Induction With Abacavir/Lamivudine/Zidovudine Plus Efavirenz
Induction With Abacavir/Lamivudine/Zidovudine Plus Efavirenz
Background: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen.
Methods: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV + EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase.
Results: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56% ≥100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV + EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing = failure]; P = 0.697) or time to treatment failure (P = 0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV + EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV + EFV group; P = 0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV + EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P = 0.057).
Conclusions: After induction with ABC/3TC/ZDV + EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.
Highly active antiretroviral therapy (HAART) has resulted in dramatic reductions in HIV-1-associated mortality and morbidity. The US Department of Health and Human Services guidelines currently recommend initiating antiretroviral therapy (ART) with 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a single nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI) (http://www.aidsinfo.nih.gov/guidelines). These recommendations are based on clinical trials in which 60% to 90% of patients had HIV-1 RNA levels below the assay detection limit at 48 weeks. Risk factors for treatment failure include high baseline HIV-1 RNA levels, low baseline CD4 cell counts, and poor adherence to ART. Although highly effective, HAART has been associated with significant short- and long-term toxicities, including hyperlipidemia, insulin resistance, and fat redistribution syndromes, which may be associated with accelerated atherosclerotic cardiovascular disease. Given these and other toxicities, interest has arisen in reducing prolonged exposure to antiretrovirals. Discontinuation of ART in patients successfully treated for prolonged periods has been associated with rapid virologic rebound and decreasing CD4 cell counts, however. Treatment strategies that improve initial virologic and immunologic responses while simplifying treatment regimens over the long term remain of great interest. Induction-maintenance is one such strategy.
The term induction-maintenance is borrowed from oncology. Intensive initial therapy is designed to induce a rapid response that may be maintained over the long term with less intense and theoretically less toxic maintenance treatment regimens. To date, 3 HIV trials have tested this concept, and all led to a suboptimal treatment response. In these trials, patients were treated with triple (2 studies) or quadruple drug therapy for 12 to 26 weeks, followed by simplification to monotherapy or dual combination therapy. Rebound rates ranged from 22% to 31% and were related to poor adherence, poor pharmacokinetic profiles, and baseline viral resistance. Despite these initial failures, interest in the induction-maintenance concept has persisted.
Here, we describe an induction-maintenance strategy in which patients were induced with a compact quadruple regimen that included a fixed-dose combination of abacavir (ABC), lamivudine (3TC), and zidovudine (ZDV) with efavirenz (EFV) for 48 weeks, followed by randomization to maintenance with ABC/3TC/ZDV or continued quadruple therapy. We hypothesized that 4-drug induction therapy would be effective in patients with diverse baseline HIV-1 RNA levels and CD4 cell counts, well-tolerated, and convenient. Additionally, we anticipated that after 48 weeks of treatment, the residual viral burden would be sufficiently small to allow for the successful removal of 1 agent, EFV, resulting in reduced toxicity and improved adherence while maintaining the desired antiviral and immunologic benefits.
Background: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen.
Methods: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV + EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase.
Results: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56% ≥100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV + EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing = failure]; P = 0.697) or time to treatment failure (P = 0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV + EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV + EFV group; P = 0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV + EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P = 0.057).
Conclusions: After induction with ABC/3TC/ZDV + EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.
Highly active antiretroviral therapy (HAART) has resulted in dramatic reductions in HIV-1-associated mortality and morbidity. The US Department of Health and Human Services guidelines currently recommend initiating antiretroviral therapy (ART) with 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a single nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI) (http://www.aidsinfo.nih.gov/guidelines). These recommendations are based on clinical trials in which 60% to 90% of patients had HIV-1 RNA levels below the assay detection limit at 48 weeks. Risk factors for treatment failure include high baseline HIV-1 RNA levels, low baseline CD4 cell counts, and poor adherence to ART. Although highly effective, HAART has been associated with significant short- and long-term toxicities, including hyperlipidemia, insulin resistance, and fat redistribution syndromes, which may be associated with accelerated atherosclerotic cardiovascular disease. Given these and other toxicities, interest has arisen in reducing prolonged exposure to antiretrovirals. Discontinuation of ART in patients successfully treated for prolonged periods has been associated with rapid virologic rebound and decreasing CD4 cell counts, however. Treatment strategies that improve initial virologic and immunologic responses while simplifying treatment regimens over the long term remain of great interest. Induction-maintenance is one such strategy.
The term induction-maintenance is borrowed from oncology. Intensive initial therapy is designed to induce a rapid response that may be maintained over the long term with less intense and theoretically less toxic maintenance treatment regimens. To date, 3 HIV trials have tested this concept, and all led to a suboptimal treatment response. In these trials, patients were treated with triple (2 studies) or quadruple drug therapy for 12 to 26 weeks, followed by simplification to monotherapy or dual combination therapy. Rebound rates ranged from 22% to 31% and were related to poor adherence, poor pharmacokinetic profiles, and baseline viral resistance. Despite these initial failures, interest in the induction-maintenance concept has persisted.
Here, we describe an induction-maintenance strategy in which patients were induced with a compact quadruple regimen that included a fixed-dose combination of abacavir (ABC), lamivudine (3TC), and zidovudine (ZDV) with efavirenz (EFV) for 48 weeks, followed by randomization to maintenance with ABC/3TC/ZDV or continued quadruple therapy. We hypothesized that 4-drug induction therapy would be effective in patients with diverse baseline HIV-1 RNA levels and CD4 cell counts, well-tolerated, and convenient. Additionally, we anticipated that after 48 weeks of treatment, the residual viral burden would be sufficiently small to allow for the successful removal of 1 agent, EFV, resulting in reduced toxicity and improved adherence while maintaining the desired antiviral and immunologic benefits.
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