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Hepatitis C - Recent advances
1. CHRONIC HEPATITIS C
- CURRENT STATUS
Dr. Subhasish Deb
Burdwan Medical College
Dept. General Medicine
Dr Subhasish Deb, BMCH
2. Background on Hep C
• Before identification was called “non A non
B hepatitis”
• Linear, single strand, positive sense, RNA
virus
• Genome codes for a virus polyprotein
• Cleaved to 10 viral proteins (proteases)
Dr Subhasish Deb, BMCH
3. Background on Hep C
• 6 genotypes
• Genotype 1:
• m/c in USA
• Lowest response rates
• Longest treatment duration
• Many intragenotypic variations = Quasispicies
• HLA allele linked with self limited disease and better
response to t/t – CC haplotype of IL28B gene
• IL28B present in ch 19 codes for interferon lambda 3, a
component of innate immune antiviral defense
Dr Subhasish Deb, BMCH
5. Hep C Genome
• The 5’ end contains an untranslated region
– Internal Ribosomal Entry Site (IRES)
• Adjacent to IRES are the 3 Structural
genes:
1. Neucleocapsid core protein C
2. Envelope protein E1
3. Envelope protein E2
• E1 & E2 are hypervariable areas – evade
host immunity
Dr Subhasish Deb, BMCH
7. Epidemiology
• 170 million
Infected
• Highest in Asia
and Africa
• Egypt>15%
• Prevalance more common in the ‘baby bloomer” – birth
cohort 1945-1965
Dr Subhasish Deb, BMCH
18. Treatment
• Goal of treatment is to achieve a SVR (Sustained virologic
response)
• SVR – HCV RNA reduction to undetectable levels >= 6
months after completion of therapy
• Standard of care (SOC) – is the use of
1. Peginterferon alpha 2a or 2b and
2. Ribavirin
• Duration of t/t –
1. Genotype 1,4,5,6 = 48 weeks
2. Genotype 2,3 = 24 weeks
Dr Subhasish Deb, BMCH
19. • Chance of inducing SVR with SOC t/t in genotype 1 = 40-
50%
• Since half of these pts with genotype 1 do not achieve
SVR, so alternative treatments continue to be tested.
• Evaluation of virologic status: diagnosis of chronic Hep C
1. Anti HCV antibodies (by 3rd
generation EIA) AND
2. HCV RNA detected my PCR
• Severity by liver biopsy:
1. Grade of inflammation
2. Stage of fibrosis
Dr Subhasish Deb, BMCH
20. Pre Treatment Evaluation
1. Haematological –Hb, platelets, WBC
• Anticipating a fall
1. ANA and Thyroid function –
• Interferon exacerbates autoimmune disorders.
• m/c risk – thyroiditis
1. Psychiatric evaluation –
• 20% may develop depression on t/t
• Severe depression C/I interferon
1. HBsAg and HIV co infection –
• Regarding time of starting t/t (CD4 >200)
1. Pregnancy –
• Interferon C/I
Dr Subhasish Deb, BMCH
22. Interferon alpha
• Pegylated IFNs advantages:
• Longer half life
• Administered once a week rather than 3/week
• Sustained conc rather than peaks and troughs after each injection
• Twice as effective as standard IFN
PEG IFN alpha 2b PEG IFN alpha 2a
12 kD, linear 40kD, branched
DOSE: 1.5 micro gm /kg
(weight based)
180 ug
STORAGE: room temp refrigerated
Dr Subhasish Deb, BMCH
23. Contraindications of IFN
• Hypersensitivity
• Autoimmune hepatitis
• Decompensated liver disease (Child-Pugh >6 [class B
and C])
• Pregnant women
• Hemoglobinopathies (e.g., thalassemia major, sickle-cell
anemia)
• Creatinine clearance less than 50 mL/min
Dr Subhasish Deb, BMCH
24. Treatment: PEG IFN + Ribavirin
• Associated with t/t response
1. Favorable genotype 2,3 (opposed to 1,4)
2. Baseline HCV RNA level < 800,000 IU/L
3. Histologically mild hepatits & minimal fibrosis
4. Age < 40yr
5. Female
6. Non obese
7. Non insulin resistant
Dr Subhasish Deb, BMCH
25. Directly Acting Agents (DAA)
• 1st
generation protease inhibitors (2011-2013)
• Telaprevir and Boceprevir
• Serine protease inhibitors that target NS3-4A
• Approved for genotype 1
• Its use not been studied in other genotypes
• As resistance develops rapidly, it is used along
with PEG IFN + Ribavirin combination
• Regimens consists of periods of triple therapy
and periods of dual therapy (IFN + ribavirin)
Dr Subhasish Deb, BMCH
31. Sofosbuvir
• a nucleotide analog used in combination with
other drugs for the treatment of Hep C
• Sofosbuvir based regimens provide a higher cure
rate, fewer side effects, and a two- to four-fold
reduced duration of therapy
• allows most patients to be treated successfully
without the use of peginterferon,an injectable
drug with severe side effects
• MOA: inhibits the RNA polymerase that the
hepatitis C virus uses to replicate its RNA (NS5B)
Dr Subhasish Deb, BMCH
33. • Cost of treatment :
• $84,000 = Rs. 50.4 lacks for 24 weeks
• In September 2014, Gilead announced that it
would permit generic manufacturers to sell
sofosbuvir in 91 developing countries
• New price would be:
• About $1,800 = Rs. 1.1lacks (less than an
IVIG course for GB)
Dr Subhasish Deb, BMCH
Positive sense strand = 5’-3’. Same as mRNA so can be directly translated. Negative sense = 3’-5’. It has the complementary strand. Has to be transcribed to positive sense by rna dependant rna polymerase and then translated.