Asia-Pacific region - Cost-effectiveness prevention and management of gastrointestinal and liver disease

Review Article
COST-EFFECTIVE OPTIONS FOR THE PREVENTION AND MANAGEMENT OF GASTROINTESTINAL AND LIVER DISEASE IN THE ASIA-PACIFIC REGION
Authors Ian C Roberts-Thomson, Thomas Lung
Accepted manuscript online: 17 August 2017
Full publication history DOI: 10.1111/jgh.13925 

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Abstract
The Asia-Pacific region contains more than half of the world's population and is markedly heterogeneous in relation to income levels and the provision of public and private health services. For low-income countries, the major health priorities are child and maternal health. In contrast, priorities for high-income countries include vascular disease, cancer, diabetes, dementia and mental health disorders as well as chronic inflammatory disorders such as hepatitis B and hepatitis C. Cost-effectiveness analyses are methods for assessing the gains in health relative to the costs of different health interventions. Methods for measuring health outcomes include years of life saved [or lost], quality-adjusted life years [QALYs] and disability-adjusted life years [DALYs]. The incremental cost-effectiveness ratio [ICER] measures the cost [usually in US dollars] per life year saved, QALY gained or DALY averted of one intervention relative to another. In low-income countries, approximately 50% of infant deaths [<5years] are caused by gastroenteritis, the major pathogen being rotavirus infection. Rotavirus vaccines appear to be cost-effective but, thus far, have not been widely adopted. In contrast, infant vaccination for hepatitis B is promoted in most countries with a striking reduction in the prevalence of infection in vaccinated individuals. Cost-effectiveness analyses have also been applied to newer and more expensive drugs for hepatitis B and C and to government-sponsored programs for the early detection of hepatocellular, gastric and colorectal cancer. Most of these studies reveal that newer drugs and surveillance programs for cancer are only marginally cost-effective in the setting of a high-income country.

Source - Journal of Gastroenterology and Hepatology

Harvoni in adolescents 12-17 years old with HCV genotype 1

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In the Journals

Harvoni safe, effective in teens with HCV genotype 1
August 24, 2017

Balistreri WF, et al. Hepatol. 2017;doi:10.1002/hep.28995

All adolescent patients available for follow-up after treatment with Harvoni for chronic hepatitis C genotype 1 achieved sustained virologic response at 12 weeks with no serious adverse events, further supporting its approval in this population.

“Treatment of pediatric patients has been controversial as the current standard of care, pegylated interferon and weight-based ribavirin, is associated with significant side effects, including growth impairment, and poor tolerability,” William F. Balistreri, MD, from the Cincinnati Children’s Hospital Medical Center, and colleagues wrote. “Similar to what has been observed in adults, treatment with ledipasvir-sofosbuvir was well tolerated in adolescents.”

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Research Article

Safety & effectiveness of LDV/SOF in adolescents 12 to 17 years old with HCV GT1 infection

Published: June 22, 2017

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record.Please cite this article as doi: 10.1002/hep.28995

No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a Phase 2, multi-center, open-label study to evaluate the efficacy and safety of ledipasvir–sofosbuvir in adolescents with chronic HCV genotype 1 infection.

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link to the above article provided by Henry E. Chang via Twitter.

Abstract

The safety and effectiveness of ledipasvir−sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection

Recommended Reading

HCV Advocate
Hepatitis C in Children
In this article, I will discuss the various aspects of hepatitis C (HCV) in children including what we know and what we don’t know!  The topics I will cover are mother-to-child transmission, hepatitis C transmission among children, HCV disease progression in children, which tests to monitor children with hepatitis C, and the newly approved medications to treat children.  The outlook for children with hepatitis C is looking better now that we have direct-acting antiviral medications to treat children with hepatitis C but we first have to identify, manage and treat them.
Read more...

New targets for drugs to treat fatty liver disease and liver cancer

New targets for drugs to treat fatty liver disease and liver cancer

KTH The Royal Institute of Technology

There may no silver bullet for treating liver cancer or fatty liver disease, but knowing the right targets will help science develop the most effective treatments. Researchers in Sweden have just identified a number of drug targets that can be used in the development of new efficient treatment strategies with minimum side effects.

Researchers from KTH Royal Institute of Technology’s Science for Life Laboratory (SciLifeLab) research center and Gothenburg University employed the biological networks generated for 46 major human tissues in order to identify the liver-specific gene targets.

The results were published in Molecular Systems Biology, an EMBO Press Journal.

The researchers mapped the metabolic changes caused by accumulated fat in liver cells, and combined this data with an analysis of biological networks of liver and other human tissues. Doing so enabled them to identify the liver-specific drug targets whose inhibition will not cause any side effect to other human tissues, says lead author Adil Mardinoglu, a SciLifeLab fellow, who had earlier established a connection between NAFLD and HCC and increased fat synthesis in liver tissue.
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Hepatic steatosis is defined as the excessive accumulation of fat in the liver and it is the key characteristic of non-alcoholic fatty liver disease (NAFLD). It is one of the most common chronic liver problems in the world and affects almost 30 percent of the adult population. The disease is the consequence of obesity, diabetes, or excessive alcohol intake and can lead to non-alcoholic steatohepatitis (NASH), cirrhosis, liver cancer and even hepatic failure. There are few treatments, even though the need is urgent.

Mardinoglu says the team’s network modeling approach, which relied on data from the Sweden-based Human Protein Atlas project and The Genotype-Tissue Expression (GTEx) project consortia, can be used in the identification of drug targets and eventually in the development of efficient strategies for treating a number of chronic liver diseases.

To validate their computer modeling predictions, researchers performed experiments in human cancer cell lines, mouse liver samples and primary human hepatocytes. They validated their predictions by demonstrating functional relationships between these liver gene, and showed that their inhibition decreases cell growth and liver fat content, Mardinoglu says.

The researchers identified liver-specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell, (PKLR), or to HCC pathogenesis, such as PKLR, patatin-like phospholipase domain containing 3 (PNPLA3) and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development.

Mathias Uhlen, director of the Human Protein Atlas project and co-author of the paper, says: “I am extremely pleased that the resource created through the Human Protein Atlas effort has been used in the analysis of clinical data obtained from liver disease patients and that this analysis has led to the identification of liver-specific drug targets that can be used for treatment of this clinically important patient group.”

Story Source:

http://www.alphagalileo.org/ViewItem.aspx?ItemId=178261&CultureCode=en

Journal Reference:
Sunjae Lee, Cheng Zhang, Zhengtao Liu, Martina Klevstig, Bani Mukhopadhyay, Mattias Bergentall, Resat Cinar, Marcus Ståhlman, Natasha Sikanic, Joshua K Park, Sumit Deshmukh, Azadeh M Harzandi, Tim Kuijpers, Morten Grøtli, Simon J Elsässer, Brian D Piening, Michael Snyder, Ulf Smith, Jens Nielsen, Fredrik Bäckhed, George Kunos, Mathias Uhlen, Jan Boren, Adil Mardinoglu. Network analyses identify liver‐specific targets for treating liver diseases. Molecular Systems Biology, 2017; 13 (8): 938 DOI: 10.15252/msb.20177703 

NCAD: The opioid crisis is a political football, and that’s not good

NCAD: The opioid crisis is a political football, and that’s not good
August 22, 2017

by Julie Miller, Editor in Chief

While addiction remains a bipartisan issue, support for treatment and recovery is not guaranteed, according to Andrew Kessler, JD, principal of consulting firm Slingshot Solutions. Speaking at the National Conference on Addiction Disorders in Baltimore, Kessler noted the attention policymakers are giving the opioid crisis.

Federal and state legislatures have moved forward on funding and programs for opioid treatment and recovery, but resources are still quite scarce. One point of context to consider is the fact that not every addiction is an opioid addiction—deaths related to alcohol misuse still outpace opioids, and in some areas, methamphetamine is on the rise, Kessler said. It also begs the question of how treatment would be skewed for those with other health issues, including hepatitis C and HIV.

Continue reading....

Baby Boomers Increase HCV Screenings, Treatment When Alert Added to Health Records

Baby Boomers Increase HCV Screenings, Treatment When Alert Added to Health Records

AUGUST 23, 2017

Gail Connor Roche

The baby boom generation born from 1945 to 1965 has a 5 times greater prevalence of HCV than individuals in other age groups, past research has shown. But fewer than 30% of boomers have been screened for the liver-attacking virus.

Konerman, a clinical lecturer in the department of internal medicine, said previous screening for HCV was "risk-based.” But studies have found that this approach has been unsuccessful, even as the US Centers for Disease Control and the US Preventative Services Task Force recommend a one-time universal screening for baby boomers to identify those missed under the risk approach.

“Unfortunately, screening rates in this population remain very low,” Konerman said.

Continue reading...

Abstracts - Viral Hepatitis: Gastroenterological Society of Australia Australian Gastroenterology Week

Special Issue: Gastroenterological Society of Australia Australian Gastroenterology Week Precision Medicine in Gastroenterology, Gold Coast Convention & Exhibition Centre, Gold Coast, Queensland, 20–22 Aug 2017

Supplement
Journal of Gastroenterology and Hepatology
Abstracts of Gastroenterological Society of Australia Australian Gastroenterology Week

Volume 32, Issue Supplement S2 Pages 1 - 197, August 2017

Abstracts - Viral Hepatitis
Hepatitis-Viral (pages 65–86)

Version of Record online: 17 AUG 2017 | DOI: 10.1111/jgh.13892

Remote consultation referral system: An effective way to treat homeless and marginalized patients with chronic hepatitis C in primary care

Comparison of direct-acting antiviral therapy for hepatitis C between specialist centers and primary care: Efficacy and adherence to response assessment
Discontinuation of nucleoside analogue therapy in e-antigen-negative chronic hepatitis B: A meta-analysis
A real-world experience treating hepatitis C patients with direct-acting antivirals
Need for hepatocellular carcinoma screening during direct-acting antiviral treatment for patients with hepatitis C and cirrhosis
Project ECHO: A novel tele-mentoring service to aid hepatitis C treatment in difficult-to-access populations
Direct-acting antiviral therapy failures in hepatitis C treatment: A tertiary hospital's experience
Applying the REACH-B model to an Australian chronic hepatitis B cohort underestimates the incidence of hepatocellular carcinoma
General practitioners' perspectives on and use of remote consultation referral system for hepatitis C treatment in primary care: Interim results
Hepatitis C viral load at 12 weeks: Only half the story
References
Efficacy, safety, and long-term outcomes in hepatitis C virus genotype 1-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin: TOPAZ-I interim data from Australia
Early experience of direct-acting antiviral treatment for chronic hepatitis C in a needle syringe program outreach service
An eHealth model of care for community hepatitis c management: The HealthElink project
Characteristics and predictors of treatment failure for hepatitis C treatment in the first 12 months of unrestricted use of direct-acting antiviral therapy
Efficacy and outcomes of treatment with direct-acting antiviral therapy: An initial 12-month tertiary experience
Use of APRI to exclude cirrhosis in correctional services: Minimizing need for FibroScan
Mental health care in chronic hepatitis C patients: The unmet need in interferon-free treatment
References
Towards hepatitis C eradication in far north Queensland: A report on models of care and direct-acting antiviral outcomes
Defining a new phase in hepatitis B: The role of viral load in immune escape
Retrospective data analysis to assess the feasibility of transitioning the management of stable chronic hepatitis B from tertiary to primary care
Real-world treatment for hepatitis C in the direct-acting antiviral era: Comparing outcomes between the tertiary liver clinic and community
Outcomes of porphyria cutanea tarda in the era of direct-acting antivirals for hepatitis C infection
Effect of direct-acting antivirals on hepatocellular carcinoma incidence in hepatitis C virus-related cirrhosis
Liver clinic waiting time reduced with the introduction of remote support for hepatitis C treatment in primary care
Long-term outcomes of patients with chronic hepatitis B previously treated with pegylated-interferon
The first year with combination direct-acting antivirals in a real-world cohort from a regional liver clinic in New South Wales
References
Outcomes of treatment for hepatitis C virus infection in the prison setting
Direct-acting antiviral treatment failure is associated with genotype 3 hepatitis C cirrhosis and the selection of NS5A resistance sequences: Implications for salvage therapy
Preliminary results from the HEDGE study: Does the hepatitis C virus cause depression?
Role of point-of-care testing for hepatitis B in culturally and linguistically diverse communities
How well used, effective, and safe is general practitioner prescription of hepatitis C therapy?
Risk of hepatocellular carcinoma among patients with hepatitis C virus cirrhosis treated with direct-acting antiviral therapy: An Australian experience
Hepatitis C and liver disease in opioid treatment program patients
References
High efficacy in patients with chronic hepatitis C virus genotype 1b infection treated with elbasvir–grazoprevir for 12 weeks: An integrated analysis
Can quantitative HBsAg threshold predict high viral load and risk of mother-to-child transmission? Like life, you get what you pay for
“Teach-back” is a simple communication tool that improves health literacy in people with chronic hepatitis B
Chronic hepatitis B infection: 25 years of nucleoside analogue therapy
Real-world Australian data replicate very high sustained virological response at 12 weeks (SVR12) results reported in clinical trials and suggest SVR12 is highly achievable even in those without an end-of-treatment response
Eliminate Hepatitis C Partnership: Clinical site scoping
Quantitative HBeAg levels at Week 24 predict on-treatment serological response to tenofovir disoproxil fumarate therapy in HBeAg-positive patients infected with chronic hepatitis B
Hepatitis B virus activity does not influence the degree of liver steatosis in patients with hepatitis B-related chronic liver disease
References
Australian tertiary hospital real-life experience: Universal access to direct-acting antivirals in a novel treatment model 

(grazoprevir-ruzasvir-uprifosbuvir) Shorter anti-HCV regimen effective in patients with or without cirrhosis

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Full Text
Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
PDF provided by @HenryEChang via Twitter

Shorter anti-HCV regimen effective in patients with or without cirrhosis

Last Updated: 2017-08-18
By Will Boggs MD
NEW YORK (Reuters Health) - An eight-week regimen containing grazoprevir-ruzasvir-uprifosbuvir appears to be effective for treating hepatitis C virus (HCV) infection in patients with or without cirrhosis, according to findings from a pair of randomized phase 2 open-label trials.

Dr. Edward J. Gane from Auckland Clinical Studies, in Auckland, New Zealand, and colleagues - in part A of the C-CREST-1 and C-CREST-2 trials - randomly assigned 240 patients with HCV genotype 1, 2 or 3 and without cirrhosis to receive an eight-week course of a daily three-drug combination:

- grazoprevir 100 mg, plus

- either elbasvir 50 mg or ruzasvir 60 mg, plus

- either 300 mg or 450 mg of uprifosbuvir.

The studies were funded by Merck and Co.

Sustained virologic response rates 12 weeks after the end of therapy (SVR12) were 92% with both doses of the grazoprevir-ruzasvir-uprifosbuvir regimen and ranged from 85% to 88% (depending on uprifosbuvir dose) with grazoprevir-elbasvir-uprifosbuvir, according to one of the reports, both online August 9 in The Lancet Gastroenterology and Hepatology.

All four regimens were well-tolerated.

"These results support the selection of grazoprevir plus ruzasvir plus uprifosbuvir 450 mg as the regimen for further clinical investigation in broader populations," the researchers conclude.

Dr. Eric Lawitz from Texas Liver Institute at the University of Texas Health San Antonio and colleagues extended these findings in part B of C-CREST-1 and C-CREST-2. In this trial, 675 patients with HCV-1, -2, -3, -4 or -6, with or without cirrhosis, received eight, 12, or 16 weeks of grazoprevir-ruzasvir-uprifosbuvir 450 mg, with or without ribavirin.

SVR12 rates with eight weeks of therapy were 93% in individuals with genotype 1a, 98% with genotype 1b, 86% with genotype 2 (without cirrhosis; patients with HCV-2 and cirrhosis received a longer course), 95% with genotype 3 (treatment naive, without cirrhosis) and 100% with genotypes 4 and 6.

"We were surprised by the relatively lower efficacy of an 8-week duration of this regimen among those with genotype 2 infection," Dr. Lawitz told Reuters Health by email. "However, extending therapy to 12 weeks overcame this effect."

SVR12 rates were generally higher among participants with or without cirrhosis who received 12 or 16 weeks of therapy.

There were no documented virologic failures after week 12 of follow-up, although 10 participants who achieved SVR12 were lost to follow-up.

As in part A of the study, treatment with this fixed-dose combination with or without ribavirin was generally well tolerated.

"Results from the current studies support further investigation of grazoprevir, ruzasvir, and uprifosbuvir as a pan-genotypic regimen in individuals infected with HCV with and without cirrhosis, and suggest that this combination has the potential to provide a safe, single-duration regimen in most populations, including individuals with cirrhosis infected with genotype 3 who had previously received treatment with pegylated interferon and ribavirin," the researchers conclude.

"We await data from phase 3 to know how this regimen might impact the current treatment landscape," Dr. Lawitz said. "We hope that this regimen will be able to give providers more options with regard to pan-genotypic regimens for the treatment of HCV."

Dr. Eleanor M. Wilson from the University of Maryland School of Medicine, Baltimore, who coauthored an accompanying comment in the journal, told Reuters Health by email, "The safety and efficacy data seem promising, but it's still investigational, so not sure about its impact on the field of hepatitis C treatment yet."

"With the recent approvals of Vosevi and Mavyret, in addition to the previously available options, I think the overall take-away is that it's fantastic that there are more hepatitis C treatment options for patients and providers," she said. "It's tremendous that previously so-called 'difficult-to-treat patients' including those with previous treatment experience, comorbid conditions like HIV or renal disease, and those with advanced fibrosis and cirrhosis now have a variety of safe and highly effective options to treat their hepatitis C."

"My area of expertise is in novel treatment approaches, including strategies to reduce the treatment duration in order to increase access and decrease treatment cost, as well as options for patients who haven't successfully cleared HCV with first-line therapy (due to problems of adherence or viral resistance), and from that standpoint, it's an exciting time to be a hepatitis C provider," Dr. Wilson said.

Dr. Mark Sulkowski, who directs the viral hepatitis center at Johns Hopkins University in Baltimore, told Reuters Health by email, "We currently have multiple outstanding HCV regimens for the treatment of all genotypes of hepatitis C, which typically include combinations of direct-acting antiviral inhibitors of HCV protein targets NS3 (protease), NS5A and NS5B (polymerase). While we have seen the regulatory approval of multiple inhibitors of the NS3 and NS5A proteins, to date, only one (nucleotide) inhibitor of the NS5B polymerase active site has been approved, sofosbuvir."

"The C-CREST-1 and -2 studies provide a phase 2 evaluation of another (nucleotide) analogue inhibitor of NS5B, uprifosbuvir," said Dr. Sulkowski, who was not involved in the research. "Based on the results of these studies, uprifosbuvir appears to be poised to move to phase 3 studies, and if successful in phase 3 trials, this agent could become a valuable addition to the available drugs to treat hepatitis C."

Dr. Gane did not respond to a request for comment.
Merck funded the trials and employed most of the authors.

SOURCE: Lancet Gastroenterol Hepatol 2017.
Abstract 

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials

Abstract 

Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials

Abstract 

Shortening the duration of therapy for chronic hepatitis C infection

Full Text
Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
PDF provided by @HenryEChang via Twitter

Direct-acting antiviral agents against hepatitis C virus and lipid metabolism

World J Gastroenterol. Aug 21, 2017; 23(31): 5645-5649
Published online Aug 21, 2017. doi: 10.3748/wjg.v23.i31.5645

Direct-acting antiviral agents against hepatitis C virus and lipid metabolism

Tatsuo Kanda, Mitsuhiko Moriyama

Core tip: Eradication of hepatitis C virus (HCV) decreases the rate of complications, including liver-related and liver-unrelated death, and improves patient quality of life. Individuals infected with HCV have an increased risk of cardiovascular diseases and intracerebral hemorrhage, which are both associated with lipid metabolism. HCV infection causes abnormal host lipid metabolism. Treatment with interferon-based and interferon-free regimens has an impact on the eradication of HCV, as well as lipid abnormalities, during treatment and after treatment. Further observations are needed to determine the long-term effects on lipid metabolism caused by HCV and by eradication of the virus.

Abstract

Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type I and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia.

INTRODUCTION

Hepatitis C virus (HCV) encodes at least 10 viral proteins, which include structural (core, E1, E2 and p7) and non-structural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins[1]. HCV is a leading cause of cirrhosis and hepatocellular carcinoma in the United States and Japan. Eradication of HCV is important for preventing death due to these liver diseases.

Associations of HCV with host lipoproteins have been reported[2]. Hepatocytes take up low-density lipoproteins (LDLs) and very low-density lipoproteins through LDL receptors. Antibodies to the HCV envelope may disrupt the HCV lipid-containing envelope[3]. These antibodies could provide an efficient mode of viral entry into liver cells[2]. HCV core protein colocalizes with apolipoprotein AII at the surface of lipid droplets, suggesting a relationship between the expression of HCV core protein and cellular lipid metabolism[4]. HCV infection or core protein expression also increases the expression of sterol regulatory element binding protein 1c and its target, fatty acid synthase (FASN), which are both involved in lipid synthesis[5].

Although interferon-free regimens could result in higher sustained virologic response (SVR) rates, Endo et al[6] reported that serum cholesterol levels were significantly increased during combination treatment with the HCV NS5B inhibitor sofosbuvir and the HCV NS5A inhibitor ledipasvir, compared with those during interferon-included regimens[7]. Of interest, the authors also observed that regardless of the regimens, total cholesterol, LDL cholesterol and high-density lipoprotein (HDL) cholesterol levels increased post-treatment[6].

HCV AND LIPID METABOLISM

HCV increases FASN levels[5], resulting in the accumulation of fatty acids in hepatocytes (Figure 1). Fatty acids are needed for cell growth, cell adhesion, extracellular matrix formation, cell migration and cell invasion, which are essential for cancer development. Synthesis of cholesterol requires 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Among HMG-CoA reductase inhibitors, fluvastatin is an anti-HCV reagent that is used in combination with interferons[8]. Steatosis and abnormal lipid metabolism caused by HCV infection may enhance lipid droplet formation in hepatocytes[9-11]. Lipid droplets, which store neutral lipids, are required for the formation of infectious HCV particles[11].

Figure 1 Hepatitis C virus and fatty acid synthesis. DAAs: Direct-acting antiviral agents; HCV: Hepatitis C virus; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A.

ADVANCED LIVER FIBROSIS AND LIPID METABOLISM

In most cells, the major source of new sterol is endogenous synthesis from acetyl-CoA[12]. HMG-CoA is formed from acetyl-CoA and acetoacetyl-CoA[12]. There are at least 4 mechanisms for acquiring cholesterol: (1) de novo synthesis within the cells and uptake of unesterified or esterified cholesterol from the external environment via; (2) the LDL receptor (LDLR); (3) scavenger receptor class B type I (SR-BI); or (4) Niemann-Pick C1-like 1 protein (NPC1L1)[13]. HDL particles containing apoA-I can be bound by SR-BI in hepatocytes and endocrine cells[13]. Interestingly, LDLR, SR-BI and NPC1L1 are candidate receptors that may be involved in HCV[14-16].

The total cholesterol pool in a human is 2.2 g/kg body weight. There is a continuous flow of cholesterol from the endoplasmic reticulum to the cell membrane and then from the plasma membrane to the liver and intestine[13]. In humans, the flux of cholesterol through the whole body is approximately 10 mg/d per kilogram body weight[17], although the half-life of plasma cholesterol is only a few days[13]. The serum lipids, total cholesterol, cholesteryl ester, LDL cholesterol and HDL cholesterol levels were significantly lower in HCV-related cirrhosis patients than in controls. HCV-related cirrhosis severely impairs liver lipid metabolism[18] (Figure 2). The serum total cholesterol level is an independent predictor of significant fibrosis[19]. When evaluating serum total cholesterol levels, liver function should also be checked (Figure 2).

Figure 2 Effects of hepatitis C virus infection on liver function and liver lipid metabolism. DAAs: Direct-acting antiviral agents; HCV: Hepatitis C virus.

LIPID METABOLISM DURING TREATMENT WITH INTERFERON-BASED REGIMENS AGAINST HCV

Total cholesterol, LDL cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when an SVR is achieved in patients with HCV genotype 1[20]. HCV eradication is closely related to lipid metabolism in patients treated with interferon-based regimens. Lange et al[21] examined the serum lipid profiles of 575 European HCV genotype 1-infected patients before, during and after treatment with peginterferon-α-2a (180 μg/wk) and ribavirin (1000-1200 mg/d) for 48 wk. The authors found substantial pretreatment hypocholesterolemia with a nonresponse to interferon-α-based therapy, and lower pretreatment cholesterol levels were an independent predictor of not attaining an SVR[21]. After treatment-induced HCV eradication, the median cholesterol levels increased above baseline. Kuo et al[22] reported that chronic HCV infection is associated with hypocholesterolemia and hypotriglyceridemia, and these conditions can be reversed by successful antiviral therapy.

HCV GENOTYPE 3

Serfaty et al[23] reported that hypobetalipoproteinemia is prevalent and associated with steatosis, especially in patients infected with HCV genotype 3. It has been reported that HCV, particularly genotype 3, is associated with steatosis. Poynard et al[24] reported that an SVR, achieved with interferon-based regimens, is associated with a reduction in steatosis in HCV genotype 3 patients, as well as a correction of serum cholesterol levels at baseline. Steatosis is significantly more common in HCV genotype 3 patients than in those with other HCV genotypes, and in patients treated with peginterferon alpha-2a plus ribavirin, an SVR is associated with reduction of steatosis[25]. New treatments using HCV NS3/4A protease inhibitors have limited activity against HCV genotype 3[26]. HCV NS5B and HCV NS5A inhibitors have also performed poorly in HCV genotype 3 patients[26].

LIPID METABOLISM DURING TREATMENT WITH INTERFERON-FREE REGIMENS AGAINST HCV

Endo et al[6] studied 276 patients with chronic HCV genotype 1b infection who were treated with interferon-free regimens. Of these 276 patients, 141 were treated with the HCV NS5A inhibitor daclatasvir plus the HCV NS3/4A inhibitor asunaprevir for 24 wk[27,28] and 135 were treated with sofosbuvir plus ledipasvir for 12 wk[6].

In the daclatasvir plus asunaprevir-SVR group, the total cholesterol levels were significantly increased throughout the observation period, and the total cholesterol levels were significantly increased at 4 wk after treatment and 12 wk after treatment, compared with those at the end of treatment (EOT)[6]. Serum LDL cholesterol levels increased after the EOT. HDL cholesterol was significantly increased throughout the treatment period, but there were no significant changes in serum triglyceride levels[6].

In the sofosbuvir plus ledipasvir-SVR group, the total cholesterol levels were markedly increased from the early stage of therapy and lasted until the EOT[6]. The total cholesterol levels were sharply decreased after the EOT (P < 0.001). Changes in the LDL cholesterol levels were quite similar to those found in the total cholesterol levels. After the EOT, the HDL cholesterol levels were decreased compared to those during therapy (P < 0.001), but there were no significant changes in triglyceride levels[6]. Hashimoto et al[29] also reported that the increase in cholesterol levels during treatment was much greater in the sofosbuvir plus ledipasvir-SVR group than in daclatasvir plus asunaprevir-SVR group. The authors also observed that a rapid increase in the serum LDL cholesterol concentration during the interferon-free treatment was associated with the type of regimen and decrease in the HCV core protein level. Morales et al[30] also reported that there was a significant increase in the LDL and total cholesterol levels after treatment, compared to the pre- and post-treatment laboratory data from 52 patients receiving sofosbuvir-based regimens, but there was no change in body mass index between pre-and post-treatment. Among HIV/HCV coinfected patients, an increase in LDL cholesterol was observed after an SVR was achieved with interferon-free treatment[31].

CONCLUSION

HCV infection induces steatosis and is accompanied by multiple metabolic alterations, such as hyperuricemia, reversible hypocholesterolemia, insulin resistance, arterial hypertension and visceral adipose tissue expansion[32-34]. Eradication of HCV with interferon-free regimens increases total cholesterol levels. Because of the worsening nutritional status as an adverse event of interferon-based regimens, it is difficult to examine the effects of HCV on serum lipid profiles[6]. It is evident that HCV affects cholesterol metabolism during interferon-free regimens because these regimens have no influence on the nutritional status of the host[6]. The increase in cholesterol levels during treatment was much greater in the sofosbuvir plus ledipasvir-SVR group than in the daclatasvir plus asunaprevir-SVR group[6,29]. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes.

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