Hepatitis c treatment 2017 2018

Hepatitis C Treatment 2017- 2018

By

DR MONKEZ M YOUSIF

Professor of Internal MedicineMember of AGA, EASL, ISC-Hepatitis WG

2017

Sources

1. Recommendations for Testing, Managing, and Treating Hepatitis C AASLD 2015. Updated September 21, 2017.

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

3. National Committee for Control of HCV. Updated December 26, 2016.

Where HCV Therapy Stands Now

• Interferon is gone; ribavirin . . . not quite

• SVR in > 95% of pts

• “Difficult-to-cure” populations no longer difficult

– HIV coinfection -- Cirrhosis

– Persons who inject drugs (PWID)

– Renal failure and kidney transplant

– Liver transplant -- Old age

• Emergent issues and controversies:

– HBV reactivation

– HCC recurrence after DAA therapy

• Cost and access issues persist but improving

Hepatitis C Treatment in 2017

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.

Patient Education and Linkage to Care

• “All persons with current active HCV infection should be linked to a practitioner who is prepared to provide comprehensive management”

• “Improvement in identification of HCV infection and advances in treatment will have limited impact on HCV morbidity and mortality without concomitant improvement in linkage to care”

AASLD/IDSA HCV Guidelines.

Use Your Collective Genius to Maximize Delivery of Comprehensive HCV Care

Multidisciplinary care

Provider Nurse

Hepatologist/ transplant

team

Casemanager

Addictions specialist

Mental health

provider

Community outreach specialist

Administrative coordinator

FibroScan technician

Pharmacist

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.

Benefits of Achieving SVR

↓ Cirrhosis↓ Decompensation

↓ HCC↓ Transplantation

↓ All-cause mortalityImproved QoL

MalignancyDiabetes

CVDRenal

Neurocognitive

Cure

Improved clinical outcomes[1,2]

1. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19.

2. Negro F, et al. Gastroenterology. 2015;149:1345-1360.

3. George SL, et al. Hepatology. 2009;49:729-738.

Hepatic Extrahepatic

Decreased transmission[1]

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.

Available Therapies

Open Reading Frame ( ORF )

Protease inhibitor

Replicaseinhibitor

Polymerase inhibitor

DAAs Approved in 2014

SofosbuvirAll

genotypes

SimeprevirG 1 , 4

DaclatasvirAll

genotypes

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


Sofosbuvir/ LedipasvirG 1,4,5,6

Ombitasvir/Paritaprevir/

rG 1 , 4

DasabuvirG 1


Sofosbuvir/ Velpatasvir

All Genotypes

Grazoprevir/ Elbasvir

G 1 , 4


Sofosbuvir/ Velpatasvir/Voxilaprevir

All Genotypes

Glecaprevir/ Pibrentasvir

All Genotypes

Investigational DAA

Ruzasvir

All Genotypes

Uprifosbuvir

All Genotypes

DAA Available In Egypt’s Market 2017

• Sofosbuvir

• Simeprevir

• Daclatasvir

• Sofosbuvir/Ledipasvir

• Ombitasvir/Paritaprevir/r

• Ribavirin

Treatment Selection

Prior Treatment Experience

HCV Genotype/

Subtype

Severity of Liver

disease

Patient’s Comrbiditi

es

PK Profile of

Treatment

Drug-Drug Interaction

Characteristics that inform drug treatment options selection

Hepatitis C Treatment

Al-Ahrar VHTC

CHC Patient’s treatment Pathway

• Preparatory Clinic

• Evaluation Clinic

• Revision Committee

• Treatment Clinic

• Awareness Clinic

• Follow up Clinic

Preparatory Clinicالعيادة التحضيرية

• Operator: Medical or Paramedical employee

• Functions:مراجعة الفحوصات المطلوبة1.

» HCV RNA PCR» HBsAg » LFTs» S.creatinine» CBC» PT» αFP» FBS» HbA1c» ABD US» ECG» Echocardiography For patients >65 y

أخذ بيانات المريض2.

Age

Weight

Height

BMI

مالها في حالة نقصان أي من هذه البيانات يوجه المريض الستك

و الرجوع للعيادة في أسرع وقت

Evaluation Clinicعيادة التقييم

• Operator: Certified Physicians of the Center

• Functions::أخذ التاريخ المرضي مع التركيز علي البيانات االتية:أوال

Naïve or T. Experienced Comorbid diseases ( DM, HTN, IHD, COPD, Malignancies, Neuropsychiatric

diseases …etc)

عمل قائمة باألدوية التي يستخدمها المريض:ثانيا

مراجعة التحاليل و األشعات:ثالثا

CTP Score & FIB-4تقييم حالة الكبد :رابعا Inclusion & Exclusion Criteriaمراجعة :خامسا: تصنيف المريض:سادسا

Easy to Treat Difficult to Treat Special Population

كتابة استمارة العالج ووضع بروتوكول العالج: سابعا

Revision Committeeلجنة المراجعة

مرسل تقوم بمراجعة استمارة التعريف و كتابة طلب العالج ال

للمجالس الطبية للموافقة علي التغطية المالية

Treatment Clinicعيادة العالج

للمرض بعد صدور قرار العالج يقوم الطبيب المعالج بفتح ملف العالج•بعد مراجعة متأنية ألي مستجدات في فحوصات المريض أو أدوية

جديدة يستخدمها ألي سبب

مريض علي عند فتح الملف يراعي استيفاء كافة البيانات خاصة موافقة ال•دويةالبروتوكول و نموذج العلم بكافة األعراض الجانبية الشائعة لأل

.فق عليهثم يقوم الطبيب بكتابة وصفة العالج حسب البروتوكول المت•

حوصات كذلك يتولي الطبيب المعالج التنبيه علي المريض بعمل الف•باعا الالزمة في المواعيد المحددة و يقوم بتدوينها في ملف المريض ت

اثناء المراجعات الشهرية

م الخاص به يقوم الطبيب المعالج بالتوقيع علي البيانات مع و ضع الخت•بصورة واضحة عند كل زيارة

عيادة يوجه المريض بعد ذلك للصيدلية لصرف الروشتة ثم يوجه لل•التثقيفية

Awareness Clinicالعيادة التثقيفية

• Operators:• Clinical Pharmacist

• Dedicated Nurse

• Educator

• Functions:مراجعة العالج المنصرف من الصيدلية و التأكد من مطابقته لقرار العالج•

مراجعة لستة األدوية التي يستخدمها المريض ألمراض أخري ثم ادخالها علي • D-D Interactionبرنامج كشف التداخالت بينها و بين أدوية عالج الفيروس

Checkerة من في حالة و جود تحذيرات يتم الرجوع للطبيب المعالج بتوصي.العيادة موضحا بها التداخل و كيفية التصرف

إعطاء المريض ارشادات و اضحة عن كيفية و مواعيد استخدام عالج الفيروس•

و إرشاد المريض ألهميتها و توقيت PCRمراجعة شيكات ال •استخدامها

هاون التنبيه علي المريض بأخذ األدوية في مواعيدها و عدم الت•ب في ذلك حيث أن ترك جرعة من العالج دون استشارة الطبي

سببا المعالج بالمركز يؤثر في االستجابة النهائية و قد يكون.لالنتكاسة

يوم قبل 3-2الحضور للمركز لصرف الجرعة التالية من العالج •.نهاية الجرعة الحالية

في حالة حدوث أي طارئ يمنع المريض من بدء العالج وذلك •48الل بعد صرفه من المركز يتم إبالغ الطبيب المعالج بذلك خ

أن ساعة علي األكثر ويتم اثبات ذلك في ملف المريض عليلبدء الجديد يراجع الطبيب بعد انتفاء سبب التأجيل إلثبات موعد ا

.قطاعوإال يعرض المريض نفسه لعدم تجديد صرف العالج لإلن

ارج إذا تعرض المريض لمشكلة صحية و نصحه طبيبه المعالج من خ•بد من المركز بإيقاف عالج الفيروس مؤقتا حتي يبرأ من هذه المشكلة الابالغ الطبيب المعالج داخل المركز بواسطة المريض نفسه أو أحد

ح أقاربه علي أن يقوم الطبيب بالمركز بمراجعة الموقف و ال ينص.بإيقاف العالج إال في ظروف محددة و بضوابط واضحة

اعطاء ارشادات واضحة بضرورة منع الحمل اثناء العالج خاصة إذا •رورة منع اشتمل العالج علي عقار ريبافيرين و في هذه الحالة ينبه بض

شهور بعد نهاية العالج علي األقل منعا لحدوث تشوهات6الحمل مدة .جنينية

ة في ارشادات عامة عن كيفية تجنب منع انتقال العدوي لآلخرين خاص•محيط األسرة

ارشادات خاصة بضرورة تغيير األدوات الشخصية كل شهر أثناء •وف ل, المقص, القصافة, عدة الحالقة, السواك, فرشة األسنان)العالج

.مع عدم استخدام أدوات الغير( االستحمام

Follow Up Clinicعيادة المتابعة

Operators: Trained Physician, Filing and IT Personnel.

Functions: تختص هذه العيادة بمتابعة و رصد تحاليل المريض خاصةHCV RNA PCR

أسبوع بعد نهاية العالج12و 4

و االتصال بالمرضي المنقطعين عن المتابعة لحثم علي مراجعة المركزعالج و اعطاء استكمال البيانات الناقصة و ذلك للتعرف علي النتيجة النهائية لل

.فرصة عالج أخري للمنتكسين

شهور بواسطة اشعة تليفزيونية و فحوصات6-4متابعة مرضي التليف كل(HCC)معملية لمتابعة كفاءة الكبد الوظيفية و ترصد حدوث أورام الكبد

FIB-4

FibroScan

Transient elastography examines a large mass of liver tissue (1 cm diameter by 5 cm in length) and thus provides a more representative assessment of the entire hepatic parenchyma.

Ultrasound transducer probe that is mounted on the axis of a vibrator. Vibration is transmitted toward hepatic tissue, the vibrations are followed by pulse echo and their velocities are measured which is related directly to liver stiffness

Sensitivities of 84 to 100% and specificities of 91 to 96%. Results limited in those with ascites, elevated central venous pressure, and obesity, as fluid and adipose tissue attenuate the echo waves.

Cut-offs for the diagnosis of cirrhosis

kPa HCV-HIV HCV HBV

Sensitivity 95% 14.6 10 6

Specificity 95% 17.6 14.1 14.3

Sensitivity + specificity 10.4 10.3

Ganne-Carrié N et al. Hepatology 2006;44:1511-7

Vergara S et al. Clin Inf Dis2007;45:969-74

Cirrhosis Spectrum

C=10-15B=7-9A=5-6Child-Pough

< 32-3> 2T.Bilirubin (mg/dl)

> 2.82.8-3.5< 3.5S.Albumin (g/dl)

< 2.31.7-2.3> 1.7PT/INR

Poorly controlled with medications

Controlled with medications

NoneAscites

Poorly controlled with medications

Controlled with medications

NoneH.Encephalopathy

Compensated → Decompensated

+++++++/-Portal hypertension severity

+++++++Liver synthetic dysfunction

Very limitedLimitedGoodHepatic reserve

Median survival > 12 yrs Median survival - 2 yrs

Drug-Drug Interactions

INITIAL TREATMENT OF HCV G4 INFECTION

NCCVH Hepatitis C Treatment ProtocolUpdate December 2016

Inclusion criteria

1. HCV RNA Positivity

2. Age: ≥ 18

– Patients ≥ 65 years old should undergo cardiological assessment prior to therapy by ECG, echocardiography and cardiological consultation.

Exclusion Criteria

Any of the following1. Child C cirrhotic patients.2. Platelet count < 50000/mm3.3. HCC except 6 months after intervention aiming at cure

with no evidence of activity by dynamic imaging (CT or MRI).

4. Extrahepatic malignancy except after 2 years of disease free interval.o In cases of lymphomas and CLL, treatment can be initiated

immediately after remission based on the treating oncologist report.

5. Pregnancy or inability to use effective contraception.6. Inadequately controlled DM (HbA1c > 9).

Patient Categories

• Easy to treat group:– Treatment naïve.– T.Bil ≤ 1.2 mg/dl.– Serum Albumin ≥ 3.5 g/dl– INR ≤ 1.2.– Platelet count ≥ 150000 /mm3.

• Difficult (not easy)to treat group:– Peg-Interferon treatment experienced.– Total serum bilirubin > 1.2 mg/dl.– Serum albumin < 3.5 g/dl.– INR > 1.2– Platelet count < 150000/mm3

• Special Population Group:

– Non-responders to previous DAAs regimens

– Advanced liver disease (Child ≥ 9)

– Post-organ transplantation

– Chronic kidney disease (CKD)

– HCV coinfection with HBV and HIV

• Assessment of fibrosis:

– With FIB-4 is a must

• Treatment monitoring:

– HCV Viral load estimation at any time point between 12 and 24 weeks post-treatment to confirm successful eradication of the virus

Treatment Protocol

• Easy to treat group: eligible to be treated by any of the following regimens for 12 weeks:

– Paritaprevir-r/Ombitasvir + RBV

– Sofosbuvir + Daclatasvir

• Difficult to treat group: eligible to be treated by any of the following regimens for 12 weeks:

– Sofosbuvir + Daclatasvir + RBV– The starting 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. Non-responders to previous DAAs regimens

2. Advanced liver disease (Child ≥ 9)

3. Post-organ transplantation

4. Chronic kidney disease (CKD)

5. HCV coinfection with HBV and HIV

Retreatment of patients with previous DAAs failure

I. Retreatment of patients with previous SOF/DAC regimen failure

A. Non-cirrhotic patients and patients with compensated cirrhosis:

- Option 1:

- SOF/QUREVO/RBV for 12 weeks ( RBV ineligible:

extend therapy for 24 weeks).

- Option 2:

- SOF/SIM/DAC/RBV for 12 weeks ( RBV ineligible:

extend therapy for 24 weeks).

B. Child’s B cirrhotic patients: (Refer to specialized centers)

SOF/DAC/RBV for 24 weeks

C. Deferral of therapy: Child’C cirrhotic patients

Previous failure to 24 weeks SOF/DAC ± RBV regimen

Previous deterioration on same treatment

2. Retreatment patients previous SOF/SIM Regimen Failure:

SOF/DAC/RBV for 12 weeks ( RBV ineligible: extend therapy for 24 weeks).

o NB: RBV dose: 1000 mg/day for patients < 75 kg

1200 mg/day for patients ≥ 75 kg

Treatment of patients with advanced liver disease (Child’s ≥ 9)

• 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.

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/dl3. 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.

Treatment of Patients with Post organ Transplantation

SOF/DCV ± RBV for 24 weeks

Treatment of combined HCV and HBV

• Patients should be treated with the same regimens, following the same rules as HCV mono-infected patients.

• If HBV replicates at significant levels before, during or after HCV clearance, concurrent HBV nucleoside/neocleotide analogue therapy is indicated.

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.

RatingDurationRegimen

Recommended

I A8 wksGlecaprevir/Pibrentasvir

I A12 wksSofosbuvir/Velpatasvir

IIa B12 wksGrazoprevir/Elbasvir

IIa B12 wksSofosbuvir/Ledipasvir

Alternative

I A12 wksOmbitasvir/Paritaprevir/r + RBV

Treatment of Naïve G4 Without Cirrhosis


Recommended


I B12 wksGlecaprevir/Pibrentasvir

IIa B12 wksGrazoprevir/Elbasvir


Alternative


Treatment of Naïve G4 With Compensated Cirrhosis


Recommended



IIa B12 wksGrazoprevir/Elbasvir (for relapsers)


Alternative


Iia B16 wksGrazoprevir/Elbasvir (for breakthrough and null responders)

PegInf/RBV- Experienced, G4 Without Cirrhosis


Recommended



IIa B12 wksGrazoprevir/Elbasvir (for relapsers)

Alternative


Iia B16 wksGrazoprevir/Elbasvir (for breakthrough and null responders)


PegInf/RBV- Experienced, G4 With Compensated Cirrhosis

DAA-Experienced (including NS5A inhibitors), G4 with and without compensated cirrhosis

RatingDuration Recommended

I A12 wksSofosbuvir/Velpatasvir/Voxilaprevir

Patients with Decompensated Cirrhosis G 1,4,5,6 (RBV-Eligible)

RatingDurationRecommended

I A12 wksSofosbuvir/Ledipasvir/RBV (Initial dose 600)

I A12 wksSofosbuvir/Velpatasvir/RBV (weight-based)

I B12 wksSofosbuvir/Daclatasvir/RBV (Initial dose 600)( G 1, 4 only)

Patients with Decompensated Cirrhosis G 1,4,5,6 (RBV-Ineligible)


I A24 wksSofosbuvir/Ledipasvir


II C24 wksSofosbuvir/Daclatasvir ( G1,4 only)

Patients with Decompensated Cirrhosis G 1,4,5,6 in whom prior Sofosbuvir or

NS5A-based treatment failed


II C24 wksFor Sofosbuvir-based treatment failure only:Sofosbuvir/Ledipasvir + Low initial dose of RBV

II C24 wksSofosbuvir/Velpatasvir + wt-based dose of RBV

Conclusions

• The multiple current regimens are highly effective and safe across genotypes; confirmed in “real-world” studies.

• The available DAAs in Egypt’s Market , especially the generics are very effective with high safety profile (SVR more than 95%).

• However, new medications for retreatment of prior DAA – failure (particularly NS5A-based therapy) are needed and should be introduced in the market.

• GLE/PIB and SOF/VEL/VOX appear poised to be an 8-wk pangenotypic regimen for DAA-naive noncirrhoticpts

74

Monkez M Yousif

Healthcare

Hepatitis c treatment 2017 2018