Reverset: first data in patients with nucleoside resistance

31 January 2005. Related: Conference reports, Antiretrovirals, ICAAC 44th Washington 2004.

Simon Collins, HIV i-Base

d-d4FC (Reverset) is a cytidine analogue reverse transcriptase inhibitor that has shown in vitro activity to HIV resistant to 3TC, AZT, tenofovir and other RTIs. First in vivo data, from exposure to 10 days monotherapy in treatment naïve patients, achieved mean viral load reductions of –1.77 log after 10 days exposure to 200mg dose, and was presented at the 2004 retrovirus conference. [1]

Results were presented at ICAAC on 10 treatment-experienced patients currently on failing treatment (viral load >1000 copies/mL; CD4 >50 cells/mm³) randomised 4:1 to add 200mg RTV or placebo for 10 days to their existing regimen. [2]

Previous treatment history in this group included 3, 1, 1 and 3 patients having failed 1, 2, 3 and 4 or more previous treatment regimens respectively. At baseline, 5/8 patients had 184V and 4/4 had 3 or more TAMS (41, 67. 70. 210, 215, 219). Two patients showed no RT mutations and none of the patients has the K65R mutation associated with tenofovir.

3TC was maintained by 6/8 patients in their regimen; 3/8 maintained AZT; 5/8 maintained tenofovir and one patient continued using each of ddI and abacavir.

Mean viral load reduction at day 10 was –0.80 +/- 0.68 log from baseline of 4.11 =/- 0.98 copies/mL with 7/8 patients showing >/= 0.5 log reduction. This response was also seen in patients who maintained 3TC and who had M184V mutation at baseline. The mean reduction in people with 3-4 TAMS was around –0.4 log.

Incidence of headache, cold, and neutropenia was similar in Reverset and placebo arms. Increases in triglycerides, lipase and sore throat were reported in 4, 3 and 3 patients respectively who were receiving RVT (compared to no reports in placebo. A PK sub-study showed drug levels to be similar to previous treatment naïve data and plasma levels exceeded IC50 for most NRTI-resistant mutations.

Comment

This indication of short-term activity in treatment-experienced patients is extremely hopeful, especially given the previously curtailed RTI-pipeline, with hopeful compounds unable to overcome toxicity problems. Tolerability will also be critical to this compound.

A larger (n=180) international Phase 2b dose-finding study of Reverset in already underway.

References:

1. Tolerance and potent anti-HIV activity of Reverset following 10 days of monotherapy in treatment naïve individuals.11th CROI, San Fransisco. Abstract 137.
2. Murphy RL et al. Tolerance and anti-HIV-1 activity of Reverset following 10 days as add-on therapy to current regimens in treatment experienced HIV-infected individuals. 44th ICAAC, Washington, 2004. Abstract H-1130.