HIV and mental illness: Are drug interactions a barrier to effective therapy?
Independently, HIV/AIDS and mental illness are two of the larger public health concerns in the United States. Estimates suggest approximately 1.1 million people in the US live with HIV, whether they are aware of their infection or not.
The most recently published estimate of lifetime HIV treatment costs was just less than $400,000, with annual costs around $20,000. Prevalence of mental illness is more extensive, with roughly 42.5 million adults experiencing some sort of mental illness, as defined by the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), in 2012. Reports from 2006 estimated the average annual cost per person was more than $1,500. These diseases can be somewhat cyclical and are considered risk factors for each other, leading to increased public health concern, health care costs, and difficulty in treatment. The prevalence of HIV among people with mental illness is up to four times greater than in the general population.
There are many barriers for effective therapy in HIV patients with mental illness, which include but are not limited to financial factors, residence instability, substance abuse, nonadherence and an inability to maintain health care support. Drug interactions also can be a large barrier to effective treatment, though one that can be reduced through proper coordination of care and utilization of clinical pharmacists. Therefore, it is important for clinicians to be aware of potential drug interactions encountered with each drug class.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
NNRTIs are metabolized in the liver by cytochrome P450 (CYP) 3A4. The most commonly used are efavirenz (Sustiva, Bristol-Myers Squibb), etravirine (Intelence, Janssen), nevirapine (Viramune, Boehringer Ingelheim Pharmaceuticals), and rilpivirine (Edurant, Janssen Therapeutics). NNRTIs can impact decision-making for depression. Looking at depression, St. John’s Wort may reduce blood levels of NNRTIs, while NNRTIs can reduce drug levels of vilazodone (Viibryd, Forest Laboratories), sertraline (Zoloft, Pfizer), nefazodone and trazodone, but have no effect on paroxetine or bupropion. There is no published data on interactions with tricyclics (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs) or monoamine oxidase inhibitors (MAOIs). For treatment of anxiety and insomnia, NNRTIs have been found to increase diazepam concentrations, but no other drug-drug interactions (DDIs) have been published with benzodiazepines or non-benzodiazepine sedative/hypnotics. When treating mood disorders and seizures, evidence suggests that carbamazepine, phenobarbital and phenytoin should be avoided, but there are no DDIs established with lithium. There currently is no published data about DDIs specific to antipsychotics (typical or atypical), stimulants or other treatments for attention-deficit disorder (ADD).
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
NRTIs are mostly eliminated renally and thus have very few DDIs. Abacavir (Ziagen, GlaxoSmithKline) and zidovudine are exceptions and undergo metabolism by alcohol dehydrogenase and glucuronyl transferase, and glucuronidation, respectively. There are few published reports on DDIs in NRTIs; however, abacavir can increase the clearance of methadone, while zidovudine levels can be increased to toxic levels by methadone, valproic acid and phenytoin. In patients on abacavir and methadone, you should monitor for signs/symptoms of methadone withdrawal. For those on zidovudine and methadone, valproic acid or phenytoin, you should monitor for signs of toxicity such as significant anemia and/or neutropenia.
Protease inhibitors (PIs)
PIs are metabolized by CYP3A4 enzymes. The most common are atazanavir (Reyataz, Bristol-Myers Squibb), darunavir (Prezista, Janssen Therapeutics), lopinavir and ritonavir (Norvir, AbbVie). Ritonavir is a potent inhibitor that is used to boost other PIs and is associated with most DDIs. Antidepressant doses should start low because ritonavir may increase levels of selective serotonin reuptake inhibitors (SSRIs), TCAs, SNRIs, bupropion, nefazodone and trazodone. This interaction increases the risk for developing serotonin syndrome. However, boosted darunavir and fosamprenavir (Lexiva, ViiV Healthcare) have been shown to decrease levels of sertraline and paroxetine. PIs should be used with caution in treating patients with anxiety or insomnia due to increased potential for prolonged sedation or respiratory depression. They are contraindicated in combination with midazolam and triazolam (Halcion, Pharmacia and Upjohn). There have been no studies looking at PIs combined with lithium for mood, but PIs can interact with anticonvulsants. They should be avoided with carbamazepine as it can reduce levels of PIs and increase carbamazepine levels. PIs also can decrease levels of phenytoin and lamotrigine (Lamictal, GlaxoSmithKline), requiring increased doses. Use caution in combining antipsychotics with PIs as ritonavir has been shown to increase levels of antipsychotics like clozapine, quetiapine (Seroquel, AstraZeneca), iloperidone (Fanapt, Novartis), risperidone (Risperdal, Janssen), lurasidone (Latuda, Sunovion Pharmaceuticals) and ziprasidone (Geodon, Pfizer). Ritonavir may decrease levels of olanzapine (Zyprexa, Eli Lilly), but the evidence is inconclusive. Ritonavir also may increase concentrations of modafinil (Provigil, Cephalon) and other stimulants and should be dosed accordingly.
Enfuvirtide (Fuzeon, Roche) is a fusion inhibitor, which undergoes catabolism to amino acids. Maraviroc (Selzentry, ViiV Healthcare) is a CCR5 inhibitor, which is metabolized by CYP3A4 enzymes. There are few known DDIs with enfuvirtide and maraviroc at this time due to a lack of published data. There is evidence that the maraviroc dose should be reduced when used with nefazodone (Serzone, Bristol-Myers Squibb). In contrast, the dose should be increased when combined with carbamazepine, phenobarbital or phenytoin.
Integrase inhibitors vary in their metabolism. Elvitegravir (Vitekta, Gilead Sciences) is metabolized by CYP3A4 and boosted with cobicistat (Tybost, Gilead Sciences), a potent CYP3A4 inhibitor. Raltegravir (Isentress, Merck) and dolutegravir (Tivicay, GlaxoSmithKline) undergo glucuronidation, with a little CYP3A4 for the latter. To date, very little DDIs have been found with the individual integrase inhibitors, with most interactions being caused by the cobicistat combined with elvitegravir. The cobicistat may increase levels of SSRIs (specifically paroxetine), TCAs, bupropion, nefazodone and trazodone, but has not been shown to affect SNRIs or MAOIs. Cobicistat is contraindicated with midazolam and triazolam and can increase sedation and risk of respiratory failure when combined with buspirone (BuSpar, Bristol-Myers Squibb), zolpidem, diazepam and clonazepam (Klonopin, Roche). However, it is unlikely to interact with lorazepam (Ativan, Valeant Pharmaceuticals), temazepam (Restoril, Mallinckrodt Pharmaceuticals) and oxazepam. Anticonvulsants such as carbamazepine, oxcarbazepine (Trileptal, Novartis), phenobarbital and phenytoin have the potential to reduce elvitegravir concentrations and should be avoided. It is recommended to start with the lowest dose for antipsychotics like perphenazine (Trilafon, Schering-Plough), thioridazine (Mellaril, Novartis) and risperidone in a patient on elvitegravir/cobicistat.
HIV and mental illness are difficult diseases to treat due to numerous factors, including variation of treatment options, adherence and variability in effectiveness from one patient to another. When a patient has both of these diseases it is much more difficult as every aspect of treatment must be carefully reviewed. One of the easiest ways to reduce a patient’s barriers for compliance is to tailor their regimens to avoid drug interactions that either reduce effectiveness or increase risk for toxicities and adverse drug reactions.
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For more information:
Corey M. Ball, PharmD, is a PGY1 pharmacy practice resident at Denver Health Medical Center.
Kati Shihadeh, PharmD, is a clinical pharmacy specialist – infectious diseases at Denver Health Medical Center. Shihadeh can be reached at email@example.com.
Disclosure: Ball and Shihadeh report no relevant financial disclosures.