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Week 24 Results and Baseline Phenotypic Susceptibility in Treatment Experienced Patients Initiating the Combination of TMC114/r and TMC 125
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Reported by Jules Levin
ICAAC
San Francisco, Sept 27-30, 2006
Marta Boffito1, Alan Winston1, Akil Jackson1, Carl Fletcher1, Anton Pozniak1, Mark Nelson1, Graeme Moyle1, Richard Hoetelmans2, Diego Miralles2, Brian Gazzard1
1 St Stephen's Centre, C&W Hospital, London, UK. 2 Tibotec BVBA, Mechelen, Belgium
Authors Concluded:
The combination was well-tolerated and showed impressive short-term efficacy against three-class resistant HIV. Further studies of this combination are warranted.
RESULTS
Ten/12 patients completed week 24; baseline demographic and clinical characteristics are summarised in Table 1. Two patients withdrew consent; one on screening and one on day 7 for personal reasons.
All patients had viruses with high level of resistance for all ARV classes (Tables 1 and 2).
Phenotypic analysis evidenced high level of resistance to all ARV classes: the median fold change for all available NNRTIs and PIs ranged from 0.6 to 104.9 and 0.4 to 137.6, respectively. Median (range) patient fold changes for etravirine and darunavir were 1.25 (0.3-3.8) and 3.6 (0.4-46.8), respectively.
Two subjects showed wild type at screening but had extensive archived resistance documented by different tests performed in the past (Table 2).
Six/10 patients had prior exposure to tipranavir and to enfuvirtide; only two used enfuvirtide for the first time (Table 2).
At week 24, nine/10 patients had achieved an undetectable viral load, only one patient exhibited a viral load of 722 copies/mL, which decrease to 59 copies/mL at week 32 (Table 2).
Median (range) HIV RNA decline and CD4 count increase were -2.7 (2.3-3.9) and 113 (41-268) cells/mm3, respectively.
No new AIDS events, serious adverse events, or changes in laboratory safety were reported. Possibly drug related adverse events were: mild diarrhoea (n = 1), headache (n = 1), grade 1 skin rash (n = 1), which all resolved with continuous dosing.
Table 1: Baseline demographics and clinical characteristics (n = 10)
This clearly appeared to be a very advanced patient group with CD4s of 75 on average, 2 NNRTI mutations, 7 NRTI mutations, and 4 primary PI mutations.
Sex (N)
Male 8
Female 2
Age (years)
Median (range) 43 (38-56)
Race (N)
Black 3
Caucasian 7
Log10 viral load (copies/mL)
Median (range) 4.6 (3.9-5.5)
CD4 count (cells/mm3)
Median (range) 75 (3-490)
NRTI associated mutations (N)
Median range 7 (2-9)
NNRTI associated mutations (N)
Median (range) 2 (0-6)
Primary PI mutations (N)*
Median (range) 4 (0-5)
PI resistance associated mutations (N)
Median (range) 11 (2-13)
BACKGROUND
Resistance and cross-resistance to ARVs remain a major reason for treatment failure and exhaustion of therapeutic options1.
Development of new, potent and tolerable ARVs with improved resistance profiles is urgently needed for the growing number of subjects with multi-drug resistant HIV and otherwise limited treatment options.
Furthermore, it is expected that the administration of two or more susceptible ARVs in this patient population would lead to enhanced treatment efficacy and durability1.
Etravirine (TMC125) is a novel NNRTI designed to have a high genetic barrier to the development of resistance2. In a 7-day trial, etravirine monotherapy produced a mean change in viral load (VL) of - 0.9 log10 copies/mL in patients failing NNRTI-based therapy3 and phase II trials in triple-class-experienced patients found that etravirine was generally safe and well tolerated and showed significant and sustained efficacy, suggesting that etravirine is the first NNRTI to show significant activity in patients with prior NNRTI failure4.
A new formulation of etravirine is today available: 100 mg tablets with significantly improved bioavailability, dosage 200 mg bid showed a comparable exposure to 800 mg bid of previous formulation5.
Darunavir (TMC114) is a potent, new non-peptidic protease inhibitor (PI) that, in combination with low dose ritonavir (RTV), has shown activity in naïve and experienced patients. In these patients, darunavir/RTV produced a rapid and robust VL reduction and was well tolerated6. Moreover, darunavir has demonstrated long term efficacy in patients with PI resistance and has recently been approved for the treatment of HIV infection.
We recently demonstrated the lack of a significant drug-drug interaction between etravirine and darunavir in HIV-infected patients7.
We here present the week 24 results and the baseline phenotypic susceptibility of the 10 highly experienced HIV patient who received etravirine and darunavir together for the first time.
METHODS
Study design and subjects:
This was an open-label, single-arm study carried out at the Pharmacokinetic Unit of the St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK. The study protocol was reviewed and approved by the Riverside Research Ethics Committee.
Following screening procedures (days -14 to -1), all subjects were administered etravirine (200 mg bid) and darunavir/RTV (600/100 mg bid) together with two or more NRTIs, plus or minus enfuvirtide (ENF).
Evaluations:
Clinical laboratory tests, physical examination, ECG and vital signs were performed throughout the study.
Plasma VLs were measured by quantitative RNA polymerase chain reaction (Roche Amplicor, version 1.5).
The immunologic effect of treatment was determined by changes in CD4 counts (absolute and %).
Phenotypic and genotypic determinations were performed by Virco BVBA by means of the Antivirogram® and Virtual PhenotypeTM, respectively.
Primary PI mutations were identified according to the international AIDS Society Guidelines, October 2005.
Phenotypic results were expressed as fold change in IC50 (concentration of drug needed to inhibit 50% of viral replication) relative to a reference wild-type virus. In vitro IC50 values for HIV wild type for efavirenz, nevirapine, and etravirine were 3.4, 5.2, and 0.0010. Those for saquinavir, amprenavir, lopinavir, atazanavir, tipranavir, and darunavir were 1.7, 1.8, 1.6, 2.0, 1.6, and 0.0028.
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