Hepatitis C genotypes, epidemiology, treatment with 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

4. Life Cycle
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

6. Hep C Genome
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

8. Transmission
Dr Subhasish Deb, BMCH

9. NOT transmitted by
• Breast feeding
• Coughing
• Sneezing
• Fecal matter
• Touching
• Bathrooms
• Contaminated food
Dr Subhasish Deb, BMCH

10. Incidence over the years
-The Lancet
*incidence in USA
50% unaware of the diagnosis
Dr Subhasish Deb, BMCH

11. •In India, the mandatory screening for
Hep C for blood donation was
started from 2002
Dr Subhasish Deb, BMCH

12. Natural History Of Disease
Dr Subhasish Deb, BMCH

13. Relevant Outcomes
Dr Subhasish Deb, BMCH

14. Hep C deaths overtake HIV Deaths
from 2006
Dr Subhasish Deb, BMCH

15. Treatment Kinetics
Responders Non Responders
Null Responders
Partial Responders
Rapid Virologic Response (RVR)
Early Virologic Response (EVR)
Complete EVR
End Treatment Response (ETR)
Dr Subhasish Deb, BMCH

16. Treatment Kinetics
• Null responders: HCV RNA reduction < 2log IU/mL
• Partial Responders: HCV RNA reduction > 2log
IU/mL but not suppressed to undetectable by week
24
• Rapid virologic response (RVR): HCV RNA
undetectable within 4 weeks
• Early virologic response (EVR): HCV RNA reduction
> 2log IU/mL with:
1. HCV RNA undetectable at 12 weeks – complete EVR
2. HCV RNA undetectable at 48 weeks – End treatment response
(ETR)
Dr Subhasish Deb, BMCH

17. 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

21. 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

26. Boceprevir Regimen
Dr Subhasish Deb, BMCH

27. Dr Subhasish Deb, BMCH

28. Telaprevir Regimen
Dr Subhasish Deb, BMCH

29. Stopping/Futility rules:
Dr Subhasish Deb, BMCH

30. 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

32. 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

34. Dr Subhasish Deb, BMCH

35. Dr Subhasish Deb, BMCH

36. Thank you
Dr Subhasish Deb, BMCH