OBJECTIVES:To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of the first protease inhibitor–based single-tablet regimen (STR) for initial ...treatment of HIV-1 infection.
METHODS:Antiretroviral therapy (ART)-naive adults with estimated glomerular filtration rate ≥70 mL/min were randomized 2:1 to receive the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) STR (TAFN = 103) or darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (TDFN = 50) once daily with matched placebos for 48 weeks.
RESULTS:At week 24, viral suppression (HIV-1 RNA <50 copies/mL) rates were similar (TAF 74.8% vs. TDF 74.0%). At week 48, rates were TAF 76.7% vs. TDF 84.0%; the difference was driven by higher rate of discontinuations in TAF (6.8%) vs. TDF (2%). Among those with virologic failure, none developed resistance. Most adverse events were of mild/moderate severity. The mean change in serum creatinine from baseline at week 48 was 0.06 mg/dL (95% confidence interval0.04 to 0.08) for TAF vs. 0.09 mg/dL (95% confidence interval0.05 to 0.14) for TDF (P = 0.053). The % change in retinol binding protein/Cr ratio was +9 (TAF) vs. +54 (TDF), P = 0.003; the % change in urine β-2 microglobulin/Cr ratio was −42.0 (TAF) vs. +2.3 (TDF), P = 0.002. The % change in hip bone mineral density (BMD) was −0.84 (TAF) vs. −3.82 (TDF), P < 0.001 and in spine BMD was −1.57 (TAF) vs. −3.62 (TDF), P = 0.003. There were no fractures in either group.
CONCLUSIONS:The TAF arm had significantly improved renal and bone safety parametersless proteinuria and less change in hip and spine BMD, consistent with results from a similarly designed study of the elvitegravir/C/F/TAF STR. This D/C/F/TAF STR offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved long-term renal and bone safety with TAF.
Abstract
Background
GSK2838232 is a second-generation, potent, small-molecule, oral human immunodeficiency virus type 1 (HIV-1) maturation inhibitor for once-daily administration boosted with a ...pharmacoenhancer.
Methods
The phase 2a, proof-of-concept study was an open-label, adaptive dose-ranging design. Safety, pharmacokinetics, and efficacy of GSK2838232 boosted by cobicistat were evaluated in individuals with HIV-1 infection. The study participants (N = 33) received GSK2838232 once daily across a range of doses (20–200 mg) with cobicistat 150 mg for 10 days.
Results
GSK2838232 was safe and well tolerated with no clinically meaningful changes in safety parameters or adverse events. Exposure (maximum concentration and area under the concentration-time curve from time zero to the concentration at 24 hours postdose) increased 2- to 3-fold with repeated dosing in an approximately dose-proportional manner, reaching steady-state by day 8 with a half-life (t½) from 16.3 to 19.2 hours. Clearance and t½ values were not dependent on dose. Viral load declined from baseline with all GSK2838232 doses. Mean maximum declines from baseline to day 11 in HIV-1 RNA log10 copies/mL with the 20-mg, 50-mg, 100-mg, and 200-mg cohorts were −0.67, −1.56, −1.32, and −1.70, respectively. CD4+ cell counts increased at doses ≥50 mg.
Conclusions
GSK2838232 with cobicistat was well tolerated and exhibited efficacy as a short-term monotherapy in participants with HIV-1. This positive proof-of-concept study supports the continued development of GSK2838232 for the treatment of HIV as part of combination antiretroviral therapy.
Clinical Trials Registration
NCT03045861.
A new oral HIV-1 maturation inhibitor, GSK2838232, when administered as capsules with cobicistat for 10 days, was well tolerated and exhibited antiviral efficacy in participants with HIV-1.
Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, ...can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV.
In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (≤100 000 or >100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading 600 mg on days 1 and 2, followed by 300 mg on day 8) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594.
Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2·6%, 95% CI -18·4 to 13·2), 85% (45 of 53) for group 2 (-7·1%, -23·4 to 9·3), 85% (44 of 52) for group 3 (-7·2%, -23·5 to 9·1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling).
Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs.
Gilead Sciences.
Introduction
Fibrin degradation product
d
-dimer can be a valuable indicator for venous thromboembolism (VTE). The use of
d
-dimer testing in primary care settings can be limited by restricted access ...to laboratory services. This performance evaluation compares a quantitative, point-of-care (POC)
d
-dimer assay (LumiraDx
d
-Dimer Test) with a reference laboratory-based
d
-dimer assay.
Methods
Plasma samples from patients presenting to secondary care in the UK, USA, and Germany were analyzed centrally using the LumiraDx
d
-Dimer Test and the reference test (bioMérieux VIDAS
d
-Dimer Exclusion II immunoassay). Method comparison used Passing–Bablok regression analysis with pre-specified equivalence criteria of
r
≥ 0.9 and slope of 0.9–1.1. The NOVEL-3 study (NCT04375982) compared equivalency of fingerstick, venous blood (VB), and plasma samples from the same patient, tested at US primary care clinics next to the patient using the POC LumiraDx
d
-Dimer device. Measurements obtained from fingerstick and VB samples were compared with results from plasma samples, using Deming regression. The healthy reference range was determined using plasma samples of healthy volunteers, collected by commercial suppliers in Germany and the USA, which were analyzed centrally using the LumiraDx
d
-Dimer Test and the reference test.
Results
The LumiraDx
d
-Dimer Test demonstrated agreement with the bioMérieux VIDAS
d
-Dimer Exclusion II immunoassay for plasma samples (
r
= 0.923, slope of 1.016,
n
= 1767). There was good agreement between fingerstick/VB samples and plasma samples (
r
= 0.980–0.986,
n
= 93) measured using the LumiraDx
d
-Dimer Test. Overall error rates were 1.8%. The healthy reference range 90% percentile for
d
-dimer was calculated as 533 µg/l fibrinogen equivalent units (FEU).
Conclusions
The quantitative LumiraDx
d
-Dimer Test is easy to use and can accurately measure
d
-dimer levels in a range of blood sample types, including fingerstick samples, which could improve assessment of VTE cases in community and hospital near-patient settings.
Osteonecrosis in HIV: A Case-Control Study Scribner, Anita N; Troia-Cancio, Paolo V; Cox, Bruce A ...
Journal of acquired immune deficiency syndromes,
2000-September-1, Letnik:
25, Številka:
1
Journal Article
Recenzirano
Odprti dostop
BACKGROUND:Osteonecrosis (avascular necrosis) has been infrequently reported in HIV-infected patients. It is not known whether HIV itself is an independent risk factor for osteonecrosis.
METHODS:We ...identified 25 patients with osteonecrosis from 1984 to 1999 from a large county teaching hospital and two large practices in Dallas County that specialize in HIV-disease related therapy. A retrospective chart review was performed to evaluate potential risk factors for osteonecrosis. Each case was matched with two controls for HIV positive status and date of osteonecrosis diagnosis.
RESULTS:In the study, 22 of 25 (88%) case patients had at least one osteonecrosis risk factor compared with 24 of 50 (48%) controls, p = .003. The most common osteonecrosis risk factors were hyperlipidemia (32%), alcoholism (28%), pancreatitis (16%), corticosteroids (12%), and hypercoaguability (12%). Of the cases, 12% were idiopathic. Multiple joints were involved in 72% of cases. Four of the case patients compared with none of the controls received megesterol acetate before the diagnosis of osteonecrosis, p = .01. No significant differences were found between cases and controls with respect to liver function tests, testosterone levels, triglyceride levels, cholesterol levels, or CD4 cell counts. Saquinavir was independently associated with osteonecrosis, p < .05. However, no differences in overall use of protease inhibitors among cases and controls were noted79% versus 76%, respectively.
CONCLUSIONS:The increased incidence of osteonecrosis in HIV/AIDS may be due to an increased frequency of risk factors previously associated with osteonecrosis such as hyperlipidemia, corticosteroid use, alcohol abuse, and hypercoaguability. Use of protease inhibitors was not independently associated with osteonecrosis.
Osteonecrosis in HIV: A Case-Control Study Scribner, Anita N.; Troia-Cancio, Paolo V.; Cox, Bruce A. ...
Journal of acquired immune deficiency syndromes,
09/2000, Letnik:
25, Številka:
1
Journal Article
Studying land snails is a good way to introduce elementary students to invertebrates and an effective way for children to learn how to answer some of their own questions.
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