MTN-016: HIV Prevention Agent Pregnancy Exposure Registry
EMBRACE
(Evaluation of Maternal and Baby outcome Registry After Chemoprophylactic Exposure)
1. What is the aim of MTN-016, or EMBRACE?
MTN-016, the HIV Prevention Agent Pregnancy Exposure Registry, is an observational study that seeks to learn whether using a vaginal microbicide or antiretroviral (ARV) tablets – products being tested for preventing HIV – can affect a woman’s pregnancy outcome or her baby’s general growth and development. Researchers are conducting the study, also known as EMBRACE (Evaluation of Maternal and Baby outcome Registry After Chemoprophylactic Exposure), because women need a product that will be safe and effective to use all the time, including when they are pregnant. The study involves the creation of a database called a registry containing health information about women who either unintentionally got pregnant while in an HIV prevention trial or who participated in a safety study of microbicides during pregnancy. In addition, the registry will include information about the health of the babies born to these women. Ongoing and future analysis of registry data will help researchers determine if there are any links between product use and problems that can occur with pregnancy, such as miscarriage, premature delivery or birth defects. Researchers also will be able to evaluate the effects, if any, products may have on an infant’s first-year development and growth. Researchers expect that eventually the registry will contain information from more than 500 women and 300 infants.
2. Why is EMBRACE important?
Women account for more than half of all HIV infections worldwide, and the majority are acquiring HIV through heterosexual intercourse. In fact, women are twice as likely as their male partners to acquire HIV during sex, due in part to biological factors that make them more susceptible. During pregnancy, the risk of acquiring HIV from an infected partner during sex is doubled, recent studies suggest. Microbicides and pre-exposure prophylaxis (PrEP), which involves the use of ARVs, are two promising HIV prevention approaches being tested in different clinical trials. However, little is known about the safety of these products during pregnancy and the effects they may have on pregnancy outcome and infant health. As such, women in HIV prevention trials must use contraception, and if unintended pregnancies occur, they must stop use of study products. In Africa, researchers can expect about 5 to 10 percent of women in a trial to become pregnant during the course of the study. If a trial finds microbicides or PrEP is effective, and either approach become widely available, it will be important to verify that they are safe to use during pregnancy. Indeed, a 2008 Institute of Medicine report on the methodological challenges in HIV prevention trials included among its key recommendations the need for evaluating the potential effects products may have on pregnant women and their babies. EMBRACE is an important component in a portfolio of MTN studies that are specifically focused on pregnancy, including first trial assessing the safety of microbicides and PrEP in pregnant women.
3. Who is conducting EMBRACE?
EMBRACE is being conducted by the Microbicide Trials Network (MTN), a clinical trials network established and funded in 2006 by the Division of AIDS (DAIDS) at the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), all components of the U.S. National Institutes of Health (NIH). NIAID/DAIDS and NICHD are funding EMBRACE, which is being led by Richard Beigi, M.D., M.Sc., of the University of Pittsburgh School of Medicine, and Samuel Kabwigu, MBChB, M.Med., from Makerere University in Kampala, Uganda.
4. What is a microbicide?
Microbicides are substances designed to prevent or reduce the sexual transmission of HIV or other sexually transmitted infections (STIs) when applied topically inside the vagina or rectum. A microbicide can be formulated in many ways, such as a gel or cream, or as a vaginal ring that would release the active ingredient over time. Different microbicide products are being tested in clinical trials, including trials being conducted by the MTN, although no microbicides are currently approved or available for use.
5. What is pre-exposure prophylaxis (PrEP)?
Pre-exposure prophylaxis, or oral PrEP, is an experimental HIV prevention approach that involves the use of ARVs by people who are HIV-negative. The idea is that by taking a medicine routinely, daily for example, HIV infection would be prevented if a person were exposed to the virus, such as through unprotected sex.
6. How is EMBRACE different from other microbicide studies or pregnancy drug exposure registries?
EMBRACE is not the kind of study that tests different products. But it is an important complement to studies that do. EMBRACE is the first registry for reporting and tracking information about the effects that vaginal microbicides or ARV tablets as HIV prevention may have on pregnancy outcome and infant health. Unlike most other pregnancy drug exposure registries, EMBRACE will also capture information about infant outcomes, including developmental milestones and growth in the first year of life. Including this information in the registry data will provide a more substantive picture of the potential impact of study product exposure on pregnancy and infant outcomes. EMBRACE is also unique because its design will allow researchers to directly compare pregnancy outcomes among women who were exposed to active agents with pregnancy outcomes among women who had used a placebo.
7. How is EMBRACE being conducted?
Because the effects of study products on pregnancy are not fully known, women participating in HIV prevention trials must agree to use contraception, in addition to male condoms. Still, pregnancies are not uncommon, occurring in at least 5 to 10 percent of participants. Researchers anticipate that most of the women who will be enrolled in the EMBRACE Study will be women who unintentionally got pregnant while taking part in MTN’s VOICE Study – Vaginal and Oral Interventions to Control the Epidemic, a large trial involving about 5,000 women that is testing daily use of a vaginal microbicide containing the ARV tenofovir and daily use of the ARV tablet tenofovir or Truvada®. If a woman in VOICE has a positive pregnancy test and the result is confirmed, she will be invited to participate in EMBRACE. Women who enroll in EMBRACE can continue participation in VOICE, but must remain off study product while pregnant or breastfeeding.
Some women who enroll in EMBRACE will be drawn from studies specifically designed to evaluate the safety of HIV prevention products during pregnancy. For example, researchers designed one trial, MTN-002, to study the extent that drug in a single dose of tenofovir gel is absorbed in the body and whether the drug can be transferred to the fetus. EMBRACE is open to women participating in non-MTN HIV prevention trials as well.
Researchers will collect and track detailed information about a woman’s medical and pregnancy history, the course and outcome of her current (or recent) pregnancy, including details about her labor and delivery. The study will also collect baseline information about infants within the first 10 days after delivery and developmental screenings conducted at one, six and 12 months of age. Information gathered at birth and all subsequent visits for an entire year will include comprehensive assessment of growth, general appearance and health – parameters that are typically measured in the evaluation of a newborns and infants. Of most interest to researchers will be whether a woman had used an active product or a placebo when she became pregnant, or in the case of women in a pregnancy safety study, whether they had been assigned to use an active product or placebo. Because each of the parent trials is blinded, neither the participants nor the researchers can know which study product a woman had been assigned to use until after that study has been completed and study group assignments have been unblinded.
8. What kind of microbicides or PrEP agents might pregnant women be exposed to?
Women enrolled in the registry may have been exposed to one of several active products being tested in MTN or other trials or to a placebo – a gel or tablet that looks identical to the active product but contains no active ingredient. Study products currently being tested in MTN trials are oral tenofovir, oral Truvada and tenofovir gel. EMBRACE will eventually include women from studies evaluating other microbicides or PrEP agents as well.
Tenofovir and Truvada are approved for the treatment of HIV when used in combination with other ARVs, a regimen called antiretroviral therapy (ART). The full name for tenofovir is tenofovir disoproxil fumarate (TDF) and is known by the brand name Viread®. Truvada is the brand name for a combination drug that contains tenofovir and another active ingredient called emtricitabine (FTC). Sometimes researchers refer to Truvada as TDF+FTC. Both tenofovir and Truvada belong to a class of anti-HIV medications called nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) that act against HIV by targeting a key enzyme the virus needs to copy its genetic material – an essential step for the virus to multiply and infect other cells inside the body. Both drugs have excellent safety profiles and are well tolerated by most HIV-infected people. In some, minor side effects can include upset stomach, dizziness, headache, joint pain or fever. Serious side effects are rare, but can include liver function problems, kidney damage or failure, or reduction in bone mineral density.
Much less is known about the safety and side effects of these drugs in people without HIV, but a study conducted by Family Health International in HIV-negative women in Ghana, Cameroon and Nigeria found no serious side effects, including to the liver, kidney or bone, associated with daily use of tenofovir. Of 859 participants for whom safety information was received, some noted stomach discomfort and headache.
In its current formulation, each dose of tenofovir gel contains approximately 40 mg of active drug. Preclinical studies have demonstrated that tenofovir gel can prevent HIV infection of vaginal tissue. Clinical safety studies performed to date indicate it is well tolerated and safe in both HIV-positive and HIV-negative women. Results from an expanded safety and acceptability trial called HPTN 059 found the gel was safe in sexually active HIV-negative women when used every day for six months. More recently, the CAPRISA 004 study found tenofovir gel reduced the risk of HIV by 39 percent among women who used it before and after sex compared to women who used a placebo gel.
Tenofovir, Truvada and tenofovir gel all were developed by Gilead Sciences, Inc., of Foster City, California, USA, which assigned a royalty-free license for the topical gel to the International Partnership for Microbicides of Silver Spring, Maryland, and CONRAD, in December 2006.
9. What do we know about tenofovir and Truvada in pregnancy?
Both tenofovir and Truvada are designated by the U.S. Food and Drug Administration as a pregnancy category B drug, a classification given to drugs in which animal studies have not found fetal risk. Since 1989, researchers have been tracking information about HIV-infected women who may have used these or other ARVs during pregnancy through the Antiretroviral Pregnancy Registry. Registry data indicates no difference in the prevalence of birth defects from the general population. Similarly, the registry’s information on more than 850 HIV-infected women who received treatment with oral tenofovir during their pregnancies has seen no differences in birth defects compared to babies whose mothers never took tenofovir. In other studies, researchers found that while some tenofovir gets transferred to the babies of HIV-infected mothers who took the drug during pregnancy, the babies had no complications or problems that were thought to be drug-related.
No information is available on the use of tenofovir or Truvada in pregnant HIV-uninfected women.
Oral tenofovir is also being studied in HIV-infected women late in pregnancy for its potential to prevent mother-to-child transmission of HIV. In a study being conducted by the NIH-funded International Maternal, Pediatric, and Adolescent AIDS Clinical Trials Group, researchers have thus far seen no significant side effects or problems among 15 women and infants following a 600 mg oral dose of tenofovir given either at the onset of labor or four hours before scheduled Cesarean delivery.
10. What do we know about tenofovir gel use during pregnancy?
MTN researchers recently completed the first study of tenofovir gel in pregnant women. MTN-002 involved giving a single dose of tenofovir gel to healthy, HIV-uninfected women hours before they gave birth by scheduled Cesarean delivery to determine how the drug is absorbed during pregnancy and whether it can transfer to the fetus. Researchers found only small amounts of drug were absorbed into the mother’s bloodstream, amniotic fluid and umbilical cord (fetal) blood after topical application of the gel. After a single dose of the gel, the amount of drug in umbilical cord blood was 40 times lower than what has been seen in studies in HIV-infected women receiving a single 600 mg dose of oral tenofovir. The median drug levels found in maternal blood were 50 to 100 times lower with the tenofovir gel than with oral dosing. Moreover, the amount of drug absorption seen in the pregnant women in MTN-002 was remarkably similar to absorption levels after one application of tenofovir gel in nonpregnant women. Importantly, there were no serious side effects attributed to the gel in either the mothers or their newborns within the first two weeks of life, the time during which researchers were collecting information. While analysis of some of the data is still to be completed, based on what is known of the results at this time, the researchers plan to conduct a larger study of tenofovir gel involving both pregnant and breastfeeding women.
11. What approvals were required for this study to get underway?
The study underwent extensive and rigorous review by NIAID, NICHD, the U.S. Food and Drug Administration (FDA) and the University of Pittsburgh Institutional Review Board (IRB), as well as local IRBs in the other countries where sites are conducting EMBRACE. IRBs ensure that studies are scientifically valid and ethically conducted by providing oversight throughout the duration of a trial.
12. What will be done to ensure the safety and wellbeing of the participants?
Because EMBRACE is an observational study that does not involve investigational products or risky procedures, few safety concerns are anticipated. Nevertheless, study investigators will closely monitor participants. Women will be referred to local services for prenatal care. If investigators find medical concerns when examining infants, referrals will be made to local pediatricians for care. The study site staff offers HIV testing for infants, as well as pre-test and post-test counseling for the infants’ parents and guardians. Staff at study sites make every effort to protect participants’ privacy, but it is still possible that others may learn of a participant’s involvement in the study. Study staff will offer counseling and other support services to participants as needed.
13. Do women and infants participating in the study provide informed consent?
Women who agree to participate in EMBRACE sign an informed consent form and parents or guardians sign an informed consent form for the infants. The process of obtaining written informed consent ensures that women understand the procedures, as well as possible risks and benefits of the study. Participants are under no obligation to participate and may leave the study at any time, without consequence.
14. When will information from the registry be available?
Researchers will be conducting ongoing analysis as data is collected into the registry. Researchers will be able to provide more comprehensive results once parent trials are closed and information about study product assignments is entered into the database.
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About the Microbicide Trials Network
The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.
More information about MTN-016 and other MTN studies can be found at http://www.mtnstopshiv.org/news.
22-October-2010
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