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A randomized trial of therapeutic drug monitoring of protease inhibitors in antiretroviral-experienced, HIV-1-infected patients

Demeter, Lisa Ma; Jiang, Hongyub; Mukherjee, A Lisab; Morse, Gene Dc; DiFrancesco, Robinc; DiCenzo, Roberta,c; Dykes, Carriea; Sista, Prakashd; Bacheler, Leed; Klingman, Karine; Rinehart, Alexf; Albrecht, Maryg

doi: 10.1097/QAD.0b013e32831f9148
Clinical Science

Objective: Whether therapeutic drug monitoring of protease inhibitors improves outcomes in HIV-infected patients is controversial. We evaluated this strategy in a randomized, open-label clinical trial, using a normalized inhibitory quotient (NIQ), which incorporates drug exposure and viral drug resistance. NIQs ≤ 1 may predict poor outcome and identify patients who could benefit from dose escalation.

Design/methods: Eligible patients had a viral load ≥1000 copies/ml on a failing regimen, and began a new protease inhibitor containing regimen at entry. All FDA-approved protease inhibitors available during the study recruitment (June 2002–May 2006) were allowed. One hundred and eighty-three participants with NIQ ≤ 1, on the basis of their week 2 protease inhibitor trough concentration and pre-entry drug resistance test, were randomized at week 4 to standard of care (SOC) or protease inhibitor dose escalation (TDM). The primary endpoint was change in log10 plasma HIV-1 RNA concentration from randomization to 20 weeks later.

Results: Ninety-one patients were randomized to SOC and 92 to TDM. NIQs increased more in the TDM arm compared to SOC (+69 versus +25%, P = 0.01). Despite this, TDM and SOC arms showed no difference in outcome (+0.09 versus +0.02 log10, P = 0.17). In retrospective subgroup analyses, patients with less HIV resistance to their protease inhibitors benefited from TDM (P = 0.002), as did black and Hispanic patients (P = 0.035 and 0.05, respectively). Differences between black and white patients persisted when accounting for protease inhibitor susceptibility.

Conclusions: There was no overall benefit of TDM. In post hoc subgroup analyses, TDM appeared beneficial in black and Hispanic patients, and in patients whose virus retained some susceptibility to the protease inhibitors in their regimen.

aInfectious Diseases Division, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

bStatistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts, USA

cDepartment of Pharmacy Practice, SUNY at Buffalo, Buffalo, New York, USA

dVircoLab Inc., Durham, North Carolina, USA

eDivision of AIDS, National Institutes of Health, Bethesda, Maryland, USA

fTibotec Therapeutics, Bridgewater, New Jersey, USA

gDivision of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Received 17 June, 2008

Revised 17 September, 2008

Accepted 19 September, 2008

Correspondence to Lisa M. Demeter, MD, 601 Elmwood Avenue, Box 689, Rochester, NY 14642, USA. Tel: +1 585 275 4764; fax: +1 585 442 9328; e-mail:

© 2009 Lippincott Williams & Wilkins, Inc.