• What's New in the Guidelines?
• Panel Roster
• Financial Disclosure
• Introduction
• Baseline Evaluation
• Laboratory Testing
  • Tests for Initial Assessment and Follow-up
  • CD4 T-Cell Count
  • Plasma HIV RNA Testing
  • Drug-Resistance Testing
  • Co-receptor Tropism Assays
  • HLA-B* 5701 Screening
• Treatment Goals
• Initiating ART in Treatment-Naïve Patients
• What to Start
• What Not to Use
• Management of the Treatment-Experienced Patient
  • Virologic and Immunologic Failure
  • Regimen Simplification
  • Therapeutic Drug Monitoring
  • Discontinuation or Interruption of Antiretroviral Therapy
• Special Patient Populations
  • Acute and Recent (Early*) HIV Infection
  • HIV-Infected Adolescents and Young Adults
  • HIV and Illicit Drug Users
  • HIV-Infected Women
  • HIV-2 Infection
  • HIV and the Older Patient
• Considerations for Antiretroviral Use in Patients with Coinfections
  • HIV/HBV
  • HIV/HCV
  • HIV/TB
• Limitations to Treatment Safety and Efficacy
  • Adherence to ART
  • Adverse Effects of ARV
• Drug Interactions
  • Drugs Not Recommended With ARV Agents
  • PI Drug Interactions
  • NNRTI Drug Interactions
  • NRTI Drug Interactions
  • INSTI Drug Interactions
  • CCR5 Antagonist Drug Interactions
  • Interactions Among PIs
  • Interactions Between PIs and NNRTIs
  • Interactions Between INSTI, Maraviroc & NNRTI or PI
• Preventing HIV Transmission
• Conclusion
• Appendix A: Key to Acronyms
  • Drug Name Abbreviations
  • General Terms
• Appendix B: Drug Characteristics Tables
  • NRTIs Characteristics
  • NNRTIs Characteristics
  • PIs Characteristics
  • INSTI Characteristics
  • Fusion Inhibitor Characteristics
  • CCR5 Antagonist Characterstics
  • ARV Dosing for Renal or Hepatic Insufficiency
  • ARV Cost Table

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

Knowledge of the relationship between systemic exposure (or concentration) and drug responses (beneficial and/or adverse) is key in selecting the dose of a drug, in understanding the variability in the response of patients to a drug, and in designing strategies to optimize response and tolerability.

TDM is a strategy applied to certain antiarrhythmics, anticonvulsants, antineoplastics, and antibiotics that utilizes measured drug concentrations to design dosing regimens to improve the likelihood of the desired therapeutic and safety outcomes. The key characteristic of a drug that is a candidate for TDM is knowledge of the exposure-response relationship and a therapeutic range of concentrations. The therapeutic range is a range of concentrations established through clinical investigations that are associated with a greater likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions.

Several ARV agents meet most of the characteristics of agents that can be considered candidates for a TDM strategy [1]. The rationale for TDM in managing antiretroviral therapy (ART) derives from the following:

• data showing that considerable interpatient variability in drug concentrations exists among patients who take the same dose;
• data indicating that relationships exist between the concentration of drug in the body and anti-HIV effect and, in some cases, toxicities; and
• data from small prospective studies demonstrating that TDM improved virologic response and/or decreased the incidence of concentration-related drug toxicities [2-3].

TDM for ARV agents, however, is not recommended for routine use in the management of the HIV-infected adult (CIII).

Multiple factors limit the routine use of TDM in HIV-infected adults [4-5]. These factors include:

• lack of large prospective studies demonstrating that TDM improves clinical and virologic outcomes. (This is the most important limiting factor for the implementation of TDM at present.);
• lack of established therapeutic range of concentrations for all ARV drugs that is associated with achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions;
• intrapatient variability in ARV drug concentrations;
• lack of widespread availability of clinical laboratories that perform quantitation of ARV concentrations under rigorous quality assurance/quality control standards; and
• shortage of experts to assist with interpretation of ARV concentration data and application of such data to revise patients’ dosing regimens.

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 (TPV) and MVC were derived only from studies in ART-experienced persons. It is likely that use of PIs and NNRTIs in the setting of reduced viral susceptibility may require higher trough concentrations than those needed for wild-type virus. The inhibitory quotient (IQ), which is the ratio of ARV drug concentration to a measure of susceptibility (genotype or phenotype) of the patient’s strain of HIV to that drug, may additionally improve prediction of virologic response—as has been shown, for example, with DRV in ART-experienced persons [10-11]. Exposure-response data for DRV, ETR, and 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.

Using Drug Concentrations to Guide Therapy. There are several challenges and considerations for implementation of TDM in the clinical setting. Use of TDM to monitor ARV concentrations in a patient requires multiple steps:

• quantification of the concentration of the drug, usually in plasma or serum;
• determination of the patient’s pharmacokinetic characteristics;
• integration of information on patient adherence;
• interpretation of the concentrations; and
• adjustment of the drug dose to achieve concentrations within the therapeutic range, if necessary.

Guidelines for the collection of blood samples and other practical suggestions can be found in a position paper by the Adult AIDS Clinical Trials Group Pharmacology Committee [4].

A final caveat to the use of measured drug concentrations in patient management is a general one—drug concentration information cannot be used alone; it must be integrated with other clinical information. In addition, as knowledge of associations between ARV concentrations and virologic response continues to accumulate, clinicians who employ a TDM strategy for patient management should consult the most current literature.

Table 9a.  Trough Concentrations of Antiretroviral Drugs for Patients Who Have Drug-Susceptible Virus
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Table 9b.  Trough Concentrations of Antiretroviral Drugs for Treatment-Experienced Patients with Virologic Failure
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References

1. Spector R, Park GD, Johnson GF, et al. Therapeutic drug monitoring. Clin Pharmacol Ther. 1988;43(4):345-353.
2. Fletcher CV, Anderson PL, Kakuda TN, et al. Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS. 2002;16(4):551-560.
3. Fabbiani M, Di Giambenedetto S, Bracciale L, et al. Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice. J Antimicrob Chemother. 2009;64(1):109-117.
4. Acosta EP, Gerber JG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses. 2002;18(12):825-834.
5. van Luin M, Kuks PF, Burger DM. Use of therapeutic drug monitoring in HIV disease. Curr Opin HIV AIDS. 2008;3(3):266-271.
6. Boffito M, Acosta E, Burger D, et al. Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy. Antivir Ther. 2005;10(3):375-392.
7. LaPorte CJL, Back BJ, Blaschke T, et al. Updated guidelines to perform therapeutic drug monitoring for antiretroviral agents. Rev Antivir Ther. 2006;3:4-14.
8. Pfizer Inc. Selzentry (maraviroc) tablets prescribing information NY. 2007.
9. McFayden L, Jacqmin P, Wade J, et al. Maraviroc exposure response analysis: phase 3 antiviral efficacy in treatment-experienced HIV+ patients. Paper presented at: 16th Population Approach Group in Europe Meeting; June 2007, 2007; Kobenhavn, Denmark. Abstract P4-13.
10. Molto J, Santos JR, Perez-Alvarez N, et al. Darunavir inhibitory quotient predicts the 48-week virological response to darunavir-based salvage therapy in human immunodeficiency virus-infected protease inhibitor-experienced patients. Antimicrob Agents Chemother. 2008;52(11):3928-3932.
11. Sekar V, DeMeyer S, Vangeneugden T, et al. Pharmacokinetic/pharmacodynamic (PK/PD) analysies of TMC114 in the POWER 1 and POWER 2 trials in treatment-experienced HIV-infected patients. Paper presented at: 13th Conference on Retroviruses and Opportunistic Infections;  February 5, 2006, 2006; Denver, CO. Abstract J-121.
12. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006;43(5):509-515.
13. Kakuda TN, Wade JR, Snoeck E, et al. Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients. Clin Pharmacol Ther. 2010;88(5):695-703.
14. Food and Drug Administration (FDA). Prezista (package insert). 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021976s016lbl.pdf.