Human Immunodeficiency Virus 1, Antiretroviral Drug Resistance Testing - HIV Drug Resistance

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • All newly diagnosed HIV patients prior to initiating therapy (International Antiviral Society – USA Panel, 2014)
  • Patients receiving antiretroviral therapy (ART) experiencing treatment failure
  • Patients demonstrating viral load rebound

Laboratory Testing

  • Reverse transcriptase and protease resistance testing is recommended for initial HIV drug resistance testing as soon as possible after HIV diagnosis and prior to therapy initiation (Gunthard, 2014)
  • Genotyping
    • Most useful in initial evaluation or after failure of first- and second-line regimens
    • Genotype only if patient is highly adherent to antiretroviral therapy and is already receiving highly active ART
    • Baseline genotypic testing in patients from areas with evidence of HIV drug resistance may help determine etiology of treatment failure
    • Current tests are relatively insensitive at detecting drug-resistant minority variants (Smit, 2014)
  • Phenotyping in combination with genotyping
    • Most useful in patients with complex history of treatment failure
  • Specific drug resistance testing
    • Integrase inhibitor resistance
    • Trofile co-receptor tropism assay
      • Guides use of maraviroc therapy in adult patients infected with CCR5-tropic HIV-1 virus strain resistant to multiple antiretroviral agents and who have evidence of viral replication and multidrug failure
      • Lacks sensitivity if patient has low CD4 count (Smit, 2014)
  • Drug hypersensitivity screening – abacavir genotyping (HLA-B*57:01)
  • Quantitative HIV-1 RNA testing
    • Successful therapy results in suppression to <20-75 copies/mL
    • Recommended by the International Antiviral Society – USA Panel (2014)
    • HIV-1 RNA should be measured ~4 weeks after initiation of testing
    • Every 3-4 months the first year

Drug resistance testing is considered an important part of managing HIV-infected adults and is a widespread practice in the developed world. It can be determined using phenotypic and genotypic methods.

Epidemiology

  • Prevalence – new mutations associated with drug resistance occur in 16-65% of patients

Genetics

  • Histocompatibility – HLA-B*57:01 genotype associated with risk of abacavir hypersensitivity
    • Autosomal dominant inheritance
    • Most common in Indian and Thai individuals; less common in Caucasians; rare in East Asians

Pathophysiology

  • Reasons for failure include the following
    • Lack of access to care
    • Patient noncompliance
    • Drug pharmacology issues – absorption, elimination, interactions
    • Development of antiretroviral resistance
  • Highest resistance – nucleoside reverse transcriptase inhibitors
  • Role of resistance testing in primary infection
    • Identify mutations present
    • Identify etiology of treatment failures
  • Role of resistance testing in established infections that are currently being treated
    • Failure of current therapy – decreasing CD4 count, increasing viral load
    • Patient noncompliance with highly active antiretroviral therapy (HAART) regimen
    • Increased risk of resistance to newly resumed therapy
  • Abacavir hypersensitivity reaction can be identified pretherapeutically through laboratory detection of HLA-B*57:01
    • Most useful for patients deemed to be at high risk
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Human Immunodeficiency Virus 1, Genotype by Sequencing 0055670
Method: Reverse Transcription Polymerase Chain Reaction/Sequencing

Limitations 

Treatment failure can be caused by factors other than drug resistance; interpretation of resistance genotyping results must be done in conjunction with other clinical and laboratory information 

Uses the Viroseq HIV-1 Genotyping System for sequencing; some insertions or deletions may be difficult to detect

Absence of resistance mutations does not rule out presence of reservoirs of resistant viruses that cannot be detected

May not detect HIV-1 populations <20% of the total population

Human Immunodeficiency Virus Type 1 (HIV-1) Drug Resistance (PhenoSense GT Plus Integrase) (Testing experiencing extended turnaround times at Monogram Biosciences.) 2010808
Method: Phenotyping/Genotyping  

Human Immunodeficiency Virus (HIV) Phenotype Comprehensive (Testing experiencing extended turnaround times at Monogram Biosciences.) 0092050
Method: Drug Susceptibility using HIV Culture
(Cell Culture)

Limitations 

Treatment failure can be caused by factors other than drug resistance; interpretation of resistance genotyping results must be done in conjunction with other clinical and laboratory information

Comparisons between assays performed in different laboratories are not recommended; no standardization exists among methods of HIV-1 drug resistance testing

Absence of resistance mutations does not rule out the presence of reservoirs of resistant viruses that cannot be detected

Human Immunodeficiency Virus Type 1 (HIV-1) Drug Resistance (GenoSURE PRIme) (Testing experiencing extended turnaround times at Monogram Biosciences.) 2008438
Method: Polymerase Chain Reaction/Sequencing 

HIV1 Genotype and Integrase Inhibitor Resistance by Sequencing 2009256
Method: Polymerase Chain Reaction/Sequencing

Trofile Co-Receptor Tropism (Temporary Delay as of 4/28/2016 - no referral available) 0093370
Method: Recombinant virus, single replication

Trofile DNA Co-Receptor Tropism Assay (Testing experiencing extended turnaround times at Monogram Biosciences.) 2004747
Method: CD4 Cell Culture Assay for Phenotypic Recombinant-virus Co-receptor Tropism

HLA-B*57:01 for Abacavir Sensitivity 2002429
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Diagnostic errors can occur due to rare sequence variations

Rare recombination events between HCP5 SNP rs2395029 and HLA-B*57:01 may occur

Nongenetic factors that may affect drug sensitivity are not identified

Testing for a genetic variant associated with ABC HSR does not replace the need for therapeutic drug or other clinical monitoring

Guidelines

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services (U.S.) - Federal Government Agency. 1998 December (Revised 2014 May). NGC: 010355

PENTA Steering Committee, Welch S, Sharland M, Lyall EG, Tudor-Williams G, Niehues T, Wintergerst U, Bunupuradah T, Hainaut M, Negra MD, Pena MJ, Amador JT, Gattinara GC, Compagnucci A, Faye A, Giaquinto C, Gibb DM, Gandhi K, Forcat S, Buckberry K, Harper L, Königs C, Patel D, Bastiaans D. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med. 2009; 10(10): 591-613. PubMed

Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, Eron JJ, Günthard HF, Hammer SM, Reiss P, Richman DD, Rizzardini G, Thomas DL, Jacobsen DM, Volberding PA. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012; 308(4): 387-402. PubMed

Vandekerckhove LP, Wensing AM, Kaiser R, Brun-Vézinet F, Clotet B, De Luca A, Dressler S, Garcia F, Geretti AM, Klimkait T, Korn K, Masquelier B, Perno CF, Schapiro JM, Soriano V, Sönnerborg A, Vandamme A, Verhofstede C, Walter H, Zazzi M, Boucher CA, European Consensus Group on clinical management of tropism testing. European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infect Dis. 2011; 11(5): 394-407. PubMed

General References

Dunn DT, Coughlin K, Cane PA. Genotypic resistance testing in routine clinical care. Curr Opin HIV AIDS. 2011; 6(4): 251-7. PubMed

Grant PM, Zolopa AR. The use of resistance testing in the management of HIV-1-infected patients. Curr Opin HIV AIDS. 2009; 4(6): 474-80. PubMed

Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, Burger DM, Cahn P, Gallant JE, Glesby MJ, Reiss P, Saag MS, Thomas DL, Jacobsen DM, Volberding PA, International Antiviral Society-USA Panel. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA. 2014; 312(4): 410-25. PubMed

Smit E. Antiviral resistance testing. Curr Opin Infect Dis. 2014; 27(6): 566-72. PubMed

Taylor S, Jayasuriya A, Smit E. Using HIV resistance tests in clinical practice. J Antimicrob Chemother. 2009; 64(2): 218-22. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Melis R, Lewis T, Millson A, Lyon E, McMillin GA, Slev PR, Swensen J. Copy number variation and incomplete linkage disequilibrium interfere with the HCP5 genotyping assay for abacavir hypersensitivity. Genet Test Mol Biomarkers. 2012; 16(9): 1111-4. PubMed

Pyne MT, Wilson A, Hillyard DR. Large-scale comparison of Roche Cobas AmpliPrep/Cobas TaqMan and Abbott RealTime HIV assays. J Virol Methods. 2012; 184(1-2): 106-8. PubMed

Taborda NA, Cataño JC, Delgado JC, Rugeles MT, Montoya CJ. Higher SLPI expression, lower immune activation, and increased frequency of immune cells in a cohort of Colombian HIV-1 controllers. J Acquir Immune Defic Syndr. 2012; 60(1): 12-9. PubMed

Medical Reviewers

Last Update: August 2016