Fasiha Kanwal

Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) has been implicated as a cause of hepatocellular carcinoma (HCC). We performed a systematic review of epidemiology studies to confirm the association between these disorders. METHODS We searched PubMed for original reports published from January 1992 to December 2011 that evaluated the association between NAFLD, nonalcoholic steatohepatitis (NASH), cryptogenic cirrhosis presumed to be NASH-related, and the risk of HCC. Studies were categorized as offering potential direct evidence (eg, cohort studies) or indirect evidence (eg, case-control, cross-sectional, or case-series studies) for an association. We analyzed data from a total of 17 cohort studies (3 population based, 9 clinic based [6 limited to patients with cirrhosis], and 5 natural history), 18 case-control and cross-sectional studies, and 26 case series. RESULTS NAFLD or NASH cohorts with few or no cases of cirrhosis cases had a minimal risk for HCC (cumulative HCC mortality of 0%-3% for study periods up to 20 y). Cohorts with NASH and cirrhosis had a consistently higher risk (cumulative incidence ranging from 2.4% over 7 y to 12.8% over 3 y). However, the risk for HCC was substantially lower in these cohorts than for cohorts with hepatitis C-related cirrhosis. Factors that increased risk among cohorts with NASH and cirrhosis could not be determined, because most studies were not sufficiently powered for multivariate analysis. CONCLUSIONS This systematic review shows that despite several limitations, there is epidemiologic evidence to support an association between NAFLD or NASH and an increased risk of HCC; risk seems to be limited to individuals with cirrhosis.

Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment.

Hepatitis C virus (HCV) diminishes health related quality of life (HRQOL), and it is now common to measure HRQOL in clinical trials. We sought to summarize the HRQOL data in HCV, and to establish the minimally clinically important difference (MCID) in HRQOL scores in HCV. We performed a systematic review to identify relevant studies, and converted HRQOL data from each study into clinically interpretable statistics. An expert panel used a modified Delphi technique to estimate the MCID in HCV. We found that patients with HCV scored lower than controls across all scales of the SF‐36. Patients achieving sustained virological response (SVR) scored higher across all scales versus patients without SVR, especially in the physical health domains. HRQOL differences did not correspond with differences in liver histology or ALT levels. Based upon the published data, the expert panel concluded that the SF‐36 vitality scale was most relevant in patients with HCV, and generated a mean MCID of 4.2 points on this scale. In conclusion, patients with HCV have a clinically significant decrement in HRQOL versus controls, and physical HRQOL improves in patients achieving SVR but not in those without SVR. The data further suggest that traditional outcomes fail to capture the full spectrum of illness related to chronic HCV. A difference of 4.2 points on the SF‐36 vitality scale can be used as an estimate of the MCID in HCV, and this value may be used as the basis for power calculations in clinical trials evaluating HRQOL. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;41:790–800.)

Increasing Prevalence of HCC and Cirrhosis in Patients With Chronic Hepatitis C Virus Infection

BACKGROUND & AIMS Patients with hepatitis C virus (HCV) infection are at risk for developing costly and morbid complications, although the actual prevalence of these complications is unknown. We examined time trends in the prevalence of cirrhosis and its related complications, such as hepatic decompensation and hepatocellular carcinoma (HCC). METHODS We calculated the annual prevalence of cirrhosis, decompensated cirrhosis, and HCC in a national sample of veterans diagnosed with HCV between 1996 and 2006. Patients with HCV who had at least one physician visit in a given calendar year were included in the analysis of prevalence for that year. We used direct standardization to adjust the prevalence of cirrhosis and related complications for increasing age of the cohort as well as sex and changes in clinical characteristics. RESULTS In this cohort, the number of individuals with HCV increased from 17,261 in 1996 to 106,242 in 2006. The prevalence of cirrhosis increased from 9% in 1996 to 18.5% in 2006. The prevalence of patients with decompensated cirrhosis doubled, from 5% in 1996 to 11% in 2006, whereas the prevalence of HCC increased approximately 20-fold (0.07% in 1996 to 1.3% in 2006). After adjustment, the time trend in the prevalence of cirrhosis (and its complications) was lower than the crude trend, although it still increased significantly. CONCLUSIONS The prevalence of cirrhosis and HCC in HCV-infected patients has increased significantly over the past 10 years. An aging cohort of patients with HCV could partly explain our findings. Clinicians and health care systems should develop strategies to provide timely and effective care to this high-risk population of patients.

Epidemiology of hepatocellular carcinoma in the United States: Where are we? Where do we go?

The incidence of hepatocellular carcinoma (HCC) has almost tripled since the early 1980s in the United States, where it is the fastest rising cause of cancerrelated deaths. According to population-based Surveillance Epidemiology and End Results registry data, the overall HCC age-adjusted incidence rates for liver and intrahepatic ducts cancer is as high as 8 per 100,000 underlying population in 2010 (Fig. 1) of which at least 6 per 100,000 are related to HCC. Men are at approximately three times higher risk than women. Asian men (i.e., Chinese, Korean, Filipino, and Japanese) have the highest age-adjusted incidence rates. However, the largest proportional increases have occurred among Hispanics followed by blacks and non-Hispanic whites, whereas the lowest proportional increases have occurred among Asians. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics. HCC incidence rates have increased in each successive birth cohort born between 1900 and 1959 (Fig. 2). In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45-60 years old (Fig. 2). There is a south to north gradient in the incidence and mortality of HCC; southern states, including Texas, Louisiana, and Mississippi, have some of the highest HCC incidence rates in the nation (Fig. 3). In one study, Texas Latinos and, especially, South Texas Latinos had the highest age-adjusted HCC incidence rates (as high as 10.6 per 100,000). Risk Factors for HCC

Utilization of Surveillance for Hepatocellular Carcinoma Among Hepatitis C Virus–Infected Veterans in the United States

BACKGROUND Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with hepatitis C virus (HCV) infection and cirrhosis. However, whether surveillance is being done as recommended is unknown. OBJECTIVE To examine the prevalence and determinants of HCC surveillance among HCV-infected patients with cirrhosis in Veterans Affairs (VA) health care facilities in the United States. DESIGN Retrospective cohort study of HCV-infected patients using data obtained from the national VA Hepatitis C Clinical Case Registry. SETTING 128 VA medical centers. PATIENTS HCV-infected patients with cirrhosis diagnosed between fiscal years 1998 and 2005. MEASUREMENTS Abdominal ultrasonography and measurement of α-fetoprotein for HCC surveillance were identified from administrative data by using a previously validated algorithm. Patients were categorized as having routine (tests done during at least 2 consecutive years in the 4 years after cirrhosis diagnosis), inconsistent (at least 1 test, but not routine), or no surveillance in the 4 years after cirrhosis diagnosis. Predictors of surveillance were identified by using hierarchical random-effects regression. RESULTS 126 670 patients with HCV were identified; 13 002 (10.1%) had cirrhosis. Approximately 42.0% of patients with cirrhosis received 1 or more HCC surveillance tests within the first year after the cirrhosis index date; however, a decline in receipt of surveillance was observed in the following 2 to 4 years. Among patients with cirrhosis and at least 2 years of follow-up, routine surveillance occurred in 12.0%, inconsistent surveillance in 58.5%, and no surveillance in 29.5%. Lower medical and psychological comorbid conditions, presence of varices, and the absence of decompensated liver disease were associated with a higher likelihood of receiving routine surveillance. LIMITATIONS Hepatocellular carcinoma surveillance tests were indirectly identified from registry data. Physician recommendations could not be captured. CONCLUSION Few HCV-infected veterans with cirrhosis received routine HCC surveillance. New strategies are needed to improve the implementation of HCC surveillance in clinical practice. PRIMARY FUNDING SOURCE Houston Veterans Affairs Health Services Research and Development Center of Excellence and the National Cancer Institute.

Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection

The long‐term prognosis in terms of risk or predictors of developing hepatocellular carcinoma (HCC) among patients with sustained virological response (SVR) remains unclear. We conducted a retrospective cohort study using data from the Veterans Affairs VA hepatitis C virus (HCV) Clinical Case Registry in patients with positive HCV RNA between October 1999 and August 2009 and follow‐up through December 2010. HCV treatment (interferon with or without ribavirin) and SVR (RNA test negative at least 12 weeks after the end of treatment) were determined. We used Coxs proportional hazards models to calculate hazard ratios (HRs) for potential predictors (demographic, virological, and clinical) associated with HCC development post‐SVR. We identified 33,005 HCV‐infected individuals who received treatment, of whom 10,817 achieved SVR. Among these patients, 100 developed new HCC during a total follow‐up of 30,562 person‐years for an overall incidence rate of 0.33% per year. Annual risk of HCC remained considerably high among patients with cirrhosis (1.39%) and those cured after age 64 (0.95%). Patients with diabetes (adjusted HR = 1.88; 1.21‐2.91) or genotype 3 infection (adjusted HR = 1.62; 0.96‐2.734) were significantly more likely to develop HCC. Conclusions: Risk of HCC after HCV cure, though considerably reduced, remains relatively high at 0.33% per year. Older age and/or presence of cirrhosis at the time of SVR are associated with a high enough risk to warrant surveillance. Diabetes is also a risk factor for post‐SVR HCC. (Hepatology 2016;64:130–137)

Treatment Alternatives for Chronic Hepatitis B Virus Infection: A Cost-Effectiveness Analysis

Context Because current treatment options for chronic hepatitis B virus (HBV) infection have varying effects and costs, choosing among them is often difficult. Contribution Using a third-party payer perspective and lifetime horizon, this costutility analysis found that monotherapy with interferon but not lamivudine or adefovir was cost-effective. A salvage strategy that used adefovir only in case of lamivudine-associated viral resistance also seemed cost-effective. Cautions The findings apply only to patients with persistently elevated aminotransferase levels and no cirrhosis. The authors did not model the cost-effectiveness of nucleoside analogue salvage after interferon therapy failure. The Editors Chronic hepatitis B virus (HBV) infection is a prevalent and expensive condition, affecting 350 million people worldwide and 1.25 million people in the United States (1) at a cost of more than

Risk of Hepatocellular Carcinoma after Sustained Virologic Response in Veterans with HCV‐infection

700 million annually (2). Chronic HBV infection can progress to cirrhosis, liver failure, and hepatocellular carcinoma and is a major cause of morbidity and mortality (1, 3). Traditional therapy for chronic HBV infection with either interferon-2b (interferon) or lamivudine is difficult and has limited long-term efficacy (4). Interferon has clinically significant side effects and results in durable virologic response in only 15% to 30% of patients (5-8). Lamivudine is easy to administer and is associated with minimal side effects (9-11), but it has a higher rate of viral resistance (12), lower durable response rate (9-11), and greater need for prolonged therapy (9, 11) compared with interferon. The efficacy of both interferon and lamivudine is even more limited in patients with hepatitis B e antigennegative (HBeAg-negative) disease (4). This burgeoning population now accounts for more than half of patients with HBV in the United States (13) and up to 80% of patients with HBV in Asia (14, 15). Data from 2 randomized, controlled trials indicate that adefovir is efficacious in HBeAg-positive and HBeAg-negative patients (16, 17). Adefovir has a low risk for side effects and viral resistance (18) compared with interferon and lamivudine, but it is more expensive (19). Therefore, the improved therapeutic benefits of adefovir in chronic HBV infection may offset its increased cost compared with interferon and lamivudine, therapies that are less effective yet less expensive. The most effective and cost-effective therapeutic approach to chronic HBV infection must be established. Given the uncertainty on how best to initiate therapy in HBV, this information may assist clinicians in everyday clinical decision making. We therefore performed an economic analysis to estimate the cost-effectiveness of 5 competing strategies for managing chronic HBV infection in patients with elevated liver enzyme levels and no evidence of cirrhosisthe most prevalent and clinically relevant presentation of chronic HBV infection in the primary care setting. We sought to determine whether and under what circumstances the improved therapeutic benefits of adefovir offset its increased cost compared with lamivudine or interferon in managing chronic HBV infection. Methods Decision Model Framework Model Overview Using decision analysis software (DATA, version 4.0, TreeAge Software, Inc., Williamstown, Massachusetts), we evaluated a hypothetical cohort of patients 40 years of age with chronic HBV infection, elevated aminotransferase levels, and no clinical or histologic evidence of cirrhosis. To emulate the case mix in clinical practice in the United States (13), we assumed that 55% of the cohort was HBeAg-negative. We subsequently varied this estimate between 0% and 100% in our sensitivity analysis. Patients entered the hypothetical model without previous treatment for HBV infection and received 1 of 5 competing strategies for managing chronic HBV infection: 1) no pharmacologic treatment of chronic HBV infection (do nothing strategy), 2) interferon monotherapy, 3) lamivudine monotherapy, 4) adefovir monotherapy, or 5) lamivudine with crossover to adefovir upon development of viral resistance (adefovir salvage strategy). Because the clinical course, prognosis, and response to therapy vary in patients with HBeAg-positive and HBeAg-negative HBV (4), we stratified our analysis by HBeAg status and assigned separate probability estimates for each group. Patients entering the model received either no treatment (do nothing strategy) or active treatment for chronic HBV infection. We then followed the cohort over a lifetime horizon through a series of Markov cycles governing patient transitions between relevant health states. The Appendix describes the model structure in detail. Competing Strategies Do Nothing Strategy. In this strategy, which served as the referent case for our analysis, we assumed that patients were followed clinically but did not receive pharmacologic therapy for chronic HBV infection. Patients followed the natural history of chronic HBV infection according to their HBeAg status. We further assumed that all patients received regular ongoing care, including hepatocellular cancer screening, and that patients developing cirrhosis were managed for complications, as outlined by published management guidelines (4, 20). We assumed that a proportion of patients with cirrhosis became eligible for liver transplantation and that a subgroup of these patients subsequently underwent liver transplantation at the rate reported by the United Network for Organ Sharing (21). Interferon Monotherapy Strategy. Patients in this strategy received up-front active therapy with interferon, 10 million units subcutaneously 3 times per week. We assumed that HBeAg-positive and HBeAg-negative patients received 4 and 12 months of treatment, respectively, as suggested by published guidelines (4, 20). Patients without virologic response did not receive additional HBV therapy and followed the natural history of chronic HBV infection. Lamivudine Monotherapy Strategy. Patients in this strategy received up-front lamivudine, 100 mg orally once daily. Lamivudine therapy was discontinued 6 months after a virologic response. Patients without virologic response, including those developing viral resistance, continued to receive long-term lamivudine therapy as recommended by published guidelines (4, 20). We then assigned patients to receive lifetime lamivudine therapy and discontinued therapy if patients developed a subsequent virologic response. Adefovir Monotherapy Strategy. Patients in this strategy received up-front adefovir, 10 mg orally once daily. Adefovir therapy was discontinued 6 months after a virologic response. Patients without virologic response, including those developing viral resistance, continued to receive long-term adefovir therapy as recommended by published guidelines (20). We then assigned patients to receive lifetime adefovir therapy and discontinued therapy if patients developed a subsequent virologic response. Adefovir Salvage Strategy (Lamivudine to Adefovir Crossover). A relevant therapeutic alternative available to clinicians is a hybrid strategy of up-front lamivudine followed by adefovir salvage if lamivudine-related viral resistance develops. We assumed that patients in this strategy initially received lamivudine as described in the lamivudine monotherapy strategy. We then crossed patients over to adefovir when they developed viral resistance, and we subsequently managed patients as described in the adefovir monotherapy strategy. Patients without viral resistance continued to receive lamivudine. Therefore, we reserved adefovir therapy only for patients developing viral resistance while they were receiving lamivudine therapy. Tables 1 and 2 and the Appendix describe the probability estimates governing all 5 strategies. Table 1. Base-Case Probability Estimates Table 2. Base-Case Treatment-Related Probability Estimates Model Assumptions The Appendix contains information about our key model assumptions, including base-case patient characteristics, survival assumptions, definition of virologic response, relationship between virologic response or resistance and subsequent health, and effect of treatment-related adverse events. Clinical Probability Estimates Our base-case model incorporated a wide range of estimates governing relevant clinical probabilities in the management and natural history of chronic HBV infection (Tables 1 and 2). To derive these estimates, we systematically reviewed MEDLINE to identify relevant English-language studies published from January 1970 to February 2005. The Appendix describes our systematic review methods. Outcomes Because the main objective of cost-effectiveness analysis is to permit comparisons among different interventions in medicine, and because quality-adjusted life-years (QALYs) are the exchange currency that allows these comparisons to be made, we adopted QALYs as our main outcome (120). Our analysis reports the incremental cost per QALY gained among the competing strategies, along with the respective 2.5th and 97.5th percentiles around the point estimates as generated by a Monte Carlo analysis of 1000 trials (see Sensitivity Analyses section for details). Utilities We incorporated a wide range of relevant health state utilities in our model. Table 1 contains the specific utility estimates, and the Appendix describes these estimates in detail. Cost Estimates We conducted our analysis from the perspective of a third-party payer and incorporated the direct health care costs for many therapies, physician visits, diagnostic tests, and complications of chronic liver disease (Table 3). We obtained costs for physician services and procedures from the 2004 American Medical Association Current Procedural Terminology codebook and the 2004 Medicare Fee Schedule (121) and derived our base-case pharmaceutical costs from the average wholesale prices listed in the 2004 Red Book (19). Because large buying consortiums can often obtain prices lower th

Predictors of Treatment in Patients with Chronic Hepatitis C Infection—Role of Patient Versus Nonpatient Factors

The long‐term prognosis in terms of risk or predictors of developing hepatocellular carcinoma (HCC) among patients with sustained virological response (SVR) remains unclear. We conducted a retrospective cohort study using data from the Veterans Affairs VA hepatitis C virus (HCV) Clinical Case Registry in patients with positive HCV RNA between October 1999 and August 2009 and follow‐up through December 2010. HCV treatment (interferon with or without ribavirin) and SVR (RNA test negative at least 12 weeks after the end of treatment) were determined. We used Coxs proportional hazards models to calculate hazard ratios (HRs) for potential predictors (demographic, virological, and clinical) associated with HCC development post‐SVR. We identified 33,005 HCV‐infected individuals who received treatment, of whom 10,817 achieved SVR. Among these patients, 100 developed new HCC during a total follow‐up of 30,562 person‐years for an overall incidence rate of 0.33% per year. Annual risk of HCC remained considerably high among patients with cirrhosis (1.39%) and those cured after age 64 (0.95%). Patients with diabetes (adjusted HR = 1.88; 1.21‐2.91) or genotype 3 infection (adjusted HR = 1.62; 0.96‐2.734) were significantly more likely to develop HCC. Conclusions: Risk of HCC after HCV cure, though considerably reduced, remains relatively high at 0.33% per year. Older age and/or presence of cirrhosis at the time of SVR are associated with a high enough risk to warrant surveillance. Diabetes is also a risk factor for post‐SVR HCC. (Hepatology 2016;64:130–137)

HBsAg Seropositive Status and Survival After Renal Transplantation: Meta‐Analysis of Observational Studies

Treatment with interferon and ribavirin is effective in patients with chronic infection with hepatitis C virus (HCV). Previous data indicate that treatment rates are suboptimal. We sought to identify patient and provider‐level predictors of treatment receipt in HCV by conducting a retrospective cohort study of 5701 HCV patients in a large regional Veterans Administration (VA) healthcare network. We also determined the degree of variation in treatment rates attributable to patient, provider, and facility factors. Three thousand seven hundred forty‐three patients (65%) were seen by a specialist and 894 (15.7%) received treatment. Treatment rates varied from 6% to 29% across the 5 facilities included in the analysis. Patients were less likely to receive treatment if they were older [RR, 0.55; 95% CI, 0.45, 0.67), single (RR, 0.77; 95%CI, 0.67, 0.88), had hepatic dysfunction (RR, 0.73; 95%CI, 0.66, 0.89), had normal alanine aminotransferase (ALT) (RR, 0.73; 95%CI, 0.59, 0.89), had HCV genotype 1 (RR, 0.78; 95%CI, 0.71, 0.86), were African American with genotype 1 (RR, 0.78; 95% CI, 0.71, 0.86), or were anemic (RR, 0.70; CI, 0.60, 0.89). In addition, patients evaluated by less experienced providers were 77% less likely to receive treatment than those evaluated by more experienced providers. The patient, provider, and facility factors explained 23%, 25%, and 7% of variation in treatment rates, respectively. Conclusion: These data suggest that although patient characteristics are important predictors of treatment in HCV, a significant proportion of variation in treatment rates is explained by provider factors. These potentially modifiable provider‐level factors may serve as high‐yield targets for future quality improvement initiatives in HCV. (HEPATOLOGY 2007;46:1741–1749.)