ACTG 5095: Triple Nucleosides Redux
ACTG 5095: Triple Nucleosides Redux
In a randomized, double-blind, placebo-controlled study, AZT + 3TC + abacavir performed well, but efavirenz-based therapy was even more effective.
The appeal of triple-NRTI therapy with fixed-dose AZT + 3TC + abacavir is its simplicity. Despite concerns regarding lower antiretroviral efficacy -- especially in patients with high baseline viral loads -- the convenience of this single-pill, twice-daily regimen and the absence of significant drug interactions have made it preferable in some cases to more complex PI-based combinations. Indeed, three clinical trials comparing this regimen with indinavir (two studies) or nelfinavir (one study) showed largely similar antiretroviral responses among study arms, especially in the two studies that were open-label. In the current study (ACTG 5095), AZT + 3TC + abacavir was compared for the first time with efavirenz-based regimens.
Eligible subjects were antiretroviral-naive and had a detectable viral load; no CD4-cell count requirement was specified. Participants were randomized to receive one of three treatment regimens, all at standard doses: Trizivir (AZT + 3TC + abacavir) alone, Combivir (AZT + 3TC) + efavirenz, or Trizivir + efavirenz. Participants took a total of 7 pills daily, including placebos. Virologic failure was defined as the occurrence of two consecutive viral-load measurements >200 copies/mL. In the event of treatment-limiting toxicity, substitutions of d4T for AZT, ddI for abacavir, or nevirapine for efavirenz were permitted and did not constitute a primary study endpoint.
In February 2003, at the second annual review by the Data Safety Monitoring Board of the National Institute of Allergy and Infectious Diseases, it was found that the triple-NRTI-alone regimen was unlikely to be demonstrated noninferior to the efavirenz regimens according to predefined study criteria; as a result, this arm was unblinded and discontinued. This article presents the results of the comparison between the triple-NRTI arm and pooled data from the two efavirenz-containing arms; comparison between the two efavirenz regimens is ongoing.
Between March 2001 and November 2002, 1147 patients enrolled in the study; 81% were male, and 60% were nonwhite. The mean baseline viral load was 71,000 copies/mL, and 43% of patients had viral loads >100,000 copies/mL. The mean baseline CD4 count was 238 cells/mm.
After a median of 32 weeks of follow-up, protocol-defined virologic failure occurred in 21% of the triple-NRTI group, versus 11% in the pooled efavirenz groups. Time to virologic failure was shorter in the triple-NRTI group. The superiority of efavirenz was undiminished in a study-specified analysis that stratified patients according to whether their baseline viral load was above or below 100,000 copies/mL. Efavirenz remained superior in several other analyses: For example, the proportions of patients achieving viral loads <200 copies/mL and <50 copies/mL were both higher with efavirenz than with the triple-NRTI regimen. In addition, among patients who achieved at least one viral-load measurement <50 copies/mL, those who received the triple-NRTI regimen showed a trend towards a shorter time to virologic failure compared with those who received efavirenz (P=0.08). No significant differences between treatment groups were seen in CD4-cell count responses. Treatment-limiting adverse events occurred with equal frequency in both the triple-NRTI arm and the pooled efavirenz arms.
These results were initially announced last year, and then presented at the IAS conference in Paris (see ACC Meeting Notes September 2003). Since first publicized, they have had a major influence on treatment guidelines, with the result that triple-NRTI based therapy with AZT + 3TC + abacavir is considered acceptable only in cases in which NNRTIs or PIs cannot be used. It should be emphasized, however, that despite the superiority of the efavirenz treatment in this study, the AZT + 3TC + abacavir results were actually quite good, especially in light of the dismal antiviral activity of other more recently studied triple-NRTI regimens such as abacavir + 3TC + tenofovir or ddI + 3TC + tenofovir (see ACC Research Notes December 2003). As a result, fixed-dose AZT + 3TC + abacavir remains an acceptable therapy for a small subset of individuals, including those who may have severe drug interactions with PIs or NNRTIs and those who present otherwise intractable adherence challenges. This regimen might even be useful for pregnant women in whom antiretroviral therapy would not otherwise be indicated. The question remains of what to do about patients in clinical practice who are doing well on fixed-dose AZT + 3TC + abacavir. In ACTG 5095, patients successfully treated with triple-NRTIs were offered a second randomization in which either efavirenz or tenofovir was added to their treatment regimens; however, patients and providers outside of the study setting generally have been reluctant to alter a successful regimen.
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In a randomized, double-blind, placebo-controlled study, AZT + 3TC + abacavir performed well, but efavirenz-based therapy was even more effective.
The appeal of triple-NRTI therapy with fixed-dose AZT + 3TC + abacavir is its simplicity. Despite concerns regarding lower antiretroviral efficacy -- especially in patients with high baseline viral loads -- the convenience of this single-pill, twice-daily regimen and the absence of significant drug interactions have made it preferable in some cases to more complex PI-based combinations. Indeed, three clinical trials comparing this regimen with indinavir (two studies) or nelfinavir (one study) showed largely similar antiretroviral responses among study arms, especially in the two studies that were open-label. In the current study (ACTG 5095), AZT + 3TC + abacavir was compared for the first time with efavirenz-based regimens.
Eligible subjects were antiretroviral-naive and had a detectable viral load; no CD4-cell count requirement was specified. Participants were randomized to receive one of three treatment regimens, all at standard doses: Trizivir (AZT + 3TC + abacavir) alone, Combivir (AZT + 3TC) + efavirenz, or Trizivir + efavirenz. Participants took a total of 7 pills daily, including placebos. Virologic failure was defined as the occurrence of two consecutive viral-load measurements >200 copies/mL. In the event of treatment-limiting toxicity, substitutions of d4T for AZT, ddI for abacavir, or nevirapine for efavirenz were permitted and did not constitute a primary study endpoint.
In February 2003, at the second annual review by the Data Safety Monitoring Board of the National Institute of Allergy and Infectious Diseases, it was found that the triple-NRTI-alone regimen was unlikely to be demonstrated noninferior to the efavirenz regimens according to predefined study criteria; as a result, this arm was unblinded and discontinued. This article presents the results of the comparison between the triple-NRTI arm and pooled data from the two efavirenz-containing arms; comparison between the two efavirenz regimens is ongoing.
Between March 2001 and November 2002, 1147 patients enrolled in the study; 81% were male, and 60% were nonwhite. The mean baseline viral load was 71,000 copies/mL, and 43% of patients had viral loads >100,000 copies/mL. The mean baseline CD4 count was 238 cells/mm.
After a median of 32 weeks of follow-up, protocol-defined virologic failure occurred in 21% of the triple-NRTI group, versus 11% in the pooled efavirenz groups. Time to virologic failure was shorter in the triple-NRTI group. The superiority of efavirenz was undiminished in a study-specified analysis that stratified patients according to whether their baseline viral load was above or below 100,000 copies/mL. Efavirenz remained superior in several other analyses: For example, the proportions of patients achieving viral loads <200 copies/mL and <50 copies/mL were both higher with efavirenz than with the triple-NRTI regimen. In addition, among patients who achieved at least one viral-load measurement <50 copies/mL, those who received the triple-NRTI regimen showed a trend towards a shorter time to virologic failure compared with those who received efavirenz (P=0.08). No significant differences between treatment groups were seen in CD4-cell count responses. Treatment-limiting adverse events occurred with equal frequency in both the triple-NRTI arm and the pooled efavirenz arms.
These results were initially announced last year, and then presented at the IAS conference in Paris (see ACC Meeting Notes September 2003). Since first publicized, they have had a major influence on treatment guidelines, with the result that triple-NRTI based therapy with AZT + 3TC + abacavir is considered acceptable only in cases in which NNRTIs or PIs cannot be used. It should be emphasized, however, that despite the superiority of the efavirenz treatment in this study, the AZT + 3TC + abacavir results were actually quite good, especially in light of the dismal antiviral activity of other more recently studied triple-NRTI regimens such as abacavir + 3TC + tenofovir or ddI + 3TC + tenofovir (see ACC Research Notes December 2003). As a result, fixed-dose AZT + 3TC + abacavir remains an acceptable therapy for a small subset of individuals, including those who may have severe drug interactions with PIs or NNRTIs and those who present otherwise intractable adherence challenges. This regimen might even be useful for pregnant women in whom antiretroviral therapy would not otherwise be indicated. The question remains of what to do about patients in clinical practice who are doing well on fixed-dose AZT + 3TC + abacavir. In ACTG 5095, patients successfully treated with triple-NRTIs were offered a second randomization in which either efavirenz or tenofovir was added to their treatment regimens; however, patients and providers outside of the study setting generally have been reluctant to alter a successful regimen.
Click here for AIDS Clinical Care subscription information.