National Medical Policy Subject:

HIV Antiretroviral (ART) Drug Resistance Testing and Coreceptor Tropism Assays (e.g. Trofile Test)

Policy Number:

NMP366

Effective Date*: September 2007 Updated:

September 2015

This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use

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Source National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other None

Reference/Website Link

Use Health Net Policy

Instructions  Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions.  Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under “Reference/Website” and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2)  If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual.

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

If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance.

Current Policy Statement Adults and Adolescents I. Health Net, Inc. considers HIV drug resistance testing for adults and adolescents medically necessary for any of the following: 1.

Persons with HIV infection when they enter into care regardless of whether therapy will be initiated immediately or deferred. [If treatment is deferred, testing should still be performed because of the greater likelihood that transmitted resistance-associated mutations will be detected earlier in the course of HIV infection. Results of resistance testing may be important when treatment is initiated. Repeat testing at the time antiretroviral therapy is initiated should be considered because the patient may have acquired a drug-resistant virus (i.e., superinfection)].

2.

To assist in the selection of active drugs when changing antiretroviral regimens in patients with virologic failure and HIV RNA levels >1,000 copies/mL. In persons with >500 but 500 to 1,000 copies/mL) unless they have already been tested for ARV resistance)

5.

HIV drug-resistance studies should be performed before modifying ARV regimens for those entering pregnancy with detectable HIV RNA levels that are above the threshold for resistance testing (i.e., >500 to 1,000 copies/mL) while receiving ARV drugs or who have suboptimal viral suppression after starting ARV drugs during pregnancy.

6.

Genotypic testing is recommended as the preferred resistance testing to guide therapy in antiretroviral naïve patients and in patients with suboptimal virologic responses or virologic failure while on first or second regimens.

7.

Addition of phenotypic testing to genotypic testing is generally preferred for persons with known or suspected complex drug resistance mutation patterns, particularly to protease inhibitors.

8.

A coreceptor tropism assay should be performed whenever the use of a CCR5 antagonist is being considered. (In both treatment-experienced and

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treatment-naive subjects, detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virologic response to maraviroc). In addition, coreceptor tropism testing should also be considered for patients who exhibit virologic failure on a CCR5 inhibitor. Virologic failure also may be caused by resistance of a CCR5-using virus to a CCR5 antagonist, but such resistance is uncommon. Compared to genotypic testing, phenotypic testing has more evidence supporting its usefulness. Therefore, a phenotypic test for co-receptor usage is generally preferred. . However, because phenotypic testing is more expensive and requires more time to perform, a genotypic test to predict HIV-1 co-receptor usage should be considered as an alternative test. (Repeat tropism testing may be considered if a patient has virologic failure after initiating a CCR5 antagonist since a minority species of CXCR-4 or dual-tropic viruses may have been present at baseline, but not detected) 9.

In persons failing integrase strand transfer inhibitor (INSTI)-based regimens, (e.g. Raltegravir ) a genotypic assay for INSTI resistance should be performed to determine whether to include a drug from this class in subsequent regimens (genotypic testing is preferred for this purpose).

10. Screening for HLA-B*5701 before starting patients on an abacavir (ABC)containing regimen to reduce the risk of hypersensitivity reaction (HSR) . HLA-B*5701-positive patients should not be prescribed ABC. Refer to Health Net Medical Policy, “Pharmacogenetic Testing”. Recommendations above from the Department of Health and Human Services (DHHS Panel on Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Updated December 1, 2009. Updated March 2012. Updated Feb 2013 Children II. Health Net, Inc. considers HIV drug resistance testing for children medically necessary for any of the following: 1.

At the time of HIV diagnosis, prior to initiation of therapy in all treatmentnaïve children (Genotypic resistance testing is preferred for this purpose); or

2.

Prior to changing therapy for virologic failure; or

3.

Phenotypic resistance testing should be used (usually in addition to genotypic resistance testing) for patients with known or suspected complex drug resistance mutation patterns, which generally arise after virologic failure of successive ARV therapy regimens

4.

Viral coreceptor (tropism) assays should be used whenever the use of a CCR5 antagonist is being considered. (Viruses in the majority of untreated individuals, including infants and children infected by mother-to-child transmission of HIV, are initially CCR5 tropic. However, a shift in coreceptor tropism often occurs over time, from CCR5 usage to either CXCR4 or both CCR5 and CXCR4 tropism (dual- or mixed-tropic; D/M-tropic. Antiretroviraltreated patients with extensive drug resistance are more likely to harbor detectable X4- or D/M-tropic virus than untreated patients with comparable CD4 T-cell counts).

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5.

Tropism assays may also be considered for patients who demonstrate virologic failure while receiving therapy that contains a CCR5 antagonist. (Repeat tropism testing may be considered if a patient has virologic failure after initiating a CCR5 antagonist since a minority species of CXCR-4 or dual-tropic viruses may have been present at baseline, but not detected)

Note 

In the setting of virological failure, drug resistance testing should be obtained while the patient is still on the failing regimen or within 4 weeks of discontinuing the regimen.



The absence of detectable resistance to a drug does not ensure that use of the drug will be successful, as mutations may not be detected once the drug has been discontinued. A history of all previously used antiretroviral agents and available resistance tests results must be reviewed when making decisions regarding the choice of new agents.



Consultation with a specialist in pediatric HIV infection is recommended for interpretation of resistance assays when considering starting or changing an antiretroviral regimen in a pediatric patient.

Recommendations above from the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. August 16, 2010 (Updated August 2011) Updated Nov 2012. Updated Feb 2014. Updated March 2015

Not Medically Necessary Health Net Inc., considers HIV drug resistance and susceptibility tests not medically necessary for all other indications, including any of the following: 1. Testing in individuals following discontinuation of antiretroviral drugs after four weeks or more, since the assays at this time, may not detect minor drugresistant species. 

Drug resistance mutations might become minor species in the absence of selective drug pressure, and available assays might not detect minor drug-resistant species. If testing is performed in this setting, the detection of drug resistance may be of value, but its absence does not rule out the presence of minor drug resistant species.

2. Individuals with a plasma viral load < 500 copies/mL (Resistance assays cannot be consistently performed given low HIV RNA levels).

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Definitions DHHS AIDS HIV NRTI NNRTI HAART IC RVAs GPT

U.S. Department of Health and Human Services Acquired Immune Deficiency Human immunodeficiency virus Nucleoside Reverse Transcriptase Inhibitor Non-Nucleoside Reverse Transcriptase Inhibitors Highly active antiretroviral therapy Inhibitory Concentration Recombinant Virus Assays Genotypic and phenotypic susceptibility testing

Codes Related To This Policy NOTE: 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 noncovered 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 042 079.53 795.71 V08

Human immunodeficiency virus (HIV) disease Human immunodeficiency virus, type 2 (HIV 2) Nonspecific serologic evidence of human immunodeficiency virus (HIV) Asymptomatic human immunodeficiency virus (HIV) infection status

ICD-10 Codes B20 B97.35 R75 Z21

Human immunodeficiency virus [HIV] disease Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere Inconclusive laboratory evidence of human immunodeficiency virus [HIV] Asymptomatic human immunodeficiency virus [HIV] infection status

CPT Codes 87901 87903 87904 87906 87999

Infectious agent genotype analysis by nucleic acid (DNA or RNA); HIV 1, reverse transcriptase and protease regions Infectious agent phenotype analysis by nucleic acid (DNA or RNA) with drug resistance tissue culture analysis, HIV 1; first through 10 drugs tested Each additional drug tested Infectious agent genotype analysis by nucleic acid (DNA or RNA); HIV-1, other region (eg, integrase, fusion) Unlisted microbiology procedure

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HCPCS Codes N/A

Scientific Rationale - Update September 2015 Buchacz et al (2015) analysed data from HIV Outpatient Study (HOPS) participants from nine US HIV clinics who were diagnosed with HIV infection during 1999-2011. Using the IAS-USA December 2010 guidelines, we assessed the frequency of major drug resistance mutations (mDRMs) related to antiretroviral agents in viral isolates from patients who underwent commercial genotypic testing (GT) for resistance before initiating ART. We employed general linear regression models to assess factors associated with having undergone GT, and then factors associated with having mDRM. Among 1531 eligible patients, 758 (49.5%) underwent GT before first ART, increasing from 15.5% in 1999-2002 to 75.9% in 2009-11 (P5.0 log10 copies/mL and those with a first HOPS visit in 2006 or later were significantly (P100 000 = 63% (P < .001). Similar bell-shaped results were found when the GRT analysis was restricted to 2008-2012, although at a slightly lower prevalence. The aauthors concluded in patients failing cART with LLV, HIV-1 genotyping provides reliable and reproducible results that are informative about emerging drug resistance.

Scientific Rationale – Update September 2013 Antiretroviral Therapy (ART) has dramatically reduced HIV-associated morbidity and mortality and has transformed HIV disease into a chronic, manageable condition. A number of laboratory tests are important for initial evaluation of HIV-infected patients upon entry into care, during follow-up (if antiretroviral therapy (ART) has not been initiated), and before and after the initiation or modification of therapy to assess virologic and immunologic efficacy of ART and to monitor for laboratory abnormalities that may be associated with antiretroviral (ARV) drugs. Two surrogate markers are routinely used to assess the immune function and level of HIV viremia: CD4 T cell count (CD4 count) and plasma HIV RNA (viral load). Resistance testing (ie. Genotypic and phenotypic resistance assays) should be used to guide selection of an ARV regimen; a viral tropism assay should be performed before initiation of a CCR5 antagonist; and HLA-B*5701 testing should be performed before initiation of abacavir (ABC). Phenotypic Assays Phenotypic assays characterize the co-receptor usage of plasma-derived virus. These assays involve the generation of laboratory viruses that express patient-derived envelope proteins (i.e., gp120 and gp41). These pseudoviruses, which are replication-defective, are used to infect target cell lines that express either CCR5 or CXCR4.7, Using the Trofile assay, the co-receptor tropism of the patient-derived virus is confirmed by testing the susceptibility of the virus to specific CCR5 or CXCR4 inhibitors in vitro. This assay takes about 2 weeks to perform and requires a plasma HIV RNA level ≥1,000 copies/mL. The performance characteristics of these assays have evolved. Most, if not all, patients enrolled in premarketing clinical trials of MVC and other CCR5 antagonists were screened with an earlier, less sensitive version of the Trofile assay. This earlier assay failed to routinely detect low levels of CXCR4-utilizing variants. As a consequence, some patients enrolled in these clinical trials harbored low levels of CXCR4-utilizing virus at baseline that were below the assay limit of detection and exhibited rapid virologic failure after initiation of a CCR5 antagonist. The assay has been revised and is now able to detect lower levels of CXCR4-utlizing viruses. In vitro, the assay can detect CXCR4-utilizing clones with 100% sensitivity when those clones represent 0.3% or more of the virus population. Although this more sensitive assay has had limited use in prospective clinical trials, it is now the only one that is commercially available. For unclear reasons, a minority of samples cannot be successfully phenotyped with either generation of the Trofile assay. In patients with plasma HIV-1 RNA below the limit of detection, co-receptor usage can be determined from proviral DNA obtained from peripheral blood mononuclear cells; however, the clinical utility of this assay remains to be determined.

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Genotypic Assays Genotypic determination of HIV-1 co-receptor usage is based on sequencing of the V3-coding region of HIV- 1 env, the principal determinant of co-receptor usage. A variety of algorithms and bioinformatics programs can be used to predict co-receptor usage from the V3 sequence. When compared to the phenotypic assay, genotypic methods show high specificity (~90%) but only modest sensitivity (~50%–70%) for the presence of a CXCR4-utilizing virus. Given these performance characteristics, these assays may not be sufficiently robust to completely rule out the presence of an X4 or D/M variant.Studies in which V3 genotyping was performed on samples from patients screened for clinical trials of MVC suggest that genotyping performed as well as phenotyping in predicting the response to MVC. On the basis of these data, accessibility, and cost, European guidelines currently favor genotypic testing to determine co-receptor usage. An important caveat to these results is that the majority of patients who received MVC were first shown to have R5 virus by a phenotypic assay (Trofile). Consequently, the opportunity to assess treatment response to MVC in patients whose virus was considered R5 by genotype but D/M or X4 by phenotype was limited to a relatively small number of patients. Tropism testing is a diagnostic tool used to identify which coreceptor HIV uses to infect target immune cells. The tests can be phenotypic or genotypic and are used to determine the coreceptor tropism of the dominant HIV population in patients. Tropism testing helps to provide information to enhance understanding of available treatment options. There are currently both phenotypic and genotypic tropism tests currently available: Phenotypic Assays Trofile: The plasma viral load of a patient must be ≥1000 copies/mL for this test. This assay involves the amplification of HIV RNA from a blood sample of the infected patient to make HIV particles that are specific to that patient. These particles are used to infect CCR5- and CXCR4-expressing cell lines. Once the cells have been infected and the particles have undergone replication, a signal detected from the expression of a reporter gene will identify the patient’s viral tropism. Trofile DNA Assay: For patients who have an undetectable viral load (viral loads