Hepatitis C is a disease of the liver resulting from infection by the hepatitis C virus (HCV). HCV infection is blood-borne and can result in an acute illness, with severity ranging from mild (little or no symptoms) to severe (symptoms requiring hospitalization). According to the Centers for Disease Control and Prevention (CDC), the virus clears spontaneously in approximately 20% of patients infected with hepatitis C, but 80% of patients will experience lifelong chronic disease, which can lead to cirrhosis, liver failure, or liver cancer.1
The CDC estimates that 3.2 million people in the United States have chronic HCV, with approximately 17,000 new HCV infections and 15,000 chronic HCV–related deaths occurring annually.2 In the United States, approximately 75% of HCV infections are in individuals born between 1945 and 1965. For many of these patients, the source of infection might have been contaminated blood or blood products, which were more prevalent before widespread screening of the blood supply began in 1992, and before universal precautions for avoiding contact with bodily fluids were adopted. Other patients might have become infected through high-risk behaviors, such as injection of illicit drugs.
Because many Americans are unaware that they are infected with HCV, and symptoms may take decades to develop, the CDC and the US Preventive Services Task Force recommend that all individuals born between 1945 and 1965 be tested for HCV infection.1,3 The symptoms of chronic HCV infection often occur only with advanced disease and are similar to symptoms of acute HCV infection, which include fever, fatigue, nausea, vomiting, abdominal pain, jaundice, dark urine, and joint pain, among others.1
Historically, chronic HCV infection has been difficult to treat for several reasons. Traditional treatment consisted of interferon and ribavirin, 2 drugs associated with significant adverse reactions and reduced quality of life.4,5 Furthermore, such treatment required long durations of therapy and resulted in sustained virologic response (SVR) in less than 50% of patients with chronic HCV genotype 1.4 This led to “warehousing” of patients; namely, the decision by some patients and providers to defer treatment in anticipation of safer and more effective therapies, or until the need for treatment becomes more urgent.5 Moreover, the patients who could benefit most from treatment, such as those with decompensated cirrhosis, are not eligible to be treated with interferon.5,6 Consequently, there has been a need for improved therapies for patients whose treatment is deferred and for those who cannot tolerate interferon therapy.
Significant progress toward fulfilling the need for improved chronic HCV treatment has occurred in recent years, starting with the US Food and Drug Administration (FDA) approval of boceprevir (Victrelis) in May 2011, and telaprevir (Incivek) in November 2013, the first 2 direct-acting antiviral agents. When either of these agents is used in combination with peginterferon and ribavirin, SVR is achieved in approximately 67% to 75% of patients with chronic HCV genotype 1.7 Although the use of boceprevir or telaprevir improved the clinical efficacy for patients, these agents are associated with high rates of adverse events, many drug–drug interactions, and high pill burden, all of which limit their use.7
Additional advances have occurred with the FDA approval of 2 additional direct-acting antiviral agents—simeprevir (Olysio) in November 2013, and sofosbuvir (Sovaldi) in December 2013.8 Unlike the first 2 direct-acting antivirals, which are indicated only for chronic HCV genotype 1 infection, sofosbuvir is indicated for chronic HCV genotypes 1 through 4.8
Compared with previous chronic HCV treatments, sofosbuvir-based therapy has several advantages, including increased cure rates, reduced side effects, and a shorter treatment duration. In some patients, sofosbuvir can be used without interferon.9 Depending on the chronic HCV genotype, sofosbuvir is used with ribavirin, or with ribavirin plus peginterferon, for 12 to 24 weeks; and the reported SVR rates range from 76% to 95%.8 Patients with chronic HCV genotype 1 also have the option of using sofosbuvir plus simeprevir, with or without ribavirin.10
Because of these benefits, sofosbuvir-based regimens were a recommended treatment option for all chronic HCV genotypes in the Recommendations for Testing, Managing, and Treating Hepatitis C treatment guidelines released by the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) in January 2014.10 At the time of this analysis, these treatment guidelines also contained recommendations for assessing liver fibrosis before treatment of chronic HCV infection and for prioritizing treatment for those at highest risk for complications based on available resources.10
Given the potential “warehousing” of patients before the launch of sofosbuvir and the possibility that some patients and providers might have continued deferring treatment in anticipation of more promising, interferon-free therapies, it is not known who was prescribing and who was receiving prescriptions for sofosbuvir during its initial availability.5
The purpose of this current analysis was to understand the early use of sofosbuvir by describing the demographics, clinical characteristics, and prescribing patterns associated with members seeking treatment with sofosbuvir in a commercially insured population. This information can provide insight into potential behavior of providers during future launches of medications that offer significant advantages over current standards of care.
OptumRx (Irvine, CA) is a pharmacy care services company. At the time of our analysis, OptumRx was serving more than 30 million commercial, Medicare, and Medicaid members nationwide through a network of more than 66,000 community pharmacies and 2 home-delivery pharmacies. The OptumRx database and prior authorization system were used to identify members for whom sofosbuvir treatment was requested and to collect characteristics and treatment information pertaining to members and providers.
Information in prior authorization requests can vary, depending on the criteria that a member’s plan requires and the timing of the request. In addition to other information, requests for a prior authorization may contain details regarding chronic HCV genotype, degree of liver fibrosis, provider specialty, and reason for a member’s ineligibility to use interferon (if applicable).
The analysis was performed with a commercially insured population of members with prior authorization requests for sofosbuvir submitted by their providers between March 14, 2014, and June 14, 2014 (the identification period) from the OptumRx database. A member was eligible for study inclusion if he or she had a prior authorization request for sofosbuvir during this period, whether the request was approved or denied. Members were excluded if they initiated the prior authorization request and the request lacked follow-up information from the provider, or if a prior authorization request was initiated because their prescription exceeded allowable quantity limits but no additional information was supplied by the provider.
All members who had a prior authorization request during the specified identification period were assigned a number, and a random number generator was used to randomly select approximately 1 in 4 members to be included in the analysis. If a member had more than 1 prior authorization request during the identification period, only the most recent request was evaluated.
Data Collection and Analysis
Demographic information, clinical characteristics, and treatment information were collected for each member included in the analysis. Demographic information included age, sex, and geographic region as defined by the US Census Bureau, based on the member’s state of residence.11 Chronic HCV genotype was recorded for all members. Because some plans require additional information for members with chronic HCV genotype 1 infection, additional clinical details were collected for these members, including the degree of liver fibrosis and the method the provider used to determine it.
The degree of liver fibrosis was reported using the METAVIR scoring system. An equivalent METAVIR stage was determined for members whose providers used an alternative staging technique to determine the degree of fibrosis.12 The collected provider-related characteristics included the specialty of the provider requesting the treatment, as reported by the provider or based on the provider’s specialty code. The collected treatment information included the regimen requested and the reason for requesting an interferon-free regimen, if applicable.
Demographic information was extracted from the OptumRx database. The remaining member characteristics, provider characteristics, and treatment information were collected manually through a review of the requests and any supporting medical documents supplied by the provider using the prior authorization system. All data were collected and recorded by the same individual, using a data abstraction tool, to ensure systematic collection of the data. The results were analyzed using descriptive statistics.
Of the 1412 members who had a prior authorization request for sofosbuvir during the identification period, 344 were randomly selected for potential inclusion in the analysis. Of these 344 members, 6 were excluded because their prior authorization requests did not contain any information from the provider. Therefore, 338 members were ultimately included in the analysis.
The Table shows the member population distribution by chronic HCV genotype, sex, age, and geographic region. Chronic HCV genotype 1 was the most common genotype, accounting for 74.3% of the members, followed by genotype 2 (13.9%), genotype 3 (9.5%), and genotype 4 (1.2%). For 1.2% of members, a different chronic HCV genotype was documented, or no genotype was provided. The members in the study were predominantly male (65.1%), and their mean age was 55.4 (±9.1) years. Overall, 38% of the members were from the South, and approximately 1 in 5 members resided in each of the other regions (Midwest, Northeast, West).
Gastroenterologists and hepatologists accounted for 90% (N = 304) of the providers who requested treatment with sofosbuvir. In addition, 4% (N = 13) of providers were infectious disease specialists, and 6% (N = 21) had other or unknown specialties.
Figure 1 shows the treatment regimens requested, stratified by member genotype. For members with chronic HCV genotype 1, 129 (51.4%) requests were for sofosbuvir plus simeprevir, the most frequently requested regimen. Triple therapy comprising sofosbuvir, peginterferon, and ribavirin for 12 weeks was requested for 102 (40.6%) members with chronic HCV genotype 1, and the combination of sofosbuvir plus ribavirin, for 24 weeks, was requested for 20 (8.0%) members with genotype 1.
Among the 251 members with genotype 1, an interferon-free regimen was requested for 149 (59.4%) members. Common reasons for requesting an interferon-free regimen included active depression or a history of depression (17.4%), previous intolerance or hypersensitivity to interferon (12.8%), and low baseline hematologic parameters (9.4%). For 78 (52.3%) members, the medical reasons for interferon ineligibility were not known or could not be determined based on the information provided (Figure 2).
Among the members with chronic HCV genotype 1, 48 (19.1%) had liver fibrosis equivalent to METAVIR stage F0 to F2 and 62 (24.7%) had the equivalent of METAVIR stage F3 to F4 liver fibrosis. For the other 141 (56.2%) members with genotype 1, the degree of liver fibrosis was not known or could not be determined based on information in the prior authorization request. For 3 of these members, the documentation showed an inconclusive degree of fibrosis.
Of the 113 members with documented fibrosis, the evidence was based on liver biopsy results for 56 (49.6%) members and on providers’ attestation of the degree of liver fibrosis based on physical findings or other clinical evidence for 39 (34.5%) members (Figure 3). The remaining documentation of liver fibrosis was attained from noninvasive methods, including radiologic imaging (N = 9 [8.0%]), the FibroSURE test (N = 6 [5.3%]), or the FibroScan test (N = 3 [2.7%]).
Members with a prior authorization request for sofosbuvir in this study had demographic and clinical characteristics consistent with those of previous studies as well as epidemiologic data on patients with chronic HCV infection in the United States, including the distribution for sex and genotype.13,14 The majority of members in our study had chronic HCV genotype 1 and were prescribed regimens that did not contain the traditional therapy with interferon and/or ribavirin. We also found that members with chronic HCV genotype 1 had early-or late-stage liver fibrosis; however, fibrosis documentation was not available or not known for more than 50% of these members.
The mean age of members in our analysis was 55.4 years, which is reflective of the commercial members study population that was evaluated and may not necessarily reflect the general US population. Although the geographic distribution of members in our study is consistent with data suggesting there may be a larger prevalence of chronic HCV infection in the southern region of the United States,15 our analysis included only members in the OptumRx database, and the study population was not adjusted to reflect the overall geographic distribution of plan members.
Gastroenterologists and hepatologists accounted for the majority of providers who requested treatment with sofosbuvir during the study period. This finding is not surprising given the complexity of the disease and the timing of the study, which was shortly after the launch of sofosbuvir. Providers were quick to adopt the interferon-free regimen of sofosbuvir plus simeprevir and requested this regimen for more than 50% of the members with chronic HCV genotype 1. Although this regimen was not approved by the FDA at the time of the study, it was recommended by the AASLD/IDSA treatment guidelines based on data from a phase 2 clinical trial.10 This suggests that future updates to treatment guideline recommendations could quickly change prescribing patterns, even if they are not supported by a robust body of data. (This regimen was later approved by the FDA for chronic HCV infection genotype 1 in November 2014.)
Conversely, the AASLD/IDSA’s recommendation for the off-label use of adding peginterferon to sofosbuvir and ribavirin to shorten the duration of treatment for chronic HCV genotype 3, from 24 weeks to 12 weeks, was not widely adopted in clinical practice according to our study. This finding was not unexpected, given the subcutaneous route of administration of peginterferon and the side effects that patients and providers likely wish to avoid. Our analysis also shows that various side effects of concern could have resulted in a provider avoiding the prescribing of peginterferon.
Although more than 50% of the members with chronic HCV genotype 1 had an unknown degree of liver fibrosis, almost 20% had the equivalent of METAVIR stage F0 to F2 fibrosis, which suggests that providers did not request sofosbuvir treatment exclusively for members with advanced disease. Furthermore, nearly half the documentation submitted by providers as evidence of a member’s degree of liver fibrosis was based on liver biopsy results. Few providers submitted results of noninvasive tests as evidence of fibrosis, despite the availability of several noninvasive methods for assessing fibrosis. However, the period involved in this analysis may help to explain why the results of liver biopsies were the most common evidence used.
The AASLD/IDSA treatment guidelines released in January 2014 (and updated in December 2014) recommended the use of a liver biopsy or a noninvasive test to assess the degree of liver fibrosis.10 However, previous AASLD treatment guidelines stated that noninvasive tests may be useful but should not replace a liver biopsy in routine clinical practice.16 Fibrosis staging in members in our analysis might have been performed before the study period and before the updated recommendation from the AASLD/IDSA. For example, if a member had undergone a liver biopsy in the past and cirrhosis was detected at that time, the results of that biopsy could have been submitted with the prior authorization request and were therefore included in this analysis.
Therefore, our results may not indicate how providers are currently assessing liver fibrosis, and the findings may have differed if the analysis focused on the methods providers were using to stage liver fibrosis after sufficient time had passed to allow for the adoption of the updated recommendation.
Nevertheless, providers may benefit from additional education on noninvasive methods to assess liver fibrosis, including the aspartate transaminase to platelets ratio index score, which provides an estimate of fibrosis using biochemical and hematologic markers from a routine blood draw.12
Since the period used for our analysis, 5 new chronic HCV treatments have received FDA approval. Ledipasvir plus sofosbuvir (Harvoni) and the combination regimen of ombitasvir, paritaprevir, and ritonavir plus dasabuvir (Viekira Pak) were FDA approved in October and December 2014, respectively, for use in chronic HCV genotype 1.17,18 Ledipasvir plus sofosbuvir also received FDA approval in November 2015 for chronic HCV genotypes 4 through 6.19 The combination of ombitasvir, paritaprevir, and ritonavir (Technivie) was approved by the FDA in July 2015 in combination with ribavirin for use in chronic HCV genotype 4, and the previously approved simeprevir received a new indication in October 2015 for chronic HCV genotype 4, when used in combination with peginterferon and ribavirin.20,21 Daclatasvir (Daklinza) was approved by the FDA in July 2015 for use in combination with sofosbuvir for chronic HCV genotype 3; it is also recommended by the AASLD/IDSA for off-label use in chronic HCV genotypes 1 and 2.10,22 Finally, the combination of elbasvir plus grazoprevir (Zepatier) received FDA approval in January 2016 for treatment of chronic HCV genotypes 1 and 4.23
Despite these recent FDA approvals, there is still potential for the introduction of new therapies, including velpatasvir in combination with sofosbuvir, which has the potential for pan-genotypic activity.24 The introduction of these agents and the potential availability of newer therapies may continue to affect a patient’s or provider’s decision to initiate or defer treatment. Furthermore, as seen after the launch of sofosbuvir, updates to clinical treatment guidelines can significantly affect the treatment of chronic HCV infection and should be monitored closely.
Although our analysis provides information on members who requested treatment with sofosbuvir shortly after its launch, many other aspects related to HCV infection should be examined in the future, such as the clinical characteristics of patients who actually received treatment with new medications, and whether patients who received these treatment regimens had positive outcomes. Such information can help to determine the true impact of these new medications on the treatment of chronic HCV.
Furthermore, a study to determine whether patients who request a new therapy have been treated previously could provide insight into the number of patients being “warehoused” for improved medications, and the number who desire treatment for other reasons (such as failure or intolerance of previous therapy).
A review of the available methods to assess liver fibrosis may help to educate providers in determining the safest, most effective, and least costly options to determine a patient’s severity of disease. This could help increase the utilization of noninvasive methods by specialists and could potentially serve as a starting point for future efforts to involve primary care providers in the identification, screening, and selection of patients who could benefit from treatment of their HCV infection.
This analysis has several limitations. First, the information was incomplete or limited for some of the clinical characteristics evaluated from the prior authorization requests. This could have been because providers did not submit the information, or providers did not know the information, or prior authorization request criteria may differ by insurance plan. Therefore, some clinical characteristics included in the analysis might not have been required as part of the prior authorization process for certain members.
In addition, the knowledge, or perceived knowledge, of prior authorization criteria might have influenced provider behavior. For example, some providers might have requested regimens that they thought were more likely to be approved, and others might have avoided the prior authorization process altogether if they believed their request would be denied (eg, primary care providers). Consequently, the results of this analysis may not reflect prescribing patterns in the absence of a prior authorization requirement.
Furthermore, if a member had more than 1 prior authorization request during the study period, only the most recent request was included and evaluated in the analysis. Although the most recent request should be comprehensive and contain all information from previous requests, it is possible that some information could have been missed by examining only the most recent request.
Finally, although we would have liked to include in our analysis the percentage of members who had previously received HCV treatment before the FDA approval of these newer direct-acting antiviral agents, we were not able to determine this information for many of the members in our analysis, because treatment history was not available. This should be examined in future research.
Our analysis of the early prescribing patterns for sofosbuvir shows that prescribing of the off-label regimen of sofosbuvir plus simeprevir was common before its approval by the FDA, and this may be attributable to “warehousing” of patients (ie, deferring treatment) in anticipation of more tolerable therapy. This suggests that patients and providers are moving away from interferon-based treatment regimens for the treatment of chronic HCV infection. The results also show that providers requested treatment for members with varying severity of disease. However, providers did not appear to use noninvasive methods to assess the degree of liver fibrosis before treatment; providers could potentially benefit from additional education on these tests. Given the incomplete information for staging liver fibrosis and the introduction of new treatments and treatment guidelines, future research on the treatment patterns for chronic HCV infection is needed, to assess changes in the utilization of noninvasive methods of staging liver fibrosis and to continue evaluating prescribing patterns.
Author Disclosure Statement
Dr Tambourine, Dr Sadeghi, Dr Yang, Dr Stockl, Dr Lew, Dr Solow, and Dr Tran reported no conflicts of interest.
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