chronic hepatitis c who guideline 2016

Chronic Chronic Hepatitis Hepatitis

C C InfectionInfection

WHO Guideline WHO Guideline April 2016April 2016

ByBy Dr. Syed Ghulam Dr. Syed Ghulam MogniMogniAssistant Professor of Assistant Professor of Medicine Medicine Dhaka Medical Dhaka Medical College Dhaka, College Dhaka, BangladeshBangladesh

SourceSource

IntroductionIntroduction Globally, the morbidity and mortality attributable to Globally, the morbidity and mortality attributable to

hepatitis C virus (HCV) infection continues to hepatitis C virus (HCV) infection continues to increase. About 700 000 persons die each year increase. About 700 000 persons die each year

Consequently, Consequently, the field of HCV therapeutics the field of HCV therapeutics continues to evolve rapidly as wellcontinues to evolve rapidly as well

WHO issued the first Guidelines for the screening, WHO issued the first Guidelines for the screening, care and treatment of persons with hepatitis C care and treatment of persons with hepatitis C infection in 2014. infection in 2014.

Since then, several new medicines, called direct-Since then, several new medicines, called direct-acting antivirals (DAAs), have been introducedacting antivirals (DAAs), have been introduced

Introduction…Introduction… Direct-acting antivirals (DAAs), are transforming the Direct-acting antivirals (DAAs), are transforming the

treatment of HCV, enabling regimens that –treatment of HCV, enabling regimens that –– can be administered orally, can be administered orally, – are of shorter duration (as short as eight weeks), are of shorter duration (as short as eight weeks), – result in cure rates higher than 90%, andresult in cure rates higher than 90%, and– are associated with fewer serious adverse events are associated with fewer serious adverse events

than the previous interferon containing regimens.than the previous interferon containing regimens. So an updated guideline becomes necessary to So an updated guideline becomes necessary to

incorporate the new changes incorporate the new changes

EpidemiologyEpidemiology According to estimates from the Global Burden of According to estimates from the Global Burden of

Disease study, the number of deaths due to hepatitis C Disease study, the number of deaths due to hepatitis C was:was:– 333 000 in 1990, 333 000 in 1990, – 499 000 in 2010 and 499 000 in 2010 and – 704 000 in 2013704 000 in 2013

The introduction of screening of blood for HCV, The introduction of screening of blood for HCV, improvements in infection control and safer injection improvements in infection control and safer injection practices has reduced incidence, but a large number of practices has reduced incidence, but a large number of persons previously infected are now dying from HCV-persons previously infected are now dying from HCV-related complicationsrelated complications

The virus and distribution of The virus and distribution of genotypesgenotypes

The HCV is a small, positive The HCV is a small, positive stranded RNA-enveloped stranded RNA-enveloped virus. virus.

It has a highly variable It has a highly variable genome, which has been genome, which has been classified into six distinct classified into six distinct Genotypic groupsGenotypic groups

Genotype 1 is the most Genotype 1 is the most common, accounting for 46.2% common, accounting for 46.2% of all HCV infections, followed of all HCV infections, followed by genotype 3 (30.1%)by genotype 3 (30.1%)

Global Distribution of Global Distribution of Genotypes of HCVGenotypes of HCV

Natural History Natural History HCV causes both acute and chronic hepatitisHCV causes both acute and chronic hepatitis Spontaneous clearance of acute HCV infection Spontaneous clearance of acute HCV infection

occurs within six months of infection in 15–45% occurs within six months of infection in 15–45% of infected individuals in the absence of of infected individuals in the absence of treatment. treatment.

Almost all the remaining 55–85% of persons will Almost all the remaining 55–85% of persons will harbour HCV for the rest of their lives (if not harbour HCV for the rest of their lives (if not treated)treated)

Natural History…Natural History…

Highlights of 2016 Highlights of 2016 RecommendationsRecommendations

Screening Assessment for HCV treatment Clinical assessment or care of patients Treatment of Chronic HCV Infection Treatment in special situations Prevention

Recommendations on Recommendations on ScreeningScreening

HCV Case Detection:HCV Case Detection:

Screening…Screening…

Many a times HCV testing is done when patients Many a times HCV testing is done when patients present with symptoms of cirrhosis or HCCpresent with symptoms of cirrhosis or HCC

Therefore, it is critical to identify approaches that Therefore, it is critical to identify approaches that will lead to a diagnosis of chronic HCV infection will lead to a diagnosis of chronic HCV infection earlier in the course of diseaseearlier in the course of disease

Consider the possibility of other infections offer Consider the possibility of other infections offer screening for-screening for-– HBV HBV – HIV HIV – TBTB

Populations for screening are those with Populations for screening are those with a high HCV prevalence or who have a a high HCV prevalence or who have a history of HCV risk exposure/behaviourhistory of HCV risk exposure/behaviour

When to confirm?When to confirm?

RationaleRationale Approximately 15–45% of persons who are Approximately 15–45% of persons who are

infected with HCV will spontaneously clear the infected with HCV will spontaneously clear the infection.infection.

A NAT for HCV RNA, which detects the A NAT for HCV RNA, which detects the presence of the virus, is needed to distinguish presence of the virus, is needed to distinguish persons with chronic HCV infectionpersons with chronic HCV infection

A NAT for HCV RNA is also important prior to A NAT for HCV RNA is also important prior to commencing and during treatment to assess the commencing and during treatment to assess the response to treatmentresponse to treatment

Recommendations on Recommendations on Assessment for HCV treatmentAssessment for HCV treatment

Whom to Assess for TreatmentWhom to Assess for Treatment

Rationale for treatmentRationale for treatment Success of treatment for HCV infection as Success of treatment for HCV infection as

measured by SVR has steadily increased. measured by SVR has steadily increased. SVR (sustained virological response) defined as SVR (sustained virological response) defined as

the continued absence of detectable HCV RNA the continued absence of detectable HCV RNA for 12 or more weeks after completionfor 12 or more weeks after completion

Pegylated interferon increased SVR rates to 40–Pegylated interferon increased SVR rates to 40–70%, and the more recent introduction of DAAs 70%, and the more recent introduction of DAAs increased the SVR rate for genotype 1 from 40% increased the SVR rate for genotype 1 from 40% to more than 90%.to more than 90%.

The benefits of treatment The benefits of treatment clearly outweighed the clearly outweighed the

potential harmspotential harms Virological cure (SVR) offers: Virological cure (SVR) offers:

– a decrease in liver inflammation, a decrease in liver inflammation, – regressionof fibrosis in most cases, and resolution regressionof fibrosis in most cases, and resolution

of cirrhosis in half.of cirrhosis in half.– Among the latter group, portal hypertension, Among the latter group, portal hypertension,

splenomegaly, and other clinical manifestations of splenomegaly, and other clinical manifestations of advanced liver disease also improve. advanced liver disease also improve.

– More than 70% reduction in the risk of liver cancer More than 70% reduction in the risk of liver cancer (HCC) and a 90% reduction in the risk of liver-(HCC) and a 90% reduction in the risk of liver-related mortality and liver transplantation.related mortality and liver transplantation.

Recommendations on Clinical Recommendations on Clinical Assessment or Care of PatientAssessment or Care of Patient

Clinical AssessmentClinical Assessment Severity of the diseaseSeverity of the disease Staging of the diseaseStaging of the disease GenotypeGenotype

Severity of diseaseSeverity of disease

Standard laboratory tests prior Standard laboratory tests prior to treatment initiation includeto treatment initiation include a full blood count (FBC),a full blood count (FBC), international normalized ratio (INR), international normalized ratio (INR), renal function and renal function and liver function tests: ALT, AST, bilirubin, albumin liver function tests: ALT, AST, bilirubin, albumin

and alkaline phosphatase. and alkaline phosphatase. In patients undergoing treatment with interferon, In patients undergoing treatment with interferon,

thyroid function tests and fundoscopythyroid function tests and fundoscopy

Extrahepatic manifestations of Extrahepatic manifestations of HCV include:HCV include:

cryoglobulinaemia, cryoglobulinaemia, glomerulonephritis, glomerulonephritis, thyroiditisthyroiditis Sjogren syndrome,Sjogren syndrome, insulin resistance, type 2 diabetes, insulin resistance, type 2 diabetes, skin disorders such as porphyria cutanea tarda skin disorders such as porphyria cutanea tarda

and lichen planus. and lichen planus. cognitive dysfunction, fatigue and depressioncognitive dysfunction, fatigue and depression

Staging: the degree of liver Staging: the degree of liver fibrosis and cirrhosisfibrosis and cirrhosis

Assessing the degree of Assessing the degree of liver fibrosis and cirrhosisliver fibrosis and cirrhosis

Assessing the degree of liver fibrosis Assessing the degree of liver fibrosis is important to-is important to-– Assess disease severityAssess disease severity– Choose treatment regimenChoose treatment regimen– Prioritizing patients with cirrhosis Prioritizing patients with cirrhosis

for treatmentfor treatment– Predict prognosisPredict prognosis

Methods for assessing the Methods for assessing the degree of liver fibrosis and degree of liver fibrosis and

cirrhosiscirrhosis Liver biopsy is considered the gold standard Liver biopsy is considered the gold standard

method for fibrosis assessmentmethod for fibrosis assessment Several liver biopsy-scoring systems have been Several liver biopsy-scoring systems have been

developed, of which the METAVIR system is most developed, of which the METAVIR system is most widely usedwidely used


cirrhosiscirrhosis But, liver biopsy is not widely used in low-income But, liver biopsy is not widely used in low-income

countries (LMIC) for countries (LMIC) for – its high cost,its high cost,– invasiveness, invasiveness, – patient discomfort, patient discomfort, – risk of complications, risk of complications, – need for expert histological interpretationneed for expert histological interpretation.. So, Non-invasive methods are recommended So, Non-invasive methods are recommended

for low income countriesfor low income countries


cirrhosiscirrhosis On the basis of the results systematic reviews, On the basis of the results systematic reviews,

the most useful non-invasive tests are: the most useful non-invasive tests are: – APRI: aminotransferase/platelet ratio index APRI: aminotransferase/platelet ratio index – FIB-4 scores: which measure indirect FIB-4 scores: which measure indirect

markers of fibrosis such as ALT, aspartate markers of fibrosis such as ALT, aspartate aminotransferase (AST) and platelet countaminotransferase (AST) and platelet count

– Transient elastography or Fibro-scan: Transient elastography or Fibro-scan: ultrasound technology that assess the ultrasound technology that assess the degree of fibrosis and cirrhosis by measuring degree of fibrosis and cirrhosis by measuring liver stiffnessliver stiffness

Components of Non Invasive Components of Non Invasive TestsTests

Calculation (A) and Scoring (B) of Calculation (A) and Scoring (B) of APRI & FIB-4APRI & FIB-4

(A)

(B)

InterpretationInterpretation High cut-off value would be prioritized for treatment High cut-off value would be prioritized for treatment

as they have a high probability (94%) of having F4 as they have a high probability (94%) of having F4 cirrhosis.cirrhosis.

Below the low cut-off value, treatment could be Below the low cut-off value, treatment could be deferred as they have a very low probability (18%) of deferred as they have a very low probability (18%) of having advanced fibrosis (F2 fibrosis or higher) and having advanced fibrosis (F2 fibrosis or higher) and could thus be reassured and reassessed periodically.could thus be reassured and reassessed periodically.

Those in between: could either be retested every one Those in between: could either be retested every one or two years or, if resources are available, could be or two years or, if resources are available, could be treated.treated.

Genotype testingGenotype testing The 2016 Guidelines provide recommendations on the The 2016 Guidelines provide recommendations on the

preferred and alternative DAA regimens by HCV preferred and alternative DAA regimens by HCV genotype. genotype.

Therefore, knowing a patient’s genotype is still Therefore, knowing a patient’s genotype is still important for determining the most appropriate important for determining the most appropriate treatment regimen. treatment regimen.

Genotyping is usually carried out following sequencing Genotyping is usually carried out following sequencing of the 5'UTR (untranslated region) or of the NS5B of the 5'UTR (untranslated region) or of the NS5B region of the HCV genome.region of the HCV genome.

Genotype determination, however, is expensive and Genotype determination, however, is expensive and not available in all settings.not available in all settings.

Key Data for HCV decisionsKey Data for HCV decisions Fibrosis stage?Fibrosis stage? If cirrhosis, is it decompensated?If cirrhosis, is it decompensated? Child Child

Pugh B or C?Pugh B or C? Other comorbidities- any special situation?Other comorbidities- any special situation? HCV treatment past historyHCV treatment past history– Interferon and ribavirin regimen?Interferon and ribavirin regimen?– Protease inhibitor? Sofosbuvir?Protease inhibitor? Sofosbuvir?

http://www.hcvguidelines.org

Recommendations on Recommendations on TreatmentTreatment

The Direct Acting Anti-viral AgentsThe Direct Acting Anti-viral Agents

The Direct Acting Anti-viral The Direct Acting Anti-viral Agents….Agents….

Oral medicines that directly inhibited the replication cycle Oral medicines that directly inhibited the replication cycle of HCV.of HCV.

They target three important regions within the HCV They target three important regions within the HCV genome: NS3/4A protease, NS5A and NS5B RNA-genome: NS3/4A protease, NS5A and NS5B RNA-dependent polymerase.dependent polymerase.

These medicines These medicines – have higher sustained virological responses (SVRs) have higher sustained virological responses (SVRs)

than interferon-based regimens, than interferon-based regimens, – are shorter in treatment duration, are shorter in treatment duration, – are orally administered and are orally administered and – have fewer side-effectshave fewer side-effects

Classes of DAAs licensed for the Classes of DAAs licensed for the treatment of HCV treatment of HCV (as of October 2015)(as of October 2015)

Removal of recommendation for Removal of recommendation for treatment with telaprevir or treatment with telaprevir or

boceprevirboceprevir

Recommendation for Recommendation for persons with HCV genotype persons with HCV genotype

1 infection1 infection

Recommendation for persons Recommendation for persons with HCV genotype 5 or 6 with HCV genotype 5 or 6

infectioninfection

Special NotesSpecial Notes Regimens with daclatasvir, ledipasvir and sofosbuvir Regimens with daclatasvir, ledipasvir and sofosbuvir

can be prescribed to patients without cirrhosis as well can be prescribed to patients without cirrhosis as well as those with compensated and decompensated as those with compensated and decompensated cirrhosis.cirrhosis.

Regimens with paritaprevir, simeprevir and pegylated Regimens with paritaprevir, simeprevir and pegylated interferon can be prescribed to persons without interferon can be prescribed to persons without cirrhosis or with compensated cirrhosis but not to cirrhosis or with compensated cirrhosis but not to persons with decompensated cirrhosis because they persons with decompensated cirrhosis because they can cause liver failure can cause liver failure

If prescribed to persons with cirrhosis, they should be If prescribed to persons with cirrhosis, they should be used only in special care settingsused only in special care settings

Recommended preferred Recommended preferred and alternative regimensand alternative regimens

Summary of recommended Summary of recommended preferred regimens preferred regimens with treatment with treatment

durationsdurations

Summary of recommended Summary of recommended alternative regimens alternative regimens with treatment with treatment

durationsdurations

Contraindications/warnings: Contraindications/warnings: Therapy with direct-acting Therapy with direct-acting

antivirals:antivirals:

Contraindications/warnings: Contraindications/warnings: Therapy with RibavirinTherapy with Ribavirin

Contraindications/warnings: Contraindications/warnings: Therapy with Therapy with pegylated pegylated

interferoninterferon

Common adverse drug Common adverse drug effectseffects

FatigueFatigue HeadacheHeadache NauseaNausea PruritusPruritus Increase in total bilirubin in liver cirrhosis.Increase in total bilirubin in liver cirrhosis. Mild to moderate rashes and photosensitivityMild to moderate rashes and photosensitivity

Monitoring of Patients on Monitoring of Patients on TreatmentTreatment

Patient Treatment Pathway

HCV in Special SituationsHCV in Special Situations

Special considerations for specific populations:Special considerations for specific populations:People who inject drugs (PWID)People who inject drugs (PWID) PWID are at increased risk of HCV related PWID are at increased risk of HCV related

disease and transmissiondisease and transmission Priority for HCV treatmentPriority for HCV treatment Screening for HBV and HIV recommendedScreening for HBV and HIV recommended PWID treated with pegylated interferon/ribavirin PWID treated with pegylated interferon/ribavirin

have outcomes similar to those among non-have outcomes similar to those among non-PWIDPWID

Few data on the success of DAAs among PWID. Few data on the success of DAAs among PWID.

Special considerations for specific populations:Special considerations for specific populations:Persons with HIV/HCV coinfectionPersons with HIV/HCV coinfection More rapid progression of liver fibrosis (especially with CD4 More rapid progression of liver fibrosis (especially with CD4

count of <200 cells/mm3) count of <200 cells/mm3) Risk of hepatic decompensation higherRisk of hepatic decompensation higher SVR rates lower than HCV-monoinfected patients with SVR rates lower than HCV-monoinfected patients with

treatment with interferon/ribavirin regimentreatment with interferon/ribavirin regimen DAA therapy has substantially simplified the treatment of DAA therapy has substantially simplified the treatment of

persons with HIV and HCV persons with HIV and HCV Fewer DDIs between DAAs and ARV medicines, and SVR Fewer DDIs between DAAs and ARV medicines, and SVR

rates with DAA-based therapy are higher than 95% rates with DAA-based therapy are higher than 95% But, DDIs between HIV and HCV medications should be But, DDIs between HIV and HCV medications should be

checkedchecked

Special considerations for specific populations:Special considerations for specific populations:Children and AdolescentsChildren and Adolescents

None of the DAAs have been approved for use None of the DAAs have been approved for use among childrenamong children

the only approved treatment for children remains the only approved treatment for children remains pegylated interferon/ribavirinpegylated interferon/ribavirin

recommended for children older than 2 years. recommended for children older than 2 years. Clinical trials are urgently needed for approval of Clinical trials are urgently needed for approval of

DAAs among children. DAAs among children.

Special considerations for specific populations:Special considerations for specific populations:Persons with Chronoc Kidney Persons with Chronoc Kidney

DiseaseDisease There is an unmet need for DAA treatment in There is an unmet need for DAA treatment in

patients with severe renal disease (eGFR <30 patients with severe renal disease (eGFR <30 mL/min/1.73 m2) and those requiring mL/min/1.73 m2) and those requiring haemodialysis. haemodialysis.

Sofosbuvir, which is used in many approved Sofosbuvir, which is used in many approved regimens, does not have the safety and efficacy regimens, does not have the safety and efficacy data to support its use in these situations. data to support its use in these situations.

Both ribavirin and pegylated interferon require Both ribavirin and pegylated interferon require dose adjustment in persons with renal failure. dose adjustment in persons with renal failure.

Special considerations for specific populations:Special considerations for specific populations:Persons with Tb/HCV coinfectionPersons with Tb/HCV coinfection People at increased risk of infection with HCV are also often People at increased risk of infection with HCV are also often

at increased risk of infection with TB.at increased risk of infection with TB. Active TB should be part of the clinical evaluation of Active TB should be part of the clinical evaluation of

patients being considered for HCV treatment, if the patient patients being considered for HCV treatment, if the patient has any one of the following symptoms – current cough, has any one of the following symptoms – current cough, fever, weight loss or night sweatsfever, weight loss or night sweats

The drug level of DAAs increases and/or decreases when The drug level of DAAs increases and/or decreases when co-administered with antimicrobial medicines such as co-administered with antimicrobial medicines such as rifabutin, rifampin and rifapentine . rifabutin, rifampin and rifapentine .

Therefore, concurrent treatment of HCV infection and TB Therefore, concurrent treatment of HCV infection and TB should be avoided. Active TB should generally be treated should be avoided. Active TB should generally be treated before commencing therapybefore commencing therapy

PreventionPrevention

WHO guidance on prevention of HCV WHO guidance on prevention of HCV infection in health-care settingsinfection in health-care settings

WHO recommendations for WHO recommendations for prevention of HCV infection among prevention of HCV infection among

people who inject drugspeople who inject drugs

ConclusionConclusion The successful implementation of the The successful implementation of the

recommendations will depend on recommendations will depend on – a well-planned and appropriate process of a well-planned and appropriate process of

adaptation andadaptation and– integration into relevant regional and national integration into relevant regional and national

strategies. strategies. It is a process that will be determined by It is a process that will be determined by

– available resources, available resources, – existing enabling policies and practices, and existing enabling policies and practices, and – levels of support from partner agencies and levels of support from partner agencies and

organizationsorganizations

QuestionsQuestions

Thank YouThank You

chronic hepatitis c who guideline 2016

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