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Table 1.  
Characteristics of Included Trials
Characteristics of Included Trials
Table 2.  
Factors Associated With Inclusion of Patients with HIV in ICI Trials
Factors Associated With Inclusion of Patients with HIV in ICI Trials
1.
Palella  FJ  Jr, Delaney  KM, Moorman  AC,  et al; HIV Outpatient Study Investigators.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.  N Engl J Med. 1998;338(13):853-860. doi:10.1056/NEJM199803263381301PubMedGoogle ScholarCrossref
2.
Samji  H, Cescon  A, Hogg  RS,  et al; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA.  Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada.  PLoS One. 2013;8(12):e81355. doi:10.1371/journal.pone.0081355PubMedGoogle Scholar
3.
Engels  EA, Yanik  EL, Wheeler  W,  et al; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS.  Cancer-attributable mortality among people with treated human immunodeficiency virus infection in North America.  Clin Infect Dis. 2017;65(4):636-643. doi:10.1093/cid/cix392PubMedGoogle ScholarCrossref
4.
Cook  MR, Kim  C.  Safety and efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and advanced-stage cancer: a systematic review.  JAMA Oncol. 2019;5(7):1049-1054. doi:10.1001/jamaoncol.2018.6737PubMedGoogle ScholarCrossref
5.
Uldrick  TS, Gonçalves  PH, Abdul-Hay  M,  et al; Cancer Immunotherapy Trials Network (CITN)-12 Study Team.  Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer—a phase 1 study.  JAMA Oncol. 2019;5(9):1332-1339. doi:10.1001/jamaoncol.2019.2244PubMedGoogle ScholarCrossref
6.
Uldrick  TS, Ison  G, Rudek  MA,  et al.  Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group.  J Clin Oncol. 2017;35(33):3774-3780. doi:10.1200/JCO.2017.73.7338PubMedGoogle ScholarCrossref
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    Research Letter
    Oncology
    November 8, 2019

    Characteristics of Immune Checkpoint Inhibitors Trials Associated With Inclusion of Patients With HIV: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
    JAMA Netw Open. 2019;2(11):e1914816. doi:10.1001/jamanetworkopen.2019.14816
    Introduction

    Since antiretroviral therapy became widely available in the late 1990s, there has been a dramatic reduction in AIDS-related deaths due to opportunistic infections.1 The life expectancy of people living with HIV (PLWH) receiving antiretroviral therapy now approaches that of the general population, particularly for those with a CD4+ T-cell count within the normal range.2 Conversely, cancer has become a leading cause of morbidity and mortality in PLWH. From 1995 to 2009, cancer resulted in nearly two-fold as many deaths per 100 000 person-years in PLWH than in the general population (327 deaths per 100 000 person-years vs 186 deaths per 100 000 person-years).3 Non–AIDS-defining cancers represent 70% of these deaths and will increase with aging of the PLWH population.3

    During the past decade, clinical trials of immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many cancers. Historically, PLWH have been excluded from participation in oncology trials, which may affect generalizability of findings. In this systematic review and meta-analysis, we investigated characteristics of ICI trials associated with inclusion of PLWH.

    Methods

    We performed a systematic search using the key word “checkpoint” to identify prospective trials involving programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) or cytotoxic T-lymphocyte–associated protein 4 ICIs published in 6 high-profile general medicine and oncology journals (Table 1) between January 1, 2016 and March 31, 2019. Two independent reviewers (D.V.A. and H.S.) assessed articles, including supplements and protocols, as well as ClinicalTrials.gov data to determine whether PLWH were eligible for enrollment. In cases of ambiguity, results were discussed with a third reviewer (D.H.). This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

    Logistic and linear regression were used to assess factors associated with inclusion of PLWH. We used the Peto odds ratio method for associations with 0-counts. P values were 2-tailed, and statistical significance was defined as P less than .05. No corrections were made for multiple significance testing. Data analysis was performed using SPSS statistical software version 25.0 (IBM) and Revmen review software version 5.3 (Cochrane) and conducted from June 1, 2019, to June 21, 2019.

    Results

    Of 569 articles screened, 126 articles were trials of ICIs. We excluded 8 studies: 4 studies were duplicates, and 4 studies involved ICIs other than PD-1, PD-L1, or cytotoxic T-lymphocyte–associated protein 4. Our final analysis included 118 articles comprising 30 693 patients. Demographic data for the 118 articles are summarized in Table 1. For PLWH eligibility analysis, we excluded 11 trials owing to unavailability of data. Of 107 trials with PLWH inclusion criteria data, 5 trials (4.7%, 258 patients) allowed enrollment of PLWH. All 5 trials that allowed PLWH were academic, whereas no trials sponsored by a pharmaceutical company included PLWH (odds ratio, 259.77; 95% CI, 26.25-2570.61; P < .001) (Table 2). Only phase 2 trials permitted PLWH entry; however, this is likely a confounder, as most academic trials were phase 2 (17 of 20 trials; 85%). No other factors were associated with PLWH inclusion.

    Discussion

    Limitations of our study include the lack of multivariable adjustment and absence of reporting the justification for PLWH exclusion. Nonetheless, our results demonstrate an almost universal exclusion of PLWH from trials involving ICIs. There are no good justifications for this practice. A 2019 systematic review4 demonstrated that the safety profile of PD-1 or PD-L1 ICIs in PLWH was similar to that of the general population, with no unusual adverse events. A study by Uldrick et al5 of a phase 1 trial involving 30 patients with HIV and advanced cancer treated with pembrolizumab reported a safety profile in keeping with studies of participants without HIV. While academic studies were more likely to allow PLWH, even within this group only 5 trials permitted PLWH. Whereas the reasons for PLWH exclusion are not disclosed in any protocols, we suspect that this practice results from dogma rather than reasoned decision.

    A recent American Society of Clinical Oncology task force6 recommended inclusion of PLWH in oncology trials, particularly patients with T-cell CD4+ counts of 350 cells/μL or higher, who constitute a group with intact immunological function and survival in keeping with the general population. In contrast, the exclusion of PLWH is unsupported by current data, denies patients the benefit of ICI therapy, and is ethically unjustifiable. We advocate for a broader inclusion of these patients in oncology trials.

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    Article Information

    Accepted for Publication: September 17, 2019.

    Published: November 8, 2019. doi:10.1001/jamanetworkopen.2019.14816

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Sorotsky H et al. JAMA Network Open.

    Corresponding Author: Daniel V. Araujo, MD, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 700 University Ave, 7W440, Toronto, ON M5G 1X6, Canada (daniel.araujo@uhn.ca).

    Author Contributions: Drs Sorotsky and Araujo had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Sorotsky, Hogg, Araujo.

    Acquisition, analysis, or interpretation of data: Sorotsky, Amir, Araujo.

    Drafting of the manuscript: Sorotsky, Araujo.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Araujo.

    Administrative, technical, or material support: Sorotsky, Araujo.

    Supervision: Hogg.

    Conflict of Interest Disclosures: Dr Hogg reported receiving personal fees from Bristol-Myers Squibb, Novartis, Merck Serono, and Roche Holding outside the submitted work. Dr Amir reported receiving personal fees from Genentech/Roche, Apobiologix, Sandoz, Myriad Genetics, Agendia, and AstraZeneca outside the submitted work. Dr Araujo reported receiving a grant from Alamos Gold and personal fees from Bristol-Myers Squibb and Libbs outside the submitted work. No other disclosures were reported.

    References
    1.
    Palella  FJ  Jr, Delaney  KM, Moorman  AC,  et al; HIV Outpatient Study Investigators.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.  N Engl J Med. 1998;338(13):853-860. doi:10.1056/NEJM199803263381301PubMedGoogle ScholarCrossref
    2.
    Samji  H, Cescon  A, Hogg  RS,  et al; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA.  Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada.  PLoS One. 2013;8(12):e81355. doi:10.1371/journal.pone.0081355PubMedGoogle Scholar
    3.
    Engels  EA, Yanik  EL, Wheeler  W,  et al; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS.  Cancer-attributable mortality among people with treated human immunodeficiency virus infection in North America.  Clin Infect Dis. 2017;65(4):636-643. doi:10.1093/cid/cix392PubMedGoogle ScholarCrossref
    4.
    Cook  MR, Kim  C.  Safety and efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and advanced-stage cancer: a systematic review.  JAMA Oncol. 2019;5(7):1049-1054. doi:10.1001/jamaoncol.2018.6737PubMedGoogle ScholarCrossref
    5.
    Uldrick  TS, Gonçalves  PH, Abdul-Hay  M,  et al; Cancer Immunotherapy Trials Network (CITN)-12 Study Team.  Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer—a phase 1 study.  JAMA Oncol. 2019;5(9):1332-1339. doi:10.1001/jamaoncol.2019.2244PubMedGoogle ScholarCrossref
    6.
    Uldrick  TS, Ison  G, Rudek  MA,  et al.  Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group.  J Clin Oncol. 2017;35(33):3774-3780. doi:10.1200/JCO.2017.73.7338PubMedGoogle ScholarCrossref
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