This presentation describes the updated protocols for management of HCV G4 infection highlighting the most recent Egyptian Consensus

1. Revision of Treatment Protocols for HCV
Genotype 4 Infection 2016
By
DR MONKEZ M YOUSIF
Professor of Internal Medicine
Zagazig University , Egypt
2016

2. Sources
1. Recommendations for Testing, Managing, and
Treating Hepatitis C AASLD 2015. Updated 24 Feb
2016.
2. EASL Recommendations for management of HCV
2015.
3. National Committee for Control of HCV. Updated
November 2015

3. CDC Recommended Testing Sequence for
Identifying Current HCV Infection
• For persons who
might have been
exposed to HCV
within the past 6
months, testing for
HCV RNA or follow-up
testing for HCV
antibody should be
performed.
• For persons who are
immunocom , testing
for HCV RNA should
be performed.
† To differentiate past, resolved
HCV infection from biologic false
positivity for HCV antibody, testing
with another HCV antibody assay
can be considered. Repeat HCV
RNA testing if the person tested is
suspected to have had HCV
exposure within the past 6 months
or has clinical evidence of HCV
disease, or if there is concern
regarding the handling or storage of
the test specimen.

4. • Persons with current (active) HCV infection
should receive education and interventions
aimed at:
−Reducing progression of liver disease
−And preventing transmission of HCV.

5. 1. Abstinence from alcohol.
2. Evaluation for other conditions that may
accelerate liver fibrosis,
‒ Co HBV and HIV infections
3. Evaluation for advanced fibrosis
‒ Using liver biopsy, imaging, or noninvasive markers:
• Help treatment strategy and
• To determine the need for initiating additional
measures for the management of cirrhosis (HCC
screening).

6. 4. Vaccination against HAV and HBV
5.Vaccination against pneumococcal
infection : Recommended to all
patients with cirrhosis.
6. Education on how to avoid HCV
transmission to others.

7. WHEN AND IN WHOM TO INITIATE
HCV THERAPY

8. Goal of treatment
• The goal of treatment of HCV-infected persons
is to reduce all-cause mortality and liver-
related health adverse consequences,
including end-stage liver disease and
hepatocellular carcinoma, by the achievement
of virologic cure as evidenced by an SVR.

9. Recommendations for when and in
whom to initiate treatment
• Treatment is recommended for all patients
with chronic HCV infection, except those with
short life expectancies owing to comorbid
conditions.

10. Recommendations for
pretreatment assessment

11. An assessment of the degree of hepatic fibrosis
• Liver Biopsy
• Non-invasive testing including
–Indirect serum biomarkers (routine tests)
–Direct serum markers
• Vibration transient liver elastography:

12. APRI cutoff of ≥0.7 had an estimated sensitivity of 77% and specificity of 72% for
detection of significant hepatic fibrosis (≥F2 by METAVIR).
A cutoff score of at least 1.0 has an estimated sensitivity of 61% to 76% and
specificity of 64% to 72% for detection of severe fibrosis/cirrhosis (F3 to F4 )
A cutoff score of at least 2.0 was more specific (91%) but less sensitive (46%) for
Cirrhosis.
Aspartate Aminotransferase-to-Platelet-Ratio Index (APRI)

13. FIB-4

14. FIBROSCAN
Source: Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient
elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in
chronic hepatitis C. Gastroenterology. 2005;128:343-50.

15. MONITORING PATIENTS WHO ARE STARTING
HEPATITIS C TREATMENT, ARE ON
TREATMENT, OR HAVE COMPLETED
THERAPY

16. Recommended assessments prior to starting
antiviral therapy
• Assessment of potential drug-drug interactions with
concomitant medications is recommended prior to starting antiviral
therapy.
• The following laboratory tests are recommended within 12
weeks prior to starting antiviral therapy:
– CBC ; INR
– LFTs(albumin, total and direct bilirubin, ALT, AST, and ALKP)
– TSH if IFN is used
– Calculated glomerular filtration rate (eGFR)
• The following laboratory testing is recommended at any
time prior to starting antiviral therapy:
– HCV genotype and subtype
– Quantitative HCV viral load

17. • Patients scheduled to receive an protease inhibitor
should be assessed for a history of decompensated liver
disease and for severity of liver disease using CTP score.
– Patients with current or prior history of
decompensated liver disease or with a current CTP
score of 7 or greater should NOT receive treatment
with regimens that contain NS3 protease inhibitors
due to increased exposures and/or lack of safety data.
• Similarly, patients with a CTP score of 5 or 6, who cannot
be closely monitored for laboratory or clinical symptoms
during treatment, should not receive treatment with a
regimen that contains paritaprevir/ ritonavir.

18. Recommended monitoring during antiviral therapy
• Clinic visits or telephone contact are recommended as
clinically indicated during potential drug-drug
interactions with newly prescribed medications.
• CBC, creatinine level, eGFR, and LFTs are
recommended after 4 weeks of treatment and as
clinically indicated. More frequent assessment for drug
related toxic effects (eg, CBC for patients receiving RBV)
is recommended as clinically indicated.

19. Prompt discontinuation of therapy is
recommended for any
1. 10-fold increase ALT activity at week 4; or
2. Any increase in ALT of less than 10-fold at week 4
that is accompanied by
• any weakness, nausea, vomiting, or jaundice, or
• accompanied by increased Bilirubin, ALKP, or INR
ratio. .
3. Asymptomatic increases in ALT of less than 10-fold
elevated at week 4 should be closely monitored and
repeated at week 6 and week 8

20. • Quantitative HCV viral load testing is recommended
1. After 4 weeks of therapy and
2. At 12 weeks following completion of therapy.
• Antiviral drug therapy should NOT be interrupted
or discontinued if HCV RNA levels are not
performed or available during treatment.
• Quantitative HCV viral load testing can be considered
1. At the end of treatment and
2. 24 weeks or longer following the completion of
therapy.

21. • Patients with compensated cirrhosis who are
receiving paritaprevir/ritonavir-based regimens
– should be assessed for clinical signs of
decompensated liver disease (eg, ascites,
encephalopathy) and for biochemical evidence of
liver injury with a hepatic function panel at week 2
and week 4 of treatment, and as needed during the
remainder of treatment.
• Paritaprevir/ritonavir-based regimens should be
discontinued
– If patients develop ascites or encephalopathy or
– Significant increase in direct bilirubin or ALT or AST.

22. Recommendations for discontinuation of
treatment because of lack of efficacy
• If quantitative HCV viral load is detectable at week 4 of
treatment,
– repeat quantitative HCV RNA viral load testing is
recommended after 2 additional weeks of treatment
(treatment week 6).
– If quantitative HCV viral load has increased by greater than
10-fold (>1 log10 IU/mL) on repeat testing at week 6 (or
thereafter), then discontinuation of HCV treatment is
recommended.
• The significance of a positive HCV RNA test result at week 4
that remains positive, but lower, at week 6 or week 8 is
unknown.
– No recommendation to stop therapy or extend therapy can be
provided at this time.

23. Recommended monitoring for patients in whom
treatment failed to achieve a SVR
• Disease progression assessment every 6 months to 12
months with a hepatic function panel, complete blood
count (CBC), and INR is recommended.
• Surveillance for hepatocellular carcinoma with
ultrasound testing every 6 months is recommended for
patients with advanced fibrosis .
• Endoscopic surveillance for esophageal varices is
recommended if present.
• Evaluation for retreatment is recommended as
effective alternative treatments become available.

24. Recommended follow-up for patients who achieve SVR
• For patients who do not have advanced fibrosis (ie,
those with Metavir stage F0-F2), recommended follow-
up is the same as if they were never infected with HCV.
• Assessment for HCV recurrence or reinfection is
recommended only if the patient has ongoing risk for
HCV infection or otherwise unexplained hepatic
dysfunction develops.
– In such cases, a quantitative HCV RNA assay rather than an
anti-HCV serology test is recommended to test for HCV
recurrence or reinfection.

25. • Surveillance for hepatocellular carcinoma with twice-
yearly ultrasound testing is recommended for patients
with advanced fibrosis (ie, Metavir stage F3 or F4) who
achieve an SVR.
• A baseline endoscopy is recommended to screen for
varices if cirrhosis is present. Patients in whom varices
are found should be treated and followed up as
indicated.
• Assessment of other causes of liver disease is
recommended for patients who develop persistently
abnormal liver tests after achieving an SVR.

26. INITIAL TREATMENT OF HCV G4
INFECTION

27. AASLD/IDSA Guidelines Updated
24 Feb 2016

28. A summary of recommendations for initial treatment
• Recommended regimens favored for most based on
– optimal efficacy,
– favorable tolerability and toxicity profiles and duration.
• Alternative regimens effective but have
– potential disadvantages,
– limitations for use in certain patient populations, or
– less supporting data than Recommended regimens.
• Not Recommended regimens inferior compared to
Recommended or Alternative regimens due to factors such as
– lower efficacy,
– unfavorable tolerability and toxicity,
– duration, and/or higher pill burden. longer

29. DurationRegimen
12 wk with RBV
Ritonavir-boosted Paritaprevir/ Omb
(Curevo)
12 wk
Elbasvir/Grasoprevir
(Zepatier)
12 wk
Sofosbuvir/Ledipasvir
(Harvoni)
Genotype 4 Treatment-naïve without Cirrhosis
Recommended

30. DurationRegimen
12 wk with RBV
Ritonavir-boosted Paritaprevir/ Omb
(Curevo)
12 wk
Elbasvir/Grasoprevir
(Zepatier)
12 wk
Sofosbuvir/Ledipasvir
(Harvoni)
Genotype 4 Treatment-naïve with
Compensated Cirrhosis: Recommended

31. DurationRegimen
12 wk
SOF/RBV/Peg INF*
Genotype 4 Treatment-naïve ± Cirrhosis:
Alternative
* For INF-eligible patients

32. AASLD/IDSA Guidance for Pts With
Decompensated Cirrhosis
• Refer to experienced HCV practitioner (ideally liver transplant
center)
• Avoid IFN, TVR, BOC, SMV, OMV/PTV/RTV + DSV,
Elbasvir/Grazoprevir or monotherapy with RBV or DAA
*Initial dose of 600 mg/day, increased as tolerated.
Population
RBV Eligible RBV Ineligible
DCV** + SOF LDV/SOF DCV** + SOF LDV/SOF
GT1/4
12 wks +
low-dose RBV*
12 wks +
low-dose RBV*
24 wks 24 wks
GT1/4, SOF
failure
Not
recommended
24 wks +
low-dose RBV*
Not
recommended
Not
recommended
**The dose of daclatasvir may need to increase or decrease when used concomitantly
with cytochrome P450 3A/4 inducers and inhibitors, respectively.

33. RETREATMENT OF PERSONS WITH
HCV G4 IN WHOM PRIOR THERAPY
HAS FAILED

34. DurationRegimen
12 wk with RBV
Ritonavir-boosted
Paritaprevir/ Omb
(Curevo)
12 w for relapsers
16 w + RBV for non-responders
during previous treatment and
breakthrough cases
Elbasvir/Grasoprevir
(Zepatier)
12 wk
Sofosbuvir/Ledipasvir
(Harvoni)
Genotype 4 PEG-IFN/RBV Treatment-experienced
Patients without Cirrhosis -Recommended

35. DurationRegimen
12 wk with RBV
Ritonavir-boosted
Paritaprevir/ Omb
(Curevo)
12 w for relapsers
16 w + RBV for non-responders
during previous treatment and
breakthrough cases
Elbasvir/Grasoprevir
(Zepatier)
12 wk with RBV
24 for RBV ineligible
Sofosbuvir/Ledipasvir
(Harvoni)
G4 PEG-IFN/RBV Treatment-experienced with
Compensated Cirrhosis -Recommended

36. DurationRegimen
12 wkSOF / RBV / PegINF*
24 wkSOF / RBV * *
G4 PEG-IFN/RBV Treatment-experienced
without Cirrhosis -Alternative
* For INF-eligible patients
* * For INF-ineligible patients

37. Genotype 1 Sofosbuvir plus Ribavirin with or
without PEG-IFN Treatment-experienced
Patients - Recommended
• No Cirrhosis:
–SOF/LDV/RBV for 12 wk
• Compensated Cirrhosis:
–SOF/LDV/RBV for 24 wk

38. Genotype 1 SOF/SIM or SOF/NS5A inhibitor
Treatment-experienced Patients - Recommended
• No Cirrhosis and non-urgent cases:
– Deferral of treatment is recommended, pending
availability of data.
• Compensated cirrhosis and urgent cases:
– Testing for resistance-associated variants that
confer decreased susceptibility to NS3 protease
inhibitors and to NS5A inhibitors .
– The specific drugs used in the retreatment regimen
should be tailored to the results of this testing

39. • When using nucleotide-based (eg, sofosbuvir)
dual DAA therapy a treatment duration of 24
weeks is recommended, and weight-based RBV,
unless contraindicated, should be added.
• If available, nucleotide-based (eg, sofosbuvir)
triple or quadruple DAA regimens may be
considered. In these settings treatment
duration ranges from 12 weeks to 24 weeks and
weight-based ribavirin, unless contraindicated,
are recommended.

40. EASL HCV 2015 Guidelines

41. DurationRegimen
12 WkP-INF/ RBV/ SOF
NoSOF/ RBV
12 wkSOF/ LED
NoRitonavir-boosted Parita/ Ombi/ Dasabuvir
12 wk with RBVRitonavir-boosted Parita/ Omb
12 wkSOF/SIM
12 wkSOF/ DCL
Patients with chronic hepatitis C G4
without cirrhosis, treatment-naïve and with
prior failure to PegIFN/RBV

42. DurationRegimen
12 WkP-INF/ RBV/ SOF
NoSOF/ RBV
12 wk with RBV or 24 wk without RBV or 24
wk with RBV if –ve predictors of response
SOF/ LED
NoRitonavir-boosted Parita/
Ombi/ Dasabuvir
24 wk with RBVRitonavir-boosted Parita/ Omb
12 wk with RBV and 24 wk without RBVSOF/SIM
12 wk with RBV and 24 wk without RBVSOF/ DCL
Patients with chronic hepatitis C G4
with Compensated cirrhosis, treatment-naïve and with
prior failure to PegIFN/RBV

43. DurationRegimen
12 wk with RBV or
24 wk with RBV if F3 or cirrhosis
SOF/ LED
Ritonavir-boosted
Parita/ Omb
SOF/SIM
SOF/ DCL
Retreatment of patients with CHC G 1,4 with
prior failure to SOF/RBV or SOF/PegINF/RBV

44. Retreatment patients with CHC G 1,4
with prior failure to SIM/SOF
DurationRegimen
12 wk with RBV or
24 wk with RBV if F3 or cirrhosis
SOF/ LED
SOF/ DCL

45. Retreatment patients with CHC G 1,4
with prior failure to SOF/DAC or SOF/LDV
DurationRegimen
12 wk with RBV or
24 wk with RBV if F3 or cirrhosis
SIM/SOF

46. Retreatment of patients with CHC G4
with prior failure to antiviral therapy containing
Ritonavir-boosted paritaprevir and ombitasvir
DurationRegimen
12 wk with RBV or
24 wk with RBV if F3 or
cirrhosis
SOF/LDV
SOF/SIM
SOF/DAC

47. • SOF/RBV1,4
• SOF/LDV±RBV for 12 or 24 wks preferred1,4,5,6
1
1,4
• SOF/Daclatasvir ±RBV for 12 or 24 wksAll
4
All
1,4
INTERFERON-Free RegimenGenotype
EASL 2015 Recommendations for Treatment of
CHC with Decompensated cirrhosis

48. NCCVH Hepatitis C Treatment Protocol
Update November 2015

49. Medications available in Al-Ahrar VHTC
• Sofosbuvir
• Sovaldi
• Mpiviropack
• Daclatasvir
• Clatasive
• Daclavirocyrl
• Pvaritaprevir/ritonavir/Ombitasir
• Curevo
• Sofosbuvir/Ledipasvir
• Harvoni
• Ribavirin

50. NCCVH Hep C Treatment Protocol
Update November 2015
Inclusion Criteria:
1. HCV RNA Positivity
2. Age: 18-75
Exclusion Criteria: any of the following:
1. T.Bil > 3 mg
2. Serum Albumin < 2.8 gm/dl
3. INR > 1.7
4. Platelet count < 50.000/mm3
5. If any of the criteria from 1-4 is not caused by liver disease, the patient can be
included in treatment protocol.
6. HCC, except 4 weeks after intervention aiming at cure with no evidence of
activity by dynamic imaging (CT or MRI).
7. Extra hepatic malignancy except after 2 years of disease free interval. In case of
lymphomas and CLL, treatment can be initiated immediately after remission
based on the treating oncologist report.
8. Pregnancy or inability to use effective contraception.
9. Inadequately controlled DM (HbA1c > 9%)

51. Patients will be categorized to:
Easy to treat group:
1. Treatment naïve
2. T.Bil ≤ 1.2 mg/dl
3. Serum albumin ≥ 3.5 gm/dl
4. INR ≤ 1.2
5. Platelet count ≥ 150.000 mm3
Difficult to treat group:
1. Peg-INF Treatment experienced
2. T.Bil > 1.2 mg/dl
3. Serum albumin < 3.5 gm/dl
4. INR > 1.2
5. Platelet count < 150.000 mm3

52. Protocol for Easy and Difficult to Treat
DurationDrugsCategory
12 wkSOF/DACEasy to Treat
12 wkSOF/DAC/RBV
Difficult to
Treat
* The dose of RBV is 600 mg/day. A trial should be done to
reach a dose of 1000 mg/day based on the patient tolerability.

53. Treatment of Special Populations
1. Advanced liver disease ( Child score ≥ 8).
2. Post organ transplantation.
3. CKD
4. Non responders to SOF-containing regemens.
5. Combined HCV/HIV.

54. Treatment of Patients with Advanced
Liver Disease:
• Treatment is allowed only in one of several
assigned specialized centers.
• The following regimen is used for 12 weeks
SOF/DCV/RBV
– The dose of RBV is 600 mg/day. A trial should be
done to reach a dose of 1000 mg/day based on
the patient tolerability.

55. Treatment of Patients with Post organ
Transplantation
SOF/DCV for 24 weeks

56. Treatment of Patient with Chronic Kidney
Disease (CKD)
• In patients with serum creatinine exceeding the upper limit of
normal, eGFR is calculated and accordingly:
1. eGFR > 30 ml/min treat by the usual regimens.
2. eGFR ≤ 30 ml/min treat by:
Paritaprevir/retonavir/ombitasvir + RBV
Provided the following are fulfilled:
1. Patients have compensated liver (cirrhosis Child A or no cirrhosis)
2. Hb level at least 10 gm/dl
3. The patient has no associated uncontrolled co-morbidity (cardiac,
neuropsych;..)
4. A nephrologist consultation is done. A report determining the
treatment eligibility and necessity and the exact RBV recommended
dosage (and time of administration in relation to dialysis).
5. In case of dialysis, the patient should be aware of the high risk of
reinfection by signing a consent form.

58. Treatment of Patients who Failed
Previous SOF-containing Regimens:
SOF/DCV/RBV for 24 weeks
– The dose of RBV is 600 mg/day. A trial should be
done to reach a dose of 1000 mg/day based on
the patient tolerability.

59. Treatment of Patients with
Combined HCV and HIV:
• Co-management by the hepatologist and the
treating infectious disease physician is
needed.
• SOF should not be received in combination
with tipranavir.

60. • Patients ≥ 65 years old should undergo
cardiological assessment prior to therapy by
ECG, echocardiography and cardiological
consultation.
• N.B. An update will be released as soon as
possible based on availability of other
treatment regimens

61. Egyptian Consensus for
Management of HCV
(June 2016)

62. Format
• Experts were divided over 5 working
groups:
Group 1: Non cirrhotics
Group 2: Cirrhotics and HCC
Group 3: Renal dysfunction
Group 5: Liver Transplantation
Group 6: DAA Failures

63. Pre treatment evaluation of patients
• Should emphasize on 2 issues:
– Is the patient cirrhotic or not?
– Has the patient received antiviral trearment fot
HCV before?
• Evaluation of Fibrosis:
– Clinical examination
– Lab results
– Abdominal US
– Fibroscan

64. Non Cirrhotics
Treatment Naïve
• SOF/SIM
• SOF/DAC
• SOF/LDV
• 3 D/RBV
12 weeks

65. Non Cirrhotics
Treatment Experienced
• SOF/SIM
• SOF/DAC/RBV
• SOF/LDV/RBV
• 3 D/RBV
12 weeks

66. Cirrhotic Patients
• Child Pugh A: Treat
• Child Pough B & C : Treatment should be in
specialized center under strict supervision
• DO NOT Treat cirrhotic patients if
– Child-Pough score is > 12 and/or
– MELD score > 20.

67. Compensated Cirrhosis
(Child A)
• SOF/SIM
• SOF/DAC/RBV
• SOF/LDV/RBV
• 3 D/RBV
12 weeks

68. Decompensated Cirrhosis
(Child B&C)
• SOF/LDV/RBV
• SOF/DAC/RBV
– Initializing dose of RBV is 600 mg daily to be
increased as tolerated to 1000-1200 mg
12 weeks

69. Liver Transplant Patients
• All patients with HCV recurrence post-LTX
should be considered for treatment.
• Liver biopsy is preferred but not mandatory. If
liver biopsy is not available a fibroscan should
be done.

70. Liver Transplant Patients
• SOF/SIM 12 weeks
• SOF/DAC/RBV* 12 weeks
• SOF/LDV/RBV * 12 weeks
• 3 D/RBV 24 weeks
– * If the patient can not tolerate RBV treat with 2 D
for 24 weeks.

71. HCV Patient with Renal Dysfunction
• Creatinine Clearance ≥ 30 ml/min:
–No dose adjustment when using
• SOF, DAC, LDV, SIM, Paritaprevir,
Ombitasvir, Dasabuvir.

72. HCV Patient with Renal Dysfunction
• Creatinine Clearance < 30 ml/min:
–NOT Cirrhotic OR Compensated Cirrhotic:
• Paitaprevir/r + Ombitasvir + RBV
–Decompensated Cirrhotic or RBV Intolerant:
• SOF 400 mg one hour before dialysis +
DAC 60 mg daily (VERY CAUSIOUSLY).

73. DAA Failures
Failure of SOF/RBV ± PEG INF
• SOF/LDV
• SOF/SIM
• SOF/DAC
If the patient is Decompensated Cirrhotic:
• SOF/LDV
• SOF/DAC
With RBV for 12 weeks or
without RBV for 24 weeks
24 weeks

74. DAA Failures
• SIM/SOF Failure:
–Are you in hurry?
–If yes, do GENOTYPE + RAVs Test
SOF/DAC ± RBV 24 weeks
SOF/LDV ± RBV 24 weeks

75. DAA Failures
• SOF/DAC Failure:
–Are you in hurry?
–If yes, do GENOTYPE + RAVs Test
SIM/SOF 24 weeks

76. DAA Failures
• SOF/LDV Failure:
–Are you in hurry?
–If yes, do GENOTYPE + RAVs Test
SIM/SOF 24 weeks

77. DAA Failures
• Paritaprevir/r/Ombitasvir + RBV Failure:
–Are you in hurry?
–If yes, do GENOTYPE + RAVs Test
SIM/SOF 24 weeks

78. Conclusions
• Guidance for HCV Treatment is changing
constantly and any treatment consensus
needs updating, perhaps every 6 months, or
whenever new data become available.

79. 79
Monkez M Yousif