Managing failure to antiretroviral therapies implies the addressing of several issues: the clinical stage, the virological and the immunological response to the failing regimen, together with drug history, resistance and exposure. Each of these issues will be discussed with the aim of providing useful data to design an optimal antiretroviral rescue therapy.
MellorsJ.W.MunozA.GiorgiJ. V.MargolickJ.B.TassoniC.J.GuptaP.KingsleyL.A.ToddJ.A.SaahA. J.DetelsR.PhairJ.P. and RinaldoC.R.Jr. 1997. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann. Intern. Med.126:946.
2.
PallelaF.J.DelaneyK.M.MoormanA.C.LovelessM.O.FuhrerJ.SattenG.A.AschmanD.J. and HolmbergS.D.. 1998. Declining morbidity and mortality among patients with advanced immunodeficiency virus infection. N. Engl. J. Med.338:853.
3.
PowderlyW.G.SaagM.S.ChapmanS.YuG.QuartB. and ClendeninnN.J.. 1999. Predictors of virological response to potent antiretroviral therapy. AIDS13:1873.
4.
DeeksS.HecthF. M.SwansonM.ElbeikT.LoftusR.CohenP.T. and GrantR.M.. 1999. HIV-RNA and CD4 cell count response to PI therapy in an urban AIDS clinic: response to both initial and salvage therapy. AIDS13:F35.
5.
LucasG.M.ChaissonR.E. and MooreR.D.. 1999. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann. Intern. Med.131:81.
6.
KaufmannD.PantaleoG.SudreP. and TalentiA.. 1998. CD4-cell count in HIV-1 infected individuals remaining viremic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study. Lancet351:723.
7.
PikettyC.CastielP.BelecL.BatisseD.Si MohamedA.GilquinJ.Gonzalez-CanaliG.JayleD.KarmochkineM.WeissL.AboulkerJ.P. and KazatchkineM.D.. 1998. Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease. AIDS12:745.
8.
StrackP.R.FreyM.W.RizzoC.J.CordovaB.GeorgeH.J.MeadeR.HoS.P.CormanJ.TritchR. and KorantB.D.. 1996. Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. Proc. Natl. Acad. Sci. USA93:9571.
9.
SloandE.M.KumarP.N.KimS.ChaudhuriA.WeicholdF.F. and YoungN.S.. 1999. Human Immunodeficiency Virus type 1 protease inhibitor modulates activation of peripheral blood CD4+ T cells and decreases their susceptibility to apoptosis in vitro and in vivo. Blood94:1021.
10.
DeeksS.G.WrinT.DuecyE.BarbourJ.D.HellmannN.PetropoulosC. and GrantR.M.. 2000. Decreased HIV-1 Fitness after Long-Term Virologic Failure of Protease Inhibitor-Based Therapy: Relationship to Immunologic Response. In Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco (Abstract No. 156).
11.
Martinez-PicadoX.SavaraA.SuttonL. and D'AquilaR.. 1999. Replicative fitness of protease inhibitor-resistant mutants of HIV-1. J. Virol.73:3744.
12.
StoddartC.MammanoF.MorenoM.Linquist-SteppsV.BareC.ClavelF. and McCuneJ. M.. 1999. Lack of fitness of protease inhibitor-resistant HIV-1 in vivo. In Program and abstracts of the 6th Conference on Retroviruses and Opportunistic Infections. Chicago (Abstract No. 4).
13.
FayeA.RaceE.ObryV.PrevotM. H.JolyV.MatheronS.DamondF.DamE.PaulousS. and ClavelF.. 1999. Viral fitness in patients with discordant CD4 and plasma HIV-RNA evolution following protease inhibitor failure. In Program and abstracts of the 6th Conference on Retroviruses and Opportunistic Infections. Chicago (Abstract No. 331).
14.
LedergerberB.EggerM.OpravilM.TelentiA.HirschelB.BattegayM.VernazzaP.SudreP.FleppM.FurrerH.FrancioliP. and WeberR.. 1999. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet353:863.
15.
GrabarS.Le MoingV.GoujardC.LeportC.KazatchkineM.D.CostagliolaD. and WeissL.. 2000. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann. Intern. Med.133:401.
16.
BahraniA.RamaswamyR. and OldfieldE.C.. 2001. Effects of virologic rebound on CD4 cell counts. Clin. Infect. Dis.32:1231.
17.
PikettyC.WeissL.ThomasF.MohamedA.S.BelecL. and KazatchkineM.D.. 2001. Long-term clinical outcome of Human Immunodeficiency virus-infected patients with discordant immunologic and virologic responses to a protease inhibitor-containing regimen. J. Infect. Dis.183:1328.
18.
HirschM.S.ConwayB.D'AquilaR.T.JohnsonV.A.Brun-VezinetF.ClotetB.DemeterL.M.HammerS.M.JacobsenD.M.KuritzkesD.R.LovedayC.MellorsJ.W.VellaS. and RichmanD.D.. 1998. Consensus statement. Antiviral drug resistance testing in adults with HIV infection. Implication for clinical management. JAMA279:1984.
19.
ParaM.F.GliddenD.V.CoombsR.W.CollierA.C.CondraJ.H.CraigC.BassettR.LeavittR.SnyderS.McAuliffeV. and BoucherC.. 2000. Baseline human immunodeficiency virus type 1 phenotype, genotype and RNA response after switching from long-term hard-capsule saquinavir to indinavir or soft-gel-capsule saquinavir in AIDS Clinical Trial Groups Protocol 333. J. Infect. Dis.182:733.
20.
DurantJ.ClevenberghP.HalfonP.PorsinS.SimonetP.MontagneN.BoucherC.A.SchapiroJ.M. and DellamonicaP.. 1999. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet353:2195.
21.
BaxterJ.D.MayersD.L.WentworthD.N.NeatonJ.D.HooverM.L.WintersM.A.MannheimerS.B.ThompsonM.A.AbramsD.I.BrizzB.J.IoannidisJ.P. and MeriganT.C.. 2000. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. AIDS14:F83.
22.
CohenC.HuntS.SensionM.FarthingC.ConantM.JacobsonS.NadlerJ.VerbiestW.HertogsK.AmesM.RinehartA. and GrahamN.. 2000. Phenotypic resistance testing significantly improves response to therapy: a randomized trial (VIRA3001). In Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco (Abstract No. 237).
23.
TuralC.RuizL.HoltzerC.VicianaP.GonzalezJ.FerrerE.Martinez-PicadoJ.RuizI.DalmauD.DomingoP.BeenA.BoucherC.A.B.SchapiroJ.RomeuJ.SireraG. and ClotetB.. 2000. The potential role of resistance decision support software with or without expert advice in atrial of HIV genotyping versus standard of care — The Havanna Trial. In Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto (Abstract No. L-10).
24.
DescampsD.FlandreP.CalvezV.PeytavinG.MeiffredyV.CollinG.DelaugerreC.Robert-DelmasS.BazinB.AboulkerJ.P.PialouxG.RaffiF. and Brun-VezinetF.. 2000. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial on induction-maintenance therapy. JAMA283:205.
25.
HirschM.S.Brun-VézinetF.D'AquilaR.T.HammerS.M.JohnsonV.A.KuritzkesD.R.LovedayC.MellorsJ.W.ClotetB.ConwayB.DemeterL.M.VellaS.JacobsenD.M. and RichmanD.D.. 2000. Antiretroviral drug resistance testing in adult HIV-1 infection. Recommendations of an International AIDS Society-USA Panel. JAMA283:2417.
26.
D'AquilaR.T.JohnsonV.A.WellesS.L.JapourA.J.KuritzkesD.R.DeGruttolaV.ReichelderferP.S.CoombsR.W.CrumpackerC.S. and KahnJ.O.. 1995. Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy: AIDS Clinical Trial Group Protocol 116B/117 Team and the Virology Committee Resistance Working Group. Ann. Intern. Med.122:401.
27.
JapourA. J.WellesS.D'AquilaR.T.JohnsonV.A.RichmanD.D.CoombsR.W.ReichelderferP.S.KahnJ.O.CrumpackerC.S. and KuritzkesD.R.. 1995. Prevalence and clinical significance of zidovudine resistance mutations in Human Immunodeficiency Virus isolated from patients after long-term zidovudine treatment. AIDS Clinical Trial Group 116B/117 Study team and the Virology Committee Resistance Working Group. J. Infect. Dis.171:1172.
28.
SchuurmanR.NijhuisM.van LeeuwenR.SchipperP.de JongD.CollisP.DannerS.A.MulderJ.LovedayC. and ChristophersonC.. 1995. Rapid changes in Human Immunodeficiency Virus Type 1 RNA load and appearance of drug-resistant virus population in persons treated with lamivudine (3TC). J. Infect. Dis.171:1411.
29.
WainbergM.A.DrosopoulosW.C.SalomonH.HsuM.BorkowG.ParniakM.GuZ.SongQ.ManneJ.IslamS.CastriotaG. and PrasadV.R.. 1996. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science271:1282.
30.
NijhuisM.SchuurmanR.de JongD.EricksonJ.GustchinaE.AlbertJ.SchipperP.GulnikS. and BoucherC.A.. 1999. Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS13:2349.
31.
SchmittM.HarrerE. and GoldwichA.. 2000. Specific recognition of lamivudine-resistant HIV-1 by cytotoxic T lymphocytes. AIDS14:653.
32.
SamriA.HaasG.DuntzeJ.BouleyJ.M.CalvezV.KatlamaC. and AutranB.. 2000. Immunogenicity of mutations induced by nucleoside reverse transcriptase inhibitors for Human Immunodeficiency Virus Type 1-specific cytotoxic T cells. J. Virol.74:9306.
HuangW.GamarnikA.WrinT.ParkinN.T.HellmannN.S.DeeksS.G.LieglerT.GrantR.M.PetropoulosC.J. and WhitcombJ.M.. 2000. HIV-1 isolates that exibit dose-dependent NNRTI stimulation of reverse transcriptase activity and viral replication. Antiviral Ther. 5(S3):23.
35.
LarderB.A.KempS.D. and HarriganP.R.. 1995. Potential mechanisms for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science269:696.
36.
ZiermannR.LimoliK.DasK.ArnoldE.PetropoulosC.J. and ParkinN.T.. 2000. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. J. Virol.74:4414.
37.
LarderB.A.1992. 3′-Azido-3′deoxythymideresistance suppressed by a mutationconferring human deficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 36:2664.
38.
WhitcombJ.DeeksS.HuangW.WrinT.PaxinosE.LimoliK.HohR.HellmannN. and PetropoulosC.. 2000. Reduced susceptibility to NRTIs is associated with NNRTI hypersensitivity in virus from HIV-1-infected patients. In Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco (Abstract No. 234).
39.
DeeksS.HellmannN.S. and GrantR.M.. 1999. Novel four-drug salvage treatment regimen after failure of a human immunodeficiency virus type 1 protease inhibitor-containing regimen: antiviral activity and correlation of baseline phenotypic drug susceptibility with virologic outcome. J. Infect. Dis.179:1375.
40.
ClumeckN.BrunS.SylteJ.IsaacsonJ.ChenS.LazzarinA.GirardP. M.RockstrohJ.BeckerS.TelentiA.BergmannF.DannerS.HoD.TubianaR.CarosiG.BertzR.HsuA.KingM.KempfD., and SunE.. 2001. Kaletra (ABT-378/r) and efavirenz: one-year safety/efficacy evaluation and phenotypic breakpoints in multiple-PI-experienced patients. In Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections Chicago (Abstract No. 525).
41.
DeeksS.G.GrantR.M.BeattyG.W.HortonC.DetmerJ. and EastmanS.. 1998. Activity of ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure. AIDSI2:F97.
LarderB.A.KellamP. and KempS.D.. 1991. Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes. AIDS5:137.
44.
GianottiN.SettiM.ManconiP.E.LeonciniF.ChiodoF.MinoliL.MoroniM.AngaranoG.MazzottaF.CarosiG.AntonelliG. and LazzarinA.. 2002. Reverse transcriptase mutations in HIV-1 infected patients treated with two nucleoside analogues: the SMART study. Int. J. Immunopathol. Pharmacol.15:129.
45.
PellegrinI.IzopetJ.ReynesJ.DenayrollesM.MontesB.PellegrinJ.L.MassipP.PuelJ.FleuryH. and SegondyM.. 1999. Emergence of zidovudine and multidrug-resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus didanosine combination therapy. AIDS13:1705.
46.
CoakleyE.P.GillisJ.M. and HammerS.M.. 2000. Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine. AIDS14. F9.
47.
ColonnoR.J.WachtfogelY.T.HertogsK. and LarderB.A.. 2000. Frequency of stavudine and didanosine resistance among a large number of randomly selected HIV-1 isolates. Antiviral Ther. 5 (S 3):85.
48.
LarderB.A.WangD. and HarriganR.. 2001. Identification of a set of “nucleoside associated mutations” (NAMS) that are the common cause of nucleoside cross-resistance. Antiviral Ther. 6:S7.
49.
TisdaleM.AlnadafT. and CousensD.. 1997. Combination of mutations in Human Immunodeficiency Virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89. Antimicrob. Agents Chemother. 41:1094.
50.
LanierE.R.ScottJ.SteelH.HetheringtonS.Ait-KhaledM.PearceG.SpreenW. and LafonS.. 1999. Multivariate analysis of predictors of response to abacavir: comparison of prior antiretroviral therapy, baseline HIV RNA, CD4 count and viral resistance. Antiviral Ther. 4(S1):56.
51.
ShirasakaT.KavlickM.F.UenoT.GaoW.Y.KojimaE.AlcaideM.L.ChokekijchaiS.RoyB.M.ArnoldE. and YarchoanR.. 1995. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc. Natl. Acad. Sci. USA92:2398.
52.
MasA.PareraM.BrionesC.SorianoV.MartinezM.A.DomingoE. and Menendez-AriasL.. 2000. Role of dipeptide insertion between codons 69 and 70 of HIV-1 RT in the mechanism of AZT resistance. EMBO J. 19:5752.
53.
SrinivasR.V. and FridlandA.. 1998. Antiviral activities of 9-R-2-phosphonomethoxypropyl adenine (PMPA) and bis(isopropyloxymethylcarbonyl) PMPA against various drug-resistant human immunodeficiency virus strains. Antimicrob. Agents Chemother. 42:1484.
54.
BachelerL.T.AntonE.D.KudishP.BakerD.BunvilleJ.KrakowskiK.BollingL.AujayM.WangX.V.EllisD.BeckerM.F.LasutA.L.GeorgeH. J.SpaldingD.R.HollisG. and AbremskiK.. 2000. HIV type 1 selected in patients failing efavirenz combination therapy. Antimicrob. Agents Chemother. 44:2475.
55.
CasadoJ.L.HertogsK.RuizL.DrondaF.Van CauwenbergeA.ArnoA.Garcia-ArataI.BloorS.BonjochA.BlazquezJ.ClotetB. and LarderB.. 2000. Non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen. AIDS14:Fl.
56.
BrionesC.SorianoV.DonaC.BarreiroP. and Gonzalez-LahozJ.. 2000. Can early failure with nevirapine be rescued with efavirenz?J. Acquir. Immune Defic. Syndr.24:76.
57.
GianottiN.CastagnaA.VacchiniD.BoeriE.FinazziR.LazzarinA.. 2001. Switching from nevirapine to efavirenz in NVR-experienced patients without the reverse transcriptase 103N mutation. In: Program and abstracts of the 8th European Conference on Clinical Aspects and Treatment of HIV-Infection. Athens (Abstract), p. 59.
58.
ZaccarelliM.CingolaniA.ForbiciF.RizzoM.G.TrottaM.P.BertoliA.Di GianbenedettoS.D'ArrigoR.BaldiniF.LiuzziG.CiancioB.BellocchiM.C.MurriR.GirardiE.AmmassariA.IppolitoG.De LucaA.AntinoriA. and PernoC.F.. 2001. Cross-resistance among NNRTIs: evaluation of the opinion of recycling efavirenz after nevirapine failure. Antiviral Ther. 6(S):26.
59.
HavlirD.V.HellmannN.S.PetropoulosC.J.WhitcombJ.M.CollierA.C.HirschM.S.TebasP.SommadossiJ.P. and RichmanD.D.. 2000. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir containing regimens. JAMA283:229.
60.
BernsteinB.MoseleyJ.KempfD.KingM.GuK.BauerE. and SunE.. 2001. Absence of resistance to Kaletra (ABT-378/r) observed through 48 weeks of therapy in antiretroviral naïve subjects. In Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections. Chicago (Abstract No. 453).
61.
HertogsK.BloorS.KempS.D.Van den EyndeC.AlcornT.M.PauwelsR.Van HoutteM.StaszewskiS.MillerV. and LarderB.A.. 2000. Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of 6000 samples. AIDS14:1203.
62.
GianottiN.TambussiG.BoeriE. and LazzarinA.. 2001. Comparison of protease genotype and phenotype in HIV-1 infected patients exposed to more than one protease inhibitor. J. Biol. Regul. Homeost. Agents15:166.
63.
TebasP.PatickA.K.KaneE.M.KlebertM.K.SimpsonJ.H.EriceA.PowderlyW.G. and HenryK.. 1999Virologic responses to a ritonavir-saquinavir-containing regimen in patients who have previously failed nelfinavir. AIDS13:F23.
64.
AtkinsonB.IsaacsonJ.KnowlesM.MazabelE. and PatickA.K.. 2000. Correlation between HIV genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine. J. Infect. Dis.182:420.
65.
CondraJ.H.HolderD.J.SchleifW.A.BakshiKDanovichR.M.GrahamD.J.ShivaprakashM.HolmesK.SaahA. J.LeavittR.Y.ChodakewitzJ. A. and EminiE.A.. 1999. Genetic correlates of virological response to an indinavir-containing salvage regimen in patients with nelfinavir failure. Antiviral Ther. 4(S. 1):44.
66.
CondraJ.H.HolderD.J.SchleifW.A.BlahyO.M.DanovichR.M.GabryelskiL.J.GrahamD.J.LairdD.QuinteroJ.C.RhodesA.RobbinsH.L.RothE.ShivaprakashM.YangT.ChodakewitzJ.A.DeutschP.J.LeavittR.Y.MassariF.E.MellorsJ.W.SquiresK.E.SteigbigelR.T.TepplerH. and EminiE.A.. 1996. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J. Virol.70:8270.
67.
CondraJ.H.PetropoulosC.J.ZiermannR.SchleifW.A.ShivaprakashM. and EminiE.A.. 2000. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J. Infect. Dis.182:758.
68.
SnowdenW.ShortinoD.KleinA.HarrisW.ManohitharajahV.ElstonR.TisdaleM. and MaguireM.. 2000. Development of amprenavir resistance in NRTI-experienced patients: alternative mechanisms and correlation with baseline resistance to concomitant NRTIs. Antiviral Ther. 5 (S3):84.
69.
SchmidtB.KornK.MoschikB.PaatzC.UberlaK. and WalterH.. 2000. Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors. Antimicrob. Agents Chemother. 44:3213.
70.
Lo Caputo S., C. Torti, L. Tomasoni, P. Pierotti, L. Scudeller, G. Angarano, N. Gianotti, R. Maserati, G. Carosi, F. Mazzotta and the GENPHEREX Group - Italy. 2001. Phenotype class-resistance in a cohort of heavily pre-treated non-trial population of HIV-infected patients. Antiviral Ther. 6(S):22.
71.
MurphyR.GulickR.SmeatonL.D'AquilaR.EronJ.CurrierJ.SommadossiJ.P.TungR. and KurtizkesD.. 1998. Treatment with indinavir, nevirapine, stavudine and 3TC following therapy with an amprenavir-containing regimen. AIDS12 (S4):S9.
72.
CarrilloA.StewartK.D.ShamH.L.NorbeckD.W.KohlbrennerW.E.LeonardJ.M.KempfD.J. and MollaA.. 1998. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J. Virol.72:7532.
73.
LarderB.PeetersM.VerbiestW.HarriganR. and GrahamN.. 2001. The virtual phenotype is an independent predictor of clinical response. Antiviral Ther. 6(S):32.
74.
GazzardB.PozniakA.PeetersM.LarderB.HertogsK. and GrahamN.. 2001. Long-term impact of drug resistance testing on virologic response. Antiviral Ther. 6(S):14.
75.
HsuA.GrannemanG.R.KempfD.J.IsaacsonJ.KingM.BrunS.BernsteinB. and SunE.. 2000. The Ctrough inhibitory quotient predicts virologic response to ABT-378/ritonavirtherapy in treatment-experienced patients. AIDS14 (S4):S12.
76.
MillerV.SabinC.HertogsK.BloorS.Martinez-PicadoJ.D'AquilaR.LarderB.LutzT.GuteP.WeidmannE.RabenauH.PhillipsA. and StaszewskiS.. 2000. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS14:2857.
77.
IzopetJ.MassipP.SouyrisC.SandresK.PuissantB.ObadiaM.PasquierC.BonnetE.MarchouB. and PuelJ.. 2000. Shift in HIV-1 resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen. AIDS14:2247.
78.
DeeksS.G.WrinT.LieglerT.HohR.HaydenM.BarbourJ.D.HellmannN.S.PetropoulosC.J.McCuneJ.M.HellersteinM.K. and GrantR.M.. 2001. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N. Engl. J. Med.344:472.