Ribavirin (Virazole)

Number: 0155

Policy

  1. Aetna considers ribavirin (Virazole) medically necessary for the treatment of respiratory syncytial virus (RSV) infection in immunosuppressed and high risk children and adults, and for the treatment of viral hemorrhagic fever (Crimean-Congo, Ebola, Lassa, and Marburg), Rift valley fever and Hantaan, a hanta virus.

  2. Aetna considers ribavirin in combination with interferon alpha or pegylated interferon alpha medically necessary for persons with chronic hepatitis C according to the criteria set forth in CPB 0404 - Interferons.  Clinical research suggests that there are synergistic effects of ribavirin and interferon alpha in the treatment of chronic hepatitis. 

  3. Aetna considers ribavirin monotherapy for the treatment of persons with chronic hepatitis C infection experimental and investigational because there is insufficient evidence to support the effectiveness of this approach.

  4. Aetna considers ribavirin experimental and investigational for all other indications (e.g., acute myeloid leukemia, glioblastomas, hepatitis E infection, multiple sclerosis, oral cancer, and thyroid cancer; not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established.

See also CPB 0318 - Synagis (Palivizumab).

Background

Ribavirin is indicated for use in the treatment and prevention of certain viral infections in selected patients.  Ribavirin is marketed as a inhalation solution (Virazole), oral capsule (Rebetol) and tablet (Copegus), but can also be prepared for intravenous administration.

Mallet et al (2010) reported 2 patients in whom ribavirin therapy seemed to alter the natural history of chronic hepatitis E virus (HEV) infection.  A kidney and pancreas transplant recipient and a patient with idiopathic CD4(+) T lymphocytopenia, both with biopsy-proven chronic HEV infection were included in this study.  Patients received oral ribavirin, 12 mg/kg of body weight daily for 12 weeks.  Liver function tests, detection of HEV RNA (viremia and stool shedding) by reverse transcriptase polymerase chain reaction, and anti-HEV IgM and IgG antibodies wer performed.  Both patients had normalized liver function test results after 2 weeks of treatment and cleared HEV after 4 weeks of treatment.  Hepatitis E virus RNA remained undetectable in the serum and stools throughout follow-up (3 months and 2 months for the 1st and 2nd patient, respectively).  Side effects were considered mild.  The authors concluded that ribavirin is a potentially effective treatment of HEV infection and should be evaluated in patients with chronic HEV infection.  The main drawback of this study was that given the relatively short follow-up, the achievement of HEV eradication could not be claimed.

In a pilot study, Kamar and colleagues (2010) evaluated the ant-iviral effect of ribavirin monotherapy in patients with chronic HEV infection following kidney transplantation.  A total of 6 patients who received kidney transplants and were positive for HEV RNA (infected with HEV for 36.5 months; [range of 11 to 46 months]) were given ribavirin monotherapy for 3 months.  Ribavirin was given at 600 to 800 mg/day in 2 separate doses, based on the patient's ability to clear creatinine.  Median serum concentration of HEV RNA at baseline was 5.77 log copies/mL (range of 4.35 to 7.35 log copies/ml).  Three months after ribavirin therapy commenced, HEV RNA was undetectable in serum samples from all patients.  A sustained virologic response was observed in 4 patients; the other 2 patients relapsed at 1 and 2 months after ribavirin therapy ended.  At the end of the study, all patients had normal levels of alanine and aspartate aminotransferase.  Anemia was the main side effect caused by ribavirin therapy.  The authors concluded that ribavirin monotherapy inhibits the replication of HEV in vivo and might induce a sustained virological response in patients with chronic HEV infections.  They stated that further studies are needed to determine the optimal duration of ribavirin therapy.

Kamar et al (2014) noted that there is no established therapy for HEV infection.  In a retrospective, multi-center case-series study, these researchers evaluated the effects of ribavirin as monotherapy for solid-organ transplant (SOT) recipients with prolonged HEV viremia.  They examined the records of 59 patients who had received a solid-organ transplant (37 kidney-transplant recipients, 10 liver-transplant recipients, 5 heart-transplant recipients, 5 kidney and pancreas-transplant recipients, and 2 lung-transplant recipients).  Ribavirin therapy was initiated a median of 9 months (range of 1 to 82) after the diagnosis of HEV infection at a median dose of 600 mg per day (range of 29 to 1,200), which was equivalent to 8.1 mg/kg body weight/day (range of 0.6 to 16.3).  Patients received ribavirin for a median of 3 months (range of 1 to 18); 66 % of the patients received ribavirin for 3 months or less.  All the patients had HEV viremia when ribavirin was initiated (all 54 in whom genotyping was performed had HEV genotype 3).  At the end of therapy, HEV clearance was observed in 95 % of the patients.  A recurrence of HEV replication occurred in 10 patients after ribavirin was stopped.  A sustained virologic response, defined as an undetectable serum HEV RNA level at least 6 months after cessation of ribavirin therapy, occurred in 46 of the 59 patients (78 %).  A sustained virologic response was also observed in 4 patients who had a recurrence and were re-treated for a longer period.  A higher lymphocyte count when ribavirin therapy was initiated was associated with a greater likelihood of a sustained virologic response.  Anemia was the main identified side effect and required a reduction in ribavirin dose in 29 % of the patients, the use of erythropoietin in 54 %, and blood transfusions in 12 %.  The authors concluded that the findings of this retrospective, multi-center study showed that ribavirin as monotherapy may be effective in the treatment of chronic HEV infection; a 3-month course seemed to be an appropriate duration of therapy for most patients.

Unzueta and Rakela (2014) stated that HEV infection (genotype 3) has been described in developed countries as a cause of chronic hepatitis in recipients of SOT.  Immunosuppression seems to play a major role in the pathogenesis of chronic infections.  The current gold standard for the diagnosis of HEV infection is the detection of HEV RNA in serum, stools, or both.  In liver transplant recipients, HEV infection is considered an uncommon disease; however, a high index of suspicion is needed for patients with graft hepatitis of an unclear etiology.  Liver transplant recipients seem more likely to develop chronic HEV after an acute infection, and there is accelerated progression to advanced fibrosis and cirrhosis.  A decrease in immunosuppression is considered the first line of treatment, and pegylated interferon can be considered the second line of treatment for liver transplant recipients.  At the present time, there are not enough data to recommend treatment with ribavirin for adult liver transplant recipients, although this has been tried in other SOT populations.

An UpToDate review on “Hepatitis E virus infection” (Umashanker and Chopra, 2014) states that “Case reports and series have suggested a benefit from ribavirin monotherapy in solid-organ transplant recipients with chronic HEV, but prospective studies are needed to confirm these findings and to determine the dose, duration, and timing of ribavirin therapy”.

Zhang et al (2015) noted that an estimated 170 million people worldwide are infected with hepatitis C virus (HCV); and HCV genotype 4 (HCV-4) -- the most prevalent hepatitis C strain in the Middle East and Africa -- is difficult to treat, with an estimated sustained virological response (SVR) of 53 % when using pegylated interferon and ribavirin (P/R) in treatment-naïve patients with HCV-4 infection.  In regions where access to direct-acting anti-virals is limited, re-treatment of patients who failed therapy with another course of P/R may be an option if the success rate is acceptable.  These investigators determined the SVR from re-treatment with P/R in treatment-experienced patients with HCV-4 infection.  They performed a meta-analysis using Medline and Embase searches, and by reviewing article bibliographies and abstracts from recent Liver Society Meetings.  Original studies featuring at least 10 adult, treatment-experienced patients with HCV-4 infection failing prior interferon-based therapy and receiving subsequent re-treatment with P/R were included.  A total of 3 studies were included.  Overall pooled SVR was 32.7 %, or 41/126 patients.  No significant heterogeneity existed among the studies; 1 study reported higher SVR of 50 % in previous relapsers, compared with 23 % in previous non-responders.  The authors concluded that as expected, treatment-experienced patients achieved lower rate of SVR compared with previously reported SVR for treatment-naïve patients with HCV-4 infection.  They stated that the abysmal rate of success from re-treatment with P/R supports the use of direct-acting anti-virals whenever re-treatment is considered, even in resource-limited regions.

Glioblastomas:

Ochiai and colleagues (2018) stated that ribavirin has been used as an anti-viral agent against RNA and DNA viruses and has become the standard agent used for chronic hepatitis C in combination with interferon (IFN)-α2a.  Furthermore, the potential anti-tumor efficacy of ribavirin has attracted increasing interest.  Recently, these researchers demonstrated a dose-dependent anti-tumor effect of ribavirin for 7 types of malignant glioma cell lines.  However, the mechanism underlying the anti-tumor effect of ribavirin has not yet been fully elucidated.  These investigators provided further relevant data using 2 types of malignant glioma cell lines (U-87MG and U-138MG) with different expression of MGMT.  Dotted accumulations of γH2AX were found in the nuclei and increased levels of ATM and phosphorylated ATM protein expression were also observed following ribavirin treatment (10 µM of ribavirin, clinical relevant concentration) in both the malignant glioma cells, indicating double-strand breaks as one possible mechanism underlying the anti-tumor effect of ribavirin.  In addition, based on evaluations using FACS, ribavirin treatment tended to increase the G0/G1 phase, with a time-lapse, indicating the induction of G0/G1-phase arrest.  Furthermore, an increased phosphorylated p53 and p21 protein expression was confirmed in both glioma cells.  Additionally, analysis by FACS indicated that apoptosis was induced following ribavirin treatment and caspase cascade, down-stream of the p53 pathway, which indicated the activation of both exogenous and endogenous apoptosis in both malignant glioma cell lines.  The authors concluded that these findings may provide an experimental basis for the clinical treatment of glioblastomas with ribavirin.

Oral Cancer:

Dai and co-workers (2017) noted that up-regulation of eukaryotic translation initiation factor 4E (eIF4E) is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target.  However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC).  In this study, these researchers showed that ribavirin augmented sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway.  Ribavirin dose-dependently inhibited proliferation and induced apoptosis in SCC-9 and CAL27 cells.  Combination of ribavirin and paclitaxel were more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells.  More importantly, the in-vivo efficacy of ribavirin and its synergism with paclitaxel was confirmed by 2 independent OTSCC xenograft mouse models.  Mechanistically, ribavirin significantly decreased mTOR/eIF4E signaling pathway in OTSCC cells via suppressing phosphorylation of Akt, mTOR, 4EBP1 and eIF4E.  Over-expression of the phosphor-mimetic form of eIF4E (eIF4E S209D) but not the non-phosphorylatable form (eIF4E S209A) reversed the effects of ribavirin, confirming that eIF4E inhibition is the mechanism of action of ribavirin in OTSCC cells.  In addition, eIF4E depletion significantly enhanced the anti-proliferative and pro-apoptotic effects of paclitaxel, demonstrating the critical role of eIF4E in OTSCC cell response to paclitaxel.  The authors concluded that this study was the first to demonstrate the efficacy of ribavirin as a single agent and synergism as combination with paclitaxel in OTSCC in-vitro and in-vivo.  They stated that their findings also demonstrated the therapeutic value of inhibiting eIF4E in OTSCC treatment.

Thyroid Cancer:

Shen and associates (2017) noted that although eIF4E is important in cancer development and progression, its role in thyroid cancer is not well understood.  Ribavirin has been identified as an eIF4E inhibitor.  These researchers examined the effects of ribavirin on thyroid cancer and its molecular mechanisms of action.  The effects of ribavirin on thyroid cancer was investigated using in-vitro cellular assays and in-vivo xenograft mouse model.  The mechanism of its action on eIF4E-β-catenin axis was examined using genetic and biochemical approaches.  These investigators showed that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133.  Ribavirin inhibited thyroid cancer growth in a xenograft mouse model.  Ribavirin also sensitized thyroid cancer's response to paclitaxel.  Mechanistically, ribavirin suppressed eIF4E phosphorylation and over-expression of its wildtype and phosphor-mimetic form (S209D); but not of the non-phosphorylatable form (S209A), which rescued the inhibitory effects of ribavirin in thyroid cancer cells.  These researchers further demonstrated that ribavirin suppressed phosphorylation and activities of β-catenin and its subsequent gene transcriptional expression. β-catenin over-expression rescued the effects of ribavirin in thyroid cancer cells.  More importantly, they showed that eIF4E regulated β-catenin and that the regulation depended on phosphorylation at S209.  The in-vivo inhibitory effects of ribavirin on phosphorylation of eIF4E and β-catenin were also observed in thyroid tumor.  The authors concluded that these findings demonstrated that ribavirin acted on thyroid cancer cells by inhibiting eIF4E/β-catenin signaling; suggesting that ribavirin has the potential to be re-purposed for thyroid cancer treatment and also highlighted the therapeutic value of inhibiting eIF4E-β-catenin in thyroid cancer.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

90378 Respiratory syncytial virus, monoclonal antibody, recombinant for intramuscular use, 50 mg each

Other HCPCS codes related to the CPB:

J9213, J9214, J2915 Interferon alpha-2a, 2b, and n3

ICD-10 codes covered if selection criteria are met:

A92.0 - A92.9 Other mosquito-borne fever (e.g., Rift valley)
A96.2, A98.3 - A98.4
B33.24, B33.8
Other specified diseases due to viruses (e.g., Marburg disease, Tanapox)
A98.0 Crimean-Congo hemorrhagic fever
A98.8 Other specified viral hemorrhagic fevers (e.g., mite-borne hemorrhagic fever)
B18.2 Chronic viral hepatitis C [not covered for ribavirin monotherapy]
B33.4 Hantavirus (cardio)-pulmonary syndrome [HPS] [HCPS]
B97.4 Respiratory syncytial virus (RSV) as the cause of diseases classified elsewhere
J21.0 Acute bronchiolitis due to respiratory syncytial virus (RSV)

ICD-10 codes not covered for indications listed in the CPB:

B17.2 Acute hepatitis E
C00.0 - C10.9 Malignant neoplasm of lip and oral cavity
C72.0 - C72.9 Malignant neoplasm of central nervous system [glioblastoma]
C73 Malignant neoplasm of thyroid gland
C92.00 - C92.92 Myeloid leukemia
D00.00 - D00.08 Carcinoma in situ of lip, oral cavity, and pharynx
D37.01 - D37.02, D37.04 - D37.09 Neoplasm of uncertain behavior of lip, oral cavity, and pharynx
G35 Multiple sclerosis

The above policy is based on the following references:

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