As part of National Institutes of Health (NIH) continuing efforts to provide useful resources for extramural awardees and applicants, answers have been compiled to the most frequently asked questions (FAQs) that are anticipated surrounding the renewal and expansion of the Women's Interagency HIV Study (WIHS-V). The purpose of this FAQ site is to clarify issues that may arise, and assist applicant institutions as they develop potential submissions to the recent Funding Opportunity Announcement (FOA) for WIHS-V.
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What is the WIHS, how many participants are included, and where are the current study sites?
The WIHS a multicenter, prospective, observational study of women who are either HIV-infected or at risk for HIV acquisition. Until the release of the current FOA inviting applications for the WIHS-V, the study has been a closed cohort of women from three prior enrollment waves: 1) cohort inception between 1994–1995 in which 2,625 women were enrolled (2,056 HIV-infected [including those with AIDS or low CD4 cell count] and 569 HIV-negative women); 2) cohort expansion in 2001–2002 in which 1,143 additional women were enrolled (254 HIV-positive [no AIDS and HAART naïve]; 484 HIV-positive [no AIDS prior to HAART/HAART experienced]; and 406 HIV-negative women); 3) cohort replenishment during 2011-2012, when existing clinical sites began to recruit new participants to replace those who had died since 2000 (target of 292 HIV-positive women [age 30–55 years, either HAART naïve or started HAART with a regimen that did not include ddI or d4T] and 121 HIV-negative women age 35–60 years with one or more risk factors for HIV-infection). As of September 2011, over 2,200 women were reported in active follow-up (completed at least one study visit).
WIHS is conducted at six clinical research sites (CRSs), each of which represents the population of HIV-infected women in or out of care within their geographical region, and is administered by the following grantee institutions: Montefiore Medical Center in Bronx, New York; SUNY Downstate in Brooklyn, New York; Hektoen Research Center in Chicago, Illinois; Georgetown University in Washington, DC; University of California at San Francisco in San Francisco; University of Southern California in Los Angeles. The current WIHS data management and analysis center (WDMAC) is located at the Johns Hopkins University Bloomberg School of Public Health in Baltimore, Maryland.
How is WIHS funded?
The WIHS is primarily funded by NIAID, with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Cancer Institute (NCI), and National Institute on Drug Abuse (NIDA). Co-funding has been provided also for specific substudies by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Institute on Deafness and Other Communication Disorders (NIDCD). New to WIHS-V will be the National Institute of Mental Health (NIMH) as an additional NIH co-funding institute.
How is the WIHS research relevant to the NIAID portfolio?
WIHS is an integral part of NIAID’s portfolio of research on HIV in women, and plays an important role in NIAID’s effort to understand the current epidemiology of HIV infection, disease progression, treatment use and outcomes, and related co-morbidities among HIV-positive individuals in the United States. Understanding differences in HIV disease and treatment outcomes between women compared to men, and in different racial and ethnic groups, is a critical research goal.
How does WIHS contribute to what is known about the current state of the HIV/AIDS epidemic?
HIV/AIDS continues to be a significant public health problem around the world. More than 56,000 people become infected with HIV each year in the United States, with 600,000 deaths among people with AIDS to date in this country alone. The HIV-1 epidemic in the United States has undergone substantial changes since the inception of WIHS in 1993. Originally an epidemic of men who have sex with men, HIV/AIDS is now a generalized heterosexual epidemic in some U.S. cities. Rates of HIV-1 infection among women, particularly minority women, have risen over time. HIV is now the third leading cause of death for African American men and women ages 35-44. The Centers for Disease Control and Prevention reported that 40 percent of the 455,636 persons living with AIDS and half of those dying from AIDS in the United States in 2007 lived in the South. Research indicates that women and men with HIV infection can achieve nearly normal life-spans if treated with effective antiretroviral agents. However, barriers to treatment reduce the proportion of Americans who achieve optimal therapy. In 2011, the HIV Prevention Therapy Network (HPTN) demonstrated in protocol HPTN 052 that the risk of HIV transmission was reduced 92 percent within discordant dyads when the infected partner was treated with anti-retroviral therapy. This confirmed multiple observational studies and supports the idea that HIV treatment will be an effective method to prevent HIV infection. Understanding how to achieve optimal therapy effectiveness is a public health priority for improving individual outcomes and for controlling the spread of HIV. Because WIHS enrolls women without regard to their clinical care status, the study is well positioned to study the uptake of antiretroviral medications, as well as the predictors of successful and sustained viral suppression. WIHS also has the capacity to conduct research to define the clinical outcomes for women with HIV across their full lifespan. Determining the causal factors in disease manifestation requires extensive evaluation of women with and without HIV, and women across several decades of life.
How is the WIHS managed?
The WIHS Executive Committee (EC) is responsible for managing the overall scientific aims of the WIHS, and is composed of the Principal Investigators (PIs) from each awardee institution, a WIHS community advisory board member selected by study subjects to represent their interests, and the NIH Project Scientists. EC members prioritize the WIHS Scientific Agenda, oversee the completion of research within WIHS, and work with external investigators who wish to conduct research using current WIHS data, specimens, and other resources. In addition, changes to existing study procedures, and proposals for new research (submitted by internal and external investigators) are reviewed with approval and prioritization based on a consensus decision of the EC. Each awardee PI is a voting member of the EC. In the case of multiple-PI awards, consensus is reached to cast a single vote that is representative of the site. All members of the Executive Committee are required to accept and implement policies approved by the WIHS EC.
In managing cooperative agreements (U01s) such as the WIHS awards, Project Scientists from NIAID and the co-funding Institutes have substantial programmatic involvement that is above and beyond the normal stewardship role for NIH research grants. The NIH Project Scientists will likewise do so through technical assistance, advice and coordination across the NIH Institutes during the conduct of all WIHS-V activities. Each NIH Project Scientist is a voting member of the EC. The NIAID Program Official will be responsible for the normal scientific and programmatic stewardship of each WIHS award, facilitate co-funding issues, and will be named in the award notice. However, the Program Official is NOT a member of the WIHS EC.
Specific areas of scientific focus are cultivated by collective groups of investigators with common research interests and goals, collectively known as the WIHS Working Groups (WGs). Each WG membership includes WIHS Project Directors and/or PIs, as well as senior and junior investigators at grantee institutions, with external consultations sought as needed.
What is the role of the WIHS External Advisory Board?
NIAID and the co-funding Institutes will assemble a WIHS External Advisory Board for WIHS-V. This Board will advise NIAID, co-funding Institutes, and the WIHS EC on current progress, suggest revisions to timelines, and establish scientific and funding priorities for projects proposed across WIHS. The Board will be comprised of trans-NIH staff, other governmental experts, members of academia, and industry representatives. It is anticipated that the Board will meet once per year for the duration of WIHS-V.
What is the purpose of renewing and expanding WIHS?
The purpose of renewing the WIHS is to continue support for pathogenesis, virology, epidemiologic outcomes, and comparative effectiveness research in a representative cohort of U.S. women. The specific goals of WIHS-V are to continue characterizing the long-term, natural and treated history of HIV infection, and by recruiting and retaining new women into the cohort, provide insight into the changing demographics of the HIV-1 epidemic among women in the United States. In addition, WIHS will move to a rolling cohort design whereby new women will be enrolled to account for prior cohort members who are later lost to follow-up.
WIHS is a unique global resource because it includes a comparable control group of HIV seronegative women, is a source of information on highly characterized, rare phenotypes, is a study of predominately minority women, and documents co-morbidities faced by women that are not well represented in other clinical studies. Evaluations performed in the WIHS go beyond clinical care and includes assessments of long-term outcomes in the era of effective antiretroviral therapy, in-depth interviewer administered questionnaires, comprehensive physical and gynecologic examinations, ascertainment of HIV- and related health care, and provides clinical and laboratory data linked to a high quality repository of stored samples. Enrolling more women to the study in WIHS-V, and accounting for women lost to follow-up, will better reflect current treatment practices, and is crucial in order to maintain study power and relevance to U.S. HIV epidemic in women.
What institutions are eligible to apply?
The current WIHS clinical grantee institutions are eligible to apply to the WIHS-V FOA. In addition, applications will be accepted from institutions with the capacity to enroll the target populations of HIV-positive and HIV-negative but at risk women from the Southern region of the United States (Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, or Texas only). The current WDMAC is eligible to submit a renewal application as the data management and analysis center in response to the WIHS-V FOA. Applications for the WIHS data management and analysis center will be accepted only from the current WDMAC.
What are the enrollment criteria for women to be recruited in WIHS-V?
Existing WIHS CRSs may propose to recruit up to 100 new HIV+ and HIV- women at the site during the period covered by WIHS-V. Applicant institutions for a new Southern U.S. CRS may recruit 200-300 HIV+ and HIV- women. The goal of WIHS-V is to recruit around 1,000 new women (250 HIV+ recent HAART initiators, 250 HIV+ HAART naïve, and 500 HIV-negative matching the age distribution of HIV+ women). While all applicants should describe their enrollment plans, the final determination of the specific sample sizes and enrollment criteria for existing and the new Southern U.S. CRSs will be determined by NIH and the WIHS EC after consultation with the WIHS External Advisory Board. In general the target strata at each CRS may differ by age, race, documented previous use of anti-HIV medications, and clinical health history as determined from medical record abstraction. A focus will include ensuring that the most at-risk HIV-negative women are targeted for enrollment in addition to enrolling HIV+ women. Having access to consistent clinical care is not an inclusion requirement for enrollment to the current WIHS, and documenting the disassociation of WIHS participants from HIV and related clinical care is a key element to understanding the true epidemiology of HIV among women. However, all WIHS CRS applications should describe how the site facilitates access to clinical care for all enrollees. WIHS will also move to a rolling cohort, and successful CRSs should anticipate replacing women who become lost to follow-up during the period of WIHS-V.
For the purposes of the WIHS-V FOA, what is a Clinical Research Site vs Clinical Site?
All WIHS-V clinical applicants must submit proposals to serve as a WIHS CRS. The CRS is responsible for not only adhering to the standard WIHS data and specimen collection protocols, and recruiting and retaining the target population of women in WIHS, but also must carry out a scientific agenda of research that is either limited to the applicant organization (and collaborators) or extended WIHS-wide. While each application should be distinct, all WIHS-V applicants must demonstrate integration of a proposed “local” research agenda into the larger WIHS cohort goals. Only those applications that propose outstanding research, as deemed by the outcome of the peer review process, will be eligible to receive funding as a CRS. Applicant budgets are expected to include project costs to carry out local and WIHS-wide scientific goals using the local population. However, it is acceptable to also mention, albeit not budget, the costs for which support would be required to extend such projects to other WIHS CRSs. In addition, because resources are limited for the WDMAC to perform all conceivable WIHS analyses, budgets associated with local and WIHS-wide scientific agendas can include costs for local statistical and analytic support to carry out the research plans.
In order to balance the WIHS cohort geographically and maintain the sample sizes to address study objectives on long-term outcomes, NIAID may choose to continue funding one or more existing WIHS CRSs as a Clinical Site (CS). A CS will be responsible for adhering to the standard WIHS data and specimen collection protocols, and recruiting and retaining the target population of women in WIHS. The decision to fund a site at the CS level will be made based on the outcome of the peer review process, with funding to be based on per-patient cost negotiated between the institution and NIAID prior to issuing an award. The new Southern U.S. CRS must be competitive at the CRS level in order to receive funding.
Is the scope of the WDMAC expected to change in WIHS-V?
No. No additional activities are expected that are beyond the current scope of the WDMAC in supporting the WIHS Consortium. Sufficient resources will be provided for the WDMAC to maintain existing central functions as well as fully integrate the new Southern CRS into processes necessary to routinely access standardized WIHS core and substudy protocols; manuals of operation; source documents, informed consent templates, and data collection forms; web-based communication and document storage tools; central data management and reporting systems; programmer consultation and analytic support at WDMAC for EC-approved projects; committee conference calls and meetings, and prepare for data audit site visits.
Are Multiple Principal Investigator (MPI) applications allowed?
Yes, MPI applications are highly encouraged for CRS and the WDMAC applications. Meritorious MPI applications for a CRS would include a team with diverse expertise in clinical infectious diseases and HIV epidemiology. Applications for the new Southern CRS can include MPIs from one or more institutions within the Southern states of interest listed in the FOA but must have access to patient populations from one or more of these Southern states.
Current WIHS CRS awardees are not eligible to submit applications proposing either single or MPI leadership for the new Southern CRS. However, existing CRS awardees may be included as collaborators in applications proposed for the new Southern CRS.
What is the page limit for the Research Strategy section? Are there requirements specific to this FOA that will be included in the scored criteria?
All applicant organizations can submit a response to the WIHS-V FOA that includes a maximum of 30 pages for the Research Strategy Section of the SF-424. This is the only exception for this FOA; all other page limits for U01 applications must be followed: http://grants.nih.gov/grants/forms_page_limits.htm. In addition to standard criteria, additional WIHS-specific element are included in the scored review criteria for the WIHS-V FOA. All applicants should be sure to thoroughly review all elements in “Section V, Application Review Information“ of the FOA.
What are the qualifications for the clinical health practitioners who will perform the physical examinations each study visit?
Healthcare practitioners who perform the required WIHS physical examinations can include physicians, nurse practitioners, and physician assistants. However, all study practitioners must be certified and state licensed. In addition, as documented by the WDMAC, study practitioners must complete the required WIHS physical examination training process and must maintain routine proficiency assessments in following study procedures.
Will training be required for WIHS study interviewers?
Yes, WIHS study interviewers must complete the required, centralized interview training process managed by the WDMAC and must maintain routine proficiency assessments in following study procedures.
Are there additional requirements for public use data access and data sharing?
All clinical and laboratory data collected by WIHS sites become part of the overall WIHS database (each CRS submits patient visit and testing results on a regular basis to WDMAC via a Web-based system). In turn, WDMAC returns datasets to the sites after data curation is completed. The most current WIHS clinical and laboratory data are made available to internal and external collaborators through the “concept sheet” mechanism, which can be accessed on the public WIHS website. All applicants to the WIHS-V FOA should describe how site investigators will adhere to WIHS concept sheet and publication policies. All CRS and the WDMAC applicants should describe how data from local research will be made available to the internal WIHS and external research investigators.
All WIHS-V applications must include a plan describing how data documentation and sharing will be accomplished within one year after data collection, as well as appropriate safeguards to protect patient privacy implemented at the national WIHS level. In addition, all applications should describe any current ethical and/or logistical challenges to full data sharing and how the CRS or WDMAC intends to overcome or remediate such conflicts.
As a reminder that in accordance with NIH Data Sharing policies, the WDMAC is responsible for the annual creation of a WIHS public-use data (PUD) electronic file covering the data collection period up to 18 months before the file's creation. All collected variables must be provided in a widely useable format with appropriate, complete data dictionaries to accompany the data. This compilation of de-identified data is released for public use each year, and is available for purchase from the National Technical Information Service.
What types of comparative effectiveness research will be allowed?
Proven health interventions that do not require Investigational New Drug (IND) applications and are of low risk to participants will be allowed in WIHS-V. These include, but are not limited to research on: Smoking cessation, alcohol and/or drug abuse interventions; amelioration of depression or depressive symptoms; measures to improve ARV adherence; exercise regimens for weight loss, to reduce toxicity, and/or impact HIV-related frailty; measures to improve cervical and other cancer screening.
How do I find information about the groups with whom WIHS collaborates?
The public WIHS website is a useful source of information about WIHS including how the consortium collaborates with non-WIHS investigators. Some NIH-funded collaborators include: North America region of the International Epidemiologic Databases to Evaluate AIDS, the Centers for AIDS Research, Multicenter AIDS Cohort Study.
The WIHS-V FOA suggests areas of focus in the “Research Scope of WIHS-V” section, but are applications limited to only those areas?
The areas of focus suggested in the “Research Scope of WIHS-V” section were not intended to be all inclusive. In addition, proposed projects are expected to be well integrated across several areas and disciplines whether or not the proposed scientific topics were suggested in the FOA.
How can substance use aims, sub-aims, or hypotheses reflect the integrated objectives and research scope examples in the FOA?
Substance use-related research in the WIHS should take advantage of the unique opportunities of a long-term clinical cohort, and should be consistent with the major priority research domains (treatment, co-morbidities and pathogenesis) as presented in the FOA. The effects of substance use on factors such as specific risk behaviors (e.g., sexual practices), health behaviors, or psychological status associated with aging, should occur in the context of clinical outcomes that reflect the larger priority objectives of WIHS. Similarly, substance use and patterns of substance use over time, and their relationship to natural and treated disease history should be considered with respect to the broader clinical research agenda, including co-morbidities (e.g., metabolic consequences, liver function, cardiovascular disease, HCV, neurocognitive functioning), therapeutics (e.g., adherence, treatment impact, resistance), and pathogenesis (e.g., immune function, host genetics). Proposed projects should highlight opportunities for both focused and integrated investigations not possible in typical community or clinic samples.
How many applications does NIH intend to fund?
Based on funding anticipated to be available in FY13, six to seven meritorious clinical research site awards, and one meritorious WDMAC award, are expected to be funded. This will include one new CRS in the Southern U.S. The cooperative agreement (U01) mechanism will be utilized. All awards funded under the WIHS-V FOA will comprise the WIHS-V epidemiologic cohort.
What is the maximum total costs and project period for WIHS-V applications?
The first-year budget associated with all clinical research site applications is capped at $3.5 million in total costs. The first-year budget associated with the WDMAC application is capped at $2.2 million in total costs. The maximum project period for all WIHS-V applications is five years.
To assist with budget preparations, what evaluations must WIHS study visits include?
Provided below is a summary of data collection elements included in WIHS study visits. Although the National Repository will provide the containers and cover the costs to ship specimens from local sites to this Repository, applicant budgets should include all costs for the collection, processing, and temporary storage of specimens. The specific protocol procedures and documentation can be obtained on the public WIHS website; WIHS Study Forms mentioned below can be obtained on the public WIHS website for the most current visit, Visit 35.
How do WIHS CRSs support the WIHS National Community Advisory Board (NCAB) and local CABs?
Each local WIHS CAB conducts regular events for outreach to study participants, engages in recruitment efforts, and makes recommendations concerning proposed study changes. In addition, each WIHS CRS nominates one to three local CAB representatives to serve on the WIHS NCAB. Support from grantee institutions includes expenses for the designed NCAB members to present and/or participate in one annual national conference of interest to community advisors and advocates for HIV-related research (e.g., U.S. conference on AIDS, International AIDS Society). Information made available on the public WIHS website for the WIHS NCAB is aimed at keeping participants informed about HIV-related health and research developments, as well as sharing local CAB newsletters.
The WIHS-V budget and project periods will begin in FY13, but does the recent decrease in the salary cap for grants, cooperative agreements, grants, and contracts affect WIHS-V applications?
The NIH recently revised the salary limit for grants, cooperative agreements, and contracts (see NIH Notice of Salary Limitation on Grants, Cooperative Agreements, and Contracts). Because WIHS-V applications are due before the FY13 start dates for all WIHV-V awards, and it is not known if the salary limit will change for FY13, the FY12 Executive II Salary Limit should be used in Year 1 of all WIHS-V CRS applications. Institutional base salaries can be used for Years 2-5, however, appropriate adjustments will be made by NIAID based on salary limits in place at that time.
Should I budget to anticipate a new CRS will initiate and complete enrollment and baseline visits within one year of the award?
The goal of each CRS should be to complete recruitment and baseline visits as quickly as possible. Given the logistics of integrating a new CRS into the WIHS Consortium (and based on the history of prior WIHS enrollment waves), it is reasonable to budget one and a half years to complete enrollment and baseline evaluations.
Is the WIHS data management system (DMS) web-based at the point of the study visit?
The current WIHS DMS is a web-based system but not web-based at the point of the visit. The web system mirrors the data collection forms to simplify data entry. Specific details about the current WIHS DMS are contained within Section 11 of the WIHS Manual of Operations (PDF), available on the Public WIHS Website.
My on-site or subcontract laboratory that I wish to propose for processing WIHS specimens is currently not participating in the DAIDS Immunology and/or Virology Quality Assurance Programs. How can I budget for this in my application, and is certification required before review of my application?
Successful applicants using laboratories that are not currently enrolled will be required to participate in the DAIDS IQA and VQA programs as a WIHS CRS. Because access to these programs is initiated by DAIDS and limited to sites performing DAIDS-funded research, certification for successful applicants will be addressed prior to final funding determinations. The specific details on these programs can be found on the Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures Documents Website.
Questions regarding this Q&A site should be directed to the NIAID Program Official (Joana Darc Roe [NED]). Other contacts are provided in the WIHS-V FOA.
Although WIHS is an observational, natural history study, recruitment information can be found on the ClinicalTrials.gov website.
NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov/.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.
Last Updated January 31, 2012
Last Reviewed October 13, 2011