Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Human Immunodeficiency Virus (HIV) Genotyping and Phenotyping (Independence Administrators)

Policy #:06.02.09g

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.


This policy only applies to members for whom Independence Administrators serves as the claims administrator. For all other Independence members, refer to the policy entitled eviCore Lab Management Program.

The intent of this policy is to communicate the medical necessity criteria for human immunodeficiency virus (HIV) genotyping or phenotyping.

For information on policies related to this topic, refer to the Cross References section in this policy.


MEDICALLY NECESSARY

Human immunodeficiency virus (HIV) genotyping is considered medically necessary and, therefore, covered for any of the following:
  • For resistance testing at baseline for individuals with acute HIV infection, regardless of whether antiretroviral therapy (ART) is initiated or deferred
  • To guide therapy in antiretroviral (ARV)--naive individuals with chronic HIV infection, regardless of whether ART is initiated or deferred
  • For all pregnant women prior to initiation of therapy and for those entering pregnancy with detectable HIV RNA levels while on therapy
  • To assist in the selection of active drugs when changing ARV regimens in individuals with virologic failure or suboptimal response on their first or second regimens
  • For individuals with known or suspected complex drug-resistance patterns

HIV phenotyping is considered medically necessary and, therefore, covered when genotypic results do not allow for drug selection in either of the following instances:
  • To assist in the selection of active drugs when changing ARV regimens in individuals with virologic failure or suboptimal response on their third and subsequent regimens, or if the individual had initially acquired multidrug-resistant virus
  • For individuals with known or suspected complex drug-resistance patterns

NOT MEDICALLY NECESSARY

HIV genotyping and phenotyping performed at the same time is duplicative and is considered not medically necessary and, therefore, not covered.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.
Guidelines

Virtual phenotyping should be used with discretion as a testing option with respect to newer drugs used in antiretroviral therapy (ART) because there are typically fewer matching genotypes and phenotypes in the correlative database. Standard phenotyping should be used in these circumstances.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, human immunodeficiency virus (HIV) genotyping or phenotyping is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met. However, services that are identified in this policy as experimental/investigational are not eligible for coverage or reimbursement by the Company.

Description

Human immunodeficiency virus (HIV) has been known to replicate rapidly, particularly in response to antiretroviral (ARV) therapies. These replications are a result of substitutions in the viral protease, reverse transcriptase, or integrase enzymes among other regions of the infectious agents, such as the location of fusion, which are targeted by various ARV drugs that can lead to drug-resistant mutations (quasi species). The end result is virologic treatment failure. Because of the rapidity of these replications, highly active antiretroviral therapy (HAART) has been designed to employ different mechanisms to reduce mutations to drug-resistant variants including, but not limited to, nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors, and fusion inhibitors. Examples of US Food and Drug Administration (FDA)--approved ARV drug classes include Fuzeon (enfuviritide), the first FDA-approved HIV-1 fusion inhibitor, and Isentress (raltegravir), an integrase inhibitor.

The effectiveness of HAART in suppressing HIV replication for prolonged periods has allowed HIV to be considered a chronic, rather than a fatal, disease. However, drug failure continues to occur because HAART regimens do not completely suppress replication in all cases. Other factors, such as nonadherence, inadequate potency, or suboptimal levels of drugs may play a part in drug failure. Historically, the initiation of, or a change in, antiretroviral therapy has been based on HIV ribonucleic acid (RNA) levels and CD4 cell counts, both of which are essential components of the clinical management of HIV. Because treatment decisions can irrevocably alter an individual's response to future therapy, clinicians can also utilize genotypic or phenotypic assays as additional clinical tools for selecting safe and efficacious treatment regimens.

Genotypic resistance assays look for mutations that are present in HIV genes (eg, reverse transcriptase [RT], protease, fusion, integrase). Some assays sequence the entire gene, while others use probes to detect mutations that are known to accord drug resistance. Phenotypic resistance assays measure the ability of the virus to replicate in vitro in the presence of an antiviral drug. The medical literature, the Department of Health and Human Services (DHHS) Guidelines, and the International AIDS Society--US Panel support the use of HIV genotyping and/or phenotyping to identify drug-resistant viruses and assist with selecting the most appropriate antiretroviral drugs for an individual.

Virtual phenotyping is a modified genotypic test that looks for mutations in the genetic structure of the HIV virus. When mutations are found, the information is entered into a database that contains data on thousands of HIV samples. If the genotype of the virus being studied matches a genotype in the database, the assumption is that the phenotype will also match. Virtual phenotyping is not a direct measure; rather, it is a prediction based on genotypic analysis and database matches. An example of a virtual phenotype assay is the VircoType (Virco NV, Belgium). Current clinical practice guidelines do not provide specific guidance about the role of virtual phenotyping in HIV resistance testing. However, based on current clinical practice, it appears there is correlation between genotypic interpretation and virtual phenotypic results, particularly when the drug(s) used in ART have been on the market long enough for the correlative database to garner enough matching genotypes and phenotypes to provide accurate phenotypic results. As a result, a limitation of virtual phenotyping is with respect to newer and experimental drugs because there are fewer matching genotypes and phenotypes in the correlative database.
References


AIDSinfo. Adult and Adolescent Guidelines: Drug Resistance Testing. [AIDSinfo Web site]. 01/10/11. Available at: http://www.aidsinfo.nih.gov/Guidelines/GuidelineHTML.aspx?GuidelineID=7&docID=1&NodeID=6. Accessed April 16, 2013.

Arasteh K, Yeni P, Pozniak A, et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther.2009;14(6):859-864.

Baxter JD, Mayers DL, Wentworth DN, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS. 2000;14(9):F83-F93.

Blanco JL, Valdecillos G, Arroyo JR, et al. A prospective randomized study on the usefulness of genotypic resistance tests versus real phenotypic resistance tests in heavily pretreated patients with virological failure (VIHRES study). 14th International AIDS Conference; 2002; Barcelona, Spain: Abstract TuPeB4624.

Booth CL, Geretti AM. Prevalence and determinants of transmitted antiretroviral drug resistance in HIV-1 infection. J Antimicrob Chemother.2007;59(6):1047-1056.

Borroto-Esoda K, Waters JM, Bae AS, et al. Baseline genotype as a predictor of virological failure of emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses.2007;23(8):988-995.

Chargari C, Zefkili S, Kirova YM. Potential of helical tomotherapy for sparing critical organs in a patient with AIDS who was treated for Hodgkin lymphoma. Clin Infect Dis.2009;48(5):687-689.

Cingolani A, Antinori A, Rizzo MG, et al. Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study (ARGENTA). AIDS. 2002;16(3):369-379.

Cohen CJ, Hunt S, Sension M, et al. A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy. AIDS. 2002;16(4):579-588.

Cohen CJ, Hunt S, Sension M, et al. Phenotypic resistance testing significantly improves response to therapy (Tx): randomized trial (VIRA 3001). Seventh Conference on Retroviruses and Opportunistic Infections; January 30 - February 2, 2000; San Francisco, CA: Abstract 237.

Cohen OJ. Antiretroviral therapy: time to think strategically. Ann Intern Med. 2000;132(4):320-322.

Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med.2008;359(4):355-365.

Deeks SG, Hellmann NS, Grant RM, et al. Novel four-drug salvage treatment regimens after failure of a human immunodeficiency virus type 1 protease inhibitor-containing regimen: antiviral activity and correlation of baseline phenotypic drug susceptibility with virologic outcome. J Infect Dis. 1999;179(6):1375-1381.

De Luca A, Di Giambenedetto S, Cingolani A, et al. Three-year clinical outcomes of resistance genotyping and expert advice: extended follow-up of the Argenta trial. Antivir Ther. 2006;11(3):321-327.

Dunn DT, Green H, Loveday C, et al. A randomized controlled trial of the value of phenotypic testing in addition to genotypic testing for HIV drug resistance: evaluation of resistance assays (ERA) trial investigators. J Acquir Immune Defic Syndr. 2005;38(5):553-559.

Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet. 1999;353(9171):2195-2199.

Dybul M, Fauci AS, Bartlett JG, et al. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med. 2002;137(5 Pt 2):381-433.

ECRI Institute. Human immunodeficiency virus (HIV) drug-resistance testing to guide choice of antiretroviral regimen. Plymouth Meeting (PA): ECRI Institute Health Technology Assessment Information Service; 2004 July. (Evidence Report: no. 111). Available at: www.ecri.org. Accessed June 2, 2011.

Eshleman SH, Husnik M, Hudelson S, et al. Antiretroviral drug resistance, HIV-1 tropism, and HIV-1 subtype among men who have sex with men with recent HIV-1 infection. AIDS.2007;21(9):1165-1174.

Falloon J. Time to genotype for selection of antiretroviral regimes in previously treated patients? Lancet. 1999;353(9171):2173-2174.

Gallant JE. Strategies for long-term success in the treatment of HIV infection. JAMA. 2000;283(10):1329-1334.

Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA. 2000;283(2):229-234.

Hirsch HH, Drechsler H, Holbro A, et al. Genotypic and phenotypic resistance testing of HIV-1 in routine clinical care. Eur J Clin Microbiol Infect Dis. 2005;24(11):733-738.

Hirsch MS, Guthard HR, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an international AIDS society--USA panel. CID.2008:47(2):266-285.

Kane B. Beyond HIV viral load testing. Ann Intern Med.1999;131(8):637-638.

Kredo T, Van der Walt JS, Siegfried N, Cohen K. Therapeutic drug monitoring of antiretrovirals for people with HIV. Cochrane Database of Systematic Reviews.2009, Issue 3. Art No.: CD007268.

Kuritzkes DR, Lalama CM, Ribaudo HJ, et al. Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. J Infect Dis.2008;197(6):867-870.

LaHart CJ. The infectious diseases. In: Rakel RE, Bope ET, eds. Conn's Current Therapy 2001. Philadelphia, PA: WB Saunders Company; 2001: 40-50.

Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet.2007:370(9581):39-48.

Little SJ, Frost SD, Wong JK, et al. Persistence of transmitted drug resistance among subjects with primary human immunodeficiency virus. J Virol.2008;82(11):5510-5518.

Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet.2007;370(9581):49-58.

Mazzotta F, Lo Caputo S, Torti C, et al. Real vs. virtual phenotype: 12-month results from the GenPherex study. Ninth Conference on Retroviruses and Opportunistic Infections; 2002; Seattle, WA: Abstract 589-T.

Melnick D, Rosenthal J, Cameron M, et al. Impact of phenotypic antiretroviral drug resistance testing on the response to salvage antiretroviral therapy (ART) in heavily experienced patients. Seventh Conference on Retroviruses and Opportunistic Infections; January 30 - February 2, 2000; San Francisco, CA: Abstract 786.

Meynard JL, Vray M, Morand-Joubert L, et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. AIDS. 2002;16(5):727-736.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 10/14/2011. [AIDSInfo Web site]. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed April 16, 2013.

Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. 5/24/2010. [National Guidelines Clearinghouse Web site]. Available at: http://www.guidelines.gov. Accessed April 16, 2013.

Parker MM, Gordon D, Reilly A, et al. Prevalence of drug-resistant and nonsubtype B HIV strains in antiretroviral-naive, HIV-infected individuals in New York state. AIDS Patient Care STDS.2007;21(9):644-652.

Parkin N, Chappey C, Maroldo L, et al. Phenotypic and genotypic HIV-1 drug resistance assays provide complementary information. J Acquir Immune Defic Syndr. 2002;31(2):128-136.

Pavlakis GN. The molecular biology of human immunodeficiency virus type I. In: DeVita VT, Hellman S, Rosenberg SA, eds. AIDS: Etiology, Diagnosis, Treatment and Prevention. 4th ed. Philadelphia, PA: Lippincott-Raven; 1997: 45-74.

Perez-Elias MJ, Garcia-Arata I, Munoz V, et al. A randomized, prospective study of phenotype (P) versus virtual phenotype (VirtualP) testing for patients failing antiretroviral therapy. Ninth Conference on Retroviruses and Opportunistic Infections; 2002; Seattle, WA: Abstract 586-T.

Pomerantz RJ. Primary HIV-1 resistance: a new phase in the epidemic? JAMA. 1999;282(12):1177-1179.

Qari SH, Garcia Lerma JG, Vazquez-Rosales G, et al. A rapid and inexpensive approach for phenotypic analysis of drug resistance to reverse transcriptase (RT) inhibitors by direct analysis of RT activity in plasma. Seventh Conference on Retroviruses and Opportunistic Infections; January 30 - February 2, 2000; San Francisco, CA: Abstract 790.

Rodriguez-Rosado R, Briones C, Soriano V. Introduction of HIV drug-resistance testing in clinical practice. AIDS. 1999;13(9):1007-1014.

Romanelli F, Pomeroy C. Human immunodeficiency virus drug resistance testing: state of the art in genotypic and phenotypic testing of antiretrovirals. Pharmacotherapy. 2000;20(2):151-157.

Saracino A, Monno L, Locaputo S, et al. Selection of antiretroviral therapy guided by genotypic or phenotypic resistance testing: an open-label, randomized, multicenter study (PhenGen). J Acquir Immune Defic Syndr.2004;37(5):1587-1598.

Schuurman R, Demeter L, Reichelderfer P, et al. Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase. J Clin Microbiol. 1999;37(7):2291-2296.

Sherer R. Is antiretroviral resistance testing the standard of care? Paper presented at: Diagnostic Technologies in the Management of HIV/AIDS and Other Life-Threatening Coinfectious Diseases: An IAPAC Symposium. October 10, 1999; Vienna, Austria.

Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the international AIDS society--USA panel. JAMA. 2010;304(3):321-333. Available at: http://jama.ama-assn.org/content/304/3/321.full.pdf+html. Accessed April 16, 2013.

Tural C, Ruiz L, Holtzer C, et al. Clinical utility of HIV-1 genotyping and expert advice: the Havana trial. AIDS. 2002;16(2):209-218.

Up to Date. Clinical trials of HIV drug resistance testing. 02/11/11. Available at: http://www.uptodate.com [via subscription only]. Accessed April 16, 2013.

Up to Date. Drug resistance testing in the clinical management of HIV infection. 02/17/11. Available at: http://www.uptodate.com [via subscription only]. Accessed April 16, 2013.

Up to Date. Evaluation of the treatment-experienced patient with drug-resistant HIV infection. 02/17/11. Available at: http://www.uptodate.com [via subscription only]. Accessed April 16, 2013.

Up to Date. Overview of HIV drug resistance testing assays. 02/14/11. Available at: http://www.uptodate.com [via subscription only]. Accessed April 16, 2013.

Up to Date. Primer on interpretation of HIV drug resistance testing. 06/07/11. Available at: http://www.uptodate.com [via subscription only]. Accessed April 16, 2013.

Wegner SA, Wallace M, Aronson N, et al. Long-term clinical efficacy of resistance testing: results of the CERT trial. 14th International AIDS Conference; 2002; Barcelona, Spain: Abstract ThOrB1389.

Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society - USA Panel. JAMA. 2002;288(2):222-235.

Yeni PG, Hammer SM, Hirsch MS, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society - USA Panel. JAMA. 2004;292(2):251-265.

Vermeiren H, Van Craenenbroeck E, Alen P, et al. Prediction of HIV-1 susceptibility phenotype from the viral genotype using linear regression modeling. J Virol Methods.2007;145(1):47-55.

Zolopa AR. Incorporating drug-resistance measurements into the clinical management of HIV-1 infection. J Infect Dis. 2006;194(Suppl 1):S59-S64.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

87900, 87901, 87903, 87904, 87906


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

B20 Human immunodeficiency virus [HIV] disease

Z21 Asymptomatic human immunodeficiency virus [HIV] infection status



HCPCS Level II Code Number(s)

G0452 Molecular pathology procedure; physician interpretation and report


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

Revisions from 06.02.09g
08/29/2018The policy has been reviewed and reissued to communicate the Company’s continuing position on Human Immunodeficiency Virus (HIV) Genotyping and Phenotyping (Independence Administrators).


Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date: 07/01/2016
Version Issued Date: 07/01/2016
Version Reissued Date: 08/29/2018

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