Hepatitis C - Recent advances

CHRONIC HEPATITIS C - CURRENT STATUS

Dr. Subhasish DebBurdwan Medical CollegeDept. General Medicine

Dr Subhasish Deb, BMCH

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)


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


Life Cycle


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 C2. Envelope protein E13. Envelope protein E2

• E1 & E2 are hypervariable areas – evade host immunity


Hep C Genome


Epidemiology• 170 million Infected

• Highest in Asia and Africa

• Egypt>15%

• Prevalance more common in the ‘baby bloomer” – birth cohort 1945-1965


Transmission


NOT transmitted by• Breast feeding• Coughing• Sneezing• Fecal matter• Touching• Bathrooms • Contaminated food


Incidence over the years

-The Lancet *incidence in USA

50% unaware of the diagnosis


•In India, the mandatory screening for Hep C for blood donation was started from 2002


Natural History Of DiseaseDr Subhasish Deb, BMCH

Relevant Outcomes


Hep C deaths overtake HIV Deaths from 2006


Treatment Kinetics

Responders Non Responders

Null Responders

Partial Responders

Rapid Virologic Response (RVR)

Early Virologic Response (EVR)

Complete EVR

End Treatment Response (ETR)


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 EVR2. HCV RNA undetectable at 48 weeks – End treatment response

(ETR)


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 and2. Ribavirin

• Duration of t/t – 1. Genotype 1,4,5,6 = 48 weeks2. Genotype 2,3 = 24 weeks


• 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 C1. Anti HCV antibodies (by 3rd generation EIA) AND2. HCV RNA detected my PCR

• Severity by liver biopsy:1. Grade of inflammation 2. Stage of fibrosis


Pre Treatment Evaluation1. Haematological –Hb, platelets, WBC

• Anticipating a fall

2. ANA and Thyroid function – • Interferon exacerbates autoimmune disorders.• m/c risk – thyroiditis

3. Psychiatric evaluation – • 20% may develop depression on t/t• Severe depression C/I interferon

4. HBsAg and HIV co infection – • Regarding time of starting t/t (CD4 >200)

5. Pregnancy – • Interferon C/I


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


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


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/L3. Histologically mild hepatits & minimal fibrosis4. Age < 40yr5. Female6. Non obese7. Non insulin resistant


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)


Boceprevir Regimen


Telaprevir Regimen


Stopping/Futility rules:


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)


• 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)


Thank you


Hepatitis C - Recent advances

Health & Medicine

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