Efficacy and Safety of Etravirine (TMC125) in Treatment-experienced HIV Patients: 24-week Results from the DUET-1 and DUET-2 Trials 

By Ronald Baker, PhD

An important and as yet unmet medical need is the development of new antiretrovirals that show activity against resistant HIV and have a high barrier to the development of cross-resistance.

In vitro, the experimental NNRTI etravirine (TMC125) has shown potent activity against both wild-type and NNRTI-resistant strains of HIV-1 and has a higher genetic barrier to the development of resistance than the currently available NNRTIs efavirenz (Sustiva), nevirapine (Viramune), and delavirdine (Rescriptor).

In addition, in Phase IIb clinical trials, etravirine has demonstrated anti-HIV activity in treatment-experienced patients infected with virus resistant to both NNRTIs and protease inhibitors (PIs), and has been shown to have a safety and tolerability profile similar to that of the control groups in these studies.

At the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Sydney, Australia (July 22-25, 2007), researchers presented the findings of the DUET-1 and DUET-2 trials, which examined the efficacy, tolerability, and safety of etravirine in treatment-experienced patients. Results of these 2 trials were published earlier this month in The Lancet (July 7, 2007).

At the Sydney meeting, Drs. Anthony Mills and Christine Katlama reported 24-week results from DUET-1 and DUET-2, respectively, which assessed the outcomes of etravirine in combination with the second-generation PI darunavir (Prezista) boosted with ritonavir.

DUET-1

DUET-1 is a 96-week randomized, double-blind, Phase III trial evaluating the efficacy and safety of etravirine versus placebo, both given with antiretroviral therapy consisting of twice-daily darunavir/ritonavir (600 mg/100 mg), investigator-selected NRTI(s) and optional enfuvirtide (Fuzeon, T-20).

Eligible subjects had documented NNRTI resistance and >/=3 primary PI resistance mutations at screening. Primary analysis was performed when all patients were treated for at least 24 weeks or discontinued earlier. The primary endpoint was the proportion with confirmed virological response (<50 copies/mL) at week 24 (TLOVR imputation algorithm). Safety was assessed throughout the study.

DUET-1 Results

• 1220 patients were screened; of these, 612 were randomized and treated (304 in the etravirine group, 308 in the placebo group). All had reached week 24 or discontinued earlier at the time of analysis.
  
  
• At week 24, confirmed viral load below 50 copies/mL was achieved by 170 patients (56%) in the etravirine group and 119 patients (39%) in the placebo group.
  
  
• 125 patients (68%) with baseline viral load under 100,000 copies/mL and 45 patients (38%) with baseline viral load of 100,000 copies/mL or greater achieved the primary endpoint in the etravirine group, compared with 85 (47%) with baseline viral load under 100,000 copies/mL and 34 (27%) with baseline viral load of 100,000 copies/mL or greater in the placebo group.
  
  
• At week 24, a confirmed viral load of less than 400 copies/mL was achieved by 224 patients (74%) in the etravirine group and 158 patients (51%) in the placebo group.
  
  
• Larger proportions of patients in the etravirine group achieved viral loads below 50 copies/mL and less than 400 copies/mL than in the placebo group, irrespective of the number of active background agents.
  
  
• A viral load below 50 copies/mL was achieved by 21 (47%) of the 45 patients in the etravirine group with no active agents in their background regimen, compared with four (9%) of 46 such patients in the placebo group.
  
  
• CDC category C AIDS-defining illnesses or death were reported in 8 patients (3%) in the etravirine group and 21 patients (7%) in the placebo group.
  
  
• CDC category C AIDS-defining illnesses alone were reported in 5 patients (2%) in the etravirine group and 20 (7%) in the placebo group.
  
  
• Any AIDS-defining illnesses were reported in 3 patients (1%) in the etravirine group and 17 (7%) in the placebo group.
  
  
• There were 4 (1%) deaths in the etravirine group and 8 (3%) in the placebo group.
  
  
• A statistically significant interaction effect was identified between etravirine and enfuvirtide use. Further statistical analyses comparing efficacy between the etravirine and placebo groups were therefore based on 2 enfuvirtide subgroups: patients who re-used or did not use enfuvirtide, and patients who used enfuvirtide de novo.
  
  
• Of the patients re-using or not using enfuvirtide, more patients in the etravirine group (126 patients [55%]) reached the primary endpoint than in the placebo group (75 patients [33%]).
  
  
• Of the patients who used enfuvirtide de novo, the primary endpoint was reached by 44 patients (59%) in the etravirine group and 44 (56%) in the placebo group.
  
  
• The proportion of patients achieving a viral load below 50 copies/mL was generally greater in the etravirine group than in the placebo group, irrespective of the baseline number of NNRTI resistance-associated mutations.
  
  
• More patients re-using or not using enfuvirtide in the etravirine group achieved a viral load below 50 copies/mL, irrespective of baseline darunavir use, than did those in the placebo group.
  
  
• In the subgroup of patients that re-used or did not use enfuvirtide, AIDS-defining illnesses or deaths were recorded in 5 patients (2%) in the etravirine group and 18 (8%) in the placebo group (P = 0.0081 in a logistic regression analysis).
  
  
• The frequencies of adverse events were comparable in the etravirine and placebo groups, and were mostly grade 1 or 2 (mild to moderate) in severity.
  
  
• The frequencies of individual grade 3 or 4 (severe) adverse events, irrespective of causality, in the etravirine group were comparable to those in the placebo group.
  
  
• Adverse events leading to permanent treatment discontinuation were seen in 16 patients (5%) in both the etravirine and the placebo group.
  
  
• Rash of any type was seen in 61 patients (20%) in the etravirine group and 30 (10%) in the placebo group.
  
  
• In the etravirine group, most cases of rash were grade 1 or 2 in severity; grade 3 rash was recorded in 4 (1%) patients; no grade 4 rashes were reported.
  
  
• One patient (0.3%) in the etravirine group and 9 (3%) in the placebo group experienced a grade 3 neuropsychiatric adverse event; no grade 4 cases were recorded.
  
  
• Individual nervous system adverse events and psychiatric adverse events in the etravirine group were mostly mild or moderate in severity, and were no different from placebo in frequency.
  
  
• The incidence of grade 3 and 4 laboratory abnormalities (including lipid, hepatic, and pancreatic) was comparable between the treatment groups.
  
  
• 4 patients (1%) in the etravirine group and 8 (3%) in the placebo group died due to adverse events that began during the treatment period; none of these deaths was deemed related to etravirine.

Based on these findings, the study authors concluded, “TMC125 [etravirine] is the first NNRTI to demonstrate significant and sustained antiviral benefit at week 24 in patients with NNRTI resistance.” They added that, “TMC125 is generally safe and well tolerated.”

 DUET-2

The ongoing DUET-2 trial is being conducted at 103 medical centers in 12 countries: Australia, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, the UK, and the US. The trial consists of a 6-week screening period, a 48-week treatment phase, and a 4-week follow-up period.

Following enrollment, all patients received background antiretroviral therapy that consisted of the darunavir plus low-dose ritonavir (600/100 mg twice daily), plus at least 2 investigator-selected approved antiretroviral drugs chosen from NRTIs and optional enfuvirtide. No additional NNRTIs or PIs were allowed.

The primary endpoint was the proportion of patients achieving a plasma viral load of less than 50 copies/mL at week 24. Secondary endpoints were antiviral efficacy at all time points (including change from baseline in viral load and proportion of patients achieving viral load of < 400 copies/mL, or ≥ 1 log₁₀ viral load reduction), changes in CD4 cell count, and safety and tolerability.

DUET-2 Results

• 954 patients were screened and 593 were randomized and treated (304 in the etravirine group, 308 in the placebo group).
  
  
• All analyses included the 591 patients who started treatment, irrespective of their eligibility or compliance with the protocol (ITT population).
  
  
• Data were collected when all patients had either received at least 24 weeks of treatment or discontinued.
  
  
• All patients used darunavir, with 23 (4%) re-using the drug.
  
  
• Enfuvirtide use was well balanced between treatment groups; overall, 148 patients (25%) re-used enfuvirtide (73 [25%] in the etravirine group and 75 [25%] in the placebo group); 283 (48%) did not use the drug (143 [49%] in the etravirine group and 140 [47%] in the placebo group), and 160 (27%) used the drug de novo (79 [27%] in the etravirine group and 81 [27%] in the placebo group).
  
  
• The number and specific NRTIs used were similar in the treatment arms.
  
  
• The median treatment duration was 33.1 weeks in the etravirine group and 32.2 weeks in the placebo group.
  
  
• 51 patients (17%) in the etravirine group and 73 (25%) in the placebo group discontinued prematurely, mainly because of virological failure.
  
  
• Viral load below 400 copies/mL at week 24 was achieved by 153 patients (71%) in the etravirine group, compared with 96 (45%) in the corresponding placebo group.
  
  
• At week 24, 170 patients (56%) in the etravirine group and 119 (39%) in the placebo group achieved a confirmed viral load of less than 50 copies/mL.
  
  
• A statistical interaction was found between enfuvirtide use and treatment outcome.
  
  
• Of the individuals who re-used or did not use enfuvirtide, 125 (58%) in the etravirine group achieved a viral load below 50 copies/mL at week 24, compared with 74 (34%) in the corresponding placebo group (P < 0.0001).
  
  
• Most adverse events were mild or moderate in severity.
  
  
• The most common adverse events were diarrhea, nausea, rash (any type), injection site reaction (related to enfuvirtide administration), headache, and fatigue.
  
  
• The type and incidence of all adverse events, including neuropsychiatric events, seen with etravirine were generally comparable to those seen with placebo, with the exception of rash and diarrhea.
  
  
• The frequency and type of serious adverse events, and the overall rate of discontinuation due to any adverse event, were similar in the etravirine and placebo groups.
  
  
• Rash was reported for 41 patients (14%) in the etravirine group and 27 (9%) in the placebo group.
  
  
• Most rashes were described as erythematous or maculopapular, and were of mild or moderate severity.
  
  
• No grade 4 skin events were reported, while grade 3 skin events were reported for 4 patients (1%) in the etravirine group and 1 (0%) in the placebo group.
  
  
• Nervous system and psychiatric adverse events were reported with a similar nature, frequency, and severity in the etravirine and placebo groups.
  
  
• These events were generally mild or moderate in severity; no grade 4 nervous system or psychiatric adverse events were reported in the etravirine group, and grade 3 neuropsychiatric adverse events were reported with similar low frequency in both treatment groups (1 patient in the etravirine group and 3 in the placebo group).
  
  
• CDC category C AIDS-defining illness or death was reported for 14 patients (5%) in the etravirine group, compared with 20 (7%) in the placebo group.
  
  
• No deaths were deemed to be related to trial medication.

In conclusion, the authors stated, “There is currently an unmet clinical need to expand the NNRTI class for treatment-experienced patients, including those with NNRTI resistance. The magnitude of the results seen with etravirine in DUET-1 and DUET-2 (56% and 62% of patients achieved undetectable viral loads at week 24), and the similarity of the responses across both trials done in different countries, indicate that the higher genetic barrier to resistance of etravirine compared with currently available NNRTIs and its activity against NNRTI-resistant virus are central to the ability of etravirine, given as part of an antiretroviral regimen, to produce significantly better virological responses than the placebo group in treatment-experienced patients.”

According to the authors, the results of DUET-2 suggest that, “the sequential use of etravirine, i.e., after virological failure on current NNRTI-based treatment, is now possible.”

Finally, they concluded, “The maintenance of the response to 24 weeks without additional clinically relevant tolerability concerns further suggests that etravirine  is an encouraging new agent in this antiretroviral class.”

08/03/07

References

A Mills, P Cahn, B Grinsztejn, and others. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 612 treatment-experienced HIV-1 infected patients. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract (late-breaker) WeSS204:1.

C Katlama, T Campbell, B Clotet, and others. DUET-2: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treatment-experienced HIV-1 infected patients. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract (late-breaker) WeSS204:2.