Kitchen et al and these differences were not associated with differences in clinical response (Clotet et al 2004, 2007). ENF is only FDA approved for patients who have failed treatment with other agents, and thus is not recommended for initial therapy. The best possible initiation time for ENF treatment is when the patient can be predicted to have a strong, sustained virologic response Treatment with ENF is optimized when there are at least two other active agents besides ENF in the OB regimen, CD4 T-cell counts are greater than 100 and plasma HIV-1 RNA burden is less than 100,000 copies/mL (Clotet et al 2004). In general, patients who have higher CD4 counts, lower viral loads and greater number of active agents are more likely to have durable favorable virologic and immunologic response to ENF + OB (Lalezari et al 2003; Lazzarin et al 2003; Nelson et al 2005; Hicks et al 2006; Clotet et al 2007; Reynes et al 2007). The fact that the TORO switch patients had a reduced immunologic and virologic response compared to patients who started with ENF+OB reinforces this observation and suggests that ENF should be initiated earlier in salvage therapy. Several sub- studies in addition to the RESIST and POWER studies sug- gest that not all OB regimens are equal when used with ENF. Negredo et al found that patients who received both tenofovir and didanosine in their OB had little increase in CD4 counts at 8 weeks compared to patients with neither or one of these antiretrovirals in their OB regimen (Negredo et al 2005). If a boosted PI such as lopinavir/ritonavir (Nelson et al 2005), tipranivir/ritonavir (Hicks et al 2006) or duranavir/ritonavir (Clotet et al 2007) is the sensitive agent, then a boosted PI should be considered in the OB (Youle et al 2006). Patients may also initiate ENF in situations where resistance to all available treatment options is present, although this is clearly a less than optimal approach. Fortunately, additional anti- retroviral agents, including integrase inhibitors, are nearing approval for use that may be combined to create successful salvage regimens for patients with advanced disease. Further concerns with ENF treatment involve safety issues of injection site reactions. Good injection technique, rotation of injection sites, and massage of the site post- injection may all aid in reducing the occurrence of injection site reactions. Further recommendations for the management of ENF- treated patients should include a multidisciplinary approach to patient education, training, and support. ENF has high viral speciﬁcity and low toxicity and has been shown to achieve a sustained virologic and immunologic response in three-class experienced patients. The main drawbacks of ENF are the high cost of the drug, the need for parenteral 436 administration, and the potential for resistance and viral evolution. Resistance As with all inhibitors of HIV, variants resistant to ENF have been reported. Resistance to ENF usually occurs due to mutations in the N-terminal heptad repeat region of gp41 (HR-1) although mutations in HR-2 have also been reported (Rimsky 1998; Roman et al 2003; Cabrera et al 2006; Lu 2006; Melby et al 2006; Johnson et al 2007; Peuchant et al 2007). ENF resistance is uncommon in patients who are naïve to ENF (Roman et al 2003; Melby et al 2006) where the most common polymorphism observed was N42S (16.2% of patients). Transmission of ENF resistance has been reported in treatment naïve patients (Peuchant et al 2007). In vitro studies have shown resistance to ENF conferred by mutations in gp41 HR-1 amino acids 36–38 (Rimsky et al 1998). In vivo resistance associated mutations were seen in gp41 amino acids 36–45 within HR-1. In the TORO trials the most common mutations (greater than 10% of the viruses) were G36D, V38A, V38M, Q40H, and N43D. Lu et al in a clonal analysis of serial samples of patients with ENF failure found rapid emergence of ENF resistance (Lu et al 2006). At week 2 they found mutations at codons 36 (G36E/D/S) and 38 (V38A/G/M), while at week 4 mutations and codon 40 (Q40H) and 43 (N43D) were found. In a separate study of 13 heavily pre-treated patients receiving ENF, mutations in HR-1 positions 36, 38, and 43 were found as well as muta- tions further upstream from HR-1 and in HR-2 (Cabrera et al 2006). They observed that mutations at V38E + N42S resulted in a 513 fold change in ENF susceptibility while mutations at V38A + N42D/T had approximately a 140 fold change in ENF susceptibility and N42T + N43K/S resulted in a 32–61 fold change in susceptibility. Single mutations V38A, G36D, G36S, and N43D conferred a 16-, 8-, 7-, and 18-fold change in ENF susceptibility respectively. According to the International AIDS Society 2007, mutations associated with resistance to ENF include: G36D/S, I37V, V38A/M/E, Q39R, Q40H, N42T, N43D (Johnson et al 2007). Furthermore these guidelines caution that mutations in HR-2, as well as corecep- tor usage and density could affect ENF susceptibility. Cross-resistance Reeves et al introduced ENF resistance mutations in HR-1 into both a CCR5 and a CXCR4 utilizing strain to test for viral sensitivity to other classes of entry inhibitors (Reeves et al 2005). They found that ENF-resistance did not confer cross- resistance to other inhibitors including fusion inhibitors, Therapeutics and Clinical Risk Management 2008:4(2)