Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principal TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV.
Methods
Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virological failure (defined as an HIV RNA>1,000 copies/ml) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors.
Results
Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major non-nucleoside reverse transcriptase inhibitor mutations in 24 (57%) and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA 3.3 versus 4.2 log10 copies/ml) and prior stavudine exposure. An additional five patients had minority K65R populations identified by allele-specific PCR.
Conclusions
These data suggest that the K65R prevalence at virological failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype-C-infected patients with up to 6 months of failure of a TDF-containing regimen.
References
1.
World Health Organization.Antiretroviral therapy for HIV infection in adults and adolescents.Geneva: WHO2010.
2.
BrennerB.G., OliveiraM., Doualla-BellF.HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture. AIDS2006; 20: F9–F13.
3.
WainbergM.A., ZaharatosG.J., BrennerB.G.Development of antiretroviral drug resistance. N Engl J Med2011; 365: 637–646.
4.
InvernizziC.F., CoutsinosD., OliveiraM., MoisiD., BrennerB.G., WainbergM.A.Signature nucleotide polymorphisms at positions 64 and 65 in reverse transcriptase favor the selection of the K65R resistance mutation in HIV-1 subtype C. J Infect Dis2009; 200: 1202–1206.
5.
LiJ.F., LipscombJ.T., WeiX.Detection of low-level K65R variants in nucleoside reverse transcriptase inhibitor-naive chronic and acute HIV-1 subtype C infections. J Infect Dis2011; 203: 798–802.
6.
OrrellC., WalenskyR.P., LosinaE., PittJ., FreedbergK.A., WoodR.HIV type-1 clade C resistance genotypes in treatment-naive patients and after first virological failure in a large community antiretroviral therapy programme. Antivir Ther2009; 14: 523–531.
7.
HosseinipourM.C., van OosterhoutJ.J., WeigelR.The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS2009; 23: 1127–1134.
8.
van ZylG.U., van der MerweL., ClaassenM., ZeierM., PreiserW.Antiretroviral resistance patterns and factors associated with resistance in adult patients failing NNRTI-based regimens in the Western Cape, South Africa. J Med Virol2011; 83: 1764–1769.
9.
PillayV., PillayC., KantorR., VenterF., LevinL., MorrisL.HIV type 1 subtype c drug resistance among pediatric and adult South African patients failing antiretroviral therapy. AIDS Res Hum Retroviruses2008; 24: 1449–1454.
10.
TheysK., VercauterenJ., SnoeckJ.HIV-1 subtype is an independent predictor of reverse transcriptase mutation K65R in HIV-1 patients treated with combination antiretroviral therapy including tenofovir. Antimicrob Agents Chemother2013; 57: 1053–1056.
11.
SunpathH., WuB., GordonM.High rate of K65R for antiretroviral therapy-naive patients with subtype C HIV infection failing a tenofovir-containing first-line regimen. AIDS2012; 26: 1679–1684.
12.
HamersR.L., SigaloffK.C., WensingA.M.Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: implications for second-line ART strategies. Clin Infect Dis2012; 54: 1660–1669.
13.
CharalambousS., GrantA.D., DayJ.H.Establishing a workplace antiretroviral therapy programme in South Africa. AIDS Care2007; 19: 34–41.
14.
InnesC., HamiltonR., HoffmannC.J.A novel HIV treatment model using private practitioners in South Africa. Sex Transm Infect2012; 88: 136–140.
15.
PillayV., LedwabaJ., HuntG.Antiretroviral drug resistance surveillance among drug-naive HIV-1-infected individuals in Gauteng Province, South Africa in 2002 and 2004. Antivir Ther2008; 13Suppl 2: 101–107.
16.
ZhouZ., WagarN., DeVosJ.R.Optimization of a low cost and broadly sensitive genotyping assay for HIV-1 drug resistance surveillance and monitoring in resource-limited settings. PLoS ONE2011; 6: e28184.
17.
JohnsonV.A., CalvezV., GunthardH.F.2011 Update of the drug resistance mutations in HIV-1. Top Antivir Med2011; 19: 156–164.
18.
GallantJ.E., DeJesusE., ArribasJ.R.Tenofovir DF, emtricitabine, and efavirenz vs zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med2006; 354: 251–260.
19.
SaxP.E., TierneyC., CollierA.C.Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med2009; 361: 2230–2240.
20.
MargotN.A., LuB., ChengA., MillerM.D.Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903. HIV Med2006; 7: 442–450.
21.
DART Virology Group and Trial Team.Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS2006; 20: 1391–1399.
22.
GallantJ.E., StaszewskiS., PozniakA.L.Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA2004; 292: 191–201.
23.
MargotN.A., IsaacsonE., McGowanI., ChengA.K., SchooleyR.T., MillerM.D.Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF. AIDS2002; 16: 1227–1235.
24.
PozniakA.Tenofovir: what have over 1 million years of patient experience taught us?Int J Clin Pract2008; 62: 1285–1293.
25.
KaganR.M., LeeT.S., RossL., LloydR.M.Jr., LewinskiM.A., PottsS.J.Molecular basis of antagonism between K70E and K65R tenofovir-associated mutations in HIV-1 reverse transcriptase. Antiviral Res2007; 75: 210–218.
26.
DelaugerreC., FlandreP., MarcelinA.G.National survey of the prevalence and conditions of selection of HIV-1 reverse transcriptase K70E mutation. J Med Virol2008; 80: 762–765.
27.
Van RompayK.K., JohnsonJ.A., BlackwoodE.J.Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection. Retrovirology2007; 4: 25.
