Wendy A. Leyden

Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease

We performed a cross‐sectional study of newly diagnosed cases of nonalcoholic fatty liver disease (NAFLD) identified between December 1998 and December 2000 in the Chronic Liver Disease Surveillance Study. We compared the demographic and clinical features of NAFLD in a racially diverse representative U.S. population (Alameda County, CA). Diagnostic criteria for probable NAFLD were persistent unexplained elevation of serum aminotransferase levels, radiology (ultrasound or computed tomography scan) consistent with fatty liver, and/or two or more of the following: (i) body mass index of 28 kg/m2 or more, (ii) type 2 diabetes, or (iii) hyperlipidemia, in the absence of significant alcohol use. Definite NAFLD cases required histological confirmation. Of the 742 persons with newly diagnosed chronic liver disease, 159 (21.4%) had definite or probable NAFLD. The majority were nonwhite: Hispanics (28%), Asians (18%), African Americans (3%), and other race(s) (6%). African Americans with NAFLD were significantly older than other racial or ethnic groups (P < .001), and in Asians, NAFLD was 3.5 times more common in males than in females (P = .016). Clinical correlates of NAFLD (obesity, hyperlipidemia, diabetes) were similar among racial and ethnic groups, except that body mass index was lower in Asians compared with other groups (P < .001). Compared with the base population (Kaiser Permanente members), Hispanics with NAFLD were overrepresented (28% vs. 10%) and whites were underrepresented (45% vs. 59%). In conclusion, these racial and gender variations may reflect differences in genetic susceptibility to visceral adiposity, including hepatic involvement, and may have implications for the evaluation of persons with the metabolic syndrome. Clinicians need to be aware of the variable presentations of NAFLD in different racial and ethnic groups. (HEPATOLOGY 2005;41:372–379.)

HIV INFECTION AND THE RISK OF CANCERS WITH AND WITHOUT A KNOWN INFECTIOUS CAUSE

Objective:To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons. Design:Retrospective cohort study. Methods:Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkins lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs). Results:We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 [95% confidence interval (CI): 31.7–44.8], with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7–11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkins lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2–1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007). Conclusion:In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.

HIV Infection, Immunodeficiency, Viral Replication, and the Risk of Cancer

Background: Few studies have compared cancer risk between HIV-infected individuals and a demographically similar HIV-uninfected internal comparison group, adjusting for cancer risk factors. Methods: We followed 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996 to 2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity. Results: We observed elevated RRs for Kaposi sarcoma (KS; RR = 199; P < 0.001), non-Hodgkin lymphoma (NHL; RR = 15; P < 0.001), anal cancer (RR = 55; P < 0.001), Hodgkin lymphoma (HL; RR = 19; P < 0.001), melanoma (RR = 1.8; P = 0.001), and liver cancer (RR = 1.8; P = 0.013), a reduced RR for prostate cancer (RR = 0.8; P = 0.012), and no increased risk for oral cavity/pharynx (RR = 1.4; P = 0.14), lung (RR = 1.2; P = 0.15), or colorectal (RR = 0.9; P = 0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P < 0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 < 200 cells/μL and for melanoma and liver cancer with CD4 < 500 cells/μL. Only KS and NHL were associated with HIV RNA. Conclusion: Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors. Impact: Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population. Cancer Epidemiol Biomarkers Prev; 20(12); 2551–9. ©2011 AACR.

HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer

Background The incidence of non-melanoma skin cancers (NMSCs), including basal cell (BCC) or squamous cell carcinoma (SCC), is not well documented among HIV-positive (HIV(+)) individuals. Methods We identified 6560 HIV(+) and 36 821 HIV-negative (HIV(-)) non-Hispanic white adults who were enrolled and followed up in Kaiser Permanente Northern California from 1996 to 2008. The first biopsy-proven NMSCs diagnosed during follow-up were identified from pathology records. Poisson models estimated rate ratios that compared HIV(+) (overall and stratified by recent CD4 T-cell counts and serum HIV RNA levels) with HIV(-) subjects and were adjusted for age, sex, smoking history, obesity diagnosis history, and census-based household income. Sensitivity analyses were adjusted for outpatient visits (ie, a proxy for screening). All statistical tests were two-sided. Results The NMSC incidence rate was 1426 and 766 per 100 000 person-years for HIV(+) and HIV(-) individuals, respectively, which corresponds with an adjusted rate ratio of 2.1 (95% confidence interval [CI] = 1.9 to 2.3). Similarly, the adjusted rate ratio for HIV(+) vs HIV(-) subjects was 2.6 (95% CI = 2.1 to 3.2) for SCCs, and it was 2.1 (95% CI = 1.8 to 2.3) for BCCs. There was a statistically significant trend of higher rate ratios with lower recent CD4 counts among HIV(+) subjects compared with HIV(-) subjects for SCCs (P trend < .001). Adjustment for number of outpatient visits did not affect the results. Conclusion HIV(+) subjects had a twofold higher incidence rate of NMSCs compared with HIV(-) subjects. SCCs but not BCCs were associated with immunodeficiency.

Immunodeficiency and risk of myocardial infarction among HIV-positive individuals with access to care.

Background:We sought to clarify the association of HIV infection and immunodeficiency on myocardial infarction (MI) risk. Methods:We conducted a cohort study from 1996 to 2009 of HIV-positive (HIV+) and demographically matched HIV-negative (HIV−) Kaiser Permanente California health plan members. Rate ratios (RRs) were obtained from Poisson regression models comparing MI incidence rates between HIV+ (overall and stratified by recent and nadir CD4 count, and recent HIV RNA levels) and HIV− subjects, adjusting for age, sex, calendar era, race/ethnicity, census-based socioeconomic status, smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy. Among HIV+ subjects, we also evaluated the independent association of CD4, HIV RNA, and antiretroviral therapy (ART) use. Results:The study population included 22,081 HIV+ and 230,069 HIV− subjects. The crude MI incidence rate per 100,000 person-years was 283 and 165 for HIV+ and HIV− subjects, respectively, with an adjusted RR of 1.4 [95% confidence interval (CI): 1.3 to 1.6]. Compared with HIV− subjects (reference), MI rates were similar for HIV+ subjects with recent CD4 ≥500 cells per microliter (RR = 1.18; 95% CI: 0.96 to 1.45) and those with nadir CD4 ≥500 cells per microliter (RR = 0.85; 95% CI: 0.55 to 1.33). Among HIV+ subjects, nadir CD4 was the only HIV-specific factor associated with MIs (RR per 100 cells = 0.88; 95% CI: 0.81 to 0.96), whereas recent CD4 and HIV RNA, prior ART use, and duration of protease inhibitors and nonnucleoside reverse transcriptase inhibitors were not associated with MIs. Conclusion:HIV+ subjects with recent or nadir CD4 ≥500 cells per microliter had similar MI rates compared with HIV− subjects. Lower nadir CD4, in particular, seems to be independently associated with MIs. These results strengthen recommendations for earlier ART initiation.

Response to Newly Prescribed Lipid-Lowering Therapy in Patients With and Without HIV Infection

Context Dyslipidemias are common in patients with HIV infection who are receiving antiretroviral therapy, but it is not known whether dyslipidemias are also more difficult to treat in this scenario. Contribution This study compared response to statins in patients with and without HIV infection and found that reductions in LDL cholesterol level with statin use and in triglyceride levels with gemfibrozil use were smaller in patients with HIV infection than in those without infection. Patients receiving nonnucleoside reverse transcriptase inhibitors plus gemfibrozil had similar triglyceride responses regardless of whether they were HIV-infected or uninfected. Implication Dyslipidemias are more difficult to treat in patients with HIV infection than in those without infection. The Editors Combination antiretroviral therapy (ART) has led to dramatic reductions in HIV-associated morbidity and mortality (1), resulting in more older persons living with HIV/AIDS (2). However, an ongoing concern for patients with HIV infection is the higher prevalence of age-related comorbid conditions, such as coronary disease, compared with general population rates (3, 4). Research indicates a higher risk for coronary events for patients with HIV infection who are prescribed protease inhibitors (PIs) (5) and, more recently, certain nucleoside reverse transcriptase inhibitors (NRTIs) (6). Factors contributing to the excess coronary disease risk in this population include dyslipidemia and other metabolic side effects associated with ART (7) and higher rates of tobacco use (8). Some data indicate possible direct atherogenic effects of the HIV virus itself (9) and ART (10). Strategies to manage the increased coronary disease risk in this population include lifestyle modifications and possible adjustment to more lipid-friendly ART regimens (11). However, pharmacologic lipid-lowering therapy may be needed to achieve target lipoprotein goals. Recent guidelines recommend that patients with HIV infection be managed according to National Cholesterol Education Panel Adult Treatment Panel III guidelines but stress that therapeutic interventions should consider known adverse drugdrug interactions between PIs and lovastatin and simvastatin (12). Therefore, in patients with HIV infection, pravastatin and atorvastatin are recommended first-line therapy for elevated low-density lipoprotein (LDL) cholesterol levels, and gemfibrozil and fenofibrate are recommended agents for hypertriglyceridemia. However, whether HIV-associated dyslipidemia responds to pharmacologic therapies similarly to dyslipidemia in the general population is not established. The few studies evaluating responses in patients with HIV infection involved relatively small samples (1328), only 1 of which included a comparison with patients without HIV infection (13). Data are also lacking on the effect of different ART regimens on lipid-lowering therapy responses (13) and whether HIV status is associated with tolerability of therapy. We address these knowledge gaps by examining a large, diverse cohort of persons with and without HIV infection receiving care in an integrated health care delivery system. We hypothesized that responses to lipid-lowering therapy may be less robust in patients with HIV infection, possibly in part because of concomitant ART. Methods Study Design, Setting, and Participants We conducted a retrospective cohort study using a new-user design (29) of persons with and without HIV infection with treated dyslipidemia. Patients were identified within Kaiser Permanente of Northern California (KPNC), which provides comprehensive medical care for more than 3.2 million members in the San Francisco and greater Bay Area. Figure 1 shows the selection of the study sample. We first identified a source sample of patients with dyslipidemia and HIV infection and matched it to patients with dyslipidemia who did not have HIV infection. The final sample consisted of patients with dyslipidemia who began lipid-lowering therapy. Figure 1. Study flow diagram. dx = diagnosis; KPNC = Kaiser Permanente of Northern California; HIV+ = HIV-infected; HIV = HIV-uninfected; LDL = low-density lipoprotein; LLT = lipid-lowering therapy. The source population with HIV infection consisted of adults (18 years of age) with HIV infection and laboratory evidence of newly identified dyslipidemia between 1 January 1996 and 31 December 2005. Dyslipidemia was classified according to Adult Treatment Panel III guidelines (30): 1) elevated LDL cholesterol levels (4.1 mmol/L [160 mg/dL] or 3.4 mmol/L [130 mg/dL] in combination with 2 coronary disease risk factors [smoking, hypertension, or diabetes] or 2.6 mmol/L [100 mg/dL] in combination with known coronary disease), and 2) elevated triglyceride levels (5.7 mmol/L [500 mg/dL]). Patients were excluded if they previously received lipid-lowering therapy, had previously diagnosed dyslipidemia, or had been a member of the health plan for less than 6 months. For each type of dyslipidemia (elevated LDL cholesterol level and elevated triglyceride level), we identified a comparison group of patients without HIV infection who were frequency-matched in 10:1 ratio to patients with HIV infection by age, sex, and year of first laboratory evidence of dyslipidemia. The final sample consisted of patients with and without HIV infection who had dyslipidemia, were beginning lipid-lowering therapy, and had at least 1 posttreatment LDL cholesterol or triglyceride measurement within 1 year. We excluded patients with missing data on posttreatment lipoprotein levels. We also excluded patients with elevated LDL cholesterol levels from the elevated triglyceride level group, resulting in patients with isolated elevated triglyceride levels. Thus, the 2 study populations (that is, elevated LDL cholesterol level and isolated elevated triglyceride level) were mutually exclusive and represent the 2 main lipid disorders requiring treatment decisions. Baseline was the date on which the first lipid-lowering therapy prescription was filled, and we followed patients for up to 12 months. Key Variables The key outcome evaluated was response to lipid-lowering therapy, defined as percentage or absolute change in LDL cholesterol or triglyceride levels during the year after therapy initiation compared with pretreatment levels. For patients with multiple measurements, we used the last test within 1 year of treatment. Secondary outcomes of interest were incident clinical and laboratory adverse events. We defined laboratory adverse events as grade 3 or 4 elevations (31) on the basis of elevation above the upper limit of normal for alanine aminotransferase (>5 times), aspartate aminotransferase (>5 times), and creatine kinase (>10 times). Patients who were not tested were classified as not having that laboratory adverse event. Clinical adverse events evaluated were hospitalizations for rhabdomyolysis, myositis, myopathy, and liver failure. The key predictor was HIV infection status. An additional key predictor was combination ART (32), defined here as regimens containing 3 or more antiretroviral agents. Analyses compared responses in patients without HIV infection to responses in patients with HIV infection with antiretroviral use categorized as no antiretrovirals; PI-based ART; nonnucleoside reverse transcriptase inhibitor (NNRTI)based ART; NRTI-based ART; and mixed ART (containing both PIs and NNRTIs). Data Sources Patients with HIV infection were identified from the KPNC HIV Registry, which has been maintained since 1988 for resource planning, clinical management, quality monitoring, and research (2, 3). To date, more than 18000 KPNC members with HIV infection have been identified, including more than 5500 persons with current health plan membership. Patients with HIV infection in KPNC reflect the epidemic in California: Current patients with HIV infection are predominantly men (89%), men who have sex with men (78%) and white (63%) (unpublished data.) These statistics are similar to those of reported AIDS cases in California (33). We ascertained age, sex, membership history, and vital status from health plan administrative databases. We obtained outpatient test results for lipoprotein, alanine aminotransferase, aspartate aminotransferase, creatine kinase, HIV RNA levels, CD4+ T-cell counts, and hepatitis B and C infection from health plan laboratory databases. We used pharmacy databases to identify outpatient prescription fills during 12 months of follow-up for antiretroviral (PIs, NNRTIs, NRTIs) and lipid-lowering agents (3-hydroxy-3-methylglutamyl coenzyme A reductase inhibitors [statins]; fibric acid derivatives [fibrates]; bile acid sequestrants; cholesterol absorption inhibitors; and niacin, 500 mg/d). We classified therapies according to all prescription fills during the first 3 months of follow-up; however, subsequent changes in treatment over 12 months were documented. We searched hospitalization discharge databases for coronary disease (International Classification of Diseases, Ninth Edition, codes 410.xx 414.xx) and potential drug-related adverse events, including rhabdomyolysis (728.88, 728.89, 791.3, or primary code of 584.x with secondary code of 728.89), myositis (729.1, 729.2, 729.5, 729.8x, 729.9), myopathy (359.4, 359.5, 359.6, 359.8x, 359.9), and liver failure (570). Rhabdomyolysis and myositis diagnoses also required a creatine kinase level of 500 U/L or greater within 7 days of admission. We excluded abnormal creatine kinase test results if they were accompanied by a laboratory profile consistent with acute myocardial infarction. We ascertained past cases of diabetes mellitus through linkage to the KPNC Diabetes Registry (34). We also searched outpatient clinical records for diagnosed dyslipidemia, hypertension, and documented smoking history. The Kaiser Foundation Research Institute institutional review board approved the study and provided a waiver of informed patient consent owing to

Race/Ethnicity and Risk of AIDS and Death Among HIV-infected Patients with Access to Care

Prior studies evaluating racial/ethnic differences in responses to antiretroviral therapy (ART) among HIV-infected patients have not adequately accounted for many potential confounders, and few have included Hispanic patients. To identify racial/ethnic differences in ART adherence, and risk of AIDS and death after ART initiation for HIV patients with similar access to care. Retrospective cohort study. 4,686 HIV-infected patients (66% White, 20% Black, and 14% Hispanic) initiating ART and who were enrolled in an integrated healthcare system. Main outcomes evaluated were ART adherence, new AIDS clinical events, and all-cause mortality. The potential confounding effects of demographics, socioeconomic status, ART parameters, HIV disease stage, and other clinical parameters were considered in multivariable models. Adjusted mean adherence levels were higher among White (70.1%; ref) compared with Black (64.2%; P < 0.001) and Hispanic patients (65.2%; P < 0.001). Adjusted hazard ratios (HR) for the risk of new AIDS events (White patients as reference) were 1.3 (P = 0.09) for Black and 0.9 (P = 0.64) for Hispanic patients. The adjusted HR for AIDS comparing Hispanic to Black patients was 0.7 (P = 0.11). Hispanic patients had fewer deaths compared with other racial/ethnic groups, particularly cancer and cardiovascular-related. However, adjusted HRs for death were 1.2 (P = 0.37) and 0.9 (P = 0.62) for Black and Hispanic patients, respectively, compared with White patients and 0.9 (P = 0.63) for Hispanic compared with Black patients. Adjustment for adherence did not change inferences for AIDS or death. In the setting of similar access to care, we did not observe a disparity for the risk of clinical events for racial/ethnic minorities, despite lower ART adherence.ABSTRACTBACKGROUNDPrior studies evaluating racial/ethnic differences in responses to antiretroviral therapy (ART) among HIV-infected patients have not adequately accounted for many potential confounders, and few have included Hispanic patients.OBJECTIVETo identify racial/ethnic differences in ART adherence, and risk of AIDS and death after ART initiation for HIV patients with similar access to care.DESIGNRetrospective cohort study.PARTICIPANTS4,686 HIV-infected patients (66% White, 20% Black, and 14% Hispanic) initiating ART and who were enrolled in an integrated healthcare system.MEASUREMENTSMain outcomes evaluated were ART adherence, new AIDS clinical events, and all-cause mortality. The potential confounding effects of demographics, socioeconomic status, ART parameters, HIV disease stage, and other clinical parameters were considered in multivariable models.RESULTSAdjusted mean adherence levels were higher among White (70.1%; ref) compared with Black (64.2%; P < 0.001) and Hispanic patients (65.2%; P < 0.001). Adjusted hazard ratios (HR) for the risk of new AIDS events (White patients as reference) were 1.3 (P = 0.09) for Black and 0.9 (P = 0.64) for Hispanic patients. The adjusted HR for AIDS comparing Hispanic to Black patients was 0.7 (P = 0.11). Hispanic patients had fewer deaths compared with other racial/ethnic groups, particularly cancer and cardiovascular-related. However, adjusted HRs for death were 1.2 (P = 0.37) and 0.9 (P = 0.62) for Black and Hispanic patients, respectively, compared with White patients and 0.9 (P = 0.63) for Hispanic compared with Black patients. Adjustment for adherence did not change inferences for AIDS or death.CONCLUSIONSIn the setting of similar access to care, we did not observe a disparity for the risk of clinical events for racial/ethnic minorities, despite lower ART adherence.

Narrowing the Gap in Life Expectancy Between HIV-Infected and HIV-Uninfected Individuals With Access to Care.

Background:It is unknown if a survival gap remains between HIV-infected and HIV-uninfected individuals with access to care. Methods:We conducted a cohort study within Kaiser Permanente California during 1996–2011, using abridged life tables to estimate the expected years of life remaining (“life expectancy”) at age 20. Results:Among 24,768 HIV-infected and 257,600 HIV-uninfected individuals, there were 2229 and 4970 deaths, with mortality rates of 1827 and 326 per 100,000 person-years, respectively. In 1996–1997, life expectancies at age 20 for HIV-infected and HIV-uninfected individuals were 19.1 and 63.4 years, respectively, corresponding with a gap of 44.3 years (95% confidence interval: 38.4 to 50.2). Life expectancy at age 20 for HIV-infected individuals increased to 47.1 years in 2008 and 53.1 years by 2011, narrowing the gap to 11.8 years (8.9–14.8 years) in 2011. In 2008–2011, life expectancies at age 20 for HIV-infected individuals ranged from a low of 45.8 years for blacks and 46.0 years for those with a history of injection drug use to a high of 52.2 years for Hispanics. HIV-infected individuals who initiated antiretroviral therapy with CD4 ≥500 cells per microliter had a life expectancy at age 20 of 54.5 years in 2008–2011, narrowing the gap relative to HIV-uninfected individuals to 7.9 years (5.1–10.6 years). For these HIV-infected individuals, the gap narrowed further in subgroups with no history of hepatitis B or C infection, smoking, drug/alcohol abuse, or any of these risk factors. Conclusions:Even with early treatment and access to care, an 8-year gap in life expectancy remains for HIV-infected compared with HIV-uninfected individuals.

Declining Relative Risk for Myocardial Infarction Among HIV-Positive Compared With HIV-Negative Individuals With Access to Care

Concerns remain for an increased myocardial infarction (MI) risk among individuals infected with human immunodeficiency virus (HIV). We conducted a cohort study evaluating MI risk from 1996 to 2011 by HIV status. The adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (95% confidence interval, .7-1.4) in 2010-2011, the most recent study period.

Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment

Standard death certificate–based methods for ascertaining deaths due to chronic liver disease (CLD), such as the U.S. vital statistics approach, rely on a limited set of diagnostic codes to define CLD. These codes do not include viral hepatitis or consider hepatocellular carcinoma (HCC) deaths, and thus, underestimate the true burden of CLD mortality. Deaths associated with CLD may be further misunderstood because of the inherent limitations of death record information. Using a comprehensive list of CLD‐related codes to search death records, we investigated the CLD mortality rate and associated etiologies (derived from medical records) in a large managed care health plan. From the 16,970 deaths among health plan members in 2000, we confirmed 355 (2.1%) as CLD related, including 75 with HCC. The age‐adjusted CLD mortality rate using the comprehensive codes was 11.9 per 100,000 compared with 6.3 per 100,000 using only conventional codes. Based on medical records, the underlying CLD was attributed to alcoholic liver disease (ALD) in 44% of deaths, HCV infection with ALD in 16%, HCV without ALD in 18%, and chronic HBV infection in 7%. Only 64% of HCV‐associated, 48% of HBV‐associated, and 64% of ALD‐associated deaths ascertained by medical record had that specific etiology mentioned on the death certificate. Conclusion: CLD mortality burden was almost doubled by using a comprehensive list of mortality codes and considering HCC deaths as CLD related. Furthermore, the contributions of viral hepatitis and ALD to CLD mortality may be underestimated if based solely on death records. (HEPATOLOGY 2008.)