National Medical Policy

National Medical Policy

Subject:

Neutralizing Antibody Testing in Multiple

Sclerosis

Policy Number: NMP498

Effective Date*: December 2009

Updated:

November 2014

This National Medical Policy is subject to the terms in the IMPORTANT NOTICE

at the end of this document

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Current Policy Statement

Health Net, Inc. considers assays of neutralizing antibodies against interferon beta for the management of individuals with Multiple Sclerosis to be investigational. Although additional studies continue to be done, there is still insufficient information on the utilization of this testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply and how results of testing would guide therapy.

Definitions

MS Multiple Sclerosis RRMS Relapsing-remitting MS NAbs Neutralizing antibodies IFNß Interferon beta

MRI Magnetic resonance imaging BAbs Binding antibodies

Nabs Neutralizing antibodies

ELISA Enzyme-linked immunosorbent assay RIPA Radio-immuno-precipitation assay CPE Cytopathic effect

MxA Myxovirus resistance protein NU Neutralizing units

OR Odds ratio

CEL Contrast-enhancing lesions TRU Tenfold reduction unit

Codes Related To This Policy

The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or non-covered health service. Coverage is determined by the benefit documents and

medical necessity criteria. This list of codes may not be all inclusive.

On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date.

ICD-9 Codes

ICD-10 Codes

CPT Codes

86382 Neutralization test, viral

87253 Virus isolation, tissue culture, additional studies or definitive

Identification (e.g. hemabsortion, neutralization, immunofluoresence stain), each isolate

HCPCS Codes

Fox et al (2014) reported that many patients with relapsing-remitting multiple sclerosis (MS) treated with high-dose interferon-β (IFNβ) develop serum binding antibodies (BAb) and neutralizing antibodies (NAb). NAb reduces the biological activity of IFNβ, which contributes to clinical failure in these patients. They

investigated whether access to antibody (Ab) test results would alter usual care of (IFNβ)-treated patients and whether BAb could predict Nab in a randomized, controlled, open-label, parallel-group, multicenter study in patients with MS.

Subjects (n=1358) were randomly assigned to Ab testing or usual care. BAb and NAb titres were measured using standard assays. Primary and secondary outcomes were the proportion of patients whose IFNβ therapy changed and the type of and reasons for therapy changes. Therapy changes differed between the Ab testing and usual care arms (19.6% and 14.0%, respectively; p=0·004). Results from Ab testing were more frequently reported as the reason for therapy change in the Ab testing arm than in the usual care arm (p<0.0001). NAb and BAb positivity significantly increased the likelihood of therapy change and reduced IFNβ-associated adverse events. BAb titres were a significant predictor of NAb positivity (p=0.0012). Initial BAb-positive and NAb-positive status in both study arms had a significant impact on the overall number of patients with a therapy change (p<0.05).The investigators concluded access to Ab test results impacted therapy management. BAb titres can predict NAb positivity in patients on high-dose IFNβ.

A Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, Neutralizing antibodies to interferon beta:

Assessment of their clinical and radiographic impact: An evidence report (Mar 2007, Reaffirmed July 2013 ) concluded the following:

1. Treatment of MS with IFNβ (Avonex, Betaseron, or Rebif) is associated with the production of NAbs to the IFNβ molecule (Level A).

2. It is probable that the presence of NAbs, especially in persistently high titers, is associated with a reduction in the radiographic and clinical effectiveness of IFNβ treatment (Level B).

3. It is probable that the rate of NAb production is less with IFNβ-1a treatment compared to IFNβ-1b treatment (Level B). However, because of the variability of the prevalence data, and because NAbs disappear in the majority of patients even with continued treatment (especially in those with low-titer NAbs), the magnitude and persistence of any difference in seroprevalence between these forms of IFNβ is difficult to determine.

4. It is probable that the seroprevalence of NAbs to IFNβ is affected by one or more of the following: its formulation, dose, route of administration, or frequency of administration (Level B). Regardless of the explanation, it seems clear that IFNβ-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNβ preparations (either IFNβ-1a or IFNβ-1b) given multiple times per week subcutaneously (Level A). Because NAbs may disappear in many patients with continued therapy, the persistence of this difference is difficult to determine (Level B).

5. Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) has been associated with a reduction in the therapeutic effects of IFNβ on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply (Level U).

Note: AAN Classification of Recommendations

A - Established as effective, ineffective or harmful (or established as

useful/predictive or not useful/predictive) for the given condition in the specified population.

B – Probably effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population.

C – Possibly effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population.

D – Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

Scientific Rationale – Update November 2012

In Dec 2010 and Jan 2012, HAYES evaluated studies on neutralizing antibody (NAb) testing using the cytopathic effect (CPE) assay for interferon beta treatment of multiple sclerosis. They concluded that the presence of Nab was associated with a statistically significant increase in relapses of MS or worsening of disability. However, several shortcomings were identified such as Nab presence didn’t accurately indicate the MS patients who would have a poor response to interferon beta therapy nor did the studies compare the CPE with a symptom based approach to patient

management as the sole criteria to continue or stop treatment.

HAYES (Jan 11, Jan 12) evaluated testing using a the myxovirus protein A (MxA) assay to assess interferon beta treatment for MS as an alternative or replacement for the CPE assay and found low quality evidence of similar diagnostic capabilities as the CPE assay but both assays may have limited capacity to identify which MS patients will respond poorly to interferon beta. They concluded that the MxA assay may be useful in managing interferon beta therapy by indicating that higher doses may be beneficial or if treatment should be discontinued but further studies are needed to determine clinical utility.

Malucchi et al (2011) reported that a recent study showed that measurement of MxA mRNA, after 1 year of treatment, predicts clinical responsiveness to IFNβ therapy. Loss of IFNβ bioactivity is mostly due to anti-IFNβ antibodies (both neutralizing and binding), non-compliance and receptor saturation. They evaluated all possible causes of loss of IFNβ bioactivity after 1 year in treated patients. MxA gene

expression was measured by real time PCR, antiviral CPE assay to detect neutralizing antibodies (NAbs), and capture-ELISA (cELISA) to measure binding antibodies

(BAbs). The study concluded that MxA mRNA should be measured after 1 year of IFNβ therapy; after 1 year of IFNβ treatment, absence of IFNβ bioactivity was detected in 22% of the patients; different biological phenomena and reduced compliance explain this absence; and that the identification of the reason for absence of IFN bioactivity improves patients' management.

Hartung et al (2011) sought to determine the frequency and consequences of NAbs in patients with a first event suggestive of MS treated with interferon ß-1b (IFNß-1b). In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment

(BENEFIT) study, patients were randomly assigned to 250 µg IFNß-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNß-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer >20 NU/mL was considered NAb-positive, with low (=20-100 NU/mL), medium (=100-400 NU/mL), and high (=400 NU/mL) titer categories. The authors examined early-treated patients, who received IFNß-1b for up to 5 years. NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not

differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers. Authors concluded that although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNß-1b and may also result from temporal changes in NAb titers and biology.

Hartung et al (2012) evaluated various methods are used for detection and quantification of Nabs against IFNB. Blood samples from 125 IFNB-1b-treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three years after first being assessed in four different laboratories that offer routine NAb testing to practicing neurologists. The MxA

induction assay, the CPE assay (two laboratories), or the luciferase assay were used. Intra- and inter-laboratory agreement between assays with respect to NAb detection and NAb titer quantification were evaluated. High agreement for NAb detection (kappa coefficient, 0.86) and for titer levels was observed for the intra-laboratory comparison in the laboratory using the MxA induction assay performed three years ago and now. A similarly high agreement for NAb detection (kappa coefficient, 0.87) and for titer quantification was noted for the MxA assay of this laboratory with one of two laboratories using the CPE assay. All other inter-laboratory comparisons showed kappa values between 0.57 and 0.68 and remarkable differences in individual titer levels. Investigators concluded there are considerable differences in the detection and quantification of IFNB-induced NAbs among laboratories offering NAb testing for clinical practice using different assay methods. It is important that these differences are considered when interpreting NAb results for clinical decision-making and when developing general recommendations for potentially clinically meaningful NAb titer levels.

Hegen et al (2012) evaluated IFNβ preparation-specific NAb cut-off titers during early treatment for prediction of NAb persistency. Patients who had at least one NAb test between 12 and 30 months (baseline) as well as after more than 48 months (follow-up) on IFNβ treatment were included in this longitudinal study. At baseline 1064 patients had a NAb test. Of those, 203 had a follow-up test. In the follow-up group 23.2% of patients were NAb positive during baseline. NAb frequency

significantly decreased by 40.7% in the IFNβ-1a and by 60% in the IFNβ-1b group at follow-up after a mean time of 75.4 months on treatment, and median NAb titers decreased significantly in both groups. During baseline, NAb titers of >258

neutralizing units (NU) had a sensitivity of 81.3% and a specificity of 90.9% in the IFNβ-1a group, whereas titers of >460 NU had a sensitivity of 100% and a specificity of 91.7% in the IFNβ-1b group to predict persistency at follow-up. When these cut-off titers are applied, 10.2% of all treated patients developed persistent NAbs. Goodin et al (2012) reported the frequency and impact of NAbs to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial. They assessed NAb impact in the BEYOND study. 2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500µg, or glatiramer acetate, 20mg, and observed for 2-3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was

considered NAb positive. Efficacy was compared between positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors. In the IFNβ-1b 250µg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative

status. In the IFNβ-1b 500µg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250µg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ

groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes. Investigators concluded there was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.

Scientific Rationale – Update November 2011

Buck et al. (2011) completed a case-control study. HLA-DRB1 genotyping was performed in a discovery cohort (n = 268) and a validation cohort (n = 825). Patients were recruited in Germany by primary care physicians and neurologists and were mainly of Northern European heritage. All patients had a diagnosis of multiple sclerosis and were receiving long-term interferon beta therapy. The main outcome measures were the antibody status to interferon beta was determined in all patients by capture enzyme-linked immunosorbent assay and in vivo myxovirus protein A assay and correlated with the HLA-DRB1 genotype. In the discovery and validation cohorts, HLA-DRB1*04:01, *04:08, *16:01 were identified as genetic markers that are associated with an increased risk of anti–interferon beta antibody development (P < .05). In addition, alleles with a protective potential were identified, including HLA-DRB1*03:01, *04:04, *11:04. However, after correction for multiple testing, protective alleles did notreach statistical significance. The HLA alleles identified in this study seem to be the major genetic determinant of antibody development, allowing the prediction of the individual risk of patients before initiation of therapy. However, additional peer-reviewed comparative or randomized controlled studies are necessary.

Scientific Rationale – Update February 2011

Koch-Henriksen et al (2009) sought to establish whether the clinical effect of neutralizing antibodies (NAbs) against interferon-beta (IFN beta) depends on the type of IFNbeta (1a or 1b) used for treatment of patients with relapsing-remitting multiple sclerosis (MS). The study included MS-patients who had started first-time treatment with IFNbeta-1a 22 microg s.c tiw (Rebif22) or IFN beta-1b 250 microg s.c. qod (Betaferon) and relapses were recorded at bi-annual visit. Nabs were measured every 12 months using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as positive. The investigators used a mixed logistic regression analysis in which NAb-status (three levels), IFN beta-preparation, and time since treatment started were included as explanatory variables, and relapse rate as response variable. In 1,309 patients, who were observed for 21,958 months, 32.3% were classified as NAb-positive. The odds-ratio (OR) for relapses in NAb-positive months compared with NAb-negative months was 1.25. The risk of relapses was higher with Betaferon than with Rebif22. The effect of NAb-level on relapses was independent of whether the patients were treated with Betaferon or Rebif22 and of time. The investigators concluded NAbs caused by IFNbeta-1a s.c. do not differ from NAbs caused by IFNbeta-1b in their detrimental clinical effect.

Van der Voort et al (2010) sought to determine if myxovirus resistance protein A (MxA) mRNA is related to clinical disease activity in MS. Baseline Myxovirus

resistance protein (MxA) mRNA levels were measured in a prospective cohort of 116 untreated patients with early MS and were related to clinical relapses and MRI at

baseline and at follow-up. Low levels of MxA mRNA were associated with the occurrence of relapses and contrast-enhancing lesions (CELs) on baseline MRI. In addition, high baseline MxA mRNA levels were related to a longer time to a first new relapse. Adding the absence of CELs to high MxA mRNA, the predictive value

increased clearly showing a cumulative value for combining both factors. The

investigators concluded MxA mRNA is related to clinical exacerbations, the number of CELs on MRI, and is indicative for the time to a subsequent relapse. If confirmed, MxA mRNA has potential as a biomarker for clinical disease activity in MS.

Van der Voort et al (2010) also sought to confirm that NAb to interferon beta can persist after therapy withdrawal and evaluated whether persisting NAb are

associated with a worse clinical disease course in MS in a retrospective study. A total of 71 patients with relapsing-remitting multiple sclerosis treated with interferon beta in the past were included in the study. Persisting NAb after therapy withdrawal were tested using the cytopathic effect assay. Patients with and without persisting NAb were compared on several outcomes: the change in annualized relapse rate from prior to interferon beta treatment initiation to after cessation of treatment, time to sustained disability on the Kurtzke Expanded Disability Status Scale, and the use of disease-modifying treatments after cessation of treatment with interferon beta. Seventeen of 71 patients (24%) tested NAb positive after a median interval of 25 months (interquartile range, 10-51 months) after interferon beta treatment

cessation. Eleven of these 17 patients (15%) were high-titer NAb positive (>150 10-fold reduction units per mL). Persisting NAb were associated with an increase in the annualized relapse rate and a reduction in time to reach a sustained Expanded Disability Status Scale score of 6.0, ie, the need for unilateral assistance to walk 100 m. Moreover, NAb-positive patients were treated with second-line therapy

significantly more often, especially mitoxantrone . The reviewers concluded anti-interferon beta NAb can persist after anti-interferon beta treatment withdrawal and are associated with overt clinical disease activity. This is made apparent by an increase in relapse rate and faster disability progression and is supported by the observed need for more aggressive therapy after interferon beta treatment cessation. Prospective studies are warranted to confirm these results.

Garcia-Montojo et al (2010) sought to correlate the detection of NAbs by the

cytopathic effect (CPE) assay, with the expression of myxovirus resistance protein A (MxA), and the ratio between matrix metalloproteinase 9 (MMP-9) and its tissular inhibitor (TIMP-1), in order to evaluate their usefulness as markers of interferon beta (IFN-beta) bioavailability. Pairs of blood and serum samples were collected from 50 patients with multiple sclerosis (MS) during 2 years of IFN-beta treatment.

Expression of MxA, MMP-9 and TIMP-1 were analysed by quantitative PCR, and NAbs were measured by CPE assay. During the study, 60% of patients presented NAbs. The number of serum samples that were NAbs+ was significantly increased amongst patients with relapses (41/92 vs. 33/108). With one serum sample and with a NAb titre >100 tenfold reduction unit (TRU), 66.7% of patients with MS suffered from relapses, 41.7% suffered from progression, and 75% was not an optimal clinical responder. The investigators did not find any significant difference in MxA. They found that 62.5% of patients with MS patients whose ratio was increased twofold after 2 years suffered from relapses, 37.5% suffered from progression, and 68.7% was not an optimal clinical responder. The investigators concluded the early

detection of NAbs by CPE assay and the finding of only one serum sample with a NAb titre >100 TRU seem to be markers of low bioavailability of IFN-beta, whilst a

twofold decrease in the MMP-9/TIMP-1 ratio by quantitative PCR assay seems to be a marker of high bioavailability of IFN-beta.

Studies suggest that the presence of neutralizing antibodies are associated with a statistically significant increase in relapses of MS or worsening of disability. The

available studies do not provide consistent evidence that the cytopathic effect (CPE) assay or the myxovirus protein A (MxA) induction assay can accurately predict response to interferon beta therapy in patients with MS. Available studies have not compared these assays with a symptom-based approach to patient management that relies on response to treatment as the sole criterion for continuation or

discontinuation. Preliminary evidence of low quality suggests that both the MxA assay and the CPE assay have the same diagnostic capabilities but both assays may have limited capacity to identify which MS patients will respond poorly to interferon beta. Additional studies are needed determine whether information provided by these assays can be used to improve management of patients undergoing interferon beta therapy for MS.

Scientific Rationale – Initial

Multiple sclerosis (MS) is a common debilitating neurologic disease that afflicts more than 1 million people worldwide. MS is characterized by areas of demyelination in the white matter of the brain and by recurrent exacerbations of neurologic dysfunction. Women are affected more than men.Symptoms of MS vary, depending in part on the location of plaques within the CNS. Common symptoms include sensory disturbances in the limbs, optic nerve dysfunction, pyramidal tract dysfunction, bladder or bowel dysfunction, sexual dysfunction, ataxia, and diplopia. Four different clinical courses of MS have been defined:

Relapsing–remitting MS (RRMS): Characterized by self-limited attacks of neurologic dysfunction. Attacks develop acutely, evolving over days to weeks. Over the next several weeks to months, most individuals experience a recovery of function that is often, but not always, complete. Between attacks the patient is neurologically and symptomatically stable.

Secondary progressive MS (SPMS): Begins as RRMS, but at some point the attack rate is reduced and the course becomes characterized by a steady deterioration in function unrelated to acute attacks.

Primary progressive MS (PPMS): Characterized by a steady decline in function from the beginning without acute attacks.

Progressive–relapsing MS (PRMS): Begins with a progressive course although these patients also experience occasional attacks.

Treatment of MS varies depending upon individual disease characteristics. The goal of disease-modifying treatment of MS (i.e., anti-inflammatory, immunomodulatory and immunosuppresive treatment) is to prevent or postpone long-term disability. However, long-term disability in MS often evolves slowly over many years. Acute attacks of MS are typically treated with glucocorticoids. Indications for treatment of a relapse include functionally disabling symptoms with objective evidence of neurologic impairment. Disease modifying therapy, such as interferon beta-1a (Avonex),

interferon beta-1b (Betaseron, Rebif), glatiramer acetate (Copaxone) and

natalizumab (Tysabri) have shown beneficial effects for individuals with relapsing-remitting multiple sclerosis (RRMS). Benefits include a decreased relapse rate, reduced progression of disability and slower accumulation of lesions on magnetic resonance imaging (MRI).

Antibodies to interferon beta (IFNß) ultimately develop in many IFNß-treated patients. Two classes of antibodies are recognized, Binding antibodies (BAbs) and neutralizing antibodies (NAbs). Babs may or may not interfere with IFNß function. However, NAbs, a subset of the BAbs, interfere with IFNß function in vitro,

the effectiveness of IFNB as measured by MRI activity, relapses, and disease

progression. The rate of NAb formation varies with the type of interferon, the dosing regimen, and duration of IFNB therapy. Not all individuals treated with interferon develop NAbs, however, when they do occur, they typically develop 12-18 months after the start of treatment.

IFNß antibodies can be detected through binding assays, including enzyme-linked immunosorbent assays (ELISAs) and radio-immuno-precipitation assays (RIPAs) that measure all BAbs. Two assays specifically measure NAbs. The cytopathic effect (CPE) assay measures a reduction in the amount of IFNß-induced inhibition of virally

mediated cell lysis. By contrast, the myxovirus resistance protein (MxA) assay measures a reduction (either in vitro or in vivo) in the amount of IFNß -induced MxA protein (or mRNA) synthesis. Both the CPE and the MxA assays depend upon assay conditions and require standardization. Either assay had a 2 to 4% false positive rate as judged by the other in a clinical trial setting. Antibodies are often measured using a two-step method, in which sera is screened by a binding assay for the presence of BAbs, and, if positive, assayed for NAbs using the CPE or MxA methods.

Some studies suggest that NAbs may have an impact on clinical effectiveness. Unfortunately, varying definitions of NAb-positivity make comparisons between studies difficult. Many studies use an arbitrary titer of 20 neutralizing units (NU) per milliliter as the cutoff value for NAb-positivity, although there is evidence that higher titers (e.g., more than 100 or 200 NU/mL) are more likely to have an impact on clinical parameters and biomarkers than lower titers. In addition, studies of the natural history of NAbs in IFNß-treated patients suggest that the NAb-positive state is often transient, noting that some patients revert from positive to NAb-negative status over time. Reversion is more likely with NAb titers of less than 200 NU/mL, although it can happen at titers as high as 3,094 NU/mL. It remains unclear whether NAbs eliminate or merely attenuate the effect of IFNß. Some individuals have demonstrated an apparently excellent response to IFNß despite having very high NAb titers. It is also uncertain whether the apparently deleterious effect of NAbs is offset by the improved efficacy reported with high-dose (more frequently administered) IFNß. Two randomized comparative trials, the EVIDENCE trial which provided Class I comparative data for both clinical and MRI outcomes, and the 2-year Independent Comparison of Interferon (INCOMIN) trial, which provided Class I comparative data for MRI outcomes and Class III data for clinical outcomes, reported short term results that NAb-positive patients (defined as positive after a single

positive titer of more than 20 NU/mL) in the high-dose (more frequent) IFNß arms had lower relapse rates and less MRI activity than the arm receiving low-dose (once weekly) IFNß regardless of their NAb status.

In a multicenter, open-label study, Pachner et al (2009) measured the in vivo effects of NAbs on IFNß bioactivity. Antibody status was measured at screening, and then antibody status, levels of myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1) were measured at baseline (< 8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNß-1a, subcutaneous (SC) IFNß 1a, or IFNß -1b. Treatment with IM IFNß-1a was associated with a lower rate of NAb formation among 718 patients screened vs SC IFNß-1a 22 microg, 44 microg, and IFNß-1b. At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-BAb-negative (NAb-) patients. Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers > 100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and

biomarker responses remained consistently depressed in these patients at month 6. The author concluded that this data provides evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.

Durelli et al (2009) reported on the OPTimization of Interferon for MS (OPTIMS) study, a multicenter trial that investigated clinical and MRI outcomes with the approved IFNß-1b dose (250 microg) and a higher dose (375 microg), s.c. every other day. The objective of the study was to analyze the occurrence of NAbs and their effect on clinical and MRI response over a long-term (4-year) follow-up using cross-sectional and longitudinal statistical analysis. Relapses or disease progression was assessed open-label and MRI scans were performed serially during the first year of the study. Neutralizing antibodies were measured using the MxA protein

production neutralization assay. A total of 145 patients with RRMS from 14 centers participated in the study. NAbs frequency was negatively associated with MRI treatment response, but no detrimental effect of NAbs on the clinical response was observed. Results obtained using cross-sectional or longitudinal statistical

approaches were similar. Over the 4-year period, NAb-positive patients treated with 375 microg had a significantly greater probability of NAb disappearance. The

investigators concluded that use of an IFNß-1b dose higher than the currently approved 250-microg dose is associated with an increased probability of NAb disappearance.

In a retrospective study, Sbardella et al (2009) studied the prevalence of NAbs in MS patients grouped according to their clinical response to IFNß during the treatment period. Patients were classified as: group A, developing > 1 relapse after the first 6 months of therapy; group B, exhibiting confirmed disability progression after the first 6 months of therapy, with or without superimposed relapses; and group C,

presenting a stable disease course during therapy. A cytopathic effect assay tested the presence of NAbs in a cohort of ambulatory MS patients treated with one of the available IFNß formulations for at least one year. NAbs positivity was defined as NAbs titre >20 TRU. Seventeen patients (12.1%) were NAbs positive. NAbs positivity correlated with poorer clinical response. As expected, the prevalence of NAbs was significantly lower in Group C (2.1%) than in Group A (17.0%) and Group B (17.0%). However, in the groups of patients with a poor clinical response (A, B), NAbs positivity was found only in a small proportion of patients. The author

concluded that the majority of patients with poor clinical response are NAbs negative suggesting that NAbs explains only partially the sub-optimal response to IFNß. Bellomi et al (2009) investigated the reproducibility of results of two different antibody detection techniques using serum from 100 patients with MS who were receiving IFNß therapy. Fifty samples were analysed using a commercially available kit-based BAb assay and a further 50 different samples were analysed using a widely used NAb cytopathic effect assay, at three different laboratories. All three centers agreed on the BAb status of all serum samples. However, only 84% agreement was reached on serum NAb status, and there was significant inter-laboratory variation in NAb titre values. Further analysis of these data revealed a correlation between the mean NAb titre and the coefficient of variation of serum samples, indicating greater discordance with higher NAb titres. The authors concluded that a significant

interlaboratory variation in NAb titres does exist; thus, caution is required when comparing titres from different centers. They recommend validated detection assays are needed to accurately quantify NAb titres.

Sominanda et al (2009) assessed NAb titres in a large sample of MS patients to identify the pattern of fluctuation during 1-3 years. Data from IFNß-treated MS patients who had been tested for NAbs twice (n = 822) were analyzed. NAb titres were compared between the first and the second samples across the critical NAb

level of 150 TRU/ml, which were previously reported to correlate with loss of bioactivity. Of patients with NAb titres high enough to indicate loss of bioactivity (>150 TRU/ml) in the first analysis 15% showed titres low enough to indicate a regained bioactivity. Conversely, 6% of those without detectable NAbs or NAb titres below the critical level of 150 TRU/ml had shifted to titres above this limit, indicating potential loss of bioactivity. Fluctuation did not differ between IFNß preparation used, treatment duration or sampling interval.

Rot et al (2008) investigated 2822 patients referred to a NAb testing facility. The reason for NAb testing was indicated for 2506 patients: routine testing (76%),

worsening of disease (14%) and other reasons (10%). Overall, 31% of patients were NAb positive and 17% had titres high enough to obliterate IFNß bioactivity. The frequency of NAbs was similar in patients in the routine testing group compared with the worsening group. Samples showing high titres failed to be associated with

worsening of symptoms. The study failed to show low NAb levels in patients responding poorly to IFNß. The authors concluded that it is not possible to predict NAb status by clinical impression of treatment response, however, this is likely to be an effect of the partial efficacy of IFNß. The authors recommend routine testing for NAbs in order to identify NAb status in patients with MS.

Goodin et al (2008) investigated the clinical impact of NAbs on IFNß efficacy in three large patient cohorts comprising 6698 MS patients receiving IFNß-1b across North America, Europe, and Australia. In North America and Europe, NAb testing was generally undertaken because of a poor clinical response; in Australia, it was mandatory for every patient. Of the 6697 patients tested, 28.9% had at least one NAb titre > 20 neutralizing units (NU)/ml, 14.4% had NAb titres > 100 NU/ml and 7.7% had NAb titres > 400 NU/ml. The NAb-positive rate of 37.0% in Australia was significantly greater than those in North America (21.3%) and Europe (27.6%), and this was observed at every NAb titre level. The author suggested that NAbs are not responsible for poor clinical responses and that NAb status is of little clinical value, noting that findings will need to be confirmed in a large independent study.

At the current time, guidelines and expert opinion are conflicting regarding the utility of NAb testing. An evidence-based review of NAbs (2007) from the American

Academy of Neurology (AAN) concluded that although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) has been associated with a reduction in the

therapeutic effects of IFNß on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply.

Evidence-based guidelines from the European Federation of Neurological Societies (EFNS) published in 2005 recommend that all patients treated with IFNß should undergo testing for the presence of NABs at 12 and 24 months of therapy and be performed in specialized laboratories. The guidelines also recommend NAB testing can be discontinued in patients remaining NAB-negative during this 12-24 month period but should be resumed if disease activity increases. The EFNS further

recommends that individuals with NAbs should undergo repeated NAB measurement at intervals of 3 to 6 months and therapy with IFNß should be discontinued in

patients with high titres of NABs (e.g., titres >100 in patients using IFN-beta-1b) sustained at repeated measurements with 3- to 6-month intervals.

Although NAbs may have an impact on relapse rates and lesion development on MRI, and possibly disease progression as well, it is difficult to make treatment decisions based on the results of a single assay, particularly if the person continues to do well clinically (i.e., relapse rate, symptoms, MRI activity). Further trials incorporating

therapeutic interventions based on NAb status are necessary before NAb testing can be widely recommended for patients with MS receiving IFNß therapy.

Review History

December 2009 Medical Advisory Council, Initial approval February 2011 Update – no revisions

November 2011 Update. Added revised Medicare Table. No revisions. November 2012 Update – no revisions

November 2013 Update – no revisions. Codes updated November 2014 Update – no revisions

This policy is based on the following evidence-based guidelines:

multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002 Jan 22;58(2):169-78.

2. Goodin DS, Frohman EM, Hurwitz B et al. Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007;68;977-984. Reaffirmed July 2013

3. Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005 Nov;12(11):817-27. Available at:

http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=9651&nbr=0 05167&string=neutralizing+AND+antibody+AND+Multiple+AND+sclerosis 4. Hayes Health Technology Brief. Neutralizing Antibody (NAb) Testing Using the

Cytopathic Effect (CPE) Assay to Assess Interferon Beta Treatment of Multiple Sclerosis. Dec 2010. Updated January 4, 2013. Archived Jan 2014

5. Hayes Health Technology Brief. Neutralizing Antibody (NAb) Testing Using the Myxovirus Protein A (MxA) Assay to Assess Interferon Beta Treatment of Multiple Sclerosis. Jan 2011. Updated January 3, 2013. Archived February 2014

References – Update November 2014

1. Creeke PI, Farrell RA. Clinical testing for neutralizing antibodies to interferon-β in multiple sclerosis. Ther Adv Neurol Disord. 2013 Jan;6(1):3-17.

2. Fox E, Green B, Markowitz C, et al. The effect of scheduled antibody testing on treatment patterns in interferon-treated patients with multiple sclerosis. BMC Neurol. 2014 Apr 4;14:73.

References – Update November 2013

1. Shahkarami MA, Vaziri B, Salami S, et al. Neutralizing antibodies in multiple sclerosis patients on weekly intramuscular Avonex and biosimilar interferon beta-1a (CinnoVex): Comparing results of measurements in two different laboratories. J Immunol Methods. 2012 Dec 6. pii: S0022-1759(12)00346-8.

References – Update November 2012

1. Goodin DS, Hartung HP, O'Connor P, et al. Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial. Mult Scler. 2012 Feb;18(2):181-95

2. Hartung HP, Freedman MS, Polman CH, et al. Interferon ß-1b-neutralizing antibodies 5 years after clinically isolated syndrome. Neurology. 2011 Aug 30;77(9):835-43.

3. Hartung HP, Kieseier B, Goodin DS, et al. Variability in detection and quantification of interferon β-1b-induced neutralizing antibodies. J Neuroinflammation. 2012 Jun 15;9:129.

4. Hegen H, Schleiser M, Gneiss C, et al. Persistency of neutralizing antibodies depends on titer and interferon-beta preparation. Mult Scler. 2012

May;18(5):610-5

5. Jensen PE, Sellebjerg F, Søndergaard HB, Sørensen PS. Correlation between anti-interferon-β binding and neutralizing antibodies in interferon-β-treated multiple sclerosis patients. Eur J Neurol. 2012 Oct;19(10):1311-7.

6. Jungedal R, Lundkvist M, Engdahl E, et al. Prevalence of anti-drug antibodies against interferon beta has decreased since routine analysis of neutralizing antibodies became clinical practice. Mult Scler. 2012 May 2.

7. Malucchi S, Gilli F, Caldano M, et al. One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients. J Neurol. 2011 May;258(5):895-903.

References – Update November 2011

1. Buck D, Cepok S, Hoffmann S, et al. Influence of the HLA-DRB1 Genotype on Antibody Development to Interferon Beta in Multiple Sclerosis. Archives of Neurology. Vol. 68 No. 4, April 2011.

2. Polman CH, Bertolotto A, Deisenhammer F, et al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 2010;9(7):740-750.

References – Update February 2011

1. Garcia-Montojo M, Dominguez-Mozo MI, de las Heras V, et al. Neutralizing antibodies, MxA expression and MMP-9/TIMP-1 ratio as markers of bioavailability of interferon-beta treatment in multiple sclerosis patients: a two-year follow-up study. Eur J Neurol. 2010;17(3):470-478

2. Hawker K, O'Connor P, Freedman MS, et al.; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.

3. Hesse D, Frederiksen JL, Koch-Henriksen N, et al. Methylprednisolone does not restore biological response in multiple sclerosis patients with neutralizing antibodies against interferon-beta. Eur J Neurol. 2009;16(1):43-47.

4. Koch-Henriksen N, Sorensen PS, Bendtzen K, Flachs EM. The clinical effect of neutralizing antibodies against interferon-beta is independent of the type of interferon-beta used for patients with relapsingremitting multiple sclerosis. Mult Scler. 2009;15(5):601-605.

5. Pachner AR, Warth JD, Pace A, et al. Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study. Neurology. 2009 Nov 3;73(18):1493-500.

6. van der Voort LF, Gilli F, Bertolotto A, et al. Clinical effect of neutralizing antibodies to interferon beta that persist long after cessation of therapy for multiple sclerosis. Arch Neurol. 2010 Apr;67(4):402-7.

7. van der Voort LF, Kok A, Visser A, et al. Interferon-beta bioactivity measurement in multiple sclerosis: feasibility for routine clinical practice. Mult Scler.

2009;15(2):212-218.

8. van der Voort LF, Vennegoor A, Visser A, et al. Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. Neurology. 2010 Oct 5;75(14):1228-33.

References - Initial

1. Aarskog NK, Marøy T, Myhr KM, Vedeler CA. Antibodies against interferon-beta in multiple sclerosis. J Neuroimmunol. 2009 Jul 25;212(1-2):148-50

2. Applebee A, Panitch H. Early stage and long term treatment of multiple sclerosis with interferon-beta. Biologics. 2009;3:257-71.

3. Bellomi F, Bramanti P, Trojano M, et al. Neutralizing and binding antibodies to interferon beta in patients with multiple sclerosis: a comparison of assay results from three Italian centers. J Immunoassay Immunochem. 2009;30(1):40-50. 4. Bertolotto A, Sala A, Caldano M, et al. Development and validation of a real

time PCR-based bioassay for quantification of neutralizing antibodies against human interferon-beta. J Immunol Methods. 2007 Apr 10;321(1-2):19-31 5. Boz C, Oger J, Gibbs E, et al. Reduced effectiveness of long-term

interferon-beta treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study. Mult Scler. 2007 Nov;13(9):1127-37.

6. Durelli L, Barbero P, Cucci A, et al. Neutralizing antibodies in multiple sclerosis patients treated with 375 microg interferon-beta-1b. Expert Opin Biol Ther. 2009 Apr;9(4):387-97.

7. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year

prospective randomized multicentre study (INCOMIN). Lancet. Apr 27 2002;359(9316):1453-60.

8. Farrell R, Kapoor R, Leary S, et al. Neutralizing anti-interferon beta antibodies are associated with reduced side effects and delayed impact on efficacy of Interferon-beta. Mult Scler. 2008 Mar;14(2):212-8

9. Gilli F, Hoffmann F, Sala A, et al. Qualitative and quantitative analysis of antibody response against IFNbeta in patients with multiple sclerosis. Mult Scler. 2006 Dec;12(6):738-46.

10. Goodin DS, Hurwitz B, Noronha A. Neutralizing antibodies to interferon beta-1b are not associated with disease worsening in multiple sclerosis. J Int Med Res. 2007 Mar-Apr;35(2):173-87.

11. Gneiss C, Brugger M, Millonig A, et al. Comparative study of four different assays for the detection of binding antibodies against interferon-beta. Mult Scler. 2008 Jul;14(6):830-6.

12. Hesse D, Sørensen PS. Using measurements of neutralizing antibodies: the challenge of IFN-beta therapy. Eur J Neurol. 2007 Aug;14(8):850-9

13. Hurwitz BJ. Important sources of variability in clinical studies of neutralizing antibodies against interferon beta. J Neurol Sci. 2008 Sep 15;272(1-2):8-19 14. Malucchi S, Gilli F, Caldano M, et al. Predictive markers for response to

interferon therapy in patients with multiple sclerosis. Neurology. 2008 Mar 25;70(13 Pt 2):1119-27

15. Millonig A, Rudzki D, Hölzl M, et al. High-dose intravenous interferon beta in patients with neutralizing antibodies (HINABS): a pilot study. Mult Scler. 2009 Aug;15(8):977-83

16. Pachner AR, Cadavid D, Wolansky L, Skurnick J. Effect of anti-IFN{beta}

antibodies on MRI lesions of MS patients in the BECOME study. Neurology. 2009 Nov 3;73(18):1485-92.

17. Pachner AR, Warth JD, Pace A, et al. Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study. Neurology. 2009 Nov 3;73(18):1493-500

18. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002; 59(10):1496-506

19. Rot U, Sominanda A, Fogdell-Hahn A, Hillert J. Impression of clinical worsening fails to predict interferon-beta neutralizing antibody status. J Int Med Res. 2008 Nov-Dec;36(6):1418-25.

20. Schwid SR, Panitch HS. Full results of the Evidence of Interferon

Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis.

21. Sbardella E, Tomassini V, Gasperini C, et al. Neutralizing antibodies explain the poor clinical response to interferon beta in a small proportion of patients with multiple sclerosis: a retrospective study. BMC Neurol. 2009 Oct 13;9:54. 22. Sominanda A, Hillert J, Fogdell-Hahn A. Neutralizing antibodies against

interferon beta: fluctuation is modest and titre dependent. Eur J Neurol. 2009 Jan;16(1):21-6.

23. Sorensen PS, Koch-Henriksen N, Flachs EM, Bendtzen K. Is the treatment effect of IFN-beta restored after the disappearance of neutralizing antibodies? Mult Scler. 2008 Jul;14(6):837-42

24. Sottini A, Capra R, Serana F, et al. Interferon-beta therapy monitoring in multiple sclerosis patients. Endocr Metab Immune Disord Drug Targets. 2009 Mar;9(1):14-28

25. Traboulsee A, Al-Sabbagh A, Bennett R, et al. Reduction in magnetic resonance imaging T2 burden of disease in patients with relapsing-remitting multiple sclerosis: analysis of 48-week data from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study. BMC Neurol. 2008 Apr 21;8:11

26. Vallittu AM, Erälinna JP, Ilonen J, et al. MxA protein assay for optimal

monitoring of IFN-beta bioactivity in the treatment of MS patients. Acta Neurol Scand. 2008 Jul;118(1):12-7.

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Reconstructive Surgery

CA Health and Safety Code 1367.63 requires health care service plans to cover reconstructive surgery. “Reconstructive surgery” means surgery performed to correct or repair abnormal structures of the body caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do either of the following:

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