A dose-ranging study to evaluate the safety and efficacy of abacavir alone or in combination with zidovudine and lamivudine in antiretroviral treatment-naive subjects

Staszewski, Schlomo; Katlama, Christine; Harrer, Thomas; Massip, Patrice; Yéni, Patrick; Cutrell, Amy; Tortell, Stephanie M.; Harrigan, Richard; Steel, Howard H.; Lanier, Randall; Pearce, Gillian

doi:10.1097/00002030-199816000-00001

Cited by 85 publications

(58 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As evidenced by the ITT switch-included analysis, the response rate for the 3TC/ZDV group was comparable to that of the of the ABC/3TC/ZDV group at week 48, indicating that an appropriate use of ABC in this population would be as an alternative nucleoside analog in salvage regimens. The potency of ABC, as demonstrated in other studies [31][32][33][34] and as indicated by the additional viral suppression achieved in the present study, suggest that ABC can be combined successfully with protease inhibitors and other antiretroviral agents in a salvage regimen.…”

Section: Discussionsupporting

confidence: 85%

“…The frequency of ABC-related hypersensitivity reaction in this study was 3%, consistent with the incidence reported in other studies. 31,33 Incidences of grades 3 and 4 hepatic, hematologic, pancreatic, and renal toxicities occurred infrequently among participants treated with ABC/3TC/ZDV and were no higher than incidences observed among participants treated with 3TC/ZDV. These tolerability/safety findings are in agreement with those reported previously in other clinical trials that have evaluated ABC/3TC/ZDV 31,33,34 or 3TC/ZDV.…”

Section: Discussionmentioning

confidence: 97%

“…30 In contrast, in antiretroviral naïve adults, ABC monotherapy resulted in median plasma HIV-1 RNA reductions of Ն1.5 log 10 copies/mL 31 and combination antiretroviral therapy with ABC reduced plasma HIV-1 RNA levels by up to 2.8 log 10 copies/mL. [32][33][34] Because improvement in immune response is associated with better clinical prognosis and a lower risk of disease progression, 26 further study is needed to determine whether the observed immune response can be maintained long-term.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A Randomized, Double-Blind Study of Triple Nucleoside Therapy of Abacavir, Lamivudine, and Zidovudine Versus Lamivudine and Zidovudine in Previously Treated Human Immunodeficiency Virus Type 1-Infected Children

et al. 2001

Self Cite

View full text Add to dashboard Cite

ABSTRACT. Objectives. Abacavir (ABC) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We compared the efficacy, safety, and tolerability of combination therapy with ABC, lamivudine (3TC), and zidovudine (ZDV) versus 3TC and ZDV in antiretroviral experienced HIV-1-infected children over 48 weeks.Methods. Two hundred five HIV-1-infected children who had received previous antiretroviral therapy and had CD4 ؉ cell counts >100 cells/mm 3 were stratified by age and by previous treatment. Participants were randomly assigned to receive ABC (8 mg/kg twice daily [BID]) plus 3TC (4 mg/kg BID) and ZDV (180 mg/m 2 BID; ABC/3TC/ZDV group) or ABC placebo plus 3TC (4 mg/kg BID) and ZDV (180 mg/m 2 ; 3TC/ZDV group). Participants who met a protocol-defined switch criteria (plasma HIV-1 RNA >0.5 log 10 copies/mL above baseline at week 8 or >10 000 copies/mL after week 16) had the option to switch to open-label ABC plus any antiretroviral combination or continue randomized therapy or withdraw from the study.Results. The Kaplan-Meier estimates (95% confidence interval) of the proportion of participants who maintained HIV-1 RNA levels <10 000 copies/mL for 48 weeks or more was significantly better in the ABC/3TC/ ZDV group compared with the 3TC/ZDV group: 33% (23%-42%) versus 21% (13%-29%). At week 48, the proportions of participants with HIV-1 RNA <10 000 copies/mL were 36% versus 26% for the ABC/3TC/ZDV and 3TC/ZDV groups, respectively, by intent-to-treat analysis. For the subgroup of participants with baseline HIV-1 RNA >10 000 copies/mL, a significantly higher proportion of participants in the ABC/3TC/ZDV group had HIV-1 RNA <10 000 copies/mL compared with the 3TC/ ZDV group (29% vs 12%) but no difference was observed in the subgroup of participants with baseline HIV-1 RNA <10 000 copies/mL (78% vs 72%). The median changes from baseline in CD4 ؉ cell counts were greater in the ABC/3TC/ZDV group than in the 3TC/ZDV group. Few participants (3%) experienced abacavir-related hypersensitivity reaction.Conclusions. ABC, in combination with 3TC and ZDV, provides additional antiretroviral activity over 48 weeks, compared with combination therapy with 3TC and ZDV in antiretroviral experienced HIV-1-infected children. ABC was safe and generally well-tolerated and should be considered an active component of combination antiretroviral therapy in this pediatric population. ABBREVIATIONS. HIV-1, human immunodeficiency virus type 1; RT, reverse transcriptase; ZDV, zidovudine; ddI, didanosine; 3TC, lamivudine; ABC, abacavir; BID, twice daily; ITT, intent-to-treat; AAUCMB, average area under the curve minus baseline; NAUC, normalized area under the curve; NRTI, nucleoside reverse transcriptase inhibitors.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Randomized, Double-Blind Study of Triple Nucleoside Therapy of Abacavir, Lamivudine, and Zidovudine Versus Lamivudine and Zidovudine in Previously Treated Human Immunodeficiency Virus Type 1-Infected Children

et al. 2001

Self Cite

View full text Add to dashboard Cite

show abstract

“…ABC is phosphorylated by a novel enzymatic pathway (15) which might contribute to its activity in resting cells. In the initial clinical trials, ABC appeared more potent than other nucleoside analogs (33,40), and subsequent clinical experience corroborates the earlier data (22,25,28). Whether this in vivo activity is related to its activity in resting (or latently infected) cells is an intriguing possibility which will require additional studies.…”

Section: Discussionsupporting

confidence: 65%

Zidovudine, Lamivudine, and Abacavir Have Different Effects on Resting Cells Infected with Human Immunodeficiency Virus In Vitro

Saavedra-Lozano¹,

McCoig²,

Cao³

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

“…Abacavir is at least as potent as the other NRTIs, has good oral bioavailability, and effectively penetrates into the central nervous system (1,5). Furthermore, abacavir has been shown to be synergistic in combination with various antiretroviral drugs (11,22). The combination with other NRTIs offers the opportunity of sparing other classes of antiretroviral drugs for subsequent use.…”

mentioning

confidence: 99%

Prediction of Abacavir Resistance from Genotypic Data: Impact of Zidovudine and Lamivudine Resistance In Vitro and In Vivo

Walter

Schmidt

Werwein

et al. 2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Abacavir is frequently used in antiretroviral combination therapies as a potent nucleoside reverse transcriptase inhibitor (NRTI). Four mutations are selected for by abacavir in vitro and in vivo: K65R, L74V, Y115F, and M184V. Abacavir resistance has also been observed in NRTI multidrug-resistant samples. Furthermore, abacavir resistance has been described in the context of zidovudine resistance. To evaluate the genetic basis of abacavir resistance, the viral genotype and phenotypic resistance were analyzed for 307 patient samples. Lowand high-level resistances were defined as 2.5-to 5.5-fold-and >5.5-fold-reduced susceptibility, respectively. If all samples with abacavir-selected and NRTI multidrug resistance-associated mutations were scored as resistant, 27.6% of the samples were misclassified, mainly due to samples falsely scored as susceptible. Therefore, the relative frequencies of other mutations were evaluated. Mutations at codons 44 and 118 were rarely detected in abacavir-susceptible samples but were overrepresented in resistant samples. Site-directed mutagenesis of E44D, V118I, and M184V resulted in low-level resistance for the double mutant 44/184 and the triple mutant. Low-level abacavir resistance was also detected for a viral clone carrying zidovudine mutations only. Additional insertion of M184V into the zidovudine background doubled the resistance, whereas 44/118 did not lead to a further increase. Incorporating combinations of zidovudine mutations and M184V into the scoring system markedly reduced the number of misclassified samples, whereas 44/118 did not improve the prediction. In conclusion, the combination of M184V with zidovudine mutations gives rise to high-level abacavir resistance, which may be clinically relevant. Thus, options for useful sequential combinations of NRTI are limited.

show abstract

A dose-ranging study to evaluate the safety and efficacy of abacavir alone or in combination with zidovudine and lamivudine in antiretroviral treatment-naive subjects

Cited by 85 publications

References 6 publications

A Randomized, Double-Blind Study of Triple Nucleoside Therapy of Abacavir, Lamivudine, and Zidovudine Versus Lamivudine and Zidovudine in Previously Treated Human Immunodeficiency Virus Type 1-Infected Children

A Randomized, Double-Blind Study of Triple Nucleoside Therapy of Abacavir, Lamivudine, and Zidovudine Versus Lamivudine and Zidovudine in Previously Treated Human Immunodeficiency Virus Type 1-Infected Children

Zidovudine, Lamivudine, and Abacavir Have Different Effects on Resting Cells Infected with Human Immunodeficiency Virus In Vitro

Prediction of Abacavir Resistance from Genotypic Data: Impact of Zidovudine and Lamivudine Resistance In Vitro and In Vivo

Contact Info

Product

Resources

About