HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

Barbara Weiser, Sean Philpott, Thomas Klimkait, Harold Burger, Christina Kitchen, Philippe Bürgisser, Meri Gorgievski, Luc Perrin, Jean Claude Piffaretti, Bruno Ledergerber, C. Aebi, M. Battegay, E. Bernasconi, J. Böni, H. Bucher, Ph Bürgisser, A. Calmy, S. Cattacin, M. Cavassini, J. CheseauxR. Dubs, M. Egger, L. Elzi, P. Erb, M. Fischer, M. Flepp, A. Fontana, P. Francioli, H. Furrer, A. Gayet-Ageron, S. Gerber, M. Gorgievski, C. Grawe, H. Günthard, T. Gyr, H. Hirsch, B. Hirschel, I. Hösli, Ch Kahlert, L. Kaiser, U. Karrer, O. Keiser, C. Kind, Th Klimkait, B. Ledergerber, G. Martinetti, B. Martinez De Tejada, N. Müller, D. Nadal, M. Opravil, F. Paccaud, G. Pantaleo, L. Perrin, S. Regenass, M. Rickenbach, C. Rudin, P. Schmid, D. Schultze, J. Schüpbach, R. Speck, P. Taffé, P. Tarr, A. Telenti, A. Trkola, Y. Vallet, P. Vernazza, A. Wechsler, R. Weber, D. Wunder, C. Wyler, S. Yerly

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/μl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

Original languageEnglish (US)
Pages (from-to)469-479
Number of pages11
JournalAIDS
Volume22
Issue number4
DOIs
StatePublished - Feb 2008
Externally publishedYes

Fingerprint

Viral Load
Disease Progression
HIV-1
Confidence Intervals
CD4 Lymphocyte Count
Acquired Immunodeficiency Syndrome
Therapeutics
Selection Bias
Proportional Hazards Models
Cohort Studies
Biomarkers
HIV
Weights and Measures
Mortality

Keywords

  • AIDS
  • Antiretroviral therapy
  • CCR5
  • CXCR4
  • Heteroduplex tracking assay
  • HIV-1 tropism

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy. / Weiser, Barbara; Philpott, Sean; Klimkait, Thomas; Burger, Harold; Kitchen, Christina; Bürgisser, Philippe; Gorgievski, Meri; Perrin, Luc; Piffaretti, Jean Claude; Ledergerber, Bruno; Aebi, C.; Battegay, M.; Bernasconi, E.; Böni, J.; Bucher, H.; Bürgisser, Ph; Calmy, A.; Cattacin, S.; Cavassini, M.; Cheseaux, J.; Dubs, R.; Egger, M.; Elzi, L.; Erb, P.; Fischer, M.; Flepp, M.; Fontana, A.; Francioli, P.; Furrer, H.; Gayet-Ageron, A.; Gerber, S.; Gorgievski, M.; Grawe, C.; Günthard, H.; Gyr, T.; Hirsch, H.; Hirschel, B.; Hösli, I.; Kahlert, Ch; Kaiser, L.; Karrer, U.; Keiser, O.; Kind, C.; Klimkait, Th; Ledergerber, B.; Martinetti, G.; Martinez De Tejada, B.; Müller, N.; Nadal, D.; Opravil, M.; Paccaud, F.; Pantaleo, G.; Perrin, L.; Regenass, S.; Rickenbach, M.; Rudin, C.; Schmid, P.; Schultze, D.; Schüpbach, J.; Speck, R.; Taffé, P.; Tarr, P.; Telenti, A.; Trkola, A.; Vallet, Y.; Vernazza, P.; Wechsler, A.; Weber, R.; Wunder, D.; Wyler, C.; Yerly, S.

In: AIDS, Vol. 22, No. 4, 02.2008, p. 469-479.

Research output: Contribution to journalArticle

Weiser, B, Philpott, S, Klimkait, T, Burger, H, Kitchen, C, Bürgisser, P, Gorgievski, M, Perrin, L, Piffaretti, JC, Ledergerber, B, Aebi, C, Battegay, M, Bernasconi, E, Böni, J, Bucher, H, Bürgisser, P, Calmy, A, Cattacin, S, Cavassini, M, Cheseaux, J, Dubs, R, Egger, M, Elzi, L, Erb, P, Fischer, M, Flepp, M, Fontana, A, Francioli, P, Furrer, H, Gayet-Ageron, A, Gerber, S, Gorgievski, M, Grawe, C, Günthard, H, Gyr, T, Hirsch, H, Hirschel, B, Hösli, I, Kahlert, C, Kaiser, L, Karrer, U, Keiser, O, Kind, C, Klimkait, T, Ledergerber, B, Martinetti, G, Martinez De Tejada, B, Müller, N, Nadal, D, Opravil, M, Paccaud, F, Pantaleo, G, Perrin, L, Regenass, S, Rickenbach, M, Rudin, C, Schmid, P, Schultze, D, Schüpbach, J, Speck, R, Taffé, P, Tarr, P, Telenti, A, Trkola, A, Vallet, Y, Vernazza, P, Wechsler, A, Weber, R, Wunder, D, Wyler, C & Yerly, S 2008, 'HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy', AIDS, vol. 22, no. 4, pp. 469-479. https://doi.org/10.1097/QAD.0b013e3282f4196c
Weiser, Barbara ; Philpott, Sean ; Klimkait, Thomas ; Burger, Harold ; Kitchen, Christina ; Bürgisser, Philippe ; Gorgievski, Meri ; Perrin, Luc ; Piffaretti, Jean Claude ; Ledergerber, Bruno ; Aebi, C. ; Battegay, M. ; Bernasconi, E. ; Böni, J. ; Bucher, H. ; Bürgisser, Ph ; Calmy, A. ; Cattacin, S. ; Cavassini, M. ; Cheseaux, J. ; Dubs, R. ; Egger, M. ; Elzi, L. ; Erb, P. ; Fischer, M. ; Flepp, M. ; Fontana, A. ; Francioli, P. ; Furrer, H. ; Gayet-Ageron, A. ; Gerber, S. ; Gorgievski, M. ; Grawe, C. ; Günthard, H. ; Gyr, T. ; Hirsch, H. ; Hirschel, B. ; Hösli, I. ; Kahlert, Ch ; Kaiser, L. ; Karrer, U. ; Keiser, O. ; Kind, C. ; Klimkait, Th ; Ledergerber, B. ; Martinetti, G. ; Martinez De Tejada, B. ; Müller, N. ; Nadal, D. ; Opravil, M. ; Paccaud, F. ; Pantaleo, G. ; Perrin, L. ; Regenass, S. ; Rickenbach, M. ; Rudin, C. ; Schmid, P. ; Schultze, D. ; Schüpbach, J. ; Speck, R. ; Taffé, P. ; Tarr, P. ; Telenti, A. ; Trkola, A. ; Vallet, Y. ; Vernazza, P. ; Wechsler, A. ; Weber, R. ; Wunder, D. ; Wyler, C. ; Yerly, S. / HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy. In: AIDS. 2008 ; Vol. 22, No. 4. pp. 469-479.
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abstract = "BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/μl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95{\%} confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95{\%} CI, 1.2-11.3) and 5.9 (95{\%} CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.",
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author = "Barbara Weiser and Sean Philpott and Thomas Klimkait and Harold Burger and Christina Kitchen and Philippe B{\"u}rgisser and Meri Gorgievski and Luc Perrin and Piffaretti, {Jean Claude} and Bruno Ledergerber and C. Aebi and M. Battegay and E. Bernasconi and J. B{\"o}ni and H. Bucher and Ph B{\"u}rgisser and A. Calmy and S. Cattacin and M. Cavassini and J. Cheseaux and R. Dubs and M. Egger and L. Elzi and P. Erb and M. Fischer and M. Flepp and A. Fontana and P. Francioli and H. Furrer and A. Gayet-Ageron and S. Gerber and M. Gorgievski and C. Grawe and H. G{\"u}nthard and T. Gyr and H. Hirsch and B. Hirschel and I. H{\"o}sli and Ch Kahlert and L. Kaiser and U. Karrer and O. Keiser and C. Kind and Th Klimkait and B. Ledergerber and G. Martinetti and {Martinez De Tejada}, B. and N. M{\"u}ller and D. Nadal and M. Opravil and F. Paccaud and G. Pantaleo and L. Perrin and S. Regenass and M. Rickenbach and C. Rudin and P. Schmid and D. Schultze and J. Sch{\"u}pbach and R. Speck and P. Taff{\'e} and P. Tarr and A. Telenti and A. Trkola and Y. Vallet and P. Vernazza and A. Wechsler and R. Weber and D. Wunder and C. Wyler and S. Yerly",
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TY - JOUR

T1 - HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

AU - Weiser, Barbara

AU - Philpott, Sean

AU - Klimkait, Thomas

AU - Burger, Harold

AU - Kitchen, Christina

AU - Bürgisser, Philippe

AU - Gorgievski, Meri

AU - Perrin, Luc

AU - Piffaretti, Jean Claude

AU - Ledergerber, Bruno

AU - Aebi, C.

AU - Battegay, M.

AU - Bernasconi, E.

AU - Böni, J.

AU - Bucher, H.

AU - Bürgisser, Ph

AU - Calmy, A.

AU - Cattacin, S.

AU - Cavassini, M.

AU - Cheseaux, J.

AU - Dubs, R.

AU - Egger, M.

AU - Elzi, L.

AU - Erb, P.

AU - Fischer, M.

AU - Flepp, M.

AU - Fontana, A.

AU - Francioli, P.

AU - Furrer, H.

AU - Gayet-Ageron, A.

AU - Gerber, S.

AU - Gorgievski, M.

AU - Grawe, C.

AU - Günthard, H.

AU - Gyr, T.

AU - Hirsch, H.

AU - Hirschel, B.

AU - Hösli, I.

AU - Kahlert, Ch

AU - Kaiser, L.

AU - Karrer, U.

AU - Keiser, O.

AU - Kind, C.

AU - Klimkait, Th

AU - Ledergerber, B.

AU - Martinetti, G.

AU - Martinez De Tejada, B.

AU - Müller, N.

AU - Nadal, D.

AU - Opravil, M.

AU - Paccaud, F.

AU - Pantaleo, G.

AU - Perrin, L.

AU - Regenass, S.

AU - Rickenbach, M.

AU - Rudin, C.

AU - Schmid, P.

AU - Schultze, D.

AU - Schüpbach, J.

AU - Speck, R.

AU - Taffé, P.

AU - Tarr, P.

AU - Telenti, A.

AU - Trkola, A.

AU - Vallet, Y.

AU - Vernazza, P.

AU - Wechsler, A.

AU - Weber, R.

AU - Wunder, D.

AU - Wyler, C.

AU - Yerly, S.

PY - 2008/2

Y1 - 2008/2

N2 - BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/μl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

AB - BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/μl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

KW - AIDS

KW - Antiretroviral therapy

KW - CCR5

KW - CXCR4

KW - Heteroduplex tracking assay

KW - HIV-1 tropism

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