Cancer Epidemiology 38 (2014) 386–392
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Longer duration of combination antiretroviral therapy reduces the risk of Hodgkin lymphoma: A cohort study of HIV-infected male veterans M.A. Kowalkowski a,b,c,*, M.A. Mims b, R.S. Day d, X.L. Du d, W. Chan e, E.Y. Chiao b,c a
Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA Department of Medicine, Baylor College of Medicine, Houston, TX, USA c Houston Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA d Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USA e Department of Biostatistics, University of Texas School of Public Health, Houston, TX, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 March 2014 Received in revised form 19 May 2014 Accepted 22 May 2014 Available online 16 June 2014
Background: Hodgkin lymphoma (HL) incidence has increased since combined antiretroviral therapy (cART) introduction. It is unclear how different cART classes (e.g., protease inhibitors (PI), nonnucleoside reverse transcription inhibitors (NNRTI)) influence HL. This study aimed to determine the effects of cART duration on HL incidence among HIV-infected veterans. Methods: We performed a retrospective cohort study utilizing the Veterans Affairs HIV Clinical Case Registry (1985–2010). HL cases were identified using ICD-9 codes (201.4-9). cART, PI, and NNRTI duration was the aggregate number of treatment days delivered. Incidence rates (IR) and rate ratios (IRR) were calculated from Poisson regression models to examine the effects of cART duration on HL. Results: 31,576 cART users contributed 288,736 person-years (PY) and 211 HL cases (IR = 7.3/10,000 person-years). HL incidence decreased from 25.1/10,000 PY (95%CI = 18.9–33.4) within the first year of cART to 0.6/10,000 PY (95%CI = 0.3–1.6) after 10 years. In multivariable models, each additional year of cART was associated with decreased HL incidence (IRR = 0.80; 95%CI = 0.75–0.86); similar effects were observed in models assessing HL incidence by PI and NNRTI. Conclusion: Our findings indicate long-term cART of any class is associated with decreased HL risk. High HL incidence directly following cART initiation supports a potential immune reconstitution mechanism in HIV-related HL. Further research is needed to evaluate the interaction between early cART, immune reconstitution, and HL. ß 2014 Elsevier Ltd. All rights reserved.
Keywords: Hodgkin lymphoma HIV Non-AIDS defining cancer Epidemiology Combined antiretroviral therapy
1. Background Combination antiretroviral therapy (cART) for HIV infection has improved immune function and reduced the burden of opportunistic infections, prolonging survival for HIV-infected individuals in the United States [1]. However, since cART, the incidence of nonAIDS-defining malignancies (NADM), e.g. Hodgkin lymphoma (HL), has increased [2–6]. Although HIV-related HL has been strongly linked to the Epstein–Barr virus (EBV), the causes for the increased HL incidence in the cART era remain unclear [7]. Martis et al. [8] have postulated several hypotheses, including (1) the alteration of the microenvironment secondary to CD4 repopulation, (2)
* Corresponding author at: Current address: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC 28204, USA. Tel.: +1 7043559902. E-mail address: [email protected] (M.A. Kowalkowski). http://dx.doi.org/10.1016/j.canep.2014.05.009 1877-7821/ß 2014 Elsevier Ltd. All rights reserved.
HL Reed–Sternberg cells are not impacted by HIV and instead proliferate via pro-inflammatory signals, and (3) decreased competing risk with AIDS-defining events. However, one mechanism that requires additional investigation is the direct effect of cART use, and the class of treatment received, on cancer development. Previous experimental studies have isolated several anticancer mechanisms directed by protease inhibitors (PI), e.g., induction of apoptosis [9] and cell cycle arrest [10], and non-nucleoside reverse transcriptase inhibitors (NNRTI), e.g., inhibition of downstream cell growth and differentiation in tumors [11,12]. However, the direct effects of the different classes of cART on HL incidence have not been adequately evaluated in population-based studies of HIV-infected persons. Additionally, studies that have been conducted have reported largely inconsistent results. Powles et al. [13] observed a 120% increased risk of HL among NNRTI users while Chao et al. [14] reported no association between cART, PI, or NNRTI use and HL incidence.
M.A. Kowalkowski et al. / Cancer Epidemiology 38 (2014) 386–392
Results from these studies highlight the contradictory findings from previous research. Furthermore, these and other studies have been limited by relatively small samples, particularly regarding the number of HL cases identified [13–16]. Previous studies have also measured treatment effects across cART users and non-users. However, due to the different disease and mortality patterns experienced by HIV-infected individuals who never received cART, results may be confounded by unmeasured factors making it difficult to derive accurate conclusions. The aim of the present study was to determine the effect of the duration of any cART, PI- and NNRTI-based regimens on HL incidence among a cohort of HIV-infected male US military veterans ever receiving cART.
387
2.1. Database We conducted a retrospective cohort study of HIV-infected US military veterans diagnosed with HIV from 1985 to 2010 and cared for within the Veterans Health Administration, the largest integrated healthcare system and provider of comprehensive HIV care in the United States [17]. HIV-infected individuals were identified from the Department of Veterans Affairs (VA) HIV Clinical Case Registry (CCR), a nationwide registry containing health-related information on all known HIV-infected VA users [17,18]. The registry draws upon the electronic medical records of over 65,000 HIV-infected patients cared for by the VA since the registry’s inception. The registry includes demographic, laboratory, pharmacy, outpatient clinic visit, hospitalization data, and dates of death.
2. Methods 2.2. Inclusion criteria This study was approved by the Institutional Review Board of Baylor College of Medicine and the Committee for the Protection of Human Subjects at UTHealth (Houston, TX).
The initial CCR population included 66,991 HIV-infected adult veterans (18 years) with an identifiable HIV diagnosis date
Fig. 1. Flow chart of selection criteria generating final cohort of HIV-infected veterans.
388
M.A. Kowalkowski et al. / Cancer Epidemiology 38 (2014) 386–392
between 1985 and 2010. Fig. 1 describes selection criteria implemented to generate the final sample. HIV diagnosis was confirmed based on (1) the presence of multiple International Classification of Diseases, Ninth Revision (ICD-9) code for HIV, or (2) a combination of ICD-9 code for HIV, positive HIV-related test (e.g., ELISA, Western blot, quantifiable HIV RNA measurement), or prescription delivery of antiretroviral therapy. Index HIV diagnosis date was defined as the earliest ICD-9 code, positive test, or prescription delivery. 6769 individuals without adequate HIV diagnostics (i.e., only a single ICD-9 code for HIV and no lab or pharmacy records) or vital statistics were removed. Only men were included in our analyses due to the small number of HIV-infected female veterans (
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Longer duration of combination antiretroviral therapy reduces the risk of Hodgkin lymphoma: A cohort study of HIV-infected male veterans M.A. Kowalkowski a,b,c,*, M.A. Mims b, R.S. Day d, X.L. Du d, W. Chan e, E.Y. Chiao b,c a
Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA Department of Medicine, Baylor College of Medicine, Houston, TX, USA c Houston Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA d Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USA e Department of Biostatistics, University of Texas School of Public Health, Houston, TX, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 March 2014 Received in revised form 19 May 2014 Accepted 22 May 2014 Available online 16 June 2014
Background: Hodgkin lymphoma (HL) incidence has increased since combined antiretroviral therapy (cART) introduction. It is unclear how different cART classes (e.g., protease inhibitors (PI), nonnucleoside reverse transcription inhibitors (NNRTI)) influence HL. This study aimed to determine the effects of cART duration on HL incidence among HIV-infected veterans. Methods: We performed a retrospective cohort study utilizing the Veterans Affairs HIV Clinical Case Registry (1985–2010). HL cases were identified using ICD-9 codes (201.4-9). cART, PI, and NNRTI duration was the aggregate number of treatment days delivered. Incidence rates (IR) and rate ratios (IRR) were calculated from Poisson regression models to examine the effects of cART duration on HL. Results: 31,576 cART users contributed 288,736 person-years (PY) and 211 HL cases (IR = 7.3/10,000 person-years). HL incidence decreased from 25.1/10,000 PY (95%CI = 18.9–33.4) within the first year of cART to 0.6/10,000 PY (95%CI = 0.3–1.6) after 10 years. In multivariable models, each additional year of cART was associated with decreased HL incidence (IRR = 0.80; 95%CI = 0.75–0.86); similar effects were observed in models assessing HL incidence by PI and NNRTI. Conclusion: Our findings indicate long-term cART of any class is associated with decreased HL risk. High HL incidence directly following cART initiation supports a potential immune reconstitution mechanism in HIV-related HL. Further research is needed to evaluate the interaction between early cART, immune reconstitution, and HL. ß 2014 Elsevier Ltd. All rights reserved.
Keywords: Hodgkin lymphoma HIV Non-AIDS defining cancer Epidemiology Combined antiretroviral therapy
1. Background Combination antiretroviral therapy (cART) for HIV infection has improved immune function and reduced the burden of opportunistic infections, prolonging survival for HIV-infected individuals in the United States [1]. However, since cART, the incidence of nonAIDS-defining malignancies (NADM), e.g. Hodgkin lymphoma (HL), has increased [2–6]. Although HIV-related HL has been strongly linked to the Epstein–Barr virus (EBV), the causes for the increased HL incidence in the cART era remain unclear [7]. Martis et al. [8] have postulated several hypotheses, including (1) the alteration of the microenvironment secondary to CD4 repopulation, (2)
* Corresponding author at: Current address: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC 28204, USA. Tel.: +1 7043559902. E-mail address: [email protected] (M.A. Kowalkowski). http://dx.doi.org/10.1016/j.canep.2014.05.009 1877-7821/ß 2014 Elsevier Ltd. All rights reserved.
HL Reed–Sternberg cells are not impacted by HIV and instead proliferate via pro-inflammatory signals, and (3) decreased competing risk with AIDS-defining events. However, one mechanism that requires additional investigation is the direct effect of cART use, and the class of treatment received, on cancer development. Previous experimental studies have isolated several anticancer mechanisms directed by protease inhibitors (PI), e.g., induction of apoptosis [9] and cell cycle arrest [10], and non-nucleoside reverse transcriptase inhibitors (NNRTI), e.g., inhibition of downstream cell growth and differentiation in tumors [11,12]. However, the direct effects of the different classes of cART on HL incidence have not been adequately evaluated in population-based studies of HIV-infected persons. Additionally, studies that have been conducted have reported largely inconsistent results. Powles et al. [13] observed a 120% increased risk of HL among NNRTI users while Chao et al. [14] reported no association between cART, PI, or NNRTI use and HL incidence.
M.A. Kowalkowski et al. / Cancer Epidemiology 38 (2014) 386–392
Results from these studies highlight the contradictory findings from previous research. Furthermore, these and other studies have been limited by relatively small samples, particularly regarding the number of HL cases identified [13–16]. Previous studies have also measured treatment effects across cART users and non-users. However, due to the different disease and mortality patterns experienced by HIV-infected individuals who never received cART, results may be confounded by unmeasured factors making it difficult to derive accurate conclusions. The aim of the present study was to determine the effect of the duration of any cART, PI- and NNRTI-based regimens on HL incidence among a cohort of HIV-infected male US military veterans ever receiving cART.
387
2.1. Database We conducted a retrospective cohort study of HIV-infected US military veterans diagnosed with HIV from 1985 to 2010 and cared for within the Veterans Health Administration, the largest integrated healthcare system and provider of comprehensive HIV care in the United States [17]. HIV-infected individuals were identified from the Department of Veterans Affairs (VA) HIV Clinical Case Registry (CCR), a nationwide registry containing health-related information on all known HIV-infected VA users [17,18]. The registry draws upon the electronic medical records of over 65,000 HIV-infected patients cared for by the VA since the registry’s inception. The registry includes demographic, laboratory, pharmacy, outpatient clinic visit, hospitalization data, and dates of death.
2. Methods 2.2. Inclusion criteria This study was approved by the Institutional Review Board of Baylor College of Medicine and the Committee for the Protection of Human Subjects at UTHealth (Houston, TX).
The initial CCR population included 66,991 HIV-infected adult veterans (18 years) with an identifiable HIV diagnosis date
Fig. 1. Flow chart of selection criteria generating final cohort of HIV-infected veterans.
388
M.A. Kowalkowski et al. / Cancer Epidemiology 38 (2014) 386–392
between 1985 and 2010. Fig. 1 describes selection criteria implemented to generate the final sample. HIV diagnosis was confirmed based on (1) the presence of multiple International Classification of Diseases, Ninth Revision (ICD-9) code for HIV, or (2) a combination of ICD-9 code for HIV, positive HIV-related test (e.g., ELISA, Western blot, quantifiable HIV RNA measurement), or prescription delivery of antiretroviral therapy. Index HIV diagnosis date was defined as the earliest ICD-9 code, positive test, or prescription delivery. 6769 individuals without adequate HIV diagnostics (i.e., only a single ICD-9 code for HIV and no lab or pharmacy records) or vital statistics were removed. Only men were included in our analyses due to the small number of HIV-infected female veterans (
