Reports

Results in Treatment-naive Patients

According to findings from the ARTEMIS (Antiretroviral Therapy with TMC114 Examined in Naive Subjects) trial presented here after 48 weeks’ follow-up, treatment-naive patients receiving the novel protease inhibitor (PI) darunavir boosted with ritonavir (DRV/r) responded at least as well as patients treated with boosted lopinavir (LPV/r) and with a greater response in patients with higher baseline viral loads. ARTEMIS randomized 689 treatment-naive individuals to either DRV/r 800/100 mg q.d. (n=343) or LPV/r at 400/100 mg b.i.d. or 800/200 mg q.d. (n=346). This was the first trial to explore the potency of once-daily dosing of DRV.

Both boosted PI regimens were given with a nucleoside reverse transcriptase inhibitor (NRTI) backbone consisting of tenofovir plus emtricitabine (TDF/FTC) 300/200 mg. At baseline, approximately 40% of patients in both treatment arms had a CD4+ cell count of <200 cell/mm3 while 36% of patients in both groups had a baseline HIV RNA >100,000 copies/mL.

As presented by Dr. Edwin DeJesus, Medical Director, Orlando Immunology Center, Florida, 84% of patients in the DRV/r arm and 78% of those in the LPV/r arm achieved an HIV RNA of <50 copies/mL at week 48, a non-significant difference between the two groups.

However, when stratified for a baseline viral load of ³100,000 copies/mL, significantly more patients achieved an undetectable HIV RNA on DRV/r than those on LPV/r (79% vs. 67%, respectively; P<0.05). For those with a baseline viral load of <100,000 copies/mL, response rates were virtually identical at 86% and 85%, respectively, in achieving undetectable levels. The median gain in CD4+ cell count was 137 cells/mm3 for the DRV/r group and 141 cells/mm3 for the LPV/r group.

Gastrointestinal adverse events were significantly more likely to occur in the LPV/r group at 14% vs. 7% in the DRV/r arm (P<0.01). Treatment discontinuation due to the incidence of grade 2 to 4 events was low in both groups at 3% in the DRV/r group and 7% in the LPV/r group. Elevations in triglycerides were more pronounced in the LPV/v arm, but no patients discontinued therapy due to renal adverse events. Overall, the total cholesterol to HDL-C ratio did not change in either group. Virologic failure was seen in <1% in the DRV/r group and in 2% of the LPV/r group.

“The use of once-daily DRV/r 800/100 mg plus TDF/FTC in treatment-naive patients resulted in excellent virologic and immunologic responses and was well tolerated, with a favourable safety profile,” Dr. DeJesus concluded, “and in comparison to the LPV/r arm, DRV/r 800/100 mg was non-inferior in the overall population and superior in patients with high viral load.”

TITAN: Preserving Future Treatment Options in the Treatment-experienced Patient

In the TITAN (TMC114/r in Treatment-experienced Patients Naive to Lopinavir) trial, the same boosted PI-based regimen is also being evaluated in an ongoing 96-week, phase III trial. Also designed as a non-inferiority trial in which DRV/r 600/100 mg b.i.d. was compared with LPV/r 400/100 mg b.i.d., both PIs were added to an individually optimized background regimen. As was previously reported, by week 48, significantly more patients on the DRV/r regimen achieved a viral load of <50 copies/mL than those on the LPV/r regimen (71% vs. 60%, respectively; P=0.005) (Lancet 2007;370(9581):49-58). Also, virologic failure occurred in 22% of patients on LPV/r and 10 % of patients on DRV/r.

In exploring the development of resistance in TITAN patients, lead author Dr. Sandra De Meyer, clinical researcher, Mechelen, Belgium, and colleagues analyzed data from the primary analysis when all patients had reached 48 weeks of treatment or had discontinued treatment earlier. All patients in TITAN were naive to LPV at baseline; 98.5% of patients were fully susceptible to DRV and 90% to LPV.

Among virologic failures, more patients receiving LPV/r failed to respond to treatment or rebounded compared with those receiving DRV/r. Even in patients who still remained susceptible to LPV, as well as those who received no or only one previous PI, twice as many patients receiving LPV/r failed to respond or rebounded compared to patients in the DRV/r group. In addition, fewer patients experiencing virologic failure on DRV/r developed primary PI mutations or NRTI resistance-associated mutations, and none who had previous use of one or no PI developed a primary PI mutation.

In contrast, 32% of patients who experienced virologic failure on the LPV/r regimen and who had used one or no PI in the past developed a primary PI mutation. Compared with LPV/r, DRV/r-based therapy was also associated with lower rates of loss of susceptibility to the PI or the NRTIs in the treatment regimen following viral failure. Researchers suggested that DRV/r was more effective than LPV/r at protecting the treatment backbone and that its earlier use may therefore better preserve future treatment options.

Maintaining Response in the Presence of Mutations

A pooled analysis of two identical trials, DUET-1 and -2, evaluating the safety and efficacy of etravirine (TMC125), a second-generation NNRTI with documented activity in the presence of NNRTI resistance, was presented by Dr. Pedro E. Cahn, Director, Fundación Huésped, Buenos Aires, Argentina. The DUET trials involved highly treatment-experienced patients who received TMC125 or placebo, both given in conjunction with DRV/r plus an optimized background NRTI regimen and optional enfuvirtide. All patients had documented NNRTI resistance and three or more primary PI mutations at baseline.

At week 24, 59% of patients receiving etravirine had achieved HIV RNA <50 copies/mL vs. 41% on an optimized background regimen alone (P<0.0001). “Even in the absence of other fully-active background drugs, 45% of patients on TMC125 achieved HIV RNA <50 copies/mL,” Dr. Cahn reported. The same significant difference was seen in those who achieved HIV RNA <400 copies/mL at 74% vs. 53% for the etravirine and placebo arm, respectively, while mean increases in CD4+ cell counts were 86 cells/mm3 for the etravirine arm and 67 cells/mm3 for the optimized background regimen alone arm (P<0.0001).

Thirteen baseline mutations were associated with a decreased response to etravirine but not the K103N mutation, a key mutation for NNRTI resistance. It also took three of the 13 TMC125-specific mutations to reduce response to the same level as was seen in the optimized background regimen arm. Rash, usually mild to moderate, occurred more frequently in the TMC125 arm than in the placebo arm (17% vs. 9%, respectively), with a discontinuation rate of 2.2%. No grade 4 rash nor any rash with mucosal involvement was observed. Fewer than 6% of TMC125 patients discontinued treatment because of toxicity. New AIDS-defining illness or death occurred in 3.7% of the TMC125 arm vs. 6.8% in the optimized background regimen cohort.

Summary

Consensus guidelines now indicate that the goal of HIV therapy is to reduce HIV RNA levels to <50 copies/mL regardless of a patient’s prior treatment experience. This is increasingly possible as new agents within existing drug classes, as well as new drug classes, are active even in the face of multiple resistance. Given the chronic nature of HIV illness today, knowing that new antiretroviral drugs are safe and well tolerated heralds an encouraging trend in HIV management.