1. HIV infection in Pregnancy
รองศาสตราจารย์ นายแพทย์ อติวุทธ กมุทมาศ
สาขาสูติศาสตร์และนรีเวชวิทยา
คณะแพทยศาสตร์ มหาวิทยาลัยธรรมศาสตร์

2. 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

3. 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

4. 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.

5. 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

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

7. 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

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

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

10. 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 percent

11. 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.

12. 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.

13. 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

14. 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

15. 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

16. 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)

17. Postpartum care 1. ARV Mother:
AIDS, HIV infection with CD4<200 ; continue ARV treatment
CD ; 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

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

19. 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.

20. 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

21. NRTI/ NNRTI FI PI

22. 2. Regimens NNRTI-based PI-based Triple NRTI-based FI-based

23. 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

24. 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

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

27. 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:
SD NVP covering the tail ; ZDV/3TC 7 days : reduce resistance from 60 % to %
TOPH Trial, SA

28. 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%

29. 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

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

32. 5. Factors for selection
Mother
Child
Medical services

33. Action reports from Thammasat Hospital

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

35. < 2540 ; no ARV important role of a termination of pregnancy
; AZT + SD NVP
> 2547 ; HAART

36. ข้อมูลจาก หน่วยเอดส์ธรรมศาสตร์ โรงพยาบาลธรรมศาสตร์เฉลิมพระเกียรติ

37. 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

38. Regimens ; Pediatrics AIDS clinical trials group, USA
Antepartum: 100 mg 5times/day, initiating at 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

39. Intrapartum; AZT 300 mg every 3 hr and single dose NVP 200 mg orally
Regimen MPH
Antepartum; 300 mg twice a day, initiating at (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

40. HAART (AZT+3TC+NVP) ปี จำนวนมารดา ลูกไม่ติดเชื้อ ลูกติดเชื้อ 2547 3635 1
2548 46
2549 34 33
2550 52 21
2551 43 8
ข้อมูลจาก หน่วยเอดส์ธรรมศาสตร์ โรงพยาบาลธรรมศาสตร์เฉลิมพระเกียรติ

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

42. 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

43. 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

44. 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 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)

45. Thank you for your attention until the end of the session