The Menace of Hepatitis B By Professor Dr Intekhab Alam Department of Medicine Khyber Medical University, PGMI, LRH, Peshawar
What is Hepatitis B ? • Hepatitis B is an infectious disease caused by hepatitis B virus which may lead to cirrhosis, hepatic decompensation and HCC. • Hepadnavirus family, DS DNA, Enveloped. • It is the 10th leading cause of death in the world • HBV is 50 to 100 times more infectious than HIV • 10% of HIV patients are co-infected with HBV WHO Fact Sheet. 2000 Keefe MD. Pocket Guide to Hepatitis B A CME accredited program developed by members of the ACT-HBV Initiative (University of Wisconsin) Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. Journal of Viral Hepatitis, Volume 11, Number 2, March 2004, pp. 97-107
HBV Genotypes and Subtypes Stuyver et al 2000
2 billion with evidence of 25% die of cirrhosis or liver cancer HBV infection 300–400 million with World population chronic HBV 6 billion The Global Impact of HBV Disease
Global Patterns of Chronic HBV Infection • High(>8%): 45% of global population • Lifetime risk of infection >60% • Early childhood infections common • Intermediate(2%-7%): 43% of global population • Lifetime risk of infection 20%-60% • Infections occur in all age groups • Low (<2%): 12% of global population • Lifetime risk of infection <20% • Most infections occur in adult risk groups
Hepatitis B – In Asia • Of all chronically infected carriers worldwide, approximately 75% are found in Asia. In Pakistan (Intermediate prevalence area): • 5% of the population is affected by hepatitis B • 67% of HCC cases are a result of HBV. R Mohamed et al. Practical difficulties in the management of hepatitis B in the Asia–Pacific region. Journal of Gastroenterology and Hepatology (2004) 19, 958–969
Transmission of HBV • HBV is ubiquitous, highly contagious and is 100 times more infectious than HIV. • Transmission is “Sexual, Parenteral, Perinatal”. • Source of infection is unknown in one third of the patients. • HBV can survive outside the body for prolonged periods.
Concentration of Hepatitis B Virus in Various Body Fluids High Moderate Undetectable Blood semen urine Serum vaginal fluid feces Wound exudates saliva sweat tears breast milk
Transmission of HBV Horizontal transmission Vertical transmission Recipient Mother Host Contaminated needles Sexual Health care worker Transfusion Perinatal Infant 6% infected after age 5 years become chronically infected 90% infected infants become chronically infected Keefe MD. Pocket Guide to Hepatitis B A CME accredited program developed by members of the ACT-HBV Initiative (University of Wisconsin) . CDC Fact Sheet. 2005
Spectrum of Disease Fatal progressive liver failure 90–95% neonatal infection 15–40%* Chronic HBV infection Acute HBV infection 50% childhood infection 5–10% adult infection ~1% Cirrhosis HCC Fulminant hepatic failure Decompensated cirrhosis Death • Ac. clinical illness (jaundice) <5 yrs: <10% • >5 yrs: 30-50% *Lok et al 2002
Aetiology and Disease Characteristics of HBVSummary • HBV is a complex virus characterised by high infectivity • Acute HBV infection usually resolves without medical intervention • Chronic infection leads to increased risk of progressive liver disease, cirrhosis and death • Chronic infection is the target of therapeutic intervention • HBeAg-negative variant is associated with a more aggressive form of the disease • Early intervention prevents development to HBeAg-negative disease
Importance of Diagnosis • Early diagnosis is important to prevent progression and transmission, and helps to: • confirm HBV infection • assess stage and grade of disease • monitor disease progression
The importance of monitoring HBV is a dynamic disease!!! Require treatment 40% 60% • Require monitoring… • Inactive disease may not remain inactive • Liver damage may occur if HBV reactivates Patients may develop the need for treatment later
Signs and symptoms of acute HBV AVH • They are the same for all types of hepatitis from A to E i.e: malaise, arthralgias, anorexia, fever, headache, dark colored urine, yellow discoloration of sclerae and pain or discomfort in RHC. • Extraheptic findings more common in HBV AVH. • Arthralgia, skin rash (papular dermatitis), polyarterits nodosa, glomerulonephritis……..etc
Acute HBV Markers Acute infection • High ALT • HBsAg • IgM Anti HBc (following parameters are present but need not be tested) • HBeAg • Elevated HBV DNA Resolving Infection • HBsAg seroconversion • HBeAg seroconversion • IgG Anti-HBc
Chronic HBV Markers Chronic infection • HBsAg measured 6 months apart • Absence of IgM anti-HBc • HBeAg +ive • HBV DNA +ive • Raised, fluctuating ALT
Characteristic phases of CHB infection Immune Immune Immune Immune tolerance clearance control escape HBeAg+ve HBeAg–ve > < < > HBV-DNA ALT HBeAg +ve chronic hepatitis HBeAg –ve active chronic hepatitis Inactive (carrier) state
The natural history of hepatitis B:the importance of immune control • Outcome of HBV infection is determined by the strength of the immune response • complex interplay between the host immune response and • replication status of the virus • 95% of adults spontaneously clear virus • However, 90% of newborns will develop chronic infection • 25% lifetime risk of end-stage liver disease or liver cancer
Importance of anti HBcAb detection(occult HBV infection) • Anti HBc positive but HBsAg and HBsAb negative???: - CHB with BDL of HBsAg & DNA:commonly seen in individuals with HIV and HCV co infection. - marker of immunity after acute infection: with BDL HBsAb, respond well to a single shot of HBV vaccine. - False positive:especially in people from low prevalence areas respond well to routine vaccination. - The only marker in the window period of HBV AVH.
Holistic approach to CHB “CHB is a lifelong infection”. • Identification of those at risk of liver disease. • Education (lifelong monitoring, reactivation) • Vaccination (all household and sexual contacts) • Judicious introduction of antiviral therapy • Appropriate screening for HCC.
Counseling after HBsAg detection • Family screening and vaccination. • Barrier protection (safe sex) for spouse till active immunity has developed in the spouse following vaccination. • Arrange HBIG and vaccine for the newborn in HBsAg +ive mothers diagnosed during pregnancy. • Regarding performing exposure prone procedures by HCWs ??? • Risk of blood transfusion and non-hepatic and hepatic transplant donation. • Sharing of tooth brushes and razors. • Cover open cuts and scratches. • Should receive 2 doses of HAV vaccine 6-18 months apart.
Don’t………….. • Impose any dietary restriction. • Restrict physical activities. • Isolate them in schools and daycare centers. • Separate their utensils. • Stop marital relations. • Stop them from kissing their near and dear ones.
Clinical terms used in HBV infection • Chronic Hepatitis B (CHB):can be further subdevided intoHBeAg Positive disease( Harbouring Wild type HBV) or HBeAg negative disease (Seen in those with longer infection with precore/ core HBV variant). • Inactive HBsAg carrier state: HBsAg +ive, anti HBc +ive with normal rest of the markers. • Resolved Hepatitis B: a known HBV AVH patient who has cleared HBsAg and has developed Anti HBs Antibodies. • Acute Exacerbation or flare of hepatitis B: intermittent elevation of ALT to 10X ULN or 2X the baseline value. • Reactivation of Hepatitis B: Reappearance of active necroinflammatory disease in a known inactive carrier. • HBeAg seroconversion: appearance of anti HBe Ab with loss of HBeAg. • HBeAg clearance: loss of HBeAg without appearance of HBeAb. • HBeAg reversion: reappearance of HBeAg in a patient who was known to have seroconverted
Inactive Carriers(previously Healthy stable carriers) • Persons who have HBsAg and Anti HBc IgG positive for > 6 months with normal ALT, HBeAg –ive, HBeAb +ive, serum DNA levels <2,000 IU/ml (in up to 67-80% pts) and normal liver histology. • 4-20% carriers may revert back to HBeAg positivity. ~30% of them have raised ALT with high HBV DNA levels. • 10-20% of carriers may reactivate and develop serious sequelae from chronic hepatitis B in their lifetime • Spontaneous HBsAg clearance rate is 0.5% per year. Take home message: • Lok and McMahon. AASLD guidelines on chronic hepatitis B. Hepatology vol. 34, no. 6, 2001
Immune Immune Immune Immune tolerance clearance control escape HBeAg+ve HBeAg–ve > < < > HBV-DNA ALT treat treat HBeAg +ve chronic hepatitis Inactive (carrier) state HBeAg –ve active chronic hepatitis Who should be considered for treatment? monitor monitor
Role of liver biopsy • It is important to note that liver histology improves significantly in patients with sustained response to treatment or spontaneous seroconversion to HBeAb. • Liver histology is most useful in patients who do not meet clear cut guidelines for treatment e.g; if ALT is 1-2 ULN with +ive HBeAG and DNA levels of > 20000 IU/ml • Revised upper limit of ALT should be 30U/l for men and 19U/l for women. • Decision to do liver biopsy should take into consideration the age, new suggested ULN for ALT, HBeAg status, HBV DNA levels and other clinical features suggestive of CLD.
Time to abandon liver biopsy? • Major issues:cost, patient acceptability and anxiety, invasive nature of the procedure, inherent complications, 80% accurate in staging liver fibrosis, must be 25mm long piece to avoid sampling error (only 20% liver biopsies fulfill this criteria). • Alternatives: • Serum biomarkers: 80-85% specific, better at extreme of stages • Fibroscans/Stiffness scans/Elastographs: 95% specific.
Aims of Therapy for Chronic HBV Infection • Short-term goals of treatment dependent on HBeAg status • HBeAg-positive: sustained* ‘e’ seroconversion/HBV DNA suppression/ALT normalisation • HBeAg-negative: sustained* HBV DNA suppression/ALT normalisation • Ultimate goal • HBsAg Seroconversion • Overall goal • prevent/stop/reduce liver damage and progression to cirrhosis and/or HCC • prolong survival “HBV never ‘cured’ but controlled” Though the sharks are circling but the lifeboats are out *treatment response maintained beyond end-of-treatment during a follow-up period of 6 months or more
Anti-HBV therapy and HBV DNA suppression • Balance between viral replication and host immune response • Aim is to reduce viral replication in order to facilitate sustained host-mediated immune control of virus • Antiviral activity alone is not always sufficient to achieve this aim • Particularly in patients with relatively inactive immune responses (e.g.. low or normal ALT levels)
Treatment strategies • Initiate and maintain remission • Sustain suppression • Prevent reactivation • Prevent progression to liver failure/HCC • Timely treatment which is safe and cost effective.
Host and viral risk factors for cirrhosis Old age HBV genotype C. High levels of HBV DNA. Alcohol consumption. Co infection with: HCV HDV or HIV. Smoking. Host and viral risk factors for HCC Male gender. Family H/O HCC. Older age. H/O HBeAg reversion. Presence of cirrhosis. HBV genotype C. Core promotor mutation. Co infection with HCV. Factors associated with progression of HBV related liver disease.
Treatment recommendations for HBeAg-positive patients 1. Lok and McMahon Hepatology 2007 (AASLD Guidelines) 2. EASL Consensus Statement J Hepatol 2003 (EASL Guidelines) 3. Liaw et al Liver International 2005 (Updated APASL Guidelines)
Treatments and molecules approved or licensed or in late-stage development for CHB Approved Lamivudine Approved pre-2005: Interferon-α Adefovir Entecavir PEG-IFNα-(2a) Approved 2005/6: Clevudine(approved in Korea) Telbivudine In development Tenofovir Active against HBV and approved for HIV: Emtricitabine Pradefovir Phase II/III–ongoing:
Pros and cons of each approach? Direct antivirals Interferon-based Subcutaneous Less potent DNA suppression Antiviral and immunomodulatory Frequent side effects No resistance HBsAg seroconversion more common Finite duration of therapy Oral administration Potent HBV DNA suppression No immunomodulatory effects Few side effects Risk of resistance HBsAg seroconversion rare Indefinite Rx – drug fatigue
The primary aim of antiviral therapy with nucleos(t)ide analogues… …is suppression of HBV DNA below the level associated with disease The primary aim of interferon-based therapy… …is to allow host-mediated immune control of the virus
Immunosuppressed Advanced liver disease IFN/PEG-IFN non-responders Immunocompetent Compensated liver disease Younger patients High ALT Low HBV DNA Liver histology Who should be treated with what? Direct antivirals Interferon-based Patient/physician preference Consider risk of drug resistance Length of treatment Side effects
HBe Ag loss or seroconversion. HBsAg loss/seroconversion Constitutes the outcome closest to a ‘cure’ of CHB in clinical practice HBV DNA suppression Usually follows HBeAg seroconversion Relevant in the context of nucleos(t)ide analogues – to prevent resistance development ALT normalisation. Improved histology. What are the most relevant markers of therapeutic success in HBeAg-positive CHB?
On-therapy response to approved NAs at 1 year in HBeAg-positive CHB PLB 23–25 16 4–6 – LAM 49–56 44 16–19 ≤1 ADV 53 21 12 0 ETV 72 67 21 2 LdT 70 60 26¥ – Histology (%) HBV DNA loss* (%) HBeAg seroconversion (%) HBsAg loss (%) EASL consensus statement. J Hepatol 2003 Lok and McMahon. 2004; Dienstag et al. N Engl J Med 1999; Lau et al. N Eng J Med 2005; Marcellin et al. N Engl J Med 2003; Chang et al. N Engl J Med 2006; Lai et al. AASLD 2005 *Hybridisation or bDNA assays for LAM, PCR for ADV and ETV ¥HBeAg loss, not seroconversion
Comparison of treatments at 1 year in antiviral-naïve HBeAg(+) patients* LLOQ Assay LLOQ Assay (copies/mL) (copies/mL) ETV 300 Cobas Amplicor HBV PCR ADV 400 Amplicor HBV DNA PCR LVD 300 Cobas Amplicor HBV PCR Peg IFN 400 Cobas Amplicor HBV PCR 80 80 % HBV DNA Undetectable % HBeAg Seroconversion 67 60 60 Entecavir  40 40 36 Lamivudine  Adefovir  27 25 21 21 Peg IFN  20 18 20 12 0 0 *Collation of currently available data – not from head-to-head studies 1. Chang T-T, et al. NEJM 2006; 354:1000–1010. 2. Marcellin P, et al. NEJM 2003; 348(9):808–816 3. Lau G, et al. NEJM 2005; 352:2682–2695
27 22 18 12 HBeAg seroconversion: Comparison of treatments at 1 year in nucleoside-naïve HBeAg(+) patients* *Collation of currently available data – not from head-to-head studies 40 30 Entecavir HBeAg seroconversion (% patients) Telbivudine 20 21 Lamivudine Adefovir 10 Peg IFN 0 Lai CL, et al. Hepatology 2005; 42:748A (AASLD abstract LB01).Lau G, et al. NEJM 2005; 352:2882–2695. Chang T-T, et al. NEJM 2006; 354:1000–1010.Marcellin P, et al. NEJM 2003;348:808–816.
32 31 30 29 26 HBeAg seroconversion: Comparison of treatments at 2 years in nucleoside-naïve HBeAg(+) patients* *Collation of currently available data – not from head-to-head studies 80 60 Entecavir† HBeAg seroconversion (% patients) Telbivudine 40 Lamivudine† Adefovir 20 Peg IFN** 0 **At 72 weeks (6 months post-treatment follow-up); †Through last observation (on- and 6-months off-treatment) Lau G, et al. NEJM 2005; 352: 2682–2695.Gish R, et al. Hepatology 2005; 42 (Suppl 1) 267A–268A (abstract 181). Marcellin P, et al. J Hepatol 2005; 42:31–32 (Abstract 73).Lai C-L, al. Hepatology 2006; 44 (Suppl. 1): 222A (abstract 91).
Off-therapy HBeAg response with conventional IFN for HBeAg-positive CHB * Intent-to-treat analyses 1. Di Bisceglie et al. Am J Gastroenterol 1993; 2. Fattovich et al. J Hepatol 1989; 3. Yalcin et al. Clin Infect Dis 2003; 4. Thomas et al. J Viral Hepat1994; 5. Cooksley et al. J Viral Hepat 2003; 6. Lok et al. Lancet 1988; 7. Lok et al. Gastroenterology 1992; 8. Yuen et al. Hepatology 2001