Managing Failure to Antiretroviral Drugs in HIV-1-Infected Patients

Abstract

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.

Keywords

HIV antiretroviral drugs drug failure drug resistance pharmacokinetic

References

Mellors

J.W.

Munoz

Giorgi

J. V.

Margolick

J.B.

Tassoni

C.J.

Gupta

Kingsley

L.A.

Todd

J.A.

Saah

A. J.

Detels

Phair

J.P.

and Rinaldo

C.R.

Jr . 1997. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann. Intern. Med. 126:946.

Pallela

F.J.

Delaney

K.M.

Moorman

A.C.

Loveless

M.O.

Fuhrer

Satten

G.A.

Aschman

D.J.

and Holmberg

S.D.

. 1998. Declining morbidity and mortality among patients with advanced immunodeficiency virus infection. N. Engl. J. Med. 338:853.

Powderly

W.G.

Saag

M.S.

Chapman

Quart

and Clendeninn

N.J.

. 1999. Predictors of virological response to potent antiretroviral therapy. AIDS 13:1873.

Deeks

Hecth

F. M.

Swanson

Elbeik

Loftus

Cohen

P.T.

and Grant

R.M.

. 1999. HIV-RNA and CD4 cell count response to PI therapy in an urban AIDS clinic: response to both initial and salvage therapy. AIDS 13:F35.

Lucas

G.M.

Chaisson

R.E.

and Moore

R.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.

Kaufmann

Pantaleo

Sudre

and Talenti

. 1998. CD4-cell count in HIV-1 infected individuals remaining viremic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study. Lancet 351:723.

Piketty

Castiel

Belec

Batisse

Si Mohamed

Gilquin

Gonzalez-Canali

Jayle

Karmochkine

Weiss

Aboulker

J.P.

and Kazatchkine

M.D.

. 1998. Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease. AIDS 12:745.

Strack

P.R.

Frey

M.W.

Rizzo

C.J.

Cordova

George

H.J.

Meade

S.P.

Corman

Tritch

and Korant

B.D.

. 1996. Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. Proc. Natl. Acad. Sci. USA 93:9571.

Sloand

E.M.

Kumar

P.N.

Kim

Chaudhuri

Weichold

F.F.

and Young

N.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. Blood 94:1021.

10.

Deeks

S.G.

Wrin

Duecy

Barbour

J.D.

Hellmann

Petropoulos

and Grant

R.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 7^th Conference on Retroviruses and Opportunistic Infections. San Francisco (Abstract No. 156).

11.

Martinez-Picado

Savara

Sutton

and D'Aquila

. 1999. Replicative fitness of protease inhibitor-resistant mutants of HIV-1. J. Virol. 73:3744.

12.

Stoddart

Mammano

Moreno

Linquist-Stepps

Bare

Clavel

and McCune

J. M.

. 1999. Lack of fitness of protease inhibitor-resistant HIV-1 in vivo. In Program and abstracts of the 6^th Conference on Retroviruses and Opportunistic Infections. Chicago (Abstract No. 4).

13.

Faye

Race

Obry

Prevot

M. H.

Joly

Matheron

Damond

Dam

Paulous

and Clavel

. 1999. Viral fitness in patients with discordant CD4 and plasma HIV-RNA evolution following protease inhibitor failure. In Program and abstracts of the 6^th Conference on Retroviruses and Opportunistic Infections. Chicago (Abstract No. 331).

14.

Ledergerber

Egger

Opravil

Telenti

Hirschel

Battegay

Vernazza

Sudre

Flepp

Furrer

Francioli

and Weber

. 1999. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet 353:863.

15.

Grabar

Le Moing

Goujard

Leport

Kazatchkine

M.D.

Costagliola

and Weiss

. 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.

Bahrani

Ramaswamy

and Oldfield

E.C.

. 2001. Effects of virologic rebound on CD4 cell counts. Clin. Infect. Dis. 32:1231.

17.

Piketty

Weiss

Thomas

Mohamed

A.S.

Belec

and Kazatchkine

M.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.

Hirsch

M.S.

Conway

D'Aquila

R.T.

Johnson

V.A.

Brun-Vezinet

Clotet

Demeter

L.M.

Hammer

S.M.

Jacobsen

D.M.

Kuritzkes

D.R.

Loveday

Mellors

J.W.

Vella

and Richman

D.D.

. 1998. Consensus statement. Antiviral drug resistance testing in adults with HIV infection. Implication for clinical management. JAMA 279:1984.

19.

Para

M.F.

Glidden

D.V.

Coombs

R.W.

Collier

A.C.

Condra

J.H.

Craig

Bassett

Leavitt

Snyder

McAuliffe

and Boucher

. 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.

Durant

Clevenbergh

Halfon

Porsin

Simonet

Montagne

Boucher

C.A.

Schapiro

J.M.

and Dellamonica

. 1999. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet 353:2195.

21.

Baxter

J.D.

Mayers

D.L.

Wentworth

D.N.

Neaton

J.D.

Hoover

M.L.

Winters

M.A.

Mannheimer

S.B.

Thompson

M.A.

Abrams

D.I.

Brizz

B.J.

Ioannidis

J.P.

and Merigan

T.C.

. 2000. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. AIDS 14:F83.

22.

Cohen

Hunt

Sension

Farthing

Conant

Jacobson

Nadler

Verbiest

Hertogs

Ames

Rinehart

and Graham

. 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.

Tural

Ruiz

Holtzer

Viciana

Gonzalez

Ferrer

Martinez-Picado

Ruiz

Dalmau

Domingo

Been

Boucher

C.A.B.

Schapiro

Romeu

Sirera

and Clotet

. 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 40^th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto (Abstract No. L-10).

24.

Descamps

Flandre

Calvez

Peytavin

Meiffredy

Collin

Delaugerre

Robert-Delmas

Bazin

Aboulker

J.P.

Pialoux

Raffi

and Brun-Vezinet

. 2000. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial on induction-maintenance therapy. JAMA 283:205.

25.

Hirsch

M.S.

Brun-Vézinet

D'Aquila

R.T.

Hammer

S.M.

Johnson

V.A.

Kuritzkes

D.R.

Loveday

Mellors

J.W.

Clotet

Conway

Demeter

L.M.

Vella

Jacobsen

D.M.

and Richman

D.D.

. 2000. Antiretroviral drug resistance testing in adult HIV-1 infection. Recommendations of an International AIDS Society-USA Panel. JAMA 283:2417.

26.

D'Aquila

R.T.

Johnson

V.A.

Welles

S.L.

Japour

A.J.

Kuritzkes

D.R.

DeGruttola

Reichelderfer

P.S.

Coombs

R.W.

Crumpacker

C.S.

and Kahn

J.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.

Japour

A. J.

Welles

D'Aquila

R.T.

Johnson

V.A.

Richman

D.D.

Coombs

R.W.

Reichelderfer

P.S.

Kahn

J.O.

Crumpacker

C.S.

and Kuritzkes

D.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.

Schuurman

Nijhuis

van Leeuwen

Schipper

de Jong

Collis

Danner

S.A.

Mulder

Loveday

and Christopherson

. 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.

Wainberg

M.A.

Drosopoulos

W.C.

Salomon

Hsu

Borkow

Parniak

Song

Manne

Islam

Castriota

and Prasad

V.R.

. 1996. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 271:1282.

30.

Nijhuis

Schuurman

de Jong

Erickson

Gustchina

Albert

Schipper

Gulnik

and Boucher

C.A.

. 1999. Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS 13:2349.

31.

Schmitt

Harrer

and Goldwich

. 2000. Specific recognition of lamivudine-resistant HIV-1 by cytotoxic T lymphocytes. AIDS 14:653.

32.

Samri

Haas

Duntze

Bouley

J.M.

Calvez

Katlama

and Autran

. 2000. Immunogenicity of mutations induced by nucleoside reverse transcriptase inhibitors for Human Immunodeficiency Virus Type 1-specific cytotoxic T cells. J. Virol. 74:9306.

33.

Decks

2001. Nonnucleoside reverse transcriptase inhibitor resistance. J. Aquir. Immune Defic. Syndr. 26(S1):S25.

34.

Huang

Gamarnik

Wrin

Parkin

N.T.

Hellmann

N.S.

Deeks

S.G.

Liegler

Grant

R.M.

Petropoulos

C.J.

and Whitcomb

J.M.

. 2000. HIV-1 isolates that exibit dose-dependent NNRTI stimulation of reverse transcriptase activity and viral replication. Antiviral Ther. 5(S3):23.

35.

Larder

B.A.

Kemp

S.D.

and Harrigan

P.R.

. 1995. Potential mechanisms for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269:696.

36.

Ziermann

Limoli

Das

Arnold

Petropoulos

C.J.

and Parkin

N.T.

. 2000. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. J. Virol. 74:4414.

37.

Larder

B.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.

Whitcomb

Deeks

Huang

Wrin

Paxinos

Limoli

Hoh

Hellmann

and Petropoulos

. 2000. Reduced susceptibility to NRTIs is associated with NNRTI hypersensitivity in virus from HIV-1-infected patients. In Program and abstracts of the 7^th Conference on Retroviruses and Opportunistic Infections. San Francisco (Abstract No. 234).

39.

Deeks

Hellmann

N.S.

and Grant

R.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.

Clumeck

Brun

Sylte

Isaacson

Chen

Lazzarin

Girard

P. M.

Rockstroh

Becker

Telenti

Bergmann

Danner

Tubiana

Carosi

Bertz

Hsu

King

Kempf

, and Sun

. 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 8^th Conference on Retroviruses and Opportunistic Infections Chicago (Abstract No. 525).

41.

Deeks

S.G.

Grant

R.M.

Beatty

G.W.

Horton

Detmer

and Eastman

. 1998. Activity of ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure. AIDS I2:F97.

42.

Soriano

2001. Sequencing antiretroviral drugs. AIDS 15:547.

43.

Larder

B.A.

Kellam

and Kemp

S.D.

. 1991. Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes. AIDS 5:137.

44.

Gianotti

Setti

Manconi

P.E.

Leoncini

Chiodo

Minoli

Moroni

Angarano

Mazzotta

Carosi

Antonelli

and Lazzarin

. 2002. Reverse transcriptase mutations in HIV-1 infected patients treated with two nucleoside analogues: the SMART study. Int. J. Immunopathol. Pharmacol. 15:129.

45.

Pellegrin

Izopet

Reynes

Denayrolles

Montes

Pellegrin

J.L.

Massip

Puel

Fleury

and Segondy

. 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. AIDS 13:1705.

46.

Coakley

E.P.

Gillis

J.M.

and Hammer

S.M.

. 2000. Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine. AIDS 14. F9.

47.

Colonno

R.J.

Wachtfogel

Y.T.

Hertogs

and Larder

B.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.

Larder

B.A.

Wang

and Harrigan

. 2001. Identification of a set of “nucleoside associated mutations” (NAMS) that are the common cause of nucleoside cross-resistance. Antiviral Ther. 6:S7.

49.

Tisdale

Alnadaf

and Cousens

. 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.

Lanier

E.R.

Scott

Steel

Hetherington

Ait-Khaled

Pearce

Spreen

and Lafon

. 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.

Shirasaka

Kavlick

M.F.

Ueno

Gao

W.Y.

Kojima

Alcaide

M.L.

Chokekijchai

Roy

B.M.

Arnold

and Yarchoan

. 1995. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc. Natl. Acad. Sci. USA 92:2398.

52.

Mas

Parera

Briones

Soriano

Martinez

M.A.

Domingo

and Menendez-Arias

. 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.

Srinivas

R.V.

and Fridland

. 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.

Bacheler

L.T.

Anton

E.D.

Kudish

Baker

Bunville

Krakowski

Bolling

Aujay

Wang

X.V.

Ellis

Becker

M.F.

Lasut

A.L.

George

H. J.

Spalding

D.R.

Hollis

and Abremski

. 2000. HIV type 1 selected in patients failing efavirenz combination therapy. Antimicrob. Agents Chemother. 44:2475.

55.

Casado

J.L.

Hertogs

Ruiz

Dronda

Van Cauwenberge

Arno

Garcia-Arata

Bloor

Bonjoch

Blazquez

Clotet

and Larder

. 2000. Non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen. AIDS 14:Fl.

56.

Briones

Soriano

Dona

Barreiro

and Gonzalez-Lahoz

. 2000. Can early failure with nevirapine be rescued with efavirenz? J. Acquir. Immune Defic. Syndr. 24:76.

57.

Gianotti

Castagna

Vacchini

Boeri

Finazzi

Lazzarin

. 2001. Switching from nevirapine to efavirenz in NVR-experienced patients without the reverse transcriptase 103N mutation. In: Program and abstracts of the 8^th European Conference on Clinical Aspects and Treatment of HIV-Infection. Athens (Abstract), p. 59.

58.

Zaccarelli

Cingolani

Forbici

Rizzo

M.G.

Trotta

M.P.

Bertoli

Di Gianbenedetto

D'Arrigo

Baldini

Liuzzi

Ciancio

Bellocchi

M.C.

Murri

Girardi

Ammassari

Ippolito

De Luca

Antinori

and Perno

C.F.

. 2001. Cross-resistance among NNRTIs: evaluation of the opinion of recycling efavirenz after nevirapine failure. Antiviral Ther. 6(S):26.

59.

Havlir

D.V.

Hellmann

N.S.

Petropoulos

C.J.

Whitcomb

J.M.

Collier

A.C.

Hirsch

M.S.

Tebas

Sommadossi

J.P.

and Richman

D.D.

. 2000. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir containing regimens. JAMA 283:229.

60.

Bernstein

Moseley

Kempf

King

Bauer

and Sun

. 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 8^th Conference on Retroviruses and Opportunistic Infections. Chicago (Abstract No. 453).

61.

Hertogs

Bloor

Kemp

S.D.

Van den Eynde

Alcorn

T.M.

Pauwels

Van Houtte

Staszewski

Miller

and Larder

B.A.

. 2000. Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of 6000 samples. AIDS 14:1203.

62.

Gianotti

Tambussi

Boeri

and Lazzarin

. 2001. Comparison of protease genotype and phenotype in HIV-1 infected patients exposed to more than one protease inhibitor. J. Biol. Regul. Homeost. Agents 15:166.

63.

Tebas

Patick

A.K.

Kane

E.M.

Klebert

M.K.

Simpson

J.H.

Erice

Powderly

W.G.

and Henry

. 1999 Virologic responses to a ritonavir-saquinavir-containing regimen in patients who have previously failed nelfinavir. AIDS 13:F23.

64.

Atkinson

Isaacson

Knowles

Mazabel

and Patick

A.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.

Condra

J.H.

Holder

D.J.

Schleif

W.A.

Bakshi

Danovich

R.M.

Graham

D.J.

Shivaprakash

Holmes

Saah

A. J.

Leavitt

R.Y.

Chodakewitz

J. A.

and Emini

E.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.

Condra

J.H.

Holder

D.J.

Schleif

W.A.

Blahy

O.M.

Danovich

R.M.

Gabryelski

L.J.

Graham

D.J.

Laird

Quintero

J.C.

Rhodes

Robbins

H.L.

Roth

Shivaprakash

Yang

Chodakewitz

J.A.

Deutsch

P.J.

Leavitt

R.Y.

Massari

F.E.

Mellors

J.W.

Squires

K.E.

Steigbigel

R.T.

Teppler

and Emini

E.A.

. 1996. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J. Virol. 70:8270.

67.

Condra

J.H.

Petropoulos

C.J.

Ziermann

Schleif

W.A.

Shivaprakash

and Emini

E.A.

. 2000. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J. Infect. Dis. 182:758.

68.

Snowden

Shortino

Klein

Harris

Manohitharajah

Elston

Tisdale

and Maguire

. 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.

Schmidt

Korn

Moschik

Paatz

Uberla

and Walter

. 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.

Murphy

Gulick

Smeaton

D'Aquila

Eron

Currier

Sommadossi

J.P.

Tung

and Kurtizkes

. 1998. Treatment with indinavir, nevirapine, stavudine and 3TC following therapy with an amprenavir-containing regimen. AIDS 12 (S4):S9.

72.

Carrillo

Stewart

K.D.

Sham

H.L.

Norbeck

D.W.

Kohlbrenner

W.E.

Leonard

J.M.

Kempf

D.J.

and Molla

. 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.

Larder

Peeters

Verbiest

Harrigan

and Graham

. 2001. The virtual phenotype is an independent predictor of clinical response. Antiviral Ther. 6(S):32.

74.

Gazzard

Pozniak

Peeters

Larder

Hertogs

and Graham

. 2001. Long-term impact of drug resistance testing on virologic response. Antiviral Ther. 6(S):14.

75.

Hsu

Granneman

G.R.

Kempf

D.J.

Isaacson

King

Brun

Bernstein

and Sun

. 2000. The C_trough inhibitory quotient predicts virologic response to ABT-378/ritonavirtherapy in treatment-experienced patients. AIDS 14 (S4):S12.

76.

Miller

Sabin

Hertogs

Bloor

Martinez-Picado

D'Aquila

Larder

Lutz

Gute

Weidmann

Rabenau

Phillips

and Staszewski

. 2000. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS 14:2857.

77.

Izopet

Massip

Souyris

Sandres

Puissant

Obadia

Pasquier

Bonnet

Marchou

and Puel

. 2000. Shift in HIV-1 resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen. AIDS 14:2247.

78.

Deeks

S.G.

Wrin

Liegler

Hoh

Hayden

Barbour

J.D.

Hellmann

N.S.

Petropoulos

C.J.

McCune

J.M.

Hellerstein

M.K.

and Grant

R.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.