Issue 165 - April 2007
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In Drug interactions, HIV pharmacist Heather Leake Date explained that it is possible to measure drug levels in the bloodstream in order to assess whether interactions between different anti-HIV drugs are resulting in unusually high or low levels. This is known as therapeutic drug monitoring, or TDM.

However, drug interactions aren’t the only reason that drug levels may be unusually low or high.

Once swallowed, anti-HIV drugs pass through the digestive system where they are absorbed into the blood stream and distributed throughout the body. The rate at which they are absorbed varies between individuals. This means that if two people take identical treatment at the same doses and with the same foods, the amount of drug which will reach their blood streams can be very different.

To a certain degree, this variability is unimportant. In order to be effective against HIV, antiretrovirals must reach a level in the blood that falls within a range that is established when new drugs are first developed. A blood level which is higher than this 'therapeutic range' can lead to more side-effects. A lower level will allow ongoing HIV replication, which provides the circumstances for drug resistance to develop, causing the treatment to fail.

Drug levels reach their peak soon after they are taken, and then taper off over the subsequent hours to a lower 'trough level' before the next dose. It is this trough level which is likely to be pivotal in determining a drug's potency and effectiveness. On the other hand, high concentrations of certain drugs in the blood may worsen the severity of side-effects. Consequently, TDM may be able to check that lower dosages with improved tolerability are still effective against HIV.

TDM has been available in UK clinics for several years. Although it is not a routine test it can be an extremely useful tool to guide treatment choices in certain circumstances. The latest British HIV Association (BHIVA) guidelines note that TDM can be beneficial in situations where drug levels are difficult to predict.[i]

These include:

  • People experiencing unusual toxicity or side-effects on standard anti-HIV drug doses.
  • People using unusual anti-HIV drug combinations.
  • People on ‘salvage’ therapy (in combination with resistance test results).
  • Women during pregnancy.
  • Children.
  • People with kidney or liver impairment, or following transplants.

[i] Gazzard B et al. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006). HIV Medicine 7, 487–503, 2006.

Question one

ATU: What does therapeutic drug monitoring actually measure and how useful is it?

 

Heather Leake Date (HLD): Therapeutic drug monitoring (TDM) can measure the levels of protease inhibitors (PIs) and non-nucleosides (NNRTIs) in a person’s blood. We don’t measure levels of nucleoside ‘backbone’ drugs (NRTIs) in clinical practice as it is a more complex procedure,. This is because it is NRTI levels in the cells of the body, rather than the blood, that are important, and they are much more difficult to measure.

Although it can be useful in certain circumstances (see TDM in real life), the exact role of TDM in the HIV clinic has not really been fully established. A few studies from several years ago demonstrated its value in certain circumstances – decreasing indinavir (Crixivan) toxicity, or ensuring adequate levels of nelfinavir (Viracept) – but neither of those particular drugs are widely used today.

 
Question two

ATU: Is TDM available at every HIV clinic in the UK?

 

HLD: Most TDM analysis in the UK is done in Liverpool. It is overseen by the Liverpool HIV Pharmacology Group (LHPG), based within the Department of Pharmacology & Therapeutics at the University of Liverpool, but since October 2005 the routine TDM service has been under the direction of a private company, Delphic Diagnostics, with LHPG having an advisory role in the running and development of the service.

Although TDM is available to any clinician who wants it, I suspect most clinicians don’t regularly use it as part of their routine practice. At our own centre in Brighton we use it when we think it might be useful (as per the BHIVA guidelines). For example, when the new Kaletra tablet formulation became available last year, there weren’t really any recommendations for dose adjustments with NNRTIs, so we routinely did TDM on patients who were taking Kaletra tablets in combination with NNRTIs. We routinely perform TDM if someone is on two drugs we think are likely to interact.

 
Question three

ATU: When is the best time to take blood for TDM?

 

That’s a very good question, and the answer isn’t straightforward. We know that drug levels vary, both from patient to patient, and within any one given patient over time. How do we know that a TDM result is accurate and consistent? How do we know we’ll get the exact same result at the same time the next day? Actually, we don’t: variations in the results are one of the reasons that TDM is not more widely used.

However, when we think TDM will be useful, generally we will take two measurements. One will be immediately before someone is due to take the next dose of the drug(s) being tested, and another will be two hours after the dose. The pre-dose measurement will correspond approximately to the minimum drug concentration in the blood, and the post-dose measurement will correspond approximately to the maximum drug concentration in the blood.

If you are having TDM done, then, it’s important to tell the person drawing the blood exactly when your last doses were taken. Even if you usually take a dose at 9am, we’d need to know whether you took your previous dose actually at 9am, or 15 minutes before or after.

 

Box: TDM in real life

Heather Leake Date provides three real life examples of how TDM has been useful for patients in Brighton. Please note that in all the examples, the drug levels quoted are an approximation: TDM requires expert, individualised interpretation.

Using TDM to enable interacting drugs to be used together safely

A patient on ritonavir-boosted atazanavir also required a more powerful acid suppressing medication for symptoms of acid reflux (severe heartburn) because regular antacids (taken at separate times from atazanavir) were not sufficient to resolve the symptoms. Before an H2 blocker (ranitidine) was prescribed (to be taken once daily, two hours after atazanavir, to minimise any interaction), atazanavir TDM was performed. Results showed that the patient had a trough (lowest) atazanavir level of 1500ng/ml (about ten times higher than the minimum required to suppress wild type virus). After a four-week trial of ranitidine the patient’s acid reflux symptoms were no better, suggesting that a proton pump inhibitor (PPI) may be useful. Although combining a PPI and atazanavir is officially contra-indicated (due to a 75% reduction in atazanavir levels), since the patient had such high trough atazanavir levels it was decided to increase the atazanavir dose from the usual 300mg once daily to 400mg (still with 100mg ritonavir) and to prescribe a PPI (omeprazole 20mg once daily, taken two hours after atazanavir). Atazanavir TDM was repeated a week later and the trough level was 1000ng/ml (i.e. still therapeutic) so the patient was able to remain on the PPI for a six-week course, which helped resolve the acid reflux symptoms.

Using TDM to help manage toxicity

A patient on ritonavir-boosted lopinavir (Kaletra) who had been experiencing diarrhoea for several years – which was thought to be related to Kaletra capsules – wanted to switch to the new formulation of Kaletra tablets, since these may be associated with less diarrhoea. However, the patient was taking Kaletra with efavirenz and tenofovir and was on four Kaletra capsules twice daily (a higher than usual dose because efavirenz reduces levels of lopinavir). The standard dose of Kaletra tablets is two tablets twice daily, but for this previously PI-experienced patient higher lopinavir levels may be required (above 4000ng/ml, rather than above 1000ng/ml for PI-naive) and so it was thought that a higher dose (e.g. three tablets, twice daily) may be required. Two weeks after the patient started on three Kaletra tablets twice daily, lopinavir TDM was performed. The lopinavir trough level was found to be much higher than necessary (8365 ng/ml), so the dose was reduced to two tablets twice daily. A repeat TDM two weeks later showed a still satisfactory trough lopinavir level (5425ng/ml), and the patient found that although the diarrhoea had not completely resolved, it was more manageable.

Using TDM to optimise efficacy

A pregnant woman was taking her first-ever ARV combination – which included Kaletra – in order to prevent mother-to-child transmission. Lopinavir TDM was performed at 29 weeks because as pregnancy progresses lopinavir levels in the blood can decrease, due to an increased volume of blood circulation. Since they were found to be just over the minimum-required trough level (1020ng/ml) it was decided to increase the Kaletra dose until the baby was born to ensure levels remained therapeutic for the remainder of the pregnancy.

Reference

[1] Gazzard B et al. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006). HIV Medicine 7, 487–503, 2006.