QUANTITATIVE HIV RNA (VIRAL LOAD)

Transcription

1 CLINICAL GUIDELINES For use with the UnitedHealthcare Laboratory Benefit Management Program, administered by BeaconLBS QUANTITATIVE HIV RNA (VIRAL LOAD) Policy Number: PDS Effective Date: October 1, 2018 Table of Contents Page GUIDELINES 1 CLINICAL EVIDENCE 3 GUIDELINES AND RECOMMENDATIONS 4 US FOOD AND DRUG ADMINISTRATION (US FDA) 6 CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) 6 APPLICABLE CODING 6 REFERENCES 7 POLICY HISTORY/REVISION HISTORY 9 INSTRUCTIONS FOR USE Physician Decision Support (PDS) is a lab ordering tool operated by BeaconLBS. This Clinical Guideline supports the Questions and Answers that appear in PDS for tests referenced in this document. UnitedHealthcare reserves the right, in its sole discretion, to modify its Clinical Guidelines as necessary. This Clinical Guideline is provided for informational purposes. It does not constitute a Medical Policy or medical advice. GUIDELINES Quantitative Human Immunodeficiency Virus (HIV) testing (viral load) for patients living with HIV in the following situations: To obtain a baseline value when the HIV patient enters care. To assess regimen efficacy (measurement within 2-4 weeks of initiation or modification of antiretroviral therapy). To monitor viral suppression (measurement every 3-4 months in patients with stable clinical and laboratory parameters). In pregnant women, should be measured at the initial visit, 2-4 weeks after antiretroviral therapy is initiated or modified, monthly until virus is undetectable and at least every 3 months thereafter. Testing should be repeated at weeks gestation to inform decisions about mode of delivery. In children, should be measured at the time of diagnosis and every 3-4 months thereafter or more frequently on the basis of clinical or laboratory parameters. May be used in infants as a confirmatory test after a positive DNA PCR test. May be used to diagnose acute antibody negative HIV infection or resolve indeterminate serologic results. Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 1

2 These recommendations are based on current guidelines from the United States Department of Health and Human Services, Panel on Antiretroviral Therapy and Medical Management of Children living with HIV., International AIDS Society-USA Panel, Panel on Treatment of Pregnant Women living with HIV and Prevention of Perinatal Transmission, and the HIV Medicine Association of the Infectious Diseases Society of America. 1,20,29 BACKGROUND The development of polymerase chain reaction (PCR) paved the way for progress in HIV testing. The detection of HIV-1 proviral DNA in peripheral blood mononuclear cells was reported in Previous viral detection studies relied on culture of virus from infected peripheral blood monocytes or plasma. The original nucleic acid tests were qualitative, and soon thereafter, quantitative assays were developed. In 1991 successful measurement of HIV RNA in plasma using polymerase chain reaction was reported. 3 That same year, researchers demonstrated that plasma HIV RNA levels correlated with disease stage and response to antiretroviral therapy. 4 In the 1990s automation improved the utility of nucleic acid testing as a clinical laboratory modality. 5 Breakthroughs in HIV nucleic acid testing revolutionized safety standards for blood banks, decreasing the number of cases of HIV transmitted by transfusion. 6-8 HIV nucleic acid testing has become a mainstay in the detection of HIV and the clinical management of HIV patients. Quantitative HIV plasma RNA viral load is used to monitor antiretroviral treatment efficacy, allowing comparisons of baseline, pretreatment and post-treatment levels to guide therapeutic decisions of when to initiate and when to modify antiretroviral therapy. 1 Because quantitative HIV RNA polymerase chain reaction is used to measure baseline viral load, assays must be able to measure high titers like those representative of peak levels of viremia. Assays must also be able to measure low titers because the goal of antiretroviral therapy is to suppress viremia below detection limits. After initiation of antiretroviral therapy, the drug regimen is considered effective if viral load falls below 50 copies/ml within 24 weeks of treatment. 9 Therefore, ideal assays should be sensitive at the lower limit of detection, but specificity is also important to avoid modifying regimens that could achieve viral suppression. Industry has attempted to improve sensitivity at the lower limit of detection while maintaining specificity, and platform comparisons have focused on assessing performance at low titers. The clinical significance of low levels of viremia remains uncertain. A challenging area of laboratory interpretation has been discriminating between low-levels of viremia in an otherwise optimally treated patient and early treatment failure. There is no consensus on how to manage patients whose plasma HIV RNA measures between 48 and 200 copies/ml. 1 Uncertainty still exists as to the source of this viremia, and possible theories include continued viral replication 10 and populations of latently infected cells. 10, 11 Even though viral blips may transiently increase HIV RNA levels to 1,000 copies/ml, they are not considered evidence of virologic failure. 12 Regardless of its etiology, the issue of persistent viremia has resulted in modification of guidelines for clinicians and has motivated industry to develop newer versions of quantitative HIV RNA assays. 1 Until further studies can elucidate the significance of viremia at the lower level of detection, expert panels have revised their guidelines, shifting cutoffs for virologic failure up from the level of detection, which for most assays is less than 20 to 75 copies/ml, depending on the assay used, to 200 copies/ml to prevent elevations caused by blips and assay variability from influencing therapeutic decisions. 1 Given that sensitivities vary with each methodology, it has also been recommended that the same testing platform is used consistently for a patient Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 2

3 Acute HIV infection is the period following viral transmission and before antibody seroconversion, during which the risk of HIV transmission is high relative to chronic HIV infection. 16 Diagnosis of acute HIV infection remains a challenge as symptoms may not be present, and standard detection methods such as antibody tests will fail to detect the new infection. 17, 18 The use of HIV RNA tests may be recommended in high incidence areas to detect these individuals. 19 Additionally, viral load or qualitative NAT could also be recommended for patients being seen with indeterminate serologic results. Clinical Implications Implications for Ordering Resistance Tests: Viral load is used to determine if drug resistance testing can be performed; when plasma HIV RNA is less than 500 copies/ml, there may not be enough sequence for amplification for genotypic or phenotypic resistance testing. Implications for When to Modify Therapy: Plasma viral load is the most important clinical test used to identify treatment failure. If the viral load is confirmed to be greater than or equal to 200 copies/ml in a treated patient, virologic failure exists according to the 2013 recommendations of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. 1 Implications for the Decision to Perform Cesarean Section in Pregnant Women: If HIV viral load is greater than 1,000 copies/ml, irrespective of administration of antiretroviral therapy, cesarean section is recommended at 38 weeks gestation according to the 2017 guidelines of the Panel on Treatment of HIV- Infected Pregnant Women and Prevention of Perinatal Transmission. In women with viral load greater than 1,000 copies/ml or unknown HIV RNA level who present in spontaneous labor or with ruptured membranes, there is insufficient evidence that cesarean reduces the risk of perinatal HIV transmission. A consultation with a perinatal expert on HIV is helpful for individualized delivery plan. Implications for When to Initiate Antiretroviral Therapy: The panel increased its strength of recommendations in 2018 to recommend that all children receive ART, regardless of symptoms and CD4 count. In adolescents and adults, antiretroviral therapy initiation is also recommended for all individuals with HIV regardless of CD4 count. Pregnant women living with HIV should have ARV therapy should be administered at all points including antepartum and intrapartum as well as postnatally to the neonate. CLINICAL EVIDENCE By the late 1990s evidence was mounting that HIV RNA viral load predicted clinical outcomes to therapy. An AIDS Clinical Trials Group study of 391 adults at an intermediate stage of disease found a 90% risk reduction for disease progression with a reduction of 1.0 log in the plasma HIV RNA posttreatment. 20 Another AIDS Clinical Trials Group study of 566 treated children showed a risk reduction for disease progression of roughly 50% for each log 10 reduction in baseline plasma HIV RNA. 21 In 1999, researchers at the FDA published a meta-analysis that correlated a reduced number of adverse clinical events in 5,000 patients with a decrease in HIV viral load at 24 weeks posttreatment. 22 Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 3

4 HIV viral load predicts mother to child transmission. 23 An AIDS Clinical Trials Group study of 497 women that controlled for covariates such as CD4+ lymphocyte count and p24 antibody levels found that only HIV-1 RNA levels correlated with risk of mother to child transmission. 24 In addition to measuring viral load in adults and children, quantitative HIV RNA serves another purpose for pediatric HIV patients. Quantitative HIV RNA assays are as sensitive as HIV DNA PCR for the diagnosis of HIV in infants. 12 One study reported sensitivities of 29% during the first week of life and greater than 90% by 29 days of age. 25 Subsequently, quantitative HIV RNA is a useful confirmatory test for diagnosis of HIV in infants. 12 Testing There are several methodologies approved by the FDA for measuring plasma HIV viral load, and reviews of platform comparisons have been published. 13, 26, 27 One FDA approved test, the COBAS AmpliPrep/COBAS TaqMan system, uses a reverse transcriptase-polymerase chain reaction that targets the gag p24 region of HIV- 1. The system combines an automated extraction unit with an automated amplification, detection and quantification system. The COBAS Ampliprep Instrument is an automated sample preparation device. COBAS Taqman is a real-time PCR system that uses a fluorogenic probe to detect specific amplification products. The assay was approved by the US Food & Drug Administration on May 11, The initial version of the COBAS Ampliprep assay (version 1) had a lower limit of detection (LLOD) of 48c/mL. This assay version has largely been replaced by the TaqMan version 2. The current Taqman version 2 has a LLOD of 20 copies/ml and better performance with non-b subtypes. The Abbott RealTime assay has a LLOD of 40 with good performance with subtypes and low viral loads. bdna assays are also available with LLOD of 75c/mL. New versions of HIV RNA assays are being developed to improve detection at the lower level of range. 15, 26 It remains to be seen if a lower level of detection will provide clinicians with clinically actionable information. 1 GUIDELINES AND RECOMMENDATIONS The following guidelines are current group consensus recommendations for measuring plasma HIV RNA and for diagnosing HIV. Department of Health and Human Services 1 In 2013, Department of Health and Human Services 1 guidelines recommended the following: Viral load testing is recommended when the HIV patient enters into care. Viral load testing is recommended every 3-6 months until therapy is initiated. Viral load testing is recommended when therapy is initiated and 2-8 weeks after. If plasma load is detectable after initiation of therapy, levels should be repeated every 4-8 weeks until the level is less than 200 counts/ml, then every 3-6 months. Viral load testing is recommended when therapy is modified and 2-8 weeks thereafter, then every 3-6 months. Viral load testing is recommended in the setting of virologic failure and if otherwise clinically indicated. For patients with viral suppression and stable clinical status for 2-3 years or more, the panel notes that some experts may extend the testing interval to monitoring HIV RNA levels every 6 months. Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 4

5 Panel on Antiretroviral Therapy and Medical Management of Children living with HIV 12 In 2012, the Panel on Antiretroviral Therapy and Medical Management of Children living with HIV 12 made the following recommendations: HIV RNA can be used as a confirmatory test for infants with a positive DNA PCR test; the benefits include confirmation at a lower cost, measurement of baseline viral load, and increased sensitivity for detection of HIV non-subtype B. Tests with low levels of HIV RNA (less than 5,000 copies/ml) should be repeated for confirmation of diagnosis of HIV in an infant. Viral load testing is recommended at the time of diagnosis and at least every 3-4 months thereafter. More frequent viral load testing should be considered on the basis of clinical and laboratory parameters. Regardless of viral load, antiretroviral treatment is recommended for children, even for those with minimal or no clinical symptoms and normal immune status. International AIDS Society-USA Panel 9 In 2012, the International AIDS Society-USA Panel 9 made the following recommendations: HIV-1 RNA should be measured at least every 3 months after therapy is initiated or changed following virologic failure, until virologic suppression is confirmed. After one year of suppression, monitoring can be done every 6 months if adherence is not a question. HIV-1 RNA should be suppressed to less than 50 copies/ml by 24 weeks of antiretroviral therapy. If viral rebound occurs, as confirmed by two HIV-1 RNA levels at least 2-4 weeks apart, clinical investigation of regimen tolerability, drug-drug interactions and adherence is recommended. Resistance testing is recommended for confirmed virologic failure. Panel on Treatment of Pregnant Women living with HIV and Prevention of Perinatal Transmission 28 In 2012, the Panel on Treatment of Pregnant Women living with HIV and Prevention of Perinatal Transmission 28 included the following recommendations: Viral load testing is recommended for HIV patients during pregnancy at the initial visit, 2-4 weeks after antiretroviral therapy is initiated or modified and then monthly until virus is undetectable and at least every 3 months thereafter. Testing is recommended more frequently if adherence is uncertain. Viral load testing is recommended at approximately 34 to 36 weeks gestation, and women with levels greater than 1,000 copies/ml should be counseled on cesarean section. Viral load testing is recommended in women with HIV to ensure viral levels are stable and suppressed before conception. HIV Medicine Association of the Infectious Diseases Society of America 29 In 2013, the HIV Medicine Association of the Infectious Diseases Society of America published new primary care guidelines for the management of patients living with HIV. 29 Those guidelines included the following recommendations for plasma HIV RNA levels (viral load testing): A quantitative HIV RNA (viral load) level should be obtained upon initiation of care. Viral load is generally monitored every 3 4 months in untreated patients and patients on stable ART. This interval may be prolonged to 6 months for adherent patients whose viral load has been suppressed for Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 5

6 more than 2 3 years and whose clinical and immunologic status is stable. Viral load should be monitored more frequently after initiation or change in ART: preferably within 2 4 weeks, and not more than 8 weeks, after initiation or modification, with repeat testing every 4 8 weeks until viral load becomes undetectable. US FOOD AND DRUG ADMINISTRATION (US FDA) There are several HIV viral load assays available that are US Food and Drug Administration (FDA) approved for clinical use. Clinicians should be aware of changes in the type of assay used and the associated variability and the interpretation of results between assays. CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) For Medicare populations, CMS does not pay for screening procedures (tests) performed in the absence of signs or symptoms. (Section 1862(a)(7) of the Social Security Act) There are several CMS policies that apply to HIV Testing (Prognosis, including Monitoring). In some cases, CMS reimbursement is limited to FDA approved and home-brew tests only. Additionally, there may be a limit to the number of viral load assays per patient per 12 month time period. Physicians should consult their state s regulations. APPLICABLE CODING CPT Code Description Infectious agent detection by nucleic acid (DNA or RNA); HIV-1, Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 6

7 REFERENCES 1. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1- infected adults and adolescents. Available at: And Last updated: July 14, 2016 (Accessed August 8, 2016). 2. Ou CY,Kwok S, et al. DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science (New York, N.Y.). 1988;239(4837): Holodniy M,Katzenstein DA, et al. Reduction in plasma human immunodeficiency virus ribonucleic acid after dideoxynucleoside therapy as determined by the polymerase chain reaction. J Clin Invest. 1991;88(5): Semple M,Loveday C, et al. Direct measurement of viraemia in patients infected with HIV-1 and its relationship to disease progression and zidovudine therapy. J Med Virol. 1991;35(1): Jungkind D. Automation of laboratory testing for infectious diseases using the polymerase chain reaction-- our past, our present, our future. J Clin Virol. 2001;20(1-2): Stramer SL,Glynn SA, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med. 2004;351(8): Kolk DP,Dockter J, et al. Significant closure of the human immunodeficiency virus type 1 and hepatitis C virus preseroconversion detection windows with a transcription-mediated-amplification-driven assay. J Clin Microbiol. 2002;40(5): Rosenfeld RM,Piccirillo JF, et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol. Head Neck Surg. 2015;152(2 Suppl):S1-S Thompson MA,Aberg JA, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012;308(4): Havlir DV,Strain MC, et al. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol. 2003;77(20): Conway JM and Coombs D. A stochastic model of latently infected cell reactivation and viral blip generation in treated HIV patients. PLoS computational biology. 2011;7(4):e Quackenbush J. Microarray data normalization and transformation. Nat. Genet. 2002;32: Peter JB and Sevall JS. Molecular-based methods for quantifying HIV viral load. AIDS Patient Care STDs. 2004;18(2): Aberg JA,Kaplan JE, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(5): Paba P,Fabeni L, et al. Performance evaluation of the COBAS/TaqMan HIV-1 v2.0 in HIV-1 positive patients Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 7

8 with low viral load: a comparative study. J Virol Methods. 2011;173(2): Cohen MS,Shaw GM, et al. Acute HIV-1 Infection. N Engl J Med. 2011;364(20): Pilcher CD, Christopoulos KA, et al. Public health rationale for rapid nucleic acid or p24 antigen tests for HIV. J Infect Dis. 2010;201 Suppl 1:S Sullivan PS,Fideli U, et al. Prevalence of seroconversion symptoms and relationship to set point viral load: Findings from a subtype C epidemic. AIDS. In Press. 2011: Advancing HIV and Mmwr. CDC. prevention: new strategies for a changing epidemic-united States,. Mortal Wkly Rep. 2033: Katzenstein DA,Hammer SM, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. N Engl J Med. 1996;335(15): Palumbo PE,Raskino C, et al. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA. 1998;279(10): Murray JS,Elashoff MR, et al. The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs. AIDS (London, England). 1999;13(7): Amrosioni J,Calmy A, et al. HIV treatment for prevention. J Int AIDS Soc ;14: Mofenson LM,Lambert JS, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine N Engl J Med. 1999;341(6): Nesheim S,Palumbo P, et al. Quantitative RNA testing for diagnosis of HIV-infected infants. J Acquired Immune Defic Syndr. 2003;32(2): Pas S,Rossen JWA, et al. Performance evaluation of the new Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test version 2.0 for quantification of human immunodeficiency virus type 1 RNA. J Clin Microbiol. 2010;48(4): Heim RA, Sugarman EA, et al. Improved detection of cystic fibrosis mutations in the heterogeneous U.S. population using an expanded, pan-ethnic mutation panel. Genet. Med. 2001;3(3): Cystic Fibrosis Mutational Database. The Hospital for Sick Children. Available at: (Accessed: August 22, 2011). 29. 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 Nov 13. Epub Ahead of print. Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 8

9 POLICY HISTORY/REVISION HISTORY Date Action/Description 11/08/2018 Annual Policy Review Completed Changes made: Changed wording from "hiv infected" to "people living with HIV" as per 2018 recommendations. implications for the decision to perform cesarean Section: Updated 38 weeks gestation for performing cesarean section. Added statement that cesarean section might not be indicated if ruptured membrane or spontaneous labor. implication for when to initiate ARV section: Removed statement for children CD4 count and added updated 2017 guidelines that all individuals with HIV should receive ARV regardless of CD4 count. 11/02/2017 Annual Policy Review Completed No Changes made 10/06/2016 Annual Policy Review Completed Changes made: References Section: Updated DHHS Reference from 2013 version to Updated Panel on Anitretroviral guidelines from 2012 version to 2016:"Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission" 12/03/2015 Annual Policy Review Completed no changes. Proprietary Information of UnitedHealthcare. Copyright 2018 United HealthCare Services, Inc. Page 9