Latest Review Date: November 2024

POLICY:

HIV drug resistance testing, either phenotypic or genotypic testing or combined phenotypic and genotypic testing in patients who have failed a course of antiviral therapy or who have suboptimal viral load reduction may be considered medically necessary.

HIV drug resistance testing, either phenotypic or genotypic, used in other applications including, but not limited to its use in patients with previously untreated HIV is considered investigational.

Drug susceptibility phenotype prediction using genotypic comparison to known genotypic/phenotypic database, also known as virtual phenotype testing, (including, but not limited to Sentosa SQ HIV-1 Genotyping Assay) is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

HIV drug resistance testing is used to determine whether a patient with HIV has a mutated form of the virus present in their body that is resistant to antiretroviral therapy (ART).

HIV is an RNA virus characterized by a high replication rate. The reverse transcription enzyme required for replication is error prone and can lead to mutations. These mutations cause different HIV strains (clones), particularly if the patient is currently or has previously been treated with ART. If an antiretroviral resistance clone develops, the patient’s viral load will rise, and over time, this resistant clone may accumulate additional secondary mutations and become the dominant strain.

Initial drug therapy recommendations suggest the use of combination therapy with antivirals with different mechanisms of action designed to reduce the viral load to as low a level as possible. The three classes of antivirals available include nucleoside reverse transcription inhibitors (NRTI), non-nucleoside reverse transcription inhibitors (NNRTI), and protease inhibitors (PI). This therapeutic principle is based on the concept that cessation of detectable HIV replication decreases the opportunity for accumulation of mutations that may give rise to drug-resistant viral variants. These regimens are referred to as HAART (highly active antiretroviral therapy). If initial drug therapy fails, as evidenced by rising HIV viral loads, it is likely that the emergent virus is drug resistant, unless failure is related to drug non-compliance. At this point, physicians must devise a salvage therapy, using drugs to which the virus likely remains sensitive. While drug resistance is most common in the setting of prior failed therapy, there have been reports of initial infection of drug-resistant strains.

HIV genotyping identifies the presence of mutations that are known to confer reduced drug susceptibility. Several studies have suggested that resistance testing may be useful in assessing the success of salvage anti-retroviral therapy, and improving short-term virological response. Mutations that are common to several different drugs within a group will confer cross-resistance. For example, cross-resistance among the protease inhibitor drugs is common. HIV phenotyping directly measures drug resistance by identifying the drug concentration necessary to inhibit virus replications. Phenotypic and genotypic tests appear to provide similar results. Currently, there is insufficient information as to which approach is preferable in any particular clinical setting.

Results of genotypes have also been used to predict the phenotype by identifying similar genotypes from a large database of other HIV genotypes for which the phenotypes are known. This data analysis is known as the Virtual Phenotype™.

The evolving understanding of the clinical significance of drug resistance has created interest in both HIV genotyping and phenotyping to identify active drug regimens in the following clinical settings: 1) to determine the most effective salvage therapy in patients with drug resistance. For example, the virus seen during treatment failure may not be resistant to all drugs in a regimen. 2) To confirm that antiviral drug failure is due to drug resistance and not patient non-compliance. 3) To determine viral resistance at initial diagnosis of HIV infection.

KEY POINTS:

This policy is based on review of medical literature most recently performed through November 4, 2024.

Summary of Evidence

In a 2018 Cochrane review, the effectiveness of anti-retroviral resistance testing in reducing mortality and morbidity in HIV positive people was investigated. Primary outcomes of interest were mortality and virological failure. Data was analyzed on an intention-to-treat (ITT) basis using a random-effects model. 11 RCTs were included in the review. All of these trials enrolled patient who had previous exposure to ART. Seven studies used genotypic testing, two studies used phenotypic testing, and two studies used both genotypic and phenotypic testing. The authors of the review concluded that resistance testing probably improved virological outcomes in people who have had virological failure in trials conducted years ago.  These researchers found no evidence in treatment-naive people; resistance testing did not demonstrate important patient benefits in terms of risk of death or progression to AIDS.  The evidence is sufficient to prove that use of the technology results in an increase in net health outcomes for patients who have failed a course of antiviral therapy or who have a suboptimal viral load reduction. The evidence is insufficient to prove that the use of the technology results in an increase in net health outcomes for all other indications, including patients who have never been treated with anti-retrovirals.

Automated DNA extraction and sequencing (Virtual phenotype testing) has been investigated. Identified studies show varying levels accuracy within different subtypes of the disease.  There currently exists of a paucity of evidence to prove that this technology is clinically superior to the current standard of care. Well-designed studies are need to further examine the accuracy and clinical utility of HIV DNA genotyping. The evidence is insufficient to prove that the use of the technology results in an increase in net health outcomes.

There have been no randomized studies that have compared genotype alone with predicted phenotype, i.e., “virtual phenotype”. The evidence is insufficient to support this technology at this time.

Practice Guidelines and Position Statements

The Department of Health and Human Services’ (DHHS’) Panel on Antiretroviral Guidelines for Adults and Adolescents

Updated in 2023, The Panel’s Recommendations Regarding Drug-Resistance Testing:

For Initial Treatment of HIV:

• HIV drug-resistance testing is recommended at entry into care for people with HIV to guide the selection of the initial antiretroviral (ARV) regimen (AII). If antiretroviral therapy (ART) is deferred, repeat testing may be considered at the time of ART initiation (CIII).
• Genotypic, rather than phenotypic, testing is the preferred resistance testing to guide therapy in ARV-naive patients (AIII).
• In people with early (acute and recent) HIV infection, in pregnant people with HIV, or in people who will initiate ART on the day of or soon after HIV diagnosis, ART initiation should not be delayed while awaiting resistance testing results; the regimen can be modified once results are reported (AIII).
• Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the reverse transcriptase and protease genes. If transmitted integrase strand transfer inhibitor (INSTI) resistance is suspected or if the person has used long-acting cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) in the past, providers should ensure that genotypic resistance testing also includes the integrase gene (AIII).

For Antiretroviral Therapy-Experienced People:

• HIV drug-resistance testing should be performed to assist the selection of active drugs when changing ARV regimens in—
  • People with virologic failure and HIV-RNA levels >200 copies/mL (AI for >1,000 copies/mL, AIII for 501–‍1,000 copies/mL, CIII for confirmed HIV RNA 201–500 copies/mL). For people with confirmed HIV-RNA levels >200 copies/mL but <500 copies/mL, drug-resistance testing may be unsuccessful but should still be considered.
  • People with suboptimal viral load reduction (AII).
• Reverse transcriptase and protease genotypic resistance testing should be performed on everyone with virologic failure; integrase resistance testing (which may need to be ordered separately) should be performed on individuals experiencing virologic failure while receiving an INSTI-based regimen (AII).
• For persons taking a non–long-acting ARV regimen, drug-resistance testing in the setting of virologic failure should be performed while the person is still taking their ARV regimen or, if that is not possible, within 4 weeks after discontinuing their ARV regimen (AII). If more than 4 weeks have elapsed since the non–long-acting agents were discontinued, resistance testing may still provide useful information to guide therapy; however, it is important to recognize that previously-selected resistance mutations can be missed due to lack of drug-selective pressure (CIII).
• Given the long half-lives of the long-acting injectable ARV drugs, resistance testing (including testing for resistance to INSTIs) should be performed in all persons who have experienced virologic failure on a regimen of long-acting CAB and rilpivirine or acquired HIV after receiving CAB-LA as PrEP, regardless of the amount of time since drug discontinuation (AIII).
• Genotypic testing is preferred over phenotypic-resistance testing to guide therapy in people with suboptimal virologic response or virologic failure while on first- or second-line regimens and in people in whom resistance mutation patterns are known or not expected to be complex (AII).
• The addition of phenotypic- to genotypic resistance testing is recommended for people with known or suspected complex drug-resistance mutation patterns (BIII).
• All prior and current drug-resistance test results, when available, should be reviewed and considered when constructing a new regimen for a patient (AIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Weak

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

U.S. Preventive Services Task Force

Not applicable.

KEY WORDS:

HIV drug resistance testing, phenotypic, genotypic, virtual phenotype, ART, antiretroviral therapy, HIV, drug susceptibility phenotype prediction, genotyping, phenotyping, viral load, virtual phenotype testing, Sentosa SQ HIV-1 Genotyping Assay, Vela Diagnostics

APPROVED BY GOVERNING BODIES:

On March 19, 2019, Vela Diagnostics USA Inc. submitted a request for De Novo classification of the SENTOSA SQ HIV Genotyping Assay. FDA reviewed the request in order to classify the device under the criteria for classification set forth in section 513(a) (1) of the FD&C Act.

On November 5, 2019, FDA issued an order to the requester classifying the device into class II. FDA is codifying the classification of the device by adding 21 CFR 866.3955. We have named the generic type of device “Human immunodeficiency virus drug resistance genotyping assay using next generation sequencing technology,” and it is identified as a prescription in vitro diagnostic device intended for use in detecting HIV genomic mutations that confer resistance to specific antiretroviral drugs. The device is intended to be used as an aid in monitoring and treating HIV infection.

BENEFIT APPLICATION:

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.

CURRENT CODING:

CPT codes:

REFERENCE:

1. Aves T, Tambe J, Siemieniuk RA, Mbuagbaw L. Antiretroviral resistance testing in HIV-positive people. Cochrane Database Syst Rev. 2018 Nov 9; 11(11):CD006495.
2. Baxter JD, Mayers DL, Wentworth DN, Neaton JD, Hoover ML, Winters MA, Mannheimer SB, Thompson MA, Abrams DI, Brizz BJ, Ioannidis JP, Merigan TC. 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 Jun 16; 14(9):F83-93.
3. Borroto-Esoda K, Waters JM, et al. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses, August 2007; 23(8): 988-99
4. Cingolani A, Antinori A, Rizzo MG, Murri R, Ammassari A, Baldini F, Di Giambenedetto S, Cauda R, De Luca A. Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study (ARGENTA). AIDS. 2002 Feb 15; 16(3):369-79.
5. Coffin J, Swanstrom R. HIV pathogenesis: dynamics and genetics of viral populations and infected cells. Cold Spring Harb Perspect Med. 2013 Jan 1; 3(1):a012526.
6. Cohen CJ, Hunt S, Sension M, Farthing C, Conant M, Jacobson S, Nadler J, Verbiest W, Hertogs K, Ames M, Rinehart AR, Graham NM; VIRA3001 Study Team. A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy. AIDS. 2002 Mar 8; 16(4):579-88.
7. De Luca A, Di Giambenedetto S, Cingolani A, Bacarelli A, Ammassari A, Cauda R. Three-year clinical outcomes of resistance genotyping and expert advice: extended follow-up of the Argenta trial. Antivir Ther. 2006; 11(3):321-7. PMID: 16759048.
8. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK; Panel on Clinical Practices for Treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med. 2002 Sep 3; 137(5 Pt 2):381-433.
9. Hales G, Birch C, Crowe S, Workman C, Hoy JF, Law MG, Kelleher AD, Lincoln D, Emery S; CREST investigators. A randomised trial comparing genotypic and virtual phenotypic interpretation of HIV drug resistance: the CREST study. PLoS Clin Trials. 2006 Jul 28; 1(3):e18.
10. Haubrich RH, Kemper CA, Hellmann NS, Keiser PH, Witt MD, Tilles JG, Forthal DN, Leedom J, Leibowitz M, McCutchan JA, Richman DD; California Collaborative Treatment Group. A randomized, prospective study of phenotype susceptibility testing versus standard of care to manage antiretroviral therapy: CCTG 575. AIDS. 2005 Feb 18; 19(3):295-302.
11. Hirsch HH, Drechsler H, Holbro A, Hamy F, Sendi P, Petrovic K, Klimkait T, Battegay M. Genotypic and phenotypic resistance testing of HIV-1 in routine clinical care. Eur J Clin Microbiol Infect Dis. 2005 Nov; 24(11):733-8.
12. Hirsch MS, Brun-Vézinet F, Clotet B, Conway B, Kuritzkes DR, D'Aquila RT, Demeter LM, Hammer SM, Johnson VA, Loveday C, Mellors JW, Jacobsen DM, Richman DD. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA Panel. Clin Infect Dis. 2003 Jul 1; 37(1):113-28.
13. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
14. Jiamsakul A, Chaiwarith R, Durier N, Sirivichayakul S, Kiertiburanakul S, Van Den Eede P, Ditangco R, Kamarulzaman A, Li PC, Ratanasuwan W, Sirisanthana T; TREAT Asia Studies to Evaluate Resistance--Monitoring Study TASER-M. Comparison of genotypic and virtual phenotypic drug resistance interpretations with laboratory-based phenotypes among CRF01_AE and subtype B HIV-infected individuals. J Med Virol. 2016 Feb; 88(2):234-43.
15. Mazzotta F, Lo Caputo S, Torti C, Tinelli C, Pierotti P, Castelli F, Lazzarin A, Angarano G, Maserati R, Gianotti N, Ladisa N, Quiros-Roldan E, Rinehart AR, Carosi G; Genotipo-Fenotipo di Resistenza (GenPheRex) Group of the Italian Management Standardizzato di Terapia Antiretrovirale (MASTER) Cohort. Real versus virtual phenotype to guide treatment in heavily pretreated patients: 48-week follow-up of the Genotipo-Fenotipo di Resistenza (GenPheRex) trial. J Acquir Immune Defic Syndr. 2003 Mar 1; 32(3):268-80.
16. Meynard JL, Vray M, Morand-Joubert L, Race E, Descamps D, Peytavin G, Matheron S, Lamotte C, Guiramand S, Costagliola D, Brun-Vézinet F, Clavel F, Girard PM; Narval Trial Group. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. AIDS. 2002 Mar 29; 16(5):727-36.
17. National Archives Federal Register. The Daily Journal of the United States Government. Food and Drug Administration Medical Device De Novo Classification Process. www.federalregister.gov/d/2021-21677.
18. Panichsillapakit T, Smith DM, Wertheim JO, Richman DD, Little SJ, Mehta SR. Prevalence of Transmitted HIV Drug Resistance Among Recently Infected Persons in San Diego, CA 1996-2013. J Acquir Immune Defic Syndr. 2016 Feb 1; 71(2):228-36.
19. Parkin N, Chappey C, Maroldo L, Bates M, Hellmann NS, Petropoulos CJ. Phenotypic and genotypic HIV-1 drug resistance assays provide complementary information. J Acquir Immune Defic Syndr. 2002 Oct 1; 31(2):128-36.
20. Perez-Elias MJ, Garcia-Arota I, Muñoz V, Santos I, Sanz J, Abraira V, Arribas JR, González J, Moreno A, Dronda F, Antela A, Pumares M, Martí-Belda P, Casado JL, Geijos P, Moreno S; Realvirfen study group. Phenotype or virtual phenotype for choosing antiretroviral therapy after failure: a prospective, randomized study. Antivir Ther. 2003 Dec; 8(6):577-84.
21. Tural C, Ruiz L, Holtzer C, Schapiro J, Viciana P, González J, Domingo P, Boucher C, Rey-Joly C, Clotet B; Havana Study Group. Clinical utility of HIV-1 genotyping and expert advice: the Havana trial. AIDS. 2002 Jan 25; 16(2):209-18.
22. U.S. Department of Health and Human Services (DHHS). 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. September 21, 2022.
23. Underwood M, Horton J, Nangle K, et al. Integrase Inhibitor Resistance Mechanisms and Structural Characteristics in Antiretroviral Therapy-Experienced, Integrase Inhibitor-Naive Adults with HIV-1 Infection Treated with Dolutegravir plus Two Nucleoside Reverse Transcriptase Inhibitors in the DAWNING Study [published correction appears in Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0032622. 
24. United States Department of Veterans Affairs. www.hiv.va.gov/patient/diagnosis/labs-resistance-test.asp.

POLICY HISTORY:

Medical Policy Group, February 2006 (3)

Medical Policy Administration Committee, March 2006

Available for comment March 14-April 27, 2006

Updated Key Points, added references, February 2008 (1)

Medical Policy Group, February 2010 (1) Updated Key Points, added references

Medical Policy Group, December 2010 (1) Coding Update-Added new CPT code and updated verbiage

Medical Policy Group, February 2013: Effective 02/06/2013: Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Group, May 2015 (3): Editing update only; added cross-reference to medical policy #322 Laboratory Testing for HIV Tropism to Policy section; no change in policy statement; no literature review update done; policy status remains unchanged.

Medical Policy Group, October 2019 (9): Updates to Description, Key Points, References. Added key words: ART, antiretroviral therapy, HIV, drug susceptibility phenotype prediction, genotyping, phenotyping, viral load, virtual phenotype testing. No change to policy statement.

Medical Policy Group, September 2020: Quarterly coding update.  Added PLA code 0219U to Current Coding.

Medical Policy Group, September 2020 (9): For clarification purposes, added to the policy statement: "including, but not limited to Sentosa SQ HIV-1 Genotyping Assay". No change to policy statement intent. Added key words: Sentosa SQ HIV-1 Genotyping Assay, Vela Diagnostics

Medical Policy Group, October 2021 (9): Reviewed by consensus. References added. No new published peer-reviewed literature available that would alter the coverage statement in this policy. Policy statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Group, October 2023 (5): Reviewed by consensus. Updates to Key Points, and Benefit Application. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, November 2024 (5): Reviewed by consensus. Updates to Key Points, and References. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

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.