New Therapeutics Approach in gastroenterology

Abou Rached Antoine, MD, MBAIP

Helicobacter pyloriHelicobacter pylori is a Gram-

negative, microaerophilic, spiral-shaped bacterium

Major cause of Chronic Gastritis

PUD

1994 WHOClass I carcinogen/definite

MALToma, Adenocarcinoma

Colonizes Stomach 30%-80%

Sero-prevalence affects CV, Respiratory, AutoimmuneTreat in PIDA & ITP

Prevalence of H. pylori infection

15-38%

68%63%

60-70%

58%

80%

5-30%43%

85%

37-50%

81%

27%

36-73%

88%

14-46%

80%80%

824 million

people

80%

90%

80%918 million

people

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 testsII. Diagnostic invasive tests

Diagnostic Testing for H. pylori: non-invasive 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 regardlessof 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 properlyselected 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. Allowsdetermination 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

Classic therapy (7-14d): Amoxicillin, Clarithromyci

n, PPI

Clarithromycin, metronidazole, PPI

Amoxicillin, levofloxacin, PPI

Quadruple therapy

Bismuth Based: Tetracycline, bismuth, m

etronidazole, PPI (10 days)

Non-bismuth based:

Clarithromycin, metronidazole, amoxicillin, PPI

(10days)

Sequential

5 days: PPI + Clarithromycin

5 days: amoxicillin, metronidaz

ole +PPI

Failure rate of triple therapy:

• 69.5% if

clarithromycin

resistance

• 25% if

metronidazol

e resistance

0

10

20

30

40

50

60

70

80

90

100

0

5

10

15

20

25

30

35

40

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

Eradicatio

n rate

after

triple

the

rapy

(%)P

rim

ary

resi

stan

ceto

cla

rith

rom

ycin

(%)

*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

ORLevofloxacin 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 TreatmentAlgorithm

ACG Recommendation

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

World population

~6 billion

2 billion with evidence of

HBV infection

350–400 million with

chronic hepatitis B

25–40% die of

cirrhosis or

liver cancer

The global impact of HBV disease

EpidemiologyWorldwide Prevalence of Hepatitis B

World prevalence of HBV carriersHBsAg carriers prevalence

<2%2-7%8%poorly documented

WHO 2003.

Child-to-child

Contaminated needles

Sexual contacts

Healthcare worker

Blood transfusion

6% of people infected over the age of 5 become chronically infected

90% of infected infants become chronically infected

Horizontal transmission

CDC Viral hepatitis B fact sheet; Lee. N Engl J Med. 1997;337:1733-45; Lavanchy. J Viral Hepat. 2004;11:97-107

HostMother

Infant

Recipient

Transmission of HBV

Vertical (perinatal) transmission

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 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

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 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

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

Slide 25

Antiviral resistance increases over time

1 Lai, Clin Infect Dis 2003; 2 Westland, Hepatology 2003; 3 Colonno R, EASL 2007; 4 Gane, EASL 2006

Year 4Year 2

Lamivudine1

0

20

40

60

80

Year 1 Year 3

Incidence of resistance (%)

Entecavir (LAM-resistant)3

Telbivudine4

Adefovir2

0% 2%

11%

18%

29%

5%

15%

Entecavir (naive)3 ***

Year 5

24%

42%

53%

70%

65%

0.3% 0.4%0.1% 0.8%

12%

20%

25%

40%

Resistance to NAs…is it just a matter of time??

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 + 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 post-

translation 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 post-

translation 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-genotypicFewer 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-/subtype-

dependent

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

Phase 2 Phase 3 Licensed

NS3/NS4A protease inhibitors

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