Description of Procedure or Service

1. Description
   Human immunodeficiency virus (HIV) is an RNA retrovirus that infects human immune cells (specifically CD4 cells) causing progressive deterioration of the immune system ultimately leading to acquired immune deficiency syndrome (AIDS) characterized by susceptibility to opportunistic infections and HIV-related cancers (CDC, 2014).
2. Literature Review
   The HIV virus replicates rapidly, with a replication cycle rate of approximately 1 day in which more than 109 virions can be produced(J. Coffin & Swanstrom, 2013; Ho et al., 1995). Furthermore, reverse transcriptase is error-prone, the overall single-step point mutation rate for HIV-1 is ∼3 × 10−5 mutations per base per replication cycle(Mansky & Temin, 1995) leading to approximately one genome in three containing a mutation after each round of replication, some of which confer drug resistance(J. M. Coffin, 1995). This rate is about average for an RNA virus and that it is the pace of replication, the duration of infection, and the size of the replicating population, allowing it to evolve rapidly in response to selective influences (J. Coffin & Swanstrom, 2013).  
   Drug-resistant variants, which generally replicate slower than wild type, can pre-exist at low levels before drug therapy is initiated and emerge to cause overt virologic failure, or become more drug resistant by the gradual accumulation of additional resistance mutations (Kozal, 2017a, 2017b).
   Drug resistant HIV variants can be assessed using phenotypic testing and genotypic testing. Both assays are limited by their decreased sensitivity for low-level minority variants that comprise less than 5 to 20 percent of the virus population(Kozal, 2017b).
   Genotypic assays detect the presence of specific drug resistance mutations in the protease, reverse transcriptase, and integrase genes. Advantages include lower cost and shorter turnaround time, however are complicated by difficulty in interpretation when many mutations as combinations of individual mutations may have a differential effect on resistance that differs from the individual mutation alone(Kozal, 2017b). Mutations are known to cause resistance to certain drugs, but increase susceptibility to others, impact viral fitness and contribute to major pathways of resistance and the interactions of mutations effecting various mechanisms can be difficult to predict, over 20 rules-based genotypic interpretation systems (GIS) have been proposed(Fox et al., 2007; Kozal, 2017b).
   Phenotypic resistance assays measure the extent to which an antiretroviral drug inhibits virus replication. The major advantages of phenotypic testing is the direct measure of drug susceptibility. Limitations include a longer turnaround time, expense, and biologic cut-offs above achievable drug levels. Phenotypic resistance assays may be helpful when evaluating HIV strains with known or suspected complex drug resistance mutation patterns as their actual resistance may not be accurately predicted by simply detecting the presence of multiple mutations(Kozal, 2017b).
   Antiretroviral therapy guided by genotypic and phenotypic susceptibility testing leads to better viral suppression(Baxter et al., 2000) and has been associated with improved survival(Palella et al., 2009). The emergence of drug resistance may also affect the rate of immunologic recovery(Trotta et al., 2010).The use of drug resistance testing further supported by a study of its cost effectiveness in a hypothetical cohort of antiretroviral-naïve patients(Sax et al., 2005).
3. Applicable Federal Regulations
   On September 26, 2001 FDA approved Visible Genetics, Inc., TrueGene HIV-1 Genotyping Kit and Open Gene DNA Sequencing System to be used to identify drug resistance in HIV patients.
   On November 26, 2002 the FDA approved the Roche Molecular Systems, Ic Cobas Ampliscreen System.
   On September 5, 2013 the FDA approved Celera Corporation’s ViroSeq HIV Genotyping System v2.0.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. 

Policy

BCBSNC will provide coverage for HIV Genotyping and Phenotyping when it is determined to be medically necessary because the medical criteria and guidelines noted below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When HIV Genotyping and Phenotyping is covered

HIV genotyping or phenotyping is considered medically necessary in patients who have failed a course of antiviral therapy OR have suboptimal viral load reduction.

HIV genotyping or phenotyping is considered medically necessary for guiding treatment decisions in patients with acute or recent infection (within the last 6 months).

HIV genotyping or phenotyping in antiretroviral naive patients entering is considered medically necessary.

HIV genotyping or phenotyping is considered medically necessary for all HIV-infected pregnant women before initiation of antiretroviral therapy and for those entering pregnancy with detectable HIV RNA levels while on therapy.

When HIV Genotyping and Phenotyping is not covered

Routine use of combined genotyping and phenotyping is considered investigational.

Drug susceptibility phenotype prediction using genotypic comparison to known genotypic/phenotypic database is considered investigational.

Policy Guidelines

1. Guidelines and Recommendations

Practice Guidelines and Position Statements

Department of Health and Human Services

The Department of Health and Human Services (DHHS, 2018) updated their guidelines for using drug resistance assays in HIV infections in 2018. The guidelines recommend HIV genotyping or phenotyping in the following situations:

• “In acute (early) HIV infection: Drug-resistance testing is recommended. A genotypic assay is generally preferred. Treatment should not be delayed while awaiting results of resistance testing.”
• “In ART-naive patients with chronic HIV infection: Drug-resistance testing is recommended at entry into HIV care to guide selection of initial ART. A genotypic assay is generally preferred.”
• “In patients with virologic failure: Drug-resistance testing is recommended in patients on combination ART with HIV RNA levels >1,000 copies/mL. In patients with HIV RNA levels >500 copies/mL <1000 copies/ml, testing may not be successful but should still be considered. A standard genotypic resistance assay is generally preferred for patients experiencing virologic failure on their first or second regimens. Adding phenotypic testing to genotypic testing is generally preferred in patients with known or suspected complex drug-resistance patterns, particularly to PIs.”
• “In patients with suboptimal suppression of viral load: Drug resistance testing is recommended in patients with suboptimal viral load suppression after initiation of ART.”
• “In HIV-infected pregnant women: Genotypic resistance testing is recommended for all pregnant women before initiation of ART (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy.”

DHHS does not recommend drug-resistance assays in the following situations:

• “After therapy is discontinued: Drug-resistance testing is not usually recommended more than 4 weeks after ARV drugs are discontinued."
• “In patients with low HIV RNA levels: Drug-resistance testing is not usually recommended in patients with a plasma viral load <500 copies/ml.”

International AIDS Society – USA Panel

The International AIDS Society recommends antiretroviral drug resistance testing in adult HIV-1 infection in the following situations(Hirsch et al., 2008):

• Untreated established HIV-1 infection: The guidelines recommend resistance testing for all patients at the time of diagnosis of HIV-1 infection as part of the initial, comprehensive assessment
• Treatment failure: The society states that “because of the high prevalence of infection due to drug-resistant virus among antiretroviral-treated patients with confirmed, detectable plasma virus, drug resistance testing should be performed in all cases of treatment failure”
• Acute and early phase HIV-1 infection: The guidelines state “genotypic resistance testing is recommended for any patient who presents within several months after HIV-1 infection because of the high reported rates of transmitted drug resistance”
• Pregnancy: The society recommends genotypic resistance testing “for all HIV-1-infected pregnant women with detectable plasma virus, both for their own health and for the health of their infants”

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Baxter, J. D., Mayers, D. L., Wentworth, D. N., Neaton, J. D., Hoover, M. L., Winters, M. A., . . . Merigan, T. C. (2000). 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, 14(9), F83-93.

CDC. (2014). Revised surveillance case definition for HIV infection--United States, 2014. MMWR Recomm Rep, 63(Rr-03), 1-10.

Coffin, J., & Swanstrom, R. (2013). HIV Pathogenesis: Dynamics and Genetics of Viral Populations and Infected Cells. In Cold Spring Harb Perspect Med (Vol. 3).

Coffin, J. M. (1995). HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science, 267(5197), 483-489.

DHHS. (2018). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Retrieved from http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf accessed on 05/10/2018

Fox, Z. V., Geretti, A. M., Kjaer, J., Dragsted, U. B., Phillips, A. N., Gerstoft, J., . . . Lundgren, J. D. (2007). The ability of four genotypic interpretation systems to predict virological response to ritonavir-boosted protease inhibitors. Aids, 21(15), 2033-2042. doi:10.1097/QAD.0b013e32825a69e4

Hirsch, M. S., Gunthard, H. F., Schapiro, J. M., Brun-Vezinet, F., Clotet, B., Hammer, S. M., . . . Richman, D. D. (2008). Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis, 47(2), 266-285. doi:10.1086/589297

Ho, D. D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M., & Markowitz, M. (1995). Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature, 373(6510), 123-126. doi:10.1038/373123a0

Kozal, M. (2017a). Drug resistance testing in the clinical management of HIV infection - UpToDate. In J. Mitty (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/drug-resistance-testing-in-the-clinical-management-of-hivinfection?source=see_link.

Kozal, M. (2017b). Overview of HIV drug resistance testing assays - UpToDate. In J. Mitty (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/overviewof-hiv-drug-resistance-testingassays?source=search_result&search=hiv%20genotyping&selectedTitle=1~57.

Mansky, L. M., & Temin, H. M. (1995). Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol, 69(8), 5087-5094.

Palella, F. J., Jr., Armon, C., Buchacz, K., Cole, S. R., Chmiel, J. S., Novak, R. M., . . . Brooks, J. T. (2009). The association of HIV susceptibility testing with survival among HIV-infected patients receiving antiretroviral therapy: a cohort study. Ann Intern Med, 151(2), 73-84.

Sax, P. E., Islam, R., Walensky, R. P., Losina, E., Weinstein, M. C., Goldie, S. J., . . . Freedberg, K. A. (2005). Should resistance testing be performed for treatment-naive HIV-infected patients? A cost-effectiveness analysis. Clin Infect Dis, 41(9), 1316-1323. doi:10.1086/496984

Trotta, M. P., Cozzi-Lepri, A., Ammassari, A., Vecchiet, J., Cassola, G., Caramello, P., . . . d'Arminio Monforte, A. (2010). Rate of CD4+ cell count increase over periods of viral load suppression: relationship with the numb

Policy Implementation/Update Information

1/1/19 New policy developed. BCBSNC will provide coverage for HIV genotyping and phenotyping when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (sk)