Over nearly two decades, the International HIV Drug Resistance Workshop has become the leading forum for new research on viral resistance to agents developed to treat infection with HIV. The XVIII workshop featured work on HIV type-1 (HIV-1) persistence, reservoirs and elimination strategies; resistance to HIV-1 entry inhibitors (including a comparison of genotyping versus phenotyping to determine HIV-1 coreceptor use before treatment with CCR5 antagonists); polymerase domain resistance to reverse transcriptase inhibitors (including hepatitis B virus and HIV-1 resistance to lamivudine, and emergence of the K65R mutation in HIV-1 subtypes B and C); connection and RNase H domain resistance to reverse transcriptase inhibitors (including the effect of mutations in those domains on response to efavirenz and etravirine); resistance to hepatitis C virus and HIV-1 protease inhibitors; resistance to the integrase inhibitor raltegravir; global resistance epidemiology (including models to predict response to second-line antiretrovirals in resource-poor settings); and the role of minority resistant variants (including the effect of such variants on prevention of mother-to-child transmission of HIV-1). This report summarizes data from the oral abstract presentations at the workshop.
BaileyJ.R., SedaghatA.R., KiefferT.Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells.J Virol2006; 80: 6441–6457.
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DinosoJ., JonesJ., McMahonD.Antiretroviral intensification does not reduce persistent HIV-1 viremia on therapy.Antivir Ther2009; 14 Suppl 1: A12.
4.
Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.US Department of Health and Human Services November 3, 2008. (Updated 3 November 2008. Accessed 10 October 2009.) Available from www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
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DinosoJ.B., KimS.Y., WiegandA.M.Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy.Proc Natl Acad Sci U S A2009; 106: 9403–9408.
6.
LiuZ., CumberlandW.G., HultinL.E.CD8+ T-lymphocyte activation in HIV-1 disease refects an aspect of pathogenesis distinct from viral burden and immunodeficiency.J Acquir Immune Defic Syndr Hum Retrovirol1998; 18: 332–340.
7.
OrendiJ.M., BloemA.C., BorleffsJ.C.Activation and cell cycle antigens in CD4+ and CD8+ T cells correlate with plasma human immunodeficiency virus (HIV-1) RNA level in HIV-1 infection.J Infect Dis1998; 178: 1279–1287.
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CossariniF., WiegandA., MicanJ.Markers of cellular immune activation do not correlate with levels of residual viremia in patients on long-term suppressive antiretroviral therapy.Antivir Ther2009; 14 Suppl 1: A10.
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De CastroN., BraunJ., CharreauI.Switch from enfuvirtide to raltegravir in highly treatment-experienced HIV-1-infected patients: a randomized open-label non-inferiority trial, Easier–ANRS 138.16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, QC, Canada. Abstract 572.
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DelaugerreC., CharreauI., BraunJ.No evolution of HIV-1 total DNA and 2-LTR circles after 24 weeks of raltegravir-containing regimen: a substudy of randomized EASIER-ANRS 138 trial.Antivir Ther2009; 14 Suppl 1: A11.
11.
PalmerS., KingM., WiegandA.Longitudinal dynamics of persistent viremia in elite controller patients versus patients on suppressive therapy.Antivir Ther2009; 14 Suppl 1: A6.
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PalmerS., MaldarelliF., WiegandA.Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy.Proc Natl Acad Sci U S A2008; 105: 3879–3884.
13.
HuntP.W., HatanoH., SinclairE.HIV-specific CD4+ T-cells may contribute to viral persistence in HIV-infected elite controllers.Antivir Ther2009; 14 Suppl 1: A7.
14.
HatanoH., DelwartE.L., NorrisP.J.Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy.J Virol2009; 83: 329–335.
15.
MensH., KearneyM., WiegandA.Single genome sequence analysis of plasma viruses from HIV-1 controllers suggests ongoing low-level replication.16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, QC, Canada. Abstract 77.
16.
BedoyaL.M., MárquezN., MartínezN.SJ23B, a jatrophane diterpene, induces HIV receptors downregulation and HIV transcription through activation of Ras-MEK pathway and classical PKCs.Antivir Ther2009; 14 Suppl 1: A5.
17.
RullasJ., BermejoM., García-PérezJ.Prostratin induces HIV activation and downregulates HIV receptors in peripheral blood lymphocytes.Antivir Ther2004; 9: 545–554.
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BedoyaL.M., MárquezN., MartínezN.SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro.Biochem Pharmacol2009; 77: 965–978.
19.
BosqueA., PlanellesV.Roles of NFAT, cell division and IL-7 stimulation on HIV-1 reactivation from latency in primary memory T-cells.Antivir Ther2009; 14 Suppl 1: A4.
20.
BosqueA., PlanellesV.Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells.Blood2009; 113: 58–65.
21.
SmithA.J., SchackerT.W., SivertsonM.B.The role of chitinase-3-like-1 in bacterial translocation during HIV-1 infection.Antivir Ther2009; 14 Suppl 1: A9.
22.
BrenchleyJ.M., PriceD.A., SchackerT.W.Microbial translocation is a cause of systemic immune activation in chronic HIV infection.Nat Med2006; 12: 1365–1371.
23.
MizoguchiE.Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells.Gastroenterology2006; 130: 398–411.
24.
HarriganP.R., McGovernR., DongW.Screening for HIV tropism using population-based V3 genotypic analysis: a retrospective virological outcome analysis using stored plasma screening samples from MOTIVATE-1.Antivir Ther2009; 14 Suppl 1: A17.
25.
GulickR.M., LalezariJ., GoodrichJ.Maraviroc for previously treated patients with R5 HIV-1 infection.N Engl J Med2008; 359: 1429–1441.
26.
OgertR.A., HouY., BaL.Modification of the CCR5 binding site by mutations in gp120 influence drug susceptibility and viral infectivity in one subject with clinical resistance to vicriviroc.Antivir Ther2009; 14 Suppl 1: A18.
27.
HuangC.C., LamS.N., AcharyaP.Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4.Science2007; 317: 1930–1934.
28.
LobritzM., RatcliffA., MarozsanA., DudleyD., ArtsE.Different mechanisms of HIV-1 inhibition by CCR5 agonists/antagonists (maraviroc, TAK-779 and PSC-RANTES) are linked to different drug resistance mechanisms.Antivir Ther2009; 14 Suppl 1: A14.
29.
LobritzM.A., MarozsanA.J., TroyerR.M., ArtsE.J.Natural variation in the V3 crown of human immunodeficiency virus type 1 affects replicative fitness and entry inhibitor sensitivity.J Virol2007; 81: 8258–8269.
30.
MarozsanA.J., MooreD.M., LobritzM.A.Differences in the fitness of two diverse wild-type human immunodeficiency virus type 1 isolates are related to the efficiency of cell binding and entry.J Virol2005; 79: 7121–7134.
31.
HuangW., CoakleyE., TomaJ.Transitions from CCR5 to CXCR4 use in the absence of antiretroviral drug pressure proceed incrementally and may occur through a multitude of genetic pathways.Antivir Ther2009; 14 Suppl 1: A15.
32.
ThielenA., AltmannA., BogojeskaJ., KaiserR., LengauerT.Estimating evolutionary pathways to CXCR4 usage from cross-sectional data.Antivir Ther2009; 14 Suppl 1: A16.
33.
BeerenwinkelN., DäumerM., SingT.Estimating HIV evolutionary pathways and the genetic barrier to drug resistance.J Infect Dis2005; 191: 1953–1960.
34.
SvicherV., AlteriC., GoriC.Lamivudine resistance mutations in HBV reverse transcriptase can be selected even at extremely low levels of viral replication.Antivir Ther2009; 14 Suppl 1: A26.
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SvicherV., AlteriC., ForbiciF.Different evolution and patterns of genotypic resistance profiles in emtricitabine plus tenofovir and lamivudine plus tenofovir containing regimen.Antivir Ther2009; 14 Suppl 1: A25.
36.
DobardC., LipscombJ., JohnsonJ.A., Garcia-LermaJ.G., HeneineW.Recombinant viruses expressing subtype B or subtype C reverse transcriptase reveal no difference in the rate of K65R resistance to tenofovir in cell culture.Antivir Ther2009; 14 Suppl 1: A23.
37.
BrennerB.G., OliveiraM., Doualla-BellF.HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture.AIDS2006; 20: F9–F13.
38.
InvernizziC., CoutsinosD., MoisiD.Introduction of the 64/65 nucleotide polymorphisms of subtype C HIV-1 into subtype B HIV-1 selects for the K65R mutational pathway in cell culture.15th Conference on Retroviruses and Opportunistic Infections. 3–6 February 2008. Boston, MA, USA. Abstract 849.
39.
KulkarniR., MargotN.A., MyrickF.The HIV-1 RT mutant Q151L shows decreased replication capacity, selective high-level resistance to GS-9148 and hypersusceptibility to tenofovir and zidovudine.Antivir Ther2009; 14 Suppl 1: A20.
40.
TchesnokovE.P., ObikhodA., MassudI.Mechanisms associated with HIV-1 resistance to acyclovir by the V75I mutation in reverse transcriptase.Antivir Ther2009; 14 Suppl 1: A21.
41.
LiscoA., VanpouilleC., TchesnokovE.P.Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues.Cell Host Microbe2008; 4: 260–270.
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McMahonM.A., SilicianoJ.D., LaiJ.The antiherpetic drug acyclovir inhibits HIV replication and selects the V75I reverse transcriptase multidrug resistance mutation.J Biol Chem2008; 283: 31289–31293.
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TchesnokovE.P., ObikhodA., MassudI.Mechanisms associated with HIV-1 resistance to acyclovir by the V75I mutation in reverse transcriptase.J Biol Chem2009; 284: 21496–21504.
44.
DasK., BandwarR., BaumanJ., TuskeS., HughesS., ArnoldE.High-resolution structures of HIV-1 RT/ RNA:DNA ternary complexes with tenofovir diphosphate and dATP.Antivir Ther2009; 14 Suppl 1: A19.
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MarchandB., MichailidisL., KodamaE.I.Mechanisms of inhibition and resistance to translocation deficient reverse transcriptase inhibitors.Antivir Ther2009; 14 Suppl 1: A22.
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NissleyD.V., AlptürkO., AmbroseZ., EatonK., StrathernJ.N., Sluis-CremerN.HIV-1 reverse transcriptase fidelity variants alter levels of mutation during replication.Antivir Ther2009; 14 Suppl 1: A24.
47.
NissleyD.V., RadzioJ., AmbroseZ.Characterization of novel non-nucleoside reverse transcriptase (RT) inhibitor resistance mutations at residues 132 and 135 in the 51 kDa subunit of HIV-1 RT.Biochem J2007; 404: 151–157.
48.
AmbroseZ., HermanB.D., SheenC.W.The human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor resistance mutation I132M confers hypersensitivity to nucleoside analogs.J Virol2009; 83: 3826–3833.
49.
Delviks-FrankenberryK.A., NikolenkoG.N., MaldarelliF., HaseS., TakebeY., PathakV.K.Subtype-specific amino acid polymorphisms in the HIV-1 reverse transcriptase connection subdomain of CRF01_AE are associated with higher 3’-azido-3’-deoxythymidine resistance.Antivir Ther2009; 14 Suppl 1: A31.
50.
BrehmJ.H., KoontzD., MeteerJ.D., PathakV., Sluis-CremerN., MellorsJ.W.Selection of mutations in the connection and RNase H domains of human immunodeficiency virus type 1 reverse transcriptase that increase resistance to 3’-azido-3’-dideoxythymidine.J Virol2007; 81: 7852–7859.
51.
Delviks-FrankenberryK.A., NikolenkoG.N., BarrR., PathakV.K.Mutations in human immunodeficiency virus type 1 RNase H primer grip enhance 3’-azido-3’-deoxythymidine resistance.J Virol2007; 81: 6837–6845.
52.
NikolenkoG.N., Delviks-FrankenberryK.A., PalmerS.Mutations in the connection domain of HIV-1 reverse transcriptase increase 3’-azido-3’-deoxythymidine resistance.Proc Natl Acad Sci U S A2007; 104: 317–322.
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RadzioJ., TachedjianG., Sluis-CremerN.Mutational analysis of residue Asn348 in HIV-1 reverse transcriptase.Antivir Ther2009; 14 Suppl 1: A32.
54.
YapS.H., SheenC.W., FaheyJ.N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance.PLoS Med2007; 4: e335.
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NikolenkoG.N., Delviks-FrankenberryK.A., PathakV.K.A novel molecular mechanism of dual resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors.Antivir Ther2009; 14 Suppl 1: A33.
56.
NikolenkoG.N., Delviks-FrankenberryK.A., JereA., PathakV.K.Mutations in the reverse transcriptase connection and RNase H domains exhibit dual resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors.Antivir Ther2008; 13 Suppl 3: A55.
57.
RiddlerS.A., HaubrichR., DiRienzoA.G.Class-sparing regimens for initial treatment of HIV-1 infection.N Engl J Med2008; 358: 2095–2106.
58.
BrehmJ., SheenC.W., HughesM.Virologic failure of regimens containing two NRTIs plus efavirenz is not associated with the selection of mutations in the connection or RNase H domains of reverse transcriptase.Antivir Ther2009; 14 Suppl 1: A34.
59.
VingerhoetsJ., TambuyzerL., ParedesR.Effect of mutations in the RT connection domain on phenotypic susceptibility and virologic response to etravirine.Antivir Ther2009; 14 Suppl 1: A35.
60.
MadrugaJ.V., CahnP., GrinsztejnB.Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial.Lancet2007; 370: 29–38.
61.
LazzarinA., CampbellT., ClotetB.Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial.Lancet2007; 370: 39–48.
62.
ParryC.M., CaneP., PillayD.Identification of HIV-1 matrix determinants of fitness compensation in a protease inhibitor resistant virus.Antivir Ther2009; 14 Suppl 1: A37.
63.
ParryC.M., KohliA., BoinettC.J., TowersG.J., McCormickA.L., PillayD.Gag determinants of fitness and drug susceptibility in protease inhibitor-resistant human immunodeficiency virus type 1.J Virol2009; 83: 9094–9101.
64.
WenningL., NguyenB., TepplerH.Pharmacokinetic/ pharmacodynamic analyses for raltegravir in Phase II and III studies in treatment experienced HIV-infected patients.9th International Workshop on Clinical Pharmacology of HIV Therapy. 7–9 April 2008, New Orleans, LA, USA. Abstract O21.
65.
GroblerJ.A., MckennaP.M., LyS.HIV integrase inhibitor dissociation rates correlate with efficacy in vitro.Antivir Ther2009; 14 Suppl 1: A27.
66.
MillerM.D., DanovichR.M., KeY.Longitudinal analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from P005, a phase II study in treatment-experienced patients.Antivir Ther2008; 13 Suppl 3: A8.
67.
MaletI., DelelisO., SoulieC.Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients.J Antimicrob Chemother2009; 63: 795–804.
68.
DamE., QuerciaR., ClavelF.Drug concentration, selective advantage and selection dynamics of raltegravir-resistant mutants.Antivir Ther2009; 14 Suppl 1: A28.
69.
ThibautL., RochasS., DourlatJ.New integrase binding inhibitors acting in synergy with raltegravir.Antivir Ther2009; 14 Suppl 1: A29.
70.
RevellA.D., WangD., HarriganR.Computational models developed without a genotype for resource-poor countries predict response to HIV treatment with 82% accuracy.Antivir Ther2009; 14 Suppl 1: A38.
71.
HuntG., LedwabaJ., El-KhatibZ.Drug resistance patterns among HIV-infected children and adults failing Kaletra-based regimens in South Africa.Antivir Ther2009; 14 Suppl 1: A39.
72.
BartlettJ.A., BudaJ.J., von ScheeleB.Minimizing resistance consequences after virologic failure on initial combination therapy: a systematic overview.J Acquir Immune Defic Syndr2006; 41: 323–331.
73.
GuptaR., HillA., SawyerA.W., PillayD.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 Dis2008; 47: 712–722.
74.
Sáez-LlorensX., ViolariA., DeetzC.O.Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children.Pediatr Infect Dis J2003; 22: 216–224.
75.
DelaugerreC., TeglasJ.P., TreluyerJ.M.Predictive factors of virologic success in HIV-1-infected children treated with lopinavir/ritonavir.J Acquir Immune Defic Syndr2004; 37: 1269–1275.
76.
PersaudD., PalumboP., ZiemniakC.Early archiving and predominance of nonnucleoside reverse transcriptase inhibitor-resistant HIV-1 among recently infected infants born in the United States.J Infect Dis2007; 195: 1402–1410.
77.
von WylV., YerlyS., BöniJ.Successful identification of sources of transmitted drug-resistant HIV-1 via a cross-sectional phylogenetic analysis.Antivir Ther2009; 14 Suppl 1: A41.
78.
BennettD.E., CamachoR.J., OteleaD.Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update.PLoS ONE2009; 4: e4724.
79.
LidstromJ., KumwendaN., HooverD.R.Addition of extended zidovudine to extended nevirapine prophylaxis reduces resistance in infants who were HIV-infected in utero: the PEPIMalawi study.Antivir Ther2009; 14 Suppl 1: A42.
JohnsonJ.A., LiJ.F., YangC.Bulk sequence-detectable resistance mutations in peripheral RNA following single-dose nevirapine are associated with poorer treatment responses but do not adequately explain treatment failure.Antivir Ther2009; 14 Suppl 1: A45.
82.
WagnerT., JourdainG., Ngo-Giang-HuongN.Resistance mutations detected by oligonucleotide ligation assay of HIV-1 DNA at time of initiation of nevirapine-containing antiretroviral therapy are associated with virologic failure.Antivir Ther2009; 14 Suppl 1: A46.
83.
JourdainG., Ngo-Giang-HuongN., Le CoeurS.Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy.N Engl J Med2004; 351: 229–240.
84.
LockmanS., ShapiroR.L., SmeatonL.M.Response to antiretroviral therapy after a single, peripartum dose of nevirapine.N Engl J Med2007; 356: 135–147.
85.
LockmanS., SmeatonL., OgwuA.Long-term maternal and pediatric virologic outcomes on nevirapine-based HAART following receipt of peripartum single-dose nevirapine or placebo, Botswana.16th Conference on Retroviruses and Opportunistic Infections. 8–11 February, 2009, Montreal, QC, Canada. Abstract 955.
86.
GoodmanD.D., MargoN.A., McCollD.J., MillerM.D.Borroto-Esoda1 E, Svarovskaia ES. Pre-existing low-levels of the K103N HIV-1 RT mutation above a threshold is associated with virological failure in treatment-naive patients undergoing EFV-containing antiretroviral treatment.Antivir Ther2009; 14 Suppl 1: A43.
87.
MetznerK.J., WalterH., RauchP.The prevalence of drug-resistant virus as a minority quasispecies before initiating art is not associated with therapy failure in persons initiating therapy with Truvada plus PI/r or NNRTI.15th Conference on Retroviruses and Opportunistic Infections. 3–6 February 2008, Boston, MA, USA. Abstract 879.
88.
Garcia-DiazA., JohnsonJ.A., FoxZ.V.Low-frequency mutations strengthen the impact of transmitted drug resistance on virological responses to first-line efavirenz or nevirapine based antiretroviral therapy.7th European HIV Drug Resistance Workshop. 25–27 March 2009, Stockholm, Sweden. Abstract 113.
89.
BraunP., EhretR., WiesmannF., MetznerK.J., KnechtenH.Prevalence of the K103N mutation at low frequencies in antiretroviral treatment-naive patients in Germany 2008.7th European HIV Drug Resistance Workshop. 25–27 March 2009, Stockholm, Sweden. Abstract 71.
90.
ArribasJ.R., PozniakA.L., GallantJ.E.Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis.J Acquir Immune Defic Syndr2008; 47: 74–78.
91.
LatailladeM., ChiarellaJ., YangR.Prevalence and clinical significance of transmitted drug-resistant (TDR) HIV mutations by ultra-deep sequencing (UDS) in HIV-infected ARV-naive subjects in CASTLE study.Antivir Ther2009; 14 Suppl 1: A44.
92.
MolinaJ.M., Andrade-VillanuevaJ., EchevarriaJ.Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study.Lancet2008; 372: 646–655.
