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Management of Antiretroviral-Related Nutritional Problems: Challenges and Future Directions
Topic: Antiretroviral-Related Nutritional Problems/Clinical Article JANAC Vol. 12, Supplement, 2001 Fields-Gardner, Keithley / Challenges and Future Directions
Management of Antiretroviral-Related Nutritional Problems: Challenges and Future Directions Cade Fields-Gardner, MS, RD, LD, CD Joyce K. Keithley, DNSc, RN, FAAN Survival has been greatly enhanced with the adequate and effective treatment of HIV infection. Surviving and surviving well are important pieces of the disease management puzzle. Nutritional well-being has been closely associated with both survival and quality of life in HIV and other diseases. The effects and interactions of currently used antiretroviral therapies can compromise nutritional well-being. The challenges posed to researchers, clinicians, and patients in evaluating and treating nutrition-related effects of life-saving antiretroviral medications affect health care goals, recommendations, and decisions. Challenges include identifying emerging problems, prioritizing clinical problems, expediting the implementation of clinical trials, developing researchbased interventions that are realistic and usable in practice, decreasing the time lag to incorporate research findings into practice, and developing or adapting evidence-based clinical guidelines. This article will explore these challenges, offer thoughtprovoking questions in the development of research and clinically viable solutions, and propose future directions for management strategies of antiretroviralrelated problems. Key words: nutrition, medication interactions, adverse effects, side effects, therapeutic decisions
changes in body composition (e.g., altered body compartment volumes, altered body patterns of fat distribution). Although studies of pharmacologic, exercise, and dietary interventions to manage these problems have shown promising results, the preliminary nature of the studies and the rapid evolution of ARV-related nutritional problems pose a number of challenges for clinicians and researchers. These challenges, potential solutions, and future directions for evidence-based practice will be presented in this article.
Challenge 1: Identifying Emerging Problems Clinicians are often in the best position to identify nutritional problems that may be related to medication therapies. Although the potential for side effects has been reported as a part of the preliminary and subsequent research during ARV development periods, the spectrum of issues may not become apparent until after widespread use of medications approved on a “fast track” development cycle. Anecdotal reports of observed adverse effects are followed by letters and case reports in peer-reviewed journals or at professional meetings as postmarketing reporting.
Antiretroviral (ARV) therapy is associated with a variety of nutritional problems including adverse nutrition-related symptoms (e.g., diarrhea, nausea and vomiting, anorexia), altered nutrition-related metabolic changes (e.g., dyslipidemia, lactic acidosis), and
Cade Fields-Gardner, MS, RD, LD, CD, is director of services at The Cutting Edge in Cary, Illinois. Joyce K. Keithley, DNSc, RN, FAAN, is a professor at the Rush University College of Nursing in Chicago, Illinois.
JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 12, Supplement, 2001, 79-84 Copyright © 2001 Association of Nurses in AIDS Care
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Side effects that become severe or are less acceptable can become the source of patient and clinician frustration. The search for answers to yet-to-bedefined questions on the direct or indirect involvement of medications, risk versus benefit in continuation of medication regimens, and adjunctive therapies that may provide symptom relief promises to be arduous. A clear and appropriate definition, consistent understanding of potential etiologies, and knowledge of the impact on clinical and psychosocial/economic well-being are lacking for many of the problems encountered. Speculation about the nature and etiologies of the problems encountered, opinions based on circumstances in other disease states, or hypotheses about treatments that affect symptoms abound in lay and professional information resources. Limited resources of personnel and funding are available to accomplish the research needed to clearly define ARV-related nutritional problems. Problems may remain untreated without clear definitions and evidence for the value of targeted prevention and treatment efforts. Clinician and patient perceptions of the nature and importance of these problems can result in a range of responses from attempts to diminish the importance of the problem encountered to an intense search for available remedies and trial of empiric treatments with little evidence to support them. The logical next step of a research agenda includes well-designed studies of the problems, potential solutions, and measurement of the actual impact of treatment or nontreatment. The major toxicities of the currently approved ARVs that are specifically related to nutritional status include mitochondrial toxicity, hyperlipidemia, insulin resistance, hormonal alterations, and altered body shape (loss of subcutaneous fat and gain in central fat). An example of the recognition process can be illustrated in the reporting of mitochondrial toxicity and lactic acidosis with the use of nucleoside reverse transcriptase inhibitors. Initial reports of problems were made to the Food and Drug Administration during the late 1990s. Characteristics of persons who experienced mitochondrial toxicities suggested, but did not prove, that taking nucleoside analogue ARV medications was a common adverse occurrence. The nucleoside stavudine was strongly associated with the development of this complication (Moyle, 2000).
However, critics of this and other such studies noted the limitations of implicating a single drug when lactic acidosis may develop after long-term exposure to any of the drugs in this class of medications. For example, stavudine may have been the medication that the patients were using at the time of diagnosis, or mitochondrial toxicities could have been a result of previous exposure to other nucleoside analogues (which were later switched to stavudine) along with a combination of other contributory effects such as host risk factors. What appeared to be clear from the first few reports was that a high mortality rate was associated with severe cases of lactic acidosis and that the condition may be more common in women and during pregnancy with the use of nucleoside analogue ARV therapy. Considering the serious consequences, including the possibility of having to discontinue the use of an effective class of ARV medications (Nicole et al., 2000) and even death, treatments were recommended based on theories and evidence in other conditions without the benefit of scientific rigor on the effect and effective treatment specific to lactic acidosis in HIV disease. An examination of other recent reports of cases of lactic acidosis uncovered information about the relationship of thiamine deficiency (a B vitamin used in the mitochondrial process) to this condition in patients on intravenous nutrition support during a nationwide shortage of multivitamins used in such therapy (Centers for Disease Control and Prevention, 1997). This association is the basis for the recommendation of prevention strategies and empiric treatment with B vitamins (Community AIDS Treatment Information Exchange, 2000), although it is not based on specific evidence of efficacy and safety in chronic HIV disease. As problems are identified, several questions should be posed to formulate the plan for research and clinical practice that is specific to HIV disease. Examples of general questions that can be applied to specific problems identified in HIV disease management may include the following: • •
Which tests or observations best characterize and define a problem or syndrome? What are the consequences of the observed changes?
Fields-Gardner, Keithley / Challenges and Future Directions
• • • •
•
• •
What are the mechanisms of the observed problems? Is there precedence in other diseases and conditions? What are the outcomes and interactions of treatments used with other disease processes that can be used to address similar problems? What is a tolerable alteration from a “normal” profile for nutrition-related parameters in HIV-infected individuals? What is the upper range for lipid levels, glucose intolerance, or other clinical indicators of risk in HIV disease? Which problems are part of the natural history of HIV disease? Which problems are not necessary consequences of HIV disease and its management? What are the implications to nursing practice in assisting patients to manage ARV-related nutritional problems? Which problems are related to nonadherence to or discontinuation of therapy?
Challenge 2: Prioritizing Clinical Problems Prioritizing nutrition-related concerns with ARV therapies has not been accomplished. Several nutritionally detrimental effects that are related to the use of ARV medications are currently under investigation. The number of items that require investigation in order to characterize and effectively prevent and treat these complications continues to grow. Initially, one might expect a clinical practice–generated priority list that is concerned first with maintenance of survival, second with maintenance of a sturdy body, third with the reduction of risk factors, and fourth with addressing “annoyance” factors that may have less impact on diminishing clinical health. An effort to determine general HIV-related and HIV specialty nursing research priorities through the Delphi study technique was recently reported by Sowell (2000). Sowell used a mix of a select and random group of members from the Association of Nurses in AIDS Care over three rounds of surveys to identify, group into categories, and prioritize through scoring five primary research concerns. The results
81
characterized a framework from which nurses can begin to construct a research agenda. The top priority identified by the nursing research Delphi study is an important nutrition-related concern: the need for evidence on which to base symptom management. This Delphi technique of research can identify the current state of nutritional issues in HIV disease management and, more specifically, identify topics and tasks necessary to accomplish a foundation for nutritionrelated clinical practice. The panels selected to respond to a Delphi study survey should include nurses, dietitians, physicians, and others involved in research, clinical, and support practice. Priorities might consider the immediacy of a health threat posed by nutrition-related ARV complications, the potential for prevention, and the transient or permanent nature of an adverse event.
Challenge 3: Expediting the Implementation of Clinical Trials ARV-related nutritional problems either require immediate attention, such as metabolic disorders, or can have potentially serious sequelae, such as premature heart disease or hip fracture. Researchers should attempt to shorten the interval between research proposal conceptualization and implementation. Several factors account for the prolonged time required to implement clinical trials for time-sensitive ARVrelated nutritional problems. Three of the most challenging factors are (a) the slow processing of research proposals, (b) the dearth of collaborative projects, and (c) the lack of specific and sensitive clinical indicators of treatment effects. Processing of research proposals may require up to 1 year or longer to complete. In particular, obtaining institutional review board approval and undergoing scientific review for internal or external funding are lengthy processes. New and more rapid systems for processing time-sensitive research studies should be developed, perhaps by emulating the processes that led to the success of corporations such as McDonald’s, Federal Express, and Domino’s Pizza. In each of these corporations, streamlined procedures were established and schedules adhered to without compromising quality. The recent Rapid Action Deployment of AIDS Research program sponsored by the
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Department of Health and Human Services, the National Institutes of Health, and the National Institute of Mental Health is an excellent example of a prototype that could be adapted by various review groups. This program accepts research applications in selected areas at any time and reviews them shortly after submission, thus speeding the review and funding process (see http://www.grants.nih.gov/grants/guide/pa-files/ PA-99-132.html). Although AIDS research proposals are currently processed in an expedited fashion at the federal level, significant time delays may still occur in regional or local implementation. Using electronic submission and review procedures and shortening the length of research proposals (e.g., a 2- to 3-page detailed abstract rather than a 25-page proposal) are procedures to expedite the research. Expediting the conduct of clinical research can be accomplished through collaborative endeavors. Collaborative relationships between multiple universities and hospitals will expedite the acquisition of adequate numbers of heterogeneous study participants from the HIV-infected population. Access to a large pool of diverse study subjects not only speeds the data collection process, which is often the most protracted aspect of conducting clinical trials, but also increases the generalizability of the research findings. Despite the challenges inherent in conducting multisite studies, including multinational studies, the Internet has the potential to circumvent many previous obstacles pertaining to ongoing communication, intersite consistency, and data banking and analysis. A collaborative, interdisciplinary team approach may strengthen the study design and methodology. For example, nutritional problems related to lipodystrophy syndrome require the input of many specialists with expertise ranging from infectious disease to cardiology to psychology. By pooling the knowledge and skills of numerous experts, research proposals are apt to be better designed and holistic rather than focusing on one facet of a problem. An illustration of comprehensive management of ARV-related dyslipidemia includes assessing both conventional (e.g., antilipid drugs) and complementary/alternative (e.g., mind-body techniques) management strategies for their safety and clinical efficacy. A limitation of multiple intervention studies, such as including both medications and mind-body techniques in a single study, is that it may be difficult to determine the effects of a specific
intervention. However, rarely is a single intervention the most complete solution to a multifactorial problem such as dyslipidemia. The lack of sensitive clinical indicators of treatment effects delays the research process. Large-scale controlled, randomized studies need to include reasonable intervention periods (e.g., 6 to 12 weeks) and incorporate clinical endpoints that are sensitive indicators of resolution. Clinicians and researchers can work together to identify clinical indicators that are most sensitive to interventions for specific ARV-related nutritional problems.
Challenge 4: Making Research Interventions Realistic and Usable in Practice The last phase of the research process is to publish findings of clinical trials and to draw conclusions or make recommendations. A clear statement of the implications for clinical practice (Hench, Anderson, Grady, & Ropka, 1995) and the need for further research should be included. A narrow focus of research topics may make it difficult to integrate promising interventions into real-life situations. To make research interventions more realistic to clinical practice, researchers should find and validate the most acceptable methods of prevention, the least invasive procedures for identification of the problems, and treatments that are (preferably) “inexpensive,” effective, and accessible. Researchers should address the underlying problems that place a patient at risk for the problems addressed. The effect of mitochondrial toxicity as a side effect of the nucleoside class of ARVs is of great concern because of the resulting lactic acidosis and potential contribution to subcutaneous lipoatrophy that can lead to further metabolic abnormalities. The imbalance of mitochondrial damage and damage-preventing antioxidant nutrients and other substances has become a topic of discussion and limited research. Allard et al. (1998) suggested that the use and reduction of antioxidant availability may be ameliorated, at least in part, through pharmaceutical doses of antioxidant nutrients. Although the study showed some limited promise, the researchers suggested that the results did not adequately support recommendations that could be
Fields-Gardner, Keithley / Challenges and Future Directions
widely used in clinical practice. Because of a lack of clear evidence, many clinicians and other advisers use the theoretical rather than evidence as the foundation for the development of routine recommendations for antioxidant therapy regimens. The integration of research into clinical practice is currently a scattered process. Some efforts have been aimed at developing a set of clinical guidelines similar to the guidelines for the use of ARV medications in HIV infection. Unfortunately, the process has been bogged down, with a lack of consensus and clear evidence on which to base such decisions. Each clinician is left alone to sort out evidence, theories, and hearsay to support his or her clinical decisions. Even the best set of evidence is difficult to integrate in real-world clinical care if the recommendations do not consider the overall goals of treatment for an individual, availability of social and economic resources, contradicting factors, and contraindications in making a therapeutic choice. For example, if the evidence becomes clear that we can prevent and/or treat the nucleoside-related mitochondrial toxicity with nutraceuticals (e.g., high doses of antioxidant nutrients), access to and availability of this type of therapy may be limited. Or, potential nutrient interactions with medication or other factors may reduce the safety and value of the intervention.
Challenge 5: Decreasing the Time Lag for Incorporating Research Findings Into Practice Translating research into realistic approaches leads to an additional challenge of rapidly incorporating research findings into clinical practice. Even in this era of near instantaneous communication, months or even years may elapse between the time that research findings are reported and their inclusion into clinical practice. A number of factors are responsible for this time lag, including the quality of the research findings, failure of researchers to discuss the clinical implications of their work, and lack of resources for implementing practice changes. The preliminary nature of the studies examining interventions for ARV-related nutritional problems is a significant barrier to rapid incorporation of research findings into clinical practice. Although pilot studies are essential in determining the safety and
83
efficacy of interventions, the use of findings from uncontrolled studies with small samples would be premature. Research findings from both phase 1 and largescale follow-up studies should be quickly and widely disseminated via journals, conferences, and/or Internet sites that are readily accessible to clinicians. To speed research dissemination, some journals such as AIDS have implemented a Fast Track section so that manuscripts containing critical and time-sensitive information can quickly be published (i.e., within a few weeks). Some conferences use a similar strategy—the “late breaker”—as a way to quickly disseminate important or breaking research findings that occurred after the original abstract deadline date. Additional flexible and innovative approaches to dissemination should be explored and implemented. In disseminating preliminary research findings, researchers should clearly discuss study limitations and potential ways in which their research findings could be incorporated into clinical practice, pending verification by large-scale clinical trials. Data from large-scale clinical trials should be accompanied by a clear discussion of clinical implications and specific strategies for incorporating the findings into practice. As appropriate, researchers and clinicians could work with pharmaceutical companies and/or organizations to develop practical protocols for using the research results. For example, if a lifestyle change such as weight-bearing exercise is shown to minimize fat redistribution in lipodystrophy syndrome, the American Heart Association or other groups could assist with adapting exercise protocols that are specific to persons with HIV infection. Currently, research findings frequently do not translate into improvements in clinical care. Mechanisms described above for speeding dissemination could also be used to expedite the incorporation of research into clinical practice. For instance, a proposal could contain a component to describe the clinical utility of potential findings. More visibility and recognition should be given to presentations at conferences and published papers that describe effective clinical utilization approaches. JANAC and the annual Association of Nurses in AIDS Care conference are excellent vehicles for showcasing successful clinical research utilization strategies. Another strategy would be to publish short summaries on selected Web sites.
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Challenge 6: Developing or Adapting Evidence-Based Clinical Guidelines Until more data become available, clinicians and researchers can work together to develop or adapt evidence-based clinical guidelines. A potential (and quite possibly a temporary) guideline for bone disorders based on the best evidence available might include the following management strategies: • Investigate potentially associated events or conditions Hypogonadism Diabetes Intestinal malabsorption (e.g., fat soluble nutrients vitamin D and calcium) Inflammatory bowel disease Medication interaction (e.g., corticosteroid, thyroid, methotrexate, and others that increase risk for bone loss) Infections (e.g., direct infection of osteogenic cells by HIV, Epstein-Barr virus, and cytomegalovirus) Elevation of cytokines, alteration in parathyroid hormone activity, and increased activation of lymphocytes • Evaluate and differentially diagnose bone density changes Dual-energy x-ray absorptiometry evaluation of bone density Establish appropriate areas to use in evaluation: whole body, vertebrae, hand, hip, heel, and others (according to sensitivity to bone density changes) • Treat associated events that are identified and additional risk factors Hormone replacement therapy (men and women) Diet counseling and nutrient supplementation Treatment for fat malabsorption: pancrelipase and water-soluble fat-based micronutrients Exercise (recommended according to bone density limitations) Smoking cessation Medications that support bone building such as estrogens, bisphosphonates, calcitonin,
anabolic mediations (e.g., anabolic steroids, growth hormone, insulin sensitizers), and estrogen receptor modulators. Clinicians can only speculate about the characteristics of problems, impact of problems on health maintenance and improvement, and treatments for ARV-related nutrition problems while evidence is lacking. The management of rapidly evolving ARV-related nutritional problems, such as bone density loss and others, presents numerous challenges for clinicians. Each of the problems identified in clinical practice, prioritized for exploration, and integrated into evidence-based clinical guidelines will help to improve and standardize care. Evidence-based guidelines as a dynamic work can support the development of an advanced level of practice that is required for such a complicated disease and affect availability, accessibility, utilization, and reimbursement of appropriate care.
References Allard, J. P., Aghdassi, E., Chau, J., Tam, C., Kovacs, C. M., Salit, I. E., & Walmsley, S. L. (1998). Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects. AIDS, 12, 1653-1659. Centers for Disease Control and Prevention. (1997). Lactic acidosis traced to thiamine deficiency related to nationwide shortage of multivitamins for total parenteral nutrition—United States, 1997. Atlanta, GA: Author. Community AIDS Treatment Information Exchange–Canada (CATIE). (2000). Treatment update 109: Lactic acidosis. CATIE [Online], 12(5). Available: www.aegis.com/pubs/catie/ 2000/CATE10906.html Hench, K., Anderson, R., Grady, C., & Ropka, M. (1995). Investigating chronic symptoms in HIV: An opportunity for collaborative nursing research. Journal of the Association of Nurses in AIDS Care, 6(3), 13-17. Moyle, G. (2000). Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clinical Therapeutics, 22(8), 911-936; Discussion, 898. Nicole, B., Champagne, X., Breux, J. P., Pasdeloup, T., Remblier, C., Perault, M. C., & Vandel, B. (2000). Attitude of the clinician toward adverse effects of protease inhibitors. Therapie, 55, 643-647. Sowell, R. L. (2000). Identifying HIV/AIDS research priorities for the next millennium: A Delphi study with nurses in AIDS care. Journal of the Association of Nurses in AIDS Care, 11(3), 42-52.
Management of Antiretroviral-Related Nutritional Problems: Challenges and Future Directions Cade Fields-Gardner, MS, RD, LD, CD Joyce K. Keithley, DNSc, RN, FAAN Survival has been greatly enhanced with the adequate and effective treatment of HIV infection. Surviving and surviving well are important pieces of the disease management puzzle. Nutritional well-being has been closely associated with both survival and quality of life in HIV and other diseases. The effects and interactions of currently used antiretroviral therapies can compromise nutritional well-being. The challenges posed to researchers, clinicians, and patients in evaluating and treating nutrition-related effects of life-saving antiretroviral medications affect health care goals, recommendations, and decisions. Challenges include identifying emerging problems, prioritizing clinical problems, expediting the implementation of clinical trials, developing researchbased interventions that are realistic and usable in practice, decreasing the time lag to incorporate research findings into practice, and developing or adapting evidence-based clinical guidelines. This article will explore these challenges, offer thoughtprovoking questions in the development of research and clinically viable solutions, and propose future directions for management strategies of antiretroviralrelated problems. Key words: nutrition, medication interactions, adverse effects, side effects, therapeutic decisions
changes in body composition (e.g., altered body compartment volumes, altered body patterns of fat distribution). Although studies of pharmacologic, exercise, and dietary interventions to manage these problems have shown promising results, the preliminary nature of the studies and the rapid evolution of ARV-related nutritional problems pose a number of challenges for clinicians and researchers. These challenges, potential solutions, and future directions for evidence-based practice will be presented in this article.
Challenge 1: Identifying Emerging Problems Clinicians are often in the best position to identify nutritional problems that may be related to medication therapies. Although the potential for side effects has been reported as a part of the preliminary and subsequent research during ARV development periods, the spectrum of issues may not become apparent until after widespread use of medications approved on a “fast track” development cycle. Anecdotal reports of observed adverse effects are followed by letters and case reports in peer-reviewed journals or at professional meetings as postmarketing reporting.
Antiretroviral (ARV) therapy is associated with a variety of nutritional problems including adverse nutrition-related symptoms (e.g., diarrhea, nausea and vomiting, anorexia), altered nutrition-related metabolic changes (e.g., dyslipidemia, lactic acidosis), and
Cade Fields-Gardner, MS, RD, LD, CD, is director of services at The Cutting Edge in Cary, Illinois. Joyce K. Keithley, DNSc, RN, FAAN, is a professor at the Rush University College of Nursing in Chicago, Illinois.
JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 12, Supplement, 2001, 79-84 Copyright © 2001 Association of Nurses in AIDS Care
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Side effects that become severe or are less acceptable can become the source of patient and clinician frustration. The search for answers to yet-to-bedefined questions on the direct or indirect involvement of medications, risk versus benefit in continuation of medication regimens, and adjunctive therapies that may provide symptom relief promises to be arduous. A clear and appropriate definition, consistent understanding of potential etiologies, and knowledge of the impact on clinical and psychosocial/economic well-being are lacking for many of the problems encountered. Speculation about the nature and etiologies of the problems encountered, opinions based on circumstances in other disease states, or hypotheses about treatments that affect symptoms abound in lay and professional information resources. Limited resources of personnel and funding are available to accomplish the research needed to clearly define ARV-related nutritional problems. Problems may remain untreated without clear definitions and evidence for the value of targeted prevention and treatment efforts. Clinician and patient perceptions of the nature and importance of these problems can result in a range of responses from attempts to diminish the importance of the problem encountered to an intense search for available remedies and trial of empiric treatments with little evidence to support them. The logical next step of a research agenda includes well-designed studies of the problems, potential solutions, and measurement of the actual impact of treatment or nontreatment. The major toxicities of the currently approved ARVs that are specifically related to nutritional status include mitochondrial toxicity, hyperlipidemia, insulin resistance, hormonal alterations, and altered body shape (loss of subcutaneous fat and gain in central fat). An example of the recognition process can be illustrated in the reporting of mitochondrial toxicity and lactic acidosis with the use of nucleoside reverse transcriptase inhibitors. Initial reports of problems were made to the Food and Drug Administration during the late 1990s. Characteristics of persons who experienced mitochondrial toxicities suggested, but did not prove, that taking nucleoside analogue ARV medications was a common adverse occurrence. The nucleoside stavudine was strongly associated with the development of this complication (Moyle, 2000).
However, critics of this and other such studies noted the limitations of implicating a single drug when lactic acidosis may develop after long-term exposure to any of the drugs in this class of medications. For example, stavudine may have been the medication that the patients were using at the time of diagnosis, or mitochondrial toxicities could have been a result of previous exposure to other nucleoside analogues (which were later switched to stavudine) along with a combination of other contributory effects such as host risk factors. What appeared to be clear from the first few reports was that a high mortality rate was associated with severe cases of lactic acidosis and that the condition may be more common in women and during pregnancy with the use of nucleoside analogue ARV therapy. Considering the serious consequences, including the possibility of having to discontinue the use of an effective class of ARV medications (Nicole et al., 2000) and even death, treatments were recommended based on theories and evidence in other conditions without the benefit of scientific rigor on the effect and effective treatment specific to lactic acidosis in HIV disease. An examination of other recent reports of cases of lactic acidosis uncovered information about the relationship of thiamine deficiency (a B vitamin used in the mitochondrial process) to this condition in patients on intravenous nutrition support during a nationwide shortage of multivitamins used in such therapy (Centers for Disease Control and Prevention, 1997). This association is the basis for the recommendation of prevention strategies and empiric treatment with B vitamins (Community AIDS Treatment Information Exchange, 2000), although it is not based on specific evidence of efficacy and safety in chronic HIV disease. As problems are identified, several questions should be posed to formulate the plan for research and clinical practice that is specific to HIV disease. Examples of general questions that can be applied to specific problems identified in HIV disease management may include the following: • •
Which tests or observations best characterize and define a problem or syndrome? What are the consequences of the observed changes?
Fields-Gardner, Keithley / Challenges and Future Directions
• • • •
•
• •
What are the mechanisms of the observed problems? Is there precedence in other diseases and conditions? What are the outcomes and interactions of treatments used with other disease processes that can be used to address similar problems? What is a tolerable alteration from a “normal” profile for nutrition-related parameters in HIV-infected individuals? What is the upper range for lipid levels, glucose intolerance, or other clinical indicators of risk in HIV disease? Which problems are part of the natural history of HIV disease? Which problems are not necessary consequences of HIV disease and its management? What are the implications to nursing practice in assisting patients to manage ARV-related nutritional problems? Which problems are related to nonadherence to or discontinuation of therapy?
Challenge 2: Prioritizing Clinical Problems Prioritizing nutrition-related concerns with ARV therapies has not been accomplished. Several nutritionally detrimental effects that are related to the use of ARV medications are currently under investigation. The number of items that require investigation in order to characterize and effectively prevent and treat these complications continues to grow. Initially, one might expect a clinical practice–generated priority list that is concerned first with maintenance of survival, second with maintenance of a sturdy body, third with the reduction of risk factors, and fourth with addressing “annoyance” factors that may have less impact on diminishing clinical health. An effort to determine general HIV-related and HIV specialty nursing research priorities through the Delphi study technique was recently reported by Sowell (2000). Sowell used a mix of a select and random group of members from the Association of Nurses in AIDS Care over three rounds of surveys to identify, group into categories, and prioritize through scoring five primary research concerns. The results
81
characterized a framework from which nurses can begin to construct a research agenda. The top priority identified by the nursing research Delphi study is an important nutrition-related concern: the need for evidence on which to base symptom management. This Delphi technique of research can identify the current state of nutritional issues in HIV disease management and, more specifically, identify topics and tasks necessary to accomplish a foundation for nutritionrelated clinical practice. The panels selected to respond to a Delphi study survey should include nurses, dietitians, physicians, and others involved in research, clinical, and support practice. Priorities might consider the immediacy of a health threat posed by nutrition-related ARV complications, the potential for prevention, and the transient or permanent nature of an adverse event.
Challenge 3: Expediting the Implementation of Clinical Trials ARV-related nutritional problems either require immediate attention, such as metabolic disorders, or can have potentially serious sequelae, such as premature heart disease or hip fracture. Researchers should attempt to shorten the interval between research proposal conceptualization and implementation. Several factors account for the prolonged time required to implement clinical trials for time-sensitive ARVrelated nutritional problems. Three of the most challenging factors are (a) the slow processing of research proposals, (b) the dearth of collaborative projects, and (c) the lack of specific and sensitive clinical indicators of treatment effects. Processing of research proposals may require up to 1 year or longer to complete. In particular, obtaining institutional review board approval and undergoing scientific review for internal or external funding are lengthy processes. New and more rapid systems for processing time-sensitive research studies should be developed, perhaps by emulating the processes that led to the success of corporations such as McDonald’s, Federal Express, and Domino’s Pizza. In each of these corporations, streamlined procedures were established and schedules adhered to without compromising quality. The recent Rapid Action Deployment of AIDS Research program sponsored by the
82
JANAC Vol. 12, Supplement, 2001
Department of Health and Human Services, the National Institutes of Health, and the National Institute of Mental Health is an excellent example of a prototype that could be adapted by various review groups. This program accepts research applications in selected areas at any time and reviews them shortly after submission, thus speeding the review and funding process (see http://www.grants.nih.gov/grants/guide/pa-files/ PA-99-132.html). Although AIDS research proposals are currently processed in an expedited fashion at the federal level, significant time delays may still occur in regional or local implementation. Using electronic submission and review procedures and shortening the length of research proposals (e.g., a 2- to 3-page detailed abstract rather than a 25-page proposal) are procedures to expedite the research. Expediting the conduct of clinical research can be accomplished through collaborative endeavors. Collaborative relationships between multiple universities and hospitals will expedite the acquisition of adequate numbers of heterogeneous study participants from the HIV-infected population. Access to a large pool of diverse study subjects not only speeds the data collection process, which is often the most protracted aspect of conducting clinical trials, but also increases the generalizability of the research findings. Despite the challenges inherent in conducting multisite studies, including multinational studies, the Internet has the potential to circumvent many previous obstacles pertaining to ongoing communication, intersite consistency, and data banking and analysis. A collaborative, interdisciplinary team approach may strengthen the study design and methodology. For example, nutritional problems related to lipodystrophy syndrome require the input of many specialists with expertise ranging from infectious disease to cardiology to psychology. By pooling the knowledge and skills of numerous experts, research proposals are apt to be better designed and holistic rather than focusing on one facet of a problem. An illustration of comprehensive management of ARV-related dyslipidemia includes assessing both conventional (e.g., antilipid drugs) and complementary/alternative (e.g., mind-body techniques) management strategies for their safety and clinical efficacy. A limitation of multiple intervention studies, such as including both medications and mind-body techniques in a single study, is that it may be difficult to determine the effects of a specific
intervention. However, rarely is a single intervention the most complete solution to a multifactorial problem such as dyslipidemia. The lack of sensitive clinical indicators of treatment effects delays the research process. Large-scale controlled, randomized studies need to include reasonable intervention periods (e.g., 6 to 12 weeks) and incorporate clinical endpoints that are sensitive indicators of resolution. Clinicians and researchers can work together to identify clinical indicators that are most sensitive to interventions for specific ARV-related nutritional problems.
Challenge 4: Making Research Interventions Realistic and Usable in Practice The last phase of the research process is to publish findings of clinical trials and to draw conclusions or make recommendations. A clear statement of the implications for clinical practice (Hench, Anderson, Grady, & Ropka, 1995) and the need for further research should be included. A narrow focus of research topics may make it difficult to integrate promising interventions into real-life situations. To make research interventions more realistic to clinical practice, researchers should find and validate the most acceptable methods of prevention, the least invasive procedures for identification of the problems, and treatments that are (preferably) “inexpensive,” effective, and accessible. Researchers should address the underlying problems that place a patient at risk for the problems addressed. The effect of mitochondrial toxicity as a side effect of the nucleoside class of ARVs is of great concern because of the resulting lactic acidosis and potential contribution to subcutaneous lipoatrophy that can lead to further metabolic abnormalities. The imbalance of mitochondrial damage and damage-preventing antioxidant nutrients and other substances has become a topic of discussion and limited research. Allard et al. (1998) suggested that the use and reduction of antioxidant availability may be ameliorated, at least in part, through pharmaceutical doses of antioxidant nutrients. Although the study showed some limited promise, the researchers suggested that the results did not adequately support recommendations that could be
Fields-Gardner, Keithley / Challenges and Future Directions
widely used in clinical practice. Because of a lack of clear evidence, many clinicians and other advisers use the theoretical rather than evidence as the foundation for the development of routine recommendations for antioxidant therapy regimens. The integration of research into clinical practice is currently a scattered process. Some efforts have been aimed at developing a set of clinical guidelines similar to the guidelines for the use of ARV medications in HIV infection. Unfortunately, the process has been bogged down, with a lack of consensus and clear evidence on which to base such decisions. Each clinician is left alone to sort out evidence, theories, and hearsay to support his or her clinical decisions. Even the best set of evidence is difficult to integrate in real-world clinical care if the recommendations do not consider the overall goals of treatment for an individual, availability of social and economic resources, contradicting factors, and contraindications in making a therapeutic choice. For example, if the evidence becomes clear that we can prevent and/or treat the nucleoside-related mitochondrial toxicity with nutraceuticals (e.g., high doses of antioxidant nutrients), access to and availability of this type of therapy may be limited. Or, potential nutrient interactions with medication or other factors may reduce the safety and value of the intervention.
Challenge 5: Decreasing the Time Lag for Incorporating Research Findings Into Practice Translating research into realistic approaches leads to an additional challenge of rapidly incorporating research findings into clinical practice. Even in this era of near instantaneous communication, months or even years may elapse between the time that research findings are reported and their inclusion into clinical practice. A number of factors are responsible for this time lag, including the quality of the research findings, failure of researchers to discuss the clinical implications of their work, and lack of resources for implementing practice changes. The preliminary nature of the studies examining interventions for ARV-related nutritional problems is a significant barrier to rapid incorporation of research findings into clinical practice. Although pilot studies are essential in determining the safety and
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efficacy of interventions, the use of findings from uncontrolled studies with small samples would be premature. Research findings from both phase 1 and largescale follow-up studies should be quickly and widely disseminated via journals, conferences, and/or Internet sites that are readily accessible to clinicians. To speed research dissemination, some journals such as AIDS have implemented a Fast Track section so that manuscripts containing critical and time-sensitive information can quickly be published (i.e., within a few weeks). Some conferences use a similar strategy—the “late breaker”—as a way to quickly disseminate important or breaking research findings that occurred after the original abstract deadline date. Additional flexible and innovative approaches to dissemination should be explored and implemented. In disseminating preliminary research findings, researchers should clearly discuss study limitations and potential ways in which their research findings could be incorporated into clinical practice, pending verification by large-scale clinical trials. Data from large-scale clinical trials should be accompanied by a clear discussion of clinical implications and specific strategies for incorporating the findings into practice. As appropriate, researchers and clinicians could work with pharmaceutical companies and/or organizations to develop practical protocols for using the research results. For example, if a lifestyle change such as weight-bearing exercise is shown to minimize fat redistribution in lipodystrophy syndrome, the American Heart Association or other groups could assist with adapting exercise protocols that are specific to persons with HIV infection. Currently, research findings frequently do not translate into improvements in clinical care. Mechanisms described above for speeding dissemination could also be used to expedite the incorporation of research into clinical practice. For instance, a proposal could contain a component to describe the clinical utility of potential findings. More visibility and recognition should be given to presentations at conferences and published papers that describe effective clinical utilization approaches. JANAC and the annual Association of Nurses in AIDS Care conference are excellent vehicles for showcasing successful clinical research utilization strategies. Another strategy would be to publish short summaries on selected Web sites.
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Challenge 6: Developing or Adapting Evidence-Based Clinical Guidelines Until more data become available, clinicians and researchers can work together to develop or adapt evidence-based clinical guidelines. A potential (and quite possibly a temporary) guideline for bone disorders based on the best evidence available might include the following management strategies: • Investigate potentially associated events or conditions Hypogonadism Diabetes Intestinal malabsorption (e.g., fat soluble nutrients vitamin D and calcium) Inflammatory bowel disease Medication interaction (e.g., corticosteroid, thyroid, methotrexate, and others that increase risk for bone loss) Infections (e.g., direct infection of osteogenic cells by HIV, Epstein-Barr virus, and cytomegalovirus) Elevation of cytokines, alteration in parathyroid hormone activity, and increased activation of lymphocytes • Evaluate and differentially diagnose bone density changes Dual-energy x-ray absorptiometry evaluation of bone density Establish appropriate areas to use in evaluation: whole body, vertebrae, hand, hip, heel, and others (according to sensitivity to bone density changes) • Treat associated events that are identified and additional risk factors Hormone replacement therapy (men and women) Diet counseling and nutrient supplementation Treatment for fat malabsorption: pancrelipase and water-soluble fat-based micronutrients Exercise (recommended according to bone density limitations) Smoking cessation Medications that support bone building such as estrogens, bisphosphonates, calcitonin,
anabolic mediations (e.g., anabolic steroids, growth hormone, insulin sensitizers), and estrogen receptor modulators. Clinicians can only speculate about the characteristics of problems, impact of problems on health maintenance and improvement, and treatments for ARV-related nutrition problems while evidence is lacking. The management of rapidly evolving ARV-related nutritional problems, such as bone density loss and others, presents numerous challenges for clinicians. Each of the problems identified in clinical practice, prioritized for exploration, and integrated into evidence-based clinical guidelines will help to improve and standardize care. Evidence-based guidelines as a dynamic work can support the development of an advanced level of practice that is required for such a complicated disease and affect availability, accessibility, utilization, and reimbursement of appropriate care.
References Allard, J. P., Aghdassi, E., Chau, J., Tam, C., Kovacs, C. M., Salit, I. E., & Walmsley, S. L. (1998). Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects. AIDS, 12, 1653-1659. Centers for Disease Control and Prevention. (1997). Lactic acidosis traced to thiamine deficiency related to nationwide shortage of multivitamins for total parenteral nutrition—United States, 1997. Atlanta, GA: Author. Community AIDS Treatment Information Exchange–Canada (CATIE). (2000). Treatment update 109: Lactic acidosis. CATIE [Online], 12(5). Available: www.aegis.com/pubs/catie/ 2000/CATE10906.html Hench, K., Anderson, R., Grady, C., & Ropka, M. (1995). Investigating chronic symptoms in HIV: An opportunity for collaborative nursing research. Journal of the Association of Nurses in AIDS Care, 6(3), 13-17. Moyle, G. (2000). Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clinical Therapeutics, 22(8), 911-936; Discussion, 898. Nicole, B., Champagne, X., Breux, J. P., Pasdeloup, T., Remblier, C., Perault, M. C., & Vandel, B. (2000). Attitude of the clinician toward adverse effects of protease inhibitors. Therapie, 55, 643-647. Sowell, R. L. (2000). Identifying HIV/AIDS research priorities for the next millennium: A Delphi study with nurses in AIDS care. Journal of the Association of Nurses in AIDS Care, 11(3), 42-52.