Unboosted ATV vs Ritonavir-Boosted PI Maintenance Therapy
Unboosted ATV vs Ritonavir-Boosted PI Maintenance Therapy
Objectives: Treatment simplification involving induction with a ritonavir (RTV)-boosted protease inhibitor (PI) replaced by a nonboosted PI (i.e. atazanavir) has been shown to be a viable option for long-term antiretroviral therapy. To evaluate the clinical evidence for this approach, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating efficacy and safety in patients with established virological suppression.
Methods: Several databases were searched without limits on time or language. Searches of conferences were also conducted. RCTs were included if they compared a PI/RTV regimen to unboosted atazanavir, after induction with PI/RTV. The meta-analysis was conducted using a random effects model for the proportion achieving virological suppression (i.e. HIV RNA < 50 and <400 HIV-1 RNA copies/mL), CD4 cell counts, lipid levels and liver function tests. Dichotomous outcomes were reported as risk ratios (RRs) and continuous outcomes as mean differences (MDs).
Results: Five studies (n = 1249) met the inclusion criteria. The meta-analysis demonstrated no statistically significant difference in efficacy (i.e. HIV RNA < 50 copies/mL) between PI/RTV and unboosted atazanavir [RR = 1.04; 95% confidence interval (CI) 0.99 to 1.10], with no heterogeneity. Findings were similar in a subanalysis of studies where atazanavir/RTV was the only PI/RTV used during induction. Additional efficacy results support these findings. A significant reduction in total cholesterol (P < 0.00001), triglycerides (P = 0.0002), low-density lipoprotein (LDL) cholesterol (P = 0.009) and hyperbilirubinaemia (P = 0.02) was observed with unboosted atazanavir vs. PI/RTV.
Conclusions: The meta-analysis demonstrated that switching patients with virological suppression from an RTV-boosted PI to unboosted atazanavir leads to improvements in safety (i.e. blood parameter abnormalities) without sacrificing virological efficacy.
HIV type 1 (HIV-1) infection can be successfully treated with a broad range of antiretroviral therapies. Current guidelines recommend that initial regimens consist of two nucleoside reverse transcriptase inhibitors (NRTIs), plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), an integrated strand transfer inhibitor (INSTI) or a ritonavir (RTV)-boosted protease inhibitor (PI). RTV is an antiretroviral drug from the PI class that is co-administered at low doses with other agents (including other PIs) for its 'boosting' effect through inhibition of the cytochrome P450 34A (CYP34A) enzyme, thus increasing drug levels and allowing for less frequent administration of medications.
Some patients, however, experience high levels of adverse events (e.g. hyperbilirubinaemia, unfavourable lipid profiles and increased gastrointestinal toxicity) on a boosted PI-based triple combination regimen. Studies have suggested that cardiovascular disease is associated with antiretroviral therapy, with recent data demonstrating an increased risk of myocardial infarction associated with a longer duration of PI use. This could be explained, in part, by alterations in lipid profiles associated with therapy. In particular, RTV has been shown to significantly increase plasma lipid levels (e.g. total cholesterol), although recent data do not show any difference in myocardial infarction between RTV-boosted and unboosted PI regimens. Options to address this include switching to an NNRTI- or INSTI-based regimen, or removing the RTV boosting.
Atazanavir (ATV) (Reyataz™, Bristol-Myers Squibb, Princeton, NJ, USA) was the first once-daily PI approved for the treatment of HIV infection and is the only PI that can be currently given without RTV boosting with a relatively low daily dose and pill burden. ATV has been associated with a more favourable lipid profile when compared with other PI-based therapies. Recent trials have investigated whether patients can effectively continue on unboosted ATV regimens after an induction phase that included RTV. Results have suggested that such a regimen is noninferior to and potentially safer than an RTV-boosted PI regimen for patients with a suppressed HIV plasma viral load at the time of switching. In contrast, when HIV plasma viral load is detectable, as in treatment-naïve patients or in those failing treatment, unboosted ATV is not recommended because its plasma drug concentrations are variable and may fall below the minimum threshold for maximal activity. In fact, Malan et al. showed that RTV-boosted ATV was associated with a lower virological failure rate than unboosted ATV in treatment-naïve patients.
To evaluate the clinical evidence, a systematic review and meta-analysis were conducted of randomized trials that evaluated the efficacy and safety of switching from an RTV-boosted PI to unboosted ATV compared with continuing on an RTV-boosted PI regimen in adult HIV-1-positive patients after patients showed established virological suppression through an induction phase of PI/RTV-based highly active antiretroviral therapy (HAART).
Abstract and Introduction
Abstract
Objectives: Treatment simplification involving induction with a ritonavir (RTV)-boosted protease inhibitor (PI) replaced by a nonboosted PI (i.e. atazanavir) has been shown to be a viable option for long-term antiretroviral therapy. To evaluate the clinical evidence for this approach, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating efficacy and safety in patients with established virological suppression.
Methods: Several databases were searched without limits on time or language. Searches of conferences were also conducted. RCTs were included if they compared a PI/RTV regimen to unboosted atazanavir, after induction with PI/RTV. The meta-analysis was conducted using a random effects model for the proportion achieving virological suppression (i.e. HIV RNA < 50 and <400 HIV-1 RNA copies/mL), CD4 cell counts, lipid levels and liver function tests. Dichotomous outcomes were reported as risk ratios (RRs) and continuous outcomes as mean differences (MDs).
Results: Five studies (n = 1249) met the inclusion criteria. The meta-analysis demonstrated no statistically significant difference in efficacy (i.e. HIV RNA < 50 copies/mL) between PI/RTV and unboosted atazanavir [RR = 1.04; 95% confidence interval (CI) 0.99 to 1.10], with no heterogeneity. Findings were similar in a subanalysis of studies where atazanavir/RTV was the only PI/RTV used during induction. Additional efficacy results support these findings. A significant reduction in total cholesterol (P < 0.00001), triglycerides (P = 0.0002), low-density lipoprotein (LDL) cholesterol (P = 0.009) and hyperbilirubinaemia (P = 0.02) was observed with unboosted atazanavir vs. PI/RTV.
Conclusions: The meta-analysis demonstrated that switching patients with virological suppression from an RTV-boosted PI to unboosted atazanavir leads to improvements in safety (i.e. blood parameter abnormalities) without sacrificing virological efficacy.
Introduction
HIV type 1 (HIV-1) infection can be successfully treated with a broad range of antiretroviral therapies. Current guidelines recommend that initial regimens consist of two nucleoside reverse transcriptase inhibitors (NRTIs), plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), an integrated strand transfer inhibitor (INSTI) or a ritonavir (RTV)-boosted protease inhibitor (PI). RTV is an antiretroviral drug from the PI class that is co-administered at low doses with other agents (including other PIs) for its 'boosting' effect through inhibition of the cytochrome P450 34A (CYP34A) enzyme, thus increasing drug levels and allowing for less frequent administration of medications.
Some patients, however, experience high levels of adverse events (e.g. hyperbilirubinaemia, unfavourable lipid profiles and increased gastrointestinal toxicity) on a boosted PI-based triple combination regimen. Studies have suggested that cardiovascular disease is associated with antiretroviral therapy, with recent data demonstrating an increased risk of myocardial infarction associated with a longer duration of PI use. This could be explained, in part, by alterations in lipid profiles associated with therapy. In particular, RTV has been shown to significantly increase plasma lipid levels (e.g. total cholesterol), although recent data do not show any difference in myocardial infarction between RTV-boosted and unboosted PI regimens. Options to address this include switching to an NNRTI- or INSTI-based regimen, or removing the RTV boosting.
Atazanavir (ATV) (Reyataz™, Bristol-Myers Squibb, Princeton, NJ, USA) was the first once-daily PI approved for the treatment of HIV infection and is the only PI that can be currently given without RTV boosting with a relatively low daily dose and pill burden. ATV has been associated with a more favourable lipid profile when compared with other PI-based therapies. Recent trials have investigated whether patients can effectively continue on unboosted ATV regimens after an induction phase that included RTV. Results have suggested that such a regimen is noninferior to and potentially safer than an RTV-boosted PI regimen for patients with a suppressed HIV plasma viral load at the time of switching. In contrast, when HIV plasma viral load is detectable, as in treatment-naïve patients or in those failing treatment, unboosted ATV is not recommended because its plasma drug concentrations are variable and may fall below the minimum threshold for maximal activity. In fact, Malan et al. showed that RTV-boosted ATV was associated with a lower virological failure rate than unboosted ATV in treatment-naïve patients.
To evaluate the clinical evidence, a systematic review and meta-analysis were conducted of randomized trials that evaluated the efficacy and safety of switching from an RTV-boosted PI to unboosted ATV compared with continuing on an RTV-boosted PI regimen in adult HIV-1-positive patients after patients showed established virological suppression through an induction phase of PI/RTV-based highly active antiretroviral therapy (HAART).
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