AIDS Treatment Update, Issue 60, December 1997
Edward King

As a result, for some or all of the period between doses, levels of the drug may fall below the concentration that is needed to inhibit HIV effectively. This can have two harmful consequences:

- Viral load may not be optimally suppressed, increasing the risk of disease progression

- HIV may be able to develop resistance to one or more of the drugs you are taking. This means that your current drugs may lose their effectiveness sooner, and you may also lose the ability to benefit from related drugs that you have never taken because of cross-resistance

Doctors at St James' Hospital in Dublin, working closely with researchers at the Department of Pharmacology & Therapeutics at the University of Liverpool, have been exploring the use of blood tests to measure the levels of anti-HIV drugs on a case-by-case basis, allowing therapy to be tailored to the individual. We spoke to Dr C.A. Merry of St James' and Professor David Back of the University of Liverpool about this work.

**Why measure drug levels?

AIDS Treatment Update: Why is it useful to measure levels of anti-HIV drugs?

Dr Merry: The best example of why it's useful to measure drug levels is saquinavir. The problem with saquinavir is that we know it has poor bioavailability. In some patients you get good levels in the blood, and they do terribly well. But in others you get low levels, and for them you need to try something else instead.

Our studies show that 26% of patients who start on saquinavir have sub-therapeutic levels. They have a couple of options. They could add in ritonavir or nelfinavir, both of which boost saquinavir levels, but this is only a good option for patients who can cope with taking lots of tablets. Alternatively they can change to a different triple therapy regimen altogether.

Professor Back: Most of our data relates to saquinavir, where there's no doubt that it's worthwhile performing these tests. As discussed by Dr Merry, in at least 25% of people taking saquinavir in combination with two NRTIs the levels of saquinavir are below that required to get an antiviral effect. When you combine saquinavir with ritonavir or nelfinavir, levels are markedly enhanced.

AIDS Treatment Update: What other drug levels is it useful to measure?

Dr Merry: We're also measuring drug levels for the other protease inhibitors and the non-nucleosides (NNRTIs).

With ritonavir we've found the opposite problem to saquinavir. To date all our patients have achieved good levels, but some patients complain of side-effects about two to four hours after taking each dose of ritonavir, which is when levels of ritonavir in the blood reach their peak. We wanted to try changing the dose regimen to avoid these peak levels, but we also have to ensure that the levels don't drop too low between doses. We've found that if you take 300 mg four times daily, instead of the recommended dose of 600 mg twice daily, you maintain adequate drug levels but patients can tolerate the drug much better.

We haven't looked at many people on indinavir yet, but they all seem to be getting good levels as long as they take the drug at the correct eight-hourly intervals. Levels on nelfinavir haven't been a problem either.

So many anti-HIV drugs are being released early through expanded access schemes that there often isn't much data on how best to use them, especially in combination with other new drugs.

AIDS Treatment Update: American researchers recently reported that among people taking indinavir, those with the lowest trough levels were the first to experience viral load rebounds. Doesn't that suggest that indinavir levels should be measured routinely too?

Professor Back: There is an ongoing debate about the value of measuring trough levels for other drugs. For example, when you combine indinavir and nevirapine, you get an average 28% fall in indinavir levels, but it's not clear whether that really matters. Given the inherent variability in indinavir levels between individuals, some people are of the opinion that you don't need to worry about a 28% drop, while others think you need to increase the dose from 800 to 1000 mg three times daily. We're still in the early days of understanding the rel ationship between drug levels and antiviral effects.

AIDS Treatment Update: Do you see therapeutic drug monitoring as a research programme, or part of your routine clinical practice?

Dr Merry: We're trying to make it part of routine practice. It's been of huge value to us, and we would be very reluctant to go back to the days when we didn't have it. It's certainly expensive, but when you balance the cost against the amount of money you may be wasting by prescribing expensive drugs that aren't actually doing any good, economically it seems to make sense.

**Issues for drug users

AIDS Treatment Update: Many of your patients are `recreational' drug users. Does this raise particular issues?

Dr Merry: One of the reasons why saquinavir was our first-choice protease inhibitor for the last eighteen months was because it doesn't have serious interactions with opiates or benzodiazepines, which many of our drug-using patients are taking.

When you find that someone is only getting low levels of the drug into the blood, it could be because they're having difficulty with compliance. But in most cases they seem to be taking the drugs properly, and the problem seems to be poor bioavailability of the drug.

Many drug users have impaired liver function because of hepatitis B or hepatitis C infection [Editor's note: see the article on page 1 of this issue]. It's our impression that people with abnormal liver function tests get higher levels of saquinavir. Ironically, that makes saquinavir a better drug for them, because you want the higher levels.

**Practicalities

AIDS Treatment Update: How do you take the samples for testing?

Dr Merry: Some patients come into the day ward and we take a number of blood samples throughout a day. For others, we ask them to come in to see us first thing in the morning or at lunchtime, just before they are due to take a dose, and take a sample to measure their trough levels. The samples are all shipped off to Professor Back in Liverpool.

AIDS Treatment Update: For which drugs can you offer therapeutic monitoring?

Professor Back: We're currently set up to measure trough levels of all the protease inhibitors, and we can also measure levels of all the nucleoside analogues, although on the whole it's not clear how useful that is.

AIDS Treatment Update: How much does it cost for a clinic to get samples tested by you?

Professor Back: We've probably spent somewhere in the region of ?100,000 setting up all the assays, and we have to try to recoup some of that. We now charge ?25 per blood sample, plus there's the practical issue of getting the sample sent to Liverpool, ideally on dry ice.

Obviously we have to give a fairly fast turn-around if patient management decisions are to be made on the basis of the data.

There's growing interest in this area though. As well as the Royal Liverpool Hospital and St James' in Dublin, we've done tests for centres in Glasgow, Edinburgh, Manchester, Birmingham and St Mary's in London, and I've been contacted by groups in the USA and Australia who are setting up similar systems.

I think it would be useful if there was a London centre performing these assays, but in the meantime I've made it clear that this service is available for any clinic who wants to use it.

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