mp-322 - Medical Policies - Alabama
Laboratory Testing for HIV Tropism
Policy Number: MP-322
Latest Review Date: January 2021
Policy Grade: Effective January 31, 2019: Active Policy but no longer scheduled for regular literature reviews and updates
HIV tropism testing with either the phenotypic assay or V3 population (via Sanger or V3 deep sequencing method) genotyping may be considered medically necessary for selecting patients for treatment with HIV co-receptor antagonists, such as maraviroc (Selzentry), when there is an immediate plan to prescribe a co-receptor antagonist.
HIV tropism testing without immediate plans to prescribe HIV co-receptor antagonists, such as maraviroc (Selzentry), is considered investigational.
Repeat HIV tropism testing during co-receptor antagonist treatment or after failure with co-receptor antagonists is considered investigational.
HIV tropism testing to predict disease progression (irrespective of co-receptor antagonist treatment) is considered investigational.
*Refer also to medical policy #264: HIV Genotyping and Phenotyping for additional information.
DESCRIPTION OF PROCEDURE OR SERVICE:
HIV tropism testing can determine the predominant co-receptor protein used by the human immunodeficiency virus (HIV) to infect target cells. Tropism testing can help select patients for treatment with HIV co-receptor antagonists, such as Maraviroc, which block specific co-receptor 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-naive 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.
HIV Co-receptor Antagonists
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 states “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 cardiotoxicity), maraviroc should only be used in indicated patients.
Other HIV co-receptor 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 TrofileTM assay (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 co-receptor, and mutations in V3 are associated with measurable changes in HIV tropism. Tropism assignment is derived from the sequence data using a bio-informatic algorithm such as geno2pheno (G2P). In the U.S., the only commercially available genotypic HIV co-receptor tropism assay is available from Quest Diagnostics, which uses triplicate population sequencing with reflex to ultra-deep sequencing if only CCR5-tropic virus is detected. Quest Diagnostics also offers a pro-viral 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 ultra-deep sequencing.
This policy was updated with the literature available through January 4, 2021.
Summary of Evidence
For individuals who have HIV infection who are being considered for HIV co-receptor antagonist therapy who receive HIV tropism testing, the evidence includes RCTs. Relevant outcomes are overall survival, disease-specific survival, morbid events, quality of life, hospitalizations, medication use, and treatment-related morbidity. RCTs on treatment-naive and treatment-experienced HIV-infected patients have provided evidence that selection of candidates for HIV co-receptor antagonist therapy using HIV tropism testing results in higher rates of treatment success compared with HIV co-receptor antagonist therapy without HIV tropism testing. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals with HIV infection receiving HIV co-receptor antagonist therapy or who have failed co-receptor antagonist therapy who receive HIV tropism testing, the evidence includes post hoc analysis of RCTs and observational studies. Relevant outcomes are overall survival, disease-specific survival, morbid events, quality of life, hospitalizations, medication use, and treatment-related mortality and morbidity. Current evidence does not indicate improved outcomes with additional tropism monitoring during treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with HIV infection who are undergoing tests to predict disease progression who receive HIV tropism testing, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, morbid events, quality of life, hospitalizations, and medication use. Current evidence is inconsistent in as relates to whether HIV tropism testing independently predicts disease progression among HIV-infected patients. The evidence is insufficient to determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
HIV Medicine Association of the Infectious Disease society of North America
The HIV Medicine Association of the Infectious Disease Society of North America released updated guidelines on the on the management of persons infected with HIV in 2013. These guidelines state that tropism testing should be performed if the use of a CCR5 antagonist is being considered (strong recommendation, high quality evidence). The guidelines also state that “routine tropism testing is not recommended prior to initiation of other regimens because of cost and lack of demonstrated benefit.” The guidelines do not specify the preferred method of tropism testing.
European Consensus Group
The European Consensus Group on clinical management of tropism testing states that tropism testing is indicated for patients who fail treatment or have unacceptable toxicity and a CCR5 inhibitor is being considered. In the absence of evidence, the group provides no guidance regarding tropism testing for newly diagnosed patients whose immediate treatment plan does not include a CCR5 inhibitor. In the absence of adequate data, the group could provide no guidance regarding the question of testing treatment-naïve patients prior to the start of a regimen not including a CCR5 inhibitor, in anticipation of need for a fast change to a CCR5 inhibitor due to the toxicity of the initial treatment regimen. For patients with a plasma HIV RNA load >1,000 copies/mL, tropism testing can be done by Trofile ESTA or by population genotypic analysis of the V3 loop, indicating for both a moderate level of evidence based on well-designed, nonrandomized trials or cohort studies with long-term clinical outcomes. For patients with a plasma HIV RNA load <1,000 copies/mL, genotyping is the preferred method.
Department of Health and Human Services
The U.S. DHHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV (DHHS, 2018) recommends the use of co-receptor tropism assays (including a phenotypic tropism assay) in clinical practice as follows:
- A co-receptor tropism assay should be performed whenever the use of a CCR5 co-receptor antagonist is being considered (Level of Evidence AI);
- Co-receptor tropism testing is also recommended for patients who exhibit virologic failure on a CCR5 antagonist (Level of Evidence BIII);
- A phenotypic tropism assay is preferred to determine HIV-1 co-receptor usage (A1);
- A proviral DNA tropism assay can be utilized for patients with undetectable HIV-1 RNA when CCR5 antagonist is considered for use in a new regimen (e.g., as part of a regimen switch or simplification) (BII).
- Rating of Recommendations: A = Strong; B = Moderate; C = Optional
- Rating of Evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion.
In addition, the DHHS guidelines state:
A tropism assay may potentially be used in clinical practice for prognostic purposes or to assess tropism before starting ART if future use of a CCR5 antagonist is anticipated (e.g., a regimen change for toxicity). Currently, sufficient data do not exist to support these uses.
International Antiviral Society
The Antiretroviral Drug for Treatment and Prevention of HIV Infection in Adults - 2018 Recommendations of the International Antiviral Society-USA Panel (Saag, 2018) states that CCR5 tropism testing results must be confirmed prior to initiating ART that includes maraviroc and at time of virologic failure.
U.S. Preventive Services Task Force Recommendations
Maraviroc (Selzentry™, Pfizer), Trofile™ (Monogram Biosciences, South San Francisco, CA) assay, SensiTrop assay, HIV-1 Coreceptor Tropism, Tropism testing, Genotypic tropism testing, tropism assay, V3 genotyping, HIV V3, ESTA, antiretroviral drug resistance testing
APPROVED BY GOVERNING BODIES:
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 laboratory developed tests (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 the Clinical Laboratories Improvement Act (CLIA). HIV tropism tests are is available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
Unlisted microbiology procedure
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Medical Policy Group, July 2008 (3)
Medical Policy Administration Committee, July 2008
Available for comment July 15-August 28, 2008
Medical Policy Group, July 2010 (1): Policy statement update, Key Points updated
Medical Policy Administration Committee, June 2010
Available for comment June 18-August 2, 2010
Medical Policy Group, December 2010 (1): Coding update, Added new CPT code, and updated verbiage
Medical Policy Group, July 2011 (2): Key Words update
Medical Policy Group, March 2012 (1): Update to Descriptions, Policy, Key Points and References related to addition of coverage criteria for V3 population genotyping per MPP update
Medical Policy Administration Committee, May 2012
Medical Policy Panel, March 2013
Medical Policy Group, April 2013 (1) Updates to Key Points and References; no change to policy statement
Medical Policy Panel, March 2014
Medical Policy Group, March 2014 (1): Update to Description, Policy, Key Points, Key Words and References related to removal of V3 deep sequencing non-coverage statement
Medical Policy Administration Committee, April 2014
Available for comment April 4 through May 19, 2014
Medical Policy Panel, March 2015
Medical Policy Group, May 2015 (3): Updates to Description, Policy statement (removed patient indications for testing), Key Points, Approved by Governing Bodies, Coding, and References; no change in policy intent.
Available for comment May 16 through June 29, 2015
Medical Policy Panel, December 2017
Medical Policy Group, January 2018 (3): 2017 Updates to Description, Key Points, and References; no changes to current policy statements. Removed policy statements that were effective for dates of service prior to March 1, 2014
Medical Policy Panel, January 2019
Medical Policy Group, January 2019 (3): Updates to Key Points and References. No change to policy statement or intent. Active policy but no longer scheduled for regular reviews and updates.
Medical Policy Group, January 2021 (9): Updates to Key Points, Description, References. Removed policy statements for dates March 1, 2014 through April 30, 2015, removed dates descriptor "on or after May 1, 2015" from current policy criteria. Added common brand name to generic name maraviroc (Selzentry) in policy statement for clarification purposes. No change to policy statement intent. Policy section updated to remove not medically necessary from statement, no change to intent. Active policy but no longer scheduled for regular reviews and updates.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.
The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.
As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:
1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.