Download U.S. Public Health Service Perinatal Guidelines

Recommendations for Use of Antiretroviral Drugs in
Pregnant HIV-1-Infected Women for Maternal Health and
Interventions to Reduce Perinatal HIV Transmission
in the United States
HHS Panel on the Treatment of HIV-infected Pregnant Women and
Prevention of Perinatal Transmission – A Working Group of the Office of AIDS
Research Advisory Council
AETC NRC Slide Set
About This Presentation
 These slides were developed from the March 28, 2014,
revisions to the guidelines.
 The goal of the guidelines is to provide guidance to HIV
care practitioners. Because the field of HIV care is
changing rapidly, users of this slide set are advised to
check http://aidsinfo.nih.gov/guidelines/html/3/perinatalguidelines/0 for updates.
 It is intended that these slides be used as prepared,
without changes in either content or attribution. Users are
asked to honor this intent.
 AETC National Resource Center
2
March 2014
Table of Contents
Topic



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

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3
Introduction
Pre-Conception Counseling
Antepartum Care
Intrapartum Care
Postpartum Care
Care of the Neonate
Lessons Learned from Clinical Trials
Slide Number
4
6
24
106
116
122
145
March 2014
Introduction (1)
 Providers considering the use of antiretrovirals (ARVs)
for HIV-infected women during pregnancy must take into
account:
 ARV treatment (ART) for maternal HIV infection; and
 ARV chemoprophylaxis to reduce the risk of perinatal
transmission of HIV
 With universal prenatal HIV counseling and testing,
preconception care, ARV prophylaxis, scheduled Csection delivery (if indicated), and avoidance of breastfeeding, perinatal HIV infection has diminished to <2% in
the United States.
4
March 2014
Introduction (2)
Recommendations in these guidelines are based on
scientific evidence and expert opinion and are rated using
the system below:
Strength of
Recommendation
A: Strong
B: Moderate
C: Optional
Quality of Evidence
I: One or more randomized trials with
clinical outcomes and/or validated
laboratory end points
II: One or more well-designed,
nonrandomized trials or observational
studies with long-term clinical outcomes
III: Expert opinion
5
March 2014
PRECONCEPTION
COUNSELING AND CARE FOR
HIV-INFECTED WOMEN OF
CHILDBEARING AGE
Preconception Counseling and Care (1)
 Comprehensive family planning and
preconception care is part of routine primary
care and is recommended by CDC, ACOG,
and other national organizations.
 Purpose:
 Prevention of unintended pregnancies
 Optimization of maternal health prior to
pregnancy
 Prevention of perinatal transmission
 Prevention of HIV transmission to an
uninfected partner while trying to conceive
7
March 2014
Preconception Counseling and Care (2)
Recommendations
 Discuss childbearing intentions with all women of
childbearing age on an ongoing basis throughout
the course of their care. (AIII)
 Include information about effective and appropriate
contraceptive methods to reduce the likelihood of
unintended pregnancy. (AI)
8
March 2014
Preconception Counseling and Care (3)
 During preconception counseling, include
information on safer sexual practices and
elimination of alcohol, illicit drugs, and smoking,
which are important for the health and of all women
as well as for fetal/infant health, should pregnancy
occur. (AII)
 All HIV-infected women contemplating pregnancy
should be on a maximally suppressive antiretroviral
regimen. (AII)
9
March 2014
Preconception Counseling and Care (4)
 When selecting or evaluating combination
(cART) for HIV-infected women of childbearing
age, consider the following (AII):
 A regimen’s effectiveness
 Hepatitis B virus disease status
 Teratogenic potential of the drugs in the cART
regimen, should pregnancy occur
 Possible adverse outcomes for the mother and
fetus
10
March 2014
Preconception Counseling and Care (5)
 Women who do not desire pregnancy should be offered
contraception.
 All available methods can be used, including
hormonal contraception and intrauterine devices.
 Interactions between some ARVs and hormonal
contraceptives may lower contraceptive efficacy
 Emergency contraception can be used as appropriate ̶
either pills or copper IUD
 Again, be aware of potential interactions with ARVs that could
lower contraceptive efficacy
 Interactions between ARVs and ulipristal acetate have not been
defined but are likely
11
March 2014
Drug Interactions between ARVs and Hormonal
Contraceptives (CIII) (1)
NNRTIs:
ARV
Drug
Recommendation for
Combined Hormonal
Methods and
Progestin-Only Pills
Recommendation
for DMPA
Recommendation for
Etonogestrel Implants
EFV
Use alternative or
additional contraception
No additional
contraceptive needed
Use alternative or
additional contraception
ETR
No additional
contraceptive needed
No additional
contraceptive needed
No additional
contraceptive needed
NVP
Consider alternative
contraceptive, or barrier
+ oral hormonal methods
No additional
contraceptive needed
Consider alternative
contraceptive, or
barrier + implant
RPV
No additional
contraceptive needed
No additional
contraceptive needed
No additional
contraceptive needed
12
March 2014
Drug Interactions between ARVs and Hormonal
Contraceptives (CIII) (2)
RTV-Boosted PIs:
ARV
Drug
Recommendation for
Combined Hormonal
Methods and
Progestin-Only Pills
Recommendation for
DMPA
Recommendation
for Etonogestrel
Implants
ATV/r
Use alternative or
additional contraception
No additional
contraceptive needed
Consider alternative
contraceptive, or
barrier + implant
DRV/r
Use alternative or
additional contraception
No additional
contraceptive needed
No additional
contraceptive needed
FPV/r
Use alternative or
additional contraception
No additional
contraceptive needed
Consider alternative
contraceptive, or
barrier + implant
LPV/r
Use alternative or
additional contraception
No additional
contraceptive needed
Consider alternative
contraceptive, or
barrier + implant
13
March 2014
Drug Interactions between ARVs and Hormonal
Contraceptives (CIII) (3)
RTV-Boosted PIs:
ARV
Drug
Recommendation for
Combined Hormonal
Methods and ProgestinOnly Pills
Recommendation for
DMPA
Recommendation for
Etonogestrel Implants
SQV/r
Use alternative or
additional contraception
No additional
contraceptive needed
Consider alternative
contraceptive, or barrier +
implant
TPV/r
Use alternative or
additional contraception
No additional
contraceptive needed
Consider alternative
contraceptive, or barrier +
implant
14
March 2014
Drug Interactions between ARVs and Hormonal
Contraceptives (CIII) (4)
PIs without RTV:
ARV
Drug
ATV
Recommendation for Combined
Hormonal Methods and ProgestinOnly Pills
Recommendation
for DMPA
Recommendation
for Etonogestrel
Implants
No additional contraceptive needed
No additional
contraceptive
needed
No additional
contraceptive
needed
No additional
contraceptive
needed
Use alternative or
additional
contraception
•
•
FPV
OC should contain ≤30 μg ethinyl
estradiol (EE), or use alternative
method
No data on OCs with <25 μg EE or
progestins other than norethindrone or
norgestimate
Use alternative contraception
(use with estradiol/norethindrone may
cause virologic failure)
15
March 2014
Drug Interactions between ARVs and Hormonal
Contraceptives (CIII) (5)
PIs without RTV:
ARV
Drug
Recommendation for
Combined Hormonal
Methods and Progestin-Only
Pills
Recommendation
for DMPA
Recommendation
for Etonogestrel
Implants
IDV
No additional contraceptive
needed
No additional
No additional
contraceptive needed contraceptive needed
NFV
Use alternative or additional
contraception
No additional
Use alternative or
contraceptive needed additional
contraception
16
March 2014
Drug Interactions between ARVs and Hormonal
Contraceptives (CIII) (6)
Integrase Inhibitors:
ARV Drug
Recommendation for
Combined Hormonal
Methods and
Progestin-Only Pills
Recommendation for
DMPA
Recommendation for
Etonogestrel Implants
RAL
DTG
No additional
contraceptive needed
No additional
contraceptive needed
No additional
contraceptive needed
EVG/COBI
CCR5 Antagonist:
All categories: No additional contraceptive needed
17
March 2014
Reproductive Options for HIV-Concordant and
Serodiscordant Couples (1)
For both concordant (both partners are HIV
infected) and discordant couples:
 Expert consultation is recommended so that approaches
can be tailored to specific needs, which may vary from
couple to couple. (AIII)
 Partners should be screened for genital tract infections.
(AII)
 The HIV-infected partner should attain maximum viral
suppression before attempting conception. (AIII)
18
March 2014
Reproductive Options for HIV-Concordant
and Serodiscordant Couples (2)
For discordant couples:
 cART for the infected partner may not be fully protective
against sexual transmission of HIV.
 Periconception administration of antiretroviral preexposure
prophylaxis (PrEP) for HIV-uninfected partners may offer an
additional tool to reduce the risk of sexual transmission.
(CIII) The utility of PrEP for the uninfected partner when the
infected partner is receiving cART and has a suppressed
viral load has not been studied.
19
March 2014
Reproductive Options for HIV-Concordant
and Serodiscordant Couples (3)
Discordant couples with HIV-infected female:
 The safest conception option is artificial
insemination, including the option of selfinsemination with a partner’s sperm during the
periovulatory period. (AIII)
20
March 2014
Reproductive Options for HIV-Concordant
and Serodiscordant Couples (4)
Discordant couples with HIV-infected male:
 The use of donor sperm from an HIV-uninfected male with
artificial insemination is the safest option.
 When the use of donor sperm is unacceptable, the use of
sperm preparation techniques coupled with either
intrauterine insemination or in vitro fertilization should be
considered. (AII)
 Semen analysis is recommended for HIV-infected males
before conception is attempted to prevent unnecessary
exposure to infectious genital fluid when the likelihood of
getting pregnant is low because of semen abnormalities.
(AIII)
21
March 2014
Reproductive Options for HIV-Concordant
and Serodiscordant Couples (5)
 Periconception PrEP
 Very few data to date on periconception PrEP; studies
under way
 Infected partner should be on ART with fully suppressed
HIV viral load
 Only combination tenofovir/emtricitabine is currently being
studied in heterosexual PrEP trials
 Couples should use condoms at all times except during
periovulatory intercourse
 No reported increase in congenital anomalies for children
whose mothers were exposed to tenofovir or emtricitabine
during pregnancy
Review Table 4 “Clinical Trials of PrEP” for more information
22
March 2014
Reproductive Options for HIV-Concordant
and Serodiscordant Couples (6)
 Laboratory testing for HIV infection, baseline
renal function, and chronic HBV infection should
be performed before initiating PrEP.
 HBV-uninfected individuals should be vaccinated.
 Monitor for potential side effects such as renal
dysfunction and clinical toxicities.
 Frequent testing of HIV-uninfected partner; if result is
HIV positive, discontinue PrEP to minimize drug
resistance and refer for treatment.
23
March 2014
ANTEPARTUM CARE
Principles of ARV Use during Pregnancy (1)
 Initial evaluation of HIV-infected pregnant women should
include assessment of HIV disease status and
recommendations regarding initiation or modification of
cART. (AIII)
 All pregnant women should receive ART to prevent perinatal
transmission regardless of HIV RNA and CD4 levels. (AI)
 Combined antepartum, intrapartum, and infant ARV
prophylaxis is recommended because ARV drugs reduce
perinatal transmission by several mechanisms, including
lowering maternal antepartum viral load and providing infant
pre- and postexposure prophylaxis. (AI)
25
March 2014
Principles of ARV Use during Pregnancy (2)
 The known benefits and potential risks of ARV use during
pregnancy should be discussed with all HIV-infected women.
(AIII)
 In counseling patients, the importance of adherence to their
ARV regimens should be emphasized. (AII)
 ARV drug-resistance studies should be performed before
starting or modifying ARV drug regimens in women whose
HIV RNA is above the threshold for resistance testing. (AIII)
 When HIV is diagnosed later in pregnancy, cART should be
initiated promptly without waiting for results of resistance testing
(BIII)
*see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy
26
March 2014
Principles of ARV Use during Pregnancy (3)
 Coordination of services among prenatal care
providers, primary care and HIV specialty
care providers, and when appropriate, mental
health and drug abuse treatment services,
and public assistance programs, is essential
to ensure that infected women adhere to their
ARV drug regimens. (AIII)
27
March 2014
Clinician Consultation Center
(formerly the National Perinatal HIV Hotline)
(1-888-448-8765)
For free clinical consultation for providers caring
for HIV-infected women and their infants
28
August 2012
March 2014
General Principles of Drug Selection
 Guidelines for use of cART for maternal health during pregnancy
generally are the same as for women who are not pregnant
 Some modifications based on concerns about specific ARVs during
pregnancy
 Consider benefits vs risks of ARV drug use during pregnancy
 Ensure that at least 1 NRTI with high placental transfer is included in
cART regimen for sufficient infant preexposure prophylaxis
 Counsel women on the importance of close adherence to ARV
regimen
 Offer support services, mental health services, smoking cessation,
and drug abuse treatment plans as indicated
 Coordinate between HIV and OB specialists
29
March 2014
Teratogenicity (1)
 All cases of ARV drug exposure during pregnancy should
be reported to the Antiretroviral Pregnancy Registry at:
http://www.APRegistry.com. (AIII)
 Efavirenz (EFV):
 Nonpregnant women of childbearing potential should
undergo pregnancy testing before initiation of EFV and
receive counseling about the potential risk to the fetus and
desirability of avoiding pregnancy while on EFV-containing
regimens. (AIII)
 Alternative ARV regimens that do not include EFV should be
strongly considered in women who are planning to become pregnant
or are sexually active and not using effective contraception,
assuming these alternative regimens are acceptable to the provider
and are not thought to compromise the woman’s health. (BIII)
30
March 2014
Teratogenicity (2)
 Because the risk of neural tube defects is restricted to the
first 5-6 weeks of pregnancy and pregnancy is rarely
recognized before 4-6 weeks of pregnancy, and
unnecessary changes in ARV drugs during pregnancy may
be associated with loss of viral control and increased risk of
perinatal transmission, EFV can be continued in pregnant
women receiving an EFV-based regimen who present for
antenatal care in the first trimester, provided the regimen
produces virologic suppression. (CIII)
31
March 2014
Teratogenicity (3)
 Tenofovir:
 No known teratogenicity
 Possible decrease in length and head circumference
following in utero exposure
 Folate antagonists (eg, TMP-SMX) may have
increased risk of birth defects during firsttrimester use
32
March 2014
Nevirapine and Hepatic/Rash Toxicity (1)
 Nevirapine (NVP)-based regimens should be
initiated in women with CD4 counts >250 cells/µL
only if the benefits outweigh the risks because of
the drug’s potential for causing hepatic
toxicity/hypersensitivity reaction. (AII)
 Women who become pregnant while receiving
NVP-containing regimens and who are tolerating
the regimen can continue regardless of CD4
count. (AII)
33
March 2014
Nevirapine and Hepatic/Rash Toxicity (2)
 Non-NVP ARVs should be considered for
women with preexisting liver disease.
 Data from 3,582 pregnant women in 20 studies
did not find evidence of increased risk of NVPrelated events compared with nonpregnant
women.
34
March 2014
NRTI Drugs and Mitochondrial Toxicity
 The combination of stavudine (d4T) and didanosine (ddl)
should not be prescribed during pregnancy because of
reports of lactic acidosis and maternal/neonatal mortality
with prolonged use in pregnancy. (AII)
 Mitochondrial dysfunction should be considered in
uninfected children with perinatal exposure to ARV drugs
who present with severe clinical findings, particularly
neurological. (AII)
 Long-term clinical follow-up is recommended for any
child with in utero exposure to ARV drugs. (AIII)
35
March 2014
Combination ARV Drug Regimens and
Pregnancy Outcome
 Clinicians should be aware of a possible
small increased risk of preterm birth in
pregnant women receiving protease inhibitor
(PI)-based ART; however, given the clear
benefits of such regimens for both a women’s
health and prevention of perinatal
transmission, PIs should not be withheld for
fear of altering pregnancy outcome. (AII)
36
March 2014
Recommendations for Use of ARVs during
Pregnancy
 In general, the same regimens as recommended for treatment of
nonpregnant adults should be used in pregnant women unless there are
known adverse effects for women, fetuses, or infants that outweigh
benefits. (AIII)
 Multiple factors must be considered when choosing a regimen for a
pregnant woman including comorbidities, convenience, adverse effects,
drug interactions, resistance testing results, pharmacokinetics (PK), and
experience with use in pregnancy. (AII)
 PK changes may lead to lower plasma drug levels of drugs and
necessitate increased dosages, more frequent dosing, or boosting,
especially of protease inhibitors. (AII)
37
March 2014
ART for Pregnant Women
 All HIV-infected pregnant women should receive
a potent combination ARV) regimen to reduce
the risk of perinatal transmission of HIV. (AI)
 The choice of regimen should take into account current
adult treatment guidelines, what is known about the use
of specific drugs in pregnancy, and the risk of
teratogenicity.
 Reducing HIV RNA to undetectable levels lowers the risk
of perinatal transmission, lessens the need for elective Csection to reduce risk of HIV transmission, and reduces
risk of ARV drug resistance in the mother.
38
March 2014
ART for Pregnant Women (2)
 The decision as to whether to start the regimen
in the first trimester or delay until 12 weeks’
gestation will depend on CD4 count, HIV RNA
levels, and maternal conditions. (AIII)
 Earlier initiation of a combination ARV regimen may
be more effective in reducing transmission, but
benefits must be weighed against potential fetal
effects of first-trimester drug exposure.
 Fetuses are most susceptible to potential teratogenic effects
in the first trimester.
 Although most transmission occurs late in pregnancy or
during delivery, recent analyses suggest that early control of
viral replication may be important.
39
March 2014
ART for Pregnant Women (3)
 ARV drug-resistance studies should be
performed before starting the ARV regimen if
HIV RNA is above the threshold for resistance
testing unless drug-resistance studies have
already been performed. (AI)
 If HIV is diagnosed later in pregnancy, the ARV
regimen should be initiated promptly without
waiting for the results of resistance testing. (BIII)
40
March 2014
ART for Pregnant Women (4)
 If there is no evidence of resistance, combination ARV
regimens that are preferred for the treatment of ARTnaive HIV-infected pregnant women include: a dual NRTI
combination (abacavir/lamivudine, tenofovir/emtricitabine
or lamivudine, or zidovudine/lamivudine) and either a
ritonavir-boosted protease inhibitor (ritonavir-boosted
atazanavir or ritonavir-boosted lopinavir) or an NNRTI
(efavirenz initiated after 8 weeks of pregnancy). (AIII)
* Refer to Antiretroviral Drug Resistance and Resistance Testing in
Pregnancy
41
March 2014
ART for Pregnant Women (5)
 cART regimens should include at least 3 ARVs,
as in nonpregnant adults
 Generally, 2 NRTIs + 1 ritonavir-boosted PI or 2
NRTIs + 1 NNRTI
 Individualize ARVs based on factors such as:






42
Woman’s ARV history
Possible ARV resistance
Comorbidities
PK changes in pregnancy, placental ARV transfer
Potential adverse effects on woman and on fetus
Experience in pregnancy
March 2014
ART for Pregnant Women (6)
 Preferred Drugs or Drug Combinations
 Clinical trial data in adults have demonstrated
optimal efficacy and durability with
acceptable toxicity and ease of use
 Pregnancy-specific PK data are available to
guide dosing
 No established association with teratogenic
effects or clinically significant adverse
outcomes for mothers, fetuses, or newborns
 Some recommended ARVs may have toxicity in
animal studies that has not been verified in
humans
43
March 2014
Initial ART for ARV-Naive Pregnant Women (1)
Preferred 2-NRTI Backbone Regimens
Comments
ABC/3TC
• Potential HSR: ABC should not be used in
patients who test positive for HLA-B*5701
• Available as FDC, can be given once daily
TDF/FTC or TDF +
3TC
• Can be administered once daily
• TDF has potential renal toxicity, use with
caution in patients with renal insufficiency
ZDV/3TC
• Most experience for use during pregnancy
• Twice-daily administration
• Higher risk of hematologic toxicity
44
March 2014
Initial ART for ARV-Naive Pregnant Women (2)
Preferred PI Regimens
Comments
ATV/r + preferred 2-NRTI • Once daily
backbone
LPV/r + preferred 2-NRTI • Twice-daily administration.
• Once-daily LPV/r not recommended
backbone
during pregnancy
45
March 2014
Initial ART for ARV-Naive Pregnant Women (3)
Preferred NNRTI Regimen
Comments
EFV + preferred 2-NRTI
backbone
Note:
May be initiated after the first 8 weeks
of pregnancy
46
• Birth defects in primates; risk in
humans is unclear
• Postpartum contraception must
be ensured
• Preferred regimen in women
requiring coadministration of
drugs with significant
interactions with PIs
March 2014
Initial ART for ARV-Naive Pregnant Women (4)
Alternative Regimens:
Clinical trial data demonstrate efficacy in adults
but experience in pregnancy is limited, data are
lacking or incomplete on teratogenicity, or
regimen is associated with dosing, formulation,
toxicity, or interaction issues
47
March 2014
Initial ART for ARV-Naive Pregnant Women (5)
Alternative PI Regimens
Comments
DRV/r + preferred 2NRTI backbone
• Less experience with use during
pregnancy than ATV/r and LPV/r
SQV/r + preferred 2NRTI backbone
• Baseline ECG recommended initiation
of SQV/r: potential PR and QT
prolongation; contraindicated with
preexisting cardiac conduction system
disease
• Large pill burden
48
March 2014
Initial ART for ARV-Naive Pregnant Women (6)
Alternative NNRTI Regimen
Comments
NVP + preferred 2NRTI backbone
• Caution with initiating NVP in women
with CD4 >250 cells/µL
• Caution when starting NVP and ABC
together: both can cause HSRs within
the first few weeks after initiation
Alternative Integrase Inhibitor Regimen
Comments
RAL + preferred 2NRTI backbone
49
• Limited data on RAL use in pregnancy;
may be considered when drug
interactions with PI regimens are a
concern
March 2014
Initial ART for ARV-Naive Pregnant Women (7)
Insufficient Data to Recommend:
Drugs and drug combinations are approved for use
but lack sufficient pregnancy-specific PK or safety
data
Not Recommended:
Inferior virologic response, potentially serious
maternal or fetal safety concerns, or PK
antagonism, or not recommended for ARV-naive
nonpregnant populations
50
March 2014
Initial ART for ARV-Naive Pregnant Women (8)
Insufficient Data to Recommend Routine Use
DTG
EVG/COBI/TDF/FTC
FPV/r
MVC
RPV
Not Recommended
ABC/3TC/ZDV
RTV as single PI
d4T
ETR
ddI
T-20
IDV/r
TPV
NFV
51
March 2014
Individual ARVs: Nucleoside and Nucleotide
Reverse Transcriptase Inhibitors (1)
Comments on Use during Pregnancy
Abacavir
(ABC)
PK not significantly altered. High placental transfer. No evidence
of teratogenicity.
Hypersensitivity reactions occur in 5-8% of nonpregnant
women; much smaller percentage are fatal and usually
associated with rechallenge. Testing for HLA-B*5701 identifies
patients at risk; conduct before starting ABC, do not give if
positive.
Didanosine PK not significantly altered. Low-moderate placental transfer.
(ddl)
Do not use with d4T; may cause lactic acidosis and death if
used together. Increased rate of birth defects compared with
general population noted after 1st trimester and later exposure.
52
March 2014
Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors (2)
Comments on Use during Pregnancy
Emtricitabine PK not significantly altered. High placental transfer. No
evidence of teratogenicity.
(FTC)
Active against HBV; if hepatitis B (HBV) coinfected, flare
may occur if drug stopped.
Lamivudine
(3TC)
PK not significantly altered. High placental transfer. No
evidence of teratogenicity.
Active against HBV; if HBV coinfected, flare may occur if
drug stopped.
Stavudine
(d4T)
PK not significantly altered. High placental transfer. No
evidence of teratogenicity.
Do not use with ddl or ZDV; may cause lactic acidosis
or death if used together.
March 2014
53
Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors (3)
Comments on Use during Pregnancy
Tenofovir Disopril
Fumarate
(TDF)
Preferred NRTI in combination with 3TC or FTC in women
with chronic HBV infection. AUC lower in 3rd trimester;
trough levels adequate. High placental transfer. No
evidence of teratogenicity; in monkeys, decreased fetal
growth and fetal bone porosity. One human study
demonstrated decreased length and head circumference.
Risk of renal toxicity; monitor renal function.
Active against HBV; if HBV coinfected, hepatitis flare may
occur if drug stopped.
Zidovudine
(AZT, ZDV)
54
PK not significantly altered. High placental transfer. No
evidence of teratogenicity.
March 2014
Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs) (1)
Comments on Use during Pregnancy
Efavirenz
(EFV)
AUC decreased in 3rd trimester. Moderate placental transfer.
FDA Pregnancy Class D: CNS or other malformations
observed in 3 of 20 monkeys; 6 human reports + 1 case report
of CNS defects and 1 report of anophthalmia.
• Counsel nonpregnant women on risks and conduct
pregnancy test prior to initiation of EFV.
• Consider alternative regimen in women planning to become
pregnant and those who are sexually active and not using
effective contraception, assuming alternatives are
acceptable to provider and will not compromise health of the
woman.
• Continue EFV in pregnant women receiving and EFV-based
regimen who present for care in 1st trimester if there is
virologic suppression on the regimen.
55
March 2014
Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs) (2)
Comments on Use during Pregnancy
Etravirine
(ETR)
Safety and PK data in pregnancy insufficient; no significant
changes in 4 women. Moderate placental transfer.
Teratogenicity data insufficient in humans; no evidence of
teratogenicity in rats or rabbits.
Nevirapine PK not significantly altered. High placental transfer. No
evidence of teratogenicity.
(NVP)
Increased risk of potentially life-threatening hepatotoxicity
(often rash-associated) in women with high CD4 count at the
time of NVP initiation. If CD4 is >250 cells/µL, start NVP only
if benefit outweighs risk. Elevated transaminase levels at
baseline may also increase risk. Women who become
pregnant while on NVP and are tolerating it well can continue,
regardless of CD4 count.
56
March 2014
Non-nucleoside Reverse Transcriptase
Inhibitors (NNRTIs) (3)
Comments on Use during Pregnancy
Rilpivirine
(RPV)
57
No PK studies in human pregnancy. Unknown
placental transfer and insufficient data to assess for
teratogenicity in humans. No evidence of
teratogenicity in rats or rabbits.
March 2014
Protease Inhibitors (1)
Class concerns for PIs: hyperglycemia, diabetes mellitus, diabetic
ketoacidosis, question of increased risk of preterm delivery
Recommendations for Use during Pregnancy
Atazanavir
(ATV)
Decreased ATV plasma concentrations during pregnancy. Also
reduced when given concomitantly with TDF or H2-receptor
antagonist. Low placental transfer. No evidence of human
teratogenicity.
Must be given with RTV boosting during pregnancy.
Unknown effect of in utero ATV exposure on infant indirect
bilirubin levels; nonpathologic elevations of hyperbilirubinemia
observed in some neonates.
58
March 2014
Protease Inhibitors (2)
Comments on Use during Pregnancy
Darunavir
(DRV)
Limited safety and PK data during pregnancy but some
experts recommend twice-daily dosing. Low placental
transfer. Insufficient data to assess teratogenicity risk in
humans; no evidence of teratogenicity in mice, rats, or
rabbits.
Must be combined with low-dose RTV.
Fosamprenavir AUC reduced during 3rd trimester. Low placental transfer.
Insufficient data to assess teratogenicity risk in humans;
(FPV)
increased fetal loss in rabbits; no increase in defects in
rats and rabbits.
Must be given with RTV boosting during pregnancy.
59
March 2014
Protease Inhibitors (3)
Comments on Use during Pregnancy
Indinavir
(IDV)
Minimal placental transfer. No evidence of human
teratogenicity.
Must be given with RTV boosting during pregnancy.
Theoretical concern regarding increased bilirubin in
neonates.
Ritonavirboosted
lopinavir
(LPV/r)
Low placental transfer. No evidence of human
teratogenicity.
Must be given twice daily during pregnancy, dosage
increase may be needed in 2nd and 3rd trimesters.
Oral solution contains 42% alcohol and 15% propylene
glycol and is not recommended for use during pregnancy.
60
March 2014
Protease Inhibitors (4)
Comments on Use during Pregnancy
Nelfinavir Lower NFV exposure in 3rd trimester. Twice daily dosing.
Minimal to low placental transfer. No evidence of human
(NFV)
teratogenicity.
Contains aspartame, should not be used in individuals with
phenylketonuria.
Ritonavir Recommended only as PK booster for other PIs.
(RTV)
Minimal to low placental transfer. No evidence of human
teratogenicity.
Oral solution not optimal during pregnancy owing to alcohol
content.
61
March 2014
Protease Inhibitors (5)
Comments on Use during Pregnancy
Saquinavir
(SQV)
SQV exposure may be reduced in pregnancy but not
significantly. Low placental transfer. Insufficient data to
assess for teratogenicity in humans; no evidence of
teratogenicity in rats or rabbits.
Must be combined with low-dose RTV boosting.
PR and/or QT interval prolongations have been observed;
baseline ECG recommended before starting.
Contraindicated if cardiac conduction system disease. SQV
contraindicated in patients with preexisting cardiac
conduction system disease. Twice-daily dosing.
Tipranavir
(TPV)
62
No PK data in human pregnancy. Minimal-low placental
transfer.
No data on human teratogenicity.
March 2014
Integrase Inhibitors
Comments on Use during Pregnancy
Dolutegravir
(DTG)
No data in pregnancy; insufficient data to recommend use.
Elvitegravir
plus cobicistat
(EVG/COBI)
No data in pregnancy; insufficient data to recommend use.
Raltegravir
(RAL)
Limited PK data suggest no significant changes in
pregnancy. High placental transfer. Insufficient data to
assess teratogenicity.
63
March 2014
Entry Inhibitors
Comments on Use during Pregnancy
Enfurvirtide
(T-20)
No PK or teratogenicity data. Minimal/low placental
transfer.
Insufficient data to recommend use
Maraviroc
(MVC)
Limited PK data, no teratogenicity data.
Minimal/low placental transfer.
Insufficient data to recommend use
64
March 2014
HIV-Infected Pregnant Women Who Are
Currently Receiving Antiretroviral Therapy (1)
 HIV-infected pregnant women receiving cART who present for
care in the 1st trimester should continue treatment during
pregnancy, assuming the regimen is tolerated and effective in
suppressing viral replication (HIV-1 viral load less than lower
limits of detection of the assay).(AII)
 It is recommended that efavirenz be continued in pregnant
women receiving efavirenz-based cART who present for
antenatal care in the first trimester provided the regimen is
achieving virologic suppression. (CIII)
 HIV antiretroviral drug resistance testing is recommended for
pregnant women who have detectable viremia on therapy. (AI)
 >500-1,000 copies/mL
65
March 2014
HIV-Infected Pregnant Women Who Are
Currently Receiving Antiretroviral Therapy (2)
 Rationale for continuing EFV in pregnancy:
 1st-trimester exposure is not definitely
associated with increased risk of neural tube
defects.
 The risk of neural tube defects is limited to the
first 5-6 weeks of pregnancy, before most
pregnancies are recognized.
 Unnecessary ARV changes during pregnancy
may increase the risk of loss of virologic control
and transmission to infant.
66
March 2014
Pregnant Women Who Are ARV-Experienced
but Not Currently on ARVs (1)
 Obtain an accurate history of all prior ARV regimens used
for treatment of HIV disease or prevention of transmission,
including virologic efficacy, tolerance, results of prior
resistance testing, and any adherence issues. (AIII)
 If HIV RNA is above the threshold for resistance testing (ie,
>500 to 1,000 copies/mL), do ARV drug-resistance studies
before starting ART (see Antiretroviral Drug Resistance and
Resistance Testing in Pregnancy). (AIII)

67
In women who present late in pregnancy, therapy or prophylaxis
should be initiated promptly without waiting for the results of
resistance testing. (BIII)
March 2014
Pregnant Women Who Are ARV-Experienced
but Not Currently on ARVs (2)
 Choose and initiate a combination ARV regimen based on
results of resistance testing and prior history of ART while
avoiding drugs with teratogenic potential or with known
adverse potential for the mother. (AII)
 Consult specialists in treatment of HIV infection about the
choice of a cART regimen for women who previously
received ARV drugs for their own health. (AIII)
 Perform repeat ARV resistance testing (AI), assess
adherence, and consult with an HIV treatment specialist to
guide changes in ARV drugs in women who do not achieve
virologic suppression on their ARV regimens.
68
March 2014
Pregnant Women Who Are ARV-Experienced but
Not Currently on ARVs (3)
 Pregnant women with HIV infection who have
received ARVs previously for prevention of
perinatal transmission:
 Concern that time-limited use may lead to genotypic
resistance and reduced efficacy in subsequent
pregnancies.
 Rates of resistance appear to be low after prophylaxis
with cART.
 NVP prophylaxis may cause resistance and failure of
subsequent NVP-based cART.
 Longer, more complex ARV tails after stopping pregnancylimited NVP appear to reduce risk of resistance.
69
March 2014
Pregnant Women Who Are ARVExperienced but Not Currently on ARVs (4)
 Treatment failure has not been demonstrated
with reinitiation of cART following prophylactic
use of cART in pregnancy.
 Pregnant women with HIV infection who have
received ARVs previously for their own health:
 Choice of ARV regimen may be challenging and will
vary by:





70
History of ART
Indication for stopping treatment
Efficacy of previous ART
Results of past and current resistance testing
Lab testing, including HLA-B*5701
March 2014
Maternal and Fetal Monitoring during
Pregnancy (1)
 More frequent VL monitoring in pregnancy is
recommended to identify women in whom the
decline in VL is slower than expected.
 Viral suppression generally achieved in 12-24
weeks in ARV-naive adherent individuals; rare
cases take longer.
71
March 2014
Maternal and Fetal Monitoring during
Pregnancy (2)
 Monitor VL:
 At the initial visit (AI)
 2-4 weeks after initiating or changing ARV
regimen (BI)
 Monthly until VL is undetectable (BIII)
 At least every 3 months during pregnancy
(BIII)
 VL should also be assessed at approximately
34-36 weeks’ gestation to inform decisions
about mode of delivery (AIII)
72
March 2014
Maternal and Fetal Monitoring during
Pregnancy (3)
 Monitor CD4 count:
 At initial antenatal visit (AI)
 At least every 3 months during pregnancy (BIII)
 Can monitor every 6 months in patients on
stable cART with consistently suppressed VL
and immune reconstitution (CD4 count increase
well above threshold for opportunistic infection
risk) (CIII)
73
March 2014
Maternal and Fetal Monitoring during
Pregnancy (4)
 Genotypic resistance testing should be performed at
baseline in all HIV-infected pregnant women with HIV RNA
levels >500 to 1,000 copies/mL, whether they are ARV
naive or currently on therapy. (AIII)
 However, it is not necessary to repeat a genotype in pregnancy if
the woman already had a genotype prior to pregnancy and was
ARV naive.
 Repeat testing if suboptimal viral suppression on cART or
persistent viral rebound to detectable levels after prior viral
suppression on an ARV regimen. (AII)
74
March 2014
Maternal and Fetal Monitoring during
Pregnancy (5)
 Monitoring for complications of ARV drugs should be based on what is
known about the adverse effects of the drugs a woman is receiving. (AIII)
 Women taking cART during pregnancy should undergo standard glucose
screening at 24-28 weeks’ gestation. (AIII)
 Some experts would perform earlier glucose screening in women
receiving PI-based regimens initiated before pregnancy, similar to
recommendations for women with high risk factors for glucose intolerance.
(BIII)
 Early ultrasound is recommended to confirm gestational age and, if
scheduled cesarean delivery is necessary, to guide its timing. (AII)
75
March 2014
Maternal and Fetal Monitoring during
Pregnancy (6)
 In women on effective cART, no perinatal transmissions
have been reported after amniocentesis, but a small risk
of transmission cannot be ruled out.
 If amniocentesis is indicated, it should be done only after
initiation of an effective cART regimen and, if possible,
when HIV RNA levels are undetectable. (BIII)
 If amniocentesis is deemed necessary with detectable VL,
consult with an expert.
 Consider using cell-free, fetal DNA as a noninvasive
alternative to decrease need for amniocentesis.
76
March 2014
ARV Resistance during Pregnancy (1)
 Drug resistance:
 Is one of the major factors leading to treatment failure
 May limit future maternal treatment options and
decrease effectiveness of ARV prophylaxis during
current and future pregnancies.
 Increased risk of resistance during pregnancy with:
 Nausea and vomiting (poor ARV adherence or
absorption)
 PK changes
 Postpartum:
 If taking ARVs with low genetic barrier to resistance
and simultaneous discontinuation of drugs with
different half-lives
77
March 2014
ARV Resistance during Pregnancy (2)
 HIV drug-resistance studies should be performed before starting ARV
regimens in all ARV-naïve pregnant women whose HIV RNA levels
are above the threshold for resistance testing unless they have
already been tested for ARV resistance. (AIII)
 HIV drug-resistance studies should be performed before modifying
ARV regimens for those entering pregnancy with a detectable VL that
is above the threshold for resistance testing while receiving ARV
drugs and those who have suboptimal viral suppression after starting
ARV drugs during pregnancy. (AII)
 In women who present late in pregnancy, an empiric ARV regimen
should be initiated promptly without waiting for the results of
resistance testing, with adjustment as needed after test results are
available, for optimal prevention of perinatal transmission and
maternal health. (BIII)
78
March 2014
ARV Resistance during Pregnancy (3)
 Women who have documented AZT resistance and are on regimens
that do not include AZT for their own health should still receive
intravenous AZT during labor along with their established ARV regimens
if they have HIV RNA >1,000 copies/mL near delivery unless a history of
hypersensitivity is documented. (AII)
 The optimal prophylactic regimen for newborns of women with ARV
resistance is unknown. Therefore, ARV prophylaxis for an infant born to
a woman with known or suspected drug resistance should be
determined in consultation with a pediatric HIV specialist, preferably
before delivery. (AIII)
 HIV-infected pregnant women should be given cART to maximally
suppress viral replication, which is the most effective strategy for
preventing development of resistance and minimizing risk of perinatal
transmission. (AII)
79
March 2014
ARV Resistance during Pregnancy (4)
 All pregnant and postpartum women should be
counseled about the importance of adherence to
prescribed ARV medications to reduce the potential
for development of resistance. (AII)
 Several studies demonstrated that women’s adherence to
cART may worsen in the postpartum period.
 Clinicians should specifically address adherence including
evaluating specific factors that facilitate or impede
adherence.
80
March 2014
ARV Resistance during Pregnancy (5)
 To minimize development of resistance, pregnant women
who receive an NNRTI-based combination ARV regimen
that is discontinued after delivery should receive either
dual NRTI agents alone (AI) or with a PI (BII) for 7-30 days
(AII) after stopping the NNRTI drug.
 NNRTIs have longer half-lives than other ARVs.
 The optimal interval between stopping an NNRTI and the
other ARV drugs is unknown.
81
March 2014
Failure of Viral Suppression (1)
 High baseline VL and later start of ART reduce
the likelihood of HIV RNA suppression at
delivery.
 Suppression of HIV RNA to undetectable levels
should be achieved as quickly as possible.
 Evaluate and support ART adherence.
82
March 2014
Failure of Viral Suppression (2)
 If an ultrasensitive VL assay indicates failure of viral
suppression (persistent HIV RNA >20-75 copies/mL,
depending on the assay used) after an adequate period
of treatment:
 Assess resistance and adherence (AII)
 Consult an HIV treatment expert (AIII)
 Scheduled C-section is recommended for HIV-infected
pregnant women who have HIV RNA >1,000 copies/mL
near the time of delivery. (AII)
83
March 2014
Failure of Viral Suppression (3)
 Addition of RAL in late pregnancy if the HIV RNA
is high or if incomplete virologic suppression:
 RAL can rapidly suppress HIV RNA
 Efficacy and safety of this approach have not been
evaluated and it is not routinely recommended
 In setting of drug resistance, addition of RAL may lead
to RAL resistance
84
March 2014
Stopping ARVs during Pregnancy (1)
 HIV-infected women on cART who present for care during
the 1st trimester should continue treatment during
pregnancy. (AII)
 Although EFV should be avoided during the 1st trimester when
possible, ART should not be interrupted in women taking EFV who
present in the 1st trimester, if the HIV RNA is suppressed.
 Discontinuation of ART during pregnancy may be indicated in some
situations.
 If an ARV drug regimen is stopped acutely for severe or lifethreatening toxicity, severe pregnancy-induced hyperemesis
unresponsive to antiemetics, or other acute illnesses that
preclude oral intake, all ARV drugs should be stopped and
reinitiated at the same time. (AIII)
85
March 2014
Stopping ARVs during Pregnancy (2)
 If an ARV drug regimen is being stopped for nonlife-threatening reasons and the patient is receiving
an NNRTI, consider either:
 Stopping the NNRTI first and continuing the other ARV
drugs for a period of time; or
 Switching from an NNRTI to a protease inhibitor (PI)
before interruption and continuing the PI with the other
ARV drugs for a period of time before electively stopping.
86
March 2014
Stopping ARVs during Pregnancy (3)
 The optimal interval between stopping an NNRTI and the
other ARV drugs is unknown; at least 7 days is
recommended. Given the potential for prolonged
detectable EFV concentrations for >3 weeks in patients
receiving EFV-based therapy, some experts recommend
continuing the other ARV agents or substituting a PI plus 2
other agents for up to 30 days after stopping the NNRTI
drug. (CIII)
 If NVP is stopped and more than 7 days have passed
before restarting therapy, NVP should be restarted with
the 2-week half-dose escalation period. (AII)
87
March 2014
HIV/Hepatitis B Virus Coinfection (1)
 All HIV-infected pregnant women should be screened
during pregnancy for hepatitis B virus (HBV) and hepatitis
C virus (HCV) unless they are known to be coinfected or
have already been screened during the current pregnancy.
(AIII)
 All pregnant women who screen negative for HBV surface
antibody should receive the HBV vaccine series. (AII)
Women with chronic HBV also should be screened for
hepatitis A virus (HAV) because they are at increased risk
of complications from coinfection with other viral hepatitis
infections. (AIII)
 HAV vaccine series if negative for HAV IgG
88
March 2014
HIV/Hepatitis B Virus Coinfection (2)
 The management of HIV/HBV coinfection in pregnancy is
complex ;consultation with an expert in HIV and HBV is
strongly recommended. (AIII)
 Interferon-alfa and pegylated interferon-alfa are not
recommended during pregnancy. (AIII)
 All pregnant women with HIV/HBV coinfection should
receive cART, including a dual NRTI/NtRTI backbone with
2 drugs active against both HIV and HBV. (AII)
 TDF + 3TC or FTC preferred (A1)
 Initiation of an ARV regimen that does not include anti-HBV drugs
may be associated with reactivation of HBV and development of
IRIS
89
March 2014
HIV/Hepatitis B Virus Coinfection (3)
 Pregnant women with HIV/HBV coinfection receiving
ARVs should be counseled about signs and symptoms of
liver toxicity, and liver transaminases should be assessed
1 month following initiation of ARV drugs and at least
every 3 months thereafter during pregnancy. (BIII)
 If ARVs are discontinued postpartum in women with
HIV/HBV coinfection, frequent monitoring of liver function
tests for potential exacerbation of HBV infection is
recommended, with prompt reinitiation of treatment for
both HIV and HBV if a flare is suspected. (BIII)
90
March 2014
HIV/Hepatitis B Virus Coinfection (4)
 Decisions concerning mode of delivery in HIV/HBVcoinfected pregnant women should be based on
standard obstetric and HIV-related indications alone.
(BIII)
 Within 12 hours of birth, infants born to women with HBV
infection should receive hepatitis B immune globulin and
the first dose of the HBV vaccine series. The second and
third doses of vaccine should be administered at ages 1
and 6 months, respectively. (AI)
 Postvaccination testing for anti-HBs and HBsAg should be performed
after completion of the vaccine series, at age 9 months to 18 months.
91
March 2014
HIV/Hepatitis C Virus Coinfection (1)
 All HIV-infected pregnant women should be screened during
pregnancy for HCV if they have not been screened during the
current pregnancy unless they are known to be coinfected. (AIII)
 Use the most sensitive immunoassays to detect HCV antibody.
(AIII)
 All pregnant women who screen negative for HBV should
receive the HBV vaccination series (AII).
 Women with chronic HCV infection also should be screened for
hepatitis A virus (HAV) because they are at increased risk of
complications from coinfection with other viral hepatitis
infections. (AIII)
92
March 2014
HIV/Hepatitis C Virus Coinfection (2)
 The management of HIV/HCV coinfection in pregnancy is
complex, given currently approved medications for HCV. If
considering treatment of HCV in a coinfected pregnant woman,
consultation with an expert in HIV and HCV is strongly
recommended. (AIII)
 Interferon-alfa and pegylated interferon-alfa are not
recommended and ribavirin is contraindicated during pregnancy.
(AII)
 No pregnancy data on newer oral agents
 Recommendations for ARV use during pregnancy are the same
for women with and without HCV coinfection (BIII).
93
March 2014
HIV/Hepatitis C Virus Coinfection (3)
 Pregnant women with HIV/HCV coinfection receiving
ARV drugs should be counseled about signs and
symptoms of liver toxicity, and liver transaminases
should be assessed 1 month following initiation of ARV
drugs and at least every 3 months thereafter during
pregnancy. (BIII)
 Decisions concerning mode of delivery in HIV/HCVcoinfected pregnant women should be based on
standard obstetric and HIV-related indications alone.
(BIII)
94
March 2014
HIV/Hepatitis C Virus Coinfection (4)
 Infants born to women with HIV/HCV coinfection should
be evaluated for HCV infection with anti-HCV antibody
testing after age 18 months. (AII)
 Infants who screen positive should undergo confirmatory HCV
RNA testing. HCV RNA virologic testing can be done after age 2
months, if earlier diagnosis is indicated. (AIII)
 HCV viremia can be intermittent, so 2 negative HCV RNA test
results at or after age 2 months, including one at or after age 12
months, are needed to definitively exclude HCV infection. (BIII)
 Children are considered to be HCV infected if they have 2 or
more positive HCV RNA result results or are HCV antibody
positive beyond age 18 months. (AII)
95
March 2014
HIV-2 Infection and Pregnancy (1)
 HIV-2 infection should be suspected in pregnant women
who are from ̶ or have partners from ̶ countries in which
the disease is endemic, who are HIV antibody positive on
an initial enzyme-linked immunoassay screening test, and
who have repeatedly indeterminate results on HIV-1
Western blot along with HIV-1 RNA viral loads at or below
the limit of detection. (BII)
 A regimen with 2 NRTIs and a boosted PI is recommended
for HIV-2-infected pregnant women who require treatment
for their own health because they have significant clinical
disease or CD4 count of <500 cells/µL. (AIII)
96
March 2014
HIV-2 Infection and Pregnancy (2)
 Preferred ART regimen for HIV-2-infected
pregnant women who require treatment:
 Lopinavir/ritonavir + AZT/3TC or ABC/3TC or
TDF/FTC (AIII)
97
March 2014
HIV-2 Infection and Pregnancy (3)
 Optimal prophylactic regimens have not been
defined for HIV-2-infected pregnant women who do
not require treatment for their own health (ie, CD4
counts >500 cells/µL and no significant clinical
disease). Experts have recommended:
 2 NRTIs plus lopinavir/ritonavir for prophylaxis, with the
drugs stopped postpartum (BIII); or
 Zidovudine prophylaxis alone during pregnancy and
intrapartum (BIII)
98
March 2014
HIV-2 Infection and Pregnancy (4)
 NNRTIs and enfuvirtide are not active against HIV-2 and
should not be used for treatment or prophylaxis. (AIII)
 All infants born to HIV-2-infected mothers should receive
the standard 6-week zidovudine prophylactic regimen.
(BIII)
 In the United States, where safe infant formula is readily
available, breast-feeding is not recommended for infants of
HIV-2-infected mothers. (AIII)
99
March 2014
HIV-2 Infection and Pregnancy (5)
 HIV-2 is endemic in West African countries and
occurs in France and Portugal; rare in the United
States.
 In the United States, 166 cases met CDC criteria
for HIV-2 diagnosis between 1998 and 2010.
100
March 2014
HIV-2 Infection and Pregnancy (6)
FDA approved tests for HIV-2
 Alere Determine HIV-1/2 Ag/Ab Combo:
 Rapid test that can detect HIV-1 and HIV-2 antibodies
and HIV-1 p24 antigen
 Can be used on serum, plasma, and venous or
fingerstick specimens
 Does not distinguish between antibodies to HIV-1 and
HIV-2
 Multispot HIV-1/HIV-2 Rapid Test:
 Distinguishes between HIV-1 and HIV-2 antibodies
101
March 2014
HIV-2 Infection and Pregnancy (7)
 Other available HIV-2 supplemental tests are
not FDA approved.
 Commercially available HIV-1 viral load
assays do not reliably detect or quantify HIV-2.
 No validated HIV-2 genotype or phenotype
resistance assays are available in the United
States.
 State or local health departments can arrange
for additional testing by the CDC.
102
March 2014
Acute HIV Infection (1)
 When acute retroviral syndrome is suspected in pregnancy
or during breast-feeding, a plasma HIV RNA test should be
obtained in conjunction with an HIV antibody test. (AII)
 Repeat HIV antibody testing during the 3rd trimester is
recommended for pregnant women with initial negative HIV
antibody test results (AII):
 Who are known to be at risk of acquiring HIV
 Who are receiving care in facilities that have an HIV incidence
among pregnant women of at least 1 per 1,000 per year
 Who are incarcerated
 Who reside in jurisdictions with elevated HIV incidence
103
March 2014
Acute HIV Infection (2)
 All pregnant women with acute or recent HIV infection should start
a combination ARV regimen as soon as possible to prevent
perinatal transmission, with the goal of suppressing plasma VL to
below detectable levels. (AI)
 In women with acute HIV infection, baseline genotypic resistance
testing should be performed simultaneously with initiation of the
combination ARV regimen, and the ARV regimen should be
adjusted, if necessary, to optimize virologic response. (AIII)
 Because clinically significant resistance to PIs is less common
than resistance to NNRTIs in ARV-naive individuals in general, an
RTV-boosted PI-based regimen should be initiated. (AIII)
104
March 2014
Acute HIV Infection (3)
 Primary or acute HIV infection during pregnancy or
breast-feeding is associated with increased risk of
transmission.
 Counsel all pregnant or breast-feeding women about
prevention of HIV. Reinforce importance of using
condoms.
 Consider the use of pre- or postexposure ARV
prophylaxis for those whose partners are HIV infected.
 Maintain a high level of suspicion for acute HIV in women
who have a compatible clinical syndrome, even if highrisk behaviors are not reported.
105
March 2014
INTRAPARTUM CARE
Intrapartum ARV Therapy/Prophylaxis (1)
 Women should continue their antepartum combination
ARV drug regimen on schedule as much as possible
during labor and before scheduled cesarean delivery. (AIII)
 Intravenous (IV) AZT should be administered to HIVinfected women with VL >1,000 copies/mL (or unknown
VL) near delivery (AI), but is not required for HIV-infected
women receiving combination ARV regimens who have VL
≤1,000 copies/ mL consistently during late pregnancy and
near delivery and no concerns regarding adherence to the
regimen. (BII)
107
March 2014
Intrapartum ARV Therapy/Prophylaxis (2)
 For women who have suboptimal viral suppression near
delivery, scheduled cesarean delivery is recommended. (AI)
 Women whose HIV status is unknown who present in labor
should undergo rapid HIV antibody testing. (AII)
If positive result:
 Do a confirmatory HIV test ASAP and initiate maternal (IV AZT) and
infant (combination ARV prophylaxis) ARV drugs pending results of
the confirmatory test. (AII)
 If the confirmatory HIV test result is positive, infant ARV drugs should
be continued for 6 weeks (AI); if the confirmatory result is negative,
infant ARV drugs should be stopped.
108
March 2014
Intrapartum ARV Therapy/Prophylaxis (3)
 Studies demonstrating use of IV AZT:
 The benefit of adding IV AZT in women on
cART regimens has not been evaluated in
randomized studies.
 In nonrandomized studies of women on cART,
addition of intrapartem AZT appears to reduce
risk of perinatal transmission if HIV RNA is not
consistently suppressed to <1,000 copies/mL
near time of delivery.
109
March 2014
Transmission and Mode of Delivery (1)
 Scheduled cesarean delivery is recommended
for women at 38 weeks’ gestation to minimize
perinatal HIV transmission with HIV RNA levels
>1,000 copies/mL or unknown levels near the
time of delivery, irrespective of administration of
antepartum ARVs. (AII)
110
March 2014
Transmission and Mode of Delivery (2)
 For pregnant women receiving cART with HIV
RNA levels <1,000 copies/mL near the time of
delivery:
 Data are insufficient to evaluate the potential benefit of
scheduled cesarean delivery for prevention of perinatal
transmission; unclear if it would confer additional benefit
(BIII)
 Low rates of transmission
 C-sections performed for standard obstetrical
indications should be scheduled for 39 weeks’
gestation
111
March 2014
Transmission and Mode of Delivery (3)
 Unclear whether cesarean delivery after rupture of
membranes or onset of labor reduces HIV
transmission. Management should be based on:
 Duration of rupture and/or labor
 Plasma HIV RNA level
 Current ARV regimen (BII)
 If unscheduled cesarean delivery is performed
and IV AZT administration is indicated, consider
giving only the loading dose before proceeding
with delivery.
112
March 2014
Transmission and Mode of Delivery (4)
 Inform pregnant women of the risks
associated with cesarean delivery. If the
indication is for prevention of perinatal
transmission of HIV, the risks should be
balanced with potential benefits expected for
the neonate. (AII)
113
March 2014
Other Intrapartum Management Considerations (1)
 Avoid the following because of potential
increased risk of transmission (unless there
are clear OB indications):
 Artificial rupture of membranes (BIII)
 Routine use of fetal scalp electrodes (BIII)
 Operative delivery with forceps or vacuum
extractor and/or episiotomy (BIII)
114
March 2014
Other Intrapartum Management Considerations (2)
 When treating excessive postpartum bleeding,
consider the ARVs a woman is receiving:
 If receiving a cytochrome (CYP) 3A4 enzyme
inhibitor (eg, a PI), use methergine only if no
alternative treatments are available and the need for
pharmacologic treatment outweighs the risks. (BIII)
 If receiving a CYP3A4 enzyme inducer such as
NVP, EFV, or etravirine, additional uterotonic
agents may be needed because of the potential for
decreased methergine levels and inadequate
treatment effect.
115
March 2014
POSTPARTUM CARE
Postpartum Care (1)
 Decisions about continuing ARVs ideally should
be made before delivery, in consultation with the
woman and her HIV provider. (AIII)
 cART is recommended for all HIV-infected
individuals, for individual health and to prevent
sexual transmission.
 Take into account current recommendations for
the initiation of cART, pretreatment CD4 counts
and trajectory, HIV RNA levels, adherence
issues, whether a woman has an HIV-uninfected
sex partner, and patient preference.
117
March 2014
Postpartum Care (2)
 For women continuing ARV drugs postpartum,
arrangement for new or continued supportive
services should be made before hospital discharge
because the immediate postpartum period poses a
unique challenge to adherence. (AII)
 Counsel women about the challenge of
adherence in the postpartum period.
 Remain vigilant for signs of depression and drug
or alcohol use.
 Consider simplifying cART regimens to improve
adherence.
118
March 2014
Postpartum Care (3)
 Contraceptive counseling should be included in the prenatal
period and immediately postpartum as a critical aspect of
postpartum care. (AIII)
 The postpartum period is a critical time to address:
 Safer sex practices
 Secondary transmission prevention
 Contraception
 Review possible drug interactions of specific ARV drugs with
hormonal contraceptives before prescribing
 Encourage dual-protection strategy of condom use plus a
second highly effective contraceptive.
119
March 2014
Postpartum Care (4)
 Women with a positive rapid HIV antibody test
result during labor require immediate linkage to
HIV care and comprehensive follow-up including:
 Confirmation of the diagnosis
 Full health assessment
 Evaluation for associated medical conditions
 Counseling related to HIV diagnosis
 Assessment of need for cART and
opportunistic infection prophylaxis (AII)
120
March 2014
Postpartum Care (5)
 Breast-feeding is not recommended for HIVinfected women in the United States, including
those on cART. (AII)
 The presence of intracellular HIV DNA in the breast
milk, may continue to pose a risk for transmission.
 Health care providers should routinely inquire about
premastication, instruct HIV-infected caregivers
against this feeding practice, and advise on safer
feeding options.
121
March 2014
CARE OF THE NEONATE
Infant Antiretroviral Prophylaxis (1)
 6 weeks of neonatal AZT chemoprophylaxis is
generally recommended for all HIV-exposed
neonates to reduce perinatal transmission of
HIV. (AI)
123
March 2014
Infant Antiretroviral Prophylaxis (2)
 Infants born to women who received standard
cART during pregnancy with consistent viral
suppression and there are no concerns related
to maternal adherence:
 6 weeks of neonatal AZT chemoprophylaxis
 Can consider a 4-week neonatal AZT
chemoprophylaxis regimen (BII)
124
March 2014
Infant Antiretroviral Prophylaxis (3)
 Infants born to women who received
antepartum/intrapartum ARVs but with
suboptimal viral suppression near delivery:
 6 weeks of neonatal AZT chemoprophylaxis
 Consider multidrug prophylaxis, though no data
address whether 2-3 drug infant regimen is more
effective in this scenario
 Scheduled C-section is recommended if women
have VL >1,000 copies/ml near time of delivery.
125
March 2014
Infant Antiretroviral Prophylaxis (4)
 Infants born to mothers who received only
intrapartum ARV drugs (AI):
 Standard 6-week course of AZT, plus
 3 doses of NVP in the first week of life
 1st dose at birth
 2nd dose 48 hours later
 3rd dose 96 hours after 2nd dose
 Begin regimen as soon as possible postdelivery
126
March 2014
Infant Antiretroviral Prophylaxis (5)
 Infants born to women who did not receive
antepartum or intrapartum ARVs:
 Standard 6-week course of AZT, plus
 3 doses of NVP in the first week of life, as above
 Begin regimen as soon as possible postdelivery
127
March 2014
Infant Antiretroviral Prophylaxis (6)
 Infants born to mothers with unknown HIV status:
 Do expedited (rapid) HIV testing of mothers and/or
infants as soon as possible (during labor or after
birth)
 If initial test result is positive:
 Initiate infant ARV prophylaxis immediately (AII)
 Do not wait for confirmatory testing
 Send confirmatory test (mother or infant)
 If negative, stop infant ARV prophylaxis (AIII)
 If positive, perform an HIV nucleic amplification
test on the infant (AIII)
128
March 2014
Infant Antiretroviral Prophylaxis (7)
 Infants born to mothers with ARV-resistant virus:
 Optimal prophylactic regimen for newborns is
unknown
 Consult with a pediatric HIV specialist before
delivery
 Standard 6-week course of AZT is recommended;
consider addition of other ARVs selected on basis
of mother’s virus resistance testing
129
March 2014
Short-Term ARV Safety in Neonatal
Prophylaxis
 AZT: transient hematologic toxicity (mainly anemia)
 3TC: in combination with AZT may cause more severe anemia and
neutropenia
 TDF and FTC: limited data and safety; not recommended for infant
prophylaxis
 NVP: no cases of severe rash or hepatotoxicity with neonatal
prophylaxis
 Resistance may occur in infants who become infected despite
prophylaxis
 PIs: not recommended for infant prophylaxis during the first few
weeks of life; no PK and safety data
 RAL: not recommended; no PK and safety data available
130
March 2014
Infant Antiretroviral Drugs – Premature
Infants
 The use of ARV drugs other than AZT and NVP is
not recommended for premature infants in the
United States. (BIII)
 A decision to combine other drugs with AZT
regimen should be made in consultation with a
pediatric HIV specialist. (BIII)
131
March 2014
Infant Antiretroviral Management:
Consultation
 Clinician Consultation Center (formerly the
National Perinatal HIV Hotline), 1-888-8765: free
clinical consultation on perinatal HIV
132
March 2014
Initial Postnatal Management of the HIVExposed Neonate (1)
 Obtain a CBC with differential before initiation
of ARV prophylaxis. (BIII)
 Frequency of monitoring blood levels is based
on: (CIII)






133
Gestational age and clinical condition of infant
Baseline values
ZDV dosage administered
Receipt of other ARV drugs
Concomitant medications
Maternal ARV regimen
March 2014
Initial Postnatal Management of the HIVExposed Neonate (2)
 Consider more frequent monitoring for infants
exposed to combination ARV regimes in utero
or neonatally: (CIII)




134
CBC
Serum chemistry
Liver function
Bilirubin levels (ATV exposure)
March 2014
Initial Postnatal Management of the HIVExposed Neonate (3)
 For infants receiving combination
ZDV/3TC-containing ARV prophylaxis: (AI)
 Recheck hemoglobin and neutrophil count
4 weeks after ARV initiation and/or at the
time HIV diagnostic testing is performed.
135
March 2014
Initial Postnatal Management of the HIVExposed Neonate (4)
 If hematological abnormalities are identified,
considerations about continuing ARV prophylaxis
include: (CIII)





Extent of abnormality
Related symptoms
Duration of prophylaxis
Risk of HIV infection
Availability of alternative interventions
 May consider reducing prophylaxis to 4 weeks ̶
consult a pediatric HIV specialist
136
March 2014
Initial Postnatal Management of the HIVExposed Neonate (5)
 Routine measurement of serum lactate is not
recommended unless infant develops severe
clinical symptoms of unknown etiology. (CIII)
 Especially neurologic symptoms
 In symptomatic infants with significantly
abnormal serum lactate levels (>5 mmol/L):
 Discontinue ARV prophylaxis
 Consult a pediatric HIV specialist for
alternative prophylaxis
137
March 2014
Diagnosing HIV Infection in Infants (1)
 Diagnostic HIV tests for infants: (AII)
 Use HIV nucleic amplification testing (eg, HIV
DNA and RNA PCR and related assays)
 Maternal HIV antibodies cross placenta and
are detectable in HIV-exposed infants for up
to 18 months
 Standard antibody tests cannot be used to
diagnose HIV infection in infants
138
March 2014
Diagnosing HIV Infection in Infants (2)
 Virologic tests should be performed at: (AII)
 14-21 days,
 1-2 months, and
 4-6 months
 Virologic test may be performed at birth:
 If mother did not have good virologic control during
pregnancy, or
 If adequate follow-up cannot be assured
 Confirm a positive HIV virologic test with a
second virologic test on a different specimen
139
March 2014
Diagnosing HIV Infection in Infants (3)
 HIV infection in an infant is diagnosed by 2
positive virologic tests on separate
specimens
 HIV DNA (rather than RNA) may be optimal
for HIV diagnosis in neonatal period
140
March 2014
Diagnosing HIV Infection in Infants (4)
 HIV infection is excluded:
 Presumptively by 2 negative virologic tests, 1 at age
≥14 days and 1 at age ≥1 month
 Definitively (in non-breast-fed infants) by 2 negative
virologic tests, 1 at age ≥1 month or older and 1 at age
≥4 months
 Many experts confirm negative status by antibody
testing at 12-18 months (HIV antibodies can
sometimes occur at or beyond 18 months)
 Diagnosis of non-subtype-B HIV may be difficult:
see Guidelines
141
March 2014
Postnatal Management of the HIV-Exposed
Neonate: Prophylaxis and Immunizations
 PCP prophylaxis should begin at age 4-6 weeks,
after completion of ARV prophylaxis. (AII)
 Unless HIV infection can be presumptively excluded
 Evaluate and treat infants as indicated for
transmittable maternal coinfection identified
through history or physical evaluation
 HIV-exposed infants should follow the routine
immunization schedule
142
March 2014
Infant Feeding Practices and Risk of HIV
Transmission
 To prevent HIV transmission to infants in the United
States:
 HIV-infected women should not breast-feed
 ART may decrease free HIV virus in breast milk, but cellassociated virus remains and may pose transmission risk
 Feeding with premasticated foods may transmit HIV

Health providers should: (AII)


143
Inquire about premastication and instruct HIV-infected
caregivers to avoid the practice
Advise on safer feeding options
March 2014
Long-Term Follow-Up of Infants Exposed to
ARVs
 Long-term data from infants exposed to ARVs in
utero are insufficient.
 Children with in utero or neonatal exposure to
ARVs who develop significant organ system
abnormalities of unknown etiology, particularly the
nervous system or heart, should be evaluated for
mitochondrial dysfunction. (CIII)
 Follow-up of children with exposure should continue to
adulthood because of theoretical concerns for
carcinogenicity of nucleoside analogues. (CIII)
144
March 2014
LESSONS LEARNED FROM
CLINICAL TRIALS OF
ANTIRETROVIRAL
INTERVENTIONS TO REDUCE
PERINATAL TRANSMISSION OF
HIV
Overview
 Pediatric AIDS Clinical Trials Group 076
 Major achievement in HIV research
 Showed administration of zidovudine (ZDV) to pregnant women
and their infants could reduce perinatal transmission by 70%
 Increased HIV testing in pregnancy and
combination ARV prophylaxis during pregnancy
has reduced perinatal transmission in the United
States to <2%
 Every HIV-infected infant is a sentinel event
representing missed opportunities
146
March 2014
ARV Prophylaxis: Mechanisms of Action
 Combined antepartum, intrapartum, and
infant ARV prophylaxis is recommended to
prevent perinatal transmission of HIV. (AI)
 ARV drugs reduce perinatal transmission by
several mechanisms, including:
 Lowering maternal antepartum VL
 Providing infant pre- and postexposure
prophylaxis
147
March 2014
ARV Prophylaxis: Summary
 Combination antenatal prophylaxis taken over longer
duration is more effective then a short-course, single-drug
regimen in reducing perinatal transmission.
 Combination infant ARV prophylaxis is recommended in the
United States for infants whose mothers have not received
antenatal ARV drugs.
 Adding single-dose intrapartum NVP is not recommended for
women in the United States who are receiving standard
recommended antenatal ARV prophylaxis.
 Breast-feeding by HIV-infected mothers is not recommended
in the United States.
148
March 2014
ARV Pregnancy Registry
To report cases of HIV-infected pregnant women and their
newborns of prenatal exposure to ARVs for the purpose of
assessing its potential teratogenicity contact:
ARV Pregnancy Registry
Research Park
1011 Ashes Drive
Wilmington, NC 28405
(T) 1-800-258-4263
(F) 1-800-800-1052
http://www.APRegistry.com
149
March 2014
Websites to Access the Guidelines
 http://www.aidsetc.org
 http://aidsinfo.nih.gov
150
March 2014