Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 μM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.

Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity

The 2008 BHIVA Guidelines have been updated to incorporate all the new relevant information (including presentations at the 15th Conference on Retroviruses and Opportunistic Infections 2008) since the last iteration. The guidelines follow the methodology outlined below and all the peer-reviewed publications and important, potentially treatment-changing abstracts from the last 2 years have been reviewed.


The translation of data into clinical practice is often difficult even with the best possible evidence (i.e. two randomized controlled trials) because of trial design, inclusion criteria and precise surrogate marker endpoints (see Appendix). The recommendations based upon expert opinion have the least good evidence but perhaps provide an important reason for writing the guidelines to produce a consensual opinion about current practice. It must, however, be appreciated that such opinion is often wrong and should not stifle research to challenge it.


Similarly, although the Writing Group seeks to provide guidelines to optimize treatment, such care needs to be individualized and we have not constructed a document that we would wish to see used as a ‘standard’ for litigation.

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British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008

Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression

Structural violence refers to the social structures that put people in harm's way. Farmer and colleagues describe the impact of social violence upon people living with HIV in the US and Rwanda.

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Structural Violence and Clinical Medicine

WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.

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Can we safely target the WNT pathway

Background Among persons in North America who are newly infected with the human immunodeficiency virus (HIV), the prevalence of transmitted resistance to antiretroviral drugs has been estimated at 1 to 11 percent. Methods We performed a retrospective analysis of susceptibility to antiretroviral drugs before treatment and drug-resistance mutations in HIV in plasma samples from 377 subjects with primary HIV infection who had not yet received treatment and who were identified between May 1995 and June 2000 in 10 North American cities. Responses to treatment could be evaluated in 202 subjects. Results Over the five-year period, the frequency of transmitted drug resistance increased significantly. The frequency of high-level resistance to one or more drugs (indicated by a value of more than 10 for the ratio of the 50 percent inhibitory concentration [IC50] for the subject's virus to the IC50 for a drug-sensitive reference virus) increased from 3.4 percent during the period from 1995 to 1998 to 12.4 percent dur...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa013552

Michael Kilby

Papers

Antiretroviral-Drug Resistance among Patients Recently Infected with HIV