Transcript Document

Women and HIV: Emerging
Issues in Clinical Management
Karen P. Beckerman, MD
Assistant Professor
Obstetrics, Gynecology and
Reproductive Sciences
University of California,
San Francisco
30 November 2001
Epidemiology in the U.S.
Heterosexual transmission of HIV-1
Manifestations of HIV in women
Initiating therapy in women
Reproductive Health and HIV
Preconceptional and early
pregnancy counseling
Vertical Transmission
Principles of care during pregnancy
The global epidemic
U.S. Total Cases:
as of June 1999
Total
711,344
Men
588,124
Women
114,621
Heterosexual 40 %
Unknown 39%
IV Drug Use 29%
Transfusion <1%
Children
8,590
Epidemiology
In the United States, women represent the
fastest growing group of new infections:
1981-87 1995
8%
19%
1996
1998
20%
23%
Heterosexual Transmission
among U.S. Youth, 1999
Age
13-19
20-24
Women
42%
37%
Men
7%
7%
Overall, 54% of youth did not
report a risk factor.
Heterosexual Transmission in
the rural U.S.


West:
52%
Southeast:
58%
33% of new infections occur
among women
2/3 of men and women
are infected sexually
69% of women had young
children at home
Heterosexual Transmission,
Observations:



These estimates are low.
“IVDU” is listed where any
history exists.
Most unknowns are probably
heterosexual.
A new female patient in your
office is likely to be:


From any socioeconomic class.
The mother of small children (who
must be tested).
And unlikely to be:


A prostitute
An IV drug user
Manifestations of HIV disease
among women



Male female transmission is
2-10x more efficient than
femalemale
More virus is found in semen
than in vaginal fluids
Vaginal surface area >> male
urethra and foreskin
Manifestations of HIV disease
among women




Women may be more likely than men to be
diagnosed by screening alone.
Most common presenting complaint in
women is candidal esophagitis.
Nevirapine rash is more common in women.
Women without transmission risk factors
often go undiagnosed when presenting with
recurrent pneumonia, candidiasis or cervical
dysplasia.
Manifestations of HIV disease
among women:
Seborrheic dermatitis
Women
Men
axilla
face
between breasts
chin
groin
nasal area
external ear
auditory canal
axilla
Manifestations of HIV disease
among women



Viral load was 50% lower in
women than men
More rapid declines in CD4
over time
Findings may be confounded
by race
Anastos et al., 2000, JAIDS.24:218
Manifestations of HIV disease
among women
Other than reproduction, there
are not major gender
differences in the natural
history of HIV disease.
Initiating antiretroviral Therapy
(NIH Guidelines 13 August 2001: hivatis.org)





When symptomatic: any CD4 and any viral load
Asymptomatic with AIDS, CD4<200
treat.
Asymptomatic with CD4 between 200 & 350
offer treatment.
Asymptomatic with CD4 > 350, VL>55,000
*3 year risk of AIDS >30%
recommend treatment, or
 defer with frequent monitoring
Asymptomatic with CD4 > 350, VL <55,000
many experts would defer therapy
Initiating antiretroviral Therapy
(NIH Guidelines 13 August 2001: hivatis.org)
For women with CD4 > 350,
clinicians may consider
beginning therapy at lower VL
than in men.
However, we have insufficient data to
recommend a VL cut-off for women.
Reproductive Health among
HIV-infected Women





Baseline colposcopy at HIV diagnosis
Pelvic and cervical pap smear every
six months, at least initially
The role of anal Pap smears remains to
be defined
Treat genital warts
Test for other sexually transmitted
diseases
Reproductive Health among
HIV-infected Women:
CERVICAL DYSPLASIA & HPV




Immunosuppression is associated with
increased susceptibility to HPV
Cervical dysplasia is 2x as common
among women with AIDS diagnosis
Standard cervical pap tests may miss
vaginal, vulvar or anal dysplasia
Colposcopy for ASCIS, AGCUS, low
grade and high grade SIL or persistant
inflammation
Contraceptive and Safe Sex
Counseling




Must be addressed!
Barrier method (male or female condom)
is required for STD protection.
Impact of hormonal contraception on HIV
shedding?
Bioavailability of ethinyl estradiol in
contraceptives may be significantly
reduced by ritonavir, nelfinavir or
nevirapine.
Contraceptive and Safe Sex
Counseling


HIV-infected women must have
access to all approved forms of
contraception!
Back-up methods (tubal ligation,
hormonal contraception) to barrier
methods are acceptable and
recommended.
Preconceptional and Early
Pregnancy Counseling


Availability of antibody testing
NON-DIRECTIVE and SUPPORTIVE for
client’s reproductive choice:
-Pregnancy does not affect course of HIV
in the industrialized world
-It is quite possible to have a normal
pregnancy and an uninfected baby
-For all women, early abortion is generally
safer than pregnancy
First things first:
Safe shelter
Food
Self-determination
Preconceptional and Early
Pregnancy Counseling




Confirm serostatus, especially in
areas of low sero-prevalence where
the positive predictive value of a
single test may be low
Obstetrical and gynecological history
History of HIV care, antiretrovirals,
resistance
Physical examination
Preconceptional and Early
Pregnancy Counseling:
LABORATORY STUDIES:







Rubella and varicella antibodies
Toxoplasma antibody
CMV serostatus
Hepatitis serology
Syphillis serology
Chlamydia, GC testing
Baseline chest radiograph
Preconceptional and Early
Pregnancy Counseling:
Optimization of care:





If already taking ART, optimize
-Switch from efavirenz to nevirapine
-Consider switch from amprenavir to Kaletra
(ritonavir/lopinavir)
-Adherence, current and future
Discuss and optimize OI prophylaxis
Address nutritional needs
Consider extra folate supplement
Optimize control of other medical conditions
Preconceptional and Early
Pregnancy Counseling:




Therapeutic options during
pregnancy
No medications
Prophylaxis alone
Other effects of ART (anemia,
resistance, etc.)
Options for labor and delivery
Prophylaxis for neonates
Diagnostic procedures for exposed
infants
Pneumocystis Pneumonia during the first year
of life carries a >90% fatality rate
Diagnostic procedures for
exposed infants:




Aimed at diagnosis at earliest time to intervene
prior to clinical immunodeficiency.
Viral test (DNA-PCR or RNA-PCR) at:
birth
three months
one month
six months
Antibody test at:
12 months, 18 months or until antibody clears
Viral test at three months is highly predictive
of infection status
*Seroreversion is gold standard*
Prophylaxis procedures for
exposed infants:





Zidovudine syrup 2mg/kg q 6h for six weeks
Trimethoprim-sulfa OI prophylaxis from 6
weeks to 6 months
Recommendations do not exist for dealing with
maternal zidovudine resistance
Rarely, an infant might be given more than one
medication for prophylaxis
Some authorities are allowing mothers not to
give TMP-sulfa when risk of transmission is low
Preconceptional and Early
Pregnancy Counseling:







Review adherence issues during pregnancy and
post-partum
Discuss guardianship and other legal issues
Domestic violence issues
Discuss fertility, conception and safe sex
Risks of vertical transmission and pediatric HIV
disease
Discuss advanced maternal age
Neural tube defect screening
Preconceptional and Early
Pregnancy Counseling:
Access to clinical trials and other
research
 Peer counseling and peer support

Preconceptional and Early
Pregnancy Counseling
Observations:




Isolation is a major problem for infected
women everywhere.
Many have never met another HIV- infected
woman.
Most have never even heard of an infected
mother or pregnant woman.
One-half of US HIV-infected women report
domestic violence.
Preconceptional and Early
Pregnancy Counseling
Risk of vertical transmission:


Among women taking potent antiretroviral
cocktails risk is not published - may be close
to 1%.
Exposed infants will need six or more blood
tests before two years of age to rule out HIV
infection.
Vertical Transmission
Mechanisms:



Unknown!
Exposure to
maternal secretions?
Exposure to maternal blood at
delivery? Via the placenta?
Vertical Transmission
Maternal risk factors:






Maternal immune status:
maternal CD4
Disease activity:
maternal viral load
(Garcia et al., NEJM 341:394)
Antiretroviral prophylaxis
Antiretroviral therapy
Prior infected child
Weight loss, Tb, OIs
Length of ruptured
Vertical Transmission
Obstetrical risk
factors:




Length of ruptured
membranes
Prematurity, low
birth weight
Immune activation during
pregnancy or at delivery?
Evidence of chorioamnionitis:
infection or inflammation of membranes/placenta
Principles of care of the HIV-1
infected pregnant mother
First things first:




Safe housing
Adequate nutrition
Transportation
Self-determination for:
reproductive choice
treatment & prophylaxis
Priniciples of care of the HIV-1
infected pregnant mother
When mother is already on stable HAART
with good control:

Encourage continuation of regimen
through 1st trimester.
>20,000 reports to the Antiretroviral Pregnancy
Registry - no increase in congenital malformations.

Offer option of brief treatment interruption
Advise patient that VL will certainly rebound, but
that stopping all ART at once may be safe for a few
months
Priniciples of care of the HIV-1
infected pregnant mother
When mother is not on stable HAART, or is
experiencing virologic breakthrough:

Do not start therapy or change therapy
until the second trimester.
>Nausea and vomiting during the first trimester
make it a very poor time to start new therapies.

Offer:
>Continuation of therapy with a change in 2nd
trimester.
>Brief treatment interruption.
>Start of therapy in 2nd trimester.
Priniciples of care of the HIV-1
infected pregnant mother
Antiretrovirals that should be avoided
if possible:
EFAVIRENZ:





Unpublished primate data show high
incidence of neural tube defects.
No reports in humans.
No indication, per se, to abort pregnancy.
Multiple ultrasound and blood tests can
rule out neural tube defects.
Consider a switch to nevirapine.
Priniciples of care of the HIV-1
infected pregnant mother
Antiretrovirals that should be avoided
if possible:
AMPRENAVIR:



Unpublished reports of abnormal
calcification of bones.
Human data are lacking.
Consider a switch to another highly potent
agent or combination, such as
lopinavir/ritonavir.
Priniciples of care of the HIV-1
infected pregnant mother
Antiretrovirals that should be avoided
if possible:
STAVUDINE/DIDANOSINE (D4T/ddI):





High potency nRTI combination.
Particularly effective in the setting of pan-resistance
and virologic breakthrough.
Given alone short term in South Africa, was highly
effective at preventing MCT, without lactic acidosis.
Reports of lactic acidosis during pregnancy.
If needed, requires very frequent monitoring of liver
transaminases.
Prophylaxis for Opportunistic
Infection
•Trimethoprim-sulfa
•Dapsone
•Azithromycin
>may all be used safely during pregnancy
>pregnancy is not a good time to stop OI
prophylaxis
Principles of care of the HIV-1
infected pregnant mother
Protection of mothers from mono- and dual
therapies likely to induce ART resistance:
Low Fidelity HIV-1 Replication
Low Fidelity HIV-1 Replication
•Two polymerases without proofreading activity
HIV-1 reverse transcriptase
Cellular RNA polymerase
•Two RNA copies per virion
Insertions and deletions are common
•RNA strand breaks force template switching
•Uracil incorporation into proviral DNA
Especially in resting cells
Pregnancy and ART resistance
in Uganda
NVP single dose prophylaxis:
HIVNET 006 & 012
Single dose to mother + single dose to infant
Transmission fell from 25 to 13%
10
of 46 mothers studied 6 weeks to 6
months later had detectable resistance
Of
the 36 infected infants, 8 had
detectable nnRTI resistance at 6 weeks
of age.
Pregnancy and ART resistance
in the developed world
Principles of care of the HIV-1
infected pregnant mother
Protection of mothers from mono- and dualtherapies likely to induce resistance:
•Nevirapine prophylaxis (even one dose)
is highly likely to result in nnRTI
resistance if not given in a safe
combination.
•In the U.S., nevirapine prophylaxis
given in addition to standard ART resulted
in no benefit to mother or baby, but did
cause significant induction of nnRTI
resistance.
(Dorenbaum, PACTG 316, CROI, 2001)
Pregnancy and ART resistance
in the developed world
•Zidovudine/lamivudine (AZT/3TC)
induces resistance (M184V) at same
frequencies in pregnant women as in
men
•In one study, 4 of 5 mothers developed
M184V (Clark, J Med Virol.59:364)
•M184V can be transmitted to neonates
Pregnancy and ART resistance
in the U.S. and Japan
Are these data relevant to us today?
Unfortunately, YES.
ACTG 185: late 1990s
86% received ZDV
14% received ZDV/3TC
30%
of mothers had nRTI resistance
by delivery
These
mothers were 3 times more
likely to transmit virus to their infant
(p=0.03)
Principles of care of the HIV-1
infected pregnant mother
Protection of mothers from mono- and dualtherapies likely to induce resistance:
•Women refusing 3 medications should be
offered zidovudine prophylaxis, never
Combivir alone.
Combivir
Alone
Priniciples of care of the HIV-1
infected pregnant mother
Aggressive use of combination
antiretroviral therapy to achieve durable
suppression of maternal HIV replication and
to protect mother from induction of
antiretroviral resistance:


Offer 3 or more medications
Twice daily dosing
Principles of care of the HIV-1
infected pregnant mother
Cytochrome p4503A reductase activity:


AUC8 for indinavir is markedly
suppressed late in pregnancy
p450 3A activity is significantly
increased in the third trimester
(Homma et al., 2001; Hayashi et al. 2001)

Increased p450 3A activity in late
pregnancy is reversed by ritonavir,
allowing twice daily dosing,
for example,
RTV200mg/IDV800mg q 12 h
Principles of care of the HIV-1
infected pregnant mother
Aggressive use of combination
antiretroviral therapy to achieve durable
suppression of maternal HIV replication and
to protect mother from induction of
antiretroviral resistance:


When likelihood of nonadherence is high, do not offer
nevirapine
If mother does not need therapy
for her own health, HAART can
be safely stopped post-partum
Route of delivery
Informed maternal choice:
•Retrospective evidence of prevention of vertical
transmission
by elective
cesarean
delivery
Hours of membrane rupture
Route of delivery
Informed maternal choice:
No data exist that demonstrate a
benefit of elective cesarean to
mother or baby when mother is
receiving potent combination
therapy.
University of California/San Francisco
General Hospital 1994-1999
University of California/San Francisco
General Hospital 1994-1999
San Francisco, 1994-1999
Shaffer et al.,
Viral Load and Transmission
Length of rupture of membranes,
(hours)
Control of maternal viral load appears to be
highly protective even in the setting of
prolonged rupture of membranes
November 2001:
> 40 million infected
>8,000 deaths
per day
600 new infections
per hour
a child dies
every minute
By 2010,
>42 million orphans.
They will suffer greatly, whether they are infected...
…or not.
Japanese AIDS Research Society
Dr. Aikichi Iwamoto
Dr. Atsushi Ajisawa
Dr. Makoto Aoki
Ms.Narumi Hori
GlaxoSmithKline
Medicus Tokyo