Trent W Nichols - PowerPoint Presentation

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Trent W Nichols

Hepatitis-2015Orlando, USAJuly 20 - 22 2015Slide2

The Growing Epidemic in HCC from Hepatitis/NASH Cirrhosis in American VeteransImplications and Economic burdens for the Health Care in the United States and the World!Trent W Nichols Jr. MD; AMRI, CNDD Hanover PAVAH Martinsburg WVSlide3

The Growing Epidemic of Hepatocelluar Carcinoma in VeteransAt DDW 2014, S Mittal showed that over 1500 Veterans in 2013 were diagnosed with HCC and that this trend is increasing every year. The greater percentage of patients with NAFLD- related HCC did not undergo HCC surveillance (Clinical Gastroenterology and Hepatology 2014). The VA now has 10 times more patients diagnosed with hepatocellular carcinoma (HCC) than it did a decade. “Unless we do something dramatic, 10,000 Vietnam veterans will die of liver cancer in the next five years.” stated Douglas Heuman MD, Chief of Hepatology and Medical Director of Liver Transplantation at VA Medical Center Richmond and Professor of Medicine at Virginia Commonwealth University!Slide4

Epidemiology of HCC from Hepatitis C, B and NASH/NAFLD CirrhosisisVietnam veterans have the greatest risk of HCC because they have the highest hepatitis C virus infection and other comorbid factors, smoking, alcohol abuse, obesity, diabetes, metabolic syndrome associated with insulin resistance and their association to (NASH) non- alcoholic steatohepatitis and the progression to cirrhosis (US Medicine 2014).Slide5

The Growing Epidemic of HCC in American Veterans;HCV!In 2002, the VA had 146,290 veterans in care who had HCV. Of those, approximately 270 patients had newly diagnosedHCC, and about 500 had ever been diagnosed with HCC, said David Ross, MD, PhD, director of the HIV, HCV and public health pathogens programs for the VA. By 2013, the VA had nearly 20% more veterans with HCV (174,302), but six times as

many with recent diagnoses (1,600) and 10 times as many who had ever been diagnosed with HCC (4,900).Slide6

Implications for Survival and Economics in HCV>HCC!While the latest wave of treatments for HCV cost much more than the interferon and ribavirin combination regimen previously recommended, they also achieve sustained viral response at far higher rates and with greatly reduced side effects. The newest treatments are “frightfully expensive, but we only need to treat patients once! “The VA’s infectious disease group has actively taken the position that financial resource

limitations will not keep us from treating people who need treatment.”Slide7

Implications for Survival and Economics in HCV>HCC!Keeping patients with HCV from developing HCC has huge implications for survival. About 4% of patients with HCV who have developed cirrhosis are diagnosed with HCC each year. While curable when caught early, liver cancer “overall is a very bad actor. The five-year survival rate is just 14% across all stages, though in its earliest stage, that may be closer to

30% to 40%,” Heuman told U.S. Medicine.Slide8

Implications for survival and Economics in HCV>HCCLiver disease is rarely caught in its early stages. “Eighty percent or more of liver cancer diagnosed in the U.S. is not curable because it is diagnosed too late,” said Tamar Taddei, MD, director of the liver cancer teams and tumor boards at the VA Connecticut Healthcare system and Smilow

Cancer Hospital at Yale-New Haven Hospital. “Most people do not develop symptoms until their liver is 80% shot.”Slide9

Implications for survival and Economics in HCV>HCCLast year at VISN6 (Mid- Atlantic ) 221 hepatitis C patient , and 55 NASH/NAFLD were treated at Martinsburg VHA and ~500 at VAH Baltimore and DC combined. 12 million dollars was spent in pharmacy costs for Hepatitis C antiviral therapy at Martinsburg VHA and 304 millions dollars by Veterans Affairs Hospitals nationwide!Slide10

Hepatitis C AntiviralsSlide11

Hepatitis C Therapy 2014-151. Sofosbuvir/ Simpravir ~$ 80,000 for 12 weeks 2014. $55,000 for 12 weeks 20152. Sofosbuvir/ Ledispravir ( Harvoni)~$34,500 for 12 weeks3. Obitasvir, paritaprevir, ritonvir

/dasabuvir (Viekira)-~$28,500 for 12 weeksAddition of Ribavirin (~800/month) for cirrhosis 12 weeksSlide12

Hepatitis C therapy: SofosbuvirApproval Status: FDA approved December 6, 2013Indication for HCV Monoinfection and HCV-HIV Coinfection- GT 1,4: Sofosbuvir + peginterferon + ribavirin (12 weeks)- GT 2: Sofosbuvir + ribavirin (12 weeks) - GT 3: Sofosbuvir + ribavirin (24 weeks)Additional Indication for HCV

Monoinfection- GT 1 (interferon ineligible): Sofosbuvir + ribavirin (24 weeks)- HCC and awaiting transplant: Sofosbuvir + ribavirin (up to 48 weeks)Class & Mechanism- Nucleotide analog inhibitor of NS5B polymerase enzymeDosing: 400 mg PO once daily with or without food Adverse Effects (AE) attributable to Sofosbuvir- Fatigue, headacheWholesaler Acquisition Cost in United States- 28 tablet bottle = $28,000; estimated 12-week cost = $84,000Slide13

Sofosbuvir + SimeprevirSimeprevir + Sofosbuvir +/- Ribavirin in Genotype 1COSMOS Trial

nationwide. Slide14

Sofosbivir and Simpepravir +and - RibavirinCOSMOS (Cohort 2 with F3-F4 Fibrosis): SVR12 by RegimenSlide15

Viekira(ombitasvir,paritaprevir,ritonavir/dasabuvir) +/-Ribavirin for HCV GT 1-3A1444-040 Treatment-Naïve 24 Week Rx: ResultsSlide16

Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: ResultsION-1: SVR 12* by Treatment Duration and Regimen

Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

211/21412-Week Regimen211/217212/217215/217 Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin*Primary end-point by intention-to-treat analysis

24-Week RegimenSlide17

High Dose Vitamin E (Cholecalciferol) to prevent HCC !A previous epidemiology study by (V. Fedirko et al. Hepatology 2014) demonstrated the risk of HCC was reduced by 49% in those Europeans in a cohort of 520,000 with the highest levels of 25(OH)DA prospective trial of cholecalciferol 50,000 IU weekly was started in veterans with hepatitis C, B. alcoholic liver disease, NASH/NAFLD and cirrhosis.High dose vitamin D3 anticancer affect may be via nuclear cell signaling via C Wnt pathways (

antiproliferative, activation of apoptosis , inhibtions of angiogenesis and sonic hedgehog target genesSlide18
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Figure 2: 1alpha,25(OH)2D3-mediated transcriptional regulation.Classical action of 1 alpha,25(OH)2D3 is mediated by binding of the vitamin D receptor (VDR)-9-cis-retinoic acid receptor (RXR) complex at the vitamin-D response elements(VDRE)s . a| Transcriptional activation involves the co-activators, steroid receptor coactivators (SRCs), nuclear coactivator-62 kDa–Ski-interacting protein (NCoA62–SKIP) and histone acetyltransferases (HATs), CREB binding protein (CBP)–p300 and

polybromo- and SWI-2-related gene 1 associated factor(PBAF–SNF) to acetylate histones to derepress chromatin. b | Binding of the vitamin D receptor-interacting protein 205 (DRIP205) to the activation function 2 (AF2) of VDR (and RXR) attracts a mediator complex containing other vitamin D receptor-interacting proteins (DRIPs) that bridge the VDR–RXR–NCoA62–SKIP-DRIP205 complex with transcription factor 2B (TF2B) and RNA polymerase II (RNA Pol II) for transcription initiation.Slide20

Figure 2:1alpha,25(OH)2D3-mediated transcriptional regulation.The presence of the multiprotein complex facilitates increased transcription of genes, such as CDKN1A (which encodes the cyclin-dependent kinase inhibitor p21), CYP24A1 (which encodes 24-OHase) and SPP1 (which encodes osteopontin)23 c | 1alpha,25(OH)2D3-mediated transcriptional repression involves VDR–RXR heterodimer association with VDR-interacting VDIR) bound to E-box-type negative VDREs (nVDREs), dissociation of the HAT co-activator and recruitment of histone deacetylase (HDAC) co-repressor.Williams

syndrome transcription factor (WSTF) potentiates transrepression by interacting with a multifunctional, ATP-dependent chromatin-remodelling complex (WINAC) and chromatin. This leads to the repression of genes, such as CYP27B1 (which encodes 1alpha-OHase) and PTH (which encodes parathyroid hormone).Slide21

NASH/NAFLD cirrhosis as leading cause of liver transplantation by 2020NAFLD has evolved as a serious public health problem in the USA and around the world. In fact, NASH—the most serious form of NAFLD—is predicted to become the leading cause of liver transplantation in the USA by the year 2020. The pathogenesis of NAFLD and NASH, in particular the mechanisms responsible for liver injury and fibrosis, is the result of a complex interplay between host and environmental factors, and is at the center of intense investigation.Slide22

NASH/NAFLD Cellular MechanismSlide23

NASH/NAFLD Therapy1. Weight Loss with low CHO, fat diet with, exercise2. Vit E and /or Pioglitazone3. Betaine,Silymarin (Milk Thistle): Phosphatidycholine, Probiotics:4. Statin, or Fibrate5. Orlistat,Locaserin Phenteramine,Toprimate

Gastric BypassSlide24

Biophysics; Moderate Magnetic Fields on Mitochondria Moderate magnetic fields change gene expression. Ob /Ob mice when treated with 0.5 Tesla direct current electromagnetic fields were found to increase their activity, loose weight and fat in a 6 day period. Gene array analysis of human embryonic stem cells in another experiment of 0.23-0.28 T static magnetic fields was conducted. Up-regulation of genes for insulin factors genes, peroxisome proliferative activity receptor were increased, and calcium channel gene and other genes for mitochondrial ribosomal protein S, and uncoupling protein 2. Down- regulation of tumor necrosis factor alpha and interleukin 6 were demonstrated for this transformation. Forkhead transcription factors are also up-regulated at 5 days!Slide25

Hepatitis– 2016 Website:

hepatitis.omicsgroup.comMeet the eminent gathering once again atHepatitis-2016

Dubai, UAEOctober 17 - 19, 2016