The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy.
OBJECTIVE
To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA.


METHODS
Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine].


METHODS
The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k.


RESULTS
A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k.


CONCLUSIONS
The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.
Hoetelmans
R M
RM
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Reijers
M H
MH
Weverling
G J
GJ
ten Kate
R W
RW
Wit
F W
FW
Mulder
J W
JW
Weigel
H M
HM
Frissen
P H
PH
Roos
M
M
Jurriaans
S
S
Schuitemaker
H
H
de Wolf
F
F
Beijnen
J H
JH
Lange
J M
JM
D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D019888:Nelfinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019888:Nelfinavir; D019258:Saquinavir