Real-world outcomes of ledipasvir/sofosbuvir in treatment-naive patients with hepatitis C.

OBJECTIVES: Studies of hepatitis C virus (HCV) regimens have documented substantially reduced effectiveness in sustained virologic response (SVR) in the context of real-world clinical practice compared with clinical trials. Real-world and clinical trial SVR and cost-per-SVR data have not been reported for the all-oral, peginterferon-free and ribavirin (RBV)-free ledipasvir/sofosbuvir (LDV/SOF) regimen. Our objective was to compare the rates of SVR achievement and cost per SVR between pooled data from clinical studies of LDV/SOF and from real-world clinical practice. METHODS: Data were derived from the Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET), a real-world, multicenter, prospective, observational study; and from the TRIO Network, a retrospective database of HCV-treated patients. The 1-year cost per SVR was calculated as the total cost of an SVR ([cost of treatment regimen, adverse events, and monitoring costs] per SVR) during the first year of treatment. RESULTS: After 12 weeks, the SVR rates obtained in real-world studies ranged from 94% to 98%, comparing favorably with the SVRs achieved in the ION-1 and ION-3 trials (94% and 95%-99% with 8 and 12 weeks of RBV-free therapy, respectively). A single SVR, on average, cost $84,989 among patients enrolled in the ION-3 trial, with higher costs ($101,204) among patients with compensated cirrhosis compared with noncirrhotic patients ($81,668). In the pooled TARGET/TRIO population, the average cost of an SVR was $84,770, with costs of $101,380 and $81,368 in patients with compensated cirrhosis and patients without cirrhosis, respectively. CONCLUSIONS: Unlike the results obtained with prior HCV regimens, this study suggests that similar SVR rates are achieved with LDV/SOF in clinical trial-based studies and real-world studies. Further, achieving an SVR in real-world clinical practice was not associated with excess costs.

Preparation, X-ray structure and reactivity of a stable glycosyl iodide.

Highly selective reaction of methyl tetra-O-pivaloyl-beta-D-glucopyranuronate 2 with iodotrimethylsilane or (Me3Si)2 and I2 affords, in excellent yield, the 'disarmed' glycosyl iodide 1 which has good stability at 20 degrees C and excellent stability at 0 degrees C; the X-ray crystal structure of 1 is described, along with a comparison of its utility as a glycosyl donor to that of the corresponding bromide.

Current pharmacologic treatment paradigms for inflammatory bowel disease and the potential role of granulocyte/monocyte apheresis.

BACKGROUND: A broad range of pharmacologic therapies are available to treat active inflammatory bowel disease (IBD), including 5-aminosalicylate preparations, corticosteroids, and immunosuppressants (e.g., azathio prine/6-mercaptopurine [AZA/6-MP] or methotrexate). Although these therapies are effective, up to 60% of patients are refractory or intolerant. Biologic therapies, such as the anti-TNF agent infliximab, offer promise but are not without controversy; despite many positive reports, steroid-refractory patients are less likely than other individuals to respond to infliximab. Effective, long-term therapies that do not add to the adverse-effects burden in patients with IBD are needed. Of these, granulocyte/monocyte apheresis (GMA) is one promising approach. SCOPE: PubMed and relevant congresses databases were searched using the terms 'granulocyte/monocyte apheresis,' 'GMA,' 'leukocytapheresis,' 'Adacolumn,' and 'Cellsorba.' These studies were further selected to include only those focusing on IBD. A time frame of 2000-2006 was used. FINDINGS: Data from open-label trials show that patients with moderate-to-severe IBD refractory to conventional pharmacologic treatment achieved clinical response and/or remission after treatment with GMA. Furthermore, recent small open-label trials of GMA show increased rates of induction and maintenance of response/remission in steroid-naïve IBD patients. CONCLUSIONS: The remission rates seen in these open-label clinical trials of GMA are consistent with those of currently available pharmacologic therapies for IBD. However, the majority of these trials enrolled only small numbers of patients, were largely open-label, and were of limited duration. These data must be confirmed in well-controlled, large-scale clinical trials.

Structure-activity relationships of some opiate glycosides.

A number of analogues of morphine-6-glucuronide 1 have been prepared and evaluated as potential analgesic agents by competitive mu-receptor binding assay and in vivo antinociceptive activity. The analogues show variation in the nature of the carbohydrate residue, the N-substituent, the O(3)-substituent and saturation of the 7,8-double bond compared to 1. In general, only the 6beta-glucoside or beta-glucuronide carbohydrate residues showed potent agonism; other modified carbohydrates were less active or exhibited potential antagonism. Variations in N-substituent led to either reduced agonism (N-H) or potential antagonism [N-allyl, N-(cyclopropyl)methyl]; a polar N-substituent, carboxymethyl, failed to bind. Saturation of the 7,8-double bond led to increased agonism compared to the parent compound in all three examples studied.