Case

A 33 year-old male inmate presents with untreated C3 HIV/AIDS in need of treatment. His CD4 cell count and HIV-1 viral load two months ago were 100 cells (13%) and 100,000 copies/ml, respectively. He is taking trimethoprim/sulfamethoxazole and azithromycin for PCP and MAC prophylaxis and has been off antiretroviral medications for six months due to intolerance and virologic failure, known because he had genotype resistance assays in his record documenting high level resistance to all available protease inhibitors. He has never taken efavirenz (Sustiva) or nevirapine (Viramune). He is an injecting drug user with a history of bipolar disorder for which he receives lithium by directly observed therapy (DOT). He has no history of suicide attempts and has been hospitalized twice with mania after cocaine use. He weighs 145 pounds and has an unremarkable physical exam. He has two years remaining in his sentence. He tells you that he would like to resume antiretroviral medications as soon as possible due to increasing fatigue and worsening memory but is concerned about his ability to remain adherent if the regimen is too complicated. You recommend he start tenofovir, lamivudine, and efavirenz.

Q: What potential adverse effects should you warn him about?

A: He should be warned about the potential for hallucinations, precipitation of mania, insomnia, depression, and nightmares on efavirenz, particularly in the first 10-14 days on the drug. You tell him that you are hesitant about placing him on the drug because of the potential for these symptoms, particularly with his history of bipolar disorder. However, you realize he has limited protease inhibitor treatment options. You rationalize that if he is going to develop adverse effects on efavirenz, at least they will occur in a supervised, safe setting while he is incarcerated. You also recommend that he see psychiatry more regularly (e.g., every two weeks) for the first few months on this regimen.

He returns for follow-up two weeks later and appears anxious with pressured speech. He reports some mild insomnia but is feeling "better than I've felt in years." Also, he loves taking the efavirenz because it is only one pill at bedtime, which he feels improves his adherence.

Q: Do you have any concerns at this time? What other questions should you ask him? When should you see him again in clinic?

A: Yes, you should be concerned about precipitation of mania with potential for it to progress over the next few weeks. You should ask him when he is taking efavirenz since it was prescribed as "keep on person," making it difficult to be sure what time he is taking it every day. If he is taking the drug within an hour or so of a high-fat meal, the absorption will be increased with higher risk for side effects. Since efavirenz is cleared in the liver via the cytochrome P450 system, a review of his other medications is warranted to be sure there are no significant drug-drug interactions, and checking a lithium level, liver function tests and evaluating for hepatitis B and C and undetected cirrhosis would be reasonable. Finally, you recommend he see you again in two weeks so you can re-evaluate his tolerability of the new regimen.

Q: Are there any other tests to consider at this time?

A: A plasma efavirenz level (trough) can be performed with a blood draw and is probably best drawn 8-15 hours after the dose is taken, which is typically in the morning since most patients take the drug in the evening to minimize side effects. This test is performed at reference laboratories and may take two-four weeks for a result to be received. If the level is above 4,000 mg/l, CNS toxicity may be three times more likely than if the level is below this cutoff. Virologic failure is more often seen when the level is below 1,000 mg/l. It is speculated that a level somewhere between 1,000 and 4,000 mg/l is best for optimal efficacy and tolerability. Unfortunately, because of the long return time for the efavirenz level, it is difficult to use the results of this test as a clinical tool in the management of the patient and is not likely cost-effective for this reason. Decisions in response to a drug level above 4,000 m/gml may be difficult as there are no published guidelines for dose reduction needed with an elevated efavirenz level.

The inmate returns to see you two weeks later. Over the last two weeks, he has received three infractions due to violent outbursts, is paranoid and delusional, and was sent to segregation, then the mental health unit due to concern for his safety and the safety of others. He is still reluctant to stop the new regimen since he "feels great" and his CD4 count is now 160 cells/ml (15%) with HIV-1 viral load of 5,000 copies/ml after three weeks on the drugs. His lithium level and LFTs were normal, and he had no evidence of chronic active hepatitis B or C.

Discussion

Though efavirenz is an attractive HIV treatment option because of its long half-life (only dosed once a day) and high tolerability after the first two weeks, it presents some challenges for use in the incarcerated setting. First, the meals in the correctional setting are typically high in fat and difficult to control, and this may contribute to risk of CNS toxicity. If the drug is taken two-three or more hours after dinner, this problem should be minimized. However, the bedtime pill line in corrections is often shortly after dinner, rather than at 9 or 10 p.m. If the inmate keeps the drug on person, the inmate could then take the dose at 10 p.m. with only a light snack or on an empty stomach. Second, though the risk for severe neurotoxicity in the general population appears low (only discontinued in approximately 4% of patients due to severity or persistence of adverse effects), it is likely higher among incarcerated individuals since they often have a history of significant prior mental illness as well as underlying significant liver disease from hepatitis C and/or alcohol. Third, when psychosis does occur in the incarcerated setting, it can be quite detrimental to the inmate. The patient in this case received numerous infractions for his behavior with an extended sentence, was placed on the mental health unit for observation, and required intensive psychiatric monitoring. The drug was discontinued as his mania and psychosis were not manageable despite intensive psychiatric care and addition of antipsychotics, and the effects lasted for several weeks, even after discontinuing the medication.

In patients who require salvage therapy and have risk factors for CNS toxicity, it is reasonable to consider use of efavirenz in a supervised setting, such as the correctional setting. The potential for problems should be weighed against potential benefits, particularly in patients who have advanced HIV/AIDS. It is important to counsel the patient and the staff about the potential complications. The role of therapeutic drug monitoring is still unclear. Optimal use requires dose adjustment on the basis of a drug level. More research on this topic is needed in order for this practice to be cost-effective and clinically meaningful for the patient.

Bethany Weaver, D.O., M.P.H., is Acting Instructor of Medicine, University of Washington Center for AIDS & STD Research (CFAR) and Northwest Correctional Medicine Education Program. Disclosures: Pfizer: Stockholder.