United States Clinical Experience with Assisted Reproductive Technology in HIV-discordant Couples

Mark V. Sauer, MD

Professor Department of Obstetrics & Gynecology

Columbia University

New York, New York

Scope of the Problem

Nearly one million Americans are infected with HIV

Most HIV-seropositive individuals are of reproductive age

Heterosexual contact greatest risk factor in women

Many infected men and women desire to have biologic offspring

“Safe sex” recommended for prevention, but also prevents pregnancy

CDC. HIV/AIDS Surveillance Report 2003

Family Planning Perspectives 2001; 33:144-152.

Changing Attitude and Outlook

HAART enhances longevity and quality of lifeCompliant patients remain healthy for many years following diagnosisDisease now considered a chronic illness rather than terminal disease

Improved awareness of epidemic

Increased social acceptance

Emphasis on maintaining productive “normal” lives of infected patients

Hurdles to Fertility Care Lack of meaningful published reports defining safety

No RCTs regarding methodology, safety or efficacy No short or long term follow-up of children or families

CDC recommendation against treatment

State laws that assign criminal penalties

Insurance contracts may preclude HIV-seropositive patients

Perceived liabilities of engaging in care Malpractice Discrimination lawsuits vs conscientious objectors Patient concerns regarding cross-contamination Civil and criminal penalties

Clinical and Basic Science Support Clinical science: large series reports attesting to general safety

Over 3,000 washed insemination cycles reported without infection Nearly 1,000 IVF cycles reported without infection

Basic science: defining relationship of virus to reproductive tract tissues Transmission through cellular elements in semen or free virus in fluids Viral cultures of semen commonly positive (10-20%) Compartmentalization in reproductive tract tissues may occur Sperm lack CD4 receptor and may not harbor virus HIV rarely if ever detected from the most motile washed fraction used in ART Sperm surface membrane may allow alternative pathway for HIV gp120 binding

(GalAAG pathway) but remains unsubstantiated

Reprod Biomed Online 2005; 10:135-140.

Programs Reportedly Accepting HIV Infected Patients

Columbia University, New York, NY

Eastern Virginia Medical College, Norfolk, VA

Albert Einstein Medical College, Bronx, NY

Washington University, St. Louis, MO

University of Colorado, Denver, CO

UMDNJ-New Jersey Medical Center, Newark, NJ

Published Clinical U.S. Experience Abstracts presented at scientific meetings

3 of 822 abstracts at ASRM related to HIV in 2002 4 of 913 abstracts at ASRM related to HIV in 2004

Peer reviewed CU manuscripts since 2002 13 papers in print 2 papers in press

Applying Essential Principles of Medical Ethics Autonomy

Informed rationale decisions Alternatives to treatment offered Individuals may participate or withdraw

Non-maleficence No evidence of needless harm Harm may result from “omission” of care

Beneficence Protects women and children Enhances quality of life

Justice Fair distribution of accessible services

Am. J. Bioethics 2003; 3:33-40.

Columbia University Experience Consultants providing interdisciplinary support

Dr. Mark Sauer- Reproductive Endocrinology Dr. Scott Hammer- Infectious Disease Dr. Jane Pitt- Infectious Disease Dr. Shreedhar Gaddipatti- Maternal Fetal Medicine Dr. Kenneth Prager- Medical Ethics

Initiation of fertility treatment of HIV-seropositive males 1997

Initiation of fertility treatment of HIV-seropositive females 2002

Columbia University IVF/ICSI Program Goals To provide HIV serodiscordant couples an opportunity to safely have a child through assisted reproduction using IVF/ICSI

Access to a common procedure available throughout the U.S. Provide a therapy that doesn’t cross legal boundries of “insemination” Decrease the time to pregnancy, and number of needed exposures by ART

To gather data to further understand the needs of HIV seropositive patients seeking fertility assistance

Social, demographic, medical and reproductive database Follow up of families and individuals treated

To report ongoing experience to patients and professional peers in hope of changing attitudes and reducing prejudice

Encourage development of new programs Seek professional collaboration within REI and other disciplines

Columbia University Experience

Enrollment Criteria Men under active medical care and surveillance Demonstration of stable viral loads and CD4 status Individuals with viral counts > 30K cps/mL required to begin HAART Semen analysis with a total motile count > 1,000,000 Female partners reproductively competent to undergo IVF therapy

COH using standard GnRH-analogues and injectable gonadotropins Cycle monitoring using serial transvaginal ultrasound and serum E2 levels Egg retrieval under anesthesia by transvaginal ultrasound guided needle aspiration Transcervical embryo transfer on day 3 or day 5 post aspiration

Columbia University Experience Laboratory: Sperm Processing and IVF-ICSI

Fresh samples with 2 day abstinence Class II biologic hood outside embryology lab for processing Double wash technique following centrifugation with discontinuous density gradient 45-60 minute swim up Only most motile fraction selected for ICSI ICSI 4-6 hours post aspiration Separate incubators ETs days 3 or 5 Cryopreserve extra embryos Separate cryotanks

Post-transfer Surveillance Serum pregnancy test 12 days post ET

HIV-RNA testing each trimester in pregnant patients and at delivery and 3 months postpartum

HIV-RNA or HIV-DNA tests at delivery and 3 months in newborns

Non-pregnant patients tested with HIV-EIA or HIV-RNA 3 and 6 months post-embryo transfer

Published Early Experience Couples treated 61

Initiated cycles 113

Retrievals performed 100 (88.5%)

Clinical pregnancy rate per ET 44.8%

Delivery rate per ET 36.5%

Delivery rate per couple (inc. fresh and frozen ET) 54.1%

Seroconversions in treated patients 0

Seropositive newborns 0

Am J Obstet Gynecol 2002; 186:627-633.

Fertil Steril 2003; 80:356-362.

Columbia University Results 195 couples evaluated from 1998-2005

178 male HIV-seropositive 12 female HIV-seropositive 5 both partners HIV-seropositive

150 couples accepted into care 135 HIV-seropositive male 12 HIV-seropositive female 3 both partners HIV-seropositive

Variety of referral 50% from infectious disease specialist 35% self referred through internet or friends 15% from obstetrics/gynecology

Increasing number of cases with increased knowledge of availability 1997-2002 total of 50 cycles initiated of IVF-ICSI 2002-2005 total of 189 cycles initiated of IVF-ICSI

Columbia University Results Male HIV Discordant Experience, 1997-2005

f/u Pendingn=43

Livebornn=3

Transfern=8

Donorn=8

Cancelledn=22

Livebornn=97

Transfern=198

No Transfern=11

Retrievaln=209

Nondonorn=231

IVF-ICSIn=239

Livebornn=13

FETn=35

Total Cycles Initiatedn=274

f/u Initiatedn=135

Initial Patient Consultationsn=178

Patient Demographics for HIV-seropositive MalesAge (years) 37.2 + 5.6 (22 - 49)

Time from HIV diagnosis (years) 8.3 + 5.6 (1 - 20)

Undetectable viral load 48.9%

Detectable viral load (cps/mL) 3,381.5 + 6,130.9 (53 – 28,424)

CD4 T-cell counts (cells/mm3) 589.0 + 309.4 (13-1,810)

Route of presumed infection

Sexual 37.8%

Transfusions 20.0%

Drug use 5.2%

Unknown 37.0%

Columbia University Results Through 4/2005Number couples reaching retrieval 135

Number of retrievals 217

Cycle cancellation rate 9.2%

Oocytes per retrieval 16.1 + 9.4 (2-63)

Fertilized oocytes/retrieval 9.1 + 5.2 (0-32)

Embryos per ET 3.2 + 1.1 (1-8)

Clinical pregnancy per retrieval 48.3%

Ongoing/delivered pregnancy rate 43.3%

Ongoing/delivered per couple (includes FETs) 69.0%

Columbia University Results: 4/2005 Obstetrical outcomes (113 deliveries; 12 ongoing pregnancies)

Pregnancies from IVF-ICSI Singletons 65.5% Twins 32.1% Triplets 13.0% Quadruplets 1.1% Multiple gestations 46.4%

Delivery data Vaginal births 42.2% Cesarean section 57.8% Term Deliveries 68.4%

Gestational age 38.9 + 1.1 (37-41 wks) Birth weights 3501.2 + 491.1 (2550-4396 grams)

Preterm Deliveries 31.6% Gestational age 33.4 + 3.0 (26-36 wks) Birth weights 2072 + 944.4 (785-2940 grams)

Projecting Efficacy: Female Age Matters Life Table Analysis of 164 consecutive fresh treatment cycles

Best prognosis in women < 34 yrs.

Majority of pregnancies in 3 cycles

Delivery rate 2-times better in younger patients

Reprod Biomed Online 2005; 10:130-134.

HCV Co-infected Patients with HIV

Clinical outcomes for men co-infected with hepatitis C not different from general population of infertile couples or from couples with HIV infection

28 of 106 HIV seropositive men also co-infected with HCV54 cycles of ART performed using IVF-ICSIDelivered pregnancy rate 40% per ET20 of 28 couples (71%) achieved at least one successful pregnancyNo HIV or HCV seroconversions in patients or offspring

Arch Gynecol Obstet 2005; In press

ASRM Annual Meeting, 2004

Understanding Attitudes and Motivations Survey of initial 50 couples regarding demographics, attitudes and motives for seeking care

9 couples experienced a previous birth; 3 after knowledge of HIV infection 12% would attempt pregnancy through intercourse in help unavailable 48% prefer donor sperm insemination if fertility care unavailable 46% seek continued assistance even if partner died (posthumous therapy) 90% had openly discussed possibility for single parenting 66% hoped to have multiple children through continued ART usage

Obstet Gynecol 2003; 101:987-994.

Columbia University: HIV and Donor Egg Experience with oocyte donation

From 8/97-2/02 53 couples enrolled for IVF-ICSI 21% deemed ineligible due to advanced reproductive age or lack of ovarian response to

COH 5 couples elected to pursue oocyte donation with HIV-seropositive partner 3 of 5 couples delivered following 6 fresh attempts

2 singleton birth; 1 twin birth

Arch Gynecol Obstet 2003; 268:202-205.

Building Families Through ART Greater than 2/3 of couples expressed desire for further attempts after delivery of a child or children

5 of 5 couples previously successful were again pregnant following a subsequent attempt

Fertil Steril 2002; 78:421-423.

Complications Related to ART

4.6% initiated cycles treated for OHSS

47% pregnancies multiple gestation

14% pregnancies higher order multiples 3 triplet 1 quadruplet

Arch Gynecol Obstet 2003; 268:198-201.

HIV: Still a Deadly Disease LM 38-y/o: died sepsis and liver failure

PC 42-y/o: died cardiomyopathy and pulmonary hypertension

MS 47-y/o: died ruptured cerebral aneurysm

PR 32-y/o: died aseptic meningitis

MK 31-y/o: died liver failure

ASRM Annual Meeting, 2003.

Importance of Advanced Directives

Written and witnessed consent for the disposition of fresh and cryopreserved specimens and embryos

Clear and convincing evidence of intent of the deceased party in the absence of a written directive. Such evidence must be personally witnessed by the physician involved with the procurement of the gametes or embryos.

Ethics Committee Columbia Presbyterian Medical Center 2002

Columbia University Results Interesting case reports

Reversible iatrogenic azospermia secondary to prescribed androgen use Posthumous reproduction following the death of a life-partner

Obstet Gynecol 2003; 101:1073-1075.

Am J Obstet Gynecol 2002; 185:252-253.

Initiating a Program for Women with HIV Opportunity for HIV seropositive women to access fertility care

Pre-cycle testing the same as conventional infertility patients

Additional requirements MFM and ID medical clearance Maintain minimally detectable titers Initiate HAART prior to pregnancy and maintain throughout pregnancy

Patent tubes: COH and IUI

Failed IUI or women with tubal obstruction: IVF/ICSI

Initiating a Program for Women with HIV Clinical activity began in 2002

IUI of patients with patent fallopian tubes IVF request initially turned down by CPMC ethics committee

Initial 3 patients treated with COH/IUI All 3 women pregnant within 4 treatment cycles All newborns HIV seronegative

IVF-ICSI initiated 2004 3 patients treated; 2 ongoing pregnancies 7 patients screened and preparing to begin therapy

A Role for Assisted Reproduction?

Persons with HIV cannot be refused medical treatment unless objective scientific evidence demonstrates a significant risk of infection.

Americans with Disabilities Act

ART should not be denied to HIV-infected couples solely on the basis of their positive status

ACOG Committee Opinion 235, 2001

Summation: American Experience

Although various techniques using washed insemination methods are available, predominant ART used in U.S. has been IVF-ICSI

Few centers are currently offering ART to HIV seropositive patients

Multidisciplinary approach best for providing integrated care by internists, reproductive endocrinologists, maternal fetal medicine specialists, social workers and skilled laboratory personnel

Despite endorsement for treatment by ASRM and ACOG, the CDC continues to recommend against insemination methods

Conclusion: American Experience A slow but growing clinical experience and published literature by U.S. centers has emerged regarding reproductive care for HIV infected patients

State laws and concerns related to civil, professional and criminal liability have hindered wide-spread introduction of methods of treatment

Studies needed to address the growing needs of HIV infected patients Uniformity of approach to care Criteria for treatment Outcome tracking Multicenter collaboration both nationally and internationally