Reporting on the Prevalence of Antiretroviral Drug Resistance in a Regional HIV Population over 20 Years: A Word of Caution

Abstract

Background

Failure to achieve complete viral suppression with antiretroviral drugs (ARV) may lead to uncontrolled HIV replication, ARV resistance and negative outcomes. Monitoring and reporting of HIV resistance trends is important but problematic. We examined prevalent resistance rates in an HIV population over 20 years and document how rates may appear to vary greatly based solely on which parameters are utilized.

Methods

We determined the annual use of geno-typic antiretroviral resistance testing (GART) from 1995 to 2014 for all patients receiving HIV care in southern Alberta, Canada, and the presence of resistance mutations in those tested. The impact on prevalent resistance rates of using cumulative or latest GART was also determined.

Results

Between 1995 and 2014, the number of patients with GART increased from <1% to 71%. Prevalent resistance in patients with GART decreased from a high of 52% in 2003 to 25.8% in 2014. However, if prevalence rates were reported using all active patients as denominator, including those without GART, prevalence increased from 0.7% to 18.5%. Prevalence rates were 7% to 9% higher in any given year if cumulative GART rather than latest GART results were used.

Conclusions

While prevalence resistance rates are decreasing, the precise rates being reported may vary due to increasing number of patients tested annually, using either the entire population as denominator or only patients with GART, and using either last or cumulative GART. Defining these parameters is critical if prevalence is to be compared over time or between HIV populations.

References

Wegner

S.A.

, Wallace

M.R.

, Aronson

N.E.

Long-term efficacy of routine access to antiretroviral-resistance testing in HIV type 1-infected patients: results of the clinical efficacy of resistance testing trial.

Clin Infect Dis 2004; 38: 723–730.

Wensing

A.M.

, van de Vijver

D.A.

, Angarano

Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management.

J Infect Dis 2005; 192: 958–966.

Garcia

, Alvarez

, Fox

Predicting antiretroviral drug resistance from the latest or the cumulative genotype.

Antivir Ther 2011; 16: 373–382.

Miller

, Sabin

, Hertogs

Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure.

AIDS 2000; 14: 2857–2867.

Finzi

, Blankson

, Siliciano

J.D.

Latent infection of CD4⁺ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy.

Nat Med 1999; 5: 512–517.

Blankson

J.N.

, Persaud

, Siliciano

R F.

The challenge of viral reservoirs in HIV-1 infection.

Annu Rev Med 2002; 53: 557–593.

Kouyos

R.D.

, Gunthard

H.F.

The irreversibility of HIV drug resistance.

Clin Infect Dis 2015; 61: 837–839.

Johnson

J.A.

, Li

J.F.

, Wei

Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacy.

PLoS Med 2008; 5: e158.

Wittkop

, Gunthard

H.F.

, de Wolf

Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study.

Lancet Infect Dis 2011; 11: 363–371.

10.

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. (Accessed 14 September 2015.) Available from http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

11.

Hurt

C.B.

, Enron

J.J.

Jr. , Cohen

M.S.

Pre-exposure prophylaxis and antiretroviral resistance: HIV prevention at a cost?

Clin Inf Dis 2011; doi 10.1093/cid/cir684.

12.

Abbas

U.L.

, Hood

, Wetzel

, Mellors

J.W.

Factors influencing the emergence and spread of HIV drug resistance arising from rollout of antiretroviral pre-exposure prophylasis (PrEP).

PLoS One 2011; 6: e18165.

13.

Benn

, Fisher

, Kulasegaram

BASHH, PEPSE Guidelines Writing Group Clinical Effectiveness Group. UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure (2011). Int J STD AIDS 2011; 22: 695–708.

14.

Krentz

H.B.

, Ko

, Beckthold

, Gill

M.J.

The cost of antiretroviral drug resistance in HIV-positive patients.

Antivir Ther 2014; 19: 341–348.

15.

Taylor

, Jayasuriya

, Smit

Using HIV resistance tests in clinical practice.

J Antimicrob Chemother 2009; 64: 218–222.

16.

Elgalib

, Perry

, Aboud

Clinical utility of genotypic resistance tests for HIV-1 patients.

J Clin Microbiol 2010; 48: 3358–3359.

17.

Drescher

S.M.

, von Wyl

, Yang

W.L.

Treatment-naive individuals are the major source of transmitted HIV-1 drug resistance in men who have sex with men in the Swiss HIV Cohort Study.

Clin Infect Dis 2014; 58: 285–294.

18.

Albrecht

, Zollner

, Feucht

H.H.

Reappearance of HIV multidrug-resistance in plasma and circulating lymphocytes after reintroduction of antiretroviral therapy.

J Clin Virol 2002; 24: 93–98.

19.

Castro

, Pillay

, Cane

Persistence of HIV-1 transmitted drug resistance mutations.

J Infect Dis 2013; 208: 1459–1463.

20.

Pou

, Noguera-Julian

, Perez-Alvarez

Improved prediction of salvage antiretroviral therapy outcomes using ultrasensitive HIV-1 drug resistance testing.

Clin Infect Dis 2014; 59: 578–588.

21.

Schultze

, Phillips

A.N.

, Paredes

HIV resistance testing and detected drug resistance in Europe.

AIDS 2015; 29: 1379–1389.

22.

Costagliola

, Descamps

, Assoumou

Prevalence of HIV-1 drug resistance in treated patients: a French nationwide study.

J Acquir Immune Defic Syndr 2007; 46: 12–18.

23.

Buchacz

, Baker

R.K.

, Young

, Brooks

J.T.

, HIV Outpatient Study (HOPS) Investigators. Changes in the use of HIV anti-retroviral resistance testing in a large cohort of U.S. patients, 1999 to 2006. J Acquir Immune Defic Syndr 2010; 53: 625–632.

24.

Gagliardo

, Brozovich

, Birnbaum

A multicenter study of initiation of antiretroviral therapy and transmitted drug resistance in antiretroviral-naive adolescents and young adults with HIV in New York City.

Clin Infect Dis 2014; 58: 865–872.

25.

Mbisa

J.L.

, Fearnhill

, Dunn

D.T.

Evidence of self-sustaining drug resistant HIV-1 lineages among untreated patients in the United Kingdom.

Clin Infect Dis 2015; 61: 829–836.

26.

Cozzi-Lepri

, Noguera-Julian

, Di Giallonardo

Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRT-based ART: a multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing.

J Antimicrob Chemother 2015; 70: 930–940.

27.

Derache

, Shin

H.S.

, Balamane

HIV drug resistance mutations in proviral DNA from a community treatment program.

PLoS One 2015; 10: e0117430.

28.

Di Giambenedetto

, Colafigli

, Pinnetti

Genotypic resistance profile and clinical progression of treatment-experienced HIV type 1 infected patients with virological failure.

AIDS Res Hum Retroviruses 2008; 24: 149–154.

29.

Gupta

, Hill

, Sawyer

A.W.

, Pillay

Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials.

Clin Infect Dis 2008; 47: 712–722.

30.

Gange

S.J.

, Kitahata

M.M.

, Saag

M.S.

Cohort profile: the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).

Int J Epidemiol 2007; 36: 294–301.

31.

Hirsch

M.S.

, Gunthard

H.F.

, Schapiro

J.M.

Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA Panel.

Clin Infect Dis 2008; 47: 266–285.

32.

Sax

P.E.

, Islam

, Walensky

R.P.

Should resistance testing be performed for treatment-naive HIV-infected patients? A cost-effectiveness analysis.

Clin Infect Dis 2005; 41: 1316–1323.

33.

Vermeiren

, Van Craenenbroeck

, Alen

Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling.

J Virol Methods 2007; 145: 47–55.

34.

Liu

T.F.

, Shafer

R.W.

Web resources for HIV type 1 genotypic-resistance test interpretation.

Clin Infect Dis 2006; 42: 1608–1618.

35.

Liu

, May

, Richman

D.D.

Comparison of algorithms that interpret genotypic HIV-1 drug resistance to determine the prevalence of transmitted drug resistance.

AIDS 2008; 22: 835–839.

36.

Bennett

D.E.

, Camacho

R.J.

, Otelea

Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update.

PLOS ONE 4: e4724.

37.

Surveillance Drug Resistance Mutation (SDRM). 2014 worksheet. Stanford University. (Accessed 15 September 2016.) Available from http://hivdb.stanford.edu/cgi-bin/AgMutPrev.cgi.

38.

De Luca

, Dunn

, Zazzi

Declining prevalence of HIV-1 drug resistance in antiretroviral treatment-exposed individuals in Western Europe.

J Infect Dis 2013; 207: 1216–1220.

39.

Buchacz

, Young

, Palella

F.J.

Jr.

Trends in use of genotypic resistance testing and frequency of major drug resistance among antiretroviral-naive persons in the HIV Outpatient Study, 1999-2011.

J Antimicrob Chemother 2015; 70: 2337–2346.

40.

Schultze

, Phillips

A.N.

, Paredes

HIV resistance testing and detected drug resistance in Europe.

AIDS 2015; 29: 1379–1389.

41.

Yang

W.L.

, Kouyos

, Scherrer

A.U.

Assessing the paradox between transmitted and acquired HIV type 1 drug resistance mutations in the Swiss HIV Cohort Study from 1998 to 2012.

J Infect Dis 2015; 212: 28–38.

42.

Cescon

, Kanters

, Brumme

C.J.

Trends in plasma HIV-RNA suppression and antiretroviral resistance in British Columbia, 1997-2010.

J Acquir Immune Defic Syndr 2014; 65: 107–114.

43.

Tang

M.W.

, Shafer

R.W.

HIV-1 antiretroviral resistance.

Drugs 2012; 72: e1–e25.

44.

Theys

, Camacho

R.J.

, Gomes

Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapine.

Clin Microbiol Infect 2015; 21: 607e1–e8.

45.

Gill

M.J.

, Krentz

H.B.

Unappreciated epidemiology: the churn effect in a regional HIV care programme.

Int J STD AIDS 2009; 20: 540–544.