Assisted Reproduction Among HIV Sero-Discordant Couples Carmen D. Zorrilla, MD Professor, OB-GYN, UPR School of Medicine Maternal-Infant Studies Center.

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 interest represented in the presentation.

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

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

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

ART: Long-term outcomes


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/

http://www.aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0/



History Physical exam

• 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

• 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

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

• 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) 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

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

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.”


“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.


Do your patients express concerns with reproduction and specifically ask for referrals for fertility evaluations and/or

treatment?

A. Yes

B. No

A. B.

0%0%

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 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

HIV- female/HIV+ male

Sperm Washing and Intrauterine Insemination (IUI)

First reported by Semprini et al. (1992) in Milan, ItalySpermatozoa lack the CD4 receptor and the CCR5 and CXCR4 co-

receptorsDensity 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 greaterSome jurisdictions in the US prohibit “insemination” of HIV-

infected 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, 0-0.09%).

• “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%)

P = .002

PlaceboFTC/TDF

Cu

mu

lati

ve P

rob

abili

ty

of

HIV

Infe

ctio

n0.12

0.10

0.08

0.06

0.04

0.02

01440 12 24 36 48 60 72 84 96 108 120 132

Wks Since RandomizationPts at Risk, n

PlaceboFTC/TDF

1248 1198 1157 1119 932 786 638 528 433 344 2391030 1061251 1190 1149 1109 939 808 651 523 419 345 2531034 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

HIV-negative partners in HIV-serodiscordant

heterosexual couples

(N = 4747)

Oral Tenofovir QD(n = 1584)

Oral Tenofovir/Emtricitabine QD(n = 1579)

Oral Placebo*(n = 1584)

*Placebo arm terminated early on July 10, 2011, by data and safety monitoring board.

Follow-up:36 mos

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

Fai

lure

Pro

bab

ility

0.02

0.04

0

0.06

0.08

0 1 2 3Yrs

TDF/FTC

Placebo

0.10Time to

Seroconversion (ITT Analysis)

Thigpen MC, et al. IAS 2011. Abstract WELBC01

HPTN 052: Immediate vs Delayed ART for HIV Prevention in Serodiscordant Couples

Immediate HAART Initiate HAART at CD4+ cell count 350-550 cells/mm3

(n = 886 couples)

Delayed HAARTInitiate HAART at CD4+ cell count ≤ 250 cells/mm3*

(n = 877 couples)

HIV-infected, sexually active serodiscordant

couples; CD4+ cell count of the infected partner:

350-550 cells/mm3

(N = 1763 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

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

Total HIV-1 Transmission Events: 39(4 in immediate arm and

35 in delayed arm; P < .0001)

Linked Transmissions: 28

Unlinked or TBD Transmissions: 11

Immediate Arm: 1

Delayed Arm: 27

Cohen MS, et al. N Engl J Med. 2011;365: 493-505.

• 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.

1) Male partner has been successfully treated with undetectable HIV-RNA 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.

Preexposure Prophylaxis and Timed Intercourse for HIV-discordant Couples Willing to

Conceive a Child

Pietro L. Vernazza, I. Graf, U. Sonnenberg-Schwan, M. Geit and A. Meurer AIDS 2011, 25:2005–2008

• 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.

Preexposure Prophylaxis and Timed Intercourse for HIV-discordant 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


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. Prescribe daily Truvada® (TDF/FTC), beginning before the first possible conception-related exposure and continuing for 28 days after the last possible exposure

B. Provide HIV risk-reduction (e.g., unprotected sex only during timed conception attempts) and adherence counseling

C. No HIV testing is necessary it the partner was tested within six months to one year prior to the treatment

D. Educate uninfected partner about the symptoms associated with acute HIV infection

E. Monitor for side effects and clinical toxicities A. B. C. D. E.

0% 0% 0%0%0%

• 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.



• 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



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

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

A. B. C. D. E.

0% 0% 0%0%0%

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])

Assisted Reproduction Among HIV Sero-Discordant Couples Carmen D. Zorrilla, MD Professor, OB-GYN, UPR School of Medicine Maternal-Infant Studies Center.

Documents