Indications

Routine follow-up

If routine pharmocokinetic monitoring is indicated, therapeutic drug monitoring should be done at week 4 and week 12 after antiretroviral treatment initiation. Thereafter, further pharmacokinetic monitoring should be done according to the recommendations provided.

Patients without prior virologic failure to antiretroviral therapy

Protease inhibitors

• Atazanavir (not boosted with ritonavir)
  If given with abacavir/lamivudine, routine pharmacokinetic monitoring is not recommended based on retrospective, observational and/or pharmacokinetic studies.  
  
  If given with other antiretrovirals, routine pharmacokinetic monitoring is optional.
   
• Atazanavir/ritonavir
  Routine pharmacokinetic monitoring is not recommended based on retrospective, observational and/or pharmacokinetic studies.
   
• Darunavir/ritonavir
  Routine pharmacokinetic monitoring is not recommended based on prospective, retrospective, observational and/or pharmacokinetic studies.
   
• Fosamprenavir/ritonavir
  If administered once a day, routine pharmacokinetic monitoring is moderately recommended based on retrospective, observational and/or pharmacokinetic studies.
  
  If administered twice daily, routine pharmacokinetic monitoring is not recommended based on prospective, retrospective, observational and/or pharmacokinetic studies.
   
• Indinavir/ritonavir
  Routine pharmacokinetic monitoring is strongly recommended based on at least one prospective pharmacokinetic trial with clinical (morbidity, mortality) or biological (virologic or immunologic) outcomes.
   
• Lopinavir/ritonavir
  If administered once a day in liquid formulation, routine pharmacokinetic monitoring is moderately recommended based on retrospective, observational and/or pharmacokinetic studies.
  
  If administered once a day in tablet formulation or twice a day (liquid or tablet form), routine pharmacokinetic monitoring is not recommended based on prospective, retrospective, observational and/or pharmacokinetic studies.
   
• Nelfinavir
  Routine pharmacokinetic monitoring is strongly recommended based on at least one prospective pharmacokinetic trial with clinical (morbidity, mortality) or biological (virologic or immunologic) outcomes.
   
• Saquinavir/ritonavir
  If administered once a day, routine pharmacokinetic monitoring is moderately recommended based on retrospective, observational and/or pharmacokinetic studies.
  
  If administered twice daily, routine pharmacokinetic monitoring is not recommended based on prospective, retrospective, observational and/or pharmacokinetic studies.
   
• Tipranavir/ritonavir
  Not applicable as tipranavir is only indicated for patients with prior virologic failure to antiretroviral therapy.

Non-nucleoside reverse transcriptase inhibitors

• Efavirenz
  Routine pharmacokinetic monitoring is not recommended based on retrospective, observational and/or pharmacokinetic studies.
   
• Etravirine
  Not applicable as etravirine is only indicated for patients with prior virologic failure to antiretroviral therapy.
   
• Nevirapine
  If administered once a day, routine pharmacokinetic monitoring is moderately recommended based on retrospective, observational  and/or pharmacokinetic studies.
  If administered twice daily, routine pharmacokinetic monitoring is not recommended based on at least one prospective pharmacokinetic trial with clinical (morbidity, mortality) or biological (virologic or immunologic) outcomes.

Raltegravir and maraviroc

• Routine pharmacokinetic monitoring is not recommended based on retrospective, observational and/or pharmacokinetic studies.
   

   

Patients with virus with mutations conferring resistance to the drug class

Protease inhibitors

For most protease inhibitors
Routine pharmacokinetic monitoring is optional based on retrospective, observational and/or pharmacokinetic studies.

Exceptions:

• Atazanavir (not boosted with ritonavir)
  Routine pharmacokinetic monitoring is strongly recommended based on retrospective, observational and/or pharmacokinetic studies. 
   
• Indinavir/ritonavir
  Routine pharmacokinetic monitoring is strongly recommended based on retrospective, observational and/or pharmacokinetic studies.
   
• Nelfinavir
  Nelfinavir use should be avoided in this population as there is a high risk of resistance in patients with a history of virologic failure to protease inhibitors. 
   

Other antiretroviral agents

• Efavirenz and nevirapine
  Not applicable as their use is not recommended when efavirenz/nevirapine mutations are present.  
   
• Etravirine
  Routine pharmacokinetic monitoring is optional based on expert opinion.
   
• Raltegravir
  Not applicable as raltegravir use is not recommended when raltegravir mutations are present.
   
• Maraviroc
  Not applicable. 

Documented virologic failure

Virologic failure can be defined as a loss of virologic suppression or a failure to suppress viral load to an undetectable level after 24 - 48 weeks on antiretroviral therapy. There are several factors which can contribute to treatment failure, including underlying resistance, inadequate drug plasma concentrations and/or poor adherence. TDM may be a strategy in patients who are experiencing virologic failure.

TDM is best requested for this indication early after the onset of virologic failure (increase in viral load or viral blip) in order to prevent the development of resistance.

• Protease inhibitors
  Pharmacokinetic monitoring is moderately recommended for all protease inhibitors in the case of virologic failure based on retrospective, observational and/or pharmacokinetic studies.
   
• Non-nucleoside reverse transcriptase inhibitors
  Pharmacokinetic monitoring is moderately recommended for efavirenz and nevirapine in the case of virologic failure based on retrospective, observational and/or pharmacokinetic studies.
  Regarding etravirine, pharmacokinetic monitoring is moderately recommended based on expert opinion.
   
• Raltegravir
  Pharmacokinetic monitoring is moderately recommended for raltegravir in the case of virologic failure based on expert opinion. Of note, considering the large intrapatient pharmacokinetic variability of raltegravir, a repeat analysis is always preferable prior to any dose modification.
   
• Maraviroc
  Pharmacokinetic monitoring is moderately recommended based on expert opinion.

Drug interactions

A drug interaction occurs when a substance (drug, food or natural product) affects the activity of a drug. TDM may be used to detect altered pharmacokinetics of an antiretroviral when administered with other substances and can be used to guide dosage adjustments.

Pharmacokinetic monitoring is strongly recommended for all antiretrovirals based on retrospective, observational and/or pharmacokinetic studies. Of note, considering the large intrapatient pharmacokinetic variability of raltegravir, a repeat analysis is always preferable prior to any dose modification.

Clinical tools for identification of possible drug interactions

Unusual dosage

Based on expert opinion, pharmacokinetic monitoring is strongly recommended if the dosage prescribed does not correlate with the product monograph. Of note, considering the large intrapatient pharmacokinetic variability of raltegravir, a repeat analysis is always preferable prior to any dose modification. 

Non-adherence to prescribed dosage

Pharmacokinetic monitoring is moderately recommended if a patient does not follow suggested dosage of the medication. Typical examples include: taking a higher or lower dose, missed doses, self-cessation of ritonavir without consultation of a healthcare professional, intake of ritonavir at a different time than the protease inhibitor, intake of medication without food when it is necessary to increase absorption. Of note, considering the large intrapatient pharmacokinetic variability of raltegravir, a repeat analysis is always preferable prior to any dose modification. 

Validation after a dosage adjustment

Whenever the dose of an antiretroviral drug is adjusted following a TDM, it is strongly recommended (based on expert opinion) to repeat a TDM to validate the impact of the dose modification. The Québec Antiretroviral Therapeutic Drug Monitoring Program recommends the following:

• Repeating an analysis one week after a dose adjustment for a protease inhibitor, raltegravir or maraviroc
• Repeating an analysis three weeks after a dose adjustment for a non-nucleoside reverse transcriptase inhibitor

For indinavir/ritonavir and nelfinavir specifically, prospective pharmacokinetic trials with clinical (morbidity, mortality) or biological (virologic or immunologic) outcomes support pharmacokinetic monitoring after dosage adjustments. Of note, considering the large intrapatient pharmacokinetic variability of raltegravir, a repeat analysis is always preferable prior to any dose modification.

Special populations

Renal insufficiency (pre-dialysis)

Pharmacokinetic monitoring is generally not recommended based on retrospective, observational, pharmacokinetic studies or expert opinion.

Therapeutic drug monitoring of nucleoside reverse transcriptase inhibitors which undergo renal elimination, are not currently done by the Québec Antiretroviral Therapeutic Drug Monitoring Program. Other drug classes are primarily metabolised by the liver before being eliminated. Pre-dialysis renal insufficiency is therefore not expected to significantly alter exposure to protease inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors or entry inhibitors.

Exceptions:

• Nevirapine
  Pharmacokinetic monitoring is optional based on retrospective, observational, pharmacokinetic studies.

• Maraviroc
  Pharmacokinetic monitoring is moderately recommended based on retrospective, observational, pharmacokinetic studies. Of note, use of maraviroc is not recommended when the creatinine clearance is less than 30 mL/minute and concomitant medications include either a strong inhibitor or inducer of cytochrome P450 3A4. If maraviroc is nonetheless used in that situation, therapeutic drug monitoring is strongly recommended based on retrospective, observational, pharmacokinetic studies.

Dialysis

Recommendation to do therapeutic drug monitoring in a patient on dialysis varies according to each antiretroviral. When recommended, therapeutic drug monitoring should be done before and after the dialysis session. On dialysis days, antiretrovirals should be taken after dialysis. 

• Protease inhibitors
  Pharmacokinetic monitoring is moderately to strongly recommended based on retrospective, observational, pharmacokinetic studies or expert opinion.

• Non-nucleoside reverse transcriptase inhibitors
  Efavirenz: pharmacokinetic monitoring is not recommended based on expert opinion.
  Etravirine and nevirapine: pharmacokinetic monitoring is optional based on retrospective, observational, pharmacokinetic studies or expert opinion.

• Raltegravir and maraviroc
  Pharmacokinetic monitoring is not recommended based on retrospective, observational, pharmacokinetic studies.

Hepatic impairment (moderate-severe)

Pharmacokinetic monitoring is moderately to strongly recommended based on retrospective, observational, pharmacokinetic studies or expert opinion.

The impact of hepatic insufficiency on antiretroviral pharmacokinetics is variable and often unpredictable. Dose adjustments according to the Child-Pugh score may be recommended according to the specific product monograph of each antiretroviral. 

Of note, atazanavir with or without ritonavir, darunavir, saquinavir, tipranavir, efavirenz and nevirapine are contra-indicated in severe hepatic impairment (see specific product monographs for details). In addition, tipranavir and efavirenz use is contra-indicated in moderate hepatic impairment. If use of these antiretrovirals remains necessary, TDM is strongly recommended.

Pregnancy

Moderate recommendation based on retrospective, observational, pharmacokinetic studies or expert opinion.
However, if the patient has a history of prior virologic failure to protease inhibitors or mutations to the measured antiretroviral, TDM is strongly recommended.

If possible, a TDM analysis should be requested prior to pregnancy (if planned) or in the first trimester to have a baseline plasma concentration. Subsequent analyses should be done between the 16th and 20th week of gestation, at the beginning of the 3rd trimester and 2 weeks post-partum. Decreased antiretroviral drug exposure during the second and third trimesters of pregnancy has been reported for certain protease inhibitors, including darunavir, lopinavir/ritonavir and nelfinavir. 

Paediatrics

Strong recommendation based on retrospective, observational, pharmacokinetic studies or expert opinion.

Generally, pharmacokinetic data of antiretroviral drugs in children is sparsely available. Children are known to have a great interpatient pharmacokinetic variability with growth and development. Antiretroviral doses need to be regularly re-evaluated as the child ages. Furthermore, there is a relatively high prevalence of subtherapeutic drug concentrations for certain antiretroviral drugs among children who are dosed in accordance with current guidelines as per the current literature. These results support routine TDM in children in order to prevent subtherapeutic concentrations. It is strongly recommended (expert opinion) to repeat routine TDMs every 3 months throughout childhood and adolescence. 

Geriatrics

Optional recommendation based on retrospective, observational, pharmacokinetic studies or expert opinion.

People infected with HIV are now living longer and are developing challenging comorbid diseases and complications that require pharmacotherapy.  In the elderly population, polypharmacy increases the potential of clinically significant drug-drug interactions and places the patient at risk of adverse drug reactions and/or therapeutic failure with possible drug resistance. Little is known on the pharmacokinetics of antiretrovirals in the elderly which can be altered by decreases in renal and hepatic function associated with aging.

Malabsorption

Moderate recommendation based on retrospective, observational, pharmacokinetic studies or expert opinion 

People living with HIV can suffer from malabsorption. This disorder can be caused by a number of different illnesses including advanced AIDS, cancer, cystic fibrosis, Crohn’s disease, short bowel syndrome, chronic pancreatitis and chronic liver disease. Malabsorption can cause chronic diarrhea, vitamin deficiency, emaciation and decreased drug absorption, all of which can consequently lead to subtherapeutic antiretroviral drug concentrations.

The administration of antiretrovirals via jejunostomy or gastrostomy can also greatly decrease their absorption. TDM can be very useful in patients who suffer from malabsorption in order to ensure adequate absorption of the antiretroviral drug. If TDM is performed for suspected malabsorption, the sample should be taken at the time post-dose associated with the maximum concentration of the antiretroviral known as T_max (see specific product monographs for detail).

Low weight or obesity

In patients with a body mass index < 18.5 kg/m² or >29.9 kg/m², the distribution of antiretroviral drugs in the body may be altered. In some cases, failure to adjust doses accordingly may result in therapeutic failure or increased toxicity. TDM guided dose adjustments may be useful in patients with extreme body weights.

• Efavirenz or lopinavir
  Moderate recommendation based on retrospective, observational or pharmacokinetic studies. 
   
• Other antiretrovirals
  Optional recommendation based on retrospective, observational, pharmacokinetic studies or expert opinion.

Drug toxicity / adverse drug reactions

The clinical utility of obtaining a drug concentration in the case of suspected toxicity or adverse drug reaction depends on the existence of a concentration-toxicity/adverse drug reaction relationship.

Associations between antiretroviral plasma concentrations and adverse reactions

• Atazanavir: hyperbilirubinemia
   
• Efavirenz: central nervous system toxicity, hepatotoxicity
   
• Indinavir: nephrolithiasis, dermatological (xerodermia, alopecia, chelitis), hyperbilirubinemia 
   
• Lopinavir : dyslipidemia
   
• Nelfinavir : lipoatrophy
   
• Nevirapine : hepatotoxicity 

Lack of association between adverse reactions and antiretroviral plasma concentrations

• Diarrhea: atazanavir, darunavir, lopinavir
   
• Dermatologic side effects: darunavir, etravirine
   
• Hepatotoxicity: atazanavir, darunavir, lopinavir
   
• Lipodystrophy: lopinavir, efavirenz