New Therapeutics Approach in gastroenterology

Abou Rached Antoine, MD, MBAIP Helicobacter pylori Helicobacter pylori is a Gram- negative, 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

1994 WHO Class I carcinogen/definite MALToma, Adenocarcinoma Prevalence of H. pylori

88% 37-50%27% 80% 14-46% 58% 80% 43% 63% 5-30% 81% 68% 60-70% 824 million 90% 80% people 918 million 80% 80% 85% 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: non- invasive tests Non-endoscopic Testing Advantages Disadvantages

Antibody testing Inexpensive, widely available, very Not recommended after H. good NPV/PPV dependent upon H. pylori therapy pylori prevalence.

Urea breath tests Identifies active H. pylori infection. Reimbursement and Excellent PPV and NPV availability remain Useful before and after therapy inconsistent

Fecal antigen test Identifies active H. pylori infection. Polyclonal test less validated Excellent PPV & NPV regardless than UBT in post-treatment. of H. pylori prevalence. Useful Monoclonal test reliable before and after H pylori therapy 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. Sensitivity significantly Excellent specificity and very good reduced in the sensitivity in properly Post-treatment setting selected patients

Culture Excellent specificity. Allows Expensive, difficult to perform, determination of antibiotic and not widely available. Only sensitivities marginal sensitivity

PCR Excellent sensitivity and specificity. Methodology not standardized Allows across laboratories and not determination of antibiotic widely available sensitivities 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 Quadruple Sequential therapy therapy

Classic therapy (7-14d): Amoxicillin, Clarithromyci Bismuth Based: n, PPI Tetracycline, bismuth, m etronidazole, PPI (10 days) 5 days: PPI + Clarithromycin Clarithromycin, metronid azole, PPI 5 days: amoxicillin, metronidaz Non-bismuth based: ole +PPI Clarithromycin, metroni Amoxicillin, levofloxacin, dazole, amoxicillin, PPI PPI (10days) Failure rate of triple therapy:

40 100

• 69.5% if 90 35

80 clarithromycin Eradication rate

30(%) resistance 70 25

60

after clarithromycin

20to 50 • 25% if triple

40 therapy 15

metronidazol resistance 30 e resistance 10 (%) Primary 20

5 10

0 0 1997-2000 2001-2003 2004-2006 2007-2008

*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 PPI- clarithromycin-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

1st line

2nd line

3rd line ACG RACGecommendation Treatment Algorithm 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 350–400 million with ~6 billion 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 6% of people infected infected over infants Mother the age of 5 become Host become chronically chronically infected 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 Epidemiology of hepatitis B and C in general population in Lebanon • Results: – 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 HBeAg Status HBV DNA Elevated? ALT Level Elevated? Treatment Indicated? Infection

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 ULNa: 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 Dosea

Lamivudine: pill or oral solution 100 mg, once daily Entecavir: pill or oral solution 0.5 mg, once daily Telbivudine: pill 600 mg, once daily Adefovir dipivoxil: pill 10 mg, once daily Tenofovir disoproxil fumarate: pill or oral solution 300 mg, once daily

Injection Immunostimulators

Drug Dose

Interferon alfa-2b Pegylated 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 1 Lamivudine 70% Adefovir2 65% 60 Entecavir (LAM-resistant)3 53% Entecavir (naive)3 *** Telbivudine4 42% 40 40% Incidence of resistance (%) 29% 24% 25% 20 20% 15% 18% 12% 11% 5% 0.1%0% 0.3% 2% 0.4% 0.8% 0 Year 1 Year 2 Year 3 Year 4 Year 5 Resistance to NAs…is it just a matter of time??

1 2 3 4 Lai, Clin Infect Dis 2003; Westland, Hepatology 2003; Colonno R, EASL 2007; Gane, EASLSlide 2006 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 – Male: 46% – Female: 54% – PCR HCV: • Positive: 84.6% • Negative: 15.4% Hépatite virale C virale hepatitis C

• Futur of the concept – new molecules – Triple therapy • Pegylated Interferon + Ribavirine + • Pegylated Interferon + Ribavirine + – 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 — —

Low genetic barrier to resistance NS3/4A protease involved in post- Cross-resistance is extensive Potent inhibitors of HCV genotype First generation translation processing of HCV between different compounds in 1 polyproteins class Drug interactions (CYP)

Higher genetic barrier to NS3/4A protease involved in post- resistance than first-generation Second generation translation processing of HCV Pan-genotypic antiviral activity PIs; activity against many polyproteins substitutions that cause resistance in first-generation PIs

NS5B RdRp is required for NS5B polymerase inhibitors copying HCV-RNA genome and — — transcribing mRNA

Analogs of natural substances; bind active site of RdRp; High barrier for resistance Nucleoside inhibitors Fewer in pipeline terminate viral RNA chain Pan-genotypic generation

Bind various allosteric sites, Multiple target sites identified Low genetic barrier Non-nucleoside inhibitors inducing conformational change Low/medium antiviral efficacy HCV genotype-/subtype- in polymerase Active against genotype 1 dependent

Bind domain I of NS5A protein, High potency NS5A inhibitors exact role in viral replication is Potential activity against multiple Low genetic barrier to resistance unclear genotypes

Target host cyclophilin enzyme; Good potency Cyclophilin Inhibitors functional regulator of HCV Pan-genotypic Drug interactions replication High barrier to resistance direct-acting antiviral therapy agents in clinical development in phases II/III clinical trials

Phase 2 Phase 3 Licensed

NS3/NS4A protease inhibitors

Danoprevir/r* (RG7227) (ACH-1625) (TMC435) GS-9256 Boceprevir First generation (BI201335) GS-9451 Telaprevir (BMS-650032) ABT-450/r* (MK7009)

Second generation MK-5172

NS5B polymerase inhibitors

Mericitabine (RG7128); Nucleos(t)ide analogs IDX-184 (GS-7977) — PSI-7851

VX-222 BMS-791325 ABT-333 ABT-072 (ANA598) Non-nucleos(t)ide analogs — — BI207127 IDX375 VCH-916 [tegobuvir (GS-9190)]

ABT-267 NS5A inhibitors GSK2336805 (BMS-790052) — GS-5885

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