Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance.
BACKGROUND
Cumulative antiretroviral exposure can result in multiclass HIV drug resistance. Experimental antiretroviral agents offer limited therapeutic benefit as resistance quickly develops after their introduction as a sole new agent.


OBJECTIVE
To assess the pharmacokinetic profile, safety and virological response of two novel investigational antiretroviral agents when used in combination in HIV-1-infected subjects with multidrug-resistant virus.


METHODS
HIV-1-infected subjects, with current virological failure on a stable antiretroviral regimen with no viable treatment options were assigned to a regimen comprising two new investigational agents, etravirine, a novel nonnucleoside reverse transcriptase inhibitor, and darunavir, a novel protease inhibitor, plus nucleoside reverse transcriptase inhibitors (and enfuvirtide in selected patients) for 24 weeks. Virological, immunological and safety parameters were collected. Detailed pharmacokinetic assessments of darunavir and etravirine were determined on days 7 and 28.


RESULTS
Follow up of 24 weeks was achieved by 10/12 patients. Median reduction in HIV RNA was 2.7 log10 copies/ml (range, 2.3-3.9) and increase in CD4 lymphocytes was 113 cells/microl (range, 41-268). HIV RNA was < 40 copies/ml in nine. No serious adverse events were recorded. Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor.


CONCLUSIONS
This first study to assess the use of etravirine and darunavir in HIV-1-infected subjects with no treatment options showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions.
Boffito
Marta
M
St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK. marta.boffito@chelwest.nhs.uk
Winston
Alan
A
Jackson
Akil
A
Fletcher
Carl
C
Pozniak
Anton
A
Nelson
Mark
M
Moyle
Graeme
G
Tolowinska
Izabela
I
Hoetelmans
Richard
R
Miralles
Diego
D
Gazzard
Brian
B
D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count; D000069454:Darunavir; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011743:Pyrimidines; D012367:RNA, Viral / Q000032:analysis; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019562:Viral Load
D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D012367:RNA, Viral; D013449:Sulfonamides; C451734:etravirine; D019438:Ritonavir; D000069454:Darunavir