Twice-Daily Trizivir Versus Combivir-Abacavir
Twice-Daily Trizivir Versus Combivir-Abacavir
Study Objective: To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg-lamivudine 150 mg-zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300-mg tablet, administered twice/day, in antiretroviral-experienced, human immunodeficiency virus (HIV)-1-infected patients.
Design: Randomized, open-label, parallel-group, multicenter, formulation-switch study.
Setting: Twenty seven outpatient treatment sites.
Patients: Adults with HIV-1 RNA levels of 400 copies/ml or less and CD4 cell counts above 200 cells/mm who had been treated for 16 weeks or more with highly active antiretroviral therapy containing Combivir-ABC.
Intervention: Patients were randomized 1:1 to Trizivir (97 patients) or Combivir-ABC (98) for 24 weeks.
Measurements and Main Results: The primary study end point was the proportion of patients who maintained less than a 0.5-log10 increase from baseline in HIV-1 RNA (virologic success) through week 24. Clinical equivalence of the treatments was established if the 95.1% lower confidence limit (LCL) for the difference in proportion of virologic success with Trizivir minus Combivir-ABC was -0.12 or greater. Trizivir was clinically equivalent to Combivir-ABC. The intent-to-treat observed analysis at week 24 with Trizivir and Combivir-ABC showed a similar rate of virologic success (83% [80/97] and 77% [75/98], respectively, 95.1% LCL -0.026), of patients with HIV-1 RNA levels of 400 or fewer copies/ml (99% [82/83] and 93% [77/83], respectively, 95.1% LCL 0.021), and of patients with HIV-1 RNA levels of fewer than 50 copies/ml (89% [74/83] and 77% [64/83], respectively, 95.1% LCL 0.038). The intent-to-treat missing = failure analysis showed comparable results. Changes in CD4 cell count from baseline, overall mean self-reported adherence (Trizivir 97%, Combivir-ABC 92%), and adverse events did not differ significantly between treatments. No ABC-related hypersensitivity reactions occurred.
Conclusion: Trizivir was clinically equivalent to Combivir-ABC and may be substituted for the latter to simplify treatment and reduce pill burden.
Highly active antiretroviral therapy (HAART) has significantly reduced the rate of human immunodeficiency virus (HIV)-related mortality and HIV-associated opportunistic infections. However, the regimens can be difficult to adhere to due to high pill burdens, multiple inconvenient dosing times, and fluid or dietary requirements. A simplified, compact HAART regimen that suppresses HIV-1 maximally while facilitating adherence consists of one combination tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir; GlaxoSmithKline, Research Triangle Park, NC) plus one tablet of abacavir (ABC) 300 mg, administered together twice/day (total pill burden, four tablets/day). This triple nucleoside reverse transcriptase inhibitor (NRTI) regimen allows protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) to be reserved for a later treatment option, thus obviating early development of mutations to these agents. In antiretroviral-experienced patients, Combivir-ABC reduced HIV-1 RNA levels below 400 copies/ml in 82% of 55 patients over 48 weeks (intent-to-treat [ITT] observed analysis).
Further simplification of HAART was made possible with the introduction of the triple-combination tablet Trizivir (GlaxoSmithKline), which contains all three components of the Combivir-ABC regimen but reduces the pill burden to two tablets/day. Pharmacokinetic studies confirmed that Trizivir is bioequivalent to Combivir-ABC and that twice-daily dosing of each regimen yields similar steady-state concentrations. In antiretroviral-experienced HIV-infected patients, switching from a HAART regimen predominantly based on an NRTI and a protease inhibitor to twice-daily Trizivir maintained the same magnitude of virologic suppression over 48 weeks while improving adherence and reducing plasma lipid levels and signs of lipodystrophy.
To our knowledge, no studies have directly compared Trizivir and Combivir-ABC in patients previously suppressed with Combivir-ABC. In our clinical trial (ESS40005), we compared twice-daily Trizivir and Combivir-ABC with respect to efficacy, safety, and adherence in virologically suppressed HIV-1-infected patients who had just completed 16 or more weeks of treatment with Combivir-ABC alone or in combination with a protease inhibitor or an NNRTI.
Study Objective: To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg-lamivudine 150 mg-zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300-mg tablet, administered twice/day, in antiretroviral-experienced, human immunodeficiency virus (HIV)-1-infected patients.
Design: Randomized, open-label, parallel-group, multicenter, formulation-switch study.
Setting: Twenty seven outpatient treatment sites.
Patients: Adults with HIV-1 RNA levels of 400 copies/ml or less and CD4 cell counts above 200 cells/mm who had been treated for 16 weeks or more with highly active antiretroviral therapy containing Combivir-ABC.
Intervention: Patients were randomized 1:1 to Trizivir (97 patients) or Combivir-ABC (98) for 24 weeks.
Measurements and Main Results: The primary study end point was the proportion of patients who maintained less than a 0.5-log10 increase from baseline in HIV-1 RNA (virologic success) through week 24. Clinical equivalence of the treatments was established if the 95.1% lower confidence limit (LCL) for the difference in proportion of virologic success with Trizivir minus Combivir-ABC was -0.12 or greater. Trizivir was clinically equivalent to Combivir-ABC. The intent-to-treat observed analysis at week 24 with Trizivir and Combivir-ABC showed a similar rate of virologic success (83% [80/97] and 77% [75/98], respectively, 95.1% LCL -0.026), of patients with HIV-1 RNA levels of 400 or fewer copies/ml (99% [82/83] and 93% [77/83], respectively, 95.1% LCL 0.021), and of patients with HIV-1 RNA levels of fewer than 50 copies/ml (89% [74/83] and 77% [64/83], respectively, 95.1% LCL 0.038). The intent-to-treat missing = failure analysis showed comparable results. Changes in CD4 cell count from baseline, overall mean self-reported adherence (Trizivir 97%, Combivir-ABC 92%), and adverse events did not differ significantly between treatments. No ABC-related hypersensitivity reactions occurred.
Conclusion: Trizivir was clinically equivalent to Combivir-ABC and may be substituted for the latter to simplify treatment and reduce pill burden.
Highly active antiretroviral therapy (HAART) has significantly reduced the rate of human immunodeficiency virus (HIV)-related mortality and HIV-associated opportunistic infections. However, the regimens can be difficult to adhere to due to high pill burdens, multiple inconvenient dosing times, and fluid or dietary requirements. A simplified, compact HAART regimen that suppresses HIV-1 maximally while facilitating adherence consists of one combination tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir; GlaxoSmithKline, Research Triangle Park, NC) plus one tablet of abacavir (ABC) 300 mg, administered together twice/day (total pill burden, four tablets/day). This triple nucleoside reverse transcriptase inhibitor (NRTI) regimen allows protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) to be reserved for a later treatment option, thus obviating early development of mutations to these agents. In antiretroviral-experienced patients, Combivir-ABC reduced HIV-1 RNA levels below 400 copies/ml in 82% of 55 patients over 48 weeks (intent-to-treat [ITT] observed analysis).
Further simplification of HAART was made possible with the introduction of the triple-combination tablet Trizivir (GlaxoSmithKline), which contains all three components of the Combivir-ABC regimen but reduces the pill burden to two tablets/day. Pharmacokinetic studies confirmed that Trizivir is bioequivalent to Combivir-ABC and that twice-daily dosing of each regimen yields similar steady-state concentrations. In antiretroviral-experienced HIV-infected patients, switching from a HAART regimen predominantly based on an NRTI and a protease inhibitor to twice-daily Trizivir maintained the same magnitude of virologic suppression over 48 weeks while improving adherence and reducing plasma lipid levels and signs of lipodystrophy.
To our knowledge, no studies have directly compared Trizivir and Combivir-ABC in patients previously suppressed with Combivir-ABC. In our clinical trial (ESS40005), we compared twice-daily Trizivir and Combivir-ABC with respect to efficacy, safety, and adherence in virologically suppressed HIV-1-infected patients who had just completed 16 or more weeks of treatment with Combivir-ABC alone or in combination with a protease inhibitor or an NNRTI.
