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 September 27, 2016

2. EASL Recommendations for management of HCV September 23, 2016.

3. National Committee for Control of HCV. Updated November 2015

HCV infection in population age 1-59 years old in 2015

• 4.4% or around 3.5 million Egyptians, had an active hepatitis C infection. 6.3% had positive HCV Ab.

• Sharkia Governorate population had HCV prevalence of 6.4% active infection and 8.7% Abs

• Rates of HCV infection increased sharply with age. Around 1 in 6 women and around 1 in 4 men age 50-59 had an active HCV infection at the time of the survey.

Egypt Health Issues Survey 2015

Trends in percentage of the population age 15-59 testing positive on the hepatitis C RNA test, Egypt 2008-2015

Ministry of Health and Population [Egypt], El-Zanaty and Associates [Egypt], and ICF International 2015. Egypt Health Issues Survey 2015. Cairo, Egypt and Rockville, Maryland, USA: Ministry of Health and Population and ICF International.

CDC Recommended Testing Sequence for Identifying Current HCV Infection

• 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.

Open Reading Frame ( ORF )

Protease inhibitor

Replicase inhibitor

Polymerase inhibitor

Drug targets in the lifecycle of the hepatitis C virus

NUC NS5B Inhibitor NS3 Inhibitor NS5A Inhibitor (buvir ) ( previr ) ( asvir)

Recommendations for pretreatment assessment

An assessment of the degree of hepatic fibrosis

• Liver Biopsy• Non-invasive testing including–APRI Test–Fib-4 Test

• 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

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

THERAPY

Recommended assessments prior to starting antiviral therapy

• Tests recommended within 12 weeks prior to starting antiviral therapy:– CBC ; INR– LFTs– Serum Cr– TSH if IFN is used– Calculated glomerular filtration rate (eGFR)

• Assessment of potential drug-drug interactions

• Tests recommended at any time prior to starting antiviral therapy:

– HCV genotype and subtype

– Quantitative HCV viral load

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.

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.

• 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 September 27, 2016

Duration Regimen

Class I, Level A 12 wk with RBV

Ritonavir-boosted Paritaprevir/ Omb (Qurevo)

Class I, Level A 12 wk Sofosbuvir/Velpatasvir(Epclusa)

Class IIa, Level B 12 wkElbasvir/Grasoprevir (Zepatier)

Class IIa, Level B 12 wk Sofosbuvir/Ledipasvir (Harvoni)

Genotype 4 Treatment-naïve without Cirrhosis and with Compensated Cirrhosis

Duration Regimen

12 wk SOF/RBV/Peg INF*

Genotype 4 Treatment-naïve ± Cirrhosis: Alternative ( February 24,2016)

* For INF-eligible patients

NO MORE IN THE LAST UPDATE

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

SOF/VEL SOF/DCV**

SOF/LDV SOF/VEL SOF/DCV** SOF/LDV

GT1/412 wks + low-dose

RBV*

12 wks + low-dose

RBV*

12 wks + low-dose

RBV*24 wks 24 wks 24 wks

GT1/4, SOF failure

24 wks + low-dose

RBV*

Not recommende

d

24 wks + low-dose

RBV*

Not recommende

d

Not recommend

ed

**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

Class I, Level A 12 wk with RBVRitonavir-boosted Paritaprevir/ Omb (Qurevo)

Class I, Level A 12 wk Sofosbuvir/ Velpatasvir(Epclusa)

Class IIa, Level B12 w for relapsers16 w + RBV for non-responders during previous treatment and breakthrough cases

Elbasvir/ Grasoprevir (Zepatier)

Class IIa, Level B 12 wk Sofosbuvir/ Ledipasvir (Harvoni)

Genotype 4 PEG-IFN/RBV Treatment-experienced Patients without Cirrhosis

Duration Regimen

Class I, Level A 12 wk with RBVRitonavir-boosted Paritaprevir/ Omb (Qurevo)

Class I, Level A 12 wkSofosbuvir/Velpatasvir(Epclusa)

Class IIa, Level B12 w for relapsers16 w + RBV for non-responders during previous treatment and breakthrough cases

Elbasvir/Grasoprevir (Zepatier)

Class IIa, Level B 12 wk with RBV

Sofosbuvir/Ledipasvir (Harvoni)

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

Duration Regimen

24 wk SOF / LDV (Harvoni)

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

NCCVH Hepatitis C Treatment ProtocolUpdate November 2015

Medications available in Al-Ahrar VHTC

• Sofosbuvir• Daclatasvir• Pvaritaprevir/ritonavir/Ombitasvir• Sofosbuvir/Ledipasvir• 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 wkSOF/DACSOF/LDVSOF/SIMParita/r/OMV+RBV

Easy to Treat

12 wk SOF/DAC/RBVSOF/LDV/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 ≥ 7).2. Post organ transplantation.3. CKD4. Non responders to SOF-containing regimens.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 weeksSOF/LDV/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

HCV & The Kidney

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Monkez M Yousif