Kitchen et al Clinical studies TORO ENF was approved in 2003 as a salvage therapy agent follow- ing the success of the Phase III TORO (T-20 vs Optimized Regimen Only) clinical trials. TORO 1 (United States, Canada, Mexico, and Brazil) and TORO 2 (Australia and Europe) assessed the safety and efﬁcacy of ENF plus an opti- mized background (ENF + OB) versus optimized background alone (OB) in approximately 1000 treatment-experienced patients (n = 663 ENF + OB and n = 334 OB) (Lalezari et al 2003; Lazzarin et al 2003). Entry criteria for these trials included previous treatment with at least one nucleoside reverse-transcriptase inhibitor, at least one non-nucleoside reverse-transcriptase inhibitor, and at least one (TORO 2) or two (TORO 1) protease inhibitors, documented resistance to these drugs, or both. After 48 weeks, 30% of the ENF + OB arm had HIV-1 RNA levels 400 copies/mL versus 12% of the OB alone. The ENF + OB arm also had greater decreases in viral load and greater increases in CD4+ T-cell counts than OB alone (Nelson et al 2005). The TORO trials are also important in that they established the importance of using an optimized background as the basis for comparison in clinical trials. Based on this evidence, ENF was granted accelerated approval by the FDA in 2003. As part of the long term follow-up for the TORO trials, at week 48 patients in the OB arm were required to switch to the ENF + OB arm to stay in the study but were allowed to switch prior to week 48 if they experienced virologic failure (Reynes et al 2007). A total of 230 (68.9%) patients from the OB arm switched, of these 222 switched prior to week 48 due to virologic failure. These patients along with the original ENF + OB arm were followed up to 96 weeks where 114 (49.6%) of the switch patients and 362 (55%) of the original ENF + OB remained on ENF + OB at week 96. At 96 weeks, 26.5% of patients on ENF + OB had a viral load less than 400 copies/mL and 17.5% achieved viral suppression below 50 copies/mL. Patients in the original ENF + OB arm had a viral load decrease of 2.1 log10 copies/mL from baseline and an increase of 166 CD4+ T-cells. In the switch arm, patients had a mean decrease of 1.1 log10 copies/mL from baseline and an increase of 116 CD4+ T-cells. The fact that the switch patients had a reduced immunologic and virologic response compared to patients who started with ENF + OB suggests that ENF should be initiated earlier in salvage therapy. RESIST and POWER Phase III clinical trial studies RESIST 1 (Randomized Evalu- ation of Strategic Intervention in multi-drug reSistant patients 434 with Tipranivir-North America and Australia) and RESIST 2 (Europe and Latin America) involved 1509 patients who experienced treatment failure with at least two PI-based regimens (Hicks et al 2006). All patients in the studies were randomized to take ritonavir-boosted tipranivir plus an opti- mized background (tipranivir/r + OB) or a ritonavir-boosted comparator PI plus OB (cPI). After 48 weeks, patients in the tipranivir/r + OB group had a greater proportion of respond- ers (33.6%) versus cPI (15.3%). The treatment response was greater in both groups if patients had ENF as part of their OB. At 48 weeks, 58.5% of ENF-naïve patients in tipranivir/r + OB who received ENF had a treatment response compared to 21.6% of ENF-naïve patients in cPI who also received ENF. After 96 weeks, 26.4% (197/746) of patients in the tip- ranivir/r + OB groups had at least a 1 log10 reduction in their plasma viremia from baseline, compared to 10.7% (79/737) of patients in the cPI group (Gazzard et al 2006). Again, this result was more pronounced in patients taking ENF with 45.2% (56/124) in the tipranivir/r + OB group showing a 1 log10 reduction in viral load below their pre-RESIST levels, compared to 16.5% (16/97) in the cPI group. The phase III clinical trials POWER 1 (Performance of TMC114/r When evaluated in treatment-Experienced patients with PI Resistance) and POWER 2 randomized highly treatment-experienced patients to ritonavir-boosted darunavir plus OB (darunavir/r + OB) or a comparator PI plus OB (cPI) (Clotet et al 2007). After 48 weeks, 61% (67/110) of patients in the darunavir/r + OB had a reduction in plasma viral load of 1 log10copies/mL from baseline versus only 15% (18/120) of patients in the cPI group. This result was also more pronounced in patients who were ENF-naive. In the darunavir/r + OB arm, 81% (29/36) of ENF-naive patients taking ENF had a 1 log10 decrease in viral load from baseline compared to 56% (34/61) of patients on darunavir/r + OB not taking ENF. The RESIST and POWER studies were similar in terms of average age, gender, race, pre-study viral loads and CD4+ T-cell counts, prior treatment experience, and evidence of drug resistance, however, there are several signiﬁcant dif- ferences (Hill and Moyle 2006). First, the POWER studies involved only 255 individuals while the RESIST study included 1,509 patients. Second, more people, 23%, in POWER used "double-boosted" comparator PIs (two PIs combined with ritonavir) compared to 0% in the RESIST studies. Third, ENF was more likely to be used in POWER than in RESIST trials (47% vs 25%, respectively). After 48 weeks in both studies, approximately 46% in the darunavir/r + OB POWER groups had viral loads below 50 copies/mL, Therapeutics and Clinical Risk Management 2008:4(2)