Summary Background Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% ...reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. Methods In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov , numbers NCT01780506 and NCT01797445. Findings We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI −0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change −3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change −1·30 vs –2·86; p<0·0001) and hip (−0·66 vs –2·95; p<0·0001) at 48 weeks. Interpretation Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. Funding Gilead Sciences.
Summary Background Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel ...tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. Methods In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov , number NCT01815736. Findings Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6–6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients 21% vs 76 16%). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. Interpretation Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. Funding Gilead Sciences.
Summary Background Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. Methods We enrolled patients ...with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0–F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3–F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov , number NCT01466790. Findings 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 90%, 95% CI 81–96 in cohort 1 and n=82 94%, 87–98 in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 31%), headache (n=33 20%), and nausea (n=26 16%). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3–4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. Interpretation Combined simeprevir and sofosbuvir was efficacious and well tolerated. Funding Janssen.
Summary Background Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the ...efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. Methods The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1–3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1–3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov , number NCT01717326. Findings 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93–98% in mono-infected and 87–97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88–100; 43/44) and 87% (95% CI 69–96; 26/30), respectively, and with ribavirin were 93% (95% CI 85–97; 79/85) and 97% (95% CI 82–100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61–92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). Interpretation Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87–98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.
Summary Background The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a ...single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care—co-formulated efavirenz (EFV)/FTC/TDF—as initial treatment for HIV infection. Methods In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov , number NCT01095796. Findings 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI −1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, −6 to 8; p<0·001). Interpretation If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. Funding Gilead Sciences.
Summary Background Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their ...use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1–3 HCV infection. Methods In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1–3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18–70 years, had an HCV RNA concentration of 50 000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000–1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov , number NCT01188772. Findings In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events—fatigue, headache, nausea, and chills—were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77–97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80–98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37–77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. Interpretation Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. Funding Gilead Sciences.
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.
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.
Emtricitabine with tenofovir disoproxil fumarate is a standard-of-care nucleoside reverse transcriptase inhibitor (NRTI) backbone. However, tenofovir disoproxil fumarate is associated with renal and ...bone toxic effects; the novel prodrug tenofovir alafenamide achieves 90% lower plasma tenofovir concentrations. We aimed to further assess safety and efficacy of fixed-dose combination emtricitabine with tenofovir alafenamide in patients switched from emtricitabine with tenofovir disoproxil fumarate.
In this controlled, double-blind, multicentre phase 3 study, we recruited virologically suppressed (HIV RNA <50 copies per mL) patients with HIV aged 18 years and older receiving regimens containing fixed-dose combination emtricitabine with tenofovir disoproxil fumartate from 78 sites in North America and Europe. Patients were randomly assigned (1:1) to switch to fixed-dose 200 mg emtricitabine with 10 mg or 25 mg tenofovir alafenamide or to continue 200 mg emtricitabine with 200 mg or 300 mg tenofovir disoproxil fumarate, while remaining on the same third agent for 96 weeks. Randomisation was done by a computer-generated allocation sequence and was stratified by the third agent (boosted protease inhibitor vs other agent). Investigators, patients, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary outcome was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the US Food and Drug Administration snapshot algorithm with a prespecified non-inferiority margin of 10%. The primary efficacy endpoint was analysed with the per-protocol analysis set, whereas the safety analysis included all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02121795.
We recruited patients between May 6, 2011, and Sept 11, 2014; 780 were screened and 668 were randomly assigned to receive either tenofovir alafenamide (n=333) or tenofovir disoproxil fumarate (n=330). Through week 48, virological success (HIV-1 RNA <50 copies per mL) was maintained in 314 (94%) of patients in the tenofovir alafenamide group compared with 307 (93%) in the tenofovir disoproxil fumarate group (difference 1·3%, 95% CI -2·5 to 5·1), showing non-inferiority of tenofovir alafenamide to tenofovir disproxil fumarate. Seven patients in the tenofovir alafenamide (2%) and three (1%) in the tenofovir disoproxil fumarate group discontinued due to adverse events. There were no cases of proximal renal tubulopathy in either group.
In patients switching from emtricitabine with tenofovir disoproxil fumarate to emtricitabine with tenofovir alafenamide, high rates of virological suppression were maintained. With its safety advantages, fixed-dose emtricitabine with tenofovir alafenamide has the potential to become an important NRTI backbone.
Gilead Sciences.
Tenofovir alafenamide, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the ...efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate.
In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of either rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per mL of plasma HIV-1 RNA at week 48 (by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT01815736.
Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the tenofovir alafenamide group and 314 to the tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on tenofovir alafenamide and 294 (94%) of 313 on tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference -0·3%, 95·001% CI -4·2 to 3·7), showing non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the tenofovir alafenamide group compared with 37 (12%) of 314 in the tenofovir disoproxil fumarate group; none of these were serious.
Switching to rilpivirine, emtricitabine, and tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.
Gilead Sciences.
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