New data on darunavir (TMC-114)

Two posters in Toronto dealt with data for POWER 3 darunavir study. This is the follow-up study in treatment experienced patients, in which all subjects received TMC114/r 600/100mg from baseline, plus optimised background regimen (OBR).

POWER 3 was non-randomised, open-label and enrolled 327 patients: 75% Caucasian, 87% male, with a mean entry viral load of 4.62 log and CD4 count of 115 cells/mm3. To assess if there was any relationship between drug exposure and efficacy or safety, trough and peak PK samples were taken at week 4, and baseline resistance measurements was used to calculate the inhibitory quotient (IQ) of the drug. The IQ calculates how much drug is needed to deal with the amount of resistance that exists in an individual to that drug. [1]

It appears from these data that TMC114 IQ was a strong predictor of virologic outcome, which is not surprising, and that most of this is driven by the baseline resistance fold change to the drug and not TMC114 exposure levels. With regard to safety, there seemed to be no association of TMC114 drug levels with adverse events and it is comforting that any signature toxicity has not appeared with this compound. The second POWER 3 analysis presented by Jean-Michel Molina showed results to be broadly similar to the first two studies with 65% having a >1log drop in HIV RNA by week 24, 40% reaching <50 copies/mL and a mean VL reduction of -1.65log. [2]

The most common adverse events were diarrhoea (14%), nasopharyngitis (11%) and nausea (10%). Grade 3 or 4 triglyceride, cholesterol, and liver function enzyme elevations occurred in 6%, 4%, 2% and 2% of patients, respectively, similar rates to these seen in previous TMC114/r studies.

Finally Sharon Walsmley from Toronto gave an oral presentation on the week 48 combined analysis of the POWER 1 and 2 studies which included 241 subjects treated with TMC114 compared to 244 patients who received comparator PI (CPI) regimens. [3]

Ninety one TMC114 subjects were <50copies/mL compared to 22 given CPI (p<0.001) and the breakdown by baseline subgroups is shown in Table 1 below. Table 1: Virologic response (<50 c/mL) at Week 48 and use of T-20

	TMC-114	OBR only
T-20 used (naive)	58%	10%
T-20 used (non-naive)	15%	5%
T-20 not used	45%	8%
0 sensitive ARV in OBR	20%	0%
>1 sensitive ARV in OBR	54%	10%

Clearly the use of enfurvitide (T-20) within the background regimen is important for those patients still sensitive to the agent. CD4 cell responses were good in the TMC114 groups +92/102 cells/mm³ compared to +17/19 cells/mm³ in the CPI group ; p<0.001 and P<0.05 respectively for Power 1 and 2). Adverse events were similar to those seen earlier with around 20% reporting diarrhoea and 15% headache; the majority of adverse events were grades 1 and 2. A word of caution is that it is always difficult to assess side effects in this group of late stage patients since immune reconstitution can produce many constitutional symptoms also.