Anchors away: new HIV entry inhibitor study creates a splash
Richard Jefferys, TAG
In December, the journal Science Translational Medicine published results from a phase I trial of a new type of anti-HIV drug named VIR-576. 
The drug inhibits the entry of HIV into target cells by blocking the mechanism the virus uses to anchor itself to the cell. This mechanism involves a harpoon-like extension called the gp41 fusion peptide, which shoots into the cell membrane. VIR-576 gloms onto the end of the gp41 fusion peptide, preventing its penetration (a bit like covering the spear end of a harpoon so it just bounces off the target). Although VIR-576 is not the first entry inhibitor HIV drug, it is the first to target the gp41 fusion peptide. The researchers have dubbed it an anchoring inhibitor.
The phase I study administered three different doses of VIR-576 to three groups of six untreated HIV-positive people with viral loads over 10,000 copies and CD4 counts above 350. Because VIR-576 is a peptide, administration was via continuous intravenous infusion. The total duration of treatment was 10 days. At the highest dose of 5 grams per day, VIR-576 caused an average viral load reduction of 1.2 logs (over 90%). The drug was well tolerated but two participants (one in each of the two lower dose groups) showed signs of an allergic reaction that resolved once treatment was stopped. No evidence of resistance to VIR-576 was documented.
The findings are potentially encouraging for several reasons:
- They show that HIVs gp41 fusion peptide is a viable drug target, which was previously uncertain.
- The gp41 fusion peptide does not appear able to tolerate mutations as easily as other drug targets, suggesting resistance will be slower to develop.
- The activity of VIR-576 is not affected by resistance to available anti-HIV drugs.
- Fusion peptides are essential to the replication of most enveloped viruses, suggesting the general approach could be applied to other viral pathogens.
However, there are also caveats that were not clearly articulated in some of the media stories that appeared when the study was published. Most obvious is that the current formulation of VIR-576 cannot practically be used as a treatment due to the requirement for continuous intravenous infusion. The high dose and potential cost are additional impediments; the dose of the approved HIV entry inhibitor Fuzeon (T-20) is 0.18 grams/day (with a cost of around $25,000 per year) whereas the most effective dose of VIR-576 was a daunting 5 grams/day. The researchers highlight these concerns in the discussion section of the paper and state: to overcome these drawbacks in costs and administration, we are currently working on the development of small-molecule inhibitors with an analogous mode of action. In interviews, investigator Frank Kirchoff has estimated that it will likely be at least a year before any oral analogs of VIR-576 are ready for testing.
Source: TAG basic science blog. (04 January 2011).
- Forssmann W-G et al. Short-Term Monotherapy in HIV-Infected Patients with a Virus Entry Inhibitor Against the gp41 Fusion Peptide. Sci Transl Med 22 December 2010: Vol. 2, Issue 63, p. 63re3. DOI: 10.1126/scitranslmed.3001697.