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      Ritonavir-Boosted Darunavir Plus Two Nucleoside Reverse Transcriptase Inhibitors versus Other Regimens for Initial Antiretroviral Therapy for People with HIV Infection: A Systematic Review

      review-article
      1 , 2 , 1 , , 1
      AIDS Research and Treatment
      Hindawi

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          Abstract

          Background

          Darunavir is a second-generation protease-inhibitor used with ritonavir (DRV/r) and two nucleoside reverse-transcriptase inhibitors as an option in first-line antiretroviral treatment (ART).

          Methods

          We systematically reviewed randomized controlled trials (RCTs) of DRV/r versus other regimens in patients initiating ART. We searched five bibliographic databases and other key resources. We had no language limitations. We assessed bias risk with the Cochrane tool and used GRADE to assess evidence quality. We report findings in terms of risk ratio (RR) with 95% confidence intervals (CI).

          Findings

          Three RCTs met inclusion criteria. In plasma viral load suppression, DRV/r outperformed ritonavir-boosted lopinavir at 48 weeks (RR 1.13, 95% CI 1.03–1.25), 96 weeks (RR 1.11, 95% CI 1.02–1.21), and 192 weeks (RR 1.20, 95% CI 1.07–1.35). DRV/r was similar to dolutegravir at 48 weeks (RR 0.96, 95% CI 0.87–1.06) but less effective at 96 weeks (RR 0.84, 95% CI 0.75–0.93). At 96 weeks, DRV/r underperformed raltegravir (RR 0.94, 95% CI 0.88–0.99) but was similar to ritonavir-boosted atazanavir (RR 1.02, 95% CI 0.96–1.09). Overall bias risk was moderate. Evidence quality was also moderate.

          Interpretation

          Initial ART regimens using DRV/r should be considered in future World Health Organization guidelines.

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          Most cited references19

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          Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study.

          Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy. In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100,000 or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration [FDA] snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, NCT01449929. Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7·1%, 95% CI 0·9-13·2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p=0·025). Confirmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four [2%] patients) than for darunavir plus ritonavir (ten [4%] patients) and contributed to the difference in response rates. The most commonly reported (≥10%) adverse events were diarrhoea (dolutegravir 41 [17%] patients vs darunavir plus ritonavir 70 [29%] patients), nausea (39 [16%] vs 43 [18%]), and headache (37 [15%] vs 24 [10%]). Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher (11 [2%] vs 36 [7%]; p=0·0001). Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir. Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected, treatment-naive patients. ViiV Healthcare and Shionogi & Co. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

              The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks.
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                Author and article information

                Contributors
                Journal
                AIDS Res Treat
                AIDS Res Treat
                ART
                AIDS Research and Treatment
                Hindawi
                2090-1240
                2090-1259
                2017
                26 September 2017
                : 2017
                : 2345617
                Affiliations
                1Global Health Sciences, University of California, San Francisco, San Francisco, CA, USA
                2School of Public Health, American University of Armenia, Yerevan, Armenia
                Author notes

                Academic Editor: David Katzenstein

                Author information
                http://orcid.org/0000-0003-4478-4129
                http://orcid.org/0000-0001-7569-3524
                Article
                10.1155/2017/2345617
                5634582
                c84bbb39-1055-4529-9ad4-a2996852f4fd
                Copyright © 2017 Tatevik Balayan et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 May 2017
                : 16 July 2017
                Categories
                Review Article

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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