Prior Auth Protocol

FDA Approved Indications:

Indicated for the treatment of chronic hepatitis C (CHC) genotype 1, 4, 5 and 6 infection in adults.

Health Net Approved Indications and Usage Guidelines:

Diagnosis of chronic hepatitis C (CHC) confirmed by detectable serum HCV RNA by quantitative assay in patients with genotype 1, 4, 5 or 6. Baseline viral load by quantitative assay including genotype and treatment status of patient (treatment naive or treatment-experienced) are required with chart note documentation and copies of lab results

AND

Prescribed by or in consultation with a gastroenterologist, hepatologist or infectious disease physician.

AND

Chart note documentation and copies of lab results are required

AND

Requests for greater than 12 weeks treatment: Failure or clinically significant adverse effects to Epclusa (sofosbuvir/velpatasvir) unless Epclusa is not indicated

AND

One of the following clinical states to identify candidates for treatment:
- Evidence of Stage 2 or greater hepatic fibrosis including one of the following:
  - Liver biopsy confirming a METAVIR score F2 or greater
  - Transient elastography (Fibroscan) score greater than or equal to 7.5 kPa
  - FibroSure (also known as FibroTest) score of greater than or equal to 0.48
  - APRI score greater than 0.7
  - FIB greater than 3.25
  - ARFI score of greater than 1.34 m/s
  - MRE score of greater than 3.20 kilopascals
  - HepaScore ≥0.55
  - FibroMeter ≥0.411
- Evidence of extra-hepatic manifestation of hepatitis C virus, such as type 2 or 3 essential mixed cryoglobulinemia with end- organ manifestations (e.g. vasculitis), or kidney disease (e.g. proteinuria, nephrotic syndrome or membranoproliferative glomerulonephritis).
- For treatment of CHC in patients with hepatocellular carcinoma with a life expectancy greater than 12 months meeting Milan criteria (awaiting liver transplantation): Milan criteria is defined as 1 lesion ≤5 cm, up to 3 lesions each of which are ≤3 cm, and no extrahepatic manifestations/no vascular invasion
- Pre- and post-liver transplant, or other solid organ transplant
- HIV-1 co-infection
- Hepatitis B co-infection
- Other coexistent liver disease (e.g. nonalcoholic steatohepatitis)
- Type 2 diabetes mellitus (insulin resistant)
- Porphyria cutanea tarda
- Debilitating fatigue impacting quality of life [(e.g., secondary to extra-hepatic manifestations and/or liver disease) Fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and causes a substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months]
- Men who have sex with men with high-risk sexual practices
- Patients with a current injectable substance abuse disorder and actively participating in treatment
- Persons on long-term hemodialysis
- Women of childbearing age who wish to get pregnant
- HCV-infected health care workers who perform exposure-prone procedures

Coverage is Not Authorized For:

Non-FDA approved indications, which are not listed in the Health Net Approved Indications and Usage Guidelines section, unless there is sufficient documentation of efficacy and safety in the published literature.

General Information:

Sovaldi (sofosbuvir) plus weight based ribavirin is FDA approved to treat patients with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplant) and those with HCV/HIV-1 co-infection.
The safety and efficacy of Harvoni have not been established in patients with decompensated cirrhosis
Treatment-experienced patients have failed treatment with either peginterferon alfa + ribavirin or an HCV protease inhibitor + peginterferon alfa + ribavirin.
Treatment-naive patients have no prior exposure to peginterferon alfa, ribavirin or an HCV protease inhibitor.
METAVIR Fibrosis Scores:
- F0 = No fibrosis
- F1 = Portal fibrosis without septa
- F2 = Portal fibrosis with few septa
- F3 = numerous septa without cirrhosis
- F4 = Cirrhosis
The FIBROSpect II is a commercially available test that combines hyaluronic acid, tissue inhibitor of a metalloproteinase-1 (TIMP-1), and alpha-2-macroglobulin in a predictive algorithm for fibrosis stages (F2 to F4). An index score of greater than 0.42 is classified with the presence of stage F2 to F4 fibrosis, but is unable to differentiate amongst each of the fibrosis stages F2, F3 and F4.
FibroSure (aka FibroTest) Scoring:
- <0.21 = Stage F0 = No fibrosis
- 0.21 - 0.26 = Stage F0 - F1
- 0.27 - 0.30 = Stage F1 = Portal fibrosis
- 0.31 - 0.47 = Stage F1 - F2
- 0.48 - 0.57 = Stage 2 = Bridging fibrosis with few septa
- 0.58 - 0.72 = Stage F3 = Bridging fibrosis with many septa
- 0.73 - 0.74 = Stage F3 - F4
- >0.74 = Stage F4 = Cirrhosis
A HepaScore ≥0.55 is considered "positive" and indicates a METAVIR score of F2 to F4. A HepaScore ≥0.60 is considered "positive" and indicates a METAVIR score of F3 to F4.
Treatment with Harvoni for 8 weeks can be considered in treatment-naive patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/mL. In the ION-3 trial, patients with a baseline HCV viral load of <6 million IU/mL and were treated with Harvoni for 8 weeks achieved SVR-12 at a rate of 97% versus 96% of those treated with Harvoni for 12 weeks.
Based on information presented as abstracts at the 2014 American Association for Study of Liver Disease (AASLD), this organization had made recommendation for the use of Harvoni outside of the approved indication. The AASLD treatment guideline include dosing recommendation for use in patients with decompensated cirrhosis, in patients with HCV infection in liver allograft, in patients with genotype 4 or genotype 6, and in patients who have failed previous treatment with a Sovaldi (sofosbuvir) based therapy.
There are no data to support combination therapy with Harvoni and a protease inhibitor (Olysio).
In patients with HCV/HIV coinfection, because ledipasvir increases tenofovir levels, concomitant use mandates consideration of creatinine clearance (CrCl) rate and should be avoided in those with CrCl below 60 mL/min. Potentiation of this effect is expected when tenofovir is used with ritonavir-boosted HIV protease inhibitors. Harvoni should be avoided with this combination (pending further data) unless antiretroviral regimen cannot be changed and the urgency of treatment is high. HIV/HCV-coinfected persons should be treated and retreated the same as persons without HIV infection, after recognizing and managing interactions with antiretroviral medications.
Serious symptomatic bradycardia may occur in patients taking Harvoni with amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered Harvoni:
- Counsel patients about the risk of serious symptomatic bradycardia
- Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Child-Pugh Score

	1 Point	2 Points	3 Points
Bilirubin	Less than 2 mg/dL Less than 34 umol/L	2-3 mg/dL 34-50 umol/L	Over 3 mg/dL Over 50 5uol/L
Albumin	Over 3.5 g/dL Over 35 g/L	2.8-3.5 g/dL 28-35 g/L	Less than 2.8 g/dL Less than 28 g/L
INR	Less than 1.7	1.7 - 2.2	Over 2.2
Ascites	None	Mild / medically controlled	Moderate-severe / poorly controlled
Encephalopathy	None	Mild / medically controlled Grade I-II	Moderate-severe / poorly controlled. Grade III-IV

Child-Pugh class is determined by the total number of points: A = 5-6 points; B = 7-9 points; C = 10-15 points

There is no dosing recommendation for patients with severe renal impairment (estimated glomerular filtration rate < 30mL/minute/1.73m² or with end stage renal disease due to higher exposures (up to 20 fold) of the predominant sofosbuvir metabolite.
Diagnostic criteria for chronic fatigue syndrome was developed by an expert committee convened by the Institute of Medicine on the basis of a comprehensive literature review and input from patient, advocacy, and research communities. These diagnostic criteria state that symptoms should persist for at least 6 months and be present at least half the time with moderate, substantial, or severe intensity to distinguish chronic fatigue syndrome from other diseases.

Therapeutic Alternatives:

Drug	Dosing Regimen	Dose Limit/ Maximum Dose
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* Requires Prior Authorization

Recommended Dosing Regimen and Authorization Limit:

Drug	Dosing Regimen	Authorization Limit
Harvoni (sofosbuvir-ledipasvir)	Genotype 1 CHC: 400 mg / 90 mg PO QD	Treatment naive patients without cirrhosis AND whose HCV viral load is less than 6 million IU/mL: 8 weeks Treatment naive patients without cirrhosis AND whose HCV viral load is greater than or equal to 6 million IU/mL: 12 weeks Treatment naive patients with compensated cirrhosis: 12 weeks Treatment-experienced without cirrhosis: 12 weeks Treatment-experienced with compensated cirrhosis: Harvoni QD plus ribavirin for 12 weeks
Harvoni	Genotype 1 or 4 CHC with 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: 400 mg/90 mg QD plus ribavirin	12 weeks
Harvoni	Treatment naive patients AND HIV co-infection without cirrhosis with Genotype 1, 4, 5 or 6 CHC: 400 mg / 90 mg PO QD	12 weeks
Harvoni	Treatment-naive or Peg-IFN + RBV treatment experienced patients with CHC genotype 4 infection 400 mg / 90 mg PO QD	12 weeks
Harvoni	Treatment-naive or Peg-IFN + RBV treatment experienced patients with CHC genotype 5 or 6 infection 400 mg / 90 mg PO QD	12 weeks
Harvoni	Treatment-naive and -experienced patients with Genotype 1 or 4 infection post liver transplantation, including compensated cirrhosis: 400 mg/90 mg PO QD plus ribavirin	12 weeks
Harvoni	Post liver transplant treatment-naive patients who are intolerant to RBV or RBV ineligible with HCV genotype 1 or 4 infection in the allograft, including compensated cirrhosis: 400 mg/90 mg QD	24 weeks
Harvoni	Genotype 1 or 4 CHC with 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 for patients in whom a prior sofosbuvir based therapy has failed: 400 mg/90 mg QD plus ribavirin	24 weeks
Harvoni	Patients with Genotype 1 or 4 who have advanced fibrosis, in whom a previous sofosbuvir-containing regimen has failed: 400 mg/90 mg QD with or without ribavirin	24 weeks

Product Availability:

Harvoni Tablet containing 400 mg sofosbuvir with 90 mg ledipasvir

References:

1. Harvoni [Prescribing Information]. Foster City, CA: Gilead Sciences, Inc.; June 2016.

2. Afdhal N, Zeuzem S, Kwo N et al. Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection. NEJM May 15, 2014 370;19: 1889-1898

3. Afdhal N, Reddy KR, Nelson DR et al. Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection. NEJM April 17,2014 370;16:1483-1493

4. Kowdley KV, Gordon SV, Reddy KR et al. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis. NEJM May 15, 2014 370;19:1879-1888

5. American Association for the Study of Liver Disease Recommendations for Testing,Managing, and Treating Hepatitis C; February 2016. (accessed at: http://www.hcvguidelines.org)

6. European Association for Study of the Liver treatment guidelines April 2014 accessed at: http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html#p=4

7. WHO guidelines for treatment of hepatitis C April 2014 accessed at: http://apps.who.int/iris/bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1&ua=1

8. Kalantari H, Hoseini H. Babak A, et al. Validation of Hepascore as a Predictor of Liver Fibrosis in Patients with Chronic Hepatitis C Infection. Hepat Res Treat. 2011:972759. doi: 10.1155/2011/972759. Epub 2011 Dec 28.

9. Ichikawa S, Motosugi U, Ichikawa T, et al. Magnetic resonance elastography for staging liver fibrosis in chronic hepatitis C. Magn Reson Med Sci. 2012;11(4):291-7.

10. Friedrich-rust M, Nierhoff J, Lupsor M, et al. Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat. 2012;19(2):e212-9.

11. Bonder A, Afdhal N.Utilization of FibroScan in clinical practice. Curr Gastroenterol Rep. 2014 Feb;16(2):372. doi: 10.1007/s11894-014-0372-6.

12. Patel K, Gordon SC, Jacobson I, et al. Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate to advanced liver fibrosis in chronic hepatitis C patients. J Hepatol 2004;41:935-942.

13. Institute of Medicine of the National Academies. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an illness. Report Brief, February 2015.

14. Institute of Medicine of the National Academies. Beyond Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Redefining an Illness. Report Brief, February 2015. Available at https://iom.nationalacademies.org/~/media/Files/Report%20Files/2015/MECFS/MECFS_ReportBrief.pdf, accessed October 7, 2015.