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