Hepatitis C medical therapy

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Overview

Treatment

Acute Hepatitis C

Since the majority of patients with acute hepatitis C are asymptomatic, the infection often goes unnoticed until the effects of chronic hepatitis begin to manifest. It is usually rare to closely monitor patients at risk to detect the development of acute hepatitis C. In the majority of patients, the response rate to treatment is higher in the acute rather than the chronic phase of infection. Moreover, treating patients with acute hepatitis has consistently shown high rates of viral clearance and significantly lower rates of chronicity. However, the best treatment regimen, the time of initiation, and the duration of therapy is still debatable. If a patient is identified as having an acute hepatitis C infection, the initial approach would include a period of monitoring of 8 - 20 weeks (often 8 - 12 weeks) to detect spontaneous viral clearance. New data suggests higher rates of viral clearance in untreated patients with acute clinical hepatitis C than previously reported.For patients who fail to clear the infection spontaneously, treatment should be initiated with Peg-IFN alfa ± ribavirin for 24 to 48 weeks, based on HCV genotype and response to therapy determined by HCV RNA measurement. Revised AASLD guidelines for the management of acute hepatitis C are expected in the summer of 2014.

Chronic Hepatitis C

Approach & Pre-treatment Assessment

Several key points need to be addressed in patients with chronic Hepatitis C prior to the initiation of therapy. Every patient with documented infection requires evaluation to determine if he/she qualifies for medical therapy. Patients with clear indications for treatment require an extensive pre-treatment assessment. Important considerations include HCV genotype, extent of liver disease, concomitant alcohol abuse, psychiatric disorders, and pregnancy among others. With current regimens being physically and financially demanding, screening is essential to identify patients requiring therapy.

Pretreatment Assessment in Patients with Chronic Hepatitis C

Necessary
Complete medical history, with emphasis on complications of liver disease, significant extrahepatic disease, and symptoms of chronic HCV that affect quality of life Psychiatric history including past or ongoing disorders with screening for depression and alcohol use Serum HBsAg, antiHBc, antiHBs, antiHAV Quantitative HCV RNA measurement HCV genotype Previous antiviral therapies and response Serum ALT, serum albumin, serum bilirubin (including direct bilirubin), and prothrombin time CBCD TSH Creatinine Glucose Uric acid (receiving telaprevir) Ferritin, iron saturation, and serum ANA Pregnancy test HIV serology ECG in patients with known cardiac disease
Recommended
Liver biopsy only if results will influence management IL28B genotype only if results will influence management Urine toxicology screen for opiates, cocaine, and amphetamines Eye exam for retinopathy in patients with diabetes or hypertension

Treatment Indications & Contraindications

Treatment accepted for patients with following characteristics: (should fulfill all characteristics)

• Age ≥ 18 years
• HCV RNA positive
• Liver biopsy showing chronic hepatitis with bridging fibrosis or higher
• Compensated liver disease:
  • Total bilirubin = 1.5 g/dL
  • INR = 1.5
  • Serum albumin > 3.4
  • Platelet count = 75,000 mm
  • No evidence of hepatic decompensation (hepatic encephalopathy or ascites)
• Acceptable hematological and biochemical profile:
  • Hemoglobin = 13 g/dL for men; 12 g/dL for women
  • Neutrophil count = 1500 /mm3
  • Serum creatinine = 1.5 mg/dL
• Willing to adhere to therapy
• No contraindications to therapy

Treatment contraindicated for patients with any of the following characteristics:

• Age ≤ 2 years
• Uncontrolled major depressive disorder
• Any solid organ transplant
• Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peg-interferon and ribavirin
• Untreated thyroid disease
• Pregnant or unwilling to comply with adequate contraception
• Severe comorbidities such as severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease
• Known hypersensitivity to drugs used

Treatment should be individualized for patients with any of the following characteristics:

• Age < 18 years of age
• Failed initial treatment (non-responder or relapser)
• Decompensated cirrhosis
• Liver transplant recipients
• Liver biopsy showing mild or no fibrosis
• Current illicit drug or alcohol abusers willing to enroll in a substance abuse program. Abstinence for a minimum of 6 months is required
• Chronic renal disease
• HIV co-infection

With the advent of newer therapies to treat hepatitis C, updated guidelines regarding when and in whom to initiate therapy are expected from the AASLD in the summer of 2014.

Antiviral Agents

Antiviral Agents used in the Treatment of Hepatitis C

Agent	Recommended Dose	Adverse Effects
PegIFN alfa-2a (Pegasys™)	180 mcg subcutaneously once weekly	Serious adverse events: <1% Depression with suicide Relapse of drug abuse/overdose Severe bacterial infections (osteomyelitis, endocarditis, pyelonephritis, pneumonia, and sepsis) Hepatic decompensation (2% of patients with HIV coinfection) Common events: 99% of patients experienced at least one Psychiatric reactions, including depression, insomnia, irritability, anxiety Flu-like symptoms such as fatigue, pyrexia, myalgia, headache, and rigors Anorexia Nausea and vomiting Diarrhea Arthralgias Injection site reactions Alopecia Pruritus
PegIFN alfa-2b (PEG-Intron™)	1.5 mc / kg SC once weekly	Serious adverse events: <1% Suicidal/Homicidal thoughts Cardiovascular events Loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis Stroke Bone marrow toxicity Development or exacerbation of autoimmune disorders Colitis Pancreatitis Pulmonary disorders including dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans Liver failure especially with HIV coinfection Common events: 50% of patients have at least one Injection site reaction Mood instability and Depression Nausea Fatigue/asthenia Headache Rigors and fevers Myalgia
Ribavirin (Rebetol™, Ribasphere™, Copegus™, RibaPak™)	Genotype 1 1,000 mg (if ≤ 75 kg) or 1,200 mg (if > 75 kg) PO daily divided into two doses Genotype 2 & 3 800 PO daily in two divided doses	Ribavirin is teratogenic and may cause birth defects and/or death of the exposed fetus. Serious adverse events: Bacterial infection (sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia) (3-5%) Hemolytic anemia (13%) Pancreatitis Liver Failure Pulmonary Disease Common events: Fatigue/asthenia Fever Myalgias Headaches
Sofosbuvir (Sovaldi™)	400 mg orally daily	x
Simeprevir (Olysio™)	150 mg orally daily	Common events: Rash Photosensitivity Pruritus Nausea Dyspnea
Boceprevir [BOC] (Victrelis™)	800 mg (4 × 200 mg capsules) PO every 7 – 9h with food in combination with PegIFN – RBV following a 4-week lead-in with PegIFN – RBV No longer recommended given the safer profile of newer protease inhibitors	x
Telaprevir [TVR] (Incivek™)	750 mg (2 × 375 mg tablets) PO every 7 – 9 h with food (20 grams fat) for 12 weeks, plus PegIFN – RBV 24 or 48 weeks No longer recommended given the safer profile of newer protease inhibitors	x

Useful Definitions

Treatment Algorithm

Genotype 1

Other Genotypes

Special Considerations

Future Therapies

Recommendations for Retreatment of Persons Who Failed to Respond to Previous Treatment : AASLD Practice Guidelines 2009

“

1. Retreatment with peginterferon plus ribavirin in patients who did not achieve an SVR after a prior full course of peginterferon plus ribavirin is not recommended, even if a different type of peginterferon is administered (for relapsers, Class III, Level C; for non-responders, Class III, Level B). 2. Retreatment with peginterferon plus ribavirin can be considered for non-responders or relapsers who have previously been treated with non-pegylated interferon with or without ribavirin, or with peginterferon monotherapy, particularly if they have bridging fibrosis or cirrhosis (Class IIa, Level B). 3. Maintenance therapy is not recommended for patients with bridging fibrosis or cirrhosis who have failed a prior course of peginterferon and ribavirin (Class III, Level B)

”

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Recommendations for Treatment of Persons with Normal Serum Aminotransferase Values: AASLD Practice Guidelines 2009

“

1. Regardless of the serum alanine aminotransferase level, the decision to initiate therapy with pegylated interferon and ribavirin should be individualized based on the severity of liver disease by liver biopsy, the potential for serious side effects, the likelihood of response, and the presence of comorbid conditions (Class I, Level B). 2. The treatment regimen for HCV-infected persons with normal aminotransferase levels should be the same as that used for persons with elevated serum aminotransferase levels (Class I, Level B).

”

Recommendations for Treatment of Persons with Acute Hepatitis C: AASLD Practice Guidelines 2009

“

1. Patients with acute HCV infection should be considered for interferon-based anti-viral therapy (Class I, Level B). 2. Treatment can be delayed for 8 to 12 weeks after acute onset of hepatitis to allow for spontaneous resolution (Class IIa, Level B). 3. Although excellent results were achieved using standard interferon monotherapy, it is appropriate to consider the use of peginterferon because of its greater ease of administration (Class I, Level B). 4. Until more information becomes available, no definitive recommendation can be made about the optimal duration needed for treatment of acute hepatitis C; however, it is reasonable to treat for at least 12 weeks, and 24 weeks may be considered (Class IIa, Level B). 5. No recommendation can be made for or against the addition of ribavirin and the decision will therefore need to be considered on a case-by-case basis (Class IIa, Level C)

”

References