Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to efavirenz (Sustiva) may be transmitted or may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug. Even small amounts of transmitted efavirenz-resistant virus may also curtail the drug's effectiveness.1 If blood levels of the drug fall too low, this will help the development of resistance to efavirenz and may affect future treatment options .

All non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a low barrier to resistance, meaning that only one mutation is needed to result in a drop in the drug’s efficacy. The major mutation is K103N in the reverse transcriptase gene. Other efavirenz resistance mutations include L100I, V108I, Y188L, G190S, and P225H.2 3 4 5

Once resistance to efavirenz has developed, use of nevirapine (Viramune) is unlikely to be effective. Similarly, patients with resistance to one of the other NNRTIs are unlikely to benefit from efavirenz. One possible exception is the Y181C mutation, one that is associated with nevirapine resistance, but that may not cause resistance to efavirenz.

In some instances, response to an NNRTI-based regimen may be enhanced by the presence of certain mutations linked to nucleoside reverse transcriptase inhibitors (NRTIs).6 NRTI resistance mutations including M41L, M184V, L210W and T215Y have been associated with better virological and immunological responses to efavirenz-based regimens.7 8 9 However, this effect may be transient and its relevance for patients remains to be established.

A genetic polymorphism in the multidrug resistance gene 1 has been associated with a reduced likelihood of efavirenz treatment failure and a decreased rate of emergence of efavirenz resistance mutations.10

References

  1. Paredes R et al. Pre-existing minority drug-resistant HIV-1 variants, adherence, and the risk of antiretroviral treatment failure. J Infect Dis 201 (advance, online publication), 2010
  2. Batchelor L et al. Virological resistance to efavirenz. Twelfth World AIDS Conference, Geneva, abstract 41213, 1998
  3. Bachelor LT et al. Efavirenz response in NNRTI-experienced patients: results from the Sustiva expanded access program. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract 2200, 1999
  4. Uhlmann EJ et al. Effects of the G190A substitution of HIV reverse transcriptase on phenotypic susceptibility of patient isolates to delavirdine. J Clin Virol 31: 198-203, 2004
  5. Koval CE et al. Relative replication fitness of efavirenz-resistant mutants of HIV-1: correlation with frequency during clinical therapy and evidence of compensation for the reduced fitness of K103N + L100I by the nucleoside resistance mutation L74V. Virology (online edition), 2006
  6. Haubrich RH et al. The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a prospective cohort analysis. AIDS 16: 33-40, 2002
  7. Tozzi V et al. Mutations in HIV-1 reverse transcriptase potentially associated with hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban observational cohort. J Infect Dis 189: 1688-1695, 2004
  8. Schulman NS et al. Genetic correlates of efavirenz hypersusceptibility. AIDS 18: 1781-1785, 2004
  9. Whitcomb JM et al. Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates. AIDS 16: 41-47, 2002
  10. Haas D et al. Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and / or nelfinavir: an Adult AIDS Clinical Trials Group study. J Infect Dis 192: 1931-1942, 2005
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