Page 109 - HIV/AIDS Guidelines

Exposure-Response Relationships and TDM with Different ARV Classes

Protease Inhibitors (PIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase
Inhibitors. Relationships between the systemic exposure to PIs and NNRTIs and treatment response have
been reviewed in various publications. 4-7 Although there are limitations and unanswered questions, the
consensus among clinical pharmacologists from the United States and Europe is that the data provide a
framework for the potential implementation of TDM for PIs and NNRTIs. However, information on
relationships between concentrations and drug-associated toxicities are sparse. Clinicians who use TDM as a
strategy to manage either ARV response or toxicities should consult the most current data on the proposed
therapeutic concentration range. Exposure-response data for darunavir (DRV), etravirine (ETR), and
raltegravir (RAL) are accumulating but are not sufficient to recommend minimum trough concentrations.
The median trough concentrations for these agents in HIV-infected persons receiving the recommended dose
are included in Table 9b.

CCR5 Antagonists. Trough maraviroc (MVC) concentrations have been shown to be an important predictor
of virologic success in studies conducted in ART-experienced persons. 8-9 Clinical experience in the use of
TDM for MVC, however, is very limited. Nonetheless, as with PIs and NNRTIs, the exposure-response data
provide a framework for TDM, and that information is presented in these guidelines (Table 9b).

Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Relationships between plasma concentrations of
NRTIs and their intracellular pharmacologically active moieties have not yet been established. Therefore,
monitoring of plasma or intracellular NRTI concentrations for an individual patient largely remains a
research tool. Measurement of plasma concentrations, however, is routinely used for studies of drug-drug
interactions.
Scenarios for Use of TDM. Multiple scenarios exist in which both ARV concentration data and expert
opinion may be useful in patient management. Consultation with a clinical pharmacologist or a clinical
pharmacist with HIV expertise may be advisable in these cases. These scenarios include the following:

• Suspect clinically significant drug-drug or drug-food interactions that may result in reduced efficacy or
increased dose-related toxicities;
• Changes in pathophysiologic states that may impair gastrointestinal, hepatic, or renal function, thereby
potentially altering drug absorption, distribution, metabolism, or elimination;
• Pregnant women who may be at risk of virologic failure as a result of changes in their pharmacokinetic
parameters during the later stage of pregnancy, which may result in plasma concentrations lower than
those achieved in the earlier stages of pregnancy and in the nonpregnant patient;

• Heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced
susceptibility to ARVs;

• Use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been
established in clinical trials;

• Concentration-dependent, drug-associated toxicities; and
• Lack of expected virologic response in medication-adherent persons.

TDM
• For patients who have drug-susceptible virus. Table 9a includes a synthesis of recommendations 2-7 for
minimum target trough PI and NNRTI concentrations in persons with drug-susceptible virus.
• For ART-experienced patients with virologic failure (see Table 9b). Fewer data are available to
formulate suggestions for minimum target trough concentrations in ART-experienced patients who have
viral isolates with reduced susceptibility to ARV agents. Concentration recommendations for tipranavir

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents H-16

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