A multi-year project funded by the u.s. national institutes of health
Led by investigators at four major U.S. universities, PHASES (Pregnancy & HIV/AIDS: Seeking Equitable Study) seeks ethical solutions to advance research at the intersection of women’s reproduction and HIV prevention, treatment, and management.
Despite tremendous advances in science of prevention, treatment, and management of HIV since the emergence of the epidemic, we still know very little about how to best address the needs of a key population affected by HIV: pregnant women.
An estimated 16.1 million women are living with HIV worldwide, with millions more at risk of becoming infected. Many of these women are of reproductive age, posing important medical questions about how best to prevent and treat HIV in pregnant women and how to properly manage HIV and concurrent medical conditions during pregnancy:
Pregnant women are up to two-times more likely to acquire HIV than other women, and infection during pregnancy has been demonstrated to increase the odds 15-fold of maternal- to-child transmission. Yet many prevention trials, including the groundbreaking CAPRISA 004 microbicide study, exclude pregnant women.
TREATMENT OF CO-INFECTION
Studies have reported that HIV-infected pregnant women have active Tuberculosis (TB) at about 10 times the rate of HIV-uninfected pregnant women, and in South African teaching hospitals TB accounted for 15% of maternal mortality. However, many current TB regimens are not recommended during the first trimester of pregnancy (or for women with childbearing potential), and the emergence of drug-resistant TB presents further challenges. While a new class of antituberculosis drugs is revolutionizing the treatment of drug-resistant TB, pregnant women have been excluded from trials and there are no data to guide dosing or treatment decisions, even though drug-resistant TB associated with HIV is a major cause of perinatal morbidity and mortality.
MANAGEMENT OF HIV
Studies of optimal dosing strategies for new antivirals in pregnant women have lagged behind the use of these new drugs in the clinical setting, meaning that pregnant women are being prescribed medication solely based on studies in non-pregnant individuals. This can lead to suboptimal or insufficient dosing with unknown associated toxicity.
In addition to these vulnerabilities, we also know that pregnancy can substantially alter drug metabolism, with implications for appropriate dosage and toxicity profiles of existing therapies. Yet in spite of the critical need to assess optimal treatment and prevention options – for both the mother and developing child – there is surprisingly little evidence on how necessary therapies will work during pregnancy.
Ethical and legal concerns of including pregnant women in studies have led to widespread exclusion of this population from medical research. But without the systematic generation of evidence, these women and their health care providers must face difficult clinical decisions in the absence of adequate information on safety and efficacy of new antivirals, preventive agents, and drugs to treat co-infections and other associated diseases.
The categorical exclusion of pregnant women from research is unacceptable. A new paradigm must be forged to safely and responsibly include pregnant women in research so that all pregnant women and their developing children will ultimately benefit from interventions critical to their health and wellbeing.
AIM OF The phases grant
One of our core projects is the PHASES grant. This project aims to develop ethically acceptable strategies to conducting research on HIV treatment and prevention during pregnancy. PHASES will focus on three specific areas of HIV research in urgent need of an evidence base applicable to pregnant women: prevention, treatment of co-infection, and disease management.
The objectives of PHASES are to:
- Identify scientific priorities for research addressing pregnancy and HIV prevention, treatment, and management
- Characterize the perceived barriers to including pregnant women and women who may become pregnant in HIV-related research
- Explore potential novel study designs that will minimize ethical and legal concerns of HIV research with pregnant women and women who may become pregnant
- Develop a conceptual ethical framework for HIV research in pregnancy that is responsive to the priority areas and current barriers
In our pursuit of ethically and scientifically responsible solutions for enhancing society’s knowledge base to effectively prevent HIV and manage HIV treatment during pregnancy, we are conducting a series of engagement meetings in the US and Africa with leading HIV investigators, bioethicists, IRB members, legal and regulatory experts, and policy leaders in agenda-setting to develop an action-guiding ethical framework to navigate the complexities of including pregnant women in research in the US and in southern Africa, with a dedicated emphasis on South Africa, Malawi, and Botswana. The goal of these consultations is to gather information on the most pressing research priorities, identify the major obstacles to conducting HIV research with pregnant women and women who may become pregnant, and strategize potential solutions within the currently legal framework.
We are also conducting qualitative research via in-depth interviews and focus groups with pregnant (or recently pregnant) women at-risk for or infected with HIV in the US and in Malawi. The aim of these interviews is to characterize reasoning around and experiences with participation in such studies, ensuring that guidance is informed by the experiences of actual and potential pregnant study participants as well.
With the partners we identify in these engagement sessions, we will develop and vet a robust conceptual framework for ethically permissible HIV research with pregnant women and women who may become pregnant and a set of practical, workable, consensus recommendations responsive to the priorities and current barriers.
The framework and recommendations will provide useful guidance to investigators, ethics review committees, and policy makers, and enable investigators and the larger research enterprise to address critical questions related to HIV and the optimal care for women who are or may become pregnant. In turn, health providers worldwide will be able to make evidence-informed clinical decisions to best promote the health of these patients.