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HIV tropism testing can determine the predominant coreceptor protein used by HIV to infect target cells. Tropism testing can help select patients for treatment with HIV coreceptor antagonists, such as maraviroc, which block specific coreceptor proteins.
The human immunodeficiency virus (HIV-1), which causes acquired immunodeficiency syndrome, uses co-receptor proteins (either CCR5 or CXCR4) on the surface of target cells to enter and infect the cells. The most commonly transmitted strains of HIV-1 bind to CCR5 and are said to have “tropism” for CCR5-expressing cells. Dual or mixed (D/M) tropic viruses can bind to either receptor type. It is estimated that around 85% of treatment-naïve patients harbor CCR5-tropic virus only, around 15% harbor D/M virus, and less than 1% are infected with CXCR4-tropic virus alone. CXCR4-tropic virus is associated with immunosuppression and later stages of disease. New, experimental drugs, termed co-receptor antagonists, have been designed to interfere with the interaction between HIV-1 and its co-receptors.
Maraviroc (Selzentry™, Pfizer) is the first co-receptor antagonist to be approved by the U.S. Food and Drug Administration (FDA). Maraviroc is a selective, slowly reversible, small-molecule antagonist of the interaction between human cell surface CCR5 and HIV-1 gp120, necessary for HIV-1 cell infection. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells. However, CXCR4-tropic HIV-1 entry is not prevented. According to the label, maraviroc, in combination with other antiretroviral agents, is indicated for adult patients who:
The FDA-approved full prescribing information for the drug states that “Tropism testing must be conducted with a highly sensitive and specific tropism assay that has demonstrated the ability to identify patients appropriate for [maraviroc] use.” This is because efficacy was not demonstrated in a phase II study of maraviroc in patients with dual/mixed or CXCR4-tropic HIV-1. Due to potential adverse effects (hepatic and cardiotoxicity), maraviroc should only be used in indicated patients.
Other HIV coreceptor antagonists are in the drug development pipeline. Cenicriviroc (Tobira Therapeutics) is a small-molecule antagonist of both CCR5 and CCR2, a receptor involved in a number of inflammatory diseases, that is currently being investigated for treatment of CCR5-tropic HIV.
HIV tropism testing is available by either phenotypic or genotypic methods. Tropism testing with a phenotypic assay, a cellular-based assay that functionally determines tropism, is available with the enhanced sensitivity Trofile™ (Monogram Biosciences, South San Francisco, CA) assay. This phenotypic assay uses virus stocks pseudotyped with envelope sequences derived from patient plasma to infect cell lines engineered to express CCR5 or CXCR4 HIV-2 co-receptors. Genotypic tropism testing is based on sequencing the third variable (V3) loop of the HIV glycoprotein 120 gene, because the V3 loop interacts with the HIV coreceptor, and mutations in V3 are associated with measurable changes in HIV tropism. Tropism assignment is derived from the sequence data using a bioinformatic algorithm such as geno2pheno. In the U.S., the only commercially available genotypic HIV coreceptor tropism assay is available from Quest Diagnostics.
POLICYHIV tropism testing with either the phenotypic assay or V3 population genotyping may be considered medically necessary for selecting patients for treatment with HIV co-receptor antagonists such as maraviroc when there is an immediate plan to prescribe a coreceptor antagonist. Patients indicated for testing:
HIV tropism testing without immediate plans to prescribe HIV co-receptor antagonists such as maraviroc is not medically necessary.
Repeat HIV tropism testing during co-receptor antagonist treatment or after failure with co-receptor antagonists is investigational.
HIV tropism testing to predict disease progression (irrespective of co-receptor antagonist treatment) is investigational.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
POLCIY GUIDELINESTesting should be conducted immediately prior to intended prescribed use of maraviroc to obtain the most accurate prediction of tropism at the start of treatment.
Either phenotypic or V3 population genotypic testing may be used to determine HIV tropism; both are not necessary.
V3 population genotypic testing may be conducted by either standard V3 sequencing via Sanger methods (amplification and population sequence analysis of patient-derived V3 region) OR V3 deep sequencing methods (synonyms: ultra-deep sequencing; pyrosequencing; next-generation sequencing). In the U.S., the only currently commercially available plasma HIV DNA coreceptor genotypic test (requires HIV viral load of 1000 copies/mL or more) includes step-wise testing, with an initial standard sequencing with reflex to V3 deep sequencing if standard sequencing detects only CCR5-tropic virus.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY1/11/2008: Policy added
1/24/2008: Added "see POLICY section" to Code Reference section for CPT 87999
3/27/2008: Reviewed and approved by the Medical Policy Advisory Committee (MPAC)
04/21/2010: Policy description updated regarding testing availability and indications. The first policy statement was revised to include treatment-naïve patients as one of the indications that may be considered medically necessary. The third policy statement was revised to replace “in advance of multiple antiretroviral treatment failures” with “without immediate plans.” FEP verbiage added to the Policy Exceptions section.
04/26/2012: Policy statement revised to indicate that HIV V3 genotyping is medically necessary for tropism testing. Deleted the following policy statement: HIV tropism testing using other assay techniques is considered investigational. Added the following policy statement: HIV V3 deep sequencing (synonyms: ultra-deep sequencing; pyrosequencing; next generation sequencing) for selecting patients for treatment with HIV co-receptor antagonists is considered investigational. Policy guidelines updated regarding testing protocol.
07/16/2013: Policy reviewed; no changes to policy statement. Added ICD-9 codes 042 and V08 to the Code Reference section.
09/16/2014: Policy reviewed; description updated. Policy statement revised to state that HIV tropism testing with either the phenotypic assay or V3 population genotyping may be considered medically necessary for selecting patients for treatment with HIV co-receptor antagonists such as maraviroc when there is an immediate plan to prescribe a coreceptor antagonist. Deleted the following policy statement: HIV V3 deep sequencing (synonyms: ultra-deep sequencing; pyrosequencing; next generation sequencing) for selecting patients for treatment with HIV co-receptor antagonists is considered investigational. Policy guidelines updated to add that V3 population genotypic testing may be conducted by either standard or deep sequencing methods.
SOURCES(S)Blue Cross & Blue Shield Association Policy # 2.04.49
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.