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Prenatal Care and Obstetrical Management of HIV+ Women Deborah Cohan, MD, MPH Bay Area Prenatal Care and Obstetrical Management of HIV+ Women Deborah Cohan, MD, MPH Bay Area Perinatal AIDS Center National Perinatal HIV Consultation and Referral Service UCSF

Overview: l Antepartum management £ Antiretroviral therapy: Benefits, Risks l Intrapartum management £ L&D Overview: l Antepartum management £ Antiretroviral therapy: Benefits, Risks l Intrapartum management £ L&D management £ Mode of delivery l Post-partum management

Perinatal HIV in the U. S. Perinatal HIV in the U. S.

Number of cases Number of cases

Perinatal HIV testing: the key to prevention Perinatal HIV testing: the key to prevention

Prenatal HIV Testing Strategies l Opt-in: voluntary, women sign consent to test l Opt-out: Prenatal HIV Testing Strategies l Opt-in: voluntary, women sign consent to test l Opt-out: voluntary, informed that test is standard, sign if decline testing (Tennessee, Canada) l Mandatory newborn screening: regardless of maternal consent (NY, Connecticut) l Uptake of HIV testing Opt-in (25 - 69%) vs. Opt-out (71 -98%) approach £ CA law mandates prenatal providers to offer HIV testing (opt-in) and explain that testing is routinely done unless pt declines £ Likely change in CA law Jan 2008: opt-out £ DHHS 2002; CDC 1998; CDC 2001; CDC 2002

Antepartum management Antepartum management

Goals of prenatal care l Optimize woman’s health and psychosocial situation ART: total viral Goals of prenatal care l Optimize woman’s health and psychosocial situation ART: total viral suppression £ Opportunistic Infection (OI) prophylaxis prn £ Immunization prn £ l Prevent vertical transmission of HIV £ ART, c/section in specific situations, Bottle-feeding l Minimize maternal risks £ Viral resistance, Obstetrical outcomes l Minimize/assess risks to fetus/neonate £ Teratogenicity, Genetic testing l Prepare for or prevent subsequent pregnancies

Maternal Risk Factors l Plasma viral load @ delivery £ per log : w Maternal Risk Factors l Plasma viral load @ delivery £ per log : w OR 3. 4 (1. 7 -6. 8) £ VL <1000: w 0. 7%-0. 9% transmission l Genital VL @ delivery £ Cell-associated w per log : OR 2. 3 (1. 1 -4. 8) £ Cell-free w OR 3. 4 (p=0. 001) l CD 4 count l Drug-resistant HIV £ £ ZDV GT resist OR 5. 16 ZDV PT resist OR 1. 25 Other possible risk factors STIs Drug Use Smoking Anemia Vitamin A deficiency Clade D virus (vs. clade A) Monocyte/macrophage tropism Viral homogeneity Class I HLA concordance Certain HLA-B alleles Rapid replication kinetics p 24 antigenemia Primary HIV infection Landesman 1996; Thea 1997; Shapiro 2002; Tuomala 2003; Chuachoowong 2000; Goedert 2001; O'Shea 1998; Mofeson 1999; Shapiro 1999; Monforte 1991; Ometto 1995; Mac. Donald 1998; Arroyo 2002; Winchester 2004; Yang 2003

HIV lifecycle and drug targets §Fusion inhibitors §NRTI and NNRTI §Integrase inhibitors §Protease Inhibitors HIV lifecycle and drug targets §Fusion inhibitors §NRTI and NNRTI §Integrase inhibitors §Protease Inhibitors www. wikipedia. org

When and How Should a non-pregnant Adult Be Treated? l When Symptomatic, at any When and How Should a non-pregnant Adult Be Treated? l When Symptomatic, at any CD 4 count £ CD 4 count <200 (AIDS) £ CD 4 count 200 -350: Treatment offered £ l How £ HAART: Highly Active Antiretroviral Therapy w 2 NRTI’s plus w PI or NNRTI l Monotherapy, dual therapy, and triple NRTI regimens no longer standard of care DHHS Guidelines for the Use of Antiretrovirals in HIV-Infected Adults and Adolescents, May 2006

Antiretrovirals in pregnancy l All HIV+ pregnant women should get ART regardless of CD Antiretrovirals in pregnancy l All HIV+ pregnant women should get ART regardless of CD 4 count and viral load. l But… £ When to start £ What to choose £ What to avoid

ART: when to start l Goal: viral suppression by 3 rd trimester l Typically ART: when to start l Goal: viral suppression by 3 rd trimester l Typically start in 2 nd trimester l Exceptions to starting in 2 nd trimester £ Continuing preconception regimen and nonteratogenic £ Needs ARV immediately for own health l If not tolerating preconception regimen in 1 st trimester despite anti-emetics, d/c all at once £ Stagger d/c of NVP-based ART Wright, SMFM, 2003; Thorne CROI 2005

ART: what to choose l Same principles as non-pregnant HIV+ adults £ Resistance/prior regimens, ART: what to choose l Same principles as non-pregnant HIV+ adults £ Resistance/prior regimens, adherence/pill burden, S/E profile, degree of immunosuppression, viral hepatitis status l Except consider… l AZT-containing regimen unless contraindicated l Purpose of ART: her health vs. prophylaxis £ If not needed for own health, less potent regimens may be acceptable w Triple NRTI regimens w AZT monotherapy for baseline viral load <1000?

Perinatal HIV Transmission U. S. Studies from 1993 -2002 HAART % Transmission ZDV 1993: Perinatal HIV Transmission U. S. Studies from 1993 -2002 HAART % Transmission ZDV 1993: 1994: 1997: 1999: 2001: 2002: WITS PACTG 076 185 247 316 Adapted from Fowler 2004

Adverse effects of antiretrovirals in pregnancy Adverse effects of antiretrovirals in pregnancy

Maternal Risks and ARVs l Lactic acidosis and d 4 T (and dd. I) Maternal Risks and ARVs l Lactic acidosis and d 4 T (and dd. I) £ £ £ 12 reports of maternal LA (3 fatal) Avoid d 4 T and dd. I if possible Think of LA if w N/V, abdominal pain, SOB, leg and arm weakness l Hepatic Toxicity and NVP £ £ £ 1 st 6 wks NVP, may persist even when d/c NVP Distinguished from other etiologies (ob and non-ob) Avoid starting NVP if CD 4 > 250 l Gestational DM and PIs £ £ Conflicting data, most studies don’t find association Not a reason to avoid using PIs

Obstetrical Risks and ARVs l Preterm delivery and ARVs? £ Conflicting data; all based Obstetrical Risks and ARVs l Preterm delivery and ARVs? £ Conflicting data; all based on observational cohorts w Europ Collaborative & Swiss Mother+Child HIV: yes w U. S. Collaborative (n=2123): no w Meta-analysis: PTD only if preconception or 1 st trimester ARV l Pre-Eclampsia and ARVs? Conflicting preliminary data £ ARVs increase risk? £ ARVs restore immune system to allow Pre-E to occur? £ Euro Collaborative Study and Swiss Mother+Child 2000; Thorne CROI 2004; Tuomala 2002; Cotter JID 2006; Wimalasundera Lancet 2002; Suy AIDS 2006

Fetal/Neonatal Risks Fetal/Neonatal Risks

FDA Drug Classification l A l B £ £ £ NRTI: dd. I, FTC, FDA Drug Classification l A l B £ £ £ NRTI: dd. I, FTC, TDF (monkey osteomalacia @ high dose) PI: ATV, NFV, RTV, SQV FI: T-20 l C £ £ £ NRTI: ABC (rats 35 x dose), 3 TC, d 4 T, dd. C, ZDV NNRTI: NVP PI: APV (rat thymic elongation/ skeletal ossification), f-APV, IDV, LPV/r l D £ EFV (monkey 15% CNS malformations; 3 human NTD, 1 Dandy Walker) l Avoid using preconception/1 st trimester EFV l 2 nd/3 rd trimester EFV only if no other options DHHS 2005

Nelfinavir l Sept. 2007, Pfizer sent a letter to providers regarding the presence of Nelfinavir l Sept. 2007, Pfizer sent a letter to providers regarding the presence of low levels of ethyl methane sulfonate (EMS) in nelfinavir. EMS is teratogenic, carcinogenic, and mutagenic in animals. No human data exist. l Not recommended unless no other alternative is available.

Benefits >>>> Potential Risks Benefits >>>> Potential Risks

Intrapartum Management l Shorten duration of ruptured membranes l No evidence of c/section to Intrapartum Management l Shorten duration of ruptured membranes l No evidence of c/section to shorten ROM l Minimize # exams to risk of chorio l Avoid FSE, fetal scalp sampling l PPROM? ? ? £ Balancing MTCT vs. prematurity £ Management should be based on maternal viral load and NICU capabilities

Standard Intrapartum ART l Intrapartum AZT regardless of antepartum ART £ 2 mg/kg IV Standard Intrapartum ART l Intrapartum AZT regardless of antepartum ART £ 2 mg/kg IV load, then 1 mg/kg IV qhr until delivery £ Loading dose can be given over 20 min-1 hr £ D/C d 4 T when receiving AZT £ Give 3 -4 hrs of IV AZT prior to elective c-section l Continue oral ART, even if getting cesarean Dorenbaum JAMA 2002

Cesarean Delivery and MTCT Cesarean Delivery and MTCT

Elective Cesarean and MTCT l 38 weeks, no labor, no ROM l Benefit seen Elective Cesarean and MTCT l 38 weeks, no labor, no ROM l Benefit seen in early studies £ AZT alone, observ studies didn’t adjust for VL l Studies in the HAART era: limited benefit £ £ PACTG 367 cohort, 1998 -2001; 72 U. S. sites, n=2875 singleton births Transmission 2. 9% overall MTCT by pre-delivery maternal viral load <1000: 0. 7% vs. 1000 -9999: 2. 1% vs. 10, 000+: 5. 9% l Elective c/s vs. vaginal delivery by maternal VL £ <1000: 0. 8% vs. 0. 7% £ 1000 -9999: 2. 8% vs. 1. 9%: OR 1. 5 (0. 4 -5. 0) £ 10, 000+: 4. 1% vs. 7. 3%: OR 0. 5 (0. 2 -1. 5) £ No RNA in chart: 8. 3% vs. 22. 4%: OR 0. 3 (0. 1 -0. 9) The European Mode of Delivery Collaboration, 1999; International Perinatal HIV Group 1999; Shapiro CROI 2004

Elective Cesarean and MTCT: Cochrane Collaboration l “Elective c/section is a good intervention for Elective Cesarean and MTCT: Cochrane Collaboration l “Elective c/section is a good intervention for the prevention of MTCT among HIV-infected women not taking antiretrovirals or taking only zidovudine… l Among women with less advanced or wellcontrolled HIV disease…the short-term risk of the intervention may exceed the long-term benefit. ” Read and Newell 2005

Post-partum maternal care l For those continuing on ART post-partum: £ Reinforce medication adherence Post-partum maternal care l For those continuing on ART post-partum: £ Reinforce medication adherence £ Dose maternal and neonatal ART on similar schedules l Remove breastfeeding literature from educational packs l Contraception

Post-partum vaccination l l Tdap Complete hepatitis A/B series prn Flu vax (if didn’t Post-partum vaccination l l Tdap Complete hepatitis A/B series prn Flu vax (if didn’t get antepartum) Rubella vax MMR: live-attenuated vaccine £ Case report of measles pneumonitis £ Advisory Committee on Immunization Practices: £ w Recommends in susceptible, asymptomatic HIV w Not recommended if cd 4 <200 or <14% w Check titers at 3 months and revaccinate prn Advisory Committee on Immunization Practices 1998; Brady CROI 2002

Conclusions l Prevent perinatal HIV transmission through 1° prevention l l l among women Conclusions l Prevent perinatal HIV transmission through 1° prevention l l l among women Ensure access to HIV testing: preconception and during pregnancy Ensure access to contraception and abortion services Keep woman healthy and preserve future ART options HIV-specific prenatal care Consider Cesarean £ if high viral load, no HAART, no labor/rupture of membranes l Avoid intrapartum interventions l Bottle feed (formula or banked human milk)

Resources l Clinical consultation £ National Perinatal HIV Consultation and Referral Service (NCCC) w Resources l Clinical consultation £ National Perinatal HIV Consultation and Referral Service (NCCC) w 24/7 coverage, based at SFGH w 1 -888 -448 -8765 (1 -888 -HIV-8765) £ Bay Area Perinatal AIDS Center (BAPAC) w 415 -206 -8919 (M-F, 8 a-5 p) £ Reproductive Infectious Disease Fellows w 719 -8726 (24/7 coverage) l Web-based resources www. aidsinfo. nih. gov (Perinatal HIV Guidelines) £ www. womenchildrenhiv. org £

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