With the exception of N42S - a polymorphism that occurs in ~15% of viruses from ENF-naive persons - positions 36-45 are highly conserved. The most well characterized ENF-associated mutations (G36D/E/S, V38A/M/E, Q40H, and N43D) reduce ENF susceptibility ~10- to 20-fold. Single point mutations are often present during initial virologic failure and may occur rapidly in persons receiving ENF without other active drugs.

Viruses containing two or more mutations in this region often emerge in persons continuing ENF for several months or longer despite ongoing HIV-1 replication. These viruses usually contain at least one common point mutation often with other mutations in this region (e.g., mutations at positions 42-45). The presence of two or more mutations may reduce ENF susceptibility >100-fold.

gp41 mutations outside of positions 36-45 may occasionally contribute to decreased susceptibility in combination with mutations at positions 36-45.

Non-gp41 changes have not convincingly been shown to influence ENF susceptibility. However, ENF targets gp41 during a kinetic window that is influenced by CD4 and co-receptor binding. Processes that influence these two processes may influence ENF activity in vivo.

ENF is not recommended for initial therapy except possibly in individuals who are primarily infected with a highly drug-resistant virus and require urgent treatment to control advancing immunosuppression.

ENF is not recommended for second-line therapy except in individuals primarily infected with a highly multidrug-resistant virus or a virus that has developed high-level NRTI and PI-resistance (an extremely rare occurrence in persons starting PI-based regimens).

ENF is recommended for salvage therapy in individuals with advancing immunosuppression who are considered unlikely to achieve sustained virus suppression with PIs and NRTIs alone. Such individuals would include (i) those infected with viruses having high-level NRTI and PI-resistance in whom there would be a high risk of rapid failure and triple-class resistance if an NNRTI were to be the only active new drug used; (ii) those infected with viruses having moderate-to-high level resistance to drugs of all three classes but who are likely to benefit from a change in their PIs or NRTIs (e. g., a change to LPV/r, intensification with a third NRTI), and (iii) those infected with viruses having high-level triple-class resistance who have advanced immunosuppression and are at high risk of an opportunistic infection unless they achieve some immunologic improvement. Although such individuals are at higher risk of virologic failure with ENF than patients in whom additional drugs retain some activity, virologic and immunologic benefit has also been reported in this setting.