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Assisted Reproduction Among
HIV Sero-Discordant Couples
Carmen D. Zorrilla, MD
Professor, OB-GYN, UPR School of Medicine
Maternal-Infant Studies Center (CEMI)
Faculty, Florida/Caribbean AETC
[email protected]
Speaker Disclosures
This speaker has significant financial
relationships with the following commercial
entities to disclose:
• Advisory Board or Panel: Janssen
• Consultant: Abbott
• Grants/Research Support: BMS, Janssen, Tobira,
Pfizer, Gilead
• Speakers Bureau: BMS
This slide set has been peer-reviewed to ensure that there are no conflicts of interest
represented in the presentation.
Speaker Disclosures
• This speaker will discuss the following off-label use
or investigational product during the program:
• Research findings on the use of tenofovir alone
(Viread®) or in combination with emtricitabine (as
Truvada®) in Pre-exposure prophylaxis (PrEP) and
their potential use in assisted contraception will be
presented. Note: Truvada® received FDA approval
for PrEP in July 2012. Studies include: iPrEX,
Partners PrEP, HPTN 052, VOICE, TDF-2
This slide set has been peer-reviewed to ensure that there are no conflicts of
represented in the presentation.
interest
Assisted Reproductive Technologies
(ART) in the USA
• 7% of couples in the U.S. have infertility (12 months of
unprotected intercourse without conception)
• Infertility treatments cost over $3 billion annually
• The number of in vitro fertilization (IVF) cycles increased
from 30,000 in 1996 to over 130,000 in 2005
• The proportion of U.S. births that resulted from IVF
increased from 0.3 percent to almost 1 percent
Effectiveness of ART: Evidence report/technology assessment; No 167 AHRQ publication No. 08-E012 May 2008
ART: Long-term outcomes
 Loss of the entire pregnancy is more common for singleton
pregnancies than for twins after ART
 Preterm delivery is twice as likely in singleton pregnancies
after infertility treatment compared to spontaneous
 The risk of preterm birth in ART twins compared to
spontaneous twins is either not elevated or elevated to a
lesser extent than in singletons
 Increased risk of disorders related to abnormal placentation
such as preeclampsia, placenta previa, and placental
abruption
Effectiveness of ART: Evidence report/technology assessment; No 167 AHRQ publication No. 08-E012 May 2008
ART: Long-term outcomes
 Children born after ART have an increased risk of
hospitalization and surgery compared to the general
population
 No increase in adverse neurodevelopmental outcomes
related to ART other than those associated to prematurity
and SGA
 No differences in psychological outcomes, including
parenting skills when comparing singletons (ART vs.
spontaneous)
 Multiple gestations increase stress and depressive
symptoms, especially for mothers of infants with chronic
disabilities
Effectiveness of ART: Evidence report/technology assessment; No 167 AHRQ publication No. 08-E012 May 2008
HIV and Fertility
• HIV infection has changed from a life-threatening illness to
a chronic illness because of the availability of combination
antiretroviral (ARV) therapy (CART)
• Some of the behaviors that place women at risk for HIV
(e.g., IDU, sex work) also place them at risk for infertility
• Even though some women will postpone pregnancy
because of an HIV diagnosis, it will not change the desire
for reproduction
Pregnancy and HIV
• Transmission rates have decreased substantially with
current management (CART, cesarean section [C/S)],
infant formula)
• Current transmission rates are around or less than 1%
• Pregnancy does not affect the progression of HIV disease
• Women living with HIV do not have to postpone
pregnancies indefinitely
Pregnancy Considerations for
Women Living with HIV
• Pre-conception care is important for those women living
with HIV who have postponed a pregnancy and want to
achieve it now
• Therapy options might be different if you acknowledge a
potential future pregnancy
• For new patients in care, the suspicion and detection of
early pregnancy is crucial
• updated USPHS guidelines: “efavirenz can be continued in
pregnant women receiving an efavirenz-based regimen who present for
antenatal care in the first trimester, provided the regimen produces virologic
suppression (CIII)” http://www.aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0/
Fertility Evaluation
History
• Menstrual cycle frequency (25-35
days), and quality (abnormal
bleeding, dysmenorrhea)
• Changes in weight (>10 lbs)
• Concurrent medications (ARVs)
• Exercise or dieting (vigorous
exercise impairs fertility)
• Cigarette smoking (impairs fertility)
• History of STIs or PID
• Substance use (IDU, methadone)
• Males: use of androgens
Physical exam
• Body habitus (metabolic
syndrome: gestational
diabetes mellitus, polycystic
ovarian syndrome [PCOS])
• Signs of insulin resistance
• BMI (<18 and >27 related to
decreased fertility)
• Hirsutism (PCOS)
• Pelvic exam with signs of PID
• Males: testicular size
Fertility Evaluation: Labs
• Preconception counseling labs
• Serum Prolactin and TSH
• Tubal patency by hysterosalpingogram (HSG) or
laparoscopy
• Ovarian reserve: Day 3 FSH (>10-15 IU/L) and estradiol
(>75-80 pg/ml)
• Ovulation tests:
– Progesterone >3 ng/ml on day 21 (1 week before
menses)
– Positive LH (commercial ovulation kits) or
– Basal body temperature (BBT) chart
Costs
• The 422 infertility clinics in the United States
operate without any regulation of cost, access, or
scope and quality of treatments.
• The average cost of an IVF cycle in the United
States is $12,400. Several cycles may be
needed.
• The specific laws concerning coverage of infertility
treatment vary widely from state to state.
http://www.thehastingscenter.org/Publications/BriefingBook/Detail.aspx?id=2210
2005 Approximate Treatment/Diagnosis Costs
(USA)
• Initial workup:
hysteroscopy, blood tests,
hysterosalpingogram,
…….………..……..$2,000
• Intrauterine Insemination
(IUI)…….………$200-900
• Sonohysterogram (SHG)
……………….$600-1,000
• Clomiphene citrate cycle
……………........$200-500
• IVF cycle….....$10-30,000
• Use of a surrogate mother
to carry the child
............................$50,000
http://jenniferfairfax.com/assisted-reproduction-technology-costs
http://dissertations.ub.rug.nl/faculties/science/2010/m.p.connolly/
http://ehealthmd.com/content/what-assisted-reproduction
• Calculate the expected
cost of establishing a
pregnancy.
• If a clomiphene treatment
has a chance to establish
a pregnancy in 8% of
cycles and costs $500,
the expected cost is
$6,000 to establish a
pregnancy
• Compared to an IVF
cycle (cycle fecundity
40%) with a
corresponding expected
cost of $30,000
($12,000/.4)
Third Party/Surrogacy Issues
• Twelve percent of IVF cycles in 2005 used “donor”
eggs, most often for women in their forties who
discovered that they could not achieve pregnancy
using their own eggs.
• “Although the development of ICSI has reduced the
number of heterosexual couples requesting sperm
donation, IVF is still sought by those who cannot
produce sperm at all, as well as by lesbian couples
and single women seeking a child genetically
connected to at least one rearing parent.”
http://www.thehastingscenter.org/Publications/BriefingBook/Detail.aspx?id=2210
“Medical Tourism”
• In an effort to avoid confusing state regulations in the
United States and the high cost of surrogacy, couples
are seeking aid overseas; the president of
PlanetHospital, a “medical tourism” agency in
California, expects to send at least 100 couples to
India this year for surrogacy, up from 25 in 2007.
• In contrast to the estimated $50,000 spent in the
United States, surrogacy in India can typically be done
for $10,000–$12,000.
http://www.thehastingscenter.org/Publications/BriefingBook/Detail.aspx?id=2210
Do your patients express concerns with reproduction and
specifically ask for referrals for fertility evaluations and/or
treatment?
A. Yes
B. No
0%
A.
0%
B.
Assisted Reproductive Technology
According to HIV Sero-status
• HIV+ female/HIV- male (HIF/HUM)
• HIV+ male/HIV- female (HIM/HUF)
• Both HIV+
HIV+ female/HIV- male
• Sperm is handled with the usual precautions (HIV-)
• Assure optimal female health: Low viral load, high CD4,
clinically stable, avoid efavirenz, didanosine (ddI), stavudine
(d4T)
• Self insemination (12-36 hrs after the LH peak) using a
syringe and an angio-cath or pediatric feeding tube
• Intrauterine insemination (IUI) when there is oligospermia,
semen is washed and re-suspended and it can be inserted
into the uterine cavity (risks: infection, anaphylaxis)
• Ovulation induction with Clomiphene or Gonadotropins
(FSH)
• In vitro fertilization with embryo transfer (IVF-ET)
HIV- female/HIV+ male
• HIV infection has been reported in 6 cases of donor
insemination*
• HIV infection was reported by the CDC after sperm
washing in 1990**
• Some states regulate (control) the use of
“contaminated semen” and consider it as a felony
*Wortley PM, Hammett TA, Flemming PL. Donor insemination and HIV transmission Obstet Gynecol
1998;91:515-518
** HIV infection and artificial insemination with processed semen; MMWR 249, 255-256; 1990
Sperm Washing and
Intrauterine Insemination (IUI)
 First reported by Semprini et al. (1992) in Milan, Italy
 Spermatozoa lack the CD4 receptor and the CCR5 and CXCR4 coreceptors
 Density gradient centrifugation combined with sperm swim-up,
effectively separate the motile fraction of spermatozoa from the seminal
plasma and non-motile cells and have reduced HIV RNA and proviral
DNA to undetectable
 Large number of patients successfully treated
 At least 3,019 cycles among 1,111 patients with 497 pregnancies,
almost 400 births and NO HIV SEROCONVERSIONS
Sperm washing techniques address the fertility needs of HIV-seropositive men: A clinical review; Mark Sauer;
Reproductive BioMedicine Online; www.rbmonline.com/Article/1541: Vol 10 No 1, 2005
Intrauterine Insemination (IUI) vs.
In Vitro Fertilization (IVF): Assessing Risks
 IUI is technically easier, less expensive, and with similar
efficacy than IVF
 Number of procedures for IUI is greater
 Some jurisdictions in the US prohibit “insemination” of HIVinfected material (issue of criminal or civil liability)
 IUI requires millions of sperm cells as compared with IVF ICSI (intracytoplasmic sperm injection) which uses less
than 20 sperm cells
 Published experience of 543 cycles of IVF-ICSI in 353
patients with 201 pregnancies and NO HIV
SEROCONVERSIONS
Sperm washing techniques address the fertility needs of HIV-seropositive men: A clinical review; Mark Sauer;
Reproductive BioMedicine Online; www.rbmonline.com/Article/1541: Vol 10 No 1, 2005
Safety and Efficacy of Sperm Washing in HIV-1-Serodiscordant
Couples Where the Male is Infected: Results From the
European CREAThE Network
• 3,390 assisted intrauterine
inseminations
– 107 IVF
– 394 ICSI
– 49 frozen embryo transfers
• 533 pregnancies resulted in
410 deliveries and 463 live
births
• 967 out of 1036 women had
HIV testing negative (7.1% lost
to follow-up)
•
•
The calculated probability of
contamination was equal to zero
(95% confidence interval, 00.09%).
“These results support the view
that assisted reproduction with
sperm washing could not be
denied to sero-discordant couples
in developed countries and, where
possible, could perhaps be
integrated into a global public
health initiative against HIV in
developing countries”
Bujan; Hollander; Coudert; Gilling-Smith; Vucetich ;Guibert; Vernazza; Ohl; Weigel; Englert; Semprini
AIDS. 2007;21(14):1909-1914
Timed Intercourse
• Considered unsafe for sero-discordant couples
• Transmission risk is small (0.1-0.2%), but cumulative
exposure will increase the risk
• Unprotected intercourse during the following 2 days after
the LH surge (ovulation kits)
Tenofovir for Pre-exposure Prophylaxis
(PrEP)
• Completed clinical trials of PrEP have tested tenofovir
– Oral TDF, oral TDF/FTC, TDF/FTC vaginal gel
• Potent: Rapid antiretroviral activity
• Safe: Substantial treatment safety experience
• Easy: Once-daily dosing, few drug-drug interactions
• Evidence that concept should work
– Animal models and postnatal prophylaxis of
breastfeeding infants showed high levels of
protection
iPrEx: Efficacy
• Efficacy through study end (mITT): 42% (95% CI: 18% to 60%)
Cumulative Probability
of HIV Infection
0.12
Placebo
FTC/TDF
0.10
0.08
0.06
P = .002
0.04
0.02
0
0
12 24 36 48 60 72 84 96 108 120 132 144
Wks Since Randomization
Pts at Risk, n
Placebo 1248 1198 1157 1119 1030 932 786 638 528 433 344 239 106
FTC/TDF 1251 1190 1149 1109 1034 939 808 651 523 419 345 253 116
Grant, Lama, Anderson et. al. N Engl J Med November 23, 2010,
Partners PrEP: TDF vs TDF/FTC vs Placebo in
HIV-Serodiscordant Couples
Follow-up:
36 mos
Oral Tenofovir QD
(n = 1584)
HIV-negative partners in
HIV-serodiscordant
heterosexual couples
Oral Tenofovir/Emtricitabine QD
(n = 1579)
(N = 4747)
Oral Placebo*
(n = 1584)
*Placebo arm terminated early on July 10, 2011, by data and
safety monitoring board.
Baeten J, et al. IAS 2011. Abstract MOAX0106
TDF2: PrEP With TDF/FTC Significantly
Reduces HIV Acquisition

9 vs 24 patients seroconverted in TDF/FTC vs placebo arms, respectively

Overall protective efficacy of TDF/FTC: 62.6% (95% CI: 21.5-83.4; P = .0133)

Reduction in HIV acquisition with TDF/FTC observed in both men and women
but study underpowered to demonstrate sex-based differences in outcomes
Time to
Seroconversion
(ITT Analysis)
Failure Probability
0.10
0.08
Placebo
0.06
0.04
TDF/FTC
0.02
0
0
Thigpen MC, et al. IAS 2011. Abstract WELBC01
1
Yrs
2
3
HPTN 052: Immediate vs Delayed ART for HIV
Prevention in Serodiscordant Couples
HIV-infected, sexually
active serodiscordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
•
•
•
Immediate HAART
Initiate HAART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed HAART
Initiate HAART at CD4+ cell count ≤ 250 cells/mm3*
(n = 877 couples)
Primary efficacy endpoint: virologically linked HIV transmission
Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe
bacterial infection and/or death
Couples received intensive counseling on risk reduction and use of
condoms
Cohen MS, et al. N Engl J Med. 2011;365: 493-505.
HPTN 052: HIV Transmission Reduced by 96% in
Serodiscordant Couples
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .0001)
Linked
Transmissions: 28
Delayed
Arm: 27
Immediate
Arm: 1
Cohen MS, et al. N Engl J Med. 2011;365: 493-505.
Unlinked or TBD
Transmissions: 11
Single transmission in patient
in immediate HAART arm
believed to have occurred
close to time therapy began
and prior to suppression of
genital tract HIV
• CDC interim guidance reinforced:
– TDF/FTC is the only proven effective PrEP regimen for MSM
– Daily dosing of PrEP is the only proven effective regimen
• Intermittent use efficacy unknown
– PrEP efficacy was demonstrated with HIV testing and other
prevention services
CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.
CDC now provides the following interim guidance for clinicians
considering the use of PrEP for adults at very high risk for HIV
acquisition through heterosexual sex:
1) TDF/FTC is contraindicated for PrEP in persons with unknown or positive
HIV status;
2) In women and men at very high risk for acquiring HIV from penile-vaginal
sex, daily doses of TDF/FTC can be safe and effective in reducing the
risk of HIV infection;
3) PrEP use may be one of several options to help protect the HIV-negative
partner in discordant couples during attempts to conceive;
4) Women of reproductive age should have a documented pregnancy test
before beginning PrEP and if not pregnant at initiation, at regular intervals
while being prescribed PrEP.
Preexposure Prophylaxis and Timed Intercourse for
HIV-discordant Couples Willing to
Conceive a Child
1) Male partner has been successfully treated with undetectable HIVRNA in plasma (<50 copies/ml) without the need of HIV-RNA
testing in semen.
2) No report of current symptoms of genital infections and no
unprotected sex with other partners.
3) LH-test in the urine is used to determine the optimal time of
conception (36 h after LH-peak).
4) Administration of PrEP with tenofovir, first dose at LH-peak and
second 24 h later.
5) After six unsuccessful attempts, a fertility evaluation was
suggested.
Pietro L. Vernazza, I. Graf, U. Sonnenberg-Schwan, M. Geit and A. Meurer AIDS 2011, 25:2005–2008
Preexposure Prophylaxis and Timed Intercourse for HIVdiscordant Couples Willing to Conceive a Child
• The first dose of tenofovir was taken by the female
partner in the morning of the LH-peak and a second
dose the next morning.
• Intercourse was timed at the evening after the second
dose of tenofovir.
• The couples were informed using written information
about the nature of the off-label use of tenofovir in the
HIV-negative partner.
Pietro L. Vernazza, I. Graf, U. Sonnenberg-Schwan, M. Geit and A. Meurer AIDS 2011, 25:2005–2008
Preexposure Prophylaxis and Timed Intercourse for HIVdiscordant Couples Willing to Conceive a Child
• 46 sero-discordant
couples were treated
• The males were
undetectable on HAART
• Two doses of tenofovir
were given 36 and 12
hours prior to
programmed coitus
• 26% pregnancies during
the first attempt
• 66% pregnancies within
the first 5 attempts
• There were 244
unprotected sex events
on 53 couples
• All the women were HIV
negative after 3 months
Pietro L. Vernazza, I. Graf, U. Sonnenberg-Schwan, M. Geit and A. Meurer AIDS 2011, 25:2005–2008
Preexposure Prophylaxis and Timed Intercourse for HIVdiscordant Couples Willing to Conceive a Child
Pietro L. Vernazza, I. Graf, U. Sonnenberg-Schwan, M. Geit and A. Meurer. AIDS 2011, 25:2005–2008
Comparison with PrEP
• PrEP described here was used as a theoretical risk
reduction strategy in a situation wherein the a priori
risk is considered to be extremely low
• PrEP was only given 36 and 12 h prior to timed
vaginal intercourse.
• Given the strong social pressure to conceive children
in many resource-limited regions, the proposed
method of timed intercourse coupled with PrEP might,
however, warrant further development.
• The role of timed intercourse coupled with PrEP might
help women at risk to significantly reduce their risk of
HIV acquisition during conception.
Which recommendation is incorrect regarding the use of
PrEP for the prevention of HIV among heterosexual
couples?
A.
B.
C.
D.
E.
Prescribe daily Truvada®
(TDF/FTC), beginning before the
first possible conception-related
exposure and continuing for 28
days after the last possible
exposure
Provide HIV risk-reduction (e.g.,
unprotected sex only during
timed conception attempts) and
adherence counseling
No HIV testing is necessary it the
partner was tested within six
months to one year prior to the
treatment
Educate uninfected partner about
the symptoms associated with
acute HIV infection
Monitor for side effects and
clinical toxicities
0%
A.
0%
0%
B.
C.
0%
0%
D.
E.
Precautions for PrEP use in Heterosexual
HIV-discordant Couples
• Provide a full explanation of the potential risks and benefits
of peri-conception PrEP (or PrEP during pregnancy) and all
available alternatives for safer conception, and document in
the patient chart.
• Before initiating PrEP, conduct laboratory screening of all
PrEP candidates to determine renal function, hepatitis B
infection status, and to confirm HIV-negative status.
• Prescribe daily oral 300 mg doses of tenofovir alone or in
combination with 200 mg of emtricitabine, beginning before
the first possible conception-related exposure and
continuing for 28 days after the last possible exposure.
Lampe MA, Smith DK, Anderson GJE, et al. Achieving safe conception in HIV-discordant couples: the potential
role of oral preexposure prophylaxis (PrEP) in the US. Am J Obstet Gynecol 2011;204:488.e1-8
Precautions for PrEP use in Heterosexual
HIV-discordant Couples
• Provide HIV risk-reduction (e.g., unprotected sex only
during timed conception attempts) and adherence
counseling
• Monitor for side effects and clinical toxicities (especially
renal dysfunction) in regular intervals (e.g., 30 days
after starting PrEP and every 2-3 months thereafter).
• Educate uninfected partner about the symptoms
associated with acute HIV infection and the need to
immediately contact the provider for HIV testing and
further evaluation.
Lampe MA, Smith DK, Anderson GJE, et al. Achieving safe conception in HIV-discordant couples: the potential
role of oral preexposure prophylaxis (PrEP) in the US. Am J Obstet Gynecol 2011;204:488.e1-8
Precautions for PrEP use in Heterosexual
HIV-discordant Couples
• Obtain follow-up HIV testing frequently during continuous
PrEP and after discontinuing PrEP (e.g., 30 day and 60
days after stopping).
• If the negative partner becomes infected, conduct testing
for resistance mutations to guide future treatment
choices.
• Monitoring for possible hepatic flares when stopping
tenofovir in a person with chronic hepatitis B infection
Lampe MA, Smith DK, Anderson GJE, et al. Achieving safe conception in HIV-discordant couples: the potential
role of oral preexposure prophylaxis (PrEP) in the US. Am J Obstet Gynecol 2011;204:488.e1-8
UK-National Institute for Health and Clinical Excellence
(Guideline Development Group-GDG)
• Though the evidence in this area was of limited quantity and quality
they were impressed by the fact that there had been no reports of
seroconversion in the woman when the HIV positive male partner was
compliant with HAART or had a viral load of less than 400 copies/ml.
• Given that evidence, the GDG were of the view that where the male
partner was compliant with HAART and the viral load was less than 50
copies/ml (currently the way in which most laboratories indicate that
there is no detectable virus), couples could be advised to have
unprotected vaginal intercourse at the time of ovulation.
• All the following conditions should be met (Swiss Criteria):
–
–
–
–
Unprotected intercourse is limited to the time of ovulation.
The man is complying with highly active antiretroviral therapy (HAART).
The man has a plasma viral load of less than 50 copies/ml.
There are no other sexually transmitted infections.
Fertility: assessment and treatment for people with fertility problems (update) National Collaborating Centre for Women’s
and Children’s Health Commissioned by the National Institute for Health and Clinical Excellence Draft for stakeholder
consultation – May 2012 http://www.nice.org.uk/nicemedia/live/12157/59278/59278.pdf
HIV DISCORDANT COUPLES LOOKING FOR
PREGNANCY OR ASSISTED REPRODUCTION HAVE
SEVERAL OPTIONS NOW. WHICH IS THE SAFEST?
A. Unprotected intercourse during
ovulation
B. Timed intercourse with treatment
of the HIV positive partner
C. In-vitro fertilization (IVF)
D. Timed intercourse with PrEP for
the HIV negative partner
E. a and b
0%
A.
0%
0%
B.
C.
0%
0%
D.
E.
Final Recommendations
• The safest method is IVF (in-vitro fertilization) or
ICSI (intra-cytoplasmic sperm injection)
• The clinic should have a protocol for Assisted
Reproduction (ART)
• Proper counseling on risks and benefits needs to be
provided
• The current FDA approval is for prevention of sexual
transmission (but not specifically directed to Assisted
Reproduction Technologies [ART])