Something about primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the destruction of interlobular and septal bile ducts. The natural history is usually one of gradual progression to cirrhosis and death. Although ursodeoxycholic acid (UDCA) has been shown to prolong survival free of liver transplantation, not all patients benefit from this therapy, and PBC remains an important indication for orthotopic liver transplantation (OLT). As therapy for end-stage PBC, OLT has been shown to prolong survival and improve quality of life.Recurrence of PBC after liver transplantation is not uncommon, yet there is little evidence to date that recurrent PBC is of major clinical importance.

Symptomatic Disease

The classic manifestation of PBC is that of a middleaged woman in whom fatigue and pruritus gradually

develop. Patients with PBC may also have conditions that affect their energy level, such as depression or sleep disturbance   Most patients report more severe symptoms at nighttime than in daylight hours. Curiously, pruritus  tends to gradually resolve with progression of hepatic disease. tends to gradually resolve with progression of hepatic disease. As many as 70% of individuals with PBC have coexistent

extrahepatic autoimmune disease states.

Disease Complications

Hypercholesterolemia and hyperlipidemia are present in up to 85% of patients with PBC. In early-stage disease, lipoprotein abnormalities are commonly found Metabolic bone disease is also common in patients with PBC and for the most part results from decreased bone mass (osteopenia and osteoporosis) rather than osteomalacia (defective bone mineralization).

Approximately one third of patients with PBC have osteopenia (defined as greater than 1.5 SD lower than controls), and 11% have osteoporosis (lower than 2.5 SD) by lumbar spine bone mineral densitometry.

 Hence, many patients are at an increased risk for bone fractures, which adds to the morbidity and decreased quality of life. In addition to chronically impaired liver function, which in general has been associated with osteopenia, the subsequent cholestasis and predilection for females are thought to underlie the high prevalence of bone disease in patients with PBC.

The increased occurrence of hepatocellular carcinoma (HCC) in PBC is increasingly being recognized in the late stages of disease. The clinical effectiveness of HCC surveillance by abdominal ultrasound and determination of serum α -fetoprotein levels every 6 to 12 months in end-stage PBC patients, however, remains unknown. An increased risk for extrahepatic malignancy such as breast cancer remains controversial

Diagnosis

The diagnosis of PBC is usually based on a clinical syndrome consisting of chronic cholestasis, including increased alkaline phosphatase, the presence of AMA, and characteristic histological features of nonsuppurative inflammation of the bile ducts on liver biopsy. In addition to elevated serum alkaline phosphatase, modestly increased values of alanine aminotransferase and aspartate  Although histological confirmation of the diagnosis may not be necessary for a typical patient with positive AMA, liver biopsy is needed for determining the histological stage of the disease. aminotransferase are common. Serum total bilirubin levels often rise during disease progression but are commonly within normal limits at diagnosis. Serum AMA is found in 95% of patients with PBC.

Natural History and Prognosis :

In the majority of patients with PBC, a progressive clinical course resulting in fibrosis and eventually cirrhosis  is often observed. Estimates of overall median survival range between 10 and 15 years from the time of diagnosis, whereas advanced histological disease (stage 3 or 4) imparts a median survival approaching 8 years.

 Elevations in total bilirubin above 8 to 10 mg/dL have been associated with a median life expectancy of

2 years.

Medical Treatment of Primary Biliary Cirrhosis

Five randomized controlled trials of adequate size and duration have provided extensive information regarding the effectiveness of UDCA for PBC  Improvements in symptom and hepatic biochemical parameters were demonstrated in all five studies. A combined analysis of three studies using UDCA at doses of 13 to 15 mg/kg/day revealed improvement in survival free of liver transplantation in patients receiving active drug.

 Long-term (10-year) survival with UDCA has also been Observed. Although some degree of response is seen almost universally in PBC patients receiving UDCA therapy, up to two thirds of patients may be classified as incomplete responders, defined as the failure to normalize serum hepatic biochemistry or histological progression, or both, despite treatment with UDCA. Higher levels of serum alkaline phosphatase and advanced fibrosis at baseline have been associated with incomplete responses.

A number of agents have been evaluated for further treatment of PBC, particularly in patients who fail to achieve a complete response. These agents include immunosuppressants such as corticosteroids, azathioprine, cyclosporine, and methotrexate; antifibrotic agents such as D -penicillamine; and colchicine alone or in combination with UDCA.

Liver Transplantation for Primary Biliary Cirrhosis

As of today, PBC remains among the most common indications for liver transplantation in the United States. Clearly, the most effective therapeutic alternative for patients with end-stage PBC is liver transplantation. Indications for OLT in PBC include complications of portal hypertension, such as hepatic encephalopathy, refractory ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome. In addition, intractable pruritus and disabling fatigue have been considered a justifiable indication for patients with PBC, although the increasing donor organ shortage has made it difficult to perform OLT for quality-of-life issues alone.

Outcome of Orthotopic Liver Transplantation for Primary Biliary Cirrhosis:

As seen in the figure survival after transplantation has significantly improved after 1990. Pretransplant disease severity has the greatest impact on short-term outcome because patients with

higher risk scores are likely to have multisystem dysfunction and be at higher risk for perioperative mortality and morbidity. Once patients survive the initial insult from the transplant operation, their longevity may not be greatly affected by the extent of injury to the replaced liver.

Conclusion

OLT represents a major advance in the care of patients with PBC. Although there will undoubtedly be more clinical trials to assess the efficacy of medical therapies, no studies to date have demonstrated that these therapies ultimately preclude death or the need for OLT. Mathematical models provide a reliable estimate of a patient’s survival with and without transplantation. As the trend continues toward progressively more favorable survival with OLT, the tendency will be to offer transplantation earlier in the course of the disease. Studies are currently under way to better assess qualityof- life and cost-effectiveness issues in liver transplantation. Most patients appear to enjoy extended periods of good health and productive work after transplantation.

Pearls and Pitfalls

• The diagnosis of PBC should be considered when the following clinical features are present:

• Cholestatic serum liver profile

• Serum AMA positivity

• Liver histology compatible with PBC

• Initial therapy with UDCA at 13 to 15 mg/kg/day for a minimum treatment period of 6 months is

recommended. The treatment goal is to achieve a reduction in the serum alkaline phosphatase

level that is less than or equal to 1.5 times the upper limit of normal (complete response).

• Survival after liver transplantation in PBC exceeds 90% at 1 year and 80% at 3 years.

•  Recurrent PBC may occur in up to 25% of patients after liver transplantation.

A complete guide for Testing, Managing, and Treating Hepatitis C – What does American Association of Study of Liver Diseases (AASLD) say in the sofosbuvir Era.

A complete guide for Testing,

Managing, and Treating Hepatitis C – What does American Association of Study of Liver Diseases (AASLD) say in the sofosbuvir Era.

This topic will be difficult to understand for general public.This topic is specially for my physician and gastro friends.

So, sofosbuvir is going to be cheaper in India in my earlier post I have written about why sofosbuvir is considered wonder drug.

AASLD is regularly updating about its managing HCV. It has released latest guidelines regarding managing HCV. This is exhausting list of guidelines but guys it covers each and every aspect. I have jotted down each and every guideline in different situation which will definitely help you how to manage HCV in the modern era when sofosbuvir will be released in Indian market.

Recommendations are based on scientific evidence and expert opinion. Each recommended statement

includes a Roman numeral (I, II, or III) that represents the level of the evidence that supports the

recommendation, and a letter (A, B, or C) that represents the strength of the recommendation.

Classification Description

Class I Conditions for which there is evidence and/or general agreement that a given

diagnostic evaluation, procedure, or treatment is beneficial, useful, and

effective

Class II Conditions for which there is conflicting evidence and/or a divergence of

opinion about the usefulness and efficacy of a diagnostic evaluation,

procedure, or treatment

Class IIa Weight of evidence and/or opinion is in favor of usefulness and efficacy

Class IIb Usefulness and efficacy are less well established by evidence and/or opinion

Class III Conditions for which there is evidence and/or general agreement that a

diagnostic evaluation, procedure, or treatment is not useful and effective or if

it in some cases may be harmful

Level of

Evidence

Description

Level A* Data derived from multiple randomized clinical trials, meta-analyses, or

equivalent

Level B* Data derived from a single randomized trial, nonrandomized studies, or

equivalent

Level C Consensus opinion of experts, case studies, or standard of care

Measures to Prevent

Transmission of HCV

Persons with HCV infection should be counseled to avoid sharing toothbrushes and

dental or shaving equipment, and be cautioned to cover any bleeding wound to prevent

the possibility of others coming into contact with their blood.

Persons should be counseled to stop using illicit drugs and enter substance abuse

treatment. Those who continue to inject drugs should be counseled to avoid reusing or

sharing syringes, needles, water, cotton, and other drug preparation equipment; use new

sterile syringes and filters and disinfected cookers; clean the injection site with a new

alcohol swab; and dispose of syringes and needles after one use in a safe, punctureproof

container.

Persons with HCV infection should be advised not to donate blood and to discuss HCV

serostatus prior to donation of body organs, other tissue, or semen.

Persons with HIV infection and those with multiple sexual partners or sexually

transmitted infections should be encouraged to use barrier precautions to prevent sexual

transmission. Other persons with HCV infection should be counseled that the risk of

sexual transmission is low and may not warrant barrier protection.

Household surfaces and implements contaminated with visible blood from an HCVinfected

person should be cleaned using a dilution of 1 part household bleach to 9 parts

water. Gloves should be worn when cleaning up blood spills.

When to test your self for Hepatitis C ??

HCV testing is recommended at least once for persons born between 1945 and

1965.

Rating: Class I, Level B

Other persons should be screened for risk factors for HCV infection, and one-time

testing should be performed for all persons with behaviors, exposures, and

conditions associated with an increased risk of HCV infection.

1. Risk behaviors

Injection-drug use (current or ever, including those who injected once)

Intranasal illicit drug use

2. Risk exposures

Long-term hemodialysis (ever)

Getting a tattoo in an unregulated setting

Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or

mucosal exposures to HCV-infected blood

Children born to HCV-infected women

Prior recipients of transfusions or organ transplants, including persons who:

were notified that they received blood from a donor who later tested positive for HCV

infection

received a transfusion of blood or blood components, or underwent an organ

transplant before July 1992

received clotting factor concentrates produced before 1987

3. Other medical conditions

HIV infection

Unexplained chronic liver disease and chronic hepatitis including elevated alanine

aminotransferase levels

Rating: Class I, Level B

Annual HCV testing is recommended for persons who inject drugs and for HIVseropositive

men who have unprotected sex with men. Periodic testing should be

offered to other persons with ongoing risk factors for exposure to HCV.

Rating: Class IIA, Level C

Evidence

An anti-HCV test is recommended for HCV testing, and if the result is positive,

current infection should be confirmed by a sensitive RNA test.

Rating: Class I, Level A

Among persons with a negative anti-HCV test who are suspected of having liver

disease, testing for HCV RNA or follow-up testing for HCV antibody is

recommended if exposure to HCV occurred within the past 6 months; testing for

HCV RNA can also be considered in persons who are immunocompromised.

Rating: Class I, Level C

Among persons suspected of reinfection after previous spontaneous or treatmentrelated

viral clearance, initial HCV-RNA testing is recommended because an anti-

HCV test is expected to be positive

Rating: Class I, Level C

Quantitative HCV RNA testing is recommended prior to the initiation of antiviral

therapy to document the baseline level of viremia (ie, baseline viral load).

Rating: Class I, Level A

Testing for HCV genotype is recommended to guide selection of the most

appropriate antiviral regimen.

Rating: Class I, Level A

If found to have positive results for anti-HCV test and negative results for HCV

RNA by PCR, persons should be informed that they do not have evidence of

current (active) HCV infection.

Rating: Class I, Level A

Persons with current (active) HCV infection should receive education and

interventions aimed at reducing progression of liver disease and preventing

transmission of HCV.

Rating: Class IIa, Level B

1. Abstinence from alcohol and, when appropriate, interventions to facilitate cessation

of alcohol consumption should be advised for all persons with HCV infection.

Rating: Class IIa, level B

2. Evaluation for other conditions that may accelerate liver fibrosis, including HBV

and HIV infections, is recommended for all persons with HCV infection.

Rating: Class IIb, level B

3. Evaluation for advanced fibrosis, using liver biopsy, imaging, or non-invasive

markers, is recommended in all persons with HCV infection to facilitate an

appropriate decision regarding HCV treatment strategy and determine the need for

initiating additional screening measures (eg, hepatocellular carcinoma [HCC]

screening).

Rating: Class I, Level B

4. Vaccination against hepatitis A and hepatitis B is recommended for all persons

with HCV infection who are susceptible to these types of viral hepatitis.

Rating: Class IIa, Level C

5. All persons with HCV infection should be provided education on how to avoid HCV

transmission to others.

Rating: Class I, level C

Evaluation by a practitioner who is prepared to provide comprehensive

management, including consideration of antiviral therapy, is recommended for all

persons with current (active) HCV infection.

Rating: Class IIa, level C

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.

Rating: Class I, Level A

Clinical Benefit of Cure

The proximate goal of HCV therapy is SVR (virologic cure), defined as the continued absence of detectable HCV RNA at least 12 weeks after completion of therapy. SVR is a marker for cure of HCV infection and has been shown to be durable in large prospective studies in more than 99% of patients followed up for 5 years or more.

Recommendations for when and in whom to initiate treatment

Treatment is recommended for patients with chronic HCV infection.

Rating: Class I, Level A

Treatment is assigned the highest priority for those patients with advanced

fibrosis (Metavir F3),(liver biopsy findings) those with compensated cirrhosis (Metavir F4), liver

transplant recipients, and patients with severe extrahepatic hepatitis C.

Based on available resources, treatment should be prioritized as necessary so that

patients at high risk for liver-related complications and severe extrahepatic

hepatitis C complications are given high priority .

When and in Whom to Initiate HCV Therapy Table 2. Persons Whose Risk of HCV

Transmission is High and in Whom HCV Treatment May Yield Transmission Reduction

Benefits

High HCV Transmission Risk*

Men who have sex with men (MSM) with high-risk sexual practices

Active injection drug users

Incarcerated persons

Persons on long-term hemodialysis

Rating: Class IIa, Level C

Recommendations for pretreatment assessment

An assessment of the degree of hepatic fibrosis, using noninvasive testing or liver

biopsy, is recommended.

Rating: Class I, Level A

Recommendation for repeat liver disease assessment

Ongoing assessment of liver disease is recommended for persons in whom

therapy is deferred.

Rating: Class I, Level C

Recommended regimen for treatment-naive patients with HCV genotype 1 who are eligible

to receive IFN.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) plus weekly pegylated interferon for 12 weeks is recommended for interferon eligible persons

with HCV genotype 1 infection, regardless of subtype.

Rating: Class I, Level A

Recommended regimen for treatment-naive patients with HCV genotype 1 who are not

eligible to receive IFN.

Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based

RBV (1000 mg [<75 kg] to 1200 mg [>75 kg] for 12 weeks is recommended

IFN-ineligible IFN ineligible is defined as one or more of the below:

• Intolerance to IFN

• Autoimmune hepatitis and other autoimmune disorders

• Hypersensitivity to PEG or any of its components

• Decompensated hepatic disease

• Major uncontrolled depressive illness

• A baseline neutrophil count below 1500/?L, a baseline platelet count below 90,000/?L

or baseline hemoglobin below 10 g/dL

• A history of preexisting cardiac disease patients with HCV genotype 1 infection,

regardless of subtype.

Alternative regimens for treatment-naive patients with HCV genotype 1 who are eligible to

receive IFN.

Daily simeprevir (150 mg) for 12 weeks and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg]) plus weekly PEG for 24 weeks is an acceptable regimen for IFNeligible

persons with either

1. HCV genotype 1b or

2. HCV genotype 1a infection in whom the Q80K polymorphism is not detected prior

to treatment.

Rating: Class IIa, Level A

Alternative regimens for treatment-naive patients with HCV genotype 1 who are not

eligible to receive IFN.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 24 weeks is an acceptable regimen for

The following regimens are NOT recommended for treatment-naive patients with HCV

genotype 1.

PEG/RBV with or without telaprevir or boceprevir for 24 to 48 weeks

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

II. Genotype 2

Recommended regimen for treatment-naive patients with HCV genotype 2, regardless of

eligibility for IFN therapy:

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 12 weeks is recommended for treatment-naive patients with HCV

genotype 2 infection.

Rating: Class I, Level A

Alternative Regimens for treatment-naive patients with genotype 2:

None

The following regimens are NOT recommended for treatment-naive patients with HCV

genotype 2.

PEG/RBV for 24 weeks

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Telaprevir-, boceprevir-, or simeprevir-based regimens

Rating: Class III, Level A

III. Genotype 3

Recommended regimen for treatment-naive patients with HCV genotype 3, regardless of

eligibility for IFN therapy:

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 24 weeks is recommended for treatment-naive patients with HCV

genotype 3 infection.

Rating: Class I, Level B

Alternative regimens for treatment-naive patients with genotype 3 who are eligible to

receive IFN.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) plus weekly PEG for 12 weeks is an acceptable regimen for IFN-eligible

persons with HCV genotype 3.

Rating: Class IIa, Level A

The following regimens are NOT recommended for treatment-naive patients with HCV

genotype 3.

PEG/RBV for 24 to 48 weeks

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Telaprevir-, boceprevir-, or simeprevir-based regimens should not be used

for patients with genoty

pe 3 HCV infection.

Rating: Class III, Level A

IV. Genotype 4

Recommended regimen for treatment-naive patients with HCV genotype 4 who are eligible

to receive IFN.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) plus weekly PEG for 12 weeks is recommended for IFN-eligible persons

Recommended regimen for treatment-naive patients with genotype 4 who are not eligible

to receive IFN.

Daily sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 24 weeks.

Alternative regimens for treatment-naive patients with HCV genotype 4 who are eligible to

receive IFN.

Daily simeprevir (150 mg) for 12 weeks and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg]) plus weekly PEG for 24 to 48 weeks is an alternative regimen for

IFN-eligible persons with HCV genotype 4 infection.

The following regimens are NOT recommended for treatment-naive patients with HCV

genotype 4.

PEG/RBV for 48 weeks

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Telaprevir- or boceprevir-based regimens

Rating: Class III, Level A

V. Genotype 5 or 6

Recommended regimen for treatment-naive patients with HCV genotype 5 or 6.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) plus weekly PEG for 12 weeks is recommended for IFN-eligible persons

with HCV genotype 5 or 6 infection.

Rating: Class IIa, Level B

Alternative regimens for treatment-naive patients with HCV genotype 5 or 6.

Daily weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG

for 48 weeks is an acceptable regimen for persons infected with HCV genotype 5

or 6.

Rating: Class IIb, Level A

The following regimens are NOT recommended for treatment-naive patients with genotype

5 or 6 HCV.

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Telaprevir- or boceprevir-based regimens

Rating: Class III, Level A

RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY

HAS FAILED

I. Genotype 1

Recommended regimen for HCV genotype 1 PEG/RBV (without an HCV protease inhibitor)

nonresponder patients:

Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based

RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for

retreatment of HCV genotype 1 infection, regardless of subtype or IFN eligibility.

Rating: Class IIa, Level B

Recommended regimen for HCV genotype 1 PEG/RBV (with an HCV protease inhibitor)

nonresponder patients:

Daily sofosbuvir (400 mg) for 12 weeks plus weight-based RBV (1000 mg [<75 kg]

to 1200 mg [>75 kg]) and weekly PEG for 12 to 24 weeks is recommended for

retreatment of HCV genotype 1 infection, regardless of subtype.

Rating: Class IIb, Level C

Alternative regimen for PEG/RBV (with or without an HCV protease inhibitor)

nonresponder patients with HCV genotype 1.

Eligible to receive IFN:

Daily sofosbuvir (400 mg) for 12 weeks and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg]) plus weekly PEG for 12 to 24 weeks is an alternative for

retreatment of IFN-eligible persons with HCV genotype 1 infection, regardless of

subtype.

Rating: Class IIb, Level C

Ineligible to receive IFN:

Daily sofosbuvir (400 mg) for 24 weeks and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg]) for 24 weeks is an alternative for retreatment of IFN-ineligible

persons with HCV genotype 1 infection, regardless of subtype.

Rating: Class IIb, Level C

Alternative regimen for PEG/RBV (without an HCV protease inhibitor) nonresponder

patients with HCV genotype 1 who are eligible to receive IFN.

Daily simeprevir (150 mg) for 12 weeks plus weight-based RBV (1000 mg [<75 kg]

to 1200 mg [>75 kg]) and weekly PEG for 48 weeks is an alternative for IFN-eligible

persons with HCV genotype 1 infection. (All patients with cirrhosis who are

receiving simeprevir should have well compensated liver disease.)

Rating: Class IIa, Level A

The following regimens are NOT recommended for PEG/RBV (with or without an HCV

protease inhibitor) nonresponder patients with HCV genotype 1:

PEG/RBV with or without telaprevir or boceprevir

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

For nonresponder patients with genotype 1 and a history of decompensated

cirrhosis (moderate or severe hepatic impairment; CTP class B or C), treatment is

not indicated because of the risks of PEG and boceprevir and telaprevir in this

population.

II. Genotype 2

Recommended regimen for genotype 2 PEG/RBV nonresponders.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 12 weeks is recommended for retreatment of HCV genotype 2

infection. (Patients with cirrhosis may benefit by extension of treatment to 16

weeks.)

Rating: Class I, Level A

Alternative regimen for PEG/RBV nonresponder patients with HCV genotype 2 infection

who are eligible to receive IFN.

Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is an alternative for IFNeligible

persons with HCV genotype 2 infection.

Rating: Class IIa Level B

The following regimens are NOT recommended for nonresponder patients with HCV

genotype 2.

PEG/RBV with or without telaprevir, boceprevir or simeprevir

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

III. Genotype 3

Recommended regimen for HCV genotype 3 PEG/RBV nonresponders.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 24 weeks is recommended for retreatment of HCV genotype 3

infection.

Rating: Class IIa, Level A

Alternate regimen for HCV genotype 3 PEG/RBV nonresponder patients who are eligible to

receive IFN.

Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75

kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is an alternative for IFNeligible

persons with HCV genotype 3 infection.

Rating: Class IIa Level B

The following regimens are NOT recommended for nonresponder patients with HCV

genotype 3 infection.

PEG/RBV with or without telaprevir, boceprevir or simeprevir

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

IV. Genotypes 4, 5, and 6

Recommended regimen for HCV genotype 4, PEG/RBV nonresponder patients.

Daily sofosbuvir (400 mg) for 12 weeks and daily weight-based RBV (1000 mg [<75

kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is recommended for

retreatment of IFN-eligible persons with HCV genotype 4 infection

Rating: Class IIa, Level C

Alternate regimen for HCV genotype 4, PEG/RBV nonresponder patients.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg

[>75 kg]) for 24 weeks is recommended for retreatment of HCV genotype 4

infection.

Rating: Class IIa, Level B

The following regimens are NOT recommended for nonresponder patients with genotype 4

HCV infection.

PEG/RBV with or without telaprevir or boceprevir

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Recommended regimen for HCV genotype 5 or 6, PEG/RBV nonresponder patients.

Daily sofosbuvir (400 mg) for 12 weeks and daily weight-based RBV (1000 mg [<75

kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is recommended for retreatment of IFN-eligible persons with HCV genotype 5 or 6 infection.

Rating: Class IIa, Level C

The following regimens are NOT recommended for nonresponder patients with HCV

genotype 5 or 6.

PEG/RBV with or without telaprevir or boceprevir

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

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.

Rating: Class I, Level C

The following laboratory tests are recommended within 6 weeks prior to starting antiviral

therapy:

Complete blood cell (CBC) count; international normalized ratio (INR)

Hepatic function panel (albumin, total and direct bilirubin, alanine

aminotransferase, aspartate aminotransferase, and alkaline phosphatase

levels)

Thyroid-stimulating hormone (TSH; if IFN is used)

Calculated glomerular filtration rate (GFR)

Rating: Class I, Level B

The following laboratory test is recommended within 12 weeks of starting antiviral

therapy:

HCV genotype and quantitative HCV viral load

Rating: Class I, Level B

Recommended monitoring during antiviral therapy

CBC count, creatinine level, calculated GFR, and hepatic function panel are

recommended every 4 weeks during antiviral therapy. TSH is recommended every

12 weeks for patients on IFN. More frequent assessment for drug-related toxic

effects (eg, CBC count for patients receiving RBV) is recommended as clinically

indicated.

Rating: Class I, Level B

Quantitative HCV viral load testing is recommended after 4 weeks of therapy, at

the end of treatment, and at 12 weeks following completion of therapy.

Rating: Class I, Level B

Quantitative Quantitative HCV viral load monitoring at 4 weeks is recommended, but

discontinuation of treatment because this test result is missing is NOT

recommended.

Rating: Class III, Level C

Recommended monitoring for pregnancy-related issues prior to and during antiviral

therapy that includes RBV

Women of childbearing age should be cautioned not to become pregnant while

receiving RBV-containing antiviral regimens, and for up to 6 months after

stopping.

Rating: Class I, Level C

Treatment with RBV is NOT recommended for pregnant women or for women who

are unwilling to adhere to use of adequate contraception, who are either receiving

RBV themselves or who are sexual partners of male patients who are receiving

RBV.

Rating: Class III, Level C

Female patients and sexual partners of male patients who have received RBV

should NOT become pregnant for at least 6 months after stopping RBV.

Rating: Class III, Level C

Recommended monitoring for patients in whom treatment failed to achieve an SVR

Disease progression assessment every 6 months to 12 months with a hepatic

function panel, CBC count, and INR is recommended.

Rating: Class I, Level C

Surveillance for hepatocellular carcinoma with ultrasound testing every 6 months

is recommended for patients with more advanced fibrosis (ie, Metavir F3 or F4).

Rating: Class I, Level C

Endoscopic surveillance for esophageal varices is recommended if cirrhosis is

present.

Rating: Class I, Level A

Evaluation for retreatment is recommended as effective alternative treatments

become available.

Rating: Class I, Level C

Monitoring for HCV drug resistance-associated variants (RAVs) on and after

therapy is NOT recommended.

Rating: Class III, Level C

Recommended follow-up for patients who achieve an SVR

For patients who do not have advanced fibrosis (ie, those with Metavir F0, F1, or

F2), recommended follow-up is the same as if they were never infected with HCV.

Rating: Class I, Level B

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.

Rating: Class I, Level A

Surveillance for hepatocellular carcinoma with twice yearly ultrasound testing is

recommended for patients with advanced fibrosis (ie, Metavir F3 or F4), who

achieve an SVR.

Rating: Class I, Level C

Rating: Class I, Level C

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.

Rating: Class I, Level C

Assessment of other causes of liver disease is recommended for patients who

develop persistently abnormal liver tests after achieving an SVR.

Rating: Class I, Level C

Routine assessment for regression in liver fibrosis after achieving SVR is NOT

recommended.

Rating: Class III, Level C

Monitoring for HCV during chemotherapy and immunosuppression

Prospective monitoring for HCV recurrence among patients who achieved an SVR

and who are receiving immunosuppressive treatment (eg, systemic corticosteroids, antimetabolites, chemotherapy, etc.) is NOT routinely

recommended.

Rating: Class III, Level C

UNIQUE PATIENT POPULATIONS

Recommended regimen(s) for treatment-naive and prior relapser HIV/HCV-coinfected

patients with genotype 1 infection who are eligible to receive IFN:

Sofosbuvir (400 mg once daily) and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg] daily) plus weekly PEG for 12 weeks is recommended for

IFN-eligible persons with HCV genotype 1 infection, regardless of subtype.

Rating: Class I, Level B

Recommended regimen(s) for treatment-naive and prior relapser HIV/HCV-coinfected

patients with genotype 1 who are ineligible or unwilling to receive IFN.

Sofosbuvir (400 mg once daily) and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg] daily) for 24 weeks is recommended for treatment-naive

HIV/HCV-coinfected patients with HCV genotype 1 infection.

Rating: Class I, Level B

Sofosbuvir (400 mg once daily) plus simeprevir (150 mg once daily), with or

without weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg] daily) for

12 weeks is recommended for treatment-naive and prior PEG/RBV relapser

HIV/HCV-coinfected patients with genotype 1 infection. Simeprevir should

only be used with antiretroviral drugs with which it does not have significant

interactions: raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir,

emtricitabine, lamivudine, and abacavir.

Rating: Class IIa Level C

Recommended regimen(s) for treatment-experienced patients with HCV genotype 1 with a

history of PEG/RBV plus telaprevir or boceprevir nonresponse

Treat as recommended for HCV-monoinfected individuals.

Recommended regimen(s) for treatment-naive and treatment-experienced HIV/HCVcoinfected

patients with genotype 2 and 3 infection

Use the same regimens as is recommended for persons with HCV

monoinfection; specifically:

For patients with genotype 2 infection: sofosbuvir (400 mg once daily) and

weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg] daily) for 12

weeks is recommended for treatment-naive and treatment-experienced

HIV/HCV-coinfected patients. Patients who are prior nonresponders and

have cirrhosis may benefit by extension of treatment to 16 weeks.

Rating: Class I, Level B

For patients with genotype 3 infection: sofosbuvir (400 mg once daily) and

weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg] daily) for 24

weeks is recommended for treatment-naive and treatment-experienced

HIV/HCV-coinfected patients.

Rating: Class I, Level B

Recommended regimen(s) for treatment-naive and treatment-experienced HIV/HCVcoinfected

patients with genotype 4, 5, or 6 HCV:

Treat as recommended for persons with HCV monoinfection.

Alternative regimen(s) for treatment-naive or treatment-experienced (prior PEG/RBV

relapse) HIV/HCV- coinfected patients with genotype 1 who are eligible to receive IFN

Simeprevir (150 mg once daily) for 12 weeks and weight-based RBV (1000

mg [<75 kg] to 1200 mg [>75 kg] daily) plus weekly PEG for 24 weeks (for

treatment-naive and treatment-experienced with prior relapse to PEG/RBV) is

an acceptable regimen for IFN-eligible HIV/HCV-coinfected persons with

either (1) HCV genotype 1b or (2) HCV genotype 1a infection in whom the

Q80K polymorphism is not detected prior to treatment. Simeprevir can only

be used with the following antiretroviral drugs: raltegravir, rilpivirine,

maraviroc, enfuvirtide tenofovir, emtricitabine, lamivudine, and abacavir.

Rating: Class IIa, Level B

Alternative regimen(s) for treatment-experienced (PEG/RBV nonresponders) HIV/HCVcoinfected

patients with genotype 1 who are eligible for IFN

Sofosbuvir (400 mg once daily) and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg] daily) plus weekly PEG for 12 weeks is an acceptable

regimen for IFN-eligible persons with HCV genotype 1 infection, regardless

of subtype.

Rating: Class IIb, Level C

Alternative regimen(s) for treatment-naive and PEG/RBV relapser HIV/HCV-coinfected

patients with genotype 1 who are ineligible or unwilling to receive IFN.

None

Alternative regimen(s) for treatment-experienced (PEG/RBV nonresponder) HIV/HCVcoinfected

patients with genotype 1 who are ineligible to receive IFN.

Sofosbuvir (400 mg once daily) and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg] daily) for 24 weeks is an acceptable regimen for treatmentexperienced

(nonresponder) HIV/HCV-coinfected patients with HCV genotype

1 infection.

Rating: Class IIb, Level C

Alternative regimen(s) for treatment-naive and PEG/RBV relapser, HIV/HCV-coinfected

patients with genotype 2 or 3 infection.

None

Alternative regimen(s) for treatment-experienced (PEG/RBV nonresponder) HIV/HCVcoinfected

patients with genotype 2 or 3 infection who are eligible to receive IFN.

Sofosbuvir (400 mg once daily) and weight-based RBV (1000 mg [<75 kg] to

1200 mg [>75 kg] daily) plus weekly PEG for 12 weeks is an acceptable

regimen for treatment-experienced IFN-eligible persons with HCV genotype 2

or 3 infection.

Rating: Class IIa, Level C

Alternative regimen(s) for treatment-naive and treatment-experienced HIV/HCV-coinfected

patients with HCV genotype 4, 5, or 6 infection.

None

The following regimens are NOT recommended for treatment-naive or treatmentexperienced

HIV/HCV-coinfected patients

PEG/RBV with or without telaprevir or boceprevir for 24 to 48 weeks

Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Patients with Cirrhosis

Treatment-naive patients with compensated cirrhosis, including those with

hepatocellular carcinoma, should receive the same treatment as recommended for

patients without cirrhosis.

Rating: Class I, Level A

Patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class

B or C) should be referred to a medical practitioner with expertise in that condition (ideally in a liver transplant center).

Rating: Class I, Level C

If the decision to treat has been made, the recommended regimen for patients with any

HCV genotype who have decompensated cirrhosis (moderate or severe hepatic

impairment; CTP class B or C) who may or may not be candidates for liver transplantation,

including those with hepatocellular carcinoma. This regimen should be used only by

highly experienced HCV providers

Daily sofosbuvir (400 mg) plus weight-based RBV (with consideration of the

patient's creatinine clearance and hemoglobin level) for up to 48 weeks

Rating: Class IIb, Level B

The following regimens are NOT recommended for patients with decompensated cirrhosis

(moderate or severe hepatic impairment; CTP class B or C):

Any IFN-based therapy

Rating: Class III, Level A Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Telaprevir-, boceprevir-, or simeprevir-based regimens

Rating: Class III, Level A

Patients Who Develop Recurrent HCV Infection Post-Liver Transplantation

Recommended regimen for treatment-naive patients with HCV genotype 1 in the allograft

liver, including those with compensated cirrhosis

Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without RBV (initial

dose 600 mg/day, increased monthly by 200 mg/day as tolerated to weight-based

dose of 1000 mg [<75 kg] to 1200 mg [>75 kg] 1200 mg), for 12 weeks to 24 weeks

is recommended for patients with compensated allograft HCV genotype 1

infection.

Rating: Class IIb, Level C

Recommended regimen for treatment-naive patients with HCV genotype 2 or 3 in the

allograft liver, including those with compensated cirrhosis

Daily sofosbuvir (400 mg) and RBV (initial dose 600 mg/day, increased monthly by

200 mg/day as tolerated to weight-based dose of 1000 mg [<75 kg] to 1200 mg [>75

kg] 1200 mg) with consideration of the patient's CrCl value and hemoglobin level

for 24 weeks is recommended for patients with compensated allograft HCV

genotype 2 or 3 infection.

Rating: Class IIb, Level C

Alternate regimen for treatment-naive patients with genotype 1 HCV in the allograft liver,

including those with compensated cirrhosis.

Daily sofosbuvir (400 mg) and RBV (initial dose 600 mg/day, increased monthly by

200 mg/day as tolerated to weight-based dose of 1000 mg [<75 kg] to 1200 mg [>75

kg] 1200 mg) with consideration of the patient's CrCl value and hemoglobin level,

with or without PEG (in the absence of contraindication to its use), for 24 weeks is

recommended for patients with compensated allograft HCV genotype 1 infection.

Rating: Class IIb, Level C

The following regimens are NOT recommended for treatment-naive patients with

compensated allograft hepatitis C virus infection.

Monotherapy with PEG, RBV, or a DAA

Rating: Class III, Level A

Telaprevir- or boceprevir- based regimens should not be used for patients with compensated allograft hepatitis C virus infection.

Rating: Class III, Level A

Decompensated Cirrhosis

Treatment-naive patients with decompensated allograft HCV infection should

receive the same treatment as recommended for patients with decompensated

cirrhosis (moderate or severe hepatic impairment; CTP class B or C).

Rating: Class I, Level C

Patients with Renal Impairment, Including Severe Renal Impairment (CrCl

<30 mL/min) or ESRD Requiring Hemodialysis or Peritoneal Dialysis

When using sofosbuvir to treat or retreat HCV infection in patients with

appropriate genotypes, no dosage adjustment is required for patients with mild to

moderate renal impairment (CrCl >30 mL/min). Sofosbuvir is not recommended in

patients with severe renal impairment/ESRD (CrCl <30 mL/min) or those who

require hemodialysis, because no dosing data are currently available for this

patient population.

Rating: Class IIa, level B

When using simeprevir in treatment/retreatment of HCV-infected patients, no

dosage adjustment is required for patients with mild to moderate to severe renal

impairment. Simeprevir has not been studied in patients with ESRD, including

those requiring hemodialysis.

Rating: Class IIa, level B

In patients with renal impairment/ESRD/HD, dosing of PEG and RBV should follow

updated FDA recommendations or package insert recommendations based on

calculated GFR. Caution should be used in administering RBV to these patients,

and close monitoring of hemoglobin is required.

Rating: Class IIa, level B