Brian P. Lam

Nonalcoholic fatty liver disease in lean individuals in the United States.

AbstractThe presence of hepatic steatosis in individuals without a known cause of chronic liver disease, including excessive alcohol consumption, is the hallmark of nonalcoholic fatty liver disease (NAFLD). Although NAFLD is usually associated with obesity, nonobese patients can also present with NAFLD (“lean NAFLD”). Our objective was to determine factors independently associated with lean NAFLD in the United States population. For this purpose, we used data from National Health and Nutrition Examination Survey III (NHANES III) conducted between 1988 and 1994 with available hepatic ultrasound, clinico-demographic, and laboratory data. NAFLD was defined as the presence of moderate-severe hepatic steatosis (by ultrasound), the absence of excessive alcohol use (>20 g/d in men and 10 g/d in women), hepatitis B surface antigen(−), and hepatitis C antibody(−). Nonalcoholic steatohepatitis (NASH) was defined as having moderate-severe steatosis and elevated aminotransferases in the presence of type 2 diabetes or insulin resistance (IR). Logistic regression was used to identify independent predictors of lean NAFLD. As a result, of the 11,613 participants included in the study, 2185 (18.77% ± 0.76%) had NAFLD; of these, 307 (11.78% ± 1.03%) had NASH. Multivariate analysis showed that lean NAFLD was independently associated with younger age, female sex, and a decreased likelihood of having IR and hypercholesterolemia (p values < 0.05). Additionally, multivariate analysis showed that NASH was independently associated with being Hispanic, having a younger age, and having components of metabolic syndrome such as hypertension (p values < 0.05). Therefore, we conclude that lean individuals with NAFLD have a different clinical profile than overweight-obese individuals with NAFLD. Furthermore, patients with NASH are commonly Hispanic and have components of metabolic syndrome.

Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study

BACKGROUND Worldwide, although predominantly in low-income countries in the Middle East and Africa, up to 13% of hepatitis C virus (HCV) infections are caused by HCV genotype 4. For patients with HCV genotype 1, the combination of ledipasvir and sofosbuvir has been shown to cure high proportions of patients with excellent tolerability, but this regimen has not been assessed for the treatment of HCV genotype 4. We assessed the efficacy, safety, and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir for patients with chronic HCV genotype 4 infections. METHODS In this single-centre, open-label cohort, phase 2a trial, patients with HCV genotype 4 who were treatment naive or interferon treatment experienced (HIV-negative) were sequentially enrolled at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. We gave patients 12 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) as a single combination tablet once per day. The primary efficacy endpoint was sustained viral response at 12 weeks (SVR12), as measured by the proportion of patients with HCV RNA concentrations less than the lower limit of quantification (COBAS TaqMan HCV test, version 1.0, 43 IU/mL). The primary safety endpoint was the frequency and severity of adverse events. We did our analyses on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS Between Sept 16, 2013, and Nov 2, 2014, we recruited 21 patients. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR12 (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events and no grade 3 or 4 adverse events occurred that were related to study medications. The most common adverse events were diarrhoea (two patients), fatigue (three patients), nausea (two patients), and upper respiratory infections (two patients). INTERPRETATION Ledipasvir and sofosbuvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 100% SVR for all patients who received all 12 weeks of study drugs, irrespective of previous treatment status and underlying liver fibrosis. This is the first report of a single-pill, all-oral, interferon-free, ribavirin-free treatment for patients with HCV genotype 4. FUNDING NIAID, National Cancer Institute and Clinical Center Intramural Program. The study was also supported in part by a Cooperative Research and Development Agreement between NIH and Gilead Sciences.

Treatment options for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has become increasingly recognized as the most common cause of abnormal liver enzymes in the last few decades and is among the most common forms of chronic liver disease in the Western world and across the globe. With the growing epidemic of obesity and diabetes, NAFLD is estimated to affect about one-quarter of the US population. Although most patients with NAFLD have nonprogressive bland steatosis, a minority of patients develop the histological subtype of nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, hepatocellular carcinoma, and liver-related death. This is especially true when NASH patients have type 2 diabetes. Treatment of NAFLD should therefore be directed towards patients with established NASH. Sustained weight loss seems to improve insulin resistance and associated NASH. In fact, weight loss with bariatric surgery leads to biochemical and histological improvement in morbidly obese patients with NASH. Several pharmacologic agents have been studied in an effort to improve insulin resistance and pro-inflammatory mediators potentially responsible for the development and progression of NASH. While some studies have shown initial promise, none has established long-term efficacy using randomized clinical trials. This paper briefly reviews the epidemiology, natural history, and pathophysiology of NAFLD and NASH and then focuses on the clinical trials of various therapeutic modalities for NAFLD. These include weight loss agents, bariatric surgery, insulin-sensitizing agents, lipid-lowering agents, antioxidants, probiotics, anti-tumor necrosis factor agents, cytoprotective and other novel agents.

The changing landscape of hepatitis C virus therapy: focus on interferon-free treatment

Chronic hepatitis C (CHC) affects over 185 million individuals worldwide, approximately 3% of the world’s population. CHC can lead to quality of life impairment, cirrhosis, hepatocellular carcinoma (HCC), liver failure and liver-related death. While CHC has been associated with increases in HCC, liver-related mortality and all-cause mortality, being cured of CHC is associated with improvement in these outcomes. Older interferon-based regimens were complex and toxic and required 6–12 months of therapy, with cure rates averaging around 40–45% for HCV genotype 1. Newer interferon-free regimens are now available in the US, Europe, Japan and in other countries. These regimens have short durations, minimal side effects, low pill burden and efficacy approaching 90–100%. We may eventually see single-tablet regimens lasting no more than 4–6 weeks. This review will summarize the data regarding these interferon-free regimens, including Gilead’s Harvoni (sofosbuvir/ledipasvir), AbbVie’s Viekira Pak (paritaprevir/ritonavir/ombitasvir with dasabuvir), and Janssen’s Olysio (simeprevir) with sofosbuvir. Some practical considerations as we move into an interferon-free era will also be discussed, such as patient adherence and drug–drug interactions.

The patient's journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life

Interferon and ribavirin negatively impact health‐related quality of life (HRQL) during treatment.

Association of hepatitis C with insulin resistance and type 2 diabetes in US general population: the impact of the epidemic of obesity

Summary.  Studies from tertiary care medical centres have linked hepatitis C virus (HCV) to the development of insulin resistance (IR) and type 2 diabetes. The aim of the study is to assess the relationship between HCV positivity and insulin resistance/diabetes in the US population. Three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted between 1988 and 2008 were used. HCV infection was diagnosed using a positive serologic anti‐HCV test. Additionally, diabetes was diagnosed as fasting blood glucose ≥126 mg/dL and/or the use of hypoglycaemic medications. Insulin resistance was defined as a homeostasis of model assessment (HOMA) score of >3.0. Logistic regression was used to estimate the odds ratios (ORs) of each of the potential risk factors for diabetes mellitus (DM). The SUDAAN 10.0 was used to run descriptive and regression analyses. A total of 39 506 individuals from three NHANES cycles (1988–1994, 1999–2004 and 2005–2008) with complete demographic and relevant clinical data were included. Over these three NHANES cycles, prevalence of hepatitis C did not significantly change. During the first NHANES cycle (1988–1994), insulin and diabetes were independently associated with hepatitis C. However, during the later study cycles (1998–2008), these associations were no longer significant. In contrast, other important known risk factors for diabetes and IR (male gender, non‐Caucasian race, age and obesity) remained significant over all three NHANES cycles. Although HCV infection was independently associated with an increased risk of diabetes and IR in the US population over a decade ago, assessment of the later NHANES cycles shows that this relationship may have become diluted by the rapid rise of other risks for diabetes, specifically, the prevalence of obesity.

Knowledge about infection is the only predictor of treatment in patients with chronic hepatitis C

HCV is the leading cause of cirrhosis and liver cancer in the U.S. The Center for Disease Control (CDC) has recently recommended ‘Birth Cohort Screening’ of the U.S. Adult population to reduce the future burden of undiagnosed HCV infections in the U.S. Our aim was to assess independent predictors of receiving treatment in a cohort of HCV‐infected patients. The Hepatitis C follow‐up questionnaires of the National Health and Nutrition Examination Surveys (NHANES) conducted from 2001 to 2010 were used. The NHANES participants who tested positive for HCV RNA were followed by CDC 6 months after initial testing with questions related to their awareness of their infection and history or intention to receive treatment. A total of 500 NHANES participants tested positive for HCV RNA and were targeted for follow‐up. Of these, only 203 had completed the follow‐up questionnaire (response rate of 40.6%). Of these, only 101 (50%) knew about their HCV positivity before NHANES, and from them, only 34 (17%) had received treatment. In multivariate analysis, prior knowledge about their HCV infection in HCV‐positive individuals was independently associated with receiving routine care from a doctor or HMO, with higher income, female gender, being in poor or fair health and not consuming excessive amounts of alcohol. On the other hand, the knowledge about HCV infection was the only independent predictor of receiving anti‐HCV treatment (odds ratio 6.14). Knowledge about having HCV infection is the only independent predictor of receiving treatment. Therefore, birth cohort screening of the U.S. General population could lead to wider identification of HCV and potentially better management of the future burden of HCV and its complications.

Moderate Sustained Virologic Response Rates With 6-Week Combination Directly Acting Anti–Hepatitis C Virus Therapy in Patients With Advanced Liver Disease

BACKGROUND Treatment of genotype 1 hepatitis C virus (HCV) infection with combination directly acting antivirals (DAA) for 8-24 weeks is associated with high rates of sustained virologic response (SVR). We previously demonstrated that adding a third DAA to ledipasvir and sofosbuvir (LDV/SOF) can result in high SVR rates in patients without cirrhosis. In this study, we investigated whether a similar regimen would yield equivalent rates of cure in patients with advanced liver fibrosis. METHODS Fifty patients were enrolled at the Clinical Research Center of the National Institutes of Health and associated healthcare centers. Enrollment and follow-up data from April 2014 to June 2015 are reported here. Eligible participants were aged ≥18 years, had chronic HCV genotype 1 infection (serum HCV RNA ≥2000 IU/mL), and stage 3-4 liver fibrosis. HCV RNA was measured using a reverse-transcription polymerase chain reaction assay. RESULTS Of patients treated with LDV, SOF, and the NS3/4A protease inhibitor GS-9451 for 6 weeks, 76% (38 of 50; 95% confidence interval, 60%-85%) had SVR achieved 12 weeks after the end of treatment. There was no statistically significant difference in treatment efficacy between treatment-naive patients (72%, 18 of 25) and those with treatment experience (80%; 20 of 25) (P = .51). Overall, 11 patients (22%) experienced virologic relapse, and 1 (2%) was lost to follow-up at 4 weeks after treatment. No serious adverse events, discontinuations, or deaths were associated with this regimen. CONCLUSIONS Adding a third DAA to LDV/SOF may result in a moderate SVR rate, lower than that observed in patients without cirrhosis. Significant liver fibrosis remains an impediment to achieving SVR with short-duration DAA therapy. CHINESE CLINICAL TRIALS REGISTRATION CT01805882.

A disease-specific quality of life instrument for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: CLDQ-NAFLD

Non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis are the most common causes of chronic liver disease with known negative impact on patients’ health‐related quality of life. Our aim was to validate a disease‐specific health‐related quality of life instrument useful for efficacy trials involving patients with non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis.

Sofosbuvir (Sovaldi) for the treatment of hepatitis C

Hepatitis C (HCV) remains an important cause of chronic liver disease worldwide. Historically, treatment included pegylated-interferon and ribavirin with low efficacy and numerous side effects contributing to poor adherence and impairment of patients’ well-being. The next step in developing better treatment regimens for HCV led to the development of the first-generation direct acting antivirals (DAAs). Although these DAAs improved efficacy, they also added substantial side effects. The next generation of DAAs include Simeprevir and Sofosbuvir (SOF) which not only further enhanced the efficacy of the regimens but also improve their safety profile. This review summarizes the current clinical experience with SOF. SOF, an HCV-specific uridine nucleotide analog which inhibits the NS5B polymerase, is now available in the USA, Canada and Europe. Clinical trials of SOF-containing regimens have shown that these regimens are safe, efficacious, and well-tolerated in all genotypes. Additionally, SOF is associated with improved patient reported outcomes.