Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects

Joel E. Gallant, Allan E Rodriguez, Winkler G. Weinberg, Benjamin Young, Daniel S. Berger, Michael L. Lim, Qiming Liao, Lisa Ross, Judy Johnson, Mark S. Shaefer

Research output: Contribution to journalArticle

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Abstract

Background. Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. Methods. This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log10 copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of ≥1.0 log10 copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. Results. We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log10 copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from ≥8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P < .001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. Conclusion. The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.

Original languageEnglish
Pages (from-to)1921-1930
Number of pages10
JournalJournal of Infectious Diseases
Volume192
Issue number11
DOIs
StatePublished - Dec 1 2005

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Tenofovir
efavirenz
HIV
HIV-1
RNA
CD4 Lymphocyte Count
Multicenter Studies
Genotype
lamivudine drug combination abacavir

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. / Gallant, Joel E.; Rodriguez, Allan E; Weinberg, Winkler G.; Young, Benjamin; Berger, Daniel S.; Lim, Michael L.; Liao, Qiming; Ross, Lisa; Johnson, Judy; Shaefer, Mark S.

In: Journal of Infectious Diseases, Vol. 192, No. 11, 01.12.2005, p. 1921-1930.

Research output: Contribution to journalArticle

Gallant, JE, Rodriguez, AE, Weinberg, WG, Young, B, Berger, DS, Lim, ML, Liao, Q, Ross, L, Johnson, J & Shaefer, MS 2005, 'Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects', Journal of Infectious Diseases, vol. 192, no. 11, pp. 1921-1930. https://doi.org/10.1086/498069
Gallant, Joel E. ; Rodriguez, Allan E ; Weinberg, Winkler G. ; Young, Benjamin ; Berger, Daniel S. ; Lim, Michael L. ; Liao, Qiming ; Ross, Lisa ; Johnson, Judy ; Shaefer, Mark S. / Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. In: Journal of Infectious Diseases. 2005 ; Vol. 192, No. 11. pp. 1921-1930.
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abstract = "Background. Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. Methods. This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log10 copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of ≥1.0 log10 copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. Results. We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log10 copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from ≥8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49{\%}) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5{\%}) of 92 of subjects in the efavirenz arm (P < .001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98{\%}) of 41 subjects and K65R and M184V or mixtures in 22 (54{\%}) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71{\%}) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. Conclusion. The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.",
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AU - Gallant, Joel E.

AU - Rodriguez, Allan E

AU - Weinberg, Winkler G.

AU - Young, Benjamin

AU - Berger, Daniel S.

AU - Lim, Michael L.

AU - Liao, Qiming

AU - Ross, Lisa

AU - Johnson, Judy

AU - Shaefer, Mark S.

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N2 - Background. Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. Methods. This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log10 copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of ≥1.0 log10 copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. Results. We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log10 copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from ≥8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P < .001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. Conclusion. The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.

AB - Background. Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. Methods. This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log10 copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of ≥1.0 log10 copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. Results. We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log10 copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from ≥8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P < .001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. Conclusion. The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.

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