As with all other anti-HIV drugs, strains of HIV that are resistant to tenofovir (Viread) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.

Tenofovir does not appear to select new resistance mutations in the vast majority of people who add the drug to a failing regimen. Genotypic analysis from the 907 study found that only 3% of the patients with detectable viral load had developed a K65R mutation, which has been associated with tenofovir resistance in test-tube studies^[1][2][3][4].

The 902 and 907 studies, in which some participants have taken tenofovir for up to 48 weeks, showed that some resistance mutations in the reverse transcriptase gene did not undermine the activity of tenofovir, including D67N, K70R, T215Y/F and K219Q/E/N. However, the thymidine analogue mutations (TAMs) M41L and L210W did reduce the response to tenofovir in these studies^[5].

Tenofovir is also active against virus with the ddI (didanosine, Videx / VidexEC) resistance mutation L74V and the ddC (zalcitabine, Hivid) resistance mutation T69D. In addition, laboratory studies suggest that virus which is resistant to NRTIs with the Q151M multidrug resistant mutation will still be sensitive to tenofovir. Multi-NRTI resistant virus with a T69S double insertion mutation may exhibit reduced susceptibility to tenofovir, although it may remain sensitive to tenofovir if the M184V mutation, which is associated with prior 3TC (lamivudine, Epivir) treatment, is also present^[6]. In general, the presence of the M184V mutation in the context of other drug resistance mutations seems to improve sensitivity to tenofovir^[7].

This has led some researchers to suggest that it may be appropriate to maintain 3TC or abacavir (Ziagen) treatment in treatment-experienced people commencing tenofovir in order to preserve this mutation. Furthermore, tenofovir seems to have a high barrier to resistance as well as being effective against HIV with NRTI resistance, making it an attractive candidate for first- and second-line treatment.