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ACTG 5273

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Lopinavir/Ritonavir + Raltegravir vs Lopinavir/Ritonavir + NRTI como esquema de segunda linea en países con recursos limitados

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ACTG 5273

  1. 1. ACTG 5273: Second-line Lopinavir/Ritonavir Plus Raltegravir Noninferior to Lopinavir/Ritonavir Plus NRTIs in Resource-Limited Settings Source: 2016 Conference on Retroviruses and Opportunistic Infections  ACTG 5273 (SELECT): multicenter, open-label, noninferiority, randomized phase III trial[1] Summary of Key Conclusions  Following failure of NNRTI-based ART in patients in resource-limited settings, second-line treatment with lopinavir/ritonavir plus raltegravir noninferior to treatment with lopinavir/ritonavir plus NRTIs o Virologic efficacy of both strategies > 90% at Week 48 o Immunologic response similar between arms  Patients with more NRTI resistance mutations at entry less likely to experience virologic failure o Similar counterintuitive relationship observed in EARNEST and SECOND-LINE trials[2,3] o Higher levels of resistance at entry may predict higher adherence to second-line treatment or may be a marker of impaired virus  Time to grade ≥ 3 toxicity shorter in NRTI-containing arm  Patients in raltegravir arm experienced higher increases in total cholesterol and triglycerides  27% of the 96 patients who experienced virologic failure developed new resistance mutations on second-line ART  Findings support World Health Organization (WHO) guidelines on choice of second-line ART in resource-limited settings[4] Background  WHO ART guidelines recommend NNRTI plus NRTIs as first-line ART followed by boosted PI plus NRTIs for second-line ART[4]  NRTI-sparing regimens under investigation as means of avoiding NRTI toxicity  Previous studies compared lopinavir/ritonavir plus raltegravir with lopinavir/ritonavir plus NRTIs as second-line ART in resource-limited settings o EARNEST trial and SECOND-LINE trial each demonstrated similar virologic efficacy between lopinavir/ritonavir plus raltegravir and lopinavir/ritonavir plus NRTIs at Week 96[2,3]  Current study evaluated safety, efficacy of lopinavir/ritonavir plus raltegravir vs lopinavir/ritonavir plus NRTIs as second-line ART in resource-limited settings Schematic of Study Design
  2. 2. Eligibility  Main inclusion criteria o HIV-1 RNA ≥ 1000 copies/mL after 24 weeks of treatment with NNRTI-based ART Baseline Characteristics  Treatment arms well matched at baseline Characteristic Lopinavir/Ritonavir + Raltegravir (n = 258) Lopinavir/Ritonavir + NRTIs (n = 254) Female, % 52 50 Median age, yrs (range) 39 (34-44) 38 (33-43) Country of residence, %  India 31 31  Malawi 22 22  South Africa 20 20 HIV-1 subtype C, % 83 79 Median duration of first-line ART, yrs (range) 4.1 (2.2-6.3) 4.0 (2.2-6.0) Median HIV-1 RNA, log10 copies/mL (range) 4.6 (4.0-5.2) 4.5 (3.9-5.1) Median CD4+ cell count, cells/mm3 (range) 138 (49-268) 133 (56-274) Resistance test before entry, % 4 4 ARTs in last regimen, %  TDF 39 35  ZDV 36 35  d4T 25 30  3TC 100 100  EFV 46 38  NVP 54 62 NRTIs in second-line ART, %  FTC, TDF -- 68  3TC, ZDV -- 19  3TC, ABC -- 8  FTC, ZDV, TDF -- 3  3TC, ZDV, ABC -- 2
  3. 3. 3TC, lamivudine; ABC, abacavir; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; NVP, nevirapine; TDF, tenofovir DF; ZDV, zidovudine. Description of Current Analysis  Study objective: to determine noninferiority of raltegravir arm vs NRTI arm at Week 48 o Study powered to detect noninferiority at 10% margin  Primary endpoint: time to virologic failure, defined as confirmed HIV-1 RNA > 400 copies/mL after ≥ 24 weeks of first-line ART  Secondary endpoints o Safety o Immunologic response o AIDS, serious non-AIDS events o Resistance at failure  Patients followed for median 87 weeks (range: 71-96) o 2.4% of patients lost to follow-up o 6 patients discontinued (4 in raltegravir arm vs 2 in NRTI arm) o 8% of patients switched NRTIs on study Main Findings  No difference in time to virologic failure between arms at Week 48 o Difference in likelihood of failure between arms: -3.4% (95% CI: -8.4% to 2.5%) o Raltegravir arm met criteria for noninferiority to NRTI arm, but did not meet criteria for superiority  No difference in proportion of patients with HIV-1 RNA ≤ 400 copies/mL, < 200 copies/mL, or < 40 copies/mL between arms through Week 96  No difference between arms in mean change in CD4+ cell count through Week 96  No differences in number of AIDS events, serious non-AIDS events, or deaths between arms Clinical Outcomes, n Lopinavir/Ritonavir + Raltegravir (n = 258) Lopinavir/Ritonavir + NRTIs (n = 254) AIDS events  Pulmonary tuberculosis 10 7  Extrapulmonary tuberculosis 0 3  Other 3 3 Serious non-AIDS events  Myocardial infarction 1 0  Stroke 0 1  Renal disease 0 2  Other 5 2 Death 3 3  Time to grade ≥ 3 toxicity shorter in NRTI arm (P = .04) o Risk not associated with specific toxicity  Patients receiving raltegravir experienced higher increases in total cholesterol (P < .05) and triglycerides (P < .05)
  4. 4. o No difference between arms in total cholesterol–to–high density lipoprotein ratio, high density lipoprotein level, or glucose level Resistance Analysis  More than 90% of patients had NNRTI and NRTI resistance at study entry o 89% to 90% had M184V/I o 21% to 23% had K65R o Approximately 50% had at least 1 thymidine analogue mutation (TAM) Resistance Mutations at Study Entry, % Lopinavir/Ritonavir + Raltegravir (n = 258) Lopinavir/Ritonavir + NRTIs (n = 254) Samples tested 95 97 Mutations by class  NRTI + NNRTI 92 96  NNRTI only 3 1  NRTI only 1 1  NRTI + NNRTI + PI 2 0  No major IAS* mutations 2 2 M184V/I 89 90 TAMs  0 54 50  1-2 22 26  3-4 22 20  ≥ 5 2 4 K65R 23 21 ≥ 3 IAS* NRTI mutations 52 53 IAS, International AIDS Society. *As defined by IAS-USA.[5]  Median NRTI genotypic sensitivity score (GSS) in NRTI arm: 1 (range: 0.25-1.00) o 48% had NRTI GSS < 1, indicating reduced susceptibility  In NRTI arm, likelihood of failure higher in patients with NRTI GSS ≥ 1 vs those with NRTI GSS < 1 (difference: -8.4% at Week 48; 95% CI: -16.6% to -0.3%; P = .04)  In overall study population, risk of virologic failure was decreased with higher levels of resistance  96 patients (19%) experienced virologic failure: 46 (18%) in raltegravir arm, 50 (20%) in NRTI arm o 84 patients (88% of those with virologic failure) had samples available for analysis o 23 patients (27% of those with virologic failure) had new resistance mutations  NRTI arm: TAMs in 4 patients, major PI mutations in 7 patients  Raltegravir arm: integrase mutations in 12 patients
  5. 5. References 1. La Rosa AM, Harrison LJ, Taiwo B, et al. ACTG 5273 randomized trial of second-line ART supports WHO guidance. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 30. 2. Paton NI, Kityo C, Hoppe A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014;371:234-247. 3. Amin J, Boyd MA, Kumarasamy N, et al. Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection. PLoS One. 2015;10:e0118228. 4. World Health Organization.Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. Available at: http://www.who.int/hiv/pub/guidelines/arv2013/download/en/. Accessed February 25, 2016. 5. Wensing AM, Calvez V, Günthard HF, et al. 2014 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2014;22:642-650.

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