Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard fi rst-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study

The Lancet (Impact Factor: 45.22). 01/2013; DOI: 10.1016/S0140-6736(13)61164-2


Background Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with
first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen.
Methods We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463.
Findings We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI –4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal.
Interpretation The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy.

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Available from: Jeganathan Sarangapany, Jan 18, 2015
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    • "Recent large clinical trials have evaluated NRTI-sparing regimens in treatment experienced patients experiencing virological failure (key studies summarised in Table 1[18-25]). The regimen most of interest has been that of a boosted-PI with raltegravir, and/or maraviroc and/or etravirine. "
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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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    • "Treatment-experienced patients can also benefit from the use of INSTIs for reasons of toxicity, convenience, or absence of drug interactions [41, 63, 64]. Although switching from LPV/r/TDF/FTC to RAL/DRV/r in individuals with suppressed viral load resulted in sustained viral suppression, it did not improve renal function at week 48 [42]. "
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    ABSTRACT: HIV drug resistance has been one of the major obstacles to HIV eradication and has contributed to the need for the constant development of new antiretroviral drugs over the past 25 years. With the recent approval of dolutegravir for human therapy by the U.S. Food and Drug Administration, health practitioners may soon have access to three integrase strand transfer inhibitors to treat individuals living with HIV. Here, we review the use of raltegravir, elvitegravir, and dolutegravir for use in first- and second-line HIV treatment regimens and the issue of HIV resistance against integrase inhibitors. Electronic supplementary material The online version of this article (doi:10.1007/s40121-013-0020-8) contains supplementary material, which is available to authorized users.
    12/2013; 2(2):83-93. DOI:10.1007/s40121-013-0020-8

  • The Lancet 06/2013; 381(9883):2062-3. DOI:10.1016/S0140-6736(13)61210-6 · 45.22 Impact Factor
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