HIV-treatment 'booster drugs' are most likely to have dangerous interactions with methamphetamine, mephedrone, MDMA and ketamine

Interactions also possible with erectile dysfunction drugs and benzodiazepines

The two drugs involved in HIV treatment that are most likely to have dangerous interactions with recreational and 'chemsex' drugs are the two that do not have direct anti-HIV effects themselves but are used to boost other drugs - ritonavir (Norvir) and cobicistat (Tybost).

Cobicistat is also a component of the combination pills Stribild (with elvitegravir, tenofovir and emtricitabine), Prezcobix (with darunavir) and Evotaz (with atazanavir). Ritonavir is often given by itself to take alongside protease inhhibitors and is also present in Kaletra/Aluvia (with lopinavir) and also in the Viekira Pak two-pill hepatitis C treatment.

While there is the potential for some directly-acting HIV drugs to interact dangerously with recreational and ‘party’ drugs, there is less cause for concern about most others than these two booster drugs. Moreover not all recreational drugs have interactions with anti-HIV drugs.

Glossary

drug interaction

When a person is taking more than one drug, and drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.

interaction

When a person is taking more than one drug, and drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

Clinicians need to be aware of the detail of this information so that they can give their patients useful advice, say the authors of an expert review published in the August 24 issue of AIDS. Given that many individuals will continue to take recreational drugs despite medical advice not to, clinicians should consider switching some patients to antiretroviral drug regimens with a lower risk of drug interactions, they recommend.

About drug interactions

When one drug is taken with another, their interaction may lower or heighten the effectiveness and/or side-effects of either one or both drugs. This is the case both for prescribed medicines and illicit, recreational drugs. However there is generally much less medical research on drug interactions with illicit drugs.

There have been concerns about interactions between antiretrovirals and recreational drugs for a number of years but recently, as new drugs like cobicistat have been introduced, the pattern of recreational drug use among gay men living with HIV in the UK has been changing too. Crystal meth and mephedrone are far more popular than they were in the past and are increasingly used in the context of ‘chemsex’ in private homes. This may involve using several substances at the same time and often for an extended period of time.

Furthermore, some men now inject recreational drugs, which by increasing the concentration of the drug rapidly absorbed into the bloodstream, increases the potential for adverse events.

A group including clinicians, pharmacologists, a pharmacist and a drugs adviser has conducted a literature review and pooled expert opinion in order to provide an up-to-date summary of the evidence on drug interactions. Rather than covering all interactions that are theoretically possible, they wanted their review to be practical and to guide clinicians on the interactions that, in their own words, “really matter”. They focus on the ‘party drugs’ that are commonly used by gay men living with HIV in the UK.

“Data on the interaction between substances of abuse and antiretrovirals are scarce, but knowledge of the potential clinical implications of such interactions may be of great importance for HIV care providers,” they say.

Ritonavir and cobicistat

The most important ‘take-home’ message of the review is that the two prescribed medications which are most likely to be involved in harmful interactions with recreational drugs are ritonavir (Norvir) and cobicistat (Tybost).

Both of these are boosting agents, taken in order to boost levels of other antiretroviral drugs. Adding a small dose of one of these agents to a drug makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

The 'boosters' are used most often alongside protease inhibitor drugs (lopinavir, darunavir, atazanavir, fosamprenavir, tipranavir - brand names Kaletra, Prezista, Reyataz, Telzir, Aptivus) but also with an integrase inhibitor (elvitegravir, in Stribild and as Vitekta) and with hepatitis C drugs (ombitasvir and pariteprevir) in Viekira Pak.

The boosting mechanism also affects some recreational drugs. Ritonavir and cobicistat are metabolised by liver enzymes known as CYP2D6 and CYP3A4. A number of recreational drugs are metabolised by the same enzymes, leading to potential interactions. The boosting agent makes the liver process the recreational drug more slowly, resulting in the recreational drug remaining in the body for longer or in greater concentrations. Sometimes this can result in serious side-effects or an overdose.

Party drugs of concern

Several widely used recreational drugs are metabolised by either CYP2D6 or CYP3A4, the same liver enzymes which metabolise ritonavir and cobicistat. These are:

  • Crystal methamphetamine (crystal, tina, meth)
  • MDMA (ecstasy, X, mandy)
  • Mephedrone (miaw miaw, plant food, bath salts)
  • Ketamine (K, vitamin K, special K)
  • Erectile dysfunction drugs (Viagra, Cialis, Levitra)
  • Benzodiazepines (benzos, Valium, Xanax)

The authors judge the potential for interactions with the first three drugs listed to be ‘moderate’ and with the last three to be ‘high’. Although erectile dysfunction drugs and benzodiazepines may be safely prescribed by doctors, when they are obtained through informal channels, the authors say that much larger doses may be taken and there will be no monitoring of side effects.

With each party drug, an interaction with ritonavir and cobicistat may increase the intensity of the effect of the illicit drug, sometimes to unpleasant or dangerous levels.

There have been case reports of deaths in people using crystal meth and ritonavir, and in people using MDMA and ritonavir. Post-mortems showed that the level of the recreational drugs in these individuals’ blood was much higher than would normally be expected. There have been case reports of acute, serious side-effects in people using ketamine and ritonavir. The authors acknowledge that only a few of these cases have ever been documented.

Overdoses of erectile dysfunction drugs are dangerous for the heart. An overdose of benzodiazepines could result in the person passing out or dangerously slowing down their breathing.

In relation to GHB (gamma-hydroxybutyrate) and GBL (gamma-butyrolactone), the authors say that the risk of interactions is "unknown".

Non-nucleoside reverse transcriptase inhibitors and party drugs

A different interaction between antiretrovirals and recreational drugs is expected in the case of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as these drugs are metabolised in a different way. The interaction may result in levels of the recreational drug being lower than would normally be expected.

This applies specifically to efavirenz (Sustiva), nevirapine (Viramune) and etravirine (Intelence). In contrast rilpivirine (Edurant) is not thought to interact with recreational drugs.

The interaction is thought to occur with cocaine, ketamine and erectile dysfunction drugs.

The NNRTI makes the liver process the illicit drug more quickly, meaning that the drug stays in the body for less time or at a lower level. While this may appear to be less harmful, the authors note that if drugs do not have the desired effect users may combine more drugs, increase doses or switch to injecting, leading to unpredictable risks.

Drugs without significant interactions

The potential for interactions with several other substances and recreational drugs is considered to be low by the authors. This includes alcohol, cannabis, poppers, heroin and other opioids.

Similarly, several antiretroviral drugs are not thought to have problems with interactions. These include:

  • All nucleoside reverse transcriptase inhibitors (NRTIs)
  • Rilpivirine (Edurant), a non-nucleoside reverse transcriptase inhibitor (NNRTI)
  • Raltegravir (Isentress) and dolutegravir (Tivicay), both integrase inhibitors
  • Maraviroc (Celsentri), a CCR5 inhibitor

Recommendations

“Clinicians should actively solicit any history of drug use, and provide counselling on toxicity, common adverse effects of substance of abuse, and potential serious drug–drug interactions with antiretrovirals in order to avoid unintentional overdosing or fatal toxicity,” the researchers conclude.

“However, many patients will persist in use of these agents despite best advice, and a switch to cART [combination antiretroviral therapy] with lower propensity for drug interactions should be considered.”