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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. 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 drug's original label, maraviroc, in combination with other antiretroviral agents, is indicated for adult patients who are infected with only CCR5-tropic detectable HIV-1, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.
The currently approved maraviroc label indicates that maraviroc is indicated for combination antiretroviral treatment for adults infected with only CCR5-tropic HIV-1, without discussion of the presence of viral replication. The FDA-approved full prescribing information for the drug states that “Tropism testing must be conducted on a current sample with a highly sensitive tropism assay that has demonstrated the ability to identify patients appropriate for use of SELZENTRY.” 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 cardiac toxicity), 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. In January 2015, cenicriviroc was granted fast track designation by FDA for the treatment of nonalcoholic steatohepatitis in patients with liver fibrosis, but the drug does not yet have FDA approval.
HIV Tropism Testing
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 (ESTA). 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 (G2P). In the U.S., the only commercially available genotypic HIV coreceptor tropism assay is available from Quest Diagnostics, which uses triplicate population sequencing with reflex to ultradeep sequencing if only CCR5-tropic virus is detected. Quest Diagnostics also offers a proviral DNA tropism test (Trofile DNA) which sequences the tropism of HIV-1 DNA that has integrated into the host genome of infected T-lymphocytes via triplicate population sequencing, without the use of ultradeep sequencing.
The FDA-approved full prescribing information for maraviroc (Selzentry™, Pfizer) 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.”
Currently-available HIV tropism tests are performed as LDTs. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of CLIA. Testing for HIV tropism is available under the auspices of CLIA Laboratories that offer LTDs and must be licensed by CLIA for high-complexity testing.
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.
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.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
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.
04/01/2015: Policy description updated regarding prescribing information for maraviroc and HIV tropism testing. Removed patient criteria from medically necessary policy statement to be consistent with FDA prescribing information for maraviroc. Policy guidelines updated to add medically necessary and investigative definitions.
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.