Introduction

Anyone who has studied the official information sheets that detail the approved uses of each protease inhibitor will be aware that these drugs can have significant interactions with other prescribed drugs. In some cases this information has been derived from clinical tests in which people took both drugs and were studied through blood tests. But these well-studied interactions are the minority. More often, drug companies' researchers decide which interactions are likely based on the way their drug is metabolised.

Even for some prescribed drugs which are used by substantial numbers of people with HIV, such as the heroin-substitute methadone used in drug treatment programmes, surprisingly little reliable research on interactions with anti-HIV drugs has been conducted. Most of the guidelines on possible interactions are 'informed guesswork' based on the way the drugs in question are metabolised by liver enzymes.

But while there is quite a lot of information about these interactions, it is much harder to find reliable advice about possible problems if they are taken with illegal drugs. Interactions can impact on effectiveness of prescribed drugs by impacting on the speed that drugs are metabolised, thereby increase side effects and decrease / increase potency of both prescribed and street drugs.

All the information that exists comes from the same process of 'informed guesswork', where predictions are made by drug company researchers, who ‘guess’ how the drug is metabolised, and from anecdotal information reported by users. However, it is made more complicated still by several additional problems of reporting from experiences.

• on rare occasions, deaths have been reported even after people have taken only a single ecstasy tablet and no other drugs that could cause interactions.
• researchers often aren't sure how some illegal drugs are processed in the body.
• any available information may relate to the pure form of the drug, such as the chemical MDMA (ecstasy), but 'street' drugs are rarely pure (an ecstasy tablet may well contain MDE or MDA rather than MDMA). For example, if a drug interaction led to a three-fold increase in blood levels of MDMA, the effect might be barely noticeable to someone who took an E containing very little MDMA, but very substantial for someone who took an E that consisted of pure MDMA. Purity of the street drug is unknown so the size of the interaction effect can vary differently for e.g. 1 ecstasy pill depending on what’s in it. The same applies to all street drugs.
• research on these issues is sometimes hampered because the government and drug companies are anxious not to be seen as 'condoning' illegal drug use.

Several of these issues were relevant to the ritonavir/ecstasy case, which came to the fore in autumn 1996 when a London club-goer, Philip Kay, died after taking ecstasy. An autopsy found that he had unusually high levels of ecstasy in his blood, which may be at least partially explained by the fact that he was also taking ritonavir. For more information see under Ecstasy above.

No formal interaction studies had taken place, although knowledge of the metabolism of the two drugs made it likely that ritonavir would boost ecstasy levels two to three-fold. Philip Kay's partner is sure that he took no more than 2.5 ecstasy tablets, yet at post-mortem he had blood levels of MDMA equivalent to taking 22 tablets - nearly a ten-fold increase. One possibility is that these particular Es contained unusually high amounts of MDMA.

Alternatively, if Kay was naturally a poor metaboliser of MDMA on account of his genetic make-up, that too could have had a bearing on the case. However, Abbott Laboratories has subsequently suggested that abnormally high peak levels of ritonavir during the early weeks of therapy may cause elevations in ecstasy levels if it is taken at this time.

Since then, hospitals have reported other cases due to adverse reactions to ecstasy among people taking protease inhibitors. However, ecstasy is not the only illegal drug that might interact dangerously with prescription drugs, and ritonavir isn't the only anti-HIV drug that may interact with illegal drugs.

Some medications can speed up how quickly the liver clears other medications from the body. When this happens the second medication is cleared faster from the body and this could result in there not being enough medication in the body to work properly. In the case of HIV, inducer drugs can cause some HIV medications to be removed form the bloodstream too quickly and this can lead to viral resistance.

Protease inhibitors are by far the most likely of the anti-HIV drugs to have interactions with recreational drugs in the liver. One key enzyme involved is called cytochrome P450 2D6 (CYP2D6), which is significantly inhibited by ritonavir. What results is a log-jam. It’s rather like rush hour at the tube stations- if all the ticket barriers are open, everyone can get through easily. If half are closed, then more people are competing for fewer gates and a build-up begins. In the body, ritonavir closes some of these gates in the liver. When chemicals in MDMA are trying to get through, they are impeded. This could lead to a large build up in the body. Other drugs affected are: speed, anabolic steroids, Diazepam (valium), Rohypnol (flunitrazepam), Prozac (fluoxetine), Lustral (sertraline), Viagra (sindenafil), GBH and methadone.

It is thought that other protease inhibitors do not inhibit the action of enzymes involved in breaking down recreational drugs to the same extent as ritonavir.

It is possible that the non-nucleoside reverse transcriptase inhibitor (NNRTI) delavirdine, which also inhibits the 3A4 enzyme, could increase levels of some recreational drugs. Another NNRTI, nevirapine has the opposite effect as it induces 3A4 so could lead to reduced levels of any recreational drugs that are metabolised by that enzyme.