Hepatitis C: New Treatment Guidelines

Jane Giang, PharmD, BCPS, CGP;

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May 13, 2014

Pharmacy Practice in Focus: Health Systems

May 2014

Volume3

Issue 3

Hepatitis C: New Treatment Guidelines

Author(s):

Jane Giang, PharmD, BCPS, CGP

Hepatitis C treatment guidelines have been updated to include several new drugs.

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the Unites States.¹ Management of HCV has been evolving with the introduction of direct-acting antivirals such as boceprevir (Victrelis) and telaprevir (Incivek) in 2011, as well as with the approval of sofosbuvir (Sovaldi) and simeprevir (Olysio) in 2013.^2,3 Recent changes to the HCV guidelines with a focus on treatment-naïve patients will be reviewed in this article.

Background

HCV is a positive-stranded RNA virus in the Flaviviridae family.⁴ It is the principal cause of death from liver disease and the leading indication for liver transplantation in the United States.5 It is estimated that up to 3.9 million people in the United States are chronically infected with HCV.³ However, 45% to 85% of infected persons are unaware of their condition.³

Transmission and Symptoms

HCV is primarily transmitted through percutaneous exposure to blood.² Individuals at risk of HCV infection are listed in Table 1.⁶

Most patients with chronic HCV infection are asymptomatic, but when symptoms do occur they are generally mild and can include fever, fatigue, dark urine, clay-colored stool, abdominal pain, loss of appetite, nausea, vomiting, and jaundice.⁶

Diagnosis

The Centers for Disease Control and Prevention and the US Preventive Services Task Force recommend that all persons born between the years 1945 and 1965 be screened for HCV and that others be screened based on behaviors, exposures, and conditions associated with high risk of HCV infection.^7,8 The first recommended test for all persons is the HCV antibody test. A positive HCV antibody test indicates either current HCV infection, past infection that has resolved, or a false-positive test result; therefore, HCV RNA testing should be performed to confirm current HCV infection and guide clinical management, including initiation of HCV treatment.⁷

Prior to initiation of therapy, genotyping is performed to predict the likelihood of response to treatment regimen and to determine the optimal duration of therapy.5,6 There are at least 6 major genotypes, 1 through 6, with genotype 1 being the most common in the United States as well as the most difficult to treat, followed by genotypes 2 and 3.^3,5

Management and Treatment

In addition to medical treatment, patients with HCV infection should be educated on how to prevent infection of others and how to prevent further damage to their liver, most importantly by abstaining from alcohol.²

Until 2011, the standard of therapy for HCV infection had been peginterferon (PEG) plus ribavirin (RBV).^2,5 Currently there are 2 types of PEG products available in the United States, PEG alfa-2a (Pegasys) and PEG alfa-2b (PegIntron).⁵ Table 2 lists the recommended dosages of PEG and RBV. This PEG/RBV regimen was recommended for 48 weeks for genotypes 1, 4, and 6 and for 24 weeks for genotypes 2 and 3.^9,12 Treatment responses are defined by sustained virological response (SVR), which is defined by the absence of HCV RNA from serum after discontinuation of therapy. In order to be considered virologically “cured,” SVR must be reached.⁵ This PEG/RBV regimen resulted in modest rates of SVR of only 40% to 50% in genotype 1 and 70% to 80% in genotypes 2, 3, and 4.²

Treatment with the combination of PEG and RBV was followed by significant adverse events (AEs), which led many patients to discontinue therapy.⁵ Common side effects of PEG include influenza-like symptoms such as fatigue, headache, fever, and rigors, as well as psychiatric side effects including depression, irritability, and insomnia.^5,9,12 Neutropenia and anemia were also common causes warranting dose reductions.^5,9,12 With RBV, the most common side effect is hemolytic anemia, which may also require dose reduction, in addition to mild lymphopenia, hyperuricemia, itching, rash, cough, and nasal stuffiness.^5,10,11 While on RBV, the strict use of contraceptive methods is recommended both during treatment and for 6 months after, as fetal death and fetal abnormalities have been reported in animals.^5,10,11

In 2011, the FDA approved 2 protease inhibitors, boceprevir (BOC) and telaprevir (TVR), for treatment of HCV genotype 1, which prompted an update on the practice guidelines by the American Association for the Study of Liver Disease (AASLD).² In these guidelines, BOC or TVR was recommended to be added on to PEG/RBV for optimal treatment in genotype 1 HCV patients.² However, regimens containing either BOC or TVR still had significant disadvantages, such as limited efficacy in patients with HCV infections other than genotype 1, and low genetic barrier to resistance, longer duration of treatment, frequent dosing, and high pill burden.^2,3

In 2013, 2 more drugs were approved by the FDA, sofosbuvir (SOF) and simeprevir (SMV), which are now integral in the updated guidelines published in 2014 by the AASLD and Infectious Disease Society of America for treatment of HCV.³ BOC and TVR are no longer recommended in the new guidelines. SOF is a nucleotide analogue NS5B polymerase inhibitor and currently is FDA indicated to be used in combination with RBV or in combination with PEG/RBV for HCV genotypes 1 through 4, including those with hepatocellular carcinoma awaiting liver transplantation as well as those with HIV co-infection.¹³ SOF is dosed at 400 mg orally once daily without regard to food. The RBV dose recommended in the treatment regimen is 1000 mg for patients who weigh <75 kg and 1200 mg for patients who weigh ≥75 kg.¹³

Efficacy of SOF along with PEG/RBV for 12 weeks was evaluated in a phase 3 NEUTRINO trial for patients with genotypes 1, 4, 5, and 6. After 12 weeks, 90% of patients achieved SVR (95% confidence interval [CI], 87-93) in the treatment arm receiving SOF plus PEG/RBV. This SVR was compared with prespecified historical control SVR of 60% and was found to be statistically significant (P <.0001).^14/

The FISSION trial was a randomized, open-label, active control, non-inferiority trial studying patients with genotypes 2 and 3. Treatment arms compared SOF and RBV for 12 weeks to the standard of therapy of PEG/RBV for 24 weeks. The SOF plus RBV arm was found to be non-inferior to PEG/RBV regimen, with both arms reaching SVR of 67% (treatment difference of 0.3% with 95% CI —7.5 to 8). SVR in patients with genotype 2 was 95% in SOF/RBV arm compared with 78% in PEG/RBV arm. In patients with genotype 3, SVR was 56% in the SOF/RBV arm and 63% in the PEG/RBV arm.¹⁴

The VALENCE trial evaluated efficacy of SOF and RBV to placebo in patients with genotypes 2 and 3 but included treatment-naïve patients as well as those who did not achieve SVR with a prior PEG-based regimen.¹⁵ Patients with genotype 2 received SOF and RBV for 12 weeks and reached SVR of 93%. Patients with genotype 3 received sofosbuvir and ribavirin for 24 weeks and reached SVR of 84%.¹³

The most common side effects observed for SOF in combination with PEG/RBV were fatigue, headache, nausea, insomnia, and anemia, while the most common for SOF in combination with RBV were fatigue and headache.^13,14 Patients receiving SOF and RBV experienced a lower incidence of influenza-like symptoms, psychiatric AEs, and hematologic abnormalities than patients receiving PEG.¹⁴

SMV is a protease inhibitor indicated for use in patients with HCV genotype 1 with compensated liver disease, including cirrhosis, in combination with PEG/RBV. It is dosed at 150 mg once daily with food with PEG/RBV for 12 weeks, after which all treatment-naïve and prior relapser patients, including those with cirrhosis, should receive an additional 12 weeks of PEG/RBV for total duration of 24 weeks. All prior non-responder patients, including partial and null responders and those with cirrhosis, should receive an additional 36 weeks of PEG/RBV for total treatment duration of 48 weeks.¹⁶

Efficacy of SMV was evaluated in 2 phase 3 trials, QUEST-1 and QUEST-2. In both trials, SMV plus PEG/RBV was compared with placebo plus PEG/RBV and the SMV arm was found to have superior SVR.³ In QUEST-1, SVR was 80% in the SMV arm compared with 50% in placebo arm (P <.0001).¹⁷ Results were similar in QUEST-2 trial with the simeprevir arm achieving SVR of 81% compared with 50% in the placebo arm (P <.0001).¹⁸

Common side effects of SMV were fatigue, headache, nausea, pruritus, and rash including photosensitivity, which may be serious. SMV also contains a sulfa moiety; therefore, precautions should be taken in patients with sulfa allergy.¹⁶

Clinical studies of SMV showed that patients with NS3 Q80k polymorphism had substantially lower SVR; therefore, screening patients for the presence of this NS3 Q80K polymorphism at baseline is strongly recommended by the manufacturer and by the latest guidelines.^3,16 SMV is a substrate and a mild inhibitor of CYP 3A4 enzyme; therefore, co-administration with other CYP3A4 inhibitors may significantly increase the plasma exposure of SMV while co-administration with CYP3A4 inducers may significantly reduce the plasma exposure of SMV, which may lead to loss of efficacy.¹⁶

In summary, both SOF and SMV have several advantages compared with previously recommended regimens. SOF-based regimens have high SVR rates, pangenotypic efficacy, simple dosing schedule, shorter duration of treatment, and lack of significant AEs and drug—drug interactions.¹⁹ SMV-containing regimens also have high SVR rates, a simple dosing schedule, and give patients the possibility of a shorter duration of treatment than previous protease inhibitors. As mentioned, these highly effective direct-acting antivirals are now included in the most recent HCV guidelines for initial treatment of HCV as well as for those who experienced relapse after prior PEG/RBV therapy (see Online Table 3). For genotypes 1, 4, 5, and 6, the guidelines recommend SOF with PEG/RBV for 12 weeks. SOF with RBV is recommended for 12 weeks in genotype 2 patients and for 24 weeks for genotype 3 patients.³ In all genotypes, recommended duration of treatment has been shortened with the addition of SOF. SOF is the first medication with which HCV genotypes 2 and 3 are able to be treated without a PEG-containing regimen. This is a major clinical achievement for patients who were intolerant of or ineligible for PEG and had no other treatment option.¹⁹ PEG-ineligible patients include those who have an intolerance or hypersensitivity to PEG, decompensated liver disease, history of depression, preexisting cardiac disease, baseline neutrophil count <1500/µL, platelets <90,000/µL, hemoglobin <10g/dL, or autoimmune diseases including autoimmune hepatitis.³

Table 3: Summary of Recommendations for Patients Who Are Initiating Therapy for Hepatitis C Virus (HCV) Infection or Who Experienced Relapse After Prior PEG/RBV Therapy, by HCV Genotype³

Genotype

Recommended

Alternative

NOT Recommended

IFN eligible: SOF + PEG/RBV x 12 weeks

IFN ineligible: SOF + SMV ± RBV x 12 weeks

IFN eligible: SMV x 12 weeks + PEG/RBV x 24 weeks*

IFN ineligible: SOF + RBV x 24 weeks

TVR + PEG/RBV x 24 or 48 weeks (RGT)

BOC + PEG/RBV x 28 or 48 weeks (RGT)

PEG/RBV x 48 weeks