PMC:7463108 / 105197-111927 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7463108","sourcedb":"PMC","sourceid":"7463108","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7463108","text":"Opioid Effects on Antiretroviral Efficacy within the CNS and Vice Versa\nOpioid misuse has been linked to poor adherence to cART (Jeevanjee et al. 2014). However, adherence to ARV therapy improves after initiation of opioid substitution therapy (Nosyk et al. 2015; Low et al. 2016; Adams et al. 2020). Although better adherence can improve therapeutic outcomes in PWH, little information is currently available on the interaction between opioids or opioid substitution therapies and cART specifically within the CNS.\nThere are several known drug-drug interactions between opioids and ARVs that affect systemic concentrations. The partial opioid agonist, buprenorphine, is metabolized primarily by cytochrome P450 (CYP) 3A4 and 2C8. Both buprenorphine and its active metabolite, norbuprenorphine, are glucuronidated by UDP-glucuronosyltransferase (UGT) 1A1 and then excreted in bile. Several ARVs inhibit or induce these metabolic pathways. However, not all interactions are clinically relevant. The boosted protease inhibitor combination, atazanavir/ritonavir, inhibits CYP 3A4 and UGT 1A1, leading to increases in overall systemic exposure of buprenorphine and norbuprenorphine and also results in symptoms of opioid excess, such as increased sedation and impaired cognition (McCance-Katz et al. 2007). Dose adjustments of buprenorphine are recommended when initiating therapy with atazanavir to avoid symptoms of opioid excess. Methadone is a full opioid substrate with multiple metabolic pathways, including CYP 3A4, 2B6, 2C19, 2C9, and 2D6. Several pharmacokinetic interactions are reported between methadone and protease inhibitors. However, withdrawal symptoms are rare, and therefore, dose adjustments are not recommended (Bruce et al. 2006; Meemken et al. 2015). In contrast, efavirenz and nevirapine induce CYP 3A4, resulting in decreased systemic concentrations of methadone and the development of opioid withdrawal symptoms. To avoid opioid withdrawal, increased methadone dosing is recommended when either efavirenz or nevirapine therapy is initiated (Marzolini et al. 2000; Clarke et al. 2001; Meemken et al. 2015). Oxycodone metabolism is inhibited by lopinavir/ritonavir, increasing oxycodone concentrations as well as the self-reported drug effects (Nieminen et al. 2010; Feng et al. 2017).\nThe pharmacokinetic studies above focused on overall systemic exposure of drugs. Plasma concentrations, however, are not always accurate indicators of tissue exposure. Similarly, CNS drug exposure is often estimated based on drug concentrations within the CSF. However, CSF drug levels may not accurately predict brain concentrations. For many drugs with high efflux activities (e.g., substrates of P-gp), CSF tends to over-predict brain tissue concentrations (Liu et al. 2006; Friden et al. 2009; Kodaira et al. 2011, 2014). This could be due, in part, to differential expression of transporters at the blood-CSF barrier vs. BBB. In a study of the ARV drug amprenavir, concentrations of [14C]-amprenavir in CSF versus brain were 23.3 ± 11.2 and 3.33 ± 0.6 nCi/g, respectively, demonstrating overprediction of brain concentrations by CSF (Polli et al. 1999). These studies illustrate the high likelihood of misinterpreting drug brain penetration when using CSF as the surrogate marker. Therefore, direct measurement of brain tissue concentrations in animal models are likely to be more predictive of the interactive effects of ARVs and opioids on ARV and/or opioid brain exposure.\nA few studies have investigated the impact of opioids and ARV administration on drug concentrations within the brain. One study investigated the impact of 5 d continuous exposure to morphine on ARV brain concentrations (dolutegravir, lamivudine and abacavir) and demonstrated that morphine exposure resulted in regionally specific decreases in the concentrations of select ARV drugs (Leibrand et al. 2019) and, furthermore, that the decreases in ARV concentrations (dolutegravir and abacavir) were likely due to increased efflux by the drug efflux transport protein, P-gp (Leibrand et al. 2019). Morphine alterations in P-gp within the brain could have wide reaching impact on other CNS active drugs.\nHIV preferentially infects microglia and perivascular macrophages within the brain, although BMECs, astrocytes, and pericytes can also be infected (Kramer-Hammerle et al. 2005). Achieving optimal intracellular ARV concentrations are essential to suppress the infection. Few studies have examined whether ARV drugs differentially accumulate within different neural cell types and especially within cells of the neurovascular unit. Although nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are efficacious in inhibiting viral replication within monocyte-derived macrophages, only a few drugs within each ARV class can effectively inhibit viral replication within astrocytes (Gray et al. 2013), which could be a result of poor intracellular accumulation within astrocytes. In vitro studies have demonstrated darunavir and raltegravir intracellular concentrations to be approximately 100-fold lower (with higher EC50 values) in microglia than in PBMCs (Asahchop et al. 2017).\nAnother study measured intracellular concentrations of dolutegravir, tenofovir and emtricitabine in primary human astrocytes, microglia, pericytes and BMECs (Patel et al. 2019). Intracellular ARV concentrations were typically significantly higher in BMECs than in the other brain cell types. Dolutegravir achieved the highest relative concentrations within each cell type, whereas tenofovir accumulated the least (Patel et al. 2019). Furthermore, 24 h treatment with morphine significantly decreased intracellular accumulation of composite ARV concentrations, but only in astrocytes. In contrast, morphine exposure significantly increased the net accumulation of drugs within BMECs compared to controls. BMECs may sequester ARV drugs as a protective mechanism (Patel et al. 2019).\nUsing experimental data from SIV-infected, morphine-addicted macaques, mathematical modeling suggests that morphine exposure increases the proportion of cells with high susceptibility to SIV infection, at least in part, because of increased co-receptor expression (Vaidya et al. 2016). In addition to promoting a higher steady state viral loads and larger CD4 count declines, the model also predicts that morphine exposure results in the need for more efficacious ARV treatment than would be necessary for animals not exposed to morphine (Vaidya et al. 2016). Although the direct impact of morphine on ARV concentrations was not investigated, the study provides evidence supporting morphine’s negative impact on ARV 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