We welcome the literature review by Bracchi et al.  describing potential drug–drug interactions (DDIs) between antiretroviral treatments (ARTs) and recreational drugs. Data on potential DDIs are important for HIV clinical management, but remain scarce. We have previously published results from the UK observational Antriretrovirals, Sexual Transmission Risk and Attitudes (ASTRA) study (2011–2012), in which half of the 2248 HIV-diagnosed MSM surveyed had used a recreational drug in the previous 3 months, with 24% using three or more drugs during the same period . Linkage of routine clinical HIV records with the ASTRA questionnaire in a large subset of participants allows for examination of the prevalence of recreational drug use according to ART regimen used. To our knowledge, there are no existing data on concurrent use of recreational drugs and ART among HIV-diagnosed MSM outpatients in the UK.
The primary mechanism of ART elimination is mediated through the hepatic cytochrome p450 complex of proteins. This pathway is also shared by recreational drugs, which can either induce cytochrome p450 activity, leading to decrease of ART concentration to subtherapeutic levels, or inhibit it, resulting in toxic drug accumulation . Bracchi et al.  suggest the potential for harm arising from DDIs is highest between recreational drugs and ritonavir or cobicistat-boosted protease inhibitors (PI/r), and to a lesser extent between recreational drugs and nonnucleoside reverse transcriptase inhibitors (NNRTIs). The potential for interaction is lowest with nucleoside reverse transcriptase inhibitors, maraviroc (C–C chemokine receptor type 5 antagonist), raltegravir and dolutegravir (integrase inhibitors), and rilpivirine (NNRTI). Specifically, PI/r have highest interaction potential with benzodiazepines, erectile dysfunction drugs (EDDs), and ketamine, moderate with crystal methamphetamine, methylenedioxymethamphetamine (MDMA), and mephedrone, and lowest interaction potential with cocaine. NNRTIs (efavirenz, nevirapine, etravirine) also have the potential to interact with cocaine. Although there is low potential for interaction between cannabis, alcohol, nitrites, and ART, when taken with γ-hydroxybutyric acid (GHB), ethanol enhances the sedative and respiratory depressant effects of GHB . The interaction between GHB and ritonavir, nucleoside reverse transcriptase inhibitors, or NNRTIs, remains unclear.
We therefore examined the prevalence of recreational drug use in the 3 months prior to ASTRA questionnaire completion according to ART regimen among HIV-diagnosed MSM on ART. A hierarchical variable was created to reflect on degree of DDI from high to low, for MSM on: first, ritonavir or cobicistat-boosted PIs (regardless of other drugs included in the regimen); second, efavirenz or nevirapine (but not on ritonavir-boosted PIs); and third, other regimens (excluding ritonavir or efavirenz/nevirapine but including rilpivirine, raltegravir, dolutegravir, or maraviroc-based regimens and emtricitabine/tenofovir/etravirine or atazanavir/lamivudine/abacavir combinations). Among 2248 MSM, 2117 (94.2%) consented to linkage with clinic data; linked data on ART history are currently available from four out of eight participating clinics for 1325 (58.9%) MSM, of whom 1167 (88.1%) reported being on ART at the time of the questionnaire and had a clinical record of being on ART for at least 3 months prior to ASTRA completion. Thus, findings reported are based on 1167 MSM, of whom 624 (53.5%) were on a regimen including a PI/r, 523 (44.8%) on efavirenz or nevirapine but not PI/r, and 20 (1.7%) on other regimens only (Table 1). Among 1167 MSM, 613 (52.5%) had used recreational drugs in the previous 3 months, of whom 295 (25.3%) had used three or more drugs.
The overall prevalence of recreational drug use was similar across regimens, with over 50% of MSM on each regimen having used recreational drugs in the previous 3 months. (Table 1). Prevalence of polydrug use was similar for MSM on PI/r regimens and those on efavirenz or nevirapine (26.8% vs. 23.3% used three or more drugs). The prevalence of specific drugs comparing PI/r and efavirenz or nevirapine regimens (according to range of DDI potential with ritonavir from high to low) was: EDDs 24.2% on ritonavir vs. 19.7% on efavirenz or nevirapine; ketamine 11.1% vs. 12.6%; chemsex drugs 16.7% vs. 15.1%; and MDMA 10.7% for both regimen types. In addition, among MSM on efavirenz or nevirapine, 22.0% used cocaine and 9.6% used GHB. Higher alcohol consumption (WHO-AUDIT modified questionnaire score ≥6) was prevalent in 14.7% of those on PI/r and 16.8% of those on efavirenz or nevirapine. Among 180 MSM with higher alcohol consumption, 61.1% (n = 110) had used recreational drugs in the previous 3 months, of whom 32.2% (n = 58) used three or more drugs; of those, 56.9% (n = 33) were on PI/r and 43.1% (n = 25) were on efavirenz or nevirapine regimens.
In summary, recreational drug and polydrug use are common among HIV-positive MSM receiving treatment in the UK, and similarly distributed across both PI/r and NNRTI regimens. This suggests that drug use may not be considered the most important issue by clinicians when deciding on an appropriate ART regimen and that competing concerns, such as choice of regimen most forgiving to periods of nonadherence, may be given higher priority. Alternatively, information on drug use may not routinely be elicited or disclosed in the clinical context. As the potential for DDIs is highest between ritonavir-boosted PI regimens and EDDs, benzodiazepines, ketamine, and chemsex drugs, we highlight the importance of clinician awareness of patients’ use of these specific recreational drugs. National HIV treatment guidelines could benefit from inclusion of potential DDIs with specific recreational drugs and guidance on choice of regimen, dosage adjustment, monitoring, and provision of information to patients. There is a need for healthcare providers to maintain a nonjudgmental attitude in discussing drug and alcohol use and DDIs, while offering support on ART adherence and well tolerated drug use (including provision of harm reduction materials), or referral to club drug clinics. Community peer-led initiatives play a key role in producing literature about DDIs; however, further studies are needed to describe DDIs between ART and recreational drugs, particularly between PI/r and ketamine, GHB, and when used in conjunction with alcohol.
This work was funded by the National Institute for Health Research (NIHR).
Conflicts of interest
There are no conflicts of interest.
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