HCV CASE REPORTS

Goals of Therapy

• To eradicate the virus

• To control infectivity
• To prevent the development of cirrhosis and
HCC
 THE OPTIMAL DRUGS

• They should be orally administered

• They should have an excellent safety profile

• The duration of therapy should be limited

 Baseline diagnostics before
treatment

• HCV RNA (PCR) and genotype

• Serum ALT level
• Liver biopsy or fibroscen
 ENDPOINTS FOR TREATMENT

• Levels of HCVRNA in the serum at the end of

therapy (ETR) and 6 months after the therapy is
finished (SVR)
• Serum ALT levels
• Improvements in liver histology
 SVR – Holy Grail

SVR – Sustained virologic response

• Undetectable viral load measured at 24 weeks

after completing therapy
• Patients achieving SVR are considered „Cured‟
 ANTIVIRAL THERAPY

DUAL therapy:
PEGIFN alpha 2a or alpha 2b +RBV
NOT RECOMANDED !

TRIPLE therapy based on IFN:

PEGIFN alpha 2a or alpha 2b +RBV+SIM orSOF
NOT RECOMANDED !

IFN-FREE REGIMES (DAAs)

standard of care!
 THE RATIONALE FOR COMBINATION
THERAPY

• Increase the virus-suppressive activity

• Induce host immunity

• Prevent the emergence of resistant mutants

 HCV DAAs approved in Europe in 2018
Product Presentation Posology
Sofosbuvir Tablets containing 400mg of One tablet once daily
sofosbuvir
Sofosbuvir/velpatasvir Tablets containing 400mg of One tablet once daily
sofosbuvir
and 100mg of velpatasvir
Sofosbuvir/velpatasvir/voxilaprevir Tablets containing 400mg of One tablet once daily with food
sofosbuvir, 100mg of velpatasvir
and 100mg of voxilaprevir

Glecaprevir/pibrentasvir Tablets containing 100mg of Three tablets once daily with food
Glecaprevir and 40mg of
pibrentasvir

Sofosbuvir/ledipasvir Tablets containing 400mg of One tablet once daily

sofosbuvir and 90mg of ledipasvir

Paritaprevir/ombitasvir/ritonavir Tablets containing 75mg of Two tablets once daily

paritaprevir, 12,5mg of ombitasvir
and 50mg of ritonavir
Dasabuvir Tablets containing 250mg of One tablet twice daily (morning and
dasabuvir evening)
Grazoprevir/elbasvir Tablets containing 100mg of One tablet once daily
grazoprevir and 50mg of elbasvir
 Side Effects of IFN Treatment

• Flu-like symptoms • Alopecia

– Headache • Injection-site reaction
– Fatigue or asthenia
• Leukopenia
– Myalgia, arthralgia
– Fever, chills • Thyroiditis
• Nausea • Autoimmunity
• Anorexia • Thrombocytopenia
• Diarrhoea
• Psychiatric symptoms
– Depression
– Insomnia
Side Effects of RBV Treatment

• Hemolytic anaemia
• Teratogenicity
• Cough and dyspnea
• Rash and pruritus
• Insomnia
• Anorexia
Predictability of Response
What Do We Want to Predict?

• Response:
– On treatment
– End-of-treatment
– End-of-follow-up
• Nonresponse:
– Early termination of treatment
– Patient selection for future studies
– Evaluate other treatment options
– Potential cost savings
Tretment decision-predictors of
response (IFN regimens)

Host Treatman Virus

• Cirrhosis • Virologic response profile • Genotyp
• Age • Treatment duration • Viremia
• Gender • Adherence
• Weight (BMI) . Side effects
• HIV co-infection
• Steatosis, Insulin-
resistence
• Genetic factors
(polymorphism of
cytocines- IL28B)
 Definitions of virological response at week 4
and week 12
0
HCV RNA decrease (IU/mL)

EOTR SVR
Undetectable
HCV RNA
(<50 IU/mL)

0 4 12 24 48 72
Weeks of therapy
cEVR = complete early virological response; EOTR = end of treatment response; eRVR = extended rapid virological response;
pEVR = partial early virological response; RVR = rapid virological response; SVR = sustained virological response.
 Definitions of virological response at week 4
and week 12
0 RVR = undetectable HCV RNA at week 4
HCV RNA decrease (IU/mL)

EOTR SVR
Undetectable
HCV RNA
(<50 IU/mL)

0 4 12 24 48 72
Weeks of therapy
cEVR = complete early virological response; EOTR = end of treatment response; eRVR = extended rapid virological response;
pEVR = partial early virological response; RVR = rapid virological response; SVR = sustained virological response.
 Definitions of virological response at week 4
and week 12
0 RVR = undetectable HCV RNA at week 4
HCV RNA decrease (IU/mL)

cEVR = no RVR but undetectable HCV RNA

at week 12

EOTR SVR
Undetectable
HCV RNA
(<50 IU/mL)

0 4 12 24 48 72
Weeks of therapy
cEVR = complete early virological response; EOTR = end of treatment response; eRVR = extended rapid virological response;
pEVR = partial early virological response; RVR = rapid virological response; SVR = sustained virological response.
 Definitions of virological response at week 4
and week 12
0 RVR = undetectable HCV RNA at week 4
HCV RNA decrease (IU/mL)

cEVR = no RVR but undetectable HCV RNA

at week 12
pEVR = no RVR and detectable HCV RNA,
but >2 log10 drop at week 12

>2 log10

EOTR SVR
Undetectable
HCV RNA
(<50 IU/mL)

0 4 12 24 48 72
Weeks of therapy
cEVR = complete early virological response; EOTR = end of treatment response; eRVR = extended rapid virological response;
pEVR = partial early virological response; RVR = rapid virological response; SVR = sustained virological response.
 Definitions of virological response at week 4
and week 12
0 RVR = undetectable HCV RNA at week 4
HCV RNA decrease (IU/mL)

eRVR = undetectable HCV RNA at week 4–24

cEVR = no RVR but undetectable HCV RNA
at week 12
pEVR = no RVR and detectable HCV RNA,
but >2 log10 drop at week 12

>2 log10

EOTR SVR
Undetectable
HCV RNA
(<50 IU/mL)

0 4 12 24 48 72
Weeks of therapy
cEVR = complete early virological response; EOTR = end of treatment response; eRVR = extended rapid virological response;
pEVR = partial early virological response; RVR = rapid virological response; SVR = sustained virological response.
 Patterns of Virological Response
Baseline Treatment

Nonresponder
HCV RNA

Breakthrough
Partial
responder
Relapser

Detection limit Sustained

HCV RNA responder
(“cure”)
Undetectable
6 months
Time
 Time to response drives probability of
achieving an SVR in genotype 1
Peginterferon alfa-2a (40KD) 180 μg/wk plus RBV 1000/1200 mg/day
for 48 weeks

No EVR RVR
20% 16%
(111/569) (90/569)

pEVR
22%
cEVR
(128/569)
42%
(240/569)

RBV = ribavirin
 Time to response drives probability of
achieving an SVR in genotype 1
Peginterferon alfa-2a (40KD) 180 μg/wk plus RBV 1000/1200 mg/day
for 48 weeks

SVR: 87%
RVR (78/90)
No EVR 16%
20% (90/569)
(111/569)

pEVR
22%
cEVR
(128/569)
42%
(240/569)

RBV = ribavirin
 Time to response drives probability of
achieving an SVR in genotype 1
Peginterferon alfa-2a (40KD) 180 μg/wk plus RBV 1000/1200 mg/day
for 48 weeks

SVR: 87%
RVR (78/90)
No EVR 16%
20% (90/569)
(111/569)

pEVR
22%
(128/569) cEVR
42%
(240/569)
SVR: 68%
(162/240)

RBV = ribavirin
 Time to response drives probability of
achieving an SVR in genotype 1
Peginterferon alfa-2a (40KD) 180 μg/wk plus RBV 1000/1200 mg/day
for 48 weeks

SVR: 87%
RVR (78/90)
No EVR 16%
20% (90/569)
(111/569)

pEVR
22%
(128/569) cEVR
42%
SVR: 27% (240/569)
(34/128)
SVR: 68%
(162/240)

RBV = ribavirin
 Time to response drives probability of
achieving an SVR in genotype 1
Peginterferon alfa-2a (40KD) 180 μg/wk plus RBV 1000/1200 mg/day
for 48 weeks

SVR: 87%
SVR: 5% No EVR RVR (78/90)
(5/111) 16%
20%
(90/569)
(111/569)

pEVR
22%
(128/569) cEVR
42%
SVR: 27% (240/569)
(34/128)
SVR: 68%
(162/240)

RBV = ribavirin
Potential treatment options for different patient
populations
TRIPLE THERAPY

GT1 naive GT1 previous

IL28B non-CC non-responders
 Potential treatment options for different patient
populations
TRIPLE THERAPY

GT1 naive GT1 previous

IL28B non-CC non-responders

GT2, GT3, GT4* and

GT1 with IL28B CC genotype
and/or RVR

DUAL THERAPY
* until DAAs active against GT2, GT3 and GT4 are licensed
 Disease state

Progression to Liver Fibrosis in HCV Infection

Progression to cirrhosis may occur more rapidly than previously estimated

Data from >3500

individuals

After 10 years of follow-up,

HCV+ persons were more
likely to have a diagnosis of
cirrhosis compared with
113 339 HCV− controls
1840 1840

Controls had 2 negative HCV antibody test results (no infection) in a comparable time frame and
were matched 1:1 on age (in 5-year blocks), race, and sex. Persons with HIV, HBV, less than 24 months of
follow-up, HCC and cirrhosis at baseline were excluded. HCV-infected persons had an initial negative and
subsequent positive test result for HCV antibody and positive HCV RNA test results. Butt AA, et al. JAMA 2015; 175:178–185.

28
 Case 1: “An easy job”
(Treatment of chronic hepatitis C without fibrosis)
 Case

• Male, 49 yr
• HCV inf. diagnosed 2005
• HCV RNA(PCR) - 638.446 kop/ml
• HCV Genotip 1b
• Liver biopsy 2006:no fibrosis
• Past history: 2000 god.hypertension (ACE
inhibitors), 2004 Menier disase,
• Naive patient
 Soc./Family history

• Employed, buisnes owner

• Married, two healthy children
• Potential risk: short-term used of PAS
when he was young
• No other risks
• Family history: no significant data
 Lab. results before antiviral treatment
June 2006

• Platelets 254.000 mm3

• Hemoglobin 148 g/l
• Leukocytes 6300mm3
• AST 53 U/L, ALT 78U/L
• Bil. 15 micromol/l
• US of abdomen: mild hepatomegaly(ap.
diametar of right lobe 13,8cm)
• ANA 1:10
• TSH - 0,89 (0,3-5,5)
 Treatment decision 1
June 2006

• Dual antiviral therapy in full doses

(PEGIFN alfa-2a+ Ribavirin)
• Self-finansed patient
• Generaly good adherence and tolerance
• After treatment week 4 granulocytes decreased, and
PEGIFN dose reduced on 135mcg
• After treatment week 12 HCVRNA(PCR) negative
 End of treatment
May 2007

• No complaints
• Good general condition
• No side effects on Hgb and Plt
• Absolute number of granulocytes 1,0
• ALT 34 U/L AST 33
• HCV RNA(PCR) 37.530 k/ml
 Follow-up
November 2007

• HCV RNA(PCR) 1.906.199 k/ml

• ALT 64 U/l (<40U/L)
• No complaints
• Good general condition
• Very motivated for further treatment!
 2008

• Regular 3-months check-ups

• Alfa feto protein in normal range
• US: hepatomeagly, no focal lesions
• ALT fluctuated up to 70 U/L
• No complaints
• Good general condition
 January 2009

• HCV RNA(PCR) 13.581.000 k/ml!

• ALT 126 U/L
 Treatment decision 2
March 2009

Re-treatment with dual antiviral therapy

 Pretreatment assessment

• TGAT > 3500 (<1:100)!

• T3 3,1 nmol/L(1,2-2,8)
• TSH 1,0 mU/L (0,3-5,5)
• Endocrinologist: Hashimoto thyreoiditis,
Hypothireosis prim. adultum
• No complaints
• Good general condition
 Discussion Questions

• Start antiviral treatment with agreement

and monitoring by endocrinologist ?

• Stopped PEG IFN?

• Wait for a new treatment option?

• “Don,t touch the patient”?

 Case 2:
Antiviral Treatment in Patient with Anemia
 Clinical Case

• Female, 35 years old

• Diagnosed HCV infection 2004
• HCV RNA(PCR) > 1.000.000 copies/ml
• HCV Genotype 1b
• Liver biopsy: mild/moderate fibrosis
• Known anemia but not diagnosed or
treated by hematologist
• Naive
 Social/Family history

• Unemployed
• Married, one healthy child
• Transfused 1999 after appendectomy
• No other risks
• No history of hepatitis or anemia in the
family
 Main lab. Results
July 2005

• Platelets count 204.000 mm3

• Baseline Haemoglobin 102 g/l
• White blood count 7580mm3
• AST 55 U/L, ALT 37U/L
• Bil. 32 micromol/l
• Ultrasound: mild splenomegaly
• ANA 1:160
 Initial management decision
July 2005
• To avoid severe anemia monotherapy with
Pegasys had been started

• Three weeks later first hemolytic crisis- Hgb

66g/l ret. 17%, Coombs+,

• Hematologist sugested to discontinue

Pegasys and start corticosteroid in dosage of
1mg/kgbw with gradually reducing dose
during one month
 Management 2
November 2005

After corticosteroid treatment baseline

Hgb 101g/l
Pegasys started again
Two months later new hemolytic crisis-
Hgb 58g/l, ret. 18% bil. 42 mmol/l
ANA 1:640
No side effects on white blood counts and
platelets
Good general condition
 Management 3
January 2006

• Pegasys therapy stoped again (only 2

months therapy)

• Hematologist recommended therapy with

low dose corticosteroid (10 mg daily) +
Pegasys
 Discussion Questions

• Should PEG IFN be continued ?

• Low dose corticosteroid with PEG IFN?

• Stop with PEG IFN?

• What should we do now?

Case 3: “An easy decision”
(Treatment of chronic hepatitis C with normal ALT)
 Case

• 35 year old woman

• Found to be HCV RNA positive whilst trying
to donate blood
• S/B GP
• Normal LFTs - no action taken
 Case

• Patient asks to see a specialist

• She wishes to conceive and is worried about

transmission

• She asks about IVF and sperm washing

 Case

Past medical history

- Ex IVDU
- Previously admitted to a mental hospital
following an acute psychosis after taking
coccaine
 Case

Investigations

• HCV RNA +ve – genotype 1

• LFTs – Normal
• Fibroscen – Normal
An easy decision ?

Would you treat her ?

 HCV and ALT

• Up to 46% of patients with CHC have ALT levels

within the currently defined „normal‟ range
• These patients were historically considered „healthy‟
or „asymptomatic‟
• However, >80% have some degree of liver damage
on biopsy and 19% have stage F2–F3 fibrosis
• Quality of life is significantly impaired in patients with
CHC (and elevated or persistently „normal‟ ALT)
compared with healthy controls
 Determination of ALT Levels

• A single ALT value may not be representative of the

true ALT status of a patient
• Current guidelines recommend that ALT status be
defined by 3 measurements over a 6-month period
• However, recent studies suggest that this time period
may not be adequate
• Patients with ALT levels within the „normal‟ range
may show further reduction in serum ALT levels
following treatment
 ALT Levels in
Chronic Hepatitis C
• Absolute measure of ALT does not always correlate
with degree or severity of liver disease
• Although elevated ALT levels are generally
associated with hepatocellular damage, lower levels
are not always associated with mild liver disease
• ALT levels fall as cirrhosis develops
• Many factors, independent of liver damage, can
affect ALT levels
• ALT levels may fluctuate throughout the course of
CHC
 Treatment and ALT:
Conclusion

The treatment of patients with CHC

should rely on the probability of viral
eradication, symptoms, histology,
anticipated progression of disease,
and/or the risk of transmission rather
than on a single biochemical
parameter such as ALT