Carina Rodriguez, MD Faculty, Florida/Caribbean AETC University of South Florida

1. HIV Case ConferenceWorking Toward Elimination of Mother-to-Child Transmission: Practical Aspects for the Perinatal Team Carina Rodriguez, MD Faculty, Florida/Caribbean AETC University of South Florida Thursday, May 8, 2014 Time: 2:00 pm-3:00 pm (EDT)

2. HIV Case Conference Series Objectives • Identify the role, uses, and complications of antiretroviral therapy as a treatment option according to the Department of Health and Human Services • Describe the major issues of age and gender appropriate HIV care including management of special populations such as pregnant women, and gay, lesbian or transgender patients • Identify and treat HIV disease, HIV complications and co-morbid conditions in the primary care setting • Identify and access resources and standard of care protocols that can be immediately applied to any clinical setting • Describe legislation and/or recommendations about HIV testing, confidentiality, access to medical care, post-exposure prophylaxis and pre-exposure prophylaxis • Identify the modes of transmission of HIV and epidemiology of the disease and related infections • Discuss strategies to increase the ability of healthcare providers to provide culturally competent care

3. Session Specific Objectives Upon completion of this program, participants will be able to: • Review current recommendations for the prevention of mother-to-child transmission • Learn virologic and serologic methods for identification of HIV infection, their use in pregnancy and special scenarios, including discordant partners, suspected acute infection and infant testing • Review current evidence regarding mode of delivery and risk for infection • Learn current antiretroviral therapies for HIV-infected pregnant women and exposed/infected children • Recognize clinical scenarios associated with increased risk for transmission and selective antiretroviral therapy/prophylaxis

4. Continuing Education Disclosure • The following presenter has financial relationships with the following commercial entities to disclose: • Carina Rodriguez, MD • Grant/Research Support: Gilead, ViiV, Merck, and NICHD • This presenter will not discuss any off-label use or investigational product during the program.

5. Continuing Education (Up to 1.0 hours of CE/CME) Continuing Education Suwannee River Area Health Education Center, Inc., is a Florida Board of Nursing, Clinical Social Work, Marriage, Family Therapy, Mental Health Counseling, Dentistry, and Pharmacy approved provider of continuing education. CE Broker Provider ID #50-1922. This program meets the requirements for up to 5.0 contact hours. Continuing Medical Education This activity has been planned and implemented in accordance with the Essentials Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Florida AHEC Network and the Florida/Caribbean AIDS Education and Training Center. The Florida AHEC Network is accredited by the Florida Medical Association to provide continuing medical education for physicians. The Florida AHEC Network designates this live activity for a maximum of 5.0 AMA PRA Category 1 Credits™. Each physician should claim only the credit commensurate with the extent of their participation in the activity. For questions regarding CE or CME, please contact our Professional Education Manager at ce@srahec.orgor 386-462-1551.

7. Perinatal guidelinesMarch 2014 Updates in terminology • The terms “mother-to-child transmission (MTCT)” and “prevention of mother-to-child transmission (PMTCT)” have been replaced with “perinatal transmission” and “prevention of perinatal transmission” • Slides are based on most recent recommendations by the Department of Health and Human Services (HHS) • Can be accessed at http://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines

8. Rating Scheme for Recommendations

9. Milestones in Perinatal HIV • Pediatric AIDS Clinical Trials Group 076 • Major Achievement in HIV research • Showed administration of zidovudine (ZDV) to pregnant women and their infants could reduce perinatal transmission by 70% • Increased HIV testing in pregnancy and combination ARV prophylaxis during pregnancy has reduced perinatal transmission to <2%. • Every HIV-infected infant is a sentinel event representing missed opportunities.

10. Perinatal HIV/AIDS Cases

11. Perinatal Transmission • Perinatal HIV transmission is the most common route of HIV transmission in children. • Since the beginning of the epidemic, 9522 cases of AIDS have been reported perinatally – 4986 of those have died. • HIV perinatal transmission peaked in 1991 to 1650 perinatally infected infants – there were 162 perinatally infected infants in 2010 • Perinatal HIV transmission is the most

12. HIV-Infected Newborns

13. HIV-Infected Infants 2013

14. HIV-Infected Infants 2014

15. Common risk factors seen in HIV infected infants • Maternal Substance Use • Late, Minimal or NO Prenatal care • Maternal Denial (or Ignoring) their Known HIV diagnosis – refusing HIV testing in pregnancy warrants further investigation/discussion • Maternal Mental Health issues • Maternal HIV diagnosis at Labor and Delivery

16. Case 1 • 23 y/o female with no history of prenatal care presents in labor at outlying hospital • Rapid HIV testing done and negative • Normal SVD, no complications • 2 months later, mom is admitted to substance abuse rehabilitation facility and HIV testing is repeated and positive • Pediatrician is contacted and performs HIV ELISA that is positive • PCP contacts DOH for further advice • Infant DNA PCR and RNA PCRs confirm HIV infection • Could this infection have been prevented?

17. 25% Unaware of diagnosis 54% of new infections 46% of new infections Awareness of Serostatus Estimates of Transmission People living with HIV / AIDS 1,039,000 – 1,185,000. New sexual infections each year ~32,000 75% aware of diagnosis Marks G et al. AIDS 2006, 20:1447 – 1450.

18. HIV Infection Before ART

19. HIV Testing in Acute Infection

20. Intrapartum Care

21. Transmission and Mode of Delivery • Scheduled cesarean delivery at 38 weeks gestation to minimize perinatal HIV transmission for women with HIV RNA levels >1000 copies/ml or unknown levels near the time of delivery. (AII) • Perform cesarean irrespective of administration of antepartum ARV drugs • IV ZDV should be administered for 3 hours total prior to scheduled delivery • Cesarean sections performed for standard obstetrical indications should be scheduled for 39 weeks gestation

22. Intrapartum Care

23. Intrapartum Care- Unknown HIV status • Conduct rapid HIV antibody testing for women in labor with unknown HIV status. (AII) • If positive: • Perform confirmatory testing ASAP • Administer maternal IV ZDV and infant combination prophylaxis pending results of confirmatory test. (AII) • Continue infant prophylaxis for 6 weeks if confirmatory tests are positive (AI); discontinue prophylaxis if confirmatory testing is negative

24. Acute HIV infection • When acute retroviral syndrome is suspected in pregnancy or during breastfeeding, a plasma HIV RNA test should be obtained in conjunction with an HIV antibody test (AII). • Repeat HIV antibody testing in the third trimester is recommended for pregnant women with initial negative HIV antibody tests who are known to be at risk of acquiring HIV, are receiving care in facilities that have an HIV incidence in pregnant women of at least 1 per 1,000 per year, are incarcerated, or who reside in jurisdictions with elevated HIV incidence (AII). • All pregnant women with acute or recent HIV infection should start a combination ARV regimen ASAP (AI).

25. Hidden in the Data • Of the 136 Infected babies born in Florida from 2000-2005: • 27% of all mothers who delivered an infected infant did not know they were positive prior to delivery. • 20% of all mothers who delivered an infected infant contracted HIV during the pregnancy.

26. Case 2

27. HIV Care Continuum

28. Model of Demonstration MMWR 2011

29. Florida Statutes: HIV Testing • Written informed consent is no longer required prior to HIV screening in health care settings (See Exceptions), however the provider needs to document in the medical record (MR) that patient provided verbal consent. • Prior to ordering an HIV test, medical providers are required to: • Inform patients that an HIV test will be performed • Provide information about the test • Advise the patient of their right to decline the HIV test • Document in MR that patient provided verbal consent • Exceptions when written consent is required: • Blood donation • HIV testing for insurance or contract purposes • Refusal for HIV testing during pregnancy needs to be in writing (testing in pregnancy is through opt-out process on first trimester and 28-32 weeks) • Minors can be tested for HIV without parental consent provided the minor gives informed consent

30. Recommendations for Initiating ART: CD4 Count or Clinical Category Recommended for all CD4 counts: • CD4 count <350 cells/µL (AI) • CD4 count 350-500 cells/µL (AII) • CD4 count >500 cells/µL (BIII) Recommended regardless of CD4 count: • Pregnancy (AI) • History of AIDS-defining illness (AI) • HIV-associated nephropathy (HIVAN) (AII) • Hepatitis B (HBV) coinfection (AII) • Age >50 years (BIII)

31. HIV cycle

32. Antiretroviral Drugs

33. Preferred ARV regimensin Pregnancy NRTI backbone • ZDV/3TC • TDF/FTC • ABC/3TC PI based • ATV/r • LPV/r II based • RAL NNRTI based • EFV (start after 8 weeks)

34. ARV prophylaxis in pregnancy

35. Recommendations for Use of Antiretroviral Drugs during Pregnancy • Preferred NRTIs for ARV-naive pregnant women have been expanded to include abacavir plus lamivudine and tenofovir plus emtricitabine or lamivudine in addition to zidovudine plus lamivudine.  • Preferred protease inhibitors (PIs) for ARV-naive pregnant women remain ritonavir-boosted atazanavir and ritonavir-boosted lopinavir. • Alternative PIs include ritonavir-boosted darunavir and ritonavir-boosted saquinavir. • Preferred NNRTI for ARV-naive pregnant women is efavirenz, initiated after the first 8 weeks of pregnancy. • Nevirapine is the alternative NNRTI for ARV-naive pregnant women.

36. Recommendations for Use of Antiretroviral Drugs during Pregnancy • Raltegravir has been moved to the Alternative category for ARV-naive pregnant women, for consideration particularly when drug interactions with PI -based regimens are a concern. • In addition, some experts may use raltegravir in late pregnancy in women with high viral load • There is insufficient data during pregnancy for dolutegravir, elvitegravir/cobicistat/tenofovir/emtricitabine fixed drug combination, ritonavir-boosted fosamprenavir, maraviroc, and rilpivirine. 

37. Adjusted Rate Ratios for Transmissionof HIV in Discordant Couples Quinn TC et al. NEJM 1996;335:1621-1629. ^ Viral load in blood may not be predictive of genital tract viral load

38. Reproductive Options for HIV-Concordant and Serodiscordant Couples • HIV-infected partner(s) in HIV-seroconcordant and HIV-serodiscordant couples planning pregnancy attain maximum viral suppression before attempting conception (AIII). • Periconception administration of ARV pre-exposure prophylaxis (PrEP) for HIV-uninfected partners may offer an additional tool to reduce the risk of sexual transmission (CIII)  • Tenofovir disaproxil fumarate/emtricitabine– approved in July 2012 for HIV prevention in individuals at high risk of HIV transmission • Pregnancy is not a contraindication to PrEP. 

39. Postpartum Follow-Up of HIV-Infected Women • Decisions about continuing cART after delivery should be made in consultation with a woman and her HIV provider, ideally before delivery (AIII). • cART is currently recommended for all HIV-infected individuals to reduce the risk of disease progression and to prevent HIV sexual transmission. Strength and evidence vary by pretreatment CD4 cell count. 

40. Infant Antiretroviral Prophylaxis • All HIV-exposed infants should receive a 6 week course of ZDV prophylaxis (AI) • Mother received standard antepartum and intrapartum ARV prophylaxis with suppressed HIV RNA: infant zidovudine alone • Mother did not receive optimal antepartum and intrapartum prophylaxis, risk of HIV transmission is higher, and additional infant ARVs may be recommended • Infants born to mothers who did not receive antepartum ARV drugs • 6 week course of ZDV, plus • 3 doses of NVP in the first week of life (AI) • 1st dose at birth • 2nd dose 48 hours later • 3rd dose 96 hours after second dose • (Begin regimen as soon as possible post delivery)

41. Infant Antiretroviral Prophylaxis • Infant Zidovudine HIV Prophylaxis Dosing

42. Infant Antiretroviral Prophylaxis Infant Nevirapine HIV Prophylaxis Dosing in addition to ZDV for high risk cases, consult expert in pediatric HIV

43. Initial Postnatal Management of the HIV-Exposed Neonate • Virologic tests should be performed at (AII) • 14-21 days, • 1 (to 2 months), and • 4 to 6 months • Virologic tests at birth may be performed • If mother did not have good virologic control during pregnancy • If adequate follow-up can not be assured • If infant received expanded prophylaxis, repeat PCR testing recommended 2-4 weeks after discontinuation • * With two negative testing by 4 to 6 weeks, do not need to initiate Pneumocystis jiroveci prophylaxis

44. Infant Antiretroviral Prophylaxis • Alternative combination ARV prophylaxis regimens in infants should be made in consultation with a pediatric HIV specialist before delivery, if possible.  • A 4-week neonatal ZDV chemoprophylaxis regimen can be considered when the mother has received standard cART with consistent viral suppression and there are no concerns related to maternal adherence (BII).

45. Diagnostic Testing in Infants • Presumptive rule-out of HIV infection • 2 or more negative virologic tests • One at age ≥14 days and one at ≥1 month; or • One negative virologic test at ≥2 months; or • One negative HIV antibody test ≥6 months • Definitive rule-out of HIV infection • 2 or more negative virologic tests • One at ≥1 month; and • One negative virologic test at ≥4 months; or • 2 negative HIV antibody tests ≥6 months Diagnosis of HIV infection • 2 positive HIV virologic tests (NAAT-HIV-1 DNA or RNA) on separate blood samples (regardless of age) • Positive HIV antibody test with confirmatory • Western blot (or IFA) at age ≥18 months

46. Functional Cure HIV replication HIV replication in tissues Latent reservoir Latent reservoir HAART during acute infection Reactivation strategy (HDACi, PD-1) and elimination of reservoir cells (vaccine, Immunotherapy) Strategies for HIV Care Latent reservLLL;l;oir • HAART optimization (Mega-HAART?) HAART

47. Viral reservoirs and their relative contribution to plasma viremia Stevenson, M. Nature Medicine  9, 853 - 860 (2003)

48. HIV Cure • 2011 - Berlin patient – Evidence of cure of HIV following Bone Marrow Transplantation (Two transplants with CCR5 Delta 32 mutation donor) • 2013 - Mississippi Child – Evidence of functional cure of HIV following treatment for HIV within 30 hours of life. • 2014 - 2nd Infant with HIV seroreversion – treated aggressively within 4 hours of life – remains on antiretrovirals. • Clinical trials are planned to address whether administration of a three-drug regimen in therapeutic doses to HIV-exposed high-risk infants could alter the establishment and long-term persistence of HIV infection.

49. Unique aspects of HIV infection in pediatrics • Unique immunologic characteristics (evolving immunity and immune tolerance) • Unique “gut” immunity (relative lack of immune activation in the gut and increased regenerative capacity) • Timing and source of infection more easily determined than in adults • Potential limitation of HIV infection prior to establishment of latent reservoirs with early treatment Tobin, N. Curr HIV/AIDS Rep 2014 • Tobin, N. Curr HIV/AIDS Rep 2014

50. Summary • Current guidelines provide excellent recommendations for the prevention of perinatal HIV transmission • There are many obstacles to effectively instituting the appropriate interventions for prevention in all scenarios for HIV + pregnant women • Utilizing the guidelines and initiating appropriate interventions at every opportunity for prevention of perinatal HIV transmission is the only way we can get to “ZERO”