1. HIV Case Conference Working Toward Elimination of Mother-to-Child Transmission: Practical Aspects for the Perinatal Team
Please include the title of your presentation, your full name and affiliations (including your role within the AETC, if applicable).
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)
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 # 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.
This slide is required for all CME/CE presentations.
For questions regarding CE or CME, please contact our Professional Education Manager at or

6. Core Marketing Slide:
Slide to replace both Slide 4 and 5 (For review, discussion, comments)

7. Perinatal guidelines March 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

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
The use of ZDV in combination with other highly active antiretroviral therapy (HAART) has been accompanied by a decrease in the number of perinatally HIV-infected children and is responsible for the dramatic decline in perinatally acquired HIV/AIDS since 1994.
Numerous initiatives have also contributed to the reduction in these cases: provider education, social marketing, and rapid testing in labor and delivery.
As a result, significant decreases in annual perinatal HIV-infected births have been observed since 2001.

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

12. HIV-Infected Newborns
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
Per Perinatal HIV transmission is the most common route of HIV transmission in children.
Perinatal HIV transmission is the most common route of HIV transmission in children.

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. Awareness of Serostatus Estimates of Transmission
25%
Unaware of
diagnosis
54% of new infections
People living with
HIV / AIDS
1,039,000 –
1,185,000.
New sexual infections each year
~32,000
75% aware of diagnosis
46% of new infections
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
If risk factors or symptoms to suspect acute infection that may be missed during window period with serologic testing consider virologic testing

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).
Baseline genotypic resistance testing should be performed simultaneously with initiation of the combination ARV regimen, and ARV adjusted, if necessary, to optimize virologic response (AIII).
Because clinically significant resistance to protease inhibitors (PIs) is less common than resistance to non-nucleoside reverse transcriptase inhibitors in ARV-naive individuals in general, a ritonavir-boosted PI-based regimen should be initiated (AIII).

25. Hidden in the Data
Of the 136 Infected babies born in Florida from :
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 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 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)
Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence.”
Patients may choose to postpone ART
Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors

31. HIV cycle HIV Replication Cycle Steps in the HIV Replication Cycle
Fusion of the HIV cell to the host cell surface.
HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell.
Viral DNA is formed by reverse transcription.
Viral DNA is transported across the nucleus and integrates into the host DNA.
New viral RNA is used as genomic RNA and to make viral proteins.
New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms.
The virus matures by protease releasing individual HIV proteins.

32. Antiretroviral Drugs Enfuvirtide (T20) (fusion inhibitor)
Raltegravir (RTV)
Lamivudine (3TC)
Nevirapine (NVP)
Saquinavir (SQV)
Maraviroc (CCR5 antagonist)
Elvitegravir (EVG)
Emtricitabine (FTC)
Delavirdine (DLV)
Indinavir (IDV)
Dolutegravir (DTG)
Stavudine (d4T)
Etravirine (ETV)
Nelfinavir (NFV)
Didanosine (ddI)
Amprenavir (APV)
Single tablet regimens
Tenofovir (TDF)
Lopinavir (LPV)
Atripla
Abacavir (ABC)
Atazanavir (ATV)
Complera
Zalcitabine (ddC)
Darunavir (DRV)
Stribild
TAM*
Tipranavir (TPV)

33. Preferred ARV regimens in 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 Transmission of HIV in Discordant Couples
Quinn TC et al. NEJM 1996;335:
^ 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
Age
Dose
Duration
≥35 weeks gestation at birth
4 mg/kg/dose PO twice daily
If unable to tolerate oral agents:
3 mg/kg/dose IV every 12 hours
Birth through 6 weeks
Give first dose as close to the time of birth as possible (preferably within 6 to 12 hours)
≥30 to <35 weeks gestation
2mg/kg/dose PO or 1.5 mg/kg/dose IV every 12 hours.
At age 15 days, increase to 3 mg/kg/dose PO or 2.3 mg/kg/dose IV every 12 hours.
<30 weeks gestation
2 mg/kg/dose PO or 1.5 mg/kg/dose IV every 12 hours
At age 4 weeks, increase to 3 mg/kg/dose PO or 2.3 mg/kg/dose IV every 12 hours

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
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
See Guidelines pgs. 7-10

46. Strategies for HIV Care
Functional Cure
Latent reservoir
Reactivation strategy (HDACi, PD-1) and elimination of reservoir cells (vaccine, Immunotherapy)
Latent reservLLL;l;oir
HAART during acute infection
HIV replication
in tissues
Member of the CD28/CTLA-4 family of T cell regulators (Ishida EMBO 1992)
Negatively regulates T cell responses (Freeman J Exp Med 2000)
2 known ligands: PD-L1 and PD-L2, mostly expressed by myeloid cells (Freeman J Exp Med 2000, Latchman Nat Immunol 2001)
Blocking PD-1 interaction with its ligands restores HIV specific CD4+ and CD8+ T cells (Day Nature 2006, Trautmann Nat Med 2006, Porichis Blood 2011)
Early HAART initiation limits the seeding of the HIV reservoir. Subjects starting HAART during Fiebig I stage display undetectable levels of integrated HIV DNA
HIV persists in central and transitional memory CD4 T cells
IL-7 therapy restores CD4 T cell numbers but expands the latent reservoir by inducing homeostatic proliferation of latently infected CD4+ T cells
Blockade of the PD-1 pathway constitutes a promising approach to achieve a functional cure
HAART optimization (Mega-HAART?)
HIV replication
HAART

47. Viral reservoirs and their relative contribution to plasma viremia
Steady-state levels of plasma viral RNA reflect the cumulative production of virus from the various cellular reservoirs and the turnover of virus-producing cells in those reservoirs. When viral replication is inhibited by HAART, plasma viral RNA decays in four distinct phases, suggesting that the various viral reservoirs are turned over to very different extents as a result of HIV-1 infection. The first phase reflects virus produced predominantly from activated CD4+ T cells. In the second phase, macrophages may be the main source of virus, because the decay characteristics of plasma viremia in this phase approximates the lifespan of the tissue macrophage. Resting (G1) T cells may also contribute to this more slowly turning over reservoir. The third phase reflects an extremely low and chronic production of virus from a stable reservoir. Presumably cells constituting this reservoir maintain a low and sustained output of virus, while simultaneously resisting cytopathic effects and killing by cytotoxic T lymphocytes. Resting CD4+ T cells or DCs may be the sources of virus in this covert reservoir. The fourth phase of decay is based on in vitro measurements of the frequency of latently infected CD4+ T cells, but FDCs harboring trapped virions might also be a long-lived source of infectious virus in this phase.
Stevenson, M.
Nature Medicine  9, (2003)

48. HIV Cure
Berlin patient – Evidence of cure of HIV following Bone Marrow Transplantation (Two transplants with CCR5 Delta 32 mutation donor)
Mississippi Child – Evidence of functional cure of HIV following treatment for HIV within 30 hours of life.
nd 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”