Human Immunodeficiency Virus (Hiv) Tropism Testing

MEDICAL POLICY HUMAN IMMUNODEFICIENCY VIRUS (HIV) TROPISM TESTING

Policy Number: 2014T0534I Effective Date: August 1, 2014

Table of Contents Page Related Policies: None BENEFIT CONSIDERATIONS………………………… 1 COVERAGE RATIONALE……………………………… 2 APPLICABLE CODES………………………………….. 2 DESCRIPTION OF SERVICES...... 2 CLINICAL EVIDENCE………………………………….. 2 U.S. FOOD AND DRUG ADMINISTRATION………… 4 CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS)………………………………………. 4 REFERENCES………………………………………….. 4 POLICY HISTORY/REVISION INFORMATION…….. 5 Policy History Revision Information INSTRUCTIONS FOR USE This Medical Policy provides assistance in interpreting UnitedHealthcare benefit plans. When deciding coverage, the enrollee specific document must be referenced. The terms of an enrollee's document (e.g., Certificate of Coverage (COC) or Summary Plan Description (SPD) and Medicaid State Contracts) may differ greatly from the standard benefit plans upon which this Medical Policy is based. In the event of a conflict, the enrollee's specific benefit document supersedes this Medical Policy. All reviewers must first identify enrollee eligibility, any federal or state regulatory requirements and the enrollee specific plan benefit coverage prior to use of this Medical Policy. Other Policies and Coverage Determination Guidelines may apply. UnitedHealthcare reserves the right, in its sole discretion, to modify its Policies and Guidelines as necessary. This Medical Policy is provided for informational purposes. It does not constitute medical advice.

UnitedHealthcare may also use tools developed by third parties, such as the MCG™ Care Guidelines, to assist us in administering health benefits. The MCG™ Care Guidelines are intended to be used in connection with the independent professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice.

BENEFIT CONSIDERATIONS

Essential Health Benefits for Individual and Small Group: For plan years beginning on or after January 1, 2014, the Affordable Care Act of 2010 (ACA) requires fully insured non-grandfathered individual and small group plans (inside and outside of Exchanges) to provide coverage for ten categories of Essential Health Benefits (“EHBs”). Large group plans (both self-funded and fully insured), and small group ASO plans, are not subject to the requirement to offer coverage for EHBs. However, if such plans choose to provide coverage for benefits which are deemed EHBs (such as maternity benefits), the ACA requires all dollar limits on those benefits to be removed on all Grandfathered and Non-Grandfathered plans. The determination of which benefits constitute EHBs is made on a state by state basis. As such, when using this guideline, it is important to refer to the enrollee’s specific plan document to determine benefit coverage.

Human Immunodeficiency Virus (HIV) Tropism Testing: Medical Policy (Effective 08/01/2014) 1

Tropism testing in human immunodeficiency virus (HIV) patients prior to initiating treatment with CCR5 inhibitors (e.g., maraviroc) is proven and medically necessary.

APPLICABLE CODES

The Current Procedural Terminology (CPT®) codes and Healthcare Common Procedure Coding System (HCPCS) codes listed in this policy are for reference purposes only. Listing of a service 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 enrollee specific benefit document and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claims payment. Other policies and coverage determination guidelines may apply. This list of codes may not be all inclusive.

CPT® Code Description Infectious agent genotype analysis by nucleic acid (DNA or RNA); 87901 HIV-1, reverse transcriptase and protease regions 87906 Infectious agent genotype analysis by nucleic acid (DNA or RNA); HIV-1, other region (e.g., integrase, fusion) 87999 Unlisted microbiology procedure CPT® is a registered trademark of the American Medical Association.

DESCRIPTION OF SERVICES

The human immunodeficiency virus (HIV) is the virus that causes acquired immunodeficiency syndrome (AIDS). HIV can be further classified as HIV-1 or HIV-2. HIV-1 is the primary cause of AIDS. HIV-2, while similar to HIV-1, is primarily found outside of the United States. For purposes of this medical policy, HIV refers to HIV-1.

HIV attacks the immune system by infecting and destroying its host cell, the CD4+ lymphocyte, a type of white blood cell that is vital to fighting off infection. HIV requires a co-receptor for entry into target cells (known as tropism). The virus can enter through a CCR5 co-receptor, a CXCR4 co-receptor or both (dual/mixed). Knowing which co-receptor the virus uses is an important predictor of a patient's response to a class of anti-HIV drugs called CCR5 inhibitors. Maraviroc is the first in this class of drugs to receive U.S. Food and Drug Administration (FDA) approval. Rather than fighting HIV inside white blood cells, maraviroc prevents the virus from entering uninfected cells by blocking the main route of entry, the CCR5 co-receptor (FDA, 2007).

Trofile is a complex diagnostic test that identifies the tropism of a patient's HIV. Earlier versions of the test failed to routinely detect low levels of CXCR4-utilizing variants; however, it has since been changed with enhanced sensitivity. Although this more sensitive test has had limited use in prospective clinical trials, it is now the only one that is commercially available. Tropism testing generally requires a plasma sample with an HIV-1 level of greater than or equal to 1000 copies/mL (DHHS, 2011; updated 2013).

CLINICAL EVIDENCE

Whitcomb, et al. (2007) conducted a validation study of an assay for determining HIV-1 coreceptor tropism (Trofile). Accuracy, reproducibility, linearity, sensitivity and specificity were established by evaluating the tropisms of well-characterized viruses and the variability among replicate results from samples tested repeatedly. The viral subtype, hepatitis B virus or hepatitis C virus coinfection, and the plasma viral load did not affect assay performance. Minority subpopulations with alternate tropisms were reliably detected when present at 5 to 10%. The plasma viral load above which samples can be amplified efficiently in the Trofile assay is 1,000 copies per ml of plasma. The minor variant was 100% detectable when present at a frequency of

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Proprietary Information of UnitedHealthcare. Copyright 2014 United HealthCare Services, Inc. 10% and was 85% detectable when present at a frequency of 5%. No false-positive or false- negative amplification results were observed in three replicate evaluations. The authors concluded that the Trofile assay can be used to identify patients most likely to benefit from treatment regimens that include a coreceptor inhibitor and to monitor patients on treatment for the emergence of resistant virus populations that switch coreceptor tropism.

Braun and Weismann (2007) reviewed the characteristics of four phenotypic recombinant virus assays (RVA) available to predict coreceptor usage: Trofile (Monogram Biosciences), Phenoscript (VIRalliance), XtrackC/ PhenX-R (inPheno) and a platform developed by Virco. Trofile and Phenoscript represent single-cycle assays and are able to determine coreceptor tropism without cocultivation of HIV particles in cell culture. Trofile offers the most clinically validated data with currently about 25,000 analyzed samples. The detection of minority variants is a limitation of all population-based assays and varies between 1 and 10%, depending on the assay used. Although all assays are validated for the assessment of coreceptor tropism in different HIV-1 subtypes, there is still a need for further evaluations. The authors conclude that overall, RVAs confirm efficiency and accuracy, making them suitable for the clinical management of HIV infected individuals treated with coreceptor antagonists.

Skrabal et al. (2007) conducted an evaluation study to measure concordance between two recombinant phenotypic assays for HIV coreceptor usage (Trofile and TRT) and an HIV envelope genotypic predictor. HIV coreceptor usage was obtained from both phenotypic assays for 74 samples, with an overall 85.1% concordance. There was no evidence of a difference in sensitivity between the two phenotypic assays. A bioinformatic algorithm based on a support vector machine using HIV V3 genotype data was able to achieve 86.5% and 79.7% concordance with the Trofile and TRT assays, respectively, approaching the degree of agreement between the two phenotype assays. In most cases, the phenotype assays and the bioinformatic approach gave similar results. However, in cases where there were differences in the tropism results, it was not clear which of the assays was "correct."

U.S. Department of Health and Human Services (DHHS) guidelines (DHHS, 2011; updated 2013) recommend that a co-receptor tropism assay be performed whenever the use of a CCR5 inhibitor is being considered (AI). Co-receptor tropism testing is also recommended for patients who exhibit virologic failure on a CCR5 inhibitor (BIII). A phenotypic tropism assay (e.g., Trofile) is preferred to determine HIV-1 co-receptor usage (AI). A genotypic tropism assay should be considered as an alternative test to predict HIV-1 co-receptor usage (BII).

Strength of recommendation: AI - strong recommendation based on data from randomized controlled trials. BII – moderate recommendation based on data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes. BIII – moderate recommendation based on expert opinion

Professional Societies Infectious Diseases Society of America (IDSA) The IDSA guidelines for the management of persons infected with HIV state that tropism testing should be performed if the use of a CCR5 antagonist is being considered (strong recommendation, high quality evidence) (Aberg et al., 2013).

International Antiviral Society - USA Panel Tropism assay to confirm R5 virus should be done before prescribing maraviroc. Maraviroc is not effective in persons who have X4 or dual/mixed X4/R5 virus infection. Drugs that block CCR5 have durable antiretroviral activity only if the individual is infected with HIV that uses CCR5 exclusively and not CXCR4. The use of these drugs thus requires receptor tropism screening. Phenotypic or genotypic assays may be used. Strength of recommendation: AIa - Strong evidence from 1 or more randomized controlled clinical trials published in the peer-reviewed literature (Thompson et al., 2012; Thompson et al., 2010).

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European Consensus Group on Clinical Management of Tropism Testing Testing for HIV tropism is recommended before prescribing a chemokine receptor blocker. The European Consensus Group panel recommends HIV-tropism testing for the following groups: drug-naive patients in whom toxic effects are anticipated or for whom few treatment options are available; patients who have poor tolerability to or toxic effects from current treatment or who have central nervous system pathology; and patients for whom therapy has failed and a change in treatment is considered. In general, an enhanced sensitivity Trofile assay and V3 population genotyping are the recommended test methods (Vandekerckhove et al., 2011).

U.S. FOOD AND DRUG ADMINISTRATION (FDA)

The Trofile™ co-receptor tropism test is regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA); therefore, premarket approval from the FDA is not required.

Pfizer, Inc. received FDA approval for maraviroc/Selzentry® on August 6, 2007. NDA 022128. Maraviroc is a CCR5 co-receptor antagonist indicated for combination antiretroviral treatment of adults infected with only CCR5-tropic HIV-1 detectable, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Maraviroc is not approved for use in patients 16 years of age or younger. Safety and efficacy are not established in treatment-naive HIV infected people or in those with dual- or mixed-tropic or with CXCR4-tropic virus. Tropism and treatment history should guide the use of maraviroc. Additional information available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022128s012lbl.pdf. Accessed May 1, 2014.

CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS)

Medicare does not have a specific National Coverage Determination (NCD) for human immunodeficiency virus (HIV) tropism testing. However, Medicare has the following NCDs for Human Immunodeficiency Virus (HIV) testing: • Human Immunodeficiency Virus (HIV) Testing (Diagnosis) (190.4) • Human Immunodeficiency Virus (HIV) Testing (Prognosis Including Monitoring) (190.13) • Serologic Testing for Acquired Immunodeficiency Syndrome (AIDS)(190.9) • Screening for the Human Immunodeficiency Virus (HIV) Infection (210.7)

Local Coverage Determinations (LCDs) that specifically mention tropism testing in HIV patients do not exist.

(Accessed April 30, 2014)

REFERENCES

Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jan;58(1):1-10.

AIDSinfo website. Available at: http://www.aidsinfo.nih.gov. Accessed May 5, 2013.

Braun P, Wiesmann F. Phenotypic assays for the determination of coreceptor tropism in HIV-1 infected individuals. Eur J Med Res. 2007 Oct 15;12(9):463-72.

Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. January 10, 2011; 1-166. Updated February 2013. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed May 5, 2013.

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Proprietary Information of UnitedHealthcare. Copyright 2014 United HealthCare Services, Inc. Food and Drug Administration (FDA). FDA Approves Novel Antiretroviral Drug. August 6, 2007. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108960.htm. Accessed May 5, 2013.

Hayes, Inc. Hayes Medical Technology Directory. Trofile™ HIV tropism assay. Lansdale, PA: Hayes, Inc.; October 2011. Updated October 2013.

Hirsch MS, GHF, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis. 2008 Jul 15;47(2):266-85.

Low AJ, Swenson LC, Harrigan PR. HIV coreceptor phenotyping in the clinical setting. AIDS Rev. 2008 Jul-Sep;10(3):143-51.

Monogram Biosciences. Trofile Co-Receptor Tropism Assay. Available at: http://www.trofileassay.com. Accessed May 5, 2013.

Selzentry website. Available at: http://www.selzentry.com. Accessed May 5, 2013.

Skrabal K, Low AJ, Dong W, et al. Determining human immunodeficiency virus coreceptor use in a clinical setting: degree of correlation between two phenotypic assays and a bioinformatic model. J Clin Microbiol. 2007 Feb;45(2):279-84.

Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012 Jul 25;308(4):387-402.

Thompson MA, Aberg JA, Cahn P, et al.; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010 Jul 21;304(3):321-33.

Vandekerckhove LP, Wensing AM, Kaiser R, et al; European Consensus Group on Clinical Management of Tropism Testing. European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infect Dis. 2011;11(5):394-407.

Whitcomb JM, Huang W, Fransen S, et al. Development and characterization of a novel single- cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. Antimicrob Agents Chemother. 2007 Feb;51(2):566-75.

POLICY HISTORY/REVISION INFORMATION

Date Action/Description • Reorganized policy content • Added benefit considerations language for Essential Health Benefits for Individual and Small Group plans to indicate: o For plan years beginning on or after January 1, 2014, the Affordable Care Act of 2010 (ACA) requires fully insured non- grandfathered individual and small group plans (inside and 08/01/2014 outside of Exchanges) to provide coverage for ten categories of Essential Health Benefits (“EHBs”) o Large group plans (both self-funded and fully insured), and small group ASO plans, are not subject to the requirement to offer coverage for EHBs; however, if such plans choose to provide coverage for benefits which are deemed EHBs (such as maternity benefits), the ACA requires all dollar limits on

Human Immunodeficiency Virus (HIV) Tropism Testing: Medical Policy (Effective 08/01/2014) 5

Proprietary Information of UnitedHealthcare. Copyright 2014 United HealthCare Services, Inc. Date Action/Description those benefits to be removed on all Grandfathered and Non- Grandfathered plans o The determination of which benefits constitute EHBs is made on a state by state basis; as such, when using this guideline, it is important to refer to the enrollee’s specific plan document to determine benefit coverage • Updated coverage rationale; added language to indicate the proven service is “medically necessary” • Updated list of applicable CPT codes; removed 87903 and 87904 • Updated supporting information to reflect the most current description of services, clinical evidence, FDA and CMS information, and references • Archived previous policy version 2013T0534H

Human Immunodeficiency Virus (HIV) Tropism Testing: Medical Policy (Effective 08/01/2014) 6