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Epidemiology

Preventing Mother to Child HIV-1 Transmission ( P MTCT ) Karin Nielsen, MD, MPH Clinical Professor Pediatric Infectious Diseases David Geffen UCLA School of Medicine. Epidemiology. Perinatal HIV-1 Infection. The majority of pediatric HIV infection occurs from maternal-fetal transmission

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Epidemiology

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  1. Preventing Mother to Child HIV-1 Transmission (PMTCT) Karin Nielsen, MD, MPHClinical Professor Pediatric Infectious DiseasesDavid Geffen UCLA School of Medicine

  2. Epidemiology

  3. Perinatal HIV-1 Infection • The majority of pediatric HIV infection occurs from maternal-fetal transmission • Transmission rates vary by population and geographic area 13% Europe 40% Africa 25%-30% USA overall without treatment • Heterosexual transmission to women is now the mostcommon route • As number of women HIV-infected increases perinatal infection will also increase

  4. Epidemiology Peds HIV • Global prevalence among pregnant women: • N America: 0.02 to 2% • S America: 0.5 to 5% • Sub-Saharan Africa: 20 to 45% • India: 1%

  5. ID: E1 1300% 20% 160% 20% 100% 60% 40% 30% 20% Increases in HIV infection 1996-2001 UNAIDS/WHO global view of HIV infection 200240 million individuals living with HIVCumulative infection: 60 million Courtesy of UNAIDS. Sourced from http://www.phrusa.org/campaigns/aids/maps.html

  6. HIV prevalence among pregnant womenin South Africa, 1990 to 1999 25 22.8 22.4 20 17 14.2 15 HIV prevalence (%) 10.4 10 7.6 5 4 2.1 1.7 0.7 0 90 91 92 93 94 95 96 97 98 99 Source: Department of Health, South Africa

  7. Estimated AIDS Prevalence among Women in the United States and Perinatally Acquired AIDS Cases by Quarter-Year, 1985 - 1999 160 300 Heterosexual contact Pediatric cases IDU 140 250 120 200 100 Number of Cases 80 150 Number of Cases (thousands) 60 100 40 50 20 0 0 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 Quarter-Year

  8. Pediatric HIV-infection Facts • 90% of HIV infections in women result from heterosexual transmission of HIV. • In the absence of interventions, rates of infection in children parallel rates of infection in women. • 1 of 3 to 1 of 4 children born to HIV-infected women are infected themselves in the absence of maternal treatment. • 2000 HIV-1 infected children are born daily. • 90% of infections in sub-Saharan Africa. • Overall MTCT rates are about 15% • 30% women in Southern Africa. • 4% in West Africa. • Worldwide < 10% of HIV-infected women benefit from any intervention. • An additional 300,000 infants acquire HIV via breastfeeding annually. • Children born to HIV-infected women have 3 x risk of death regardless of HIV-infection status.

  9. Pathogenesis

  10. Viral Virus load (cell ass./cell free) Phenotype (SI, tropism) Genotype Immune Decreased CD4 count Humoral (NAb, ADCC/ gp120 V3 loop Ab, other) Cell mediated (CTL, CD8 supression) Mucosal immunity Maternal Clinical advanced disease Primary HIV infection Co-infection Twins-first born Obstetrical Events Timing of Infection Drug use Fetal/Placental Prematurity Chorioamnionitis Infant host-immune response Factors Influencing Perinatal Transmission of HIV

  11. Perinatal HIV Infection • Timing of Infection • In utero • Intrapartum • Post-partum (breastfeeding) • HIV infected infants: • 30 - 50% have virus detectable at birth. (Presumed in utero infection) • 50 - 70% have no virus detectable at birth and develop positive virologic results after one week of age. (Presumed intrapartum infection)

  12. In Utero Transmission Maternal virus load cell-associated, cell-free  Neutralizing antibody  CD4 count / cell-mediated immunity  Virus phenotype / tropism  Placental breaks  Maternal-fetal transfusion  HIV or other infection of placenta  Fetal loss 

  13. Intrapartum Transmission Maternal virus load u - blood (cell-associated, cell-free) - cervicovaginal secretions Duration of ruptured membranes u Infant exposure to blood u -mucous membranes, swallowing Delivery mode-vaginal vs. c-section u Trauma u Maternal-fetal transfusion u Placenta - abruption u - chorioamnionitis - co-infections

  14. Breastfeeding Transmission • Breakdown of skin barrier • Intercurrent infections (mastitis) • Maternal plasma/milk viral load • Primary infection in mother • Mixed feedings • Early introduction of solids • Duration of breastfeeding

  15. Criteria for determing timing of HIV infection in the infant • In utero infection: • HIV positive peripheral blood lymphocyte culture or positive DNA or RNA HIV PCR from peripheral blood obtained from the infant within the first 48 hours of life (in the absence of breastfeeding). • Intrapartum infection: • Negative virologic assays in the first 48 hours of life followed by positive assays after 7 days of life (with persistence of positivity thereafter) in nonbreastfed infants.

  16. Natural History of HIV in Children • Rapid progressors: • Develop AIDS with rapid loss of CD4 cells within first 2 years of life (20%) • Intermediate progressors: • Develop AIDS by 7 – 8 years of age with gradual loss of CD4 cells (60%) • Slow progressors: • Minimal to no symptoms of HIV disease with a normal to minimally decreased CD4 count at age 8 years (20%)

  17. Pediatric Long Term Survivors in the U.S. 1997 (Nielsen, et al Pediatrics)

  18. Natural history of HIV-1 infection in children, Africa 2005 Cumulative mortality in the absence of treatment(n > 3000): 60% Dead by 5 years of age! 18 Newell et al

  19. Predicted loss in life expectancy due to HIV/AIDS in children born in 2000 Predicted life expectancy Loss in life expectancy due to HIV/AIDS Botswana Zimbabwe South Africa Kenya Zambia Côte d'Ivoire Rwanda Mozambique Haiti Cambodia 0 10 20 30 40 50 60 70 Life expectancy at birth (years) Source: U.S. Census Bureau, 2000

  20. Early diagnosis of HIV infection • All HIV- exposed babies are HIV EIA + • Early diagnosis is based on a + virologic assay from the infant’s peripheral blood at 2 different timepoints: • HIV DNA PCR (birth, 1 mo, 4 mo) • HIV RNA PCR (same time periods) • HIV PBL coculture (same time points)

  21. Maternal virus load and risk of perinatal transmission • HIV virus load is critical but is not the only risk factor. • The higher the virus load the higher the risk of transmission. • Women with a very high HIV virus burden have a higher chance of in utero transmission of HIV. • HIV RNA : > 50,000 copies/ ml; risk > 50%. • In many studies (PACTG 185) there is no HIV perinatal transmission in women with an undetectable HIV virus load.

  22. Delivery and Maternal Plasma HIV-1 RNA Levels at Antiretroviral use during Pregnancy: Impact on Perinatal Transmission 51.4 27.8 60 17.2 11.3 29.4 None 50 0 20.4 20 12.5 40 ZDV Mono (<4/94) Rates per 100 0 19 14.7 7.2 30 6.1 ZDV Mono (>4/94) 0 20 4.5 Multi-ART 2.6 1.8 0 0 10 HAART 2.4 1.7 0 0 0 0 >100000 >3000-40000 Undetectable (<400) Maternal Plasma HIV-1 RNA

  23. Cervical/Vaginal Secretions & HIV • 30% of HIV+ pregnant women may have detectable virus in secretions by PCR and/or culture. • Infants may have HIV detected in gastric aspirates - may be risk factor for intrapartum transmission (Nielsen et al 96) • Levels of maternal plasma RNA may not correlate with cervical/vaginal shedding (Nielsen et al., ‘96)

  24. Interruption of perinatalHIV transmission Intrauterine Intrapartum Post-partum vaccines antiretroviral therapy immune modulation vaccines antiretroviral therapy immune modulation C-section vaginal washing breast feeding 3 6 months Labor and Delivery Gestation 2 years

  25. Role of neutralizing antibodies in perinatal HIV transmission • Neutralizing antibodies against autologous viruses are specific and important in prevention of HIV vertical transmission. • Absence of neutralizing antibodies is more common in women who transmit their infection in utero; these women also tend to have a higher HIV virus load. • The vast majority of virus isolates obtained from newborns resist neutralization by maternal antibodies suggesting that what occurs is transmission of escape variants.

  26. Virus phenotype and perinatal HIV transmission • Most transmitted viruses have the R5 phenotype (non-syncytia inducing, macrophage tropic, use the R5 co-receptor for cell entry). • Even women who have viruses with X4 phenotype (syncytia inducing, T cell tropic, use the X4 co-receptor for cell entry) tend to transmit NSI viral populations to their infants. • The rare cases of vertical transmission of X4 tropic virus are associated with very rapid disease progression in the infant.

  27. Virus genotype and perinatal HIV transmission • Through biologic and molecular characterization of HIV isolates (nucleotide sequencing of viral genes) studies have demonstrated that: • Usually only one virus clone is transmitted from the mother to the newborn. • The transmitted virus is generally homogeneous. • This is similar to primary infection in adults where only one clone is preferentially transmitted.

  28. Potential Approaches for Prevention of HIV-1 Transmission • Specific HIV immunoglobulin • HIVIG, monoclonals (Combinations) • Other -immune modulators • HIV-1 Vaccine • Maternal immunization • infant • Combinations of above Antiretrovirals Immune Based Therapy • during gestation • intrapartum • postpartum - infant Local Approaches • vaginal washing • topical or oral treatment of infant • mode of delivery

  29. MODE OF DELIVERY AND RISK OF VERTICAL HIV-1 TRANSMISSION META-ANALYSIS OF 15 PROSPECTIVE COHORTS(THE INTERNATIONAL PERINATAL GROUP NEJM APRIL ‘99) 8,533 MOTHER/INFANT PAIRS • MODE OF DELIVERY N % TRANSMISSION ELECTIVE C-SECTION 809 8.2% OTHER MODES 7,031 16.7% P<0.001

  30. C-SECTION WITH/WITHOUT ZDVVERTICAL HIV-1 MODE DEL/ ZDV% TRANSMISSION OTHER MODES NO ZDV 19% ELECTIVE C-SECTION NO ZDV 10.4% OTHER MODES + ZDV 7.3% ELECTIVE C-SECTION + ZDV 2%

  31. DURATION OF RUPTURED MEMBRANES AND VERTICAL TRANSMISSIONTHE INTERNATIONAL PERINATAL GROUP META- ANALYSIS JAMA 1999 • 4721 VAGINAL DELIVERIES • RISK OF VERTICAL TRANSMISSION INCREASED LINEARLY FOR EACH ONE HOUR INCREMENT (ADJUSTED ODDS RATIO=1.02 (95%) CI 1.01,1.04) • WOMEN WITH AIDS-- HIGHER RISK - 8% 2 HR DRM - 31% 24 HRS DRM P<0.01

  32. IMPORTANT CONSIDERATIONS RE: ELECTIVE C-SECTIONS • NO EFFECT ON IN UTERO INFECTION • COMBINATION ANTIRETROVIRALS • Virtually no transmissions when <500 HIV RNAcp/ml • USE OF ANTIRETROVIRALS DURING LABOR DELIVERY such as NVP • MORBIDITY TO MOTHER: infectious complication rates ranged from 11% to 26% for WITS and PACTG 185 trials. • Elective C-sections currently recommended in the US for women with unknown virus loads or > 1000 cps/ ml HIV RNA.

  33. Perinatal HIV Efficacy Trials/ Americas & Europe

  34. 076 Protocol Infusion Zidovudine or placebo Oral Oral Zidovudine or placebo Zidovudine or placebo Mother Infant Infection outcome 16 weeks 6 weeks Gestation Labor Post delivery ZDV: 8% Placebo: 25% (p < 0.0001)

  35. ACTG 185 Trial HIVIG (Stiehm et al) Treatment Arms HIVIG IVIG Live births 206 196 Outcome 194 185 Infected Infants 7 8 Positive at Birth 0 5 Intrapartum 7 3 (-birth + 24 weeks) Transmission Rate 5% 6% Mean baseline HIV RNA - 49,000 RNA cp/ml NO PERINATAL TRANSMISSION: (N=84) UNDETECTABLE HIV RNA AT BASELINE(<500 HIV RNA) (N=107)UNDETECTABLE HIV RNA AT DELIVERY p<.006

  36. Initial Perinatal HIV Clinical TrialsEfficacy of Regimens Breast-fed Formula-fed AZT AZT/ AZT AZT NVP AZT/ NVP AZT AZT/ AZT 3TC 3TC 3TC

  37. Antenatal Antiretroviral Treatment and Perinatal Transmission in WITS, 1990-1999Blattner W. XIII AIDS Conf, July 2000, Durban S Africa (LBOr4) Type ARV vs None p value: 0.76 <0.01 <0.01 <0.01

  38. PACTG 316: Controlled trial of Nevirapine given to HIV infected pregnant women during labor and to newborn Aim:To assess whether the addition of NVP as a single dose to mother during labor and one dose to infant would further reduce perinatal transmission. Large randomized trial-USA Europe Latin America • low transmission rates in both arms. • (NVP vs placebo 1.5%, vs. 1.4%) • No additional benefit shown if mother already receiving ARVs.

  39. Infant Infection Status PACTG 316 NVP Placebo Total Mothers enrolled 754 752 1506 Mothers delivered 712 702 1414 Treatment dispensed 638 629 1267 infection status known 594 580 1174 No. (%) HIV infected 9 (1.5 %) 8 (1.4 %) 17 (1.5%) Intrauterine transmission: 5 (56 %) 5 (63 %) 10 (59 %)

  40. Resistance to NVP • PACTG 316: • New NVP resistance mutations detectable in 6 women following delivery (of 134 with detectable virus loads). • 1 in placebo arm (received EFV following delivery) • 5 of 64 (8%) in the NVP arm. • Mutations present: K103N and Y181C, V 106A.

  41. NRTIS: Zidovudine Lamivudine Didanosine Zalcitabine Stavudine Abacavir Tenofovir NNRTIS: Nevirapine Efavirenz Etravirine Rilpivirine Fusion inhibitors T-20 Protease inhibitors Saquinavir hard gel Saquinavir soft gel Ritonavir Nelfinavir Indinavir Amprenavir Lopinavir/ ritonavir Atazanavir Tipranavir Darunavir Entry Inhibitors Maraviroc Integrase inhibitors Raltegravir Elvitegravir/ cobicistat Available antiretrovirals

  42. Evaluation of new antiretrovirals for prevention of HIV perinatal transmission • Animal studies: • Teratogenicity • Risk- Benefit analysis • Antiretroviral activity • AZT only reduces viral load by 0.5 log • Activity against ZDV resistant strains. • Ability to cross the placenta • Oral use • Cost

  43. PMTCT studies in the Americas: Focus: -- Pharmacokinetics, safety and efficacy of new antiretrovirals. -- Primary infection during pregnancy -- Late presenters and post exposure prophylaxis trials. -- Pathogenesis models and trials

  44. 3% overall prevalence in women with no prenatal care through rapid HIV testing in labor 0.4% 1.4% 1 8. 2%

  45. Background • Women with undiagnosed HIV during pregnancy are at high risk of HIV-mother-to-child transmission. • Observational data show HIV transmission of 9.3% with infant ZDV started within 48 hours of birth compared to 26.6% with no ZDV in infants born to women without ARV in pregnancy. NEJM 1998:339 • Identification of HIV-exposed infants at delivery allows starting infant ARV prophylaxis , formula feeding or ARV prophylaxis during breastfeeding. • Strategies such as HIV rapid testing during labor identify women for their own medical care.

  46. Hypothesis: Multidrug antiretroviral regimens given to the HIV-exposed neonate within 48 hours of birth, in the absence of maternal ARV before labor, will be more effective in preventing intrapartum MTCT than ZDV alone. . NICHD/ HTPN 040PACTG 1043

  47. How common is HIV-infection diagnosis at delivery? Estimated coverage of women using IV ZDV during labor per Brazilian region, 2002 % 60 50 40 30 20 10 0 Central-west North Southeast South Northeast Source: Brazilian MOH 2002

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