Revision of Treatment Protocols for HCV Genotype 4 Infection 2016

By

DR MONKEZ M YOUSIFProfessor of Internal Medicine

Zagazig University , Egypt2016

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

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 issuspected 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.

• Persons with current (active) HCV infection

should receive education and interventions

aimed at:

−Reducing progression of liver disease

−And preventing transmission of HCV.

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).

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.

WHEN AND IN WHOM TO INITIATE HCV THERAPY

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.

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.

Recommendations for pretreatment assessment

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:

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)

FIB-4

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.

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

THERAPY

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

• 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.

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.

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

• Quantitative HCV viral load testing is recommended1. 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.

• 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.

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.

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.

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.

• 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.

INITIAL TREATMENT OF HCV G4 INFECTION

AASLD/IDSA Guidelines Updated 24 Feb 2016

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

Duration Regimen

12 wk with RBV Ritonavir-boosted Paritaprevir/ Omb (Curevo)

12 wk Elbasvir/Grasoprevir (Zepatier)

12 wk Sofosbuvir/Ledipasvir (Harvoni)

Genotype 4 Treatment-naïve without CirrhosisRecommended

Duration Regimen

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

Duration Regimen

12 wk SOF/RBV/Peg INF*

Genotype 4 Treatment-naïve ± Cirrhosis: Alternative

* For INF-eligible patients

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.

PopulationRBV 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.

RETREATMENT OF PERSONS WITH HCV G4 IN WHOM PRIOR THERAPY

HAS FAILED

Duration Regimen

12 wk with RBVRitonavir-boosted Paritaprevir/ Omb (Curevo)

12 w for relapsers16 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

Duration Regimen

12 wk with RBVRitonavir-boosted Paritaprevir/ Omb (Curevo)

12 w for relapsers16 w + RBV for non-responders during previous treatment and breakthrough cases

Elbasvir/Grasoprevir (Zepatier)

12 wk with RBV24 for RBV ineligible

Sofosbuvir/Ledipasvir (Harvoni)

G4 PEG-IFN/RBV Treatment-experienced with Compensated Cirrhosis -Recommended

Duration Regimen

12 wk SOF / RBV / PegINF*

24 wk SOF / RBV * *

G4 PEG-IFN/RBV Treatment-experienced without Cirrhosis -Alternative

* For INF-eligible patients* * For INF-ineligible patients

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

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

• 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.

EASL HCV 2015 Guidelines

Duration Regimen12 Wk P-INF/ RBV/ SOFNo SOF/ RBV12 wk SOF/ LEDNo Ritonavir-boosted Parita/ Ombi/ Dasabuvir12 wk with RBV Ritonavir-boosted Parita/ Omb12 wk SOF/SIM12 wk SOF/ DCL

Patients with chronic hepatitis C G4 without cirrhosis, treatment-naïve and with

prior failure to PegIFN/RBV

Duration Regimen12 Wk P-INF/ RBV/ SOF

No SOF/ RBV

12 wk with RBV or 24 wk without RBV or 24 wk with RBV if –ve predictors of response

SOF/ LED

No Ritonavir-boosted Parita/ Ombi/ Dasabuvir

24 wk with RBV Ritonavir-boosted Parita/ Omb

12 wk with RBV and 24 wk without RBV SOF/SIM

12 wk with RBV and 24 wk without RBV SOF/ DCL

Patients with chronic hepatitis C G4 with Compensated cirrhosis, treatment-naïve and with

prior failure to PegIFN/RBV

Duration Regimen

12 wk with RBV or

24 wk with RBV if F3 or cirrhosis

SOF/ LED

Ritonavir-boosted Parita/ OmbSOF/SIM

SOF/ DCL

Retreatment of patients with CHC G 1,4 with prior failure to SOF/RBV or SOF/PegINF/RBV

Retreatment patients with CHC G 1,4 with prior failure to SIM/SOF

Duration Regimen12 wk with RBV or

24 wk with RBV if F3 or cirrhosis

SOF/ LED

SOF/ DCL

Retreatment patients with CHC G 1,4 with prior failure to SOF/DAC or SOF/LDV

Duration Regimen12 wk with RBV or

24 wk with RBV if F3 or cirrhosis SIM/SOF

Retreatment of patients with CHC G4 with prior failure to antiviral therapy containing Ritonavir-boosted paritaprevir and ombitasvir

Duration Regimen

12 wk with RBV or

24 wk with RBV if F3 or cirrhosis

SOF/LDV

SOF/SIM

SOF/DAC

• SOF/RBV 1,4• 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

NCCVH Hepatitis C Treatment ProtocolUpdate November 2015

Medications available in Al-Ahrar VHTC

• Sofosbuvir• Sovaldi• Mpiviropack

• Daclatasvir• Clatasive• Daclavirocyrl

• Pvaritaprevir/ritonavir/Ombitasir• Curevo

• Sofosbuvir/Ledipasvir• Harvoni

• Ribavirin

NCCVH Hep C Treatment ProtocolUpdate November 2015

Inclusion Criteria:1. HCV RNA Positivity2. Age: 18-75

Exclusion Criteria: any of the following:3. T.Bil > 3 mg4. Serum Albumin < 2.8 gm/dl5. INR > 1.76. Platelet count < 50.000/mm3

7. If any of the criteria from 1-4 is not caused by liver disease, the patient can be included in treatment protocol.

8. HCC, except 4 weeks after intervention aiming at cure with no evidence of activity by dynamic imaging (CT or MRI).

9. 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.

10. Pregnancy or inability to use effective contraception.11. Inadequately controlled DM (HbA1c > 9%)

Patients will be categorized to:Easy to treat group:

1. Treatment naïve2. T.Bil ≤ 1.2 mg/dl3. Serum albumin ≥ 3.5 gm/dl4. INR ≤ 1.2 5. Platelet count ≥ 150.000 mm3

Difficult to treat group:6. Peg-INF Treatment experienced7. T.Bil > 1.2 mg/dl8. Serum albumin < 3.5 gm/dl9. INR > 1.2 10. Platelet count < 150.000 mm3

Protocol for Easy and Difficult to Treat

Duration Drugs Category

12 wk SOF/DAC Easy to Treat

12 wk SOF/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.

Treatment of Special Populations

1. Advanced liver disease ( Child score ≥ 8).2. Post organ transplantation.3. CKD4. Non responders to SOF-containing regemens.5. Combined HCV/HIV.

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 weeksSOF/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.

Treatment of Patients with Post organ Transplantation

SOF/DCV for 24 weeks

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:3. Patients have compensated liver (cirrhosis Child A or no cirrhosis)4. Hb level at least 10 gm/dl5. The patient has no associated uncontrolled co-morbidity (cardiac, neuropsych;..)6. 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).

7. In case of dialysis, the patient should be aware of the high risk of reinfection by signing a consent form.

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.

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.

• 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

Egyptian Consensus for Management of HCV

(June 2016)

Format

• Experts were divided over 5 working groups:

Group 1: Non cirrhoticsGroup 2: Cirrhotics and HCCGroup 3: Renal dysfunctionGroup 5: Liver TransplantationGroup 6: DAA Failures

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

Non CirrhoticsTreatment Naïve

• SOF/SIM• SOF/DAC• SOF/LDV• 3 D/RBV

12 weeks

Non CirrhoticsTreatment Experienced

• SOF/SIM • SOF/DAC/RBV• SOF/LDV/RBV• 3 D/RBV

12 weeks

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.

Compensated Cirrhosis(Child A)

• SOF/SIM • SOF/DAC/RBV• SOF/LDV/RBV• 3 D/RBV

12 weeks

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

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.

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.

HCV Patient with Renal Dysfunction

• Creatinine Clearance ≥ 30 ml/min:–No dose adjustment when using• SOF, DAC, LDV, SIM, Paritaprevir,

Ombitasvir, Dasabuvir.

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).

DAA FailuresFailure 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

DAA Failures

• SIM/SOF Failure:–Are you in hurry?– If yes, do GENOTYPE + RAVs Test

SOF/DAC ± RBV 24 weeksSOF/LDV ± RBV 24 weeks

DAA Failures

• SOF/DAC Failure:–Are you in hurry?– If yes, do GENOTYPE + RAVs Test

SIM/SOF 24 weeks

DAA Failures

• SOF/LDV Failure:–Are you in hurry?– If yes, do GENOTYPE + RAVs Test

SIM/SOF 24 weeks

DAA Failures

• Paritaprevir/r/Ombitasvir + RBV Failure:–Are you in hurry?– If yes, do GENOTYPE + RAVs Test

SIM/SOF 24 weeks

Conclusions

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

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Monkez M Yousif