Welcome to I-TECH HIV/AIDS Clinical Seminar Series

November 5, 2009

Mother to Child Transmission of HIV

Grace John Stewart MD, PhD

Overview

• Diagnosing HIV during pregnancy

• PMTCT regimens and new directions

• Breastfeeding

• Management of infants

• Transition points

Case 1

• 26 year old pregnant woman in Uganda, married, first pregnancy, how should she be offered HIV testing?

a. VCT counselor, one-on-one pre-test counseling, return for results

b. Group pre-test counseling, default HIV test, option to refuse, same day results

HIV testing in pregnancyBolu et al, AJOG 2007

• Group pre-test• Provider-initiated vs.

client-initiated• Rapid result availability• Standardized pre- and

post-test counseling– Flip charts– Videos

• Balance counseling and information issues

• Peer counselors

Pregnancy and HIV Diagnosis

• Young asymptomatic adults little incentive for HIV diagnosis

• Pregnancy currently often first HIV-test

• Pre-pregnancy HIV awareness will increase due to PMTCT/home-based VCT

KAIS 2007•64% ANC first HIV test•32% CD4<350

Dale IAS 2009 TUPEC059

Case 2

• 25 year old from Malawi in a rural clinic HIV-infected what further testing should be done?

a. No other lab tests

b. Viral load

c. CD4

d. Liver function tests

Identification of HAART-eligible mothersTaha J Infect Dis 2009

• HAART-eligible late breastmilk HIV-1 transmission risk 10.56/100 p-yrs

• On HAART HIV-1 TR 1.79/100 py (82% reduction)

• 3% initiated HAART before 14 weeks

• HAART ineligible BM TR 3.66/100 py

Reasons for no HAART or delayed HAART

•Skipped visits for CD4•Unwillingness•Treatment waiting list•Guardian or partner involvement

Case 3

• Her CD4 count is 200 cells/mm3, what regimen should be considered?

a. ZDV, 3TC, LPV/RTV

b. ZDV, 3TC, NVP

c. ZDV, 3TC, EFZ

Pregnancy may influence drug dosing, distribution, absorption, and efficacy

• Cardiovascular– Increased plasma

volume– Decreased albumin

• GI– Altered absorption

and emptying

• Renal– Altered clearance

• Hepatic– Altered enzymatic

activity

Drug Pregnancy Drug Pregnancy

NRTI PI

AZT No change APV No data

ddI No change IND AUC decreased

3TC No change LPV/r

AUC decreased

d4t No change NFV AUC decreased

ABC No change RTV

AUC decreased

FTC

TDF

No data

AUC decreased

SQV

ATZ

AUC decreased

No change?

NNRTI

DRV No Data

NVP No change Fusion Inhibitor

EFV No data T-20 No data

ART in Pregnancy Maternal and Infant Safety

Maternal Infant

NRTI Mitochondrial, lactic acidosis, hepatic failure (d4T/ddI)

Transient lactic acid elevations, mitochondrial toxicity, rare neurologic sx, transient anemia and neutropenia

NNRTI NVP hepatic EFZ teratogenicity

PI Hyperglycemia? Prematurity?LBW

Maternal NVP hepatotoxicity

• NVP hepatotoxicity increased in women

• Risk further increased in pregnancy and CD4>250

• Rash-associated• Can be

fulminant/fatal

Rate per 100 patient-years

Non-Preg Preg

P

value

ART for RX

ART for PMTCT

P Value

(N=87) (N=244) (N=102) (N=142)

Median CD4 152 277 136 414

Sx hepatitis 1.5 7.5 0.02 2.5 16.0 0.0003

Rash+liver 0.8 4.3 0.05 0.8 10.2 0.0003

Gr 1/2 liver 0.8 4.8 0.04 0.8 5.8 0.02

Gr 3/4 Rash 5.5 5.8 0.42 - -

Table courtesy of Lynne Mofenson

Phanuaphak N et al. HIV Med 2007;8:357-66

Antiretroviral Pregnancy Registry 1/89- 1/08 Prospective Cases (http://www.APRegistry.com)

% Birth Defect

CDC general birth defect surveillance

1st trimester any ARV exposure

ABC-containing (17/512)

AZT-containing (87/2808)

3TC-containing (85/2784)

d4T-containing (19/651)

Indinavir-containing (6/272)

Nelfinavir-containing (33/972)

Nevirapine-containing (18/737)

Ritonavir-containing (16/628)

Lopinavir-containing (6/328)

Tenofovir-containing (11/491)

ddI-containing (16/353)

2.7% (2.7-2.8%)

3.0% (2.5 - 3.5%)

3.3% (1.9 - 5.3%)

3.1% (2.5 - 3.8%)

3.1% (2.4 - 3.8%)

2.9% (1.8 - 4.5%)

2.2% (0.8 - 4.7%)

3.4% (2.3 – 4.7%)

2.4% (1.5 – 3.8%)

2.5% (1.5 – 4.1%)

1.8% (0.7 – 3.9%)

2.2% (1.1 – 4.0%)

4.5% (2.6 – 7.3%)

Table courtesy of Lynne Mofenson

First Trimester Efavirenz Use and Central Nervous System Defects

• Antiretroviral Pregnancy Registry no increase (10/364, overall 2.7%, 95% CI 1.3-5.0%).

• Primate studies 3/20 infant monkeys severe CNS defects (e.g., anencephaly, anophthalmia, cleft palate)

• 5 retrospective and 1 prospective human cases of CNS defects (e.g., meningomyelocele) with first trimester efavirenz exposure

• FDA Class D (animal & potential human risk)• South Africa data in 117 early EFZ-exposed pregnancy

increased elective termination, no increase in SB or miscarriages (Laher IAS 2009 TUPEC047)

Slide adapted from a slide courtesy of Dr. Lynne Mofenson

Case 3

• Her CD4 count is 800 cells/mm3, what regimen should be given during prolonged breastfeeding after peripartum PMTCT?

a. Maternal HAART

b. Infant NVP

c. No further treatment

ART Considerations in Pregnancy

• Maximize maternal survival– Same ART initiation eligibility

criteria as non-pregnant (CD4 <250-350)

– CD4 count decreased in pregnancy

– Indefinite therapy for ART-eligible

• Minimize infant HIV or mortality

• Minimize toxicity and optimize longer term outcomes– Avoidance of specific drugs,

resistance considerations

ART prevents infant HIV by maternal viral suppression and by exposure prophylaxis

Infant Age

Pro

ba

bili

ty o

f H

IV-1

Infe

cti

on

1wk 9wk 6mo 9mo 12mo 15mo 18mo 24mo

0.0

00.0

50.1

00.1

50.2

00.2

50.3

0

ControlExtended NVPExtended NVP+ZDV

•Maternal ART decreases systemic and mucosal HIV load

•ARV prophylaxis pre- and post-exposure significantly decrease transmission in the absence of maternal ARV

Kumwenda N et al. NEJM 2008:359:119-29

Maternal immunosuppressed sub-group and breastfeeding duration are key determinants of

transmission risk

• Tiered approach includes hidden interventions– ART to

immunosuppressed– Shortened breastfeeding

• PMTCT studies limited reporting CD4 stratified or numbers on cART

• Among CD4 >350 comparison of mART to infant ARV (see Kesho Bora De Vincenzi LBPEC01, BAN IAS 2009 Chasela WELBC103)

Maternal ART or Infant ARVIAS 2009: Chasela WELBC013, Shapiro WELBB101, DeVincenzi

WELBPeCO1, Marazzi TUC101

• BAN-851 maternal ART, 848 infant

ARV

-3% mART vs. 1.8% iARV

• Kesho Bora mART 2% TR• DREAM retrospective

mART 2% TR• Mma Bana mART ~1% TR

Maternal ART vs. infant ARV to prevent transmission in women with CD4 >350

Maternal HAART Infant ARV

Maternal resistance

Infant resistance Infant resistance

Toxicity (maternal/infant) and outcomes (prematurity/LBW)

Infant toxicity

Complexity/cost

Interruption

Limited regimens (NVP, EFZ)

PMTCT Guidelines in Different Settings

USPHS 2009 WHO 2006

ART-eligible ART ART-eligible ART

ART-ineligible ARTIf RNA <1000 alternative option ZDV

ART-ineligible ZDV from 28 wks, SD NVP, tail regimen (1 wk ZDV/3TC), infant 1 wk ZDV

Cesarean section if RNA >1000

IV ZDV intrapartum

No breastfeeding Breastfeeding preferred

Resistance testing

Low maternal prevalence High maternal HIV prevalence

Safe breastmilk alternatives

Low general population infant and maternal mortality

Higher general population infant and maternal mortality

1-2% 1-6%

Breastfeeding WHO recommendations

2000 2006

“when replacement feeding is acceptable, feasible, affordable, sustainable and safe, avoidance of all breastfeeding by HIV-infected mothers is recommended. Otherwise, exclusive breastfeeding is recommended during the first months of life” and should then be discontinued as soon as it is feasible.

•Exclusive BF first 6 months unless RF is acceptable, feasible, affordable, sustainable, safe (AFASS)•If RF, no BF•Revisit feeding at infant dx and/or 6 months; reassess at 6 months, if not AFASS, then BF/complementary foods; stop when nutritionally safe/adequate diet without BM is possible

WHO guideline timeline

IDEAL RECOMMENDATIONS

•One simple safe and easy-to-use ART regimen for pregnant women with HIV•One simple, safe and easy-to-use ARV regimen for prophylaxis in pregnant women with HIV•Practical, easy-to-follow advice on what to do for late presentation to pregnancy services•One simple, safe prophylactic regimen for all HIV-exposed infants•One simple prophylactic ARV regimen for infants who are breastfeeding (if their mothers are not on ART)

Feb 2009 Oct/Dec 2009 Feb 2010

Initiation Expert Review Dissemination

Case 4

• What is your country’s track-record for PMTCT coverage?

a.10%

b.90%

c.50%

Fig. 5.5. Percentage of pregnant women who received an HIV test in low- and middle-income

countries by region, 2004–2008a

PMTCT coverage critical for population efficacy

1,000,000 women, 10% prevalence, baseline TR 30%

Case 5

• Healthy 2 week old born to HIV infected mother, when should he be tested? How?

a) ELISA at 6 months

b) HIV PCR assay at 6 weeks

c) Wait until 18 months

Early Infant HIV-1 Testing

• In 2007 only 8% of infants born to HIV-infected women tested < 2 months

• 2005 to 2007 - increase from 17 to 30 LMIC national facilities for diagnosis

• Linked MCH cards

Case 6

• Child is HIV-infected at 6 weeks, what should be done?

a. Get CD4 count and stage and initiate treatment based on CD4 and WHO Stage

b. Treat with HAART

c. Start trimethoprim/sulfamethoxazole

Early Pediatric HIV-1 TreatmentViolari, et al, CHER: NEJM Nov 2008

• Early versus deferred therapy• CD4% >25%• PI-containing HAART• Diagnosis between 6-12 weeks of age• Deferred therapy started when infants met WHO

criteria for CD4% to start HAART• 125 deferred, 252 early therapy

0.00

0.20

0.40

0.60

0.80

1.00

0 3 6 9 12

Time to Death (months)

Fai

lure

Pro

bab

ility

Arm 1 Arm 2 & 3

CHER Study Mortality

Patients at risk

Month 0Month 3 Month 6 Month 9 Month 12

Arm 1 125 104 72 44 22

Arm 2 & Arm 3 252 213 145 99 52

P = 0.0002

16%

4%

Case 7

• How should the child be informed that he has HIV?

a.Age 2 by parents

b.Age 6 by a team including parents

c.Age 14 by health care worker

d.Age 18 with a video or brochure

Barriers to disclosureWariua, et al unpublished 2008

Barriers N = 205Percent (%)

Too young to understand 69

Child will be depressed 25

Unable to keep a secret 52

Fear of questions about transmission 20

Fear of discrimination 29

Child will blame parents 9

Do not know how to tell the child 24

Barriers To Disclosure

“But if it was pneumonia I would have already told the child. Even when he tested TB positive I told him because it was just TB …But for this “one” a parent sees this is death and if you disclose is like killing your child by stabbing with a knife” (Mother of 10 yr old)

“….the child doesn’t know the father. I left the father when the child was one and half years old. And you know they are aware of how this disease is transmitted …Now if the child asks me where I got it from, where will I tell the child I got it from? “(Caregiver of 12 yr old)

Reasons for DisclosureWariua et al, 2008

“One time I went to the toilet and I found that she had thrown the medicine in the toilet. I realized then I just have to tell her…At that time, she was12 years old.” (Caregiver of 16 yr old)

“She started asking because of the wounds in her hair. We used to plait her and then we had to shave her hair. She used to wonder what the problem was. Then her father took her for testing and then he told her.” (Caregiver of 12 yr old)

Consequences of DisclosureWariua et al, 2008

“From that day, she takes the medicine on her own, even when I leave her alone or she goes home for holidays” (Caregiver of 16 yr old)

She just said, “Daddy, just buy me a watch” And I bought her that and she never takes it off her hand. So when seven o’clock reaches, even if there are visitors, she will leave and take her things to the kitchen. If we are just the family, she just takes them. She doesn’t mind. (Caregiver of 10 yr old)

Effect of Disclosure on ChildWariua et al, 2008

“She came with her sister and told me she was happy she had been told, so that she can know what her illness is. She is happy because she is now taking medicine and she doesn’t have any wounds. And when she comes for testing, they tell her that she is now tall.” (Caregiver of 12 yr old)

“When the doctors told him he was shocked. For two, three days when he was at home, he was just staying like this (Sitting still)… Don’t people get this problem through having sex, and I have never done that?”, he asked “ (Caregiver of 11 yr old)

Case 8

• 26 year old mother diagnosed with HIV during pregnancy, now 12 months postpartum, stopped breastfeeding, last infant test negative. What next for the mother?

a. Recommend an HIV care programb. Continue intermittent follow-up at MCHc. Recommend referral to family planning

program

PMTCT and HIV CareOtieno et al, AIDS Care 2009

• After 1-2 yr f/u in PMTCT research, 74% accessed HIV care

• Those who did not receive HAART less likely to stay in care

• Accessing care increased if:– Better knowledge about HAART– Partner informed

• Need for standard referral process in transition to HIV care

HIV and Pregnancy Desire

• HIV decreases fertility intention (61% from baseline) (Taulo AIDS and Behav 2007 Kaida IAS 2009 TUPEC056)

• Similar pregnancy incidence as HIV-uninfected women ) (Taulo AIDS and Behav 2007)

• Contraception uptake >70% with counseling

(Balkus STD 2007) • Fertility intention

predictive (Guthris IAS 2009 LBPEC08)

Guthrie IAS 2009

Pregnancy/Lactation Impact on HIV/ART

• Pregnancy impact on HIV progression– 3.7 fold increased risk in review

developing-countries (French BJOG 1998)

– Decreased risk of AIDS/mortality in US-cohort in HAART era (Tai J Infect Dis 2007)

– Methodologic issues• Lactation clinically negligible impact

– 4 of 6 studies no effect of breastfeeding on disease progression

• Limited data on pregnancy impact on ART response– Drug levels, regimen, adherence, toxicity

differs

MCH-Treatment Program Intersection

• Diagnosis pre-pregnancy will increase

• PMTCT may contribute to age-entry differences at ART Care Programs

• Systems for referral between MCH-ART Care diverse and developing– MCH

pregnancy/immunizations, growth, well-child care

– ART focused HIV care/management, seamless integration

Mnyani IAS 2009 CDC017

Pregnancy and HIV-infected women

• Time of HIV diagnosis

• HIV-infected women desire children

• Pregnancy/lactation may influence HIV acquisition, progression, ART response

Fertility ~3-6 children, pregnancy plus lactation ~2-3 years – cumulative pregnancy/lactation dose ~6-18 years

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Email: DLinfo@u.washington.edu

Next session: November 19 – TB, Part 3

Thank you!Next session: November 19, 2009

Charles NolanTuberculosis: Part 3