Archived Policies - Medicine

Urinary Metabolite Tests for Adherence to Direct-Acting Antiviral Medications for Hepatitis C


Effective Date:02-15-2017

End Date:11-14-2018



Measurement of direct-acting antiviral drug metabolite levels for the purpose of monitoring adherence to treatment for hepatitis C infection is considered experimental, investigational and/or unproven.


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.


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. Human immunodeficiency virus (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

There are various methods that 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, i.e., if correct doses are taken near the time of measurement but not at other times, but this is more difficult than with other methods.

Regulatory Status

SOF-Adhere® (Precision Toxicology, San Diego, CA) 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. 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.”

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 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 (FDA) has chosen not to require any regulatory review of these tests. The FDA does not require approval of class I devices.


This policy was created in January 2016 with review of the published medical literature through December 15, 2015.

Measurement of serum direct-acting antiviral (DAA) metabolites is best considered a potential component of a therapeutic intervention for hepatitis C, 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 company website (Precision Toxicology, San Diego, CA).

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, i.e., 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.

Ongoing and Unpublished Clinical Trials

A search of in December 2015 revealed unpublished trials that might influence this policy are listed in Table 1.

Table 1: Ongoing, Unpublished Clinical Trials


Trial Name

Planned Enrollment

Completion Date


Triple DAAs Regimen in Treating Non-cirrhotic HCV GT1b Subjects


December 2015


Qualification of Point-of-Care Assays for Management of HCV Patients (ANRS HC POC)


March 2016

Table Key:

NCT: national clinical trial;

HCV: hepatitis C virus;

DAA: direct-acting antiviral.

Practice Guidelines and Position Statements

Collaborative Guidelines

Current treatment recommendations for hepatitis C 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.” 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

In 2015, The Department of Veterans Affairs updated and published their document titled Chronic Hepatitis C Virus (HCV) Infection: Treatment Considerations. (6) The following statement concerning adherence is included:

“Evaluating a patient’s 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 noted and adequately addressed before initiating medications. Providers should incorporate strategies for measuring and supporting adherence within their clinics.”

This document does not provide further guidance on the types of strategies for measuring and supporting adherence that are recommended.


There are no published studies that evaluate the impact of measuring DAA metabolite levels with the intent of improving compliance. To demonstrate that such testing improves outcomes, randomized controlled trials are needed assessing 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. Currently, the evidence is insufficient to determine whether measurement of DAA metabolites improves outcomes. Therefore, measurement of DDA drug metabolite levels for the purpose of monitoring adherence to treatment for hepatitis C infection is considered experimental, investigational and/or unproven.


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The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <>.


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, et al. Patient adherence to antiviral treatment for chronic hepatitis B and C: a systematic review. Ann Hepatol. May-Jun 2013; 12(3):380-91. PMID 23619254

5. Recommendation for Testing, Managing, and Treating Hepatitis C (January 29, 2014) Prepared by American Association for Study of Liver Diseases. Available at <> (accessed on 2015 December 15).

6. Chronic hepatitis C virus (HCV) infection: Treatment considerations (2015). Prepared by the Department of Veterans Affairs National Hepatitis C Resource Center and the Office of Public Health Available at <> (accessed on 2015 December 15).

7. Urinary Metabolite Tests for Adherence to Direct-Acting Antiviral Medications for Hepatitis C. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (July 2015) Medicine 2.04.134.

Policy History:

Date Reason
2/15/2017 Reviewed. No changes.
6/1/2016 New medical document. Measurement of direct-acting antiviral drug metabolite levels for the purpose of monitoring adherence to treatment for hepatitis C infection is considered experimental, investigational and/or unproven.

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