Subject:
Urinary Metabolite Tests for Adherence to Direct-Acting Antiviral Medications for Hepatitis C Infection
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Metabolites of some direct-acting antiviral (DAA) medications can be measured in the urine. Measurement of urine drug levels reflects serum drug levels and thus has the potential for use as a test of adherence.
Populations | Interventions | Comparators | Outcomes |
Individuals:
· With hepatitis C receiving treatment with direct-acting antiviral medications | Interventions of interest are:
· Monitoring adherence to direct-acting antivirals by measuring urinary metabolites | Comparators of interest are:
· Standard care without monitoring adherence to direct-acting antivirals
· Alternative methods for monitoring adherence (eg, patient report, pill counts) | Relevant outcomes include:
· Medication use |
Background
Metabolites of some direct-acting antiviral (DAA) medications (eg, sofosbuvir) can be measured in the urine. Measurement of urine drug levels reflects serum levels and thus has the potential for use as a test of adherence.
While DAA medications have been a breakthrough treatment for chronic hepatitis C infection, they are also very costly. This produces a greater incentive to manage and monitor use to avoid prescribing in situations where they will be of no benefit. Maximizing adherence will ensure that the greatest amount of treatment benefit is achieved, and that the medications are being used in the most cost-effective manner.
Adherence to Treatment for Hepatitis C
Adherence to a full course of medication treatment is largely unknown for many of the newest DAA medications. However, data from adherence to other medications for hepatitis C suggest that it may be suboptimal on average. A prior Veteran’s Administration study on rates of discontinuation for interferon/ribavirin in patients with hepatitis C infection reported that 54.9% of all patients discontinued treatment early.1 For the first-generation DAA boceprevir, Gordon et al published an analysis of adherence in the SPRINT-2 and RESPOND-2 trials.2 Adherence above 80% was reported for 63% of the treated patients in 1 trial and 71% in the other. For patients with adherence above 80%, the sustained virologic response (SVR) was 86% and 90% in the respective trials. In contrast, for patients with adherence below 80%, rates of SVR were 8% and 32%, respectively.
The newer DAA medications, such as sofosbuvir, simeprevir, and ledipasvir, have greater efficacy, fewer adverse effects, and greater convenience than earlier agents. This would be expected to improved adherence; however, empiric data for this is lacking, particularly data on treatment in real-world settings.
Some literature on factors influencing adherence to hepatitis C treatment has been published, but most is prior to availability of DAAs. A systematic review published in 2014 analyzed 9 studies on factors influencing adherence.3 Two factors had a significant negative association with adherence, psychiatric disorders and higher doses of medications. In addition, female gender showed a trend toward a negative association. HIV coinfection and hemoglobin level were positively associated with adherence. Another systematic review in 2013 evaluated adherence to treatment for hepatitis B and C, prior to availability of DAAs.4 This review included 13 studies on hepatitis C. Mean adherence rates in these studies ranged from 27% to 97%, and the percentage of patients who had adherence rates above 80% ranged from 27% to 96%.
In addition to maximizing treatment success and cost-effectiveness, knowledge about treatment adherence can assist clinicians in managing treatment failures. Some patients will not achieve a sustained response, even with the newer agents with the greatest efficacy. In these patients, retreatment is an important consideration, and can be difficult. In deciding on retreatment, information that would indicate whether the failure is due to nonadherence or nonresponse to the medication is helpful in determining whether retreatment is indicated, and in determining which medication(s) should be used during retreatment.
Methods of Measuring Adherence
Various methods can be used to monitor adherence. Patient report is the most common and efficient method, but this is the most subjective and has been shown to overestimate adherence.4 Pill count is another method for evaluating adherence, but is more cumbersome, and can be easily manipulated by patients. More sophisticated monitoring methods, such as sensors built into pill bottles, are expensive and usually reserved for research studies.
Measuring concentrations of medication in the serum or urine may be the most objective measure for evaluating adherence. This requires a blood or urine sample, and good benchmarks for levels that indicate optimal adherence. There is some ability to manipulate these results, ie, if correct doses are taken near the time of measurement but not at other times, but this is more difficult than with other methods.
SOF-Adhere
SOF-Adhere is a commercially available assay for the presence of metabolites to sofosbuvir. The test is performed on a patient’s urine sample, and uses liquid chromatography mass spectrometry to measure drug levels. It is intended for use with patients who are being treated with sofosbuvir (Sovaldi®, Harvoni®) as an aid for determining adherence.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Urine metabolite tests for adherence to antiviral medications for hepatitis C infection (eg, SOF-Adhere®; Precision Toxicology) are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Related Policies
Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
Measurement of direct-acting antiviral drug metabolite levels for the purpose of monitoring adherence to treatment for hepatitis C infection is considered investigational.
Medicare Coverage:
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. However, CMS considers CPT code 80375 an invalid code, therefore, CPT code 80375 is noncovered.
Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.
FIDE-SNP Coverage:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)
The Precision Toxicology website states that the SOF-Adhere® “also monitors for the presence and quantity of over 40 common prescription and illicit drugs that could potentially be contraindicated by the treatment plan.”
[RATIONALE: This policy was originally created in 2015 with review of the published medical literature on the MEDLINE database through Januaryt 31, 2018.
Measurement of serum direct-acting antiviral (DAA) metabolites is best considered a potential component of a therapeutic intervention for hepatitis C infection, with the intent of improving treatment response by increasing adherence. The optimal study design for a therapeutic intervention is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. RCTs are particularly important when evaluating adherence because the multiple potential variables influencing adherence will be difficult to control for in nonrandomized studies.
A review of the MEDLINE database did not identify any published studies addressing the efficacy of measuring serum DAA metabolites to assess compliance. Several abstracts and meeting presentations, representing unpublished studies, were cited on the test developer’s website (Precision Toxicology).
RCTs are needed to evaluate the efficacy of measurement of serum DAA metabolites in monitoring adherence. These RCTs should compare treatment using urine monitoring for adherence with treatment not using urine monitoring (ie, either a comparison with no adherence monitoring or a comparison with alternative methods of monitoring adherence). Outcomes of treatment should be, at minimum, adherence measured as rigorously as possible and/or treatment response.
SUMMARY OF EVIDENCE
For individuals who have hepatitis C and are receiving treatment with DAA medications who receive monitoring adherence to DAAs by measuring urinary metabolites, the evidence includes no published studies that evaluate the impact on adherence to DAA agents. Relevant outcomes are medication use. To demonstrate that such testing improves outcomes, randomized controlled trials are needed to assess treatment with measurement of DAA metabolites compared with treatment without measurement of DAA metabolites. Ideally, the outcome measures in these trials would be adherence to DAAs and sustained virologic response. The evidence is insufficient to determine the effects of the technology on health outcomes.
SUPPLEMENTAL INFORMATION
PRACTICE GUIDELINES AND POSITION STATEMENTS
Centers for Disease Control and Prevention et al
Current treatment recommendations for hepatitis C infection were created by the Centers for Disease Control and Prevention in collaboration with the American Association for Study of Liver Disease, the Infectious Diseases Society of America, and the International Antiviral Society‒USA. It provides up-to-date guidelines for the treatment of hepatitis C.5 These guidelines mention adherence in the chapter “Monitoring Patients Who Are Starting Hepatitis C Treatment, Are on Treatment, or Have Completed Therapy.” This chapter was last updated in September 2016 and there is no mention of using serum drug metabolites to monitor adherence. The following recommendation is made:
“Clinic visits or telephone contacts are recommended as clinically indicated during treatment to ensure medication adherence and to monitor for adverse events and potential drug-drug interactions with newly prescribed medications.”
U.S. Department of Veterans Affairs
The Department of Veterans Affairs updated its guidance on hepatitis C in 2016 in Chronic Hepatitis C Virus (HCV) Infection.6 The following statement on adherence is included:
“Evaluating a patient’s potential adherence to medical recommendations and the prescribed regimen is crucial to the patient selection process. Factors that may complicate adherence, such as active substance abuse, neurocognitive disorders, and lack of social support, should be adequately evaluated and addressed before initiating medications. Providers should incorporate strategies for measuring and supporting adherence within their clinics.”
The document does not provide further guidance on types of strategies for measuring and supporting adherence.
World Health Organization
In April 2016, the World Health Organization updated its guidelines on screening, care, and treatment for chronic hepatitis C infection.7 The guidelines provide a framework for the frequency of monitoring patients undergoing hepatitis C virus treatment based on the type of regimen. Adherence should be monitored during the following weeks:
Direct-antiviral agent (DAA) alone: week 4
DAA plus ribavirin: weeks 1, 2, 4, 8, and 12
DAA plus pegylated interferon plus ribavirin: weeks 1, 2, 4, 8, and 12.
The document does not provide further guidance on how to monitor adherence.
U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable.
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov on March 2019 did not identify any ongoing or unpublished trials that would likely influence this review.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Urinary Metabolite Tests for Adherence to Direct-Acting Antiviral Medications for Hepatitis C Infection
Urinary Metabolite Tests for Adherence to Direct-Antiviral Medications for Hepatitis C Infection
Urinary Metabolite Tests for Adherence to Direct-Acting Antiviral Medications for Hepatitis C
Adherence to Direct-Acting Antiviral Medications for Hepatitis C
SOF-Adhere
SOF Adhere
References:
1. LaFleur J, Hoop R, Morgan T, et al. High rates of early treatment discontinuation in hepatitis C-infected US veterans. BMC Res Notes. 2014;7:266. PMID 24758162
2. Gordon SC, Yoshida EM, Lawitz EJ, et al. Adherence to assigned dosing regimen and sustained virological response among chronic hepatitis C genotype 1 patients treated with boceprevir plus peginterferon alfa-2b/ribavirin. Aliment Pharmacol Ther. Jul 2013;38(1):16-27. PMID 23710734
3. Mathes T, Jaschinski T, Pieper D. Adherence influencing factors - a systematic review of systematic reviews. Arch Public Health. 2014;72(1):37. PMID 25671110
4. Lieveld FI, van Vlerken LG, Siersema PD, van Erpecum KJ. Patient adherence to antiviral treatment for chronic hepatitis B and C: a systematic review. Ann Hepatol. May-Jun 2013;12(3):380-391. PMID 23619254
5. American Association for Study of Liver Diseases. Recommendation for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org. Accessed November 28, 2016.
6. Department of Veterans Affairs. Chronic hepatitis C virus (HCV) infection: Treatment considerations from the Department of Veterans Affairs National Hepatitis C Resource Center Program and the HIV, Hepatitis, and Public Health Pathogens Programs in the Office of Patient Care Services. 2016; file:///C:/Users/MA06695/Downloads/treatment-considerations-2016-09-22.pdf. Accessed November 28, 2016.
7. World Heatlh Organization (WHO). Guidelines for the Screening, Care and Treatment of Persons with Chronic Hepatitis C Infection. 2016; http://apps.who.int/iris/bitstream/10665/205035/1/9789241549615_eng.pdf?ua=1. Accessed November 28, 2016.
8. Chopra S, Pockros PJ. Overview of the management of chronic hepatitis C virus infection. In: UpToDate, Bloom A (Ed), UpToDate, Waltham, MA. (Accessed on February 15, 2018.)
9. Chopra S, Pockros PJ. Overview of the management of chronic hepatitis C virus infection. In: UpToDate, Di Bisceglie AM, Bloom A (Eds), UpToDate, Waltham, MA. (Accessed on March 11, 2019.)
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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