Sofosbuvir-based hepatitis C therapies in patients with chronic and end-stage kidney disease.

Sofosbuvir (SOF), a nucleotide inhibitor of the hepatitis C virus (HCV) polymerase, is a component of several all-oral HCV therapies. GS-331007, SOF's predominant metabolite, is renally eliminated and accumulates 5- to 20-fold in patients with advanced chronic kidney disease (CKD) or undergoing hemodialysis (HD), respectively. Preclinical data did not determine whether these exposures represented a risk for toxicity. Therefore subjects with advanced CKD were not included in registrational studies and SOF was not initially approved for use in advanced CKD. Nevertheless, after initial licensing, off-label use of SOF at full or reduced doses was reported in patients with kidney disease. Two clinical trials of SOF-containing therapies were conducted in patients with end-stage kidney disease, demonstrating safety and efficacy. These led to expanded US Food and Drug Administration approval in 2019 for the use of SOF-containing regimens in patients with advanced CKD, including dialysis dependence. Even so, given the availability of protease inhibitor-containing direct-acting antiviral regimens, there was a reluctance by some practitioners to use SOF-containing regimens in moderate to severe kidney disease. Here we review the existing data on SOF's pharmacokinetics, toxicology, efficacy and safety in patients with kidney disease. Data from both clinical trials and real-world practice settings indicate that in patients with moderate to severe kidney disease, full-dose SOF-based regimens have high rates of efficacy and acceptable safety and tolerability profiles, without increased risk for cardiac adverse events or clinically meaningful changes in kidney function. SOF-based regimens are safe and effective in patients who have moderate to severe kidney disease, including those undergoing HD.

Optimal Intensity and Duration of Walking Rehabilitation in Patients With Chronic Stroke: A Randomized Clinical Trial.

Importance: For walking rehabilitation after stroke, training intensity and duration are critical dosing parameters that lack optimization. Objective: To assess the optimal training intensity (vigorous vs moderate) and minimum training duration (4, 8, or 12 weeks) needed to maximize immediate improvement in walking capacity in patients with chronic stroke. Design, Setting, and Participants: This multicenter randomized clinical trial using an intent-to-treat analysis was conducted from January 2019 to April 2022 at rehabilitation and exercise research laboratories. Survivors of a single stroke who were aged 40 to 80 years and had persistent walking limitations 6 months or more after the stroke were enrolled. Interventions: Participants were randomized 1:1 to high-intensity interval training (HIIT) or moderate-intensity aerobic training (MAT), each involving 45 minutes of walking practice 3 times per week for 12 weeks. The HIIT protocol used repeated 30-second bursts of walking at maximum safe speed, alternated with 30- to 60-second rest periods, targeting a mean aerobic intensity above 60% of the heart rate reserve (HRR). The MAT protocol used continuous walking with speed adjusted to maintain an initial target of 40% of the HRR, progressing up to 60% of the HRR as tolerated. Main Outcomes and Measures: The main outcome was 6-minute walk test distance. Outcomes were assessed by blinded raters after 4, 8, and 12 weeks of training. Results: Of 55 participants (mean [SD] age, 63 [10] years; 36 male [65.5%]), 27 were randomized to HIIT and 28 to MAT. The mean (SD) time since stroke was 2.5 (1.3) years, and mean (SD) 6-minute walk test distance at baseline was 239 (132) m. Participants attended 1675 of 1980 planned treatment visits (84.6%) and 197 of 220 planned testing visits (89.5%). No serious adverse events related to study procedures occurred. Groups had similar 6-minute walk test distance changes after 4 weeks (HIIT, 27 m [95% CI, 6-48 m]; MAT, 12 m [95% CI, -9 to 33 m]; mean difference, 15 m [95% CI, -13 to 42 m]; P = .28), but HIIT elicited greater gains after 8 weeks (58 m [95% CI, 39-76 m] vs 29 m [95% CI, 9-48 m]; mean difference, 29 m [95% CI, 5-54 m]; P = .02) and 12 weeks (71 m [95% CI, 49-94 m] vs 27 m [95% CI, 3-50 m]; mean difference, 44 m [95% CI, 14-74 m]; P = .005) of training; HIIT also showed greater improvements than MAT on some secondary measures of gait speed and fatigue. Conclusions and Relevance: These findings show proof of concept that vigorous training intensity is a critical dosing parameter for walking rehabilitation. In patients with chronic stroke, vigorous walking exercise produced significant and meaningful gains in walking capacity with only 4 weeks of training, but at least 12 weeks were needed to maximize immediate gains. Trial Registration: ClinicalTrials.gov Identifier: NCT03760016.

Sofosbuvir, a Significant Paradigm Change in HCV Treatment.

Nucleotide compounds like sofosbuvir, acyclovir, and tenofovir have proven to be amongst the most potent orally available antiviral treatments. These drugs exhibit high efficacy and a wide therapeutic index, with demonstrated utility in a number of chronic viral infections. The approval of Sovaldi™, brand name for sofosbuvir, by the U.S. Food and Drug Administration heralded improvements in chronic hepatitis C virus (HCV) treatment. Sofosbuvir was originally discovered by Pharmasset Corporation and named PSI-7977. It was subsequently acquired and advanced through phase 3 development by Gilead Sciences, Inc. In Sofosbuvir both a unique pharmacology and a high specificity for the HCV ribonucleic acid polymerase are present in a molecule that is well tolerated and highly efficacious. Phase 2 and 3 clinical trials have consistently demonstrated durable and high rates of sustained virologic response (SVR), curing patients in excess of 80% in all genotypes and >90% in treatment-naïve subjects being administered combination therapy with other agents. Harvoni(®) is the combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral tablet, and it has demonstrated high SVR rates in patients infected with HCV genotype 1, without the need for exogenous interferon and/or ribavirin. Here, we discuss the discovery, development, pharmacologic characterization, and results from the phase 3 trials of sofosbuvir. Hepatitis C is a chronic disease, for which most patients have been undiagnosed, are unwilling to start treatment, or are ineligible for treatment because of the high toxicity and low efficacy of interferon and ribavirin-based therapy. Clinical studies with sofosbuvir have demonstrated significant improvement over the prior standard of care, thus ushering in a new paradigm of HCV treatment and an update of treatment guidelines.