Hepatitis B drug entecavir reported to have anti-HIV viral activity in three patients
4 April 2007. Related: Conference reports, Hepatitis coinfection, CROI 14 (Retrovirus) 2007.
Simon Collins, HIV i-Base
Immediately prior to the conference, both the FDA and Bristol-Myers Squibb, the manufacturers of entecavir, issued a press release cautioning that this HBV drug may have anti-HIV activity. The data still remain controversial, as this was not reported in any earlier studies. The clinical importance of this finding, is the impact of entecavir monotherapy on the development of HIV drug resistance (the M184V mutation, shared with 3TC, FTC and abacavir), in the limited number of coinfected patients who are treated for HBV but not HIV.
Chloe Trio from Johns Hopkins University presented more details on three cases at the conference funded as independent research by NIAID. In each case HBV treatment was indicated by high HBV DNA while the patient still maintained high CD4 counts (>500 cells/mm3). In all three cases, in addition to drops in HBV DNA viral load (>4 logs), HIV RNA viral load reduced by 1-3 logs in the first months after entecavir monotherapy was initiated. Subsequently ARV therapy was started in 2 patients following later increases in HIV viral load.
Dose/response curves for inhibition of HIV infection were generated in vitro identified IC50 entecavir with an IC50 between 0.1 and 1 nM below the plasma concentration achieved during HBV treatment and typically 500 times lower than for AZT and 50 times lower than for 3TC. The researchers suggested that this sensitivity may explain why HIV activity was missed in earlier tests.
Activity was sufficiently potent to select for M184V resistance in patients and M184I in vitro. The prospective analysis of patient samples demonstrated accumulation of the M184V mutation with 0%, 61%, and 96% of the clones harboring this variant at the start of entecavir, and at 4 and 6 months after entecavir, respectively.
However, in the discussion after the presentations, a spokeman for BMS said that entecavir had been tested for HIV activity dozens of times over 10 years in single and multiple cells lines, without identifying any effect, other than at sub-micromolar concentrations which were not reproducible.
The package insert for entecavir has now been changed to reflect these findings with a warning not to use entecavir as HBV monotherapy.
This is the first detailed report of the potential low-level anti-HIV activity of entecavir with the emergence of HIV mutations. Although entecavir has been used in HIV/HBV co-infected patients previously (BMS Study 038); in this study the patients had well-controlled HIV disease.
While the BMS team had studied this phenomenon, this study at CROI, although only consisting of three patients, has resulted in a change in the Summary of Product characteristics (SPC) suggesting that entecavir should only be used in HIV/HBV co-infected patients with well-controlled HIV.
This leaves a big gap in the treatment options for HBV/HIV co-infection who do NOT need anti-HIV treatment.
There have been concerns about the possible anti-HIV activity of 10mg/day of adefovir (so far unsubstantiated) and in light of the above results many clinicians will need to give careful consideration to the use of telbivudine in this situation (an as yet un-licensed L-nucleoside analogue with anti-HBV activity and no anti-HIV activity).
M McMahon, B Jilek, T Brennan T et al. The Anti-Hepatitis B Drug Entecavir Inhibits HIV-1 Replication and Selects HIV-1 Variants Resistant to Antiretroviral Drugs. Oral abstract 136LB.
The oral presentation can be viewed online from the CROI website (see Wednesday, 10.00-11.45am Hepatitis B and C).