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Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 5005-5009 Published by the American Society of Clinical Oncology DOI: 10.1200/JCO.2006.05.7984 Hepatocellular Carcinoma and Non-Hodgkin's Lymphoma: The Roles of HIV, Hepatitis C Infection, and Alcohol Abuse
From the Center for Health Equity Research and Promotion, Veterans Affairs (VA) Pittsburgh Healthcare System; the University Center for Social and Urban Research, University of Pittsburgh, Pittsburgh, PA; VA Connecticut Healthcare System, West Haven; Yale University School of Medicine, New Haven, CT; University of Kentucky, Lexington, KY; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD Address reprint requests to Amy C. Justice, MD, PhD, Department of Medicine, School of Medicine, Yale University, 950 Campbell Avenue, West Haven, CT 06516; e-mail: amy.justice2{at}va.gov
Purpose: To explore the relationship of HIV, hepatitis C (HCV), and alcohol abuse/dependence to risk for hepatocellular carcinoma and non-Hodgkin's lymphoma (NHL). Patients and Methods: Male veterans (n = 14,018) with a first HIV diagnosis in the Veterans Affairs Healthcare System from October 1997 to September 2004; and 28,036 age-, race-, sex-, and location-matched HIV-negative veterans were identified. We examined the incidence of hepatocellular carcinoma and NHL and presence of HCV and alcohol abuse/dependence using International Classification of Diseases, ninth revision (ICD-9-CM) codes. HIV-positive to HIV-negative incident rate ratios (IRRs) and 95% CIs for the occurrence of hepatocellular carcinoma and NHL were calculated using Poisson regression models. Results: HIV-positive veterans were at greater risk for hepatocellular carcinoma than HIV-negative veterans (IRR = 1.68; 95% CI, 1.02 to 2.77). After adjusting for HCV infection and alcohol abuse/dependence, HIV status was not independently associated with hepatocellular cancer (IRR = 0.96; 95% CI, 0.56 to 1.63). HIV-positive veterans had 9.71 times (95% CI, 6.99 to 13.49) greater risk of NHL than HIV-negative veterans. After adjusting for HCV and alcohol abuse/dependence, the IRR for NHL comparing HIV-positive with HIV-negative veterans is similar (IRR = 10.03, 95% CI, 7.19 to 13.97). Conclusion: HIV-positive veterans have a higher relative incidence of hepatocellular carcinoma and NHL than HIV-negative veterans. For hepatocellular carcinoma, this association appears to be largely explained by the higher prevalence of HCV and alcohol abuse/dependence. Efforts to decrease hepatocellular carcinoma among persons with HIV should focus primarily on detecting and treating HCV and reducing heavy alcohol use.
Now that people with HIV are living longer because of highly active antiretroviral therapy (HAART),1 there is concern that they may be at increased risk of cancer.2-4 Hepatocellular carcinoma is a long-term adverse outcome of infection with hepatitis C virus (HCV)5,6 and has also been linked to HIV infection.7-10 Non-Hodgkin's lymphoma (NHL) is an AIDS-defining condition3,4,9,11-13 that has also been linked to HCV infection.9,10,14,15 Previous studies attempting to assess the associations between these cancers and chronic HIV and HCV infection have been limited in their ability to measure all relevant factors. One study examined the relationship of HCV and HIV to hepatocellular carcinoma and NHL by comparing HIV-positive persons by HCV risk groups rather than by HCV status.9 Because persons with HIV are at substantially greater risk for HCV and vice versa, both HIV and HCV need to be accounted for when evaluating the relationships of HCV and HIV to specific cancers.15 Alcohol use has been associated with an increased risk of hepatocellular carcinoma7,8,16 and with a decreased risk of NHL,17 so the role of alcohol abuse/dependence must also be assessed.18,19 The aim of this article is to examine whether hepatocellular carcinoma and NHL are associated with HIV, HCV, and/or alcohol abuse/dependence. Although each cancer has been examined with HIV and HCV separately, no study that we are aware of has examined hepatocellular carcinoma and NHL in a population containing information on HIV, HCV, and alcohol use or abuse. We use data from the United States Veterans Affairs (VA) Healthcare System to compare the risks of hepatocellular carcinoma and NHL in HIV-positive and HIV-negative veterans. We then examined how the risk changed after adjusting for HCV and alcohol abuse/dependence.
Data Use of VA national administrative data for this retrospective cohort study was approved by the VA Pittsburgh Healthcare System and University of Pittsburgh institutional review boards (Pittsburgh, PA). VA electronic medical record data from patient treatment files and outpatient clinic files were used. We adapted an algorithm developed by Fasciano et al20 using International Classification of Diseases, ninth revision (ICD-9-CM) diagnostic codes to identify patients with a first HIV or AIDS diagnosis from October 1997 to September 2004. Our modifications required veterans to have one or more inpatient or two or more outpatient HIV-related codes rather than a single inpatient or outpatient HIV-related codes. Our program searched for the following ICD-9-CM codes: AIDS (042), asymptomatic HIV (V08), and related Diagnostic Related Group codes (488-490). We have previously demonstrated that requiring at least two outpatient codes or one inpatient code results in substantial improvement in positive predictive value (88% v 69%) without a substantial decrement in sensitivity, specificity, or negative predictive value.21 For each HIV positive veteran identified, we identified two HIV-negative veterans matched on age, sex, race, location, and in care in the same year. This methodology is described in full elsewhere.21 Subjects were followed from the date of their first HIV-related diagnostic code, or their matching date. Subjects were censored at their date of death, or last encounter within the VA before September 2004. This analysis is limited to male veterans. We searched for diagnostic codes for cancers in inpatient files from October 1990 and in outpatient files from October 1996 through September 2004. We used ICD-9-CM site-specific cancer codes as identified by Surveillance Epidemiology and End Results (SEER) for hepatocellular carcinoma: 152.0, 155.2; and for NHL: 200.0 to 200.8, 202.0 to 202.2, and 202.8 to 202.9.22 Cancers were included if the veteran had one or more inpatient or two or more outpatient cancer diagnoses of the same type. The criterion of requiring two or more outpatient codes is based on concerns regarding the accuracy of outpatient coding. Professional coders choose inpatient codes after reviewing the medical record; however, outpatient codes are assigned by the provider at the time of the encounter.21 The methodology of requiring two or more outpatient codes has also been used in the identification of psychiatric disorders in administrative data23,24 and for identification of HIV in Medicaid data.25 This criterion was also validated using sensitivity and agreement analyses of provider and ICD-9-CM identified cancers using Veterans Aging Cohort 3-Site Study data.26 Veterans with a cancer of interest (hepatocellular carcinoma or NHL) before their baseline date were excluded from the analysis of that particular cancer. Because hepatocellular carcinoma has been shown to be associated with hepatitis C infection and excessive alcohol consumption,8 and NHL is possibly associated with HCV,9,15 we also adjusted for having had a diagnosis of HCV infection or alcohol abuse/dependence. For both conditions, we considered the condition to be present if there was one or more inpatient or two or more outpatient diagnoses at any time point. ICD-9-CM codes used to identify HCV are 070.41, 070.44, 070.51, 070.54, and V02.62. For alcohol abuse/dependence, we used the codes for alcohol abuse and complications from alcohol use: 291.xx, 303.xx, 305.0x, 357.5, 425.5, 535.3, 571.0, 571.1, 571.2, 571.3, 790.3, 980.8, 980.9, E860.0, E860.1, E860.8, and E860.9. Because of their known relationship to hepatocellular carcinoma, we also examined the prevalence of liver-related comorbidities including HCV, hepatitis B virus (ICD-9-CM codes 070.22, 070.23, 070.32, 070.33, and V02.61), cirrhosis (ICD-9-CM codes 571.2, 571.5, and 571.6), and alcohol abuse/dependence among subjects with hepatocellular carcinoma by HIV status.
Statistical Analysis
We identified 14,018 HIV-positive veterans and 28,036 matched HIV-negative veterans receiving VA care from October 1997 to September 2004. HIV-positive veterans were more likely to have had an HCV diagnosis (21.8% v 8.3%; P < .001; Table 1). Alcohol abuse/dependence was similar between HIV-positive and HIV-negative veterans (27.0% v 27.5%; P = .35). HIV-positive veterans had shorter median follow-up time than HIV-negative veterans (3.2 v 3.5 years; P < .001). Among those who survived, follow-up time was similar among HIV-positive veterans and HIV-negative veterans (median, 3.5 v 3.5 years; P = .58; Table 1).
Hepatocellular Carcinoma Four HIV-positive and 13 HIV-negative veterans were excluded from this analysis because of a hepatocellular carcinoma diagnosis before baseline. In the observation period, 28 HIV-positive and 36 HIV-negative veterans were diagnosed with hepatocellular carcinoma (age- and race-adjusted IRs per 100,000 person-years: 59.5 and 35.4, respectively). In a Poisson regression model including HIV status, age, and race, HIV-positive veterans were 1.68 times more likely to have hepatocellular carcinoma than HIV-negative veterans (95% CI, 1.02 to 2.77; Table 2). When alcohol abuse/dependence and HCV infection were added to the model, the coefficient for HIV was no longer significant (IRR = 0.96; 95% CI, 0.56 to 1.63), hepatocellular carcinoma remained independently associated with HCV (IRR = 12.54; 95% CI, 6.46 to 24.35) and alcohol abuse/dependence (IRR = 1.85; 95% CI, 1.03 to 3.35). In both models, increasing age and Hispanic race/ethnicity (compared with all other race/ethnicities) were associated with a statistically significantly greater risk of hepatocellular carcinoma (Table 2).
Of the 64 veterans with an occurrence of hepatocellular carcinoma, the prevalence of HCV was 67.2%, HBV 10.9%, cirrhosis 45.3%, and alcohol abuse/dependence 56.3%, and 10.9% had none of these diagnoses. There were no statistically significant differences in the percentage having any of these liver-related diagnoses between the HIV-positive and HIV-negative veterans, except for alcohol abuse/dependence (39.3% for HIV-positive v 69.4% for HIV-negative veterans; P = .016; Table 3).
NHL Eighty-eight HIV-positive and 68 HIV-negative veterans were excluded from the NHL analysis because of a diagnosis of NHL before baseline. In the observation period, 197 HIV-positive and 43 HIV-negative veterans were diagnosed with NHL (age- and race-adjusted IRs per 100,000 person-years: 414.2 and 42.5, respectively). In a Poisson regression model including HIV status, age, and race, HIV-positive veterans were 9.71 times more likely to have NHL than were HIV-negative veterans (95% CI, 6.99 to 13.49; Table 4). When alcohol abuse/dependence and HCV infection were included in the model, the IRR for HIV was similar (IRR = 10.03; 95% CI, 7.19 to 13.97) whereas alcohol abuse/dependence was associated with a lower risk of NHL (IRR = 0.69; 95% CI, 0.49 to 0.96). Those with HCV were at decreased risk for NHL (IRR = 0.73; 95% CI, 0.50 to 1.06), but this difference was not statistically significant. In both models, increasing age was associated with an increased risk of NHL. (Table 4)
In this analysis of more than 42,000 veterans, we demonstrated that HIV-positive veterans have a higher incidence of both hepatocellular carcinoma and NHL than do HIV-negative veterans. In the case of hepatocellular carcinoma, the association appears to be mediated by HCV infection and alcohol abuse/dependence. In the case of NHL, the association appears to be independent of these factors. Our findings extend prior work that was limited in its ability to control for all of these factors. Using data before 1997 (before widespread usage of HAART), Engels et al9 found that HIV-positive persons in groups at high-risk for HCV were at higher risk of hepatocellular carcinoma compared with HIV-positive persons at lower risk for HCV. However, they also found that all HIV-positive risk groups were at higher risk for hepatocellular carcinoma than those in the general population. Because they could not control for HCV infection, they were unable to definitively assess whether HIV is also a risk factor. In this study, we were able to identify the role of HCV and alcohol abuse/dependence diagnoses and assess the associations between HIV and hepatocellular carcinoma before and after adjustment for these factors. The higher incidence of non-Hodgkin's lymphoma in HIV-positive veterans was not explained by a higher prevalence of HCV or alcohol abuse/dependence in our analysis. Past work in this field has not been definitive. Engels et al9 found that those in groups at lower risk for HCV had higher rates of NHL. Another study of HCV and NHL found that persons with HCV had an almost two-fold greater risk of NHL; however, that study was unable to control for HIV.10 Because persons with HIV are also more likely to have HCV, and vice versa, an analysis of data containing information on both HIV and HCV is necessary to determine which factors are associated with greater risk. We demonstrate that HIV is associated with a greater risk of NHL, as expected, and that alcohol abuse/dependence is associated with lower risk for NHL. HCV was associated with a lower risk of NHL, but not statistically significantly. This result is similar to findings of a case-control study of HCV and NHL in HIV-positive persons in the pre-HAART era by Levine et al.27 They found no significant association between HCV and NHL in persons infected with HIV. The inverse relationship between alcohol use and NHL has been established in several other studies.17-19 The inverse relationship between HCV and NHL has also been observed in previous studies9 and is possibly caused by a mediating factor related to socioeconomic status.9 Our study has some important limitations. These include limitations inherent in the use of ICD-9 diagnostic codes for diagnoses of cancer, no measurement of tobacco exposure, shorter follow-up time for the HIV positives, and potential selection bias in the use of a VA sample. Because we relied on diagnostic codes, conditions are likely under-reported, as we are not able to ascertain diagnoses occurring outside the VA or diagnoses not recorded. From previous work in the Veterans Aging Cohort Study (VACS), an eight-site, ongoing longitudinal study of more than 6,000 HIV-positive and HIV-negative veterans in care, we believe this is unlikely to significantly affect our findings. Almost 65% of HIV-positive and HIV-negative veterans reported receiving 100% of their outpatient care in the previous 4 months within the VA; and, only 8% of HIV-positive and 9.5% of HIV-negative veterans reported receiving less than half of their outpatient care in the VA system in the previous 4 months.29 In addition, we found that 21.8% of HIV-positive veterans were coinfected with HCV, and this is similar to findings from the Terry Beirns Community Programs for Clinical Research on AIDS, which reported that 16.6% of enrolled persons with AIDS were also coinfected with HCV.30 Because administrative data within the VA for smoking status are poor, we were unable to determine smoking status, a known risk factor for many types of cancer. Based on data from the Veterans Aging Cohort 5-Site Feasibility Study, 75% of HIV-positive and 76% of HIV-negative veterans report ever having smoked.31 Thus, smoking rates are not substantially higher among HIV-positive veterans when compared with HIV-negative veterans. Not surprisingly, follow-up time was shorter among those with HIV infection because of a higher rate of mortality compared with the HIV uninfected. Among those who survived, follow-up time for this study was 3.2 years for HIV-positive and 3.5 years for HIV-negative veterans; we believe the large sample size provides stable estimates of incidence. With additional follow-up, this pattern may change as patients continue to age with HIV infection. Finally, veterans who receive care within the VA system are different from the general US population. Specifically, veterans who receive care within the VA are older and have a lower socioeconomic status. Clearly, veterans in care have a reason for seeking care and are therefore more likely to suffer disease than those who do not seek medical care. We do not find it surprising that the HIV-negative veterans in our sample had higher rates of disease (NHL and hepatocellular cancer) than observed in a more general population. This is why we designed the study to compare rates among veterans in care with and without HIV—to ensure that the HIV-negative sample was a fair comparison group for our veteran HIV-positive sample. Thus, we caution against focusing on the rates of cancer observed in our sample in favor of focusing on the comparison of relative rates (IRRs) among those with and without HIV infection. On the basis of our findings, HCV and alcohol abuse/dependence are not factors that contribute to the increase in NHL among persons with HIV, but do represent significant risks for hepatocellular carcinoma. Efforts to decrease the occurrence of hepatocellular carcinoma among persons with HIV infection should focus on detecting and treating HCV infection and reducing heavy alcohol use.
The authors indicated no potential conflicts of interest.
Supported by an interagency agreement between the National Institute on Aging, the National Institute of Mental Health, and the National Institute on Alcohol Abuse and Alcoholism (Grant No. U01-13566) and the Veterans Affairs Health Services Research and Development Service (Grant No. RCD 04-125-1). Presented as a poster at the XV International AIDS Conference, Bangkok, Thailand, July 11-16, 2004. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Justice AC, Landefeld CS, Asch SM, et al: Justification for a new cohort study of people aging with and without HIV infection. J Clin Epidemiol 54:S3-S8, 2001[CrossRef][Medline] 2. Engels EA: Human immunodeficiency virus infection, aging, and cancer. J Clin Epidemiol 54:S29-S34, 2001[CrossRef][Medline] 3. Frisch M, Biggar RJ, Engels EA, et al: Association of cancer with AIDS-related immunosuppression in adults. JAMA 285:1736-1745, 2001 4. Mbulaiteye SM, Biggar RJ, Goedert JJ, et al: Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr 32:527-533, 2003[Medline] 5. Anzola M: Hepatocellular carcinoma: Role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis. J Viral Hepat 11:383-393, 2004[CrossRef][Medline] 6. Giordano TP, Kramer JR, Souchek J, et al: Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without the hepatitis C virus: A cohort study, 1992-2001. Arch Intern Med 164:2349-2354, 2004 7. Smukler A, Ratner L: Hepatitis viruses and hepatocellular carcinoma in HIV-infected patients. Curr Opin Oncol 14:538-542, 2002[CrossRef][Medline] 8. Hassan M, Frome A, Patt Y, et al: Rising prevalence of Hepatitis C virus infection among patients recently diagnosed with hepatocellular carcinoma in the United States. J Clin Gastroenterol 35:266-269, 2002[CrossRef][Medline] 9. Engels E, Frisch M, Lubin J, et al: Prevalence of hepatitis C virus infection and risk for hepatocellular carcinoma and non-Hodgkin lymphoma in AIDS. J Acquir Immune Defic Syndr 31:536-541, 2002[Medline] 10. Engels EA, Catterjee N, Cerhan JR, et al: Hepatitis C virus infection and non-Hodgkin lymphoma: Results of the NCI-SEER Multi-Center case-control study. Int J Cancer 111:76-80, 2004[CrossRef][Medline] 11. Goedert JJ, Cote TR, Virgo SM, et al: Spectrum of AIDS-associated malignant disorders. Lancet 351:1833-1839, 1998[CrossRef][Medline] 12. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 41:1-19, 1992[Medline] 13. Herida M, Mary-Krause M, Kaphan R, et al: Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncology 21:3447-3453, 2003 14. Morton LM, Engels EA, Holford TR, et al: Hepatitis C virus and risk of non-Hodgkin lymphoma: A population-based case-control study among Connecticut women. Cancer Epidemiol Biomarkers Prev 13:425-430, 2004 15. Zuckerman E, Zuckerman T, Levine AM, et al: Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med 127:423-428, 1997 16. Austin H, Delzell E, Grufferman S, et al: A case-control study of hepatocellular carcinoma and the hepatitis B virus, cigarette smoking, and alcohol consumption. Cancer Res 46:962-966, 1986 17. Morton LM, Holford TR, Leaderer B, et al: Alcohol use and risk of non-Hodgkin's lymphoma among Connecticut women. Cancer Causes Control 14:687-694, 2003[CrossRef][Medline] 18. Briggs NC, Levine RS, Bobo LD, et al: Wine drinking and risk of non-Hodgkin's lymphoma among men in the United States: A population-based case-control study. Am J Epidemiol 156:454-462, 2002 19. Chiu BC, Cerhan JR, Gapstur SM, et al: Alcohol consumption and non-Hodgkin lymphoma in a cohort of older women. Br J Cancer 80:1476-1482, 1999[CrossRef][Medline] 20. Fasciano NJ, Cherlow AL, Turner BJ, et al: Profile of Medicare beneficiaries with AIDS: Application of an AIDS casefinding algorithm. Health Care Financ Rev 19:19-38, 1998[Medline] 21. Fultz SL, Skanderson M, Mole LA, et al: Development and verification of a "virtual" cohort using the National VA Health Information System. Med Care 44:S25-S30, 2006[CrossRef][Medline] 22. Ries LAG, Eisner MP, Kosary CL, et al: SEER Cancer Statistics Review, 1973-1997, Bethesda, MD, National Cancer Institute, 2000 23. Lurie N, Popkin M, Dysken M, et al: Accuracy of diagnoses of schizophrenia in Medicaid claims. Hosp Community Psychiatry 43:69-71, 1992 24. Bagchi A, Sambamoorthi U, McSpiritt E, et al: Use of antipsychotic medications among HIV-infected individuals with schizophrenia. Schizophr Res 71:435-444, 2004[CrossRef][Medline] 25. Walkup JT, Wei W, Sambamoorthi U, et al: Sensitivity of an AIDS case-finding algorithm: Who are we missing? Med Care 42:756-763, 2004[CrossRef][Medline] 26. Justice AC, Lasky E, McGinnis KA, et al: Medical disease and alcohol use among veterans with HIV infection: A comparison of disease measurement strategies. Med Care 44:S52-S60, 2006[CrossRef][Medline] 27. Levine AM, Nelson R, Zuckerman E, et al: Lack of association between hepatitis C infection and development of AIDS-related lymphoma. J Acquir Immune Defic Syndr 20:255-258, 1999 28. Ashton CM, Peterson NJ, Wray NP, et al: The Veterans Affairs medical care system: Hospital and clinic utilization statistics for 1994. Med Care 36:793-803, 1998[CrossRef][Medline] 29. Justice AC, Dombrowski E, Conigliaro J, et al: Veterans Aging Cohort Study (VACS): Overview and description. Med Care 44:S13-S24, 2006[CrossRef][Medline] 30. Tedaldi EM, Hullsiek KH, Malvestutto CD, et al: Prevalence and characteristics of hepatitis C virus coinfection in a human immunodeficiency virus clinical trials group: The Terry Beirn Community Programs for Clinical Research on AIDS. Clin Infect Dis 36:1313-1317, 2003[CrossRef][Medline] 31. Crothers K, Butt A, Gibert CL, et al: Increased chronic obstructive pulmonary disease among HIV-positive compared to HIV-negative veterans. Chest (in press) Submitted January 20, 2006; accepted September 6, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests for race, HCV, and alcohol abuse/dependence, and the Wilcoxon rank sum test for observation time. Age- and race-adjusted hepatocellular carcinoma and NHL incidence rates (IRs) per 100,000 person-years were calculated for HIV-positive and HIV-negative veterans. HIV-positive compared with HIV-negative age- and race-adjusted incident rate ratios (IRRs) and 95% CI were calculated using Poisson regression analysis. Regression models were repeated also adjusting for HCV and alcohol abuse/dependence. The prevalence of liver-related comorbidities was compared between HIV-positive and HIV-negative veterans with hepatocellular carcinoma using 
