 months) No resistance at 6-12 wks in infected babies RNA decrease -1.91 log HIV tx 4.6% (6 months) No resistance at 6-12 wks in infected babies RNA decrease -0.76 log HIV tx 5.6% (6 months) No resistance at 6-12 wks in infected babies Daily best to keep NVP>100ng/mL Phase II trial (HPTN 046) will ue daily NVP Enrolling Enrolling Enrolling Viral failure 0% placebo vs 42% SD-NVP (after 6 months on ART if ART<6 months post SD-NVP) Viral failure 8% placebo vs 12% SD-NVP (after 6 months on ART if ART>6 months post SD-NVP) CD4 response after 24 months same regardless of when ART started post SD-NVP Viral failure 9% placebo vs 77% SD-NVP (after 6 months on ART in infected infants) Enrolling Enrolling Enrolling Enrolling Enrolling HIV tx 10.5% 1st and 2nd pregnacy (South Africa) HIV tx 8.6% 1st and 2nd pregnacy (Cote d'Ivorie) MTCT during 1st pregnacy didn't predict transmission during 2nd pregnacy HIV tx 11.8% (prior SD-NVP), 17.1% (no prior SD-NVP) (Retrospective) HIV tx 18.4% (prior SD-NVP), 17.5% (no prior SD-NVP) (Prospective) SD-NVP stays effective Mother: 60% resistance (2 wk) Infant: 56% resistance (6 wk) Mother: 12% resistance (2 wk) Infant: 13% resistance (6 wk) Mother: 10% resistance (2 wk) Infant: 14% resistance (6 wk) Enrolling Enrolling Enrolling Enrolling Enrolling Enrolling Resistance 30% (2/6 wks) HIV tx 2.8% (6 wks) - if unifected at birth Resistance 13% (2/6 wks) HIV tx 1.6% (6 wks) - if unifected at birth No resistance to ZDV, NVP, TFV or FTC at 4 wks Enrolling Enrolling HIV tx 5.0% (6 months) - 5.9% (12 months) No Signif difference CD4 </> 250 or NPV vs NFV Resistance: 67% in infected infants 43% (if mother NVP) 100% (if mother NFV) Enrolling Enrolling Enrolling Enrolling Enrolling Enrolling Enrolling HIV tx 4.1% (6 wks) - 5.0% (6 months) HIV tx 3.8% (6 wks) HIV tx 4.9% (26 wks) HIV tx 5.3% (Birth to 3 ds) HIV tx 1.6% (Day 4 to day 28) HIV tx 0.8% (Week 4 to 6 months) No significant difference compared to NVP HIV tx 5.3% (6 wks) - 9.0% (6 months) Death 1.6% (6 wks) - 3.6% (6 months) HIV or death 6.8% (6 wks) - 11.6% (6 months) Resistence: Overall 50% (6 wks) If infected <6 wks 38% If infected >6 wks 18% HIV tx 2.5% (6 wks)- 6.9% (6 months) Death 0.9% (6 wks) - 1.1% (6 months) HIV or death 3.7% (6 wks)- 8.1% (6 months) Resistence: Overall 81% (6 wks) If infected <6 wks 92% If infected >6 wks 15% HIV tx 10.0% (9 months) Death 8.9% (9 months) HIV or death 16.8% (9 months) HIV tx 5.2% (9 months) Death 6.8% (9 months) HIV or death 10.6% (9 months) HIV tx 6.4% (9 months) Death 6.3% (9 months) HIV or death 11.2% (9 months) Enrolling Enrolling HIV tx 1.6% vs 6.8% (historical ZDF alone) HIV tx 2.8% vs 11.7% historical (ZDF alone) HIV tx 5.7% - 63% efficacy (6 wks) HIV tx 14.9% (18 months) HIV tx 8.9% - 42% efficacy (6 wks) HIV tx 18.1% (18 months) HIV tx 14.2% (6 wks) HIV tx 20.0% (18 months) HIV tx 15.3% (6 wks) HIV tx 22.2% (18 months) HIV tx 8.3% - 68% efficacy vs Placebo (18 months) HIV tx 9.4% - 50% efficacy vs Placebo (6 months) HIV tx 6.5% (6 months) HIV tx 4.7% (6 months) HIV tx 8.6% (6 months) HIV tx 10.5% (6 months) HIV tx 16.5% - 37% efficacy vs placebo (3 months) HIV tx 18% - 38% efficacy vs Placebo (6 months) HIV tx 11.8% - 42% efficacy (6-8 wks) HIV tx 15.7% - 41% efficacy (18 months) HIV or death 20.7% - 37% efficacy (18 months) HIV tx 20.0% (6-8 wks) HIV tx 25.8% (18 months) HIV or death 30.7% (18 months) In progress In progress In progress HIV tx 11.9% (6 wks) HIV tx 14.3% (12 wks) HIV tx 7.9% (6 wks, if not infected at birth) HIV tx 9.9% (breastfed) HIV tx 7.3% (formula fed) HIV tx 13.6% (6 wks) HIV tx 18.1% (12 wks) HIV tx 13.1% (6 wks, if not infected at birth) HIV tx 20.6% (breastfed) HIV tx 11.1% (formula fed) HIV tx 17.8% (6 wks) HIV tx 15.5% HIV tx 14.1% (6-8 wks) HIV tx 6.5% (6-8 wks, if uninfected at birth) HIV tx 16.3% (6-8 wks) HIV tx 6.9% (6-8 wks, if uninfected at birth) HIV tx 20.9% (6-8 wks, overall) HIV tx 12.1% (6-8 wks, if uninfected at birth) - 36% efficacy HIV tx 15.3% (6-8 wks, overall) HIV tx 7.7% (6-8 wks, if uninfected at birth) - 36% efficacy HIV tx 12.3% (8 wks) HIV tx 9.3% (8 wks) ???? ???? In progress In progress In progress HIV tx 4.7% (4-6 wks) vs 12.8 % (historical ZDV alone) not sign different than ZDV+NVP (6.5%) HIV tx 6.3% HIV tx 2.1% HIV tx 1.1% HIV tx 6.5% vs 12.8% (historical ZDV alone) HIV tx 4.6% HIV tx 1.4% vs 1.6% placebo Stopped due to low overall tx