Shruti H. Mehta

Prevalence of Type 2 Diabetes Mellitus among Persons with Hepatitis C Virus Infection in the United States

Approximately 2.7 million persons in the United States have chronic hepatitis C virus (HCV) infection (1). Chronic HCV infection may lead to cirrhosis and hepatocellular carcinoma and is a leading cause of liver transplantation in the United States (2). Hepatitis C virus infection may also cause extrahepatic illnesses, including essential mixed cryoglobulinemia, sporadic porphyria cutanea tarda, and thyroid disease, all of which may reflect interactions between HCV and the host immune system (2-7). An increased prevalence of diabetes mellitus among persons with HCV infection has also been observed (8-15). The data linking HCV infection and diabetes mellitus are derived from several recent clinic-based, casecontrol studies that leave several important questions unanswered (8-15). Most of these reports did not consider such factors as body mass index, illicit drug use, and socioeconomic status, which have been associated with both conditions and thus could confound the relationship (1, 16). In addition, because the studies were based principally in referral centers, the relationship may be restricted to persons with severe forms of the diseases. For example, since the liver is crucial to carbohydrate metabolism and glucose homeostasis, diabetes may occur more often in anti-HCVpositive persons simply because of hepatocyte dysfunction (17). Discovery of an increased prevalence of diabetes in the general population among persons with HCV infection and less severe liver disease might suggest an alternate mechanism, such as an HCV-related autoimmune process. Similarly, it has not been determined whether HCV infection results in an increased occurrence of type 1 or type 2 diabetes. Answers to these questions could shed light on the biological mechanisms involved. Both HCV infection and diabetes have been carefully evaluated in a representative sample of the general population of the United States through the Third National Health and Nutrition Examination Survey (NHANES III) (18, 19). We sought to test the hypothesis that persons with HCV infection have an increased prevalence of type 2 diabetes after adjustment for important confounding variables, including age, body mass index, poverty level, and history of drug and alcohol use. Methods Survey Design and Study Sample The NHANES III was conducted from 1988 to 1994 by the National Center for Health Statistics of the Centers for Disease Control and Prevention and is described in detail elsewhere (18, 19). In brief, the survey used a stratified, multistage probability cluster sampling design to obtain a representative sample of the U.S. civilian, noninstitutionalized population. It was designed to oversample Mexican-Americans and African-Americans; in our analysis, we used sampling weights to account for this fact. Approximately 34 000 persons who were at least 2 months of age at the time of the evaluation were sampled at 89 randomly selected locations throughout the United States. Persons selected for evaluation were interviewed at their residence by using a questionnaire that collected information on demographic characteristics, medical history, current and past medication use, and other risk behaviors. Ninety-one percent (30 818) of participants also underwent physical examination and laboratory assessment at a mobile examination center. Plasma glucose levels were measured and HCV antibody testing was performed in examined persons who were at least 20 years of age or 6 years of age, respectively. The institutional review board at the Centers for Disease Control and Prevention approved the study, and all participants provided written informed consent (18, 19). Because plasma glucose testing was performed only in persons older than 20 years of age, we restricted our analysis to persons 20 years of age or older at the time of examination. Of the 18 825 persons older than 20 years of age who were interviewed, 16 573 (88%) also had a complete physical examination and laboratory analysis and were thus deemed eligible for our analysis. Persons were included in our investigation if they had complete evaluations for diabetes and HCV infection. In particular, each household was randomly assigned to a morning, afternoon, or evening evaluation, and participants were instructed to abstain from intake other than water for a specific period of time. Of the 8158 persons assigned to a morning session, 7439 (91%) completed an 8- to 24-hour fast, whereas 2467 of 8415 (29%) persons assigned to a later appointment fasted for 8 to 24 hours. In addition, 562 persons who did not fast but reported use of antidiabetic medication were included in the study sample. Of the 10 468 eligible persons, 627 were excluded from analysis because of indeterminate or missing plasma glucose levels (n =212), indeterminate or missing anti-HCV information (n =290), or a history of diabetes that was unsubstantiated by hyperglycemia or use of antidiabetic medications (n =125). The remaining 9841 persons constitute the study sample (Figure 1). Figure 1. Determination of the study sample. Ascertainment of Diabetes Venous whole blood was drawn into a vacuum tube containing the glycolytic inhibitors potassium oxalate and sodium fluoride and was immediately centrifuged at 1500 g for 10 minutes, as described elsewhere (19). Plasma was frozen at 70 C and shipped to the University of Missouri Diabetes Diagnostic Laboratory, Columbia, Missouri, where plasma glucose testing was performed by using a modified hexokinase enzymatic method. During the 6 years of the survey, the within-assay and between-assay coefficients of variation were 1.6% to 3.7% (20). Type 1 and type 2 diabetes were classified according to previously defined criteria, a combination of the 1997 American Diabetes Association criteria and that used by the Early Treatment Diabetic Retinopathy Study group (21, 22). Persons were considered to have diabetes if they used insulin or oral hypoglycemic agents at the time of the survey or had a fasting plasma glucose level of 7.0 mmol/L or more ( 126 mg/dL). Persons in whom diabetes was diagnosed before 30 years of age, started receiving insulin therapy within 1 year of diagnosis, and reported insulin use at the time of the survey were categorized as having type 1 diabetes. All others who met the above criteria for diabetes were classified as having type 2 diabetes. Exposure Assessment Presence of antibody to HCV (anti-HCV) was assessed by using a second-generation enzyme immunoassay test (Abbott Laboratories, Chicago, Illinois). Positive specimens were tested in duplicate, and repeatedly positive samples were tested again by using the MATRIX assay (Abbott Laboratories). Specimens that were positive according to all three tests were considered to be anti-HCV positive. A sandwich radioimmunoassay (Abbot Laboratories, North Chicago, Illinois) was used for semiquantitative determination of hepatitis B surface antigen in human serum. Serum blood chemistries, including hematologic variables, were obtained by using a Hitachi Model 737 multichannel analyzer (Boehringer Mannheim Diagnostics, Indianapolis, Indiana) (19). Serum liver enzyme levels, including alanine aminotransferase levels, could not be determined from frozen plasma. Information on other covariates was collected during the interview and subsequent examination. Age, ethnicity, and socioeconomic status were categorized according to the survey design as suggested by the National Center for Health Statistics for analysis of NHANES III data (19). Age was analyzed in 10-year groups, and ethnicity was divided into four categories: non-Hispanic white, non-Hispanic black, Mexican-American, and other, which included other Hispanics, Asians, and Native Americans. Too few persons and potential heterogeneity in the other category prohibited its inclusion in analysis. Educational attainment and poverty level were used as proxy measures of socioeconomic status. Educational attainment was classified according to whether a participant had achieved greater than a high school diploma. Poverty level was calculated as a poverty income ratio of self-reported family income to a denominator based on poverty threshold, family size, and the calendar year of the interview. Poverty threshold values, which were standardized for inflation, were based on tables published annually by the U.S. Census Bureau (19). Participants with a poverty income ratio less than 1.0 were considered to be below the poverty level. Body mass index, measured in kg/m2, was assessed during the examination. Participants with a body mass index less than 25 kg/m2, 25 to 29.9 kg/m2, 30 to 34.9 kg/m2, and 35 kg/m2 or more were classified according to the National Heart, Lung, and Blood Institute as lean or normal, overweight, obese, or morbidly obese, respectively (23). Participants who indicated that any of their first-degree relatives had diabetes were considered to have a positive family history of diabetes. Cigarette smoking was categorized according to whether the person was a never, former, or current smoker at the time of the interview. Illicit drug use was assessed by questions about lifetime use of marijuana or cocaine (including crack cocaine), but no specific questions were asked about injection drug use. Excessive alcohol intake was defined as alcohol consumption of more than 50 g/d (approximately five drinks) during the past year. Statistical Analysis General descriptive analysis was performed to compare participants with and those without diabetes. For categorical variables, two-way tabulations calculating a Pearson chi-square statistic, corrected for complex survey design or clustered data, were used. For continuous variables, survey designcorrected t-tests were performed. Univariate and multivariate survey logistic regression techniques were used to determine the crude and adjusted odds ratios of type 2 diabetes with respect to HCV infection. Variables considered to be potential confounders in multiva

Perioperative Mortality and Long-term Survival Following Live Kidney Donation

CONTEXT More than 6000 healthy US individuals every year undergo nephrectomy for the purposes of live donation; however, safety remains in question because longitudinal outcome studies have occurred at single centers with limited generalizability. OBJECTIVES To study national trends in live kidney donor selection and outcome, to estimate short-term operative risk in various strata of live donors, and to compare long-term death rates with a matched cohort of nondonors who are as similar to the donor cohort as possible and as free as possible from contraindications to live donation. DESIGN, SETTING, AND PARTICIPANTS Live donors were drawn from a mandated national registry of 80 347 live kidney donors in the United States between April 1, 1994, and March 31, 2009. Median (interquartile range) follow-up was 6.3 (3.2-9.8) years. A matched cohort was drawn from 9364 participants of the third National Health and Nutrition Examination Survey (NHANES III) after excluding those with contraindications to kidney donation. MAIN OUTCOME MEASURES Surgical mortality and long-term survival. RESULTS There were 25 deaths within 90 days of live kidney donation during the study period. Surgical mortality from live kidney donation was 3.1 per 10,000 donors (95% confidence interval [CI], 2.0-4.6) and did not change during the last 15 years despite differences in practice and selection. Surgical mortality was higher in men than in women (5.1 vs 1.7 per 10,000 donors; risk ratio [RR], 3.0; 95% CI, 1.3-6.9; P = .007), in black vs white and Hispanic individuals (7.6 vs 2.6 and 2.0 per 10,000 donors; RR, 3.1; 95% CI, 1.3-7.1; P = .01), and in donors with hypertension vs without hypertension (36.7 vs 1.3 per 10,000 donors; RR, 27.4; 95% CI, 5.0-149.5; P < .001). However, long-term risk of death was no higher for live donors than for age- and comorbidity-matched NHANES III participants for all patients and also stratified by age, sex, and race. CONCLUSION Among a cohort of live kidney donors compared with a healthy matched cohort, the mortality rate was not significantly increased after a median of 6.3 years.

Protection against persistence of hepatitis C

BACKGROUND Neither previous hepatitis C virus (HCV) infection nor vaccination with HCV-derived antigens protects against reinfection. However, HCV infection and vaccination in chimpanzees has been shown to reduce the magnitude and duration of viraemia with re-challenge. We aimed to establish whether similar immunity could be achieved in man. METHODS From a study of injecting drug users, we identified 164 people who had no evidence of previous HCV infection and 98 individuals who had been previously, but were not currently, infected with HCV. We compared the incidence and persistence of HCV viraemia in these two groups over four consecutive 6-month periods. FINDINGS Of participants without previous infection, the incidence of HCV infection was 21% (35/164). By contrast, people previously infected were half as likely to develop new viraemia (12% [12/98]), even after accounting for risk behaviour (hazard ratio, 0.45; 95% CI 0.23-0.88). Furthermore, in HIV-1-negative people, those previously infected were 12 times less likely than people infected for the first time to develop persistent infection (odds ratio 0.05, 95% CI 0.01-0.30), and median peak HCV RNA concentration was two logs lower. HCV persisted in six of six HIV-1-positive people, even in one man who had previously cleared HCV infection when he was HIV-1 negative. INTERPRETATION There is an alarming frequency of HCV infection and persistence among injecting drug users. Our data suggest that immunity against viral persistence can be acquired, and that vaccines should be tested to reduce the burden of HCV-related liver disease.

HIV Infection Is Associated with an Increased Risk for Lung Cancer, Independent of Smoking

BACKGROUND Human immunodeficiency virus (HIV)-infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question. METHODS The Acquired Immunodeficiency Syndrome (AIDS) Link to the Intravenous Experience Study has prospectively observed a cohort of injection drug users in Baltimore, Maryland, since 1988, using biannual collection of clinical, laboratory, and behavioral data. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer risk, controlling for smoking status, drug use, and clinical variables. RESULTS Among 2086 AIDS Link to the Intravenous Experience Study participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 (96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre-highly active antiretroviral therapy period (mortality rate ratio, 4.7; 95% confidence interval, 1.7-16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (hazard ratio, 3.6; 95% confidence interval, 1.6-7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant. CONCLUSIONS HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status.

Limited uptake of hepatitis C treatment among injection drug users

We characterized hepatitis C virus (HCV) treatment knowledge, experience and barriers in a cohort of community-based injection drug users (IDUs) in Baltimore, MD. In 2005, a questionnaire on HCV treatment knowledge, experience and barriers was administered to HCV-infected IDUs. Self-reported treatment was confirmed from medical records. Of 597 participants, 71% were male, 95% African-American, 31% HIV co-infected and 94% were infected with HCV genotype 1; 70% were aware that treatment was available, but only 22% understood that HCV could be cured. Of 418 who had heard of treatment, 86 (21%) reported an evaluation by a provider that included a discussion of treatment of whom 30 refused treatment, 20 deferred and 36 reported initiating treatment (6% overall). The most common reasons for refusal were related to treatment-related perceptions and a low perceived need of treatment. Compared to those who had discussed treatment with their provider, those who had not were more likely to be injecting drugs, less likely to have health insurance, and less knowledgeable about treatment. Low HCV treatment effectiveness was observed in this IDU population. Comprehensive integrated care strategies that incorporate education, case-management and peer support are needed to improve care and treatment of HCV-infected IDUs.

Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

BACKGROUND & AIMS Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation. METHODS We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized. RESULTS HIV-related CD4(+) lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the alpha-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), eg, LPS, odds ratio, 19.0 (P = .002); AAL, odds ratio, 27.8 (P < .0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis. CONCLUSIONS Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.

Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus.

Objective: To ascertain the prevalence and severity of hepatic steatosis among patients coinfected with HIV and hepatitis C virus (HCV) who had been taking antiretroviral therapy (ART); to investigate if steatosis is associated with more advanced liver disease, and to identify factors that might contribute to the process. Methods: Steatosis was assessed among a randomly selected subset of HIV–HCV-coinfected patients who had received at least 2 years of ART in a cohort study at the Johns Hopkins University HIV clinic. Liver histology was evaluated by a single pathologist. The primary outcome measure was the hepatic steatosis grade, which was classified on a 5 point scale: 0, none; 1, steatosis involving < 5% of hepatocytes; 2, 5–29%; 3, 30–60%; 4 > 60%. Results: Liver histology was assessed in 112 patients, 74% of whom were taking ART at the time of biopsy. The median cumulative exposure to nucleoside reverse transcriptase inhibitors and protease inhibitors was 5.8 and 3.7 years, respectively. No steatosis was detected in 60%; grades 2–4 steatosis was recognized in 18%. In multivariate analysis, steatosis was independently associated with Caucasian race, weight > 86 kg, hyperglycemia, and stavudine use. Patients with steatosis also were more likely to have greater hepatic fibrosis (P = 0.02) and necroinflammatory activity (P = 0.005). Conclusions: Steatosis was observed in 40% of HIV–HCV-coinfected patients with extensive ART exposure and was associated with more severe HCV-related liver disease. Metabolic abnormalities (excess weight and hyperglycemia) and stavudine use were modifiable risk factors for steatosis in this population.

Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV

CONTEXT Human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV) disease progression; however, the effect of liver disease stage and antiviral therapy on the risk of clinical outcomes is incompletely understood. OBJECTIVE To determine the incidence of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), or death according to baseline hepatic fibrosis and antiviral treatment for HIV/HCV coinfected individuals. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort of 638 coinfected adults (80% black, 66% men) receiving care at the Johns Hopkins HIV clinic and receiving a liver biopsy and who were prospectively monitored for clinical events between July 1993 and August 2011 (median follow-up, 5.82 years; interquartile range, 3.42-8.85 years). Histological specimens were scored for hepatic fibrosis stage according to the METAVIR scoring system. MAIN OUTCOME MEASURE Incidence of composite outcome of ESLD, HCC, or death. RESULTS Patients experienced a graded increased risk in incidence of clinical outcomes based on baseline hepatic fibrosis stage (classification range, F0-F4): F0, 23.63 (95% CI, 16.80-33.24); F1, 36.33 (95% CI, 28.03-47.10); F2, 53.40 (95% CI, 33.65-84.76); F3, 56.14 (95% CI, 31.09-101.38); and F4, 79.43 (95% CI, 55.86-112.95) per 1000 person-years (P < .001). In multivariable negative binomial regression, fibrosis stages F2 through F4 and antiretroviral therapy were independently associated with composite ESLD, HCC, or all-cause mortality after adjustment for demographic characteristics, injection drug use, and CD4 cell count. Compared with F0, the incidence rate ratio (RR) for F2 was 2.31 (95% CI, 1.23-4.34; P = .009); F3, 3.18 (95% CI, 1.47-6.88; P = .003); and F4, 3.57 (95% CI, 2.06-6.19; P < .001). Human immunodeficiency virus treatment was associated with fewer clinical events (incidence RR, 0.27; 95% CI, 0.19-0.38; P < .001). For the 226 patients who underwent HCV treatment, the incidence of clinical events did not significantly differ between treatment nonresponders and untreated patients (incidence RR, 1.27; 95% CI, 0.86-1.86; P = .23). In contrast, no events were observed in the 51 patients with sustained virologic response (n = 36) and relapse (n = 15), including 19 with significant fibrosis. CONCLUSION In this cohort of patients with HIV/HCV coinfection, hepatic fibrosis stage was independently associated with a composite outcome of ESLD, HCC, or death.

Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults

Objectives:To define the incidence of fibrosis progression among hepatitis C virus (HCV)/HIV-co-infected adults, to assess whether HCV or HIV treatment alters the risk of progression, and to determine the utility of liver biopsy to predict future disease. Design:This prospective cohort evaluated 184 HIV/HCV-co-infected individuals who had at least two liver biopsies (median interval 2.9 years). Methods:Biopsies were scored according to the Ishak modified histological activity index scoring system by a single pathologist blind to biopsy sequence. Significant fibrosis progression was defined as an increase of at least two Ishak fibrosis units between the first and second liver biopsy. Logistic regression analysis was used to assess determinants of fibrosis progression. Results:A total of 174 non-cirrhotic patients were eligible; the majority were African-American men undergoing HIV treatment. On initial biopsy, no or minimal fibrosis was identified in 136 patients (77%). Significant fibrosis progression occurred in 41patients (24%). Measures of HIV disease and its treatment before and after initial biopsy were not significantly different in progressors and non-progressors. Fibrosis progression was not associated with HCV treatment, which was received by 37 patients (21%) but only three sustained HCV-RNA suppression. In adjusted analysis, only an elevated serum aspartate aminotransferase level between biopsies was associated with progression (odd ratio 3.4, 95% confidence interval 1.4–7.9). Conclusion:Over a 3-year interval, significant fibrosis progression can occur in co-infected individuals even if minimal disease was detected on initial biopsy. In this context, factors other than treatment for HIV or HCV modify the risk of fibrosis progression.

Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir.

Objective: To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development. Design: Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy. Methods: The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme ⩾ 5-times the upper limit of the normal range or 3.5-times an elevated baseline level. Results: The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200–400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity. Conclusions: Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.