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Including Persons With HIV Infection in Cancer Clinical Trials

Department of Bioethics, The Clinical Center, and The Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Therapy and Diagnosis, National Cancer Institute, The National Institutes of Health, Bethesda, MD

Clinical research endeavors to advance medical therapy. Application of research findings may not be valid for populations whose demographics diverge substantially from that of the research sample. Comparability of the study population and the general population of interest depends on adequate sampling.¹ Restricted research access may vitiate valid inferences for those not represented. If the ensuing medical research data are valid for some, but not others, then questions of fairness and justice are raised.^2-4 These considerations led the National Institutes of Health and the Food and Drug Administration to require historically excluded so-called vulnerable study participants (such as women, children, and minorities) to be included in clinical research unless there are compelling scientific and ethical grounds for exclusion.^3,5-8

Persons have also been excluded from research on the basis of specific physiologic conditions, such as HIV infection, for multiple reasons, including vulnerability. However, the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) advises researchers that "Individuals known to be HIV-positive should not be arbitrarily excluded from participation in clinical cancer treatment trials," and requires scientific justification for exclusion.⁹ Improvements in HIV medicine have led to a need for further consideration of this issue.

Since the 1996 introduction of highly active antiretroviral therapy (HAART), deaths caused by HIV and AIDS have decreased substantially; a recent Danish study found a nearly five-fold decrease in HIV-associated mortality between 1996 and 2005.^10,11 HIV treatment goals are now chronic management and health preservation. Opportunistic infections that typified the pre-HAART era are now rare. However, a higher incidence of certain non–AIDS-defining cancers (NADC) has recently been noted.¹² For example, lung cancer and Hodgkin's lymphoma occur substantially more frequently in persons with HIV infection than in the background population.¹³ In light of these trends, we argue that persons with HIV infection should be appropriately evaluated for inclusion in cancer clinical trials.

BRIEF HISTORY OF CANCER IN PERSONS WITH HIV INFECTION

Onset of the AIDS epidemic was heralded in part by a sudden change in cancer epidemiology. An aggressive, highly lethal form of Kaposi's sarcoma in young gay men was a radical departure from classic Kaposi's sarcoma, which is clinically indolent and occurs primarily in older Mediterranean men. Subsequently, aggressive B-cell lymphomas began appearing with sustained atypical frequency in young age groups. As the AIDS epidemic evolved, activists in the late 1980s successfully campaigned for more AIDS treatment clinical trials, catalyzing a broad expansion of access to research and patient advocacy.^14,15 However, because NADC were rarely seen in patients with HIV infection, clinical trial access for treatments of common cancers was not a priority.

Cancer epidemiology is again changing with the evolving HIV epidemic. Increased longevity coupled with stable rates of incident infection has led to a more than 50% increase in the prevalence of HIV/AIDS in the United States.¹⁰ Cancer now is the primary cause of mortality among HIV-infected persons where HAART is widely available.¹² The composite frequency of NADC approaches that of the AIDS-defining cancers. Affected persons often have well-controlled HIV and relatively preserved immune function.¹⁶

WHY INCLUDE PERSONS WITH HIV INFECTION IN CANCER CLINICAL TRIALS?

Inclusion of HIV-seropositive individuals with cancer in clinical trials advances knowledge (Table 1). Carefully designed investigations that include HIV-infected individuals have contributed to clinical and biologic advances.¹⁷ Unnecessary exclusion of persons with HIV infection can potentially limit the evidence base for cancer therapy.

Common motivating factors, regardless of HIV serostatus, for clinical trial participation include the perception of potential direct benefit and also the sense that participation can contribute to the greater good (Table 1). It is clear that both can occur. Advances in the treatment of certain AIDS-defining cancers have resulted in outcomes equivalent to those seen for similar cancers in the HIV-seronegative population.^17,19 This illustrates that complex and novel interventions can be successfully applied to those with HIV infection. Because access to novel treatments may be available only through clinical trial participation, unqualified exclusion of those with HIV infection denies an entire population of patients access to clinically promising therapies. HIV infection is a spectrum of disease in which some persons are likely to be suitable study participants for many cancer trials. The emphasis must be on making appropriate evaluations so that access to trials for persons with HIV infection is based on fairness and sound medical principles that insure safety, scientific integrity, and justice.

PRESENT STATE OF HIV EXCLUSIONS IN CANCER CLINICAL TRIALS

To determine how often persons with HIV infection are explicitly excluded and to assess justifications, we used lung cancer as a model and searched (in March 2007) the NCI's Physician Data Query (PDQ) clinical trial database using the terms "HIV," "AIDS," and "human immunodeficiency virus."²⁰ The text of the lung cancer trials identified was then evaluated to confirm that exclusion was based on HIV infection and to determine whether a justification was offered.

We selected lung cancer as a model for several reasons. It is the leading cause of cancer deaths in the United States.²¹ Adjusted for smoking, its incidence and mortality is increased in HIV infection and it occurs at high CD4 cell counts.²² HIV advocacy groups have expressed particular concern about this condition.^23,24

Our analysis revealed that approximately 25% (95 of 383) of phase I, II, and III treatment trials for non–small-cell lung cancer (NSCLC) explicitly exclude HIV infection (Table 2). By trial phase, approximately 35% of phase I trials, 23% of phase II trials, and 12% of phase III trials explicitly exclude persons with HIV infection. Explicit HIV exclusion was slightly more frequent for small-cell lung cancer: approximately 29% (23 of 79) of all phases of treatment trials explicitly excluded persons with HIV infection. Of 462 lung cancer treatment trial protocols, only two explicitly included persons with HIV infection.

Almost all of the offered exclusion criteria were problematic (Table 3). Some protocols seemed to view immunodeficiency and drug interactions as a single concern, failing to acknowledge scientifically distinguishing features (Table 3). Frequently, the explanations erroneously stated that antiretroviral therapy (ART) increases patient vulnerability to infections as a result of increased myelosuppression from ART, failing to appreciate that the opposite is true with modern therapy.^25,26 Some protocols used the NCI sample exclusion text almost verbatim, which seems in tension with the CTEP guidelines’ for scientific justification based on trial-specific treatments or end points.⁹

Similarly, where pharmacokinetic interactions are a concern, all medications likely affecting the study agents should be excluded. Anti-HIV drugs are metabolized by pathways determined by the specific agent rather than its use against HIV. Thus, the concern should not be singular to anti-HIV therapy. Moreover, where important, some patients can safely have their ART suspended during antineoplastic therapy to avoid potential deleterious pharmacokinetic and toxicity interaction.¹⁹

Excluding persons with so-called known HIV status is also troubling. If exclusion is important, HIV testing should be part of eligibility screening. An estimated 25% of the more than one million Americans with HIV infection have never been tested and therefore do not know they are infected.²⁷ Excluding only those with so-called known HIV infection either places unaware HIV-infected persons at undue risk or needlessly excludes and penalizes persons who know their HIV status.

Finally, the vast majority of trials that do not explicitly exclude those with HIV infection exclude persons with serious, active, or uncontrolled infections. In practice, this may exclude persons with HIV infection, which would imply that our PDQ analysis in fact underestimated the number of trials excluding persons with HIV infection. Importantly, such broad exclusions are likely to impede access to clinical investigations and may not be scientifically or medically justified.

Clear justification for HIV-related exclusion can facilitate efforts for those seeking access to investigational studies.^2,28,29 None of the phase III trials that excluded persons with HIV infection provided a justification for doing so. This raises special concern, because prospects of personal benefit may be highest in phase III trials. Unjustified exclusion perpetuates the notion that HIV infection and cancer clinical trial participation are incompatible, and may confuse prospective study participants and referring physicians.

We found that only a small minority of trials provide clear, scientifically considered justifications for HIV-based exclusion. Perhaps this is due to the relative novelty of HAART and the ongoing realization of its benefits. These rapid advances in HIV therapy pose challenges to investigators in their efforts to harmonize eligibility assessments with the NCI goals of appropriate inclusion. The growing cancer risk this population faces makes this challenge more exigent. Approximately 40,000 new cases of HIV infection occur every year in the United States, and as yet no person has been cured. As the prevalence and age of HIV-infected individuals increases, the cancer burden is likely to follow.¹⁷

EXCLUSION REVISITED

Given that HIV can alter cancer presentation and outcome, how can researchers reconcile relevant issues regarding HIV serostatus without categoric or unjustifiable trial exclusion? NSCLC may well illustrate this issue. For example, the smoking-adjusted incidence of NSCLC for persons with HIV infection younger than 40 years seems to be nearly nine-fold that expected in the general population,^16,30 suggesting that its etiology is comparatively less dependent on smoking. Rather than a justification for excluding persons with HIV infection, this should be viewed as an opportunity for study and advancing knowledge. CTEP recommends that stratification or smaller separate trials be developed for persons with HIV infection if admixed participation in larger trials poses excessive risk to patients or jeopardizes interpretation of results.⁹ Using this CTEP-endorsed approach or other innovative trial designs could improve overall accrual, generate informative scientific data, meet the ethical obligations of research, and address the disparities resulting from excluding persons with HIV infection from trials.

Exclusion from research can be ethically and scientifically essential to avoid harm in persons at particular risk. Such concerns may encourage HIV-based exclusion (Table 4). However, HIV infection should not be singled out for disproportionate concern. HIV-seronegative patients with cancer often have multiple comorbidities. Conditions such as chronic pulmonary disease, cardiovascular disease, and diabetes must be assessed to determine whether the comorbid condition's severity justifies excluding an individual from participation in certain investigational studies, or indeed from receiving a particular standard therapy. Like HIV infection, these comorbidities require concurrent medical therapy. However, our PDQ analysis revealed no evidence that concurrent therapy for non-HIV conditions was routinely considered to be an exclusion criterion, though this was quite common for anti-HIV therapy. Generally, a condition's impact on organ function and performance status is considered when assessing eligibility, not the absolute presence or absence of the chronic comorbid condition itself. Like other conditions, HIV infection presents as a continuum of actual effects from very little to quite substantial. Progression to AIDS takes years or decades, and can be forestalled with HAART, obviating impact on survival objectives in cancer trials. Nevertheless, this spectrum is often ignored when HIV infection is listed as a definitive exclusionary condition.

Concerns regarding social vulnerability may be used to exclude patients (Table 4).^34,35 HIV disproportionately affects people of color, gay or bisexual men, substance users, and economically disadvantaged persons and increasingly affects older individuals¹⁰—all groups that have been independently identified as vulnerable in research.³⁶ However, ethical considerations direct researchers to provide support and appropriate safeguards that empower vulnerable persons to enroll if they so choose, rather than automatically excluding them.³⁷ Justice requires that people not be excluded from research unless there are good scientific or safety reasons that necessitate their exclusion.

Finally, researchers may want to exclude persons with HIV infection for financial reasons (Table 4). Some have voiced concerns that the financial and human resources related to specimen handling and managing HIV-related complications could negatively impact other research-related activities. However, with the use of universal precautions, greater handling costs previously associated with HIV-infected specimens are no longer applicable.^31,38 Appropriate inclusion of those with HIV infection is unlikely to result in excess AIDS-associated complications. Moreover, researchers’ responsibility to include a representative sample of those with the disease under study is not abrogated by reasonable burdens that may be associated with this effort. Peremptory exclusion of women and minorities, for example, may have been less complex and less costly, but excluding these groups failed both at fairly distributing the direct benefits of research and at producing generalizable scientific results. Excluding all persons with HIV infection may impose similar undesirable constraints on clinical advances.

TOWARD GREATER INCLUSION: THE TRANSPLANTATION MODEL

Solid-organ transplantation exemplifies the evidence-based shift toward inclusion of persons with HIV infection in complex medical interventions. Historically, persons with HIV infection were not candidates for solid-organ transplantation. In 1997, 88% of transplant centers excluded persons with HIV infection.³⁹ Reasons included concerns about drug interactions with antiretroviral agents and the danger of antirejection immunosuppressive therapy. In response to data that confirms the feasibility of solid organ and hematopoietic stem-cell transplantation,^40-44 some centers have re-evaluated transplantation in HIV-infected patients.^39,45-47 In 2006, Qiu et al⁴⁶ asserted, "The HIV patient should be considered no different than any other patient who may have higher transplant risks than the average patient, such as African American, highly sensitized, diabetic, or older patients. Reluctance to transplant patients with HIV infection is no longer justified."

Although cancer therapy is fundamentally distinct from clinical procedures like transplantation, research-specific considerations like generalizability and scientific validity are compelling reasons to consider inclusion of persons with HIV infection in cancer trials. As transplant centers did, some cancer clinical trials are beginning to enroll persons with well-managed HIV infection. One such lung cancer treatment trial we evaluated states that "HIV-positive patients are eligible provided the following criteria are met: CD4 count 100/mm3, undetectable viral load within the past 3 months, receiving a stable antiretroviral regimen for 4 weeks before study entry." This focus on overall health, rather than mere HIV infection status, exemplifies the careful consideration that persons with HIV infection are owed and that the CTEP guidelines promote.

HOW TO INCLUDE PERSONS WITH HIV INFECTION IN CANCER RESEARCH

Inclusion of HIV-infected persons in cancer clinical trials requires careful study-specific planning. It is important to consider the relevant implications for statistical validity, study objectives, and data and safety monitoring. Careful, patient-specific criteria germane to individual studies should guide the process, rather than the grouping of persons purely by HIV status. For example, as the CTEP guidelines state, "If survival is a primary end point, it may be appropriate to exclude patients with known HIV-positive status for whom the probability of death due to underlying HIV-infection is high over the likely time course of the study."⁹ Accordingly, inclusion of persons with well-controlled HIV infection may be a reasonable and appropriate eligibility criterion. It may also be worthwhile to stratify persons with HIV infection into a separate trial group, as the CTEP sample protocols suggest.⁴⁸

Certain HIV-specific vulnerabilities do require additional safeguards. For example, erratic ART dosing should be avoided because development of drug-resistant HIV is promoted when adequate serum drug levels are not maintained.⁴⁹ Consultation with HIV specialists can help insure best care and outcome.⁵⁰

Ultimately, clinical investigators have every reason to better understand cancer in HIV-infected individuals and the potential for HIV-related interactions with the interventions they are testing. Meanwhile, the medical benefits of trial access (particularly for phase III trials) for persons with HIV infection are significant, and considerations of justice give their claims additional force. The standard method of establishing eligibility is to include patients whose participation is consistent with the study objectives, and exclusion is generally aimed at protection of vulnerable patients from undue risk. Thus consideration of HIV disease features relevant to a specific study can help guide development of appropriate criteria for assessing which HIV-infected persons should be eligible to participate in that trial. Such consideration allows clinical investigators to develop scientifically and ethically suitable strategies for including persons with HIV infection rather than viewing the issue as a bureaucratic mandate. The former may enlighten the science and promote human service, whereas the latter is likely to be counterproductive. Embracing this challenge will extend needed respect to a vulnerable population and take a crucial step toward the ideal of fair and carefully considered study participant selection that underpins clinical research.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Govind C. Persad, Richard F. Little, Christine Grady

Collection and assembly of data: Govind C. Persad, Richard F. Little, Christine Grady

Data analysis and interpretation: Govind C. Persad, Richard F. Little, Christine Grady

Manuscript writing: Govind C. Persad, Richard F. Little, Christine Grady

Final approval of manuscript: Govind C. Persad, Richard F. Little, Christine Grady

ACKNOWLEDGMENTS

We thank Susan Bates, MD, of the Medical Oncology Branch, National Cancer Institute, for encouraging the authors to initiate this work and in reviewing the manuscript, and Jon Tilburt, MD, and Ezekiel Emanuel, MD, PhD, of the Department of Bioethics for helpful suggestions.

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This Article Full Text (PDF) Publisher's Note Erratum (v26,p2604) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Persad, G. C. Articles by Grady, C. Search for Related Content PubMed Articles by Persad, G. C. Articles by Grady, C.