Medicare Payment Safeguard Administrator Proposed LMRP

4:30 version

Subject: Genotyping and Phenotyping Assay of Human Immunodeficiency Virus Type I (HIV-1)

Policy Number: XX-XX-XX

Policy Type: Local Medical Review Policy

HCPCS Section: Pathology

HCPCS Codes: 83890-83912 molecular diagnostic techniques 87252-87253-virus identification, tissue culture 84999 Unlisted chemistry procedure

Purpose: The increasing prevalence of resistance to HIV medication therapy has prompted development of drug resistance assays. High output techniques are now commercially available. This LMRP will expand Medicare coverage and explain the indications and limitations, coding, and billing for HIV resistance testing.

Description: HIV-1 drug resistance tests document those drugs to which the HIV viruses in a patient are resistant. The tests are used to determine those drugs that are unlikely to be effective. The tests are not used to determine those drugs that are most likely to be effective. Resistance tests come in two basic categories, the genotypic and the phenotypic assays. Because these assays amplify RNA sequences from a mixture of HIV virus, only the predominant variants, or subspecies, within an individual are amplified and reported.

Genotypic resistance measures particular mutations; particularly point mutations in HIV-1 viral RNA associated with, and thought to confer phenotypic resistance. The RNA mutations found are compared to a table of historical data that correlates RNA mutations to phenotypic resistance to specific drugs. Mutants at a level of 10-50% of the sample may be differentiated in the testing. This may confer greater sensitivity than phenotypic assays, with the capacity to detect a virus that constitutes as little as 10% of the viral population, assuming this pool is relatively stable. Interpretation of the findings may vary based on accuracy of the comparison historical data used to predict phenotypic responses. Test results may be generated in several hours to a few days. The presence of low but significant percentage of mutant viral strains may confound the clinical predictive value of the results.

Phenotypic resistance measures the ability of the patient's HIV-1 virus to grow in the presence of known concentration of anti-HIV drugs. The degree of virus replication inhibition at various drug concentrations is assessed. Results are used to calculate the drug concentration needed to inhibit the viral replication by 50% or 90% (IC50 or IC90) for a specific drug for a specific patient sample. The viral RNA (HIV protease and reverse transcriptidase) is amplified via recombinant technology with other HIV genes from a laboratory construct, obviating the need for a growing viral isolate. 12 or more drugs may be tested on the same sample. RNA replication can be measured by incorporating a marker into the gene product, such as the luciferase gene from fireflies that causes florescence, and other marker techniques.

Results are compared with a drug-susceptible control HIV strain, or a prior virus isolate from the same patient. Results are reported as a fold change in IC50 or IC90, typically in 2 to several weeks. An increase in the IC50 or IC90 means more drug is needed to reduce replication. This is a measurement of viral resistance to the drug. The amount of change in IC50 or IC90 that demonstrates significant resistance is established by each laboratory.

The amount may vary from 2.5 to 4.0-fold change. Therefore, comparison of tests for the same patient between laboratories may have limited value. Whether this change in concentration is sufficient to confer resistance must be considered independently by the clinician. In vitro drug concentrations must be correlated with predicted in vivo concentrations. Genotypic changes may confer increased sensitivity to some drugs, and increased resistance to others, complicating the predictive value of the test. Therefore, a detailed interpretation of the findings is required for a full appreciation of the test results.

Since only predominant circulating viral populations are sampled to yield IC50 or IC90, any minority drug-resistant species (<10%-50% of the viral population present at the time of testing), which could eventually contribute to drug failure, may not be detected. Because a small proportion of virus that is resistant can grow out rapidly and become dominant under the pressure of drug treatment against the competing susceptible strains, the absence of resistance does not suggest the patient will continue to respond after several weeks of treatment.

Quality control indicators for both types of tests are important factors for consideration by the ordering physician. Quality control items may include well-characterized drug-susceptible and drug resistant control viruses in each batch of sample tests.

• These tests do not replace measurement of HIV RNA levels (viral load) or CD-4+ helper lymphocyte cell counts.

CMS's National Policy: Title XVIII of the Social Security Act, section 1862 (a)(1)(A).

This section states that Medicare excludes coverage for items or services that are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Title XVIII of the Social Security Act, §1862 (a)(7). This section excludes routine physical examinations.

42 CFR §411.15 (a)(1) Excludes coverage for routine physical checkups and examinations performed for a purpose other than treatment or diagnosis of a specific illness, symptom, complaint, or injury.

Indications & Limitations of Coverage:

Genotypic or phenotypic testing is indicated when the testing potentially assists the clinician to determine which drugs not to use for a specific patient, when standard clinical protocols are less predictive. These tests are typically used for patients who fail first-line highly active antiretroviral therapy (HAART).

Testing is not a replacement for improving adherence to therapy and maximizing regimen tolerance. Treatment failure may be due to interruption or discontinuation of medications, failure to absorb anti-retroviral drugs, accelerated drug metabolism, in addition to emerging viral resistance to the regimen. Other clinical issues include drug treatment history; viral load; medication tolerance, absorption, and interactions; future treatment adherence likelihood; concomitant medical conditions and medications. These issues must be considered prior to ordering HIV resistance testing.

Specialty care limitation: Because interpretation of resistance testing is complicated, use of resistance testing is limited to providers who are trained HIV care specialists, even if a test reports drugs likely to be active. The value of resistance testing is to determine those drugs likely to be inactive, as opposed to active. Practitioners who do not routinely manage HIV infection should consider consulting with HIV care specialists before ordering resistance testing, and involve these specialists in the interpretation of the test results.

A genotypic and/or phenotypic drug resistance assay of HIV-1 is covered as an adjunct to anti-retroviral therapy for the following situations:

(1) treatment failure: when necessary to determine the most appropriate new medication treatment regimen during failure of current triple anti-retroviral therapy (drug failure).

• The patient must be taking the prescribed failing triple drug treatment regimen at the time the test sample is drawn.

Medicare considers drug failure to exist when either of the following occur:

(a) Treatment breakthrough: the patient has had a previously undetectable virus level by viral load testing, and the recurrence of virus is detected by viral load testing on 2 separate occasions at least 2 weeks apart and; or

(b) Sub optimal response with breakthrough: when the patient has a viral load that remained detectable despite treatment and has a 0.5 log increase in viral load

·The viral load must be greater than 1000 copies/mL. This level is required in order to generate sufficient polymerase chain reaction product for analysis.

Poor adherence to the treatment regimen and pharmacological reasons for failure must be excluded.

(2) for a patient newly infected with HIV under special circumstances.

(a) Primary drug resistance: An antiretroviral-naïve patient documented with infection from an HIV positive individual who has known anti-retroviral drug failure. The clinician must be concerned about the possibility of primary drug resistance during initial treatment for a drug-adherent patient. In this circumstance, resistance testing should not delay, but may be used to modify, anti-retroviral therapy. Regimens can be adjusted within a few weeks if resistance to any drug is detected.

(c) A pregnant patient with measurable viral load during therapy, in addition to any other indication listed in the policy, when clinically needed to select those drugs most likely reduce the risk of transmission of HIV virus to the newborn.

Coverage, when indicated, is usually limited to one test per patient. Additional testing will be considered on a case-by-case basis, after review of the medical documentation. Additional tests may be appropriate when the patient has:

(a ) inconclusive result: the result of one type of test is inconclusive, or

(b) residual multiple treatment options: a patient has failed two or more treatment regimens and for who various therapeutic options remain which require additional testing to evaluate.

(c) initial suboptinal response: a patient treated with an initial regimen, who is complaint with the treatment, and who fails to obtain viral load suppression below detectable levels by 16 (sixteen) weeks of therapy, particularly in geographic areas where the local prevalence of primary drug resistance is appreciable. Testing for patients who do not meet coverage criteria and is considered not medically necessary.

The following reasons are examples of indications that are unnecessary for resistance testing.

• In a patient who has failed multiple regimens and have limited numbers of active drugs available as treatment options,
• In a treatment-naïve patient not newly infected by a failed treatment individual,
• In post-exposure prophylaxis,
• In a patient not taking the prescribed and reasonable anti-retroviral drug treatment, · In a patient responding to therapy,
• In a patient with a stable viral load,
• In a patient with unmeasureable viral load.

Resistance testing is not reliable to determine which drugs are most likely to be effective. One reason for this is that a minor percent of resistant virus present in the sample may not change the IC50 or IC90 results. However, after a short time of treatment, the resistant virus may become dominant such that the viral load increases in the face of what appeared to be an effective drug.

Therefore, Medicare coverage is limited to the use of resistance testing to eliminate specific drugs as a treatment option, and not to validate the effectiveness of drugs selected. Resistance testing is not indicated for a decision to initiate or change anti-retroviral therapy in the absence of plasma viral load testing.

Blood samples drawn for resistance testing before the failing regimen is stopped is mandatory because in the absence of failing drug treatment, susceptible (wild-type) variants with better replicative capacity typically outgrow the mutant resistant strains, obscuring the predictive value of the testing with respect to those mutant strains.

Covered ICD-9 CM Code:

• 042 Human immune deficiency syndrome; Acquired immunodeficiency syndrome (AIDS)
• 07950 Retrovirus, unspecified
• 07951 Human T-cell lymphotropic virus, Type I (HTLV-I)
• V08 Asymptotic Human immunodeficiency virus (HIV) infection status

Non-covered ICD-9 CM Code(s):

All diagnosis codes not listed in the "Covered ICD-9-CM Diagnosis Codes" list.

Reasons for Denial:

All diagnosis code not listed in the Covered ICD-9-CM Diagnosis Codes will be denied as not reasonable and necessary under Section 1862 (a)(1)

(a). Patients who receive testing that is not covered by this policy must be given a properly completed advanced beneficiary notice in order to be held liable for payment. Documentation not meeting criteria will be considered as not reasonable and necessary. Sources of Information:

• Description of the PhenoSense™ HIV assay;
• Recommendations of an International AIDS Society - USA Panel, Antiretroviral Drug Resistance Testing in Adult HIV-1 Infection, in JAMA, May 10, 2000
• DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, updated January 28, 2000;
• Two studies utilizing ViroLogic's phenotypic assay, plus accompanying editorial on HIV resistance testing, from JAMA, September 22/29, 1999;
• Novel Four-Drug Salvage Treatment Regimens after Failure of a Human Immunodeficiency Virus Type I Protease Inhibitor - Containing Regimen: Antiviral Activity and Correlation of Baseline Phenotypic Drug Susceptibility with Virologic Outcome, Journal of infectious Diseases, June 1999;
• Sexual Transmission of an HIV-1 Variant Resistant to Multiple Reverse-Transcriptase and Protease Inhibitors, NEJM, July 30, 1998;
• Phenotypic Changes in Drug Susceptibility Associated with Failure of HTV-I Triple Combination Therapy, Journal of Infectious Diseases, September, 1999;
• Selected resistance testing abstracts from the 39" Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 26-29, 1999;
• Selected resistance testing abstracts from the 3"1 International Workshop on HIV Drug Resistance and Treatment Strategies, June 23-26, 1999;
• · Public Health Implications of Antiretroviral Therapy and HIV Drug Resistance from JAMA, June 24,1998; · Drug-Resistance Genotyping in HIV-1 Therapy: the VIRADAPT Randomized Controlled Trial, Lancet, June 26, 1999;
• The Impact of Drug Resistance Mutations in Plasma Virus of Patients Failing on Protease Inhibitor-Containing HAART Regimens on Subsequent Virological Response to the Next HAART Regimen: Results of CPCRA 046 (GART), 3'd International Workshop on HIV Drug Resistance and Treatment Strategies, June 23-26, 1999;
• Introduction of HIV Drug-Resistance Testing in Clinical Practice, AIDS, 1999;
• Carrier Medical Directors;
• Other Carrier Coverage Policy on HIV Drug Susceptibility and Resistance Test;
• Representatives from the Infectious Disease Association of California (IDAC);
• Clinical Utility of Genotypic Resistance Testing, HIV/AIDS Treatment Updates, 2000 Medscape, Inc.
• Charles Flexner, MD, Johns Hopkins University School of Medicine, presentation at the National Conference of Carrier Medical Directors, Baltimore, August 18, 2000.
• A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy; Baxter, et. al, AIDS 2000, Vol 14, 9

Coding Guideline:

Genotype and Phenotype Assays must be billed as 84999

CPT codes 83890-83912 and 87252-87253 reflect steps in the performance of these assays. However, these are not to be used for filing claims. Attach a summary of the CPT codes used in the test, including the frequency of each. NHIC encourages each lab to work with NHIC to develop a payment rate for each of the tests of each laboratory. Once the protocol for each test from a lab is established, the claim may be billed electronically with the 84999 code with the specific test performed listed in the comments section. The carrier will reference the specific protocol for each lab's test and make appropriate payment.

The specific test performed (i.e. "HIV genotype" or "HIV phenotype") must be indicated in block 19 of the CMS 1500 claims form or in the comments section for electronic claims.

The ICD-9-CM code used must be coded to the highest level of specificity and it must be submitted with the claim.

Documentation Requirements:

Documentation must meet the criteria or the claims will be denied as not reasonable and necessary. Legible physician's medical documentation must be maintained in the patient's medical record. This must justify the criteria for testing is met. If the physician's medical record does not validate the necessity of testing, the laboratory is subject to denial or recoupments.

Therefore, laboratories and HIV treatment specialists are encouraged to communicate about the Medicare requirements for coverage. Subsequent determination that the medical record is lacking such justification will result in a denial under Section 1862(a)(1)(A) and Section 1833(e) of the Act A covered diagnosis listed above must be submitted.

Start Date of Comment Period: October 18, 2000

Comments regarding this proposed policy will be accepted in writing during the comment period. Implementation will be effective 30 days following the final notice.

Please address comments to:

Transamerica Occidental Life Insurance Company Medicare Payment Safeguard Administrator ATTN [CMD name and address] This policy does not reflect the sole opinion of the carrier or Carrier Medical Director. Although the final decision rests with the carrier, this policy was developed in cooperation with the Carrier Advisory Committee, which includes representatives from a variety of specialty groups.