Summary Background Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The ...aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients. Methods HIV-infected patients with HIV-1 RNA viral load over 5000 copies per mL, CD4 cell counts over 50 cells per μL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, and one protease inhibitor were randomly assigned to receive raltegravir (200 mg, 400 mg, or 600 mg) or placebo orally twice daily in this multicentre, triple-blind, dose-ranging, randomised study. The primary endpoints were change in viral load from baseline at week 24 and safety. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov , with the number NCT00105157. Findings 179 patients were eligible for randomisation. 44 patients were randomly assigned to receive 200 mg raltegravir, 45 to receive 400 mg raltegravir, and 45 to receive 600 mg raltegravir; 45 patients were randomly assigned to receive placebo. One patient in the 200 mg group did not receive treatment and was therefore excluded from the analyses. For all groups, the median duration of previous antiretroviral therapy was 9·9 years (range 0·4–17·3 years) and the mean baseline viral load was 4·7 (SD 0·5) log10 copies per mL. Four patients discontinued due to adverse experiences, three (2%) of the 133 patients across all raltegravir groups and one (2%) of the 45 patients on placebo. 41 patients discontinued due to lack of efficacy: 14 (11%) of the 133 patients across all raltegravir groups and 27 (60%) of the 45 patients on placebo. At week 24, mean change in viral load from baseline was −1·80 (95% CI −2·10 to −1·50) log10 copies per mL in the 200 mg group, −1·87 (−2·16 to −1·58) log10 copies per mL in the 400 mg group, −1·84 (−2·10 to −1·58) log10 copies per mL in the 600 mg group, and −0·35 (−0·61 to −0·09) log10 copies per mL for the placebo group. Raltegravir at all doses showed a safety profile much the same as placebo; there were no dose-related toxicities. Interpretation In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen. The safety profile of raltegravir is comparable with that of placebo at all doses studied.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data ...suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules. Methods In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of −10%. This study is registered with ClinicalTrials.gov , number NCT00745823. Findings From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100 000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference −5·7%, 95% CI −10·7 to −0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group. Interpretation Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing. Funding Merck.
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Summary Background Chronic hepatitis C virus (HCV) infection in patients with stage 4–5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and ...chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4–5 chronic kidney disease. Methods In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4–5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov , number NCT02092350. Findings 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up n=2, non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3–100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. Interpretation Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4–5 chronic kidney disease. Funding Merck Sharp & Dohme Corp.
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Summary Background Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the ...safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients. Methods Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov , number NCT00369941. Findings 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per μL or less. The main analysis (with non-completion counted as failure) showed that 86·1% (n=241 patients) of the raltegravir group and 81·9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4·2%, 95% CI −1·9 to 10·3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0·0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 44·1%) than those on efavirenz (n=217 77·0%; difference −32·8%, 95% CI −40·2 to −25·0, p<0·0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group. Interpretation Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients. Funding Merck.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of ...their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy. Methods The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of −12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov , numbers NCT00443703 and NCT00443729. Findings 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0·0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol −12·6% vs 1·0%, non-HDL cholesterol −15·0% vs 2·6%, and triglycerides −42·2% vs 6·2%. At week 24, 293 (84·4%, 95% CI 80·2–88·1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90·6%, 87·1–93·5) of 352 patients in the lopinavir-ritonavir group (treatment difference −6·2%, −11·2 to −1·3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group. Interpretation Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir. Funding Merck.
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The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were ...assessed, 37 patients with AIDS or symptomatic HIV infection and 100–400 CD4 cells/mm
3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2–0.3 log
10 copies/ml plasma HIV RNA; these decreases persisted through 7–8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted.
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