In
recent years there has been increasing emphasis on tailoring antiretroviral
therapy for specific patients. Drug doses are set based on what works for
the average person in clinical trials, but may not be the optimal amount for a
given individual. Doses that are too low may lead to incomplete HIV suppression
and emergence of resistance, while high doses can cause worse side effects.
TDM
Laboratory
Therapeutic
drug monitoring (TDM) is a treatment strategy whereby drug concentrations
in the blood are measured and doses are adjusted accordingly. Though widely used
in Europe, TDM is not considered standard of care in the U.S.
As reported
at the 15th Conference on Retroviruses and Opportunistic
Infections (CROI 2008) in Boston, Lisa Demeter and colleagues with the ACTG
A5146 study team conducted a randomized study to see whether treatment outcomes
in patients with drug-resistant HIV might improve if TDM were used and protease
inhibitor (PI) doses were adjusted according to a normalized inhibitory quotient
(NIQ). Inhibitory quotient (IQ) is a measure of how much of a drug is needed to
suppress viral replication.
The study included 194 HIV positive patients
with at least 1 treatment failure on a PI and a viral load > 1000 copies/mL
despite antiretroviral therapy who started a new PI-based
regimen at study entry. Most (90%) were men, about half were white, one-quarter
each were black and Hispanic, and the median age was 45 years. The median baseline
viral load was 4.36 log10 copies/mL, median CD4 count was 194 cells/mm3, and patients
had a median of 0.7 active PIs (based on vircoTYPE susceptibility score).
Blood drug concentrations were measured 2 weeks after starting
the new PI, and NIQs were generated. A patient's IQ was calculated as the week
2 PI trough (lowest level between doses) divided by the screening IC50 fold-change
using the vircoTYPE virtual phenotype test (IC50, or 50% inhibitory concentration,
is the concentration of drug needed to deactivate half the virus in vitro). NIQ
was calculated as the individual patient's IQ divided by the IQ of a reference
population with known virological response to that PI.
The researchers
hypothesized that patients with a NIQ < 1 (that is, lower than that
of the reference population) might benefit from PI dose escalation. The 183 study
participants in this category were randomized 1:1 at week 4 to receive standard
of care treatment (staying on the same PI dose) or else PI dose escalation based
on TDM. The primary comparison was the difference between the standard of care
and TDM arms in viral load change at week 20.
Results
Lexiva
Tablet
•
Median
trough concentrations increased significantly more in the TDM arm compared with
standard of care for all PIs except fosamprenavir
(Lexiva, a pro-drug of amprenavir
[Agenerase]), which was taken by one-third of the patients.
•
NIQ increased more in the TDM arm than in
the standard of care arm (69% vs 5%; P = 0.01).
•
Excluding patients on fosamprenavir, the respective
increases were 87% vs 25% (P = 0.006).
•
Overall, TDM and standard of care did not
differ with regard to the primary endpoint of virological response at 20 weeks
(+0.09 vs +0.02 log10 copies/mL in an intent-to-treat analysis).
•
There also was no difference in time to virological
failure or proportions of patients achieving a viral load < 50 or < 400
copies/mL.
•
Further, there were no significant differences
observed in drug-related toxicities or other outcome measures.
•
Patients with a higher degree of PI resistance
appeared to benefit more from TDM.
•
In subgroup analyses, patients on >
0.7 active PI benefited from TDM (P = 0.002), while those on < 0.7 did not
(P = 0.35).
•
Hispanic and black patients also appeared
to benefit more from TDM compared with whites (P = 0.04, 0.05, and 0.40, respectively).
•
This difference could not be accounted for
by other factors, since the 3 racial/ethnic groups had similar body mass index,
baseline viral load and CD4 cell count, adherence, number of active PIs, rate
of fosamprenavir use, PI trough concentrations, and NIQ changes.
Conclusion
Based
on these findings the investigators concluded that, "There was no overall
benefit of TDM in this study."
They added that the inability to increase
amprenavir concentrations by raising the dose of fosamprenavir is not understood,
"but may have contributed to the lack of a detectable TDM effect."
"TDM
may confer more benefit in black and Hispanic patients than white patients, for
unclear reasons," they stated. "Subgroup analyses suggest a TDM effect
was obscured by the inclusion of patients with highly PI-resistant HIV.
Univ
of Rochester Sch of Med Dentistry, NY; Harvard Sch of Publ Hlth, Boston, MA; State
Univ of New York at Buffalo, NY; Div of AIDS, NIH, Bethesda, MD; VircoLab Inc,
Durham, NC; Tibotec Therapeutics, Bridgewater, NJ; Beth Israel Deaconess Med Ctr,
Boston, MA.
02/08/08
Reference L
Demeter, H Jiang, L Mukherjee, and others. A Prospective, Randomized, Controlled,
Open-label Trial Evaluating the Effect of Therapeutic Drug Monitoring and Protease
Inhibitor Dose Escalation on Viral Load Responses in Antiretroviral-experienced,
HIV-infected Patients with a Normalized Inhibitory Quotient. 15th Conference on
Retroviruses and Opportunistic Infections. Boston, MA. February 3-6, 2008. Abstract
35.
Therapeutic
Drug Monitoring Demonstrates No Benefit in Randomized Controlled Trial 
