HIV infection in Pregnancy รองศาสตราจารย์ นายแพทย์ อติวุทธ กมุทมาศ สาขาสูติศาสตร์และนรีเวชวิทยา คณะแพทยศาสตร์ มหาวิทยาลัยธรรมศาสตร์

Natural history The principal target=T lymphocytes Specific at CD4 surface antigen (receptor for the virus) Monocyte-macrophages may be infected Incubation period ; days to weeks Acute retroviral syndrome ; fever, night sweats, fatigue, rash, headache, lymphadenophathy, pharyngitis, myalgias, arthralgias, nausea, vomiting, diarrhea ; lasts < 10 days

After symptoms abate ; chronic viremia Median time = 10 years --- AIDS AIDS; generalized lymphadenopathy, oral hairy leukoplakia, aphthous ulcer, thrombocytopenia, opportunistic infections (candida, HSV, TB, CMV, HPV, PCP, toxo), Kaposi sarcoma, non-Hodgkin lymphoma Death

Number of People with HIV/AIDS by Region Western Europe 500,000 Eastern Europe & Central Asia 270,000 North America 890,000 East Asia & Pacific 560,000 North Africa & Middle East 210,000 Caribbean 330,000 South and South East Asia 6.7 million North America: 890,000 Caribbean: 330,000 Latin America: 1.4 million Western Europe: 500,000 Eastern Europe and Central Asia: 270,000 North Africa and the Middle East: 210,000 Sub-Saharan Africa: 22.5 million East Asia and the Pacific: 560,000 South and South East Asia: 6.7 million Australia and New Zealand: 12,000 Sub-Saharan Africa 22.5 million Latin America 1.4 million Australia and New Zealand 12,000 Source: UNAIDS/WHO 1998.

Virology DNA retrovirus HIV-1 , HIV-2 Transmission - sexually transmitted - blood-contaminated (e.g., blood transfusions, shared needles, contaminated instruments) - maternal to child -vertical 15-40% -breast feeding 30-40% HIV-1 = more common and more virulent

Maternal to child transmission (MTCT) 36 wk-labor <14 wk 14-36 wk Intrapartum 75 % uninfected 25 % infected 8 1 4 12 4% 16% 50% 30% Kourtis and colleagues, 2001

Risk factors for vertical transmission 1. Preterm birth (3.7 relative risk for intrapartum transmission ; Kuhn and assoc 1999) 2. Prolonged membrane rupture (increase rate from 15 to 25% in ROM > 4 hr ; Landesman and co-workers 1996) 3. Placental inflammation, chorioamnionitis, concurrent syphylis (Mwanyumba 2002) C/S reduce vertical transmission Antibiotics not prove to decrease the risk

4. Maternal plasma HIV RNA level ARV decrease the risk Most important factor, HIV RNA viral load > 100000 copies/ml : risk > 30 % HIV RNA viral load < 400 copies/ml : risk 1 %

5. Stage of disease 6. CD4+ T-cell count 7. Mode of delivery cesarean section vs vaginal delivery 8. Breast feeding (risk 30-40%)

Pregnancy on HIV infection HIV infection on pregnancy Pregnancy : slightly immunosuppressive : minimal effect on CD4 count : minimal effect on HIV RNA level : does not have significant effect on the clinical or immunological course of HIV infection (Minkoff 2003) Maternal morbidity and mortality : not increased Slightly increase rate of preterm birth Slightly increase rate of IUGR Slightly increase rate of PROM Fetal and neonatal infection varies from 25-40 percent

Adverse Pregnancy Outcomes and Relationship to HIV Infection Spontaneous abortion Limited data, but evidence of possible increased risk Stillbirth No association noted in developed countries; evidence of increased risk in developing countries Perinatal mortality No association noted in developed countries, but data limited; evidence of increased risk in developing countries Newborn mortality Limited data in developed countries; evidence of increased risk in developing countries Intra-uterine growth retardation Evidence of possible increased risk There may be association between HIV and: Spontaneous abortion Stillbirth Maternal mortality Newborn mortality Low birth weight Preterm delivery Amnionitis Anderson 2001.

Relationship to HIV Infection Adverse Pregnancy Outcomes and Relationship to HIV Infection (continued) Pregnancy Outcome Relationship to HIV Infection Low birth weight Evidence of possible increased risk Preterm delivery Evidence of possible increased risk, especially w/ more advanced disease Pre-eclampsia No data Gestational diabetes Amnionitis Limited data; more recent studies do not suggest an increased risk; some earlier studies found increased histologic placental inflammation, particularly in those with preterm deliveries Oligohydramnios Minimal data Fetal malformation No evidence of increased risk Anderson 2001.

Management during pregnancy Therapeutic goals ; maximal suppression of viral load and restoration of immunological function ; prevention of maternal to child transmission ARV therapy should be offered to all HIV infected pregnant women regardless of CD4 cell count or HIV RNA level To treat the mother as well as to reduce the risk of perinatal transmission Holistic care : antepartum / intrapartum / postpartum : mother / fetus-baby : psycho / bio / social

Antepartum care Posttest counseling / psychological support History taking Physical examination Per vaginal examination Oral health examination Ophthalmic examination Lab tests Tuberculin test Chest X-ray Prenatal care in high risk clinic Nutrition support / vitamin supplementation Ultrasound Prevention of opportunistic infection Immunization Anteretroviral administration

Intrapartum care ARV during labor period ; minimum viral load Mode of delivery Labor augmentation is used when needed to shorten the interval to delivery / but avoid ARM Minimize operative obstetrics : scalp electrode, fetal scalp blood sampling, forceps extraction, vacuum extraction Universal precaution ; percutaneous exposure of needle=0.3%, mucous membrane exposure=0.09%, atraumatic needle, absorbable suture, non-touch technique, 0.5% sodium hypochloride, room for isolation Additional vaccine ทำเมื่อ viral suppression is achieved

Cesarean section ; decrease vertical transmission one-half compared with vaginal delivery (metaanalysis of 15 prospective cohort studies by the international perinatal HIV group 1999) Combined cesarean section with ARV reduced the risk 87 % ACOG 2000 ; recommended C/S when HIV RNA viral loads > 1000 copies/ml Scheduled C/S is recommended at 38 wk If viral load < 1000 copies/ml ; data insufficient to estimate benefit of C/S (ACOG 2000)

Postpartum care 1. ARV Mother: AIDS, HIV infection with CD4<200 ; continue ARV treatment CD4 200-350 ; controversial for ARV CD4 > 350 ; stop ARV , monitoring CD4 Baby: ARV 1 / 6 weeks If delivery occurs before treatment is given, the newborn can receive prophylaxis for 6 weeks with zidovudine, or in some cases combination antiretroviral treatment 2. Contraceptives ; condom + OCP points of interest ; TR, injectable, norplant, IUD

3. Breast feeding Not recommended Africa ; breast feeding with continuation of ARV prophylaxis 4. Postpartum clinic and pap smear ; 6 mo / 1 year

Guidelines for ARV in pregnancy 1. Classes of ARV drugs By FDA pregnancy category classification e-text McGrawHill Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap III L, Wenstrom KD. Williams Obstetrics. 22nd ed. New York: McGRAW-HILL; 2005.

Drug Category Nucleoside reverse transcriptase inhibitors Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zalcitabine Zidovudine Non-nucleoside reverse transcriptase inhibitors Delavirdine Efavirenz Nevirapine Protease inhibitors Amprenavir Atazanavir Fosaprenavir Indinavir Lopinavir/ritonavir Nelfinavir Ritonavir Saquinavir Fusion inhibitors Enfuvirtide C B

NRTI/ NNRTI FI PI

2. Regimens NNRTI-based PI-based Triple NRTI-based FI-based http://AIDSinfo.nih.gov

3. Monitoring CD4 count at initiation then CD4 count every 3 months HIV RNA levels at 4 weeks after initiation of treatment then HIV RNA levels monthly until undetectable, then every 3 months HIV RNA level at GA 36 weeks

4. Heavy, Light, or Medium Heavy Medium Light Short course AZT NVP-single dose Short course AZT+SD NVP AZT+3TC AZT+3TC+NVP AZT+3TC+PI

Short course ZDV / SD NVP NVP-NVP P-P NVP-NVP P-NVP NVP-P HIVNET012 ; Guay, Lancet 1999;354:795-802. PHPT-2; Lallemant, NEJM 2004; 351: 217-8. MASHI; Shpiro , AIDS 2006; 20: 1281-8. Short course AZT ; TR 8% (ACTG076)

NVP concentration after SD-NVP Median T1/2 = 61.3 hours Drug can be detected up to 19 days Lower limit assay quantification 50 ng/ml ; 3-4 weeks postpartum Cressey TR. JAIDS 2005; 38: 283-8. SD NVP covering the tail ; ZDV/3TC 7 days : reduce resistance from 60 % to 10-12 % TOPH Trial, SA

Two drugs regimen Short course AZT (28 week)+SD NVP : TR 6.3% (PHPT-2) AZT+ddI (36 wk to 1 wk PP) : TR 6.9% (SIMBA trial) AZT+3TC 32 wk add SD NVP : TR 4.7% (Ditrame Plus) AZT 36 wk + SD NVP : TR 6.5%

HAART Depend on immune status of mother -low CD4 <200 ; start for maternal health -high CD4 ; consider -pro ; low TR (PACTG316, TR 1.5%) -con ; high risk of NVP toxicity, increase risk of GDM with PI, risk of preterm delivery (controversial) Which HAART? -NNRTI based HAART -PI based HAART

Toxicities concerned NVP -rash ; women>men (3.7 x) -more common with high CD4 > 250 (10X increase in women) Hepatotoxicity -symptomatic hepatotoxicity ; CD4 <250 :0.5-1.7%, CD4 > 250: 10.0-11.3% -fetal hepatic events ; CD4 250-400 : 0.42%, CD4 >400 : 1.1%) -TRC cohort ; low : high CD4 2.9% versus 7.7%

5. Factors for selection Mother Child Medical services

Action reports from Thammasat Hospital

ทีมงาน อายุรแพทย์ (อ.อนุชา) สูติแพทย์ (อ.อติวุทธ) กุมารแพทย์ (อ.อัจฉรา) ทีมพยาบาลหน่วยเอดส์ธรรมศาสตร์ (คุณกรองทิพย์) ทีมอาสาสมัครผู้ติดเชื้อ (คุณวันใหม่) เภสัชกร นักสังคมสงเคราะห์ อื่น ๆ

< 2540 ; no ARV important role of a termination of pregnancy 2541-2546 ; AZT + SD NVP > 2547 ; HAART

ข้อมูลจาก หน่วยเอดส์ธรรมศาสตร์ โรงพยาบาลธรรมศาสตร์เฉลิมพระเกียรติ

AZT regimen Prevalence of HIV infection pregnancy in TUH = 1-2 percent AZT alone = infection rate 3.9 percent AZT regimen from other studies ; infection rate 5-8 percent, ACTG 076 protocol = 8% Cesarean section = beneficial MPH ; still using AZT regimen

Regimens ; Pediatrics AIDS clinical trials group, USA Antepartum: 100 mg 5times/day, initiating at 14-34 wk,continue throughout pregnancy (or 200 mg 3times/day, 300 mg twice a day) Intrapartum: IV Zidovudine in a 1-hr initial dose of 2 mg/kg, followed by a continuous infusion of 1 mg/kg/hr until delivery Neonates: begin at 8-12 hr after birth, and give syrup at 2 mg/kg every 6 hr for 6 weeks

Intrapartum; AZT 300 mg every 3 hr and single dose NVP 200 mg orally Regimen MPH Antepartum; 300 mg twice a day, initiating at 14-34 (28) wk,continue throughout pregnancy (regardless of CD4 count) Intrapartum; AZT 300 mg every 3 hr and single dose NVP 200 mg orally Postpartum; AZT 300 mg+3TC 150 mg twice a day for 2 weeks Neonates; NVP 2 mg/kg single dose and AZT 2 mg/kg every 6 hr for 6 weeks Disadvantages (compare to HARRT) : Higher transmission rate High incidence of NVP resistance

HAART (AZT+3TC+NVP) ปี จำนวนมารดา ลูกไม่ติดเชื้อ ลูกติดเชื้อ 2547 36 35 1 2548 46 2549 34 33 2550 52 21 2551 43 8 ข้อมูลจาก หน่วยเอดส์ธรรมศาสตร์ โรงพยาบาลธรรมศาสตร์เฉลิมพระเกียรติ

Triple agents (HARRT) Thammasat Hospital ; transmission rate 1.2 % Other studies ; transmission rate 1-1.5%

Regimen : TUH 1. CD4 ≤ 200 / GA 14 weeks Antepartum; AZT(300)/3TC(150) q 12 hr + NVP(200) OD for 2 wk then AZT(300)/3TC(150) +NVP(200) q 12 hr Intrapartum; AZT 300 mg q 3 hr and AZT(300)/3TC(150) +NVP(200) q 12 hr Postpartum; AZT(300)/3TC(150) +NVP(200) q 12 hr Neonates; AZT 2 mg/kg q 6 hrx6 wk

2. CD4 > 200 / GA 28 weeks Antepartum; AZT(300)/3TC(150) q 12 hr + NVP(200) OD for 2 wk then AZT(300)/3TC(150) +NVP(200) q 12 hr Intrapartum; AZT 300 mg q 3 hr and AZT(300)/3TC(150) +NVP(200) q 12 hr Postpartum; AZT(300)/3TC(150) q 12 hr x 14 days, stop NVP Neonates; AZT 2 mg/kg q 6 hrx6 wk

Alternative regimens; AZT/3TC/Nelfinavir(NLF) (250 mg 5 tabs q 12 hr, no need for test dose, no covering tail) AZT/3TC/Efavirenz (GA>24wk) GPOvir(3TC/d4T/NVP)(follow the protocol AZT/3TC/NVP and test doses NVP for 2 wk) In case C/S Start AZT with 30 cc of water since NPO then NPO except medicine with water until delivery and postop care period 12-24 hr For no ANC patients Intrapartum; AntiHIV stat, NVP 200 mg single dose (immediately) and AZT 300 mg q 3 hr regardless of CD4 count Postpartum;AZT300/3TC150 q 12 hrx14wk Neonates; NVP 2 mg/kg single dose + AZT 2 mg/kg q 6 hr x 6 wk (start immediately)

Thank you for your attention until the end of the session