Women, HIV and PMTCT

Unit 11HIV Care and ART:

A Course for Physicians

2

Learning Objectives

Part 1: Women and HIV List women’s risk factors for HIV and identify

strategies to reduce risk Identify gynecological conditions associated with

HIV in women Describe gender differences in ARV treatment

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Learning Objectives

Part 2: HIV and PMTCT List the factors that affect HIV transmission

during pregnancy, labor, delivery and breastfeeding

Identify how to prescribe ART appropriately for pregnant women and exposed newborns

Describe labor, delivery and postpartum care for HIV+ women and their infants

Part 1:Women and HIV

5

Global Facts

Of 40 million people living with HIV/AIDS worldwide, 17.5 are women (2005)

77% of all women living with HIV are in sub-Saharan Africa (2005)

Among HIV positive adults, women account for 57% in sub-Saharan Africa, 26% in southeast Asia, 27% in Europe, and 25% in the US (2005)

6Source: UNAIDS/WHO 2004

7Source: UNAIDS/WHO 2004

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Vulnerability Factors

Biological Economic Social Cultural

“Women are most vulnerable to HIV infection, given the social and economic disadvantages they face in their day to day lives.”

• Dr. Nafis Sadik, Executive Director of the United Nations Population Fund

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Gender Differences

Viral load Disease progression Drug pharmocokinetics Lipodystrophy Lactic acidosis Contraceptives Adherence Gynecological issues

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Viral Load and Disease Progression

Women may have lower viral loads than men in early disease

Low viral load may NOT truly reflect low risk for progression

Women and men progress at similar rates Gender is not significantly associated with time

to AIDS or survival time

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Drug Pharmacokinetics

Differences in weight and body mass Fat to muscle distribution Concentration of enzymes needed for drug

metabolism is different Hormonal effects

PregnancyHormonal replacement therapyOral contraceptives

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Lipodystrophy

Fat accumulation more common in women; fat depletion more common in men

Accumulation and depletion in different body areas of same person occurs equally in men and women

Lipid abnormalities: triglyceride and cholesterol level elevations more common in men

13

Lactic Acidosis

The FDA has received 60 reports of lactic acidosis associated with dual nucleosides, with 55% mortality

83% in women; 50% >175lbs Presented with nonspecific symptoms Link between mitochondrial dysfunction and

lactic acidosis? Occurs in women with high CD4

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Contraception and ART

Because Efavirenz is contraindicated during pregnancy, dual methods of contraception are highly recommended for sexually active EFV users: barriers plusProgestins (Depo-Provera)IUCD

Nelfinavir, Nevirapine and RitonavirAssociated with decreased levels of ethinyl estradiol,

resulting in decreased contraceptive effectivenessDo not combine

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Contraception and ART (2)

NNRTIs and PIs interfere with blood levels of combination oral contraceptives

Additional barrier methods are recommended to prevent pregnancy and transmission of HIV and STIs

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Women and Adherence

Adherence issues are more complicated for women who need special attention and support: Often don’t disclose HIV status due to stigmaMay feel isolatedCaregiversChallenges in accessing and maintaining care include

child care, transportation, inexperienced providers, etc.

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Optimal Adherence for Women

Evaluate for mental health, substance abuse and other “adherence interruptus” problems

Assess HAART readiness Develop a mutually agreeable HAART regimen

specific to her lifestyle Prepare for side effects Encourage atmosphere of communication and

trust Be accessible and available

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Gynecological Issues

Conditions causing inflammation or infection increase the likelihood a woman will acquire or transmit HIVBacterial vaginosisCervicitisHerpes ulcersGenital wartsCondyloma

Recurrent candidiasisPrevalent in 25-30% of women with HIVRisk increases 20-fold with CD4<100

HPV genital warts associated with increased incidence of cervical cancer

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Care for HIV+ Women

Regular gynecologic care Pap smear (yearly and as needed)

Detects cervical dysplasia (human papillomavirus) and sexually transmitted diseases

Untreated HIV disease is associated with increased risk of cervical abnormalities

Reproductive counseling

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Care for HIV+ Women Desiring Pregnancy

Give accurate information on MTCT Maintain good health and nutrition status Provide ARVs to eligible women, or consider

delaying until after the first trimester

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Ongoing Care for Women with HIV Infection

Psychological support Social support Medical support

Nutritional adviceProphylaxis of TB, PCP, malaria, other infectionsPhysical examination that includes gynecologic exam

and cervical smears

22

Treatment Guidelines for Women

Guidelines are the same for women and men Women and men have similar responses to

initial ART Because many women weigh less than men, it is

important to monitor for toxicity

Part 2:HIV, Pregnancy and

Preventing Maternal to Child Transmission

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Introduction

HIV is a family infection Mothers and fathers have an impact on

transmission of HIV to the baby There is increased chance of transmission to the

baby when a woman becomes infected with HIV when she is pregnant or breastfeeding

Partners should have safer sex throughout pregnancy and while breastfeeding

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Pregnancy Outcome: Goals

Uncomplicated pregnancy Healthy, uninfected infant Healthy mother who has not compromised her

future options for HIV therapy

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HIV and Pregnancy

Pregnancy does not accelerate the progression of HIV disease to AIDS

Patients with AIDS are more likely to suffer from pregnancy-related complications

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Effect of Advanced HIV on Pregnancy

Decreased fertility Spontaneous abortion Infections (opportunistic, GU, postpartum, post-

surgical) Preterm labor Premature rupture of membranes Low birth weight babies Stillbirths

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Current Status of Mother-to-Child Transmission

Estimates of HIV transmission rates from women to children are about 20-40%

MTCT is by far the largest source of HIV infection in children under 15

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Estimated Risk of MTCT(Adapted from De Cock KM et al, 2000)

Timing

Transmission Rate Without Any Interventions

During pregnancy 5-10%

During labor and delivery 10-15%

During breastfeeding 5-20%

Overall without breastfeeding 15-25%

Overall with breastfeeding to six months 20-35%

Overall with breastfeeding to 18-24 months 30-45%

Note: Rates vary because of differences in population characteristics such as maternal CD4+ cell counts, RNA viral load and duration of breastfeeding.

“HIV transmission through breastfeeding: A review of available evidence.” Marie Louise Newell; endorsed by UNICEF, UNFPA, WHO, UNAIDS. 2004 (adapted from De Cock KM et al., 2000).

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Of 100 Babies Born to HIV- Infected Mothers Not on Treatment…

67 not infected*

5 infected in utero

17 infected during birth

11 infected during breastfeeding

*without treatment for parents, most will be orphaned

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Factors Influencing MTCT

Viral LoadThe higher the viral load, the higher the risk of MTCT

Lower risk through:Use of ART during pregnancy and postpartum to

mother and newborn Adequate nutrition, particularly vitamin A

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Factors Influencing MTCT (2)

Maternal factors increasing risk:Viral or parasitic placental infection (especially

malaria) Becoming infected with HIV during pregnancySevere immune deficiency Advanced clinical and immunological stateMaternal malnutrition

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Factors Influencing MTCT (3)

Labor and delivery factors increasing risk:Prolonged rupture of membranes (>4 hours)Injury to birth canal during child birthAntepartum proceduresAcute chorioamnionitis Invasive fetal monitoring Instrumental deliveryMixing of maternal and fetal body fluidsDelayed infant cleaning and eye careRoutine infant airway suctioning

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Factors Influencing MTCT (4)

Fetal Conditions increasing risk:Premature deliveryLow birth weightImmature immune status First infant in a multiple birthOral diseases

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National Strategies for PMTCT

Primary prevention of HIV in childbearing women

Prevention of unintended pregnancy in HIV-positive women

Prevention of transmission from HIV+ women to their infants

Treatment, care and support of women infected with HIV, their infants and their families

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Antenatal Care

Primary prevention during pregnancy Education about safer sex with use of condoms for

mother and fatherEarly treatment of STIsSafer sex during pregnancy and lactation

Offer VCT to all pregnant women Antenatal visits are vital opportunities for

PMTCT for both HIV-positive and HIV-negative women

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Initial Examination

All pregnant womenSyphilis testHgb HIV counseling and consentHIV test (rapid, if available)Rule out active TB

If HIV positive:Baseline TLCCD4 and CD8 countsCD4/CD8 ratio and all other baseline tests (CBC, LFT, etc.)Viral load screening

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Initial Examination (2)

Additionally, if HIV+:Duration of known HIV+ statusPast history of HIV-related illness and HAARTWHO StagingStatus of other children, partner, and partner

disclosure and referralAny medications taken for HIV-related illness since

beginning of pregnancy

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Assess Maternal PsychosocialStatus Generalities and pains Headaches Anxiety General malaise

Depression Palpitations Insomnia Irritability

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Care of the HIV+ Pregnant Woman

Treatment: OIs STI UTI Vaginal candidiasis ARV Vitamin supplements

Prophylaxis: Anemia Tetanus (Toxic-TT) Vitamin deficiency Malaria Pneumonia (PCP) TB

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PMTCT Clinical Scenarios

Six possible clinical scenarios of a pregnant woman:On ART and become pregnantPregnant and eligible for ARTPregnant and not requiring ARTPregnant and presenting after 34 weeksPregnant and presenting in laborWoman and child presenting postpartum

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Scenario 1: On ART and Become Pregnant Woman on efavirenz

Counsel about potential teratogenicity

Stop EFV and start NVP if in first trimester

Woman on D4T/3TC/nevirapine Continue treatment or change

D4T to ZDV ALT monthly & when indicated Monthly full blood count if on

ZDV

Women on ZDV/DDI/LPV/r Continue treatment Full blood count monthly Monitor blood glucose levels

as appropriate

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Scenario 2: Pregnant and Eligible for ART

Begin first line therapy:ZDV 300 mg bid or D4T 40 mg every 12 hours (or 30 mg q

12 hours if <60 kg) and3TC 150 mg q12 hrs andNVP 200 mg qd for 2 weeks, then 200 mg q12 hrs

If unable to use NVP, PI options include NFV, LPV/r or SQV/r

ALT q 2 weeks for 1 month, then q month and then as indicated

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Scenario 3: Pregnant and Not Requiring ART

Early stage HIV (WHO Stage I or II disease with CD4 >200)Follow the national PMTCT guidelines

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Scenario 4: Pregnant Woman Presenting After 34 Weeks

Defer ART Provide PMTCT Review need for ART after delivery

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Scenario 5: Pregnant Woman Presenting in Labor

NVP single dose given at the onset of labor and post delivery to the infant or

AZT & 3TC to the mother during labor and infant post delivery or

IV AZT (alone or with NVP) to the mother and AZT syrup to the infant post partum for six weeks, in addition to a single dose of Nevirapine

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Scenario 6: Woman and Child Presenting Post Partum

Initiate 6 week neonatal AZT protocol, preferably within 6-12 hours of delivery or

Single dose Nevirapine plus AZT for the infant for four weeks

Mother should be evaluated for HAART

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Four Options for PMTCT

(Scenarios 3-5)Nevirapine monotherapy to mother and infant Zidovudine monotherapy to mother and infantNevirapine + zidovudine to mother and infantZidovudine + lamivudine to mother and infant

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National PMTCT Drug Regimen to the Mother Regimen to the Baby

Antepartum Intrapartum

1) Nevirapine

200 mg po at onset of labor

^^2 mg/kg po single dose within 72 hours postpartum x1

2) Zidovudine

300 mg po BID from 36 weeks onwards

300 mg po every 3 hours

4 mg/kg BID po for 7 days beginning at 8-12 hours postpartum

600 mg at onset of labor then 300 mg every 3 hours**

Same as above

3) Combination of zidovudine and nevirapine as above

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National PMTCT (2)

Drug Regimen to the Mother Regimen to the Baby

Antepartum Intrapartum

4) Zidovudine

&

300 mg po BID

from 36 weeks onwards

&

600 mg po at onset of labor, then 300 po mg every 3 hours

&

4 mg/kg po BID for 7 days

&

Lamivudine 150 mg po BID from 36 weeks onwards

150 mg at onset of labor then 150 mg every 12 hours

2 mg/kg po BID for 7 days, both beginning within 72 hours postpartum

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Nevirapine Reduces Transmission During Birth by 41%

No intervention

17 infected during birth17 infected during birth5 infected in utero5 infected in utero11 infected during BF11 infected during BF67 not infected67 not infected

10 infected during birth*10 infected during birth*5 infected in utero5 infected in utero11 infected during BF11 infected during BF74 not infected74 not infected

Single dose NVP to mother and baby*

Source: Adapted from Lancet 2003;362:859-68

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Intrapartum Nevirapine

Single dose (200 mg) to mother in laborRapidly absorbedMay rapidly reduce mother’s viral load in blood and

birth canalNVP crosses placenta and enters babyNVP provides prophylaxis to the baby during the birthNo side effects with single dose (hepatotoxicity or

rash)

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Postpartum Nevirapine

Single dose (2 mg/kg, 0.2 ml/kg) to newborn 48-72 hours after birthMaintains therapeutic levels in baby’s bloodstream for

the first week of lifeActs as post-exposure prophylaxisNo side effects with single doseIf mother received her dose of NVP less than 2 hours

prior to delivery, give one dose of NVP to baby at birth and a second dose at 48-72 hrs

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Antiretroviral Resistance with Nevirapine

Following single-dose NVP, resistance mutations present 6 weeks postpartum in 20-30% of women46% of infants

No longer detectable 12 months postpartum (due to reappearance of wild type virus). Mutant virus archived indefinitely

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Antiretroviral Resistance with Nevirapine (2)

Following single-dose intrapartum NVP, some mothers have a decreased response to NVP-based HAARTProblem is the greatest if HAART is given within a few

months of single-dose NVP

Risk of NVP resistance appears greatly increased with second maternal dose

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Postpartum NVP levels (HPLC)

Days post dose

NVP (ng/ml)

50

100

150

200

250

5 10 15 20

Undetectable

(NVP IC50 =3-30 ng/ml)

Source: G. Jourdain et al. 11th CROI, San Francisco, CA, 2004. Abstract 41LB

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3 and 6 Month Responders (50 copies/mL)

Copyright © 1998 Massachusetts Medical Society. All rights reserved. Source: Jordain et al., NEJM 2004; 351: 229-240

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Addition of Short-course ZDV/3TC to Single-dose NVP for MTCT Prophylaxis

Interim analysis of 61 mothers (target = 300) with 6 weeks of resistance data

No NNRTI resistance at baseline in any group NVP resistance at Week 6

NVP alone 60%NVP plus combivir 10%

• NVP + ZDV/3TC x 4 d12.0%

• NVP + ZDV/3TC x 7 d10%

No 184V or NRTI resistance detected

McIntyre J, et al. XV IAC, Bangkok 2004, #LBOrB09

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ARV Therapy: HAART

Results in the lowest risk of transmission to the infant (<2%)

Reduces the risk of the mother developing resistance, thereby preserving her future treatment options

Improves maternal immune status, improving survival

Risks to infant appear to be minimal for most regimens

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Safety of NRTI Drugs in Pregnancy

Balance between PMTCT and therapy for mother vs. potential teratogenicity, toxicity, and drug resistance

Human pregnancy data only for AZT, 3TC, ddI, d4T

No increase in birth defects have been observed NRTIs and mitochondrial toxicity: symptomatic

lactic acidosis and hepatic steatosis may have a female preponderance

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Safety of NRTI Drugs in Pregnancy (2)

Fatal lactic acidosis described in pregnant women receiving ddI/d4T along with other ART

ddI/d4T SHOULD NOT BE USED IN PREGNANT WOMEN

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Safety of NNRTIs in Pregnancy

Single dose nevirapine has not been associated with adverse side effects in women and childrenNevirapine resistance risk as aboveNevirapine elimination may be accelerated in infants

whose mother received chronic nevirapine as part of ART. Significance?

No human pregnancy data on long term use of NNRTIs

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Safety of NNRTIs in Pregnancy (2)

Efavirenz causes birth defects in exposed newbornsSignificant birth defects in 15% of newborn monkeysBirth defects reported in newborn humans

Efavirenz should never be used in the first trimester

Efavirenz is best avoided entirely during pregnancy

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Safety of PIs in Pregnancy

Studies of blood levels and safety during pregnancy in progress for:IndinavirRitonavirSaquinavirNelfinavir

Studies in progress forLopinavir/ritonavir (Kaletra) Amprenavir or fosamprenavir Atazanavir

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Combination ART and Pregnancy Outcome

Development of typical adverse symptoms is common

May increase risk of pre-term deliveries Combination therapy started before pregnancy

may carry a higher risk of teratogenicity than starting in the 2nd or 3rd trimester

Until more information is known, HIV-infected pregnant women who are receiving a successful combination ART regimen should continue (unless on efavirenz or ddI/d4T)

Labor and Delivery Care

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Labor and Delivery Care

To facilitate an opportunity for PMTCT:Offer HIV testing for women in laborIf a woman accepts an HIV test, provide counseling

and rapid test

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Labor and Delivery Care (2)

Critical issues during laborEmotional supportConfidentiality Secrecy, disclosureFear and concern about transmission

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Labor and Delivery Care (3)

Do: Use partogram Perform vaginal cleansing

with 0.25% chlorhexidine Follow universal precautions

to avoid occupational exposure

Limit vaginal examinations during labor

Treat acute chorioamnionitis Perform early infant eye and

cord care

Don’t: Isolate Shave pubic area Perform routine episiotomy Rupture membranes Use vacuum extraction

and forceps if not indicated

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Cesarean Section (CS)

Reduces the risk of MTCT Not available and safe in many settings Not routinely performed for women with HIV

infection in developing countries Risks of morbidity associated with CS needs to

be carefully balanced with risk of MTCT

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Postnatal Care of Mother

Routine postnatal care Infant follow-up Close monitoring for secondary postpartum

hemorrhage Early recognition and treatment of infections Continue on HAART if patient is eligible (if on

HAART while pregnant) Commence on HAART if patient is eligible (if

HAART was not started while pregnant)

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Postnatal Care of Mother (2)

Extra nutrition and micronutrient support Counseling about safe disposal of infectious

soiled pads or other garments Family planning counseling Infant feeding counseling Social support

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Family Planning

Discuss family planning BEFORE discharge Assess risk behaviors and counsel on suitable

and effective methods Review birth control and infection control

Dual protection to prevent and reduce further HIV infection, STIs and pregnancy

Data suggests hormonal contraception is less effective with ARVs

Access to emergency contraception

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Infant Follow-up Schedule

Follow-up at 6 hours, 6 days, 6 weeks, and every 3 months

Do full reassessment, and reclassification for HIV at each visit

Virological testing after 6 weeks Cotrimoxazole prophylaxis to all exposed infants

Case Studies: PMTCT

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Case 1 – Introduction

A pregnant 22-year-old woman with previously diagnosed HIV infection comes for her first antenatal clinic visit. She is in her first trimester of her first pregnancy. No other complaints.

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Case 1 Questions

1. What information do you need from her history and physical, in addition to the usual information collected in the antenatal clinic?

2. What laboratory tests will you request?

3. What education and counseling will you provide while you wait for the results of the laboratory tests?

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Answers: Case 1, Q1

1. What information do you need from her history and physical, in addition to the usual information collected in the antenatal clinic?

Why did she have an HIV test initially? Has she disclosed her HIV status to anyone? Has she had any HIV-related illness or

treatment?

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Answers: Case 1, Q1 (2)

Do a review of HIV-related symptoms and OIs Perform a full physical exam including

assessment for STIs Do gynecological and obstetric evaluation Stage the patient and decide on ART eligibility

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Answers: Case 1, Q2

2. What laboratory tests will you request? Confirm or repeat HIV test If available, measure CD4+ count and VL RPR and other assessment for STI Other usual antenatal testing Other ARV-related testing if otherwise eligible

for combination ARV treatment (CBC, AST, ALT)

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Answers: Case 1, Q3

3. What education and counseling will you provide while you wait for the results of the laboratory tests?

Education and counseling on safe sex practices during pregnancy

You, or the counselor in clinic, may discuss with her issues about disclosure of her status to her husband/sexual partner. Ask what kind of support she has

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Answers: Case 1, Q3 (2)

Counsel on risk of MTCT. Explain about use of ARVs to reduce the risk for her newborn. Explain you will do blood tests to see if she needs ART for her own health

Educate on adequate nutrition and prenatal care Counseling regarding infant feeding options

should begin during antenatal care

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Case 2 – Introduction

A 29-year-old woman in her third pregnancy, delivered a healthy 3.5 kg baby girl an hour after she arrived at the maternity.

After the birth, she told the staff she had a positive HIV test done in clinic, but did not take the tablet given her before rushing to the maternity because she did not want her family to know about her HIV infection

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Case 2 Questions

1. What treatment does she require now?

2. What treatment does her baby require?

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Answers: Case 2, Q1

1. What treatment does she require now? Treating Sara so as to reduce the risk of

intrapartum HIV transmission is no longer an option

Sara will need a follow-up visit to assess her immunologic status and to determine if she needs HAART for her own health

Needs counseling on disclosure issues Needs counseling on family planning

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Answers: Case 2, Q2

2. What treatment does her baby require? The infant has not had any nevirapine exposure, as

Rosa did not take nevirapine at least 2 hours prior to delivery

The infant requires nevirapine 2 mg/kg: First dose within 6 hours post-partum Second dose 48-72 hours post-partum

OR NVP one dose plus AZT syrup for 6 weeks

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Case 3 – Introduction

A 21 year-old woman presents to the clinic with pain in her mouth and chest upon swallowing. She has had night sweats and diarrhea for one month. Her usual weight was 58 kg

On exam she weighed 51 kg, had no palpable lymph nodes, and had oral candidiasis. She was diagnosed with presumed esophageal candidiasis and treated with oral fluconazole for 3 weeks. Her pain subsided and she began to eat

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Case 3 – Introduction (2)

Based on the esophageal candidiasis, she had WHO Stage IV disease, although no CD4 count was available.

She began daily cotrimoxazole for opportunistic infection prophylaxis. She was started on first line HAART with stavudine 30 mg bid, lamivudine 150 mg bid, and nevirapine with the usual dose escalation over 2 weeks.

She has been adherent with her medications. The night sweats and diarrhea have stopped, her appetite has increased, and she gained 6 kg

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Case 3 – Introduction (3)

At her 6-month follow-up visit she reports that her menstrual period is 2 months late. A pregnancy test is positive

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Case 3 Questions

1. Should she continue her antiretroviral therapy?

2. How will you manage her intrapartum care?

3. How will you treat her after her delivery?

4. How will you treat her newborn?

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Answers: Case 3, Q1

1. Should she continue her ART? She is doing well on a standard ARV regimen,

which is safe in pregnancyDoes not include efavirenz or ddI+d4T

She is still in her first trimester of pregnancy, so risks to her fetus are uncertain

Options:Discontinue ARV until 10-12 weeksContinue current ART

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Answers: Case 3, Q2

2. How will you manage her intrapartum care? Practice safe obstetric procedures ART Option 1: (most practical)

Continue stavudine, lamivudine, nevirapine as usual

ART Option 2: Give zidovudine, lamivudine, nevirapine at standard

doses

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Answers: Case 3, Q2 (2)

ART Option 3Zidovudine 600 mg loading dose by mouth followed

by 300 mg by mouth every 3 hours till deliveryLamivudine 150 mg by mouth every 12 hoursNevirapine 200 mg twelve hours daily as she used to

take it

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Answers: Case 3, Q3

3. How will you treat her after her delivery? She can resume her usual antiretroviral

combination after delivery She should be counseled on infant feeding

There is no information so far on the effects of maternal ART on risks of HIV transmission through breast milk

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Answers: Case 3, Q4

4. How will you treat her newborn? Nevirapine syrup 2 mg/kg at 48-72 hours of life

as usual for HIV-exposed infants plus AZT syrup for 4- 6 weeks

Infant starts cotrimoxazole at 6 weeks Explain testing of infant at 18 months

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Key Points

Women are more vulnerable to HIV due to biological, economic, social, and cultural factors

Women with HIV have special gynecological needs and concerns

Women and men with HIV progress at similar rates; ART guidelines are not gender specific

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Key Points (2)

All pregnant women should know their HIV status in order to protect their children and themselves

Women with AIDS are more likely to suffer from pregnancy-related complications

Pregnant women who present with CD4 <200/mm3 irrespective of WHO stage should be started on first line treatment: AZT, 3TC, NVP

98

Key Points (3)

Pregnant women should not receive efavirenz or ddI/d4T

Effective strategies are available for reducing the risk of MTCT

Nevirapine can reduce the risk of MTCT by 41% Use of HAART can reduce MTCT to less than

2%