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Prevention of Mother-to-Child HIV Transmission in the U.S. and Globally Lynne M. Mofenson, M.D. Pediatric, Adolescent and Maternal AIDS Branch National Institute of Child Health and Human Development National Institutes of Health Department of Health and Human Services

Overview Perinatal transmission in the U.S.: PACTG 076 - mechanism efficacy Risk factors for transmission in antiretroviral era Transmission in the post-076 era Challenges Perinatal transmission global basis Short-course antiretroviral prophylaxis trials results and relevance to U.S. Challenges

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Perinatal HIV Transmission:  U.S. In U.S., ~6,000-7,000 HIV-infected women give birth annually. Prior to 1994, ~25% of infants born to HIV+ mothers became infected. Thus, 1,500-1,750 infants newly infected with HIV were born each year before 1994. More than 16,000 HIV-infected children born in the U.S. since the beginning of the epidemic.

PACTG 076 AZT Regimen Targeted Multiple Potential Time Points of Transmission

How Did the PACTG 076 AZT Regimen Lower Perinatal HIV Transmission? Effect on viral load:  In PACTG 076, change in HIV RNA accounted for only 17% of observed AZT efficacy (Sperling et al. NEJM 1996;335:1621-9). Two other important mechanisms through which AZT reduces transmission: Pre-exposure prophylaxis of infant (through transplacental AZT passage). Post-exposure prophylaxis of infant (through continued AZT administration to the infant after birth).

How Does AZT Lower Perinatal Transmission? Effect of AZT on Viral Load in PACTG 076  Sperling RS et al. NEJM 1996;335:1621-9

AZT Lowers Transmission Even in HIV-Infected Women with Very Low Viral Load Ioannidis JPA et al.  J Infect Dis 2001;183 Meta-analysis of 7 prospective cohorts/trials. 44 cases transmission among 1,202 HIV+ women with delivery HIV RNA <1,000. Transmission differed by receipt of AZT: Mothers receiving AZT: 8/834, 1.0% Mothers not receiving AZT: 36/368, 9.8% Multivariate analysis (adjusting for maternal CD4 count, mode delivery and infant birth weight), AZT independently reduced transmission. Data show importance of infant pre- and post-exposure prophylaxis in addition to lowering maternal viral load as mechanism prevention.

Importance of the Infant Pre- and Post-Exposure Prophylaxis Component of PACTG 076 Regimen Wade N et al.  N Engl J Med 1999;339:1409

Why Might Pre/Post-Exposure Prophylaxis Be Important? Amount of Cell-Free and Cell-Associated HIV in Cervicovaginal Canal is Associated with Transmission Chuachoowong R et al.  J Infect Dis 2000;181:99-106 Quantified CVL HIV RNA at 38 weeks gestation in 310 women in Thai short-course AZT trial. Presence CVL RNA associated with 3.4-fold increase in transmission; effect independent of plasma RNA, and greatest when plasma RNA low. AP AZT was associated with median 0.8 log decrease in HIV RNA in CVL. Tuomala RE et al.  J Infect Dis 2003;187:375-84 Assessed cell-associated HIV DNA in CVL in 78 women receiving antiretroviral therapy (65% AZT alone, 33% combination therapy). Detection/titer of CVL DNA associated with transmission; 2.3-fold increase for each 1 log increase DNA.

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Delivery Plasma HIV RNA Level is Associated with Perinatal Transmission

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Elective Cesarean Delivery Reduces Transmission When PACTG 076 AZT Regimen is Given The International Perinatal HIV Grp.  N Engl J Med 1999;340:977-87

Activities in U.S. Following the  Results of  PACTG 076 Feb 1994: PACTG 076 results announced Aug 1994: U.S. Public Health Service guidelines for use AZT to prevent transmission published. July 1995:  U.S. Public Health Service guidelines for prenatal HIV counseling and testing. Periodic updates to guidelines when new information becomes available: Latest update prophylaxis guidelines: Nov 2002 Latest update testing guidelines:  Nov 2001

Current USPHS Guidelines for Prevention of Mother-to-Child Transmission Maternal plasma HIV RNA >1,000: HAART Elective C/S if >1,000 near delivery Maternal plasma HIV RNA <1,000: HAART or use of PACTG 076 AZT alone No treatment prior to labor: Intrapartum-postpartum AZT; AZT/3TC; nevirapine; or AZT/nevirapine No treatment prior to or during labor: Infant prophylaxis for 6 weeks with combination regimen or AZT alone

Maternal Antiretroviral Use During Pregnancy at PACTG Sites,1998-2000

Increasing Rates of Cesarean Delivery Among HIV-Infected Women in U.S., 1994-2000 Pediatric Spectrum of Disease, CDC

Mother to Child HIV Transmission in the U.S. Over Time

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Progress on Reducing Mother-to-Child HIV Transmission in the U.S. Mother to child transmission has been reduced to <2% in the U.S. Number of infected infants born each year in U.S. has decreased from 2,000 before 1994 to under 300-400 currently. Reduction transmission secondary to: Enhanced prenatal HIV counseling and testing. Recognition of the importance of viral load in transmission, and increase in use of HAART by pregnant women. Increase in elective cesarean delivery.

Challenges Remain Remaining significant barriers to elimination of perinatal HIV in U.S.: Continued HIV transmission to women, especially  adolescents, who have high rates of unintended pregnancy. Lack of prenatal care, particularly in women who are illicit drug users (15% of HIV-infected women lack prenatal care). Failure to identify HIV infection during pregnancy. Antiretroviral drug resistance.

Antiretroviral Resistance in Adults with New HIV Infection, U.S./Canada Frequency of antiretroviral resistance mutations among newly infected persons increasing: Grant et al. JAMA 2002;288:181-8 (San Francisco) From 1996-97 to 2000-01(N=225) NRTI: 25% to 21% NNRTI: 0% to 13% PI: 3% to 8% Resistance correlated with viral response Little et al. NEJM 2002;347:385-94 (10 cities) From 1995-98 to 1998-2000 (N=377) Any:  8% to 23% Multidrug: 4% to 10% more pregnant women are now treatment-experienced.

More HIV-Infected Pregnant Women are Antiretroviral-Experienced and Have ARV Resistance: Resistance in Women in PACTG 316* Cunningham C et al.  J Infect Dis 2002:186:181-8

Impact of Antiretroviral Resistance on Prevention of Perinatal Transmission Mofenson L et al.  AIDS Conf 2002 PACTG 185 (86% AZT, 14% combo NRTI), case-control study of 24 transmitters, 72 controls At delivery: AZT resistance: 25% transmitters vs 11% controls (p=0.14) Any NRTI resistance: 46% transmitters, 25% controls (p=0.15) Welles S et al.  AIDS 2000;14:253-71 WITS, case-control study of 142 pregnant women Prevalence AZT resistance, 24% Multivariate analysis, genotypic AZT resistance associated with 5.1-fold increased risk transmission At present, most cases of antiretroviral failure with transmission despite antiretroviral prophylaxis are not due to drug resistance, but this may change as resistance becomes more frequent.

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Perinatal HIV Transmission:  Global12 Globally, >2 million HIV-infected women give birth annually, most in resource-poor countries, where regimens used in US are too complex and expensive to use. Transmission rates in breastfeeding women without antiretroviral prophylaxis are between 25-40%. About 2,000 children become infected daily; in 2002, an estimated 800,000 infants were newly infected with HIV. An estimated 3.2 million children were living with HIV in 2002.

Importance of Breastfeeding Postnatal Transmission: Timing of Mother-to-Child HIV Transmission with Breastfeeding and No Antiretroviral Prophylaxis

International Perinatal HIV Trials Following PACTG 076: Need to develop shorter, less expensive regimens more applicable to resource-limited settings. Studies first focused on modifications of AZT-alone prophylactic regimens. Studies also explored whether short-course combination regimens might have improved efficacy. Studies asked if similar efficacy to combination could be achieved with alternative drugs that were less expensive and could be used in simple regimens.

Completed Trials: Focused on Prevention AP/IP Transmission

Short-Course AZT Studies Short-course AZT prophylaxis is effective. Longer (28 weeks) antepartum treatment is more effective than shorter (36 weeks) antepartum therapy, showing that a significant proportion of in utero infection occurs between 28 and 36 weeks. Efficacy of prophylaxis is diminished by breastfeeding, but still persists at 24 months with short-course AZT.

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Short-Course AZT Prophylaxis, Formula-Fed Infants: Duration of AP/PP Therapy Lallemant M et al.  N Engl J Med 2000;343:982-91

Long Better than Short Maternal Antepartum Therapy for Preventing In Utero Transmission Lallemant M et al.  N Engl J Med 2000;343:982-91

Short-Course Combination Regimens After short-course AZT found effective, researchers then asked if short-course combination regimens would be more effective than AZT alone. AZT/3TC prophylaxis appears more effective than AZT alone. 3-part AP/IP/PP drug prophylaxis is more effective than IP/PP alone. IP-only not effective, showing importance of post-exposure prophylaxis component. Efficacy diminished by breastfeeding and did not persist at 18 mos for the IP/PP AZT/3TC regimen.

AZT/3TC Better than AZT Alone: Open-Label AZT/3TC Perinatal Prophylaxis Studies in Formula-Fed Populations

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Alternative Prophylaxis Regimens Research asked whether alternative drugs (like nevirapine) might provide efficacy similar to short combination regimens. When only IP/PP prophylaxis is given, single-dose NVP is superior to IP/PP AZT alone, and similar to IP/PP AZT/3TC. Efficacy diminished by breastfeeding, but  while 2-part AZT/3TC was not effective at 18 months, NVP retained efficacy. Addition of single-dose NVP to short-course AZT appears to improve efficacy. However, adding NVP to standard regimens used in U.S. does not offer additional benefit.

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Does the Addition of Single Dose NVP to Short-Course AZT Improve Efficacy?

Single-Dose NVP Does Not Improve Efficacy of Longer or More Complex ARV Regimens Dorenbaum A et al.  JAMA 2002;288:189-98

Infant Prophylaxis Many women may not present until in labor and only infant prophylaxis may be possible. Epidemiologic data suggest infant AZT for 6 weeks after birth reduces transmission. Infant prophylaxis must begin within 24-48 hours after birth to be effective when the mother has not received AP/IP drug. Preliminary data suggest: Single dose NVP given to the infant at birth may have efficacy similar to AZT. Single dose NVP plus AZT may have better efficacy than NVP alone if mother hasn’t received single dose IP NVP.

Preliminary Data: Infant Post-Exposure Prophylaxis Trials (South Africa, Malawi; ongoing)

Is Combination Better than Standard 6 Wk AZT Post-Exposure Prophylaxis in Formula-Fed Infants?

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Design of Ongoing/Planned Infant Prophylaxis Trials

Infant Prophylaxis Trials:  A Variety of Regimens/Durations Under Study

Design of Maternal HAART Prophylaxis Trials

Progress and Challenges in Reducing Mother-to-Child HIV Transmission on a Global Basis Shorter, less expensive regimens than PACTG 076 have been found to be effective in reducing in utero and intrapartum transmission by 41-63%. Although breastfeeding decreases the overall efficacy, most trials still show a significant decrement at 18-24 months. New approaches, including infant or maternal prophylaxis are targeted at reducing postnatal transmission. Implementation of known effective regimens is now key.