Randomized open-label trial of two simplified, class-sparing regimens following a first suppressive three or four-drug regimen

Harvard University, Cambridge, Massachusetts, United States
AIDS (Impact Factor: 5.55). 01/2007; 21(3):325-33. DOI: 10.1097/QAD.0b013e328011ddfa
Source: PubMed


Complex antiretroviral regimens can be associated with increased toxicity and poor adherence. Our aim was to compare the efficacy and safety of switching to two simplified, class-sparing antiretroviral regimens.
We conducted a randomized, open-label study in 236 patients with virologic suppression who were taking a three- or four-drug protease inhibitor or non-nucleoside reverse transcriptase inhibitor regimen for > or = 18 months. Patients received lopinavir/ritonavir (LPV/r) 533 mg/133 mg twice daily + efavirenz (EFV) 600 mg once daily or EFV + two nucleoside reverse transcriptase inhibitors (NRTI). Primary study endpoint was time to first virologic failure (VF, confirmed HIV-1 RNA > 200 copies/ml) or discontinuation because of study drug-related toxicity.
After 2.1 years of follow up, patients receiving LPV/r + EFV discontinued treatment at a greater rate than patients receiving EFV + NRTI (P < 0.001). Twenty-one patients developed VF (14 receiving LPV/r + EFV and seven receiving EFV + NRTI) and 26 discontinued because of a study drug-related toxicity (20 receiving LPV/r + EFV and six receiving EFV + NRTI). Time to VF or study drug related-toxicity discontinuation was significantly shorter for LPV/r + EFV than EFV + NRTIs (P = 0.0015). A significantly higher risk of drug-related toxicity occurred with LPV/r + EFV, mainly for increased triglycerides (P = 0021). A trend toward a higher VF rate occurred with LPV/r + EFV in an intent-to-treat and as-treated analyses (P = 0.088 and P = 0.063 respectively).
Switching to EFV + NRTI resulted in better outcomes, fewer drug-related toxicity discontinuations and a trend to fewer virologic failures compared to switching to LPV/r + EFV.

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    • "In the ACTG 5116 trial [34], virologically suppressed patients receiving a standard PI- or NNRTI-based ART regimen were randomised to efavirenz with LPV/r or efavirenz with NRTIs (standard ART arm). Though not a fully powered trial, the NRTI-sparing arm performed poorly due largely to higher rates of discontinuation and toxicity as well as dyslipidemia. "
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    ABSTRACT: The nucleoside(tide) reverse transcriptase inhibitors (NRTIs) have traditionally been an important 'back-bone' of an antiretroviral therapy (ART) regimen. However all agents have been associated with both short- and long-term toxicity. There have also been concerns regarding the efficacy and safety of a treatment sequencing strategy in which those with past exposure and/or resistance to one or more NRTIs are re-exposed to 'recycled' NRTIs in subsequent ART regimens. Newer, potent and possible safer, agents from various ART classes continue to become available. There has therefore been growing interest in evaluating NRTI-sparing regimens. In this review, we examined studies of NRTI-sparing regimens in adult HIV-positive patients with varying degrees of ART experience. We found that in treatment experienced patients currently on a failing regimen with detectable viral load, there now exists a robust evidence for the use of NRTI-sparing regimens including raltegravir with a boosted-protease inhibitor with or without a third agent. In those on a virologically suppressive regimen switching to a NRTI-sparing regimen or in those ART-naïve patients initiating an NRTI-sparing regimen, evidence is sparse and largely comes from small exploratory trials or observational studies. Overall, these studies suggest that caution needs to be exercised in carefully selecting the right candidate and agents, especially in the context of a dual-therapy regimen, to minimise the risks of virological failure. There is residual toxicity conferred by the ritonavir boost in protease-inhibitor containing NRTI-sparing regimens. Fully-powered studies are needed to explore the place of N (t)RTI-sparing regimens in the sequencing of ART. Additionally research is required to explore how to minimise the adverse effects associated with ritonavir-based pharmacoenhancement.
    AIDS Research and Therapy 12/2013; 10(1):33. DOI:10.1186/1742-6405-10-33 · 1.46 Impact Factor
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    • "A randomized, non-blinded study (A5116) comparing combination therapy with lopinavir/ritonavir 533 mg/133 mg twice daily and efavirenz 600 mg once daily (in an NRTI-sparing regimen) with efavirenz and two NRTIs in patients (n = 236) who switched from PI or NNRTI-based regimens, showed that the combination of two NRTIs with efavirenz was more effective in achieving virologic suppression. The lopinavir/ritonavir-based regimen in this study had significantly more toxicity-related discontinuations and shorter time to virologic failure (p = 0.001) (Fischl et al 2007). Lopinavir/ritonavir was one of the four PIs administered to patients in the RESIST (Randomized Evaluation Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir) studies. "
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    ABSTRACT: Lopinavir/ritonavir is the first and only coformulated HIV-1 protease inhibitor (PI). Large clinical trials have demonstrated lopinavir/ritonavir's clinical efficacy in both antiretroviral-naïve and -experienced patients. The immunologic and virologic benefits of treatment with this agent have been proven in HIV-infected adults, adolescents, and children. Smaller studies support the use of lopinavir/ritonavir monotherapy as a therapeutic option in certain patients. The drug is characterized by a high genetic barrier to resistance, and appears to be more forgiving of non-adherence than earlier, unboosted PIs. The most frequent side effects observed are diarrhea, nausea, and vomiting. These gastrointestinal adverse effects are generally mild to moderate. Metabolic derangements, including hyperlipidemia and glucose intolerance, have also been observed in lopinavir/ritonavir recipients. As the menu of available antiretroviral agents continues to expand, lopinavir/ritonavir remains a proven and effective drug for the treatment of HIV infection.
    Therapeutics and Clinical Risk Management 11/2008; 4(5):1023-33. · 1.47 Impact Factor
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