HLD: In order to keep HIV under control, it’s very important to take the correct doses of each antiretroviral medication, all of the time. People who take antiretrovirals are generally quite well aware of that; it’s certainly something we stress a lot. The reason is to constantly keep drug levels within the right range within the body – neither too high nor too low.

Each of your medications has what’s called a ‘minimum effective concentration’ – the absolute minimum you always need to have circulating to keep the virus under control. Dosages and schedules are based on keeping levels above that minimum amount. That’s why we stress adherence – taking meds at the right dose in the right way at the right time.

However, you also have to avoid getting too high a concentration of drug in your bloodstream. That’s usually not a good thing either – it can increase the toxicity and side-effects of the drug, sometimes dangerously so.

HLD: The term ‘drug interaction’ refers to anything that interferes with how a drug works. That might be another medicine you’re also taking, or a herbal medicine, or a recreational drug. In some cases interactions can even happen with food. Interactions can make the bodily levels of drugs go up or down, neither of which is desirable.

Let’s say you’re taking lopinavir/ritonavir (Kaletra), for example, plus another treatment such as efavirenz (Sustiva) that could potentially reduce the levels of lopinavir. If this were to happen, you’d be taking the doses correctly but your body would process the lopinavir more quickly , and you could end up with lower levels. If the lopinavir levels in your body were lower than the ‘minimum effective concentration’, you could end up with HIV becoming resistant to the medication, even though you’ve been taking it right, unless you correct for the difference (for example, by increasing the dose of Kaletra). This is a situation where therapeutic drug monitoring (TDM) can be useful. (For more on this see Measuring drug levels on page 9)

Another example is taking the herbal product, St. John’s wort, alongside protease inhibitors (PIs) – such as Kaletra , atazanavir (Reyataz), fosamprenavir (Telzir), or saquinavir (Invirase) – or non-nucleosides (NNRTIs) – such as efavirenz or nevirapine (Viramune). St. John’s wort can potentially reduce the levels of PIs and NNRTIs, which could lead to them no longer working effectively.[i]

The other scenario is drug interactions that can increase drug levels. That’s really only a concern if the drug has what’s called a ‘narrow therapeutic window’ – in other words, only a small difference between an effective level and a toxic level. With many medications, there’s a wider ‘window’ than that – you can get higher levels without that necessarily being a problem. It may even be desirable for some drugs that may not be absorbed very well, in order to get more effective levels at lower doses and reduce the number of tablets that you need to take.

Concern over interactions causing increased drug levels is frequently a consideration with PIs that use a mini boosting dose of ritonavir. Ritonavir slows down a key chemical process in the human liver, responsible for clearing many drugs out of the body. Taking any drug that relies on this pathway with ritonavir results in much higher levels of that drug in the body. So, if it is taken with a lipid-lowering medication called simvastatin (Zocor), ritonavir increases the simvastatin to much higher levels, which greatly increases the risks of potentially serious side-effects occurring.

HLD: In HIV care, interactions are most likely with PIs and NNRTIs. Those drugs are metabolised (i.e. processed) by certain liver enzymes, and are particularly susceptible to the effects of other drugs. They can also affect how efficiently those liver enzyme systems work, affecting the levels of other drugs.

One particular liver enzyme, called cytochrome P450 3A4 (CYP3A4 for short), is responsible for the processing of most of the PIs and some of the NNRTIs. Some drugs increase the action of the enzyme and therefore increase the speed at which the drug is broken down and so reduce the drug levels, whereas others do exactly the opposite by inhibiting the enzymes, leading to increases in the drug levels. So anything that affects how that enzyme functions – which quite a few medications do – can cause interactions. All of the examples of interactions that I’ve mentioned so far involve CYP3A4.

HLD: If a drug has problematic interactions, there may be alternatives – other medications that do the same job, but don’t have the same interactions. Ideally you’d use the alternative that’s least likely to cause problems. For example, if someone on a PI needs a lipid-lowering medication we will avoid simvastatin and choose another medicine from the same family that does not interact so significantly with ritonavir.

But sometimes that’s not possible. In many cases we’ll have studied the interaction enough to know how to adjust the doses – you may simply be able to take a different dosage, whether higher or lower, to get the same effect.

Now, in some cases, we may not have enough information to be sure what’s going to happen. Sometimes, we can then actually measure drug levels in your bloodstream to see what’s happening and make sure that we’re getting enough of the medication on board.

(For more on this see Measuring drug levels on page 9)

However, there are two different kinds of interactions: pharmacokinetic (PK) and pharmacodynamic. PK is the way medications are handled by the body: how they get absorbed, processed, and eliminated. PK interactions, then, are anything that influences those things. Those are the kinds of interactions that can be measured (and are what we’ve talked about so far).

On the other hand, pharmacodynamic interactions are not about drug levels per se, but about similar or overlapping medication effects. For example, sildenafil (Viagra) causes a blood pressure drop. Therefore, any other drug with a similar effect, such as poppers (inhaled nitrates) – can cause a profound drop in blood pressure if used at the same time as Viagra. That’s why combining the two can be dangerous and is not recommended. Another example of where we generally avoid combining two different drugs with similar toxicities is with ddI (Videx EC) and d4T (Zerit), both of which can cause peripheral neuropathy – nerve pain in the feet, legs or hands.

HLD: Actually, it can mean either: some drugs should not be taken close together in time; others should not be taken at all if you are taking an interacting drug. It depends on the drugs.

For example, take atazanavir (Reyataz) – a drug which needs stomach acid to be absorbed. There are two kinds of medicines that work to reduce stomach acid. There are short-acting antacids, like Gaviscon, which should not be taken within two hours of atazanavir. In other words, it’s okay to take Gaviscon if you are on atazanavir as long as you take them at separate times.

Then there are other kinds of stomach acid suppressors – H2 antagonists such as ranitidine (Zantac) and proton pump inhibitors, such as omeprazole (Losec). These have 24-hour action and should not be taken at all if you are taking atazanavir (unless your HIV doctor/pharmacist has advised you otherwise). Atazanavir levels can be reduced by 75% if you are taking a proton pump inhibitor.

HLD: First of all, there are the potential interactions between prescription drugs. We can keep a closer eye on that when we’re actually dispensing all the drugs at the same pharmacy. But sometimes drugs like Viagra can be obtained via the internet or bought in a club. Ritonavir also boosts the levels of these drugs, so you end up with a higher level that stays in the body longer. That may sound like a good thing, but it can be dangerous to have such high levels of Viagra in the body for so long – it can cause side-effects relating to the heart and blood pressure. In fact there’s been a case report of a 47 year-old man who died of a heart attack taking Viagra alongside ritonavir.[i]

If we know you’re taking the two drugs together we can make dose adjustment recommendations, for example starting off with a very low dose – no more than 25mg of Viagra within a 48 hour period – and being particularly vigilant for side-effects.

There are also non-prescription ‘over-the-counter’ medications – which includes things you may not think of as ‘medicines’. A classic example is a steroid called fluticasone. It’s found in some nasal sprays and inhalers used to treat asthma and hay fever (the three most common brands are Flixonase nasal spray, Flixotide inhaler, and Seretide inhaler). People don’t often think of these as likely to interact with their ARVs, but in fact they are metabolised by the same CYP3A4 enzyme. So if you’re also taking ritonavir (or Kaletra, which includes ritonavir) you can end up with worryingly high fluticasone levels, which can adversely affect your body’s production of certain hormones.

Even food and nutritional supplements have the potential to cause interactions. Fortunately, most of today’s HIV treatments don’t generally interact with food. However, there are certain drugs, such as tipranavir (Aptivus) or nelfinavir (Viracept), that still need to be taken with food and ddI (Videx EC) should be taken on an empty stomach. Years ago, there was a fashion for using grapefruit juice to help boost the levels of saquinavir, but nowadays there’s no particular need for someone on HIV treatment to either seek out or avoid grapefruit juice (because low dose ritonavir is a more reliable ‘booster’).

However, when it comes to nutritional supplements and herbal preparations, those can be more significant. For example, we don’t think that eating garlic in food is a big issue, but a study showed that high dose garlic capsules had an effect on saquinavir levels[ii], so we advise people not to take those. There’s also St. John’s Wort, as we mentioned, and there are others we know may be of concern.

HLD: First of all, your pharmacy will only be aware of the medicines that they themselves supply you, unless you tell them otherwise. So, if you’re getting medicines from more than one place, it’s important to inform your doctor or your HIV pharmacist. The kind of things they’d like to know about include not just the things that your GP or dentist might have prescribed, but also medicines or supplements that you buy from the supermarket, high street chemist, or health food store, as well as recreational drugs. And don’t forget to tell them about inhalers and other things that you might use occasionally or at certain times of the year!

HLD: Yes, I think there are different situations where that makes sense. You certainly don’t have to do it every month, but if you are just about to start a new medication of some sort, and you’re going to the clinic, it would be useful to bring along your medications or to make a list. Some people might find an annual ‘medicines MOT’ would be useful. Talk to your HIV pharmacist to find out if they can offer this service.

HLD: Healthcare providers certainly won’t recommend or encourage you to take any illegal or potentially harmful drugs – both because of the illegality, but also because you don’t know exactly what’s in them (you could easily end up taking a drug that contains something unexpected, so we might not be able to predict the outcome). We can certainly tell you what we know or don’t know about any given recreational drugs. We’re not going to advise you to go ahead and take them, but we could have suggestions on how to reduce the risk that might be associated with them. We’re not there to police you or to pass judgment; the idea is to give you information so you can make an informed decision. And we can only do that if we know what it is that you are taking or planning to take – so I would definitely say that honesty is the best policy!

Ordinary vitamins and minerals are generally fine to take with anti-HIV drugs. Most everyday drugs, such as paracetamol or ibuprofen, are also absolutely safe. However, if in doubt, it’s always best to check.

Remember, though, most ‘one-off’ drug interactions are generally not going to be too significant. Although they can occasionally be serious, generally if you just take something once it’s not a reason to worry too much.

However, if you’re taking anything regularly alongside your anti-HIV drugs, it’s sensible to check with your HIV pharmacist – even if, like the inhalers we discussed earlier, it’s something you might not generally think of as a ‘medication’. And if you notice any new or changed symptoms that you think could be due to combining medications, do let your HIV doctor or pharmacist know.