JAIDS Journal of Acquired Immune Deficiency Syndromes:
Optimizing the Protection of Research Participants and Personnel in HIV-Related Research Where TB Is Prevalent: Practical Solutions for Improving Infection Control
Farley, Jason E. PhD, MPH, CRNP*,†; Landers, Timothy F. PhD, CNP‡; Godfrey, Catherine MD, FRACP§; Lipke, Virginia RN, MHA, ACRN, CIC‖; Sugarman, Jeremy MD, MPH, MA¶,#,†
*Johns Hopkins University School of Nursing, Department of Community and Public Health, Baltimore, MD;
†Johns Hopkins Center for AIDS Research (CFAR), Baltimore, MD;
‡The Ohio State University College of Nursing, Columbus, OH;
§National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD;
‖Division of Global HIV/AIDS (GAP), Centers for Disease Control and Prevention, Atlanta, GA;
¶Johns Hopkins Berman Institute of Bioethics; and
#Johns Hopkins University School of Medicine, Baltimore, MD.
Correspondence to: Jason E. Farley, PhD, MPH, CRNP, Johns Hopkins University School of Nursing, 525 N. Wolfe Street, Suite 525, Baltimore, MD 21205 (e-mail: firstname.lastname@example.org).
This publication proposal was made possible with help from the Johns Hopkins University Center for AIDS Research, a National Institutes of Health (NIH)–funded program (1P30AI094189), which is supported by the following NIH cofunding and participating Institutes and Centers: National Institute of Allergy and Infectious Disease, NCI, National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, National Institute of Drug Abuse, National Institute of Mental Health, National Institute on Aging, FIC, and OAR. Work on this article was also supported in part by the National Institute of Allergy and Infectious Disease, National Institute of Drug Abuse and the National Institute of Mental Health under Cooperative Agreement # UM1AI068619 to the HIV Prevention Trials Network.
The findings and conclusions in this report are those of the author (V.L.) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.
The authors have no conflicts of interest to disclose.
This article was written by C.G. in her capacity as an NIH employee, but the views expressed in this paper do not necessarily represent those of the NIH.
Abstract: Tuberculosis (TB) is a leading cause of death among persons with HIV globally. HIV-related research in TB endemic areas raises some unique and important ethical issues in infection control related to protecting both research participants and personnel. To address such concerns, this article provides practical guidance to help research teams develop strategies to prevent TB transmission in studies involving persons with HIV in TB endemic settings.
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a leading cause of death among persons with HIV.1 Molecular epidemiologic evaluations clearly demonstrate hospital-associated transmission of TB in settings with high HIV prevalence.2,3 Research participants and personnel conducting HIV-related research may be exposed to TB, including drug-resistant TB strains through airborne exposure. Gathering participants for research purposes in some settings may therefore increase risk of transmission to research participants and personnel. Visit frequency, duration, the proximity to other participants, and many environmental factors affect this risk. Indeed, incident TB is often a primary outcome of clinical trials attempting to define the best strategies for preventing HIV infection or treating those who are infected.4,5 Even in the best of circumstances with active case finding and policies which require isolating individuals with cough,6 crowded waiting rooms, long study visits, and facilities with poor ventilation bring potentially infectious people in close contact with research personnel and research participants who are at high risk for developing TB. HIV-infected patients are more commonly sputum smear negative for TB than HIV-uninfected patients, but they remain infectious and the diagnosis of TB may be delayed.7
In settings where TB is prevalent, trial design and conduct should account for factors that may pose additional risks to research participants and take measures to minimize them. Incorporating TB infection control (TBIC) into research may be challenging because evidence-based infection control practices have not been adopted in many clinical and community settings where HIV-related research may be conducted.8–13 The AIDS Clinical Trials Group has adopted a guideline for TB prevention at its clinical sites, but it is unclear whether similar approaches are being implemented in other research settings. Furthermore, there remains a paucity of literature on the implementation of TBIC measures14 and infection control measures15 specifically in HIV-related research settings.16–19 However, it is clear that biomedical interventions that may be included in HIV-related research, such as intensified case findings, rapid diagnostics, access to isoniazid preventative therapy to prevent activation of TB, and earlier antiretroviral therapy20 confer TB prevention benefits both directly to the recipient of the intervention and to others as a result of decreased opportunities for exposure.21,22 Regardless, to minimize risk of TB transmission, it is essential that research teams implement comprehensive approaches to TB prevention that incorporate both biomedical interventions and system-level infection control interventions, including site-level guidance to facilitate appropriate implementation.
In this article, we outline practical strategies for clinical research teams in settings where TB is prevalent to follow established TBIC practices and guidelines.23–25 In addition to antiretroviral therapy and appropriate biomedical management of HIV disease, these infection control strategies are critical to mitigate risk for research participants and personnel.
PROPOSED STEPS IN PROTECTING RESEARCH PARTICIPANTS AND PERSONNEL
A comprehensive TB risk assessment is an essential first step for TBIC. This begins with evaluating the settings where initial contact with potential participants will occur. Local TB epidemiology, administrative and environmental controls (ECs) at the proposed sites, and available personal protective equipment (PPE) should be reviewed. Baseline knowledge of TBIC principles among research personnel is a critical element in the initial assessment, and the level of education regarding TBIC is a measurable outcome of TBIC initiatives.
The Centers for Disease Control and Prevention has developed a brief TBIC monitoring and evaluation checklist for use in TB/HIV clinical settings. A modified version to facilitate the completion of a research site risk assessment is shown in Table 1.26 This modified checklist for research includes the following: (1) integrating TBIC procedures into research protocols; (2) attending to managerial aspects of TBIC; (3) administrative controls; (4) ECs; and (5) promoting use of PPE among research participants and study personnel. As delineated in Table 1, the comprehensive approach to TBIC that is developed should be incorporated into relevant parts of study protocols, procedure manuals, and a managerial plan. Doing so helps to ensure transparency, accountability, and implementation.
Administrative Controls are system-level changes designed to decrease exposure to infectious patient-participants.9 These standard TBIC activities include segregating coughing participants, fast-tracking smear-positive participants, or requiring participants to wear a surgical mask. Cough hygiene and use of a simple surgical mask reduces airborne droplets27 and has been shown to be highly acceptable to patients in clinical settings28; however, in a recent survey of research sites in resource-limited settings, only 40% of sites had cough hygiene information available to participants.29
In clinical practice, these interventions are challenging because they require oversight, adequate resources for appropriate implementation, and may require sensitivity training to reduce stigma associated with mask use. Further, in many settings, there are no enforcement requirements for these interventions. Despite these challenges, efforts should be taken to implement administrative controls in research sites. For example, in designing recruitment plans, consideration should be given to incorporating a risk reduction strategy to decrease the likelihood of persons with active TB being in contact with others. Sputum specimen collection should occur in a manner that minimizes risk to others at the site, and follow-up visits should minimize transmission risk. Consideration should also be given toward adopting a robust TB diagnostic strategy, intensified case finding and the ability to offer isoniazid preventive therapy.
ECs include activities that decrease TB bacilli in the clinical environment. Practical ECs do not require costly renovations, and small environmental changes can make a large difference. Adequate ventilation, measured in air exchanges per hour (ACH), is the most commonly applied EC and may have an important impact on infectivity. ACHs can be determined through simple calculations, and standardized worksheets permit estimation in a variety of clinical settings.30
Twelve ACH are recommended in conditions requiring airborne isolation and may be achievable with open windows and cross-ventilation under the right circumstances. In determining the appropriate placement and use of ECs, site staff should consider where study personnel meet with potential participants, particularly those who have not been screened or tested for TB or who are undergoing diagnostic procedures. Examples of low-cost practical solutions include providing a covered space for outdoor sputum collection, covering a waiting area outdoors to prevent long waiting time indoors, and ensuring open window policies (including awnings that allow them to remain open in rainy weather). Wind-driven roof turbines are a less costly alternative to mechanical ventilation and have been shown to meet minimum air exchange requirements.31 Where funding is available, consideration should be given to using upper-room ultraviolet germicidal irradiation32 with scheduled cleaning, working fans,33 and a routine maintenance plan to prevent dust and debris from collecting, which reduces their effectiveness.
Personal Protective Equipment
Use of a simple paper mask by patients has been shown to reduce TB transmission by more than 50% in a guinea pig model in South Africa.27 The use of N95 respirators in clinical personnel (also known as FFP2 respirators) with appropriate annual fit testing or seal checks before entering clinical areas is a proven intervention for the prevention of nosocomial spread of TB.34 Although clinical settings in which drug-resistant TB is common tend to have policies that require PPE use, adherence to these policies may be limited, and there are few regulatory controls regarding their enforcement.8 Research teams may be better positioned to enforce such policies. For example, study personnel may be required to attend annual infection control trainings and to use PPE; failure to do so could result in a poor performance appraisal or dismissal from duty. From the participants' perspective, implemented correctly (ie, all persons attending the research site wear a mask while inside the research setting), stigma or disclosure of status is not propagated because it is an expectation of everyone in the site.
PUTTING INFECTION CONTROL PLANS INTO RESEARCH PRACTICE
Developing practical strategies for prevention of TB transmission in HIV-related research in areas where TB is prevalent can be accomplished with appropriate planning. Figure 1 provides a schematic overview of the critical elements of the necessary steps in this process. Education of personnel about TB transmission principles and personal risk is also critical. Periodic occupational health evaluation and training of staff can raise awareness of the importance of TBIC.35 As described above, internationally recognized guidance for risk assessment and mitigation is available from the Centers for Disease Control and Prevention and may be adapted for the specific research study plans26 and trainings for the research team.14 Although mathematical modeling exercises36 provide some perspective on the relative benefit of concomitant interventions, the key TBIC strategy is the careful analysis of the individual circumstances of each research study and the development of tailored standard operating procedures to mitigate risk. While outside the scope of this article, engaging local communities in TB and/or HIV research is an important step in developing TBIC plans that have buy-in within the targeted community.37
Prevention of TB transmission in HIV-related clinical research is an important means of helping to minimize risks to research participants and personnel. Transmission of TB in hospitals and clinical sites where care of patients with HIV is given is well documented and usual practices in research settings may be inadequate to protect against TB transmission. To mitigate risk and protect research participants and personnel, investigators should examine each protocol carefully and the settings in which it will be implemented. Conducting risk assessments during protocol development should help to ensure that inadequacies in TBIC could be addressed. Further research is needed on TBIC implementation within research settings, and data on the efficacy of these measures are required particularly given the added costs incurred with implementation of both biomedical and other TBIC strategies. Regulatory measures, such as funder-driven requirements, may strengthen implementation of TBIC. Although there are emerging data on the cost-effectiveness of biomedical interventions for TB prevention,38–40 such data for programmatic TBIC strategies remain sparse within both clinical and research settings. Nonetheless, until such data are available, it seems reasonable to assume that having a keen understanding of biomedical, administrative, and environmental aspects of TBIC should help reduce the likelihood of TB transmission, thereby optimizing the protection of research participants and personnel.
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infection control; TB; HIV; clinical research; human subjects protections; ethics
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