Horsburgh Jr. C.R.,Boston University |
Haxaire-Theeuwes M.,Tibotec |
Lienhardt C.,World Health Organization |
Wingfield C.,PATH |
And 4 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2013
Several new classes of anti-tuberculosis agents are likely to become available in the coming decade. Ensuring prompt access to these drugs for patients without other treatment options is an important medical and public health issue. This article reviews the current state of 'compassionate use' and 'expanded access' programs for these new drugs, and identifies several shortcomings that will limit patient access to the drugs. A series of five steps is outlined that will need to be taken by national health bodies, international agencies and non-governmental organizations to prevent undue delays in access to new tuberculosis drugs for patients who could benefit from them. Following these steps can ensure that patients will be able to benefit from access to these drugs, while minimizing the risk of emergence of resistance to the drug. © 2012 The Union.
Rimsky L.,Tibotec BVBA |
Vingerhoets J.,Tibotec BVBA |
Van Eygen V.,Tibotec BVBA |
Eron J.,University of North Carolina at Chapel Hill |
And 4 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2012
Genotypic and phenotypic characterization was performed of HIV-1 isolates from treatment-naive HIV-1-infected patients experiencing virologic failure (VF) during treatment with the nonnucleoside reverse transcriptase inhibitor (NNRTIs) rilpivirine or efavirenz in the pooled phase 3 studies ECHO and THRIVE. Among 686 patients receiving rilpivirine, 72 (10%) experienced VF versus 39 of 682 (6%) receiving efavirenz. In patients with low baseline viral load (VL) ≤100,000 copies per milliliter, the proportions of rilpivirine VFs (19 of 368) and efavirenz VFs (16 of 330) were the same (5%). In patients with high baseline VL >100,000 copies per milliliter, the proportion of VFs was higher with rilpivirine (53 of 318; 17%) than efavirenz (23 of 352; 7%). The rate of rilpivirine VF was comparable between HIV-1 subtype B-infected (11%) and nonsubtype B-infected (8%) patients. The absolute number of VFs with treatment-emergent NNRTI resistance-associated mutations (RAMs) was higher for rilpivirine (most commonly E138K or K101E) than efavirenz (most commonly K103N), but relative proportions were similar [63% (39 of 62) vs. 54% (15 of 28), respectively]. More rilpivirine VFs had treatment-emergent nucleoside/nucleotide reverse transcriptase inhibitor RAMs than efavirenz VFs [68% (42 of 62) versus 32% (9 of 28), respectively], most commonly M184I and M184V. The proportion of rilpivirine VFs with RAMs in patients with low baseline VL was lower than in those with high baseline VL [38% (6 of 16) versus 72% (33 of 46) for NNRTI RAMs and 44% (7 of 16) versus 76% (35 of 46) for nucleoside/nucleotide reverse transcriptase inhibitor RAMs, respectively]. In summary, VF and treatment-emergent reverse transcriptase RAMs were similar at low baseline VL but more frequent at high baseline VL in rilpivirine-treated than in efavirenz-treated patients. The frequent emergence of E138K, especially in combination with M184I, in rilpivirine VFs is a unique finding of these trials.
Zeuzem S.,Goethe University Frankfurt |
Andreone P.,University of Bologna |
Pol S.,University of Paris Descartes |
Lawitz E.,Alamo Medical Research |
And 18 more authors.
New England Journal of Medicine | Year: 2011
BACKGROUND: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.) Copyright © 2011 Massachusetts Medical Society.
Hohlfeld K.,University of Southampton |
Tomassi C.,University of Southampton |
Wegner J.K.,Tibotec |
Kesteleyn B.,Tibotec |
Linclau B.,University of Southampton
ACS Medicinal Chemistry Letters | Year: 2011
A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. High affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutations were identified using a cell-based assay. A number of PIs have been synthesized that show equivalent and greater activity for HIV-1 mutant strains as compared to wild-type HIV-1. The activity on the purified enzyme was confirmed for a selection of analogues. © 2011 American Chemical Society.
Roymans D.,Tibotec BVBA |
De Bondt H.L.,Tibotec BVBA |
Arnoult E.,Tibotec |
Geluykens P.,Tibotec BVBA |
And 10 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010
Six-helix bundle (6HB) formation is an essential step for many viruses that rely on a class I fusion protein to enter a target cell and initiate replication. Because the binding modes of small molecule inhibitors of 6HB formation are largely unknown, precisely how they disrupt 6HB formation remains unclear, and structure-based design of improved inhibitors is thus seriously hampered. Here we present the high resolution crystal structure of TMC353121, a potent inhibitor of respiratory syncytial virus (RSV), bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats. Binding of TMC353121 stabilizes the interaction of HR1 and HR2 in an alternate conformation of the 6HB, in which direct binding interactions are formed between TMC353121 and both HR1 and HR2. Rather than completely preventing 6HB formation, our data indicate that TMC353121 inhibits fusion by causing a local disturbance of the natural 6HB conformation.