Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Drug resistance testing in the clinical management of HIV infection

Michael J Kozal, MD
Section Editor
Martin S Hirsch, MD
Deputy Editor
Jennifer Mitty, MD, MPH


The development and transmission of HIV variants resistant to antiretroviral drugs continues to limit the efficacy of treatments for HIV infection. Factors influencing the development of HIV drug resistance and the role of genotypic and phenotypic testing in different clinical scenarios will be reviewed here [1].

The relative advantages and disadvantages of the tests and clinical trial data supporting their use, an introduction to the understanding of resistance mutations, and the issue of nevirapine resistance related to prevention of mother-to-child HIV transmission are discussed elsewhere. (See "Overview of HIV drug resistance testing assays" and "Primer on interpretation of HIV drug resistance testing".)


Multiple factors influence the development of HIV drug resistance, including the biology of HIV, genetic barriers to resistance, regimen potency, pharmacokinetics of antiretroviral drugs, and medication adherence.

HIV biology — HIV infection is characterized by high rates of replication, with more than 10(9) virions produced daily [2]. In addition, HIV reverse transcriptase, which is responsible for replicating the viral genome, is error-prone. The combination of high rates of replication and frequent introduction of mutations during each round of replication leads to the frequent occurrence of randomly generated mutations, some of which confer drug resistance [3]. The resulting population of genetically related, but distinct, HIV variants in a patient is referred to as a "quasispecies."

Some drug-resistant variants, which replicate less efficiently than drug-sensitive strains in the absence of drug, can pre-exist at low levels before drug therapy is initiated. If virus replication is not fully suppressed by the antiretroviral regimen, these mutants can emerge. Depending on their level of drug resistance, these mutants can either cause overt virologic failure, or, if replication in the presence of drug persists, become more drug resistant by the gradual accumulation of additional resistance mutations.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2017. | This topic last updated: Jan 13, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. 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. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf (Accessed on May 01, 2014).
  2. Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373:123.
  3. Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995; 267:483.
  4. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346:2039.
  5. Pursuing Later Treatment Options II (PLATO II) project team, Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Group, Nakagawa F, et al. Calendar time trends in the incidence and prevalence of triple-class virologic failure in antiretroviral drug-experienced people with HIV in Europe. J Acquir Immune Defic Syndr 2012; 59:294.
  6. Baxter JD, Dunn D, White E, et al. INSIGHT START Study Group. Global HIV-1 Transmitted Drug Resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment Study. In Press, HIV Medicine 2015.
  7. Geretti AM, Paredes R, Kozal MJ. Transmission of HIV drug resistance: lessons from sensitive screening assays. Curr Opin Infect Dis 2015; 28:23.
  8. Chabria SB, Gupta S, Kozal MJ. Deep sequencing of HIV: clinical and research applications. Annu Rev Genomics Hum Genet 2014; 15:295.
  9. Ribaudo HJ, Haas DW, Tierney C, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis 2006; 42:401.
  10. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004; 18:2391.
  11. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133:21.
  12. Bangsberg DR, Moss AR, Deeks SG. Paradoxes of adherence and drug resistance to HIV antiretroviral therapy. J Antimicrob Chemother 2004; 53:696.
  13. Bangsberg DR, Acosta EP, Gupta R, et al. Adherence-resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness. AIDS 2006; 20:223.
  14. Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis 2005; 192:1537.
  15. Gerondelis P, Archer RH, Palaniappan C, et al. The P236L delavirdine-resistant human immunodeficiency virus type 1 mutant is replication defective and demonstrates alterations in both RNA 5'-end- and DNA 3'-end-directed RNase H activities. J Virol 1999; 73:5803.
  16. Wang J, Dykes C, Domaoal RA, et al. The HIV-1 reverse transcriptase mutants G190S and G190A, which confer resistance to non-nucleoside reverse transcriptase inhibitors, demonstrate reductions in RNase H activity and DNA synthesis from tRNA(Lys, 3) that correlate with reductions in replication efficiency. Virology 2006; 348:462.
  17. Collins JA, Thompson MG, Paintsil E, et al. Competitive fitness of nevirapine-resistant human immunodeficiency virus type 1 mutants. J Virol 2004; 78:603.
  18. Harrigan PR, Bloor S, Larder BA. Relative replicative fitness of zidovudine-resistant human immunodeficiency virus type 1 isolates in vitro. J Virol 1998; 72:3773.
  19. Dykes C, Demeter LM. Clinical significance of human immunodeficiency virus type 1 replication fitness. Clin Microbiol Rev 2007; 20:550.
  20. Markowitz M, Conant M, Hurley A, et al. A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection. J Infect Dis 1998; 177:1533.
  21. Bacheler L, Jeffrey S, Hanna G, et al. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J Virol 2001; 75:4999.
  22. Miller MD, Margot N, Lu B, et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis 2004; 189:837.
  23. Shulman NS, Bosch RJ, Mellors JW, et al. Genetic correlates of efavirenz hypersusceptibility. AIDS 2004; 18:1781.
  24. Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 1995; 269:696.
  25. Trotta MP, Cozzi-Lepri A, Ammassari A, et al. Rate of CD4+ cell count increase over periods of viral load suppression: relationship with the number of previous virological failures. Clin Infect Dis 2010; 51:456.
  26. Baxter JD, Mayers DL, Wentworth DN, et al. 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; 14:F83.
  27. Palella FJ Jr, Armon C, Buchacz K, et al. The association of HIV susceptibility testing with survival among HIV-infected patients receiving antiretroviral therapy: a cohort study. Ann Intern Med 2009; 151:73.
  28. Hirsch MS, Günthard HF, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis 2008; 47:266.
  29. Le T, Chiarella J, Simen BB, et al. Low-abundance HIV drug-resistant viral variants in treatment-experienced persons correlate with historical antiretroviral use. PLoS One 2009; 4:e6079.
  30. Harrigan PR, Wynhoven B, Brumme ZL, et al. HIV-1 drug resistance: degree of underestimation by a cross-sectional versus a longitudinal testing approach. J Infect Dis 2005; 191:1325.
  31. Demeter LM, Nawaz T, Morse G, et al. Development of zidovudine resistance mutations in patients receiving prolonged didanosine monotherapy. J Infect Dis 1995; 172:1480.
  32. Shafer RW, Winters MA, Jellinger RM, Merigan TC. Zidovudine resistance reverse transcriptase mutations during didanosine monotherapy. J Infect Dis 1996; 174:448.
  33. Montaner JS, Mo T, Raboud JM, et al. Human immunodeficiency virus-infected persons with mutations conferring resistance to zidovudine show reduced virologic responses to hydroxyurea and stavudine-lamivudine. J Infect Dis 2000; 181:729.
  34. de Mendoza C, Soriano V, Briones C, et al. Emergence of zidovudine resistance in HIV-infected patients receiving stavudine. J Acquir Immune Defic Syndr 2000; 23:279.
  35. Marcelin AG, Flandre P, Pavie J, et al. Clinically relevant genotype interpretation of resistance to didanosine. Antimicrob Agents Chemother 2005; 49:1739.
  36. Desai S, Kyriakides T, Holodniy M, et al. Evolution of genotypic resistance algorithms and their impact on the interpretation of clinical trials: an OPTIMA trial substudy. HIV Clin Trials 2007; 8:293.
  37. Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008; 300:555.
  38. Vandamme AM, Sönnerborg A, Ait-Khaled M, et al. Updated European recommendations for the clinical use of HIV drug resistance testing. Antivir Ther 2004; 9:829.
  39. Novak RM, Chen L, MacArthur RD, et al. Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis 2005; 40:468.
  40. Weinstock HS, Zaidi I, Heneine W, et al. The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-infected persons in 10 US cities. J Infect Dis 2004; 189:2174.
  41. Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 2005; 192:958.
  42. Cane P, Chrystie I, Dunn D, et al. Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study. BMJ 2005; 331:1368.
  43. Kim D, Wheeler W, Ziebell R, et al. Prevalence of Transmitted Antiretroviral Drug Resistance among Newly-diagnosed HIV-1-infected Persons, US, 2007. 17th CROI 2010, February 16-19 San Francisco, CA, Abstract #580.
  44. Prejean J, Ziebell R, Wheeler W, et al. Prevalence of Mutations Associated with Transmitted Drug Resistant HIV among BED Recent Versus Long-term Infections, US, 2006, US. 17th CROI 2010, February 16-19, San Francisco, CA, Abstract #580; Abstract #581.
  45. Kuritzkes DR, Lalama CM, Ribaudo HJ, et al. Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. J Infect Dis 2008; 197:867.
  46. Simen BB, Simons JF, Hullsiek KH, et al. Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes. J Infect Dis 2009; 199:693.
  47. Paredes R, Lalama CM, Ribaudo HJ, et al. Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J Infect Dis 2010; 201:662.
  48. Johnson JA, Li JF, Wei X, et al. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naïve populations and associate with reduced treatment efficacy. PLoS Med 2008; 5:e158.
  49. Cozzi-Lepri A, Noguera-Julian M, Di Giallonardo F, et al. Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing. J Antimicrob Chemother 2015; 70:930.
  50. Yanik EL, Napravnik S, Hurt CB, et al. Prevalence of transmitted antiretroviral drug resistance differs between acutely and chronically HIV-infected patients. J Acquir Immune Defic Syndr 2012; 61:258.
  51. Jain V, Liegler T, Vittinghoff E, et al. Transmitted drug resistance in persons with acute/early HIV-1 in San Francisco, 2002-2009. PLoS One 2010; 5:e15510.
  52. Hurt CB, McCoy SI, Kuruc J, et al. Transmitted antiretroviral drug resistance among acute and recent HIV infections in North Carolina from 1998 to 2007. Antivir Ther 2009; 14:673.
  53. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. http://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0/ (Accessed on March 28, 2014).
  54. Paredes R, Cheng I, Kuritzkes DR, et al. Postpartum antiretroviral drug resistance in HIV-1-infected women receiving pregnancy-limited antiretroviral therapy. AIDS 2010; 24:45.
  55. Sax PE, Islam R, Walensky RP, et al. Should resistance testing be performed for treatment-naive HIV-infected patients? A cost-effectiveness analysis. Clin Infect Dis 2005; 41:1316.