New Therapeutics Approach in gastroenterology Abou Rached Antoine, MD, MBAIP
Helicobacter pylori is a Gramnegative, microaerophilic, spiral-shaped bacterium Major cause of Chronic Gastritis PUD Colonizes Stomach 30%-80% Sero-prevalence affects CV, Respiratory, Autoimmu ne Treat in PIDA & ITP Helicobacter pylori 1994 WHO Class I carcinogen/definite MALToma, Adenocarcinoma
Prevalence of H. pylori infection 14-46% 81% 85% 88% 37-50% 27% 80% 43% 58% 63% 68% 90% 80% 918 million people 80% 60-70% 80% 80% 5-30% 824 million people 15-38% 36-73%
INDICATIONS FOR DIAGNOSING AND TREATING H. PYLORI INFECTION? Established Active peptic ulcer disease History of peptic ulcer disease (not treated) Gastric MALT lymphoma (low grade) After endoscopic resection of early gastric cancer Uninvestigated dyspepsia Controversial Nonulcer dyspepsia GERD Persons using NSAID Unexplained iron deficiency anemia Populations at higher risk for gastric cancer
Diagnosis of H. Pylori I. Diagnostic non-invasive tests II. Diagnostic invasive tests
Diagnostic Testing for H. pylori: noninvasive tests Non-endoscopic Testing Advantages Disadvantages Antibody testing Inexpensive, widely available, very good NPV/PPV dependent upon H. pylori prevalence. Not recommended after H. pylori therapy Urea breath tests Identifies active H. pylori infection. Excellent PPV and NPV Useful before and after therapy Reimbursement and availability remain inconsistent Fecal antigen test Identifies active H. pylori infection. Excellent PPV & NPV regardless of H. pylori prevalence. Useful before and after H pylori therapy Polyclonal test less validated than UBT in post-treatment. Monoclonal test reliable before and after antibiotic therapy.
Endoscopy-Based Testing for H. pylori Endoscopic testing Advantage Disadvantage Histology Excellent sensitivity and specificity Expensive and requires infrastructure and trained personnel Rapid urease testing Inexpensive and provides rapid results. Excellent specificity and very good sensitivity in properly selected patients Sensitivity significantly reduced in the Post-treatment setting Culture Excellent specificity. Allows determination of antibiotic sensitivities Expensive, difficult to perform, and not widely available. Only marginal sensitivity PCR Excellent sensitivity and specificity. Allows determination of antibiotic sensitivities Methodology not standardized across laboratories and not widely available
Diagnostic Testing for H. pylori: Advantages of Serology Not affected by local changes in the stomach The bacterial load can be decreased under the threshold of detection with the other methods: transitorily, in case of antimicrobial or antisecretory drugs consumption permanently in case of premalignant & malignant lesions Antibodies (CagA antibodies) remain elevated for months-years after H. pylori disappearance in the stomach
Treatment Regimens Triple therapy Quadruple therapy Sequential Classic therapy (7-14d): Amoxicillin, Clarithromyci n, PPI Clarithromycin, metronid azole, PPI Amoxicillin, levofloxacin, PPI Bismuth Based: Tetracycline, bismuth, m etronidazole, PPI (10 days) Non-bismuth based: Clarithromycin, metroni dazole, amoxicillin, PPI (10days) 5 days: PPI + Clarithromycin 5 days: amoxicillin, metronidaz ole +PPI
Primary resistance to clarithromycin (%) Failure rate of triple therapy: 69.5% if clarithromycin resistance 25% if metronidazol e resistance 40 35 30 25 20 15 10 100 90 80 70 60 50 40 30 20 Eradication rate after triple therapy (%) 5 10 0 1997-2000 2001-2003 2004-2006 2007-2008 0 *Fischbach L, et al. Aliment Pharmacol Ther 2007; 26(3):343-57 ; **. Mégraud F. Gut 2004; 53(9):1374-84 ; ***. Sasaki M, et al. J Clin Biochem Nutr 2010; 47(1):53-8.
Rate of Primary Clarithromycin Resistance in H. Pylori in Europe (2008-2009)
Maastricht IV: Treatment recommendation
How to improve the standard triple therapy? Use high dose PPI: twice daily Increase the duration of the therapy from 7 to 10-14 days will increase the eradication rate by 5% PPI-clarithromycin-metronidazole (PCM) and PPIclarithromycin-amoxicillin (PCA) regimens are equivalent. Certain probiotics and prebiotics show promising results as an adjuvant therapy in reducing side effects. PPI-clarithromycin containing therapies do not need to be adapted to patient factors except for dosing
Second line therapy After failure of PPI Clarithromycin containing therapy either: Bismuth based quadruple therapy OR Levofloxacin based triple therapy (take into account rising resistance to fluoroquinolone) After failure of second-line therapy, treatment should be guided by antimicrobial susceptibility testing whenever possible.
High Clarithromycin-Resistant area In areas of high clarithromycin resistance, bismuth-containing quadruple therapies are recommended for first-line empirical treatment. If this regimen is not available sequential therapy or a non-bismuth quadruple therapy is recommended. Evidence Level: 1a Grade of Recommendation: A
Second and Third Line In areas of high clarithromycin resistance after failure of bismuth-containing quadruple therapy: Levofloxacin containing triple therapy is recommended. Rising rates of levofloxacin resistance should be taken into account After failure of second-line therapy, treatment should be guided by antimicrobial susceptibility testing whenever possible.
Treatment Algorithm: Maastricht IV 1 st line 2 nd line 3 rd line
ACG ACG Treatment Algorithm Recommendation
Hepatitis B
The global impact of HBV disease 2 billion with evidence of HBV infection 25 40% die of cirrhosis or liver cancer World population ~6 billion 350 400 million with chronic hepatitis B WHO, Fact sheet No. 204; CDC, Viral hepatitis B fact sheet; Conjeevaram HS, Lok AS. J Hepatol. 2003;38:S90-103 Lee WM. N Engl J Med. 1997;337:1733-45. Lok AS. N Engl J Med. 2002;346:1682-3
Epidemiology Worldwide Prevalence of Hepatitis B World prevalence of HBV carriers HBsAg carriers prevalence <2% 2-7% 8% poorly documented WHO 2003.
Transmission of HBV Vertical (perinatal) transmission Horizontal transmission 90% of infected infants become chronically infected Mother Host 6% of people infected over the age of 5 become chronically infected Infant Recipient Child-to-child Contaminated needles Sexual contacts Healthcare worker Blood transfusion CDC Viral hepatitis B fact sheet; Lee. N Engl J Med. 1997;337:1733-45; Lavanchy. J Viral Hepat. 2004;11:97-107
Epidemiology of hepatitis B and C in general population in Lebanon Prospective study: January 2010 December 2011 Screening of the general population in different regions for hepatitis B and hepatitis C
Epidemiology of hepatitis B and C in Results: general population in Lebanon Over 2 year period: 31,137 individuals screened ( 0.7% of population) Sex: 51% male 49% female Mean age: Male: 37.1 (range 5-89) Female: 38.4 (range 8-85)
Epidemiology of hepatitis B in general population in Lebanon Results: Prevalence of hepatitis B: 1.69% (542 patients HBsAg positive) Sex Ratio: M/F: 1.38 Male: 58% Female: 42% District distribution: Beirut: 0.73% Mount Lebanon: 1.79% South: 1.9% Bekaa Valley (East): 1.23% North: 1.7%
Indications for Treatment of HBV Infection Upon Diagnosis Phase of Chronic HBV Infection HBeAg Status HBV DNA Elevated? ALT Level Elevated? Treatment Indicated? Immune tolerant Positive Yes No No Immune active/clearance Positive/negative Yes Yes Yes Inactive carrier No No No No Reactivation Yes Yes Yes Yes
AASLD and EASL Recommendations for the Management of Chronic HBV Infection HBeAg-Positive Patients AASLD HBV DNA >20,000 IU/mL and ALT >2 x ULN a : consider treatment after 3 to 6 months of observation with absence of spontaneous loss of HBeAg HBV DNA >20,000 IU/mL and ALT 2 x ULN, and age >40 years or family history of HCC: consider liver biopsy and treat if significant histologic disease is present EASL HBV >2000 IU/mL and/or ALT >ULN: consider liver biopsy (or noninvasive markers) and treat if moderate to severe histologic disease is present HBeAg-Negative Patients AASLD HBV DNA >2000 IU/mL and ALT >2 x ULN: consider treatment HBV DNA >2000 IU/mL and ALT >ULN: consider liver biopsy and treat if significant histologic disease is present EASL HBV >2000 IU/mL and/or ALT >ULN: Consider liver biopsy (or noninvasive markers) and treat if moderate to severe histologic disease is present Cirrhotic Patients AASLD Compensated cirrhosis HBV DNA >2000 IU/mL: treat HBV DNA <2000 IU/mL and ALT >ULN: consider treatment Decompensated cirrhosis Treat with any detectable HBV DNA level EASL Compensated cirrhosis and decompensated cirrhosis Treat regardless of the HBV DNA level
Antiviral Agents Approved for the Treatment of Chronic HBV Infection Oral Antiviral Agents Drug Dose a Lamivudine: pill or oral solution Entecavir: pill or oral solution Telbivudine: pill Adefovir dipivoxil: pill Tenofovir disoproxil fumarate: pill or oral solution 100 mg, once daily 0.5 mg, once daily 600 mg, once daily 10 mg, once daily 300 mg, once daily Injection Immunostimulators Drug Dose Interferon alfa-2b Pegylated interferon alfa-2a 10 million units by SC injection 3 times/wk for 24-48 wk 180 μg by SC injection weekly for 48 wk
Cumulative Annual Incidence of Resistance of Nucleos(t)ide Analogs
Antiviral resistance increases over time 80 60 20 0 Lamivudine 1 Telbivudine 4 40 Incidence of resistance (%) 5% Adefovir 2 Entecavir (LAM-resistant) 3 Entecavir (naive) 3 *** 12% 24% 15% 20% 11% 0.1% 0% 0.3% 2% 0.4% 0.8% Year 1 Year 2 Year 3 Resistance to NAs is it just a matter of time?? 42% 25% 53% 40% 18% Year 4 70% 29% 65% Year 5 1 Lai, Clin Infect Dis 2003; 2 Westland, Hepatology 2003; 3 Colonno R, EASL 2007; 4 Gane, EASL 2006 Slide 25
Hepatitis C
Epidemiology of Hepatitis C in General Population in Lebanon Results: Prevalence of hepatitis C: 0.2% (HCV Ab positive) Sex Ratio: M/F: 0.85 PCR HCV: Male: 46% Female: 54% Positive: 84.6% Negative: 15.4%
Hépatite virale C
virale hepatitis C Futur of the concept new molecules Triple therapy Pegylated Interferon + Ribavirine + telaprevir Pegylated Interferon + Ribavirine + Boceprevir Vaccin against hépatitis C
Response-guided therapy algorithm for boceprevir
Response-guided therapy algorithm for telaprevir.
Classes of drugs in development for hepatitis C Drug class Mechanism of action Advantages Disadvantages NS3/4A protease inhibitors First generation NS3/4A protease involved in posttranslation processing of HCV polyproteins Potent inhibitors of HCV genotype 1 Low genetic barrier to resistance Cross-resistance is extensive between different compounds in class Drug interactions (CYP) Second generation NS3/4A protease involved in posttranslation processing of HCV polyproteins Pan-genotypic antiviral activity Higher genetic barrier to resistance than first-generation PIs; activity against many substitutions that cause resistance in first-generation PIs NS5B polymerase inhibitors NS5B RdRp is required for copying HCV-RNA genome and transcribing mrna Nucleoside inhibitors Analogs of natural substances; bind active site of RdRp; terminate viral RNA chain generation High barrier for resistance Pan-genotypic Fewer in pipeline Non-nucleoside inhibitors Bind various allosteric sites, inducing conformational change in polymerase Multiple target sites identified Low/medium antiviral efficacy Active against genotype 1 Low genetic barrier HCV genotype-/subtypedependent NS5A inhibitors Bind domain I of NS5A protein, exact role in viral replication is unclear High potency Potential activity against multiple genotypes Low genetic barrier to resistance Cyclophilin Inhibitors Target host cyclophilin enzyme; functional regulator of HCV replication Good potency Pan-genotypic High barrier to resistance Drug interactions
Hepatitis C virus direct-acting antiviral therapy agents in clinical development in phases II/III clinical trials NS3/NS4A protease inhibitors Phase 2 Phase 3 Licensed First generation Danoprevir/r* (RG7227) Sovaprevir (ACH-1625) GS-9256 GS-9451 ABT-450/r* Vaniprevir (MK7009) Simeprevir (TMC435) Faldaprevir (BI201335) Asunaprevir (BMS-650032) Boceprevir Telaprevir Second generation MK-5172 NS5B polymerase inhibitors Nucleos(t)ide analogs Mericitabine (RG7128); IDX-184 PSI-7851 Sofosbuvir (GS-7977) Non-nucleos(t)ide analogs VX-222 BMS-791325 ABT-333 ABT-072 Setrobuvir(ANA598) BI207127 Filibuvir IDX375 VCH-916 [tegobuvir (GS-9190)] NS5A inhibitors ABT-267 GSK2336805 GS-5885 Daclatasvir (BMS-790052) Cyclophilin NIM-811; SCY-635 [Alisporivir]
Future There are many potential therapeutic options for treatment It is not yet clear whether there will be a single major treatment option used for all genotypes of HCV or whether there will be an individualized therapeutic approach that considers viral genotype, IL28B genotype, resistance mutations other factors in planning a treatment for each patient. there may be a truly realizable goal of providing curative management for the majority of patients with HCV who are treated