ddI

  • ddI resistance may occur as a result of mutations at codons 65, 69, 74, 75 and 151.
  • The Stanford and IAS-USA databases cite K65R and L74V/I as key ddI mutations. 1 2
  • Stanford also lists K70E and V75T/M. 1
  • IAS-USA also indicates that ddI resistance is associated with three or more of: M41L, D67N, L210W, T215Y/F, and K219Q/E. 2
  • L74V is specific to ddI, and increases viral sensitivity to AZT.
  • ddI becomes less effective in people with increasing numbers of NRTI resistance mutations (NAMs).

The combination of d4T and ddI appears to select for TAMs more commonly than it selects for the L74V mutation. A comparison of d4T and FTC combined with ddI and efavirenz has shown that whilst d4T-treated patients predominantly developed TAMs, FTC-treated patients predominantly developed the L74V mutation.

An analysis of 301 samples held in the Virco company database showed no significant reduction in ddI sensitivity in the presence of up to five TAMs.3 However, a randomised study of adding ddI to salvage therapy found that response declined with the number of NAMs, including M184V: those with greater than three NAMs had no significant response. 4

A cohort analysis of treatment-experienced patients who commenced ddI treatment found that patients with the M184V mutation had a significantly better virological response, suggesting that ddI may be best used after 3TC. 5

The ddI-associated L74V mutation increases sensitivity to AZT in much the same way as the M184V mutation. 6 7 L74V may also increase viral sensitivity to tenofovir, but there is contradictory evidence on this matter. 8

References

  1. Stanford HIV Drug Resistance Summaries. Stanford HIV Drug Resistance Summaries Online at http://hivdb.stanford.edu/pages/drugSummaries.html, accessed 2007
  2. IAS-USA Drug Resistance Mutations Group. Update of the drug resistance mutations in HIV-1: 2007. Topics in HIV Medicine 15(4):119-125, 2007
  3. Craig C et al. Nucleoside reverse transcriptase inhibitor-associated resistance substitutions and susceptibility to abacavir, didanosine and stavudine. Antivir Ther 7: S27, 2002
  4. Molina J et al. Didanosine in treatment-experienced HIV-infected patients: results from a randomised double-blind study (A1454-176 Jaguar). 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-447, 2003
  5. Pozniak A et al. Influence of the M184V mutation on virological outcome of highly active antiretroviral therapy with or without didanosine. Antivir Ther 7: S124, 2002
  6. Frankel F et al. The L74V mutation in HIV-1 RT diminishes synthesis of viral DNA in real-time PCR and impairs rescue of ZDV-terminated DNA synthesis. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 698, 2005
  7. Miranda LR et al. Differential effects of L74V and M184V mutations on ATP-mediated primer unblocking in HIV-1 reverse transcriptase carrying thymidine analog resistance mutations. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 699, 2005
  8. Bae AS et al. Pre-existing L74V is a risk factor for virological non-response and development of K65R in patients taking tenofovir DF (TDF). Antivir Ther 9: S174, 2004