Relapse of Intravenous Drug Use Triggered by Enfuvirtide,a Parenteral Antiretroviral Medication

Introduction

F uzeon® (enfuvirtide; Hoffmann-LaRoche, Nutley, NJ), the first HIV fusion inhibitor antiretroviral drug, has been successfully prescribed to antiretroviral-experienced patients. ^1,2 It is well tolerated by the majority of HIV patients under treatment, ³ and can be highly effective in many clinical conditions. ⁴ However, because it is a peptide rapidly degraded following oral administration, it must be administered by subcutaneous injection twice daily. This may restrict its use among patients with difficulties in handling needles. Of further concern, enfuvirtide use and the ritual of self-injection may trigger associations with the addictive behavior and ultimately lead to illicit drug use relapse in patients with a history of intravenous drug addiction, both recovering or fully abstinent. This issue has been previously assessed in guidelines for enfuvirtide use, ^5,6 but to our knowledge, no previous report has described a case concerning such adverse event. Here, we describe two patients with long abstinence periods who experienced strong drug-related memories triggered by enfuvirtide injection.

Case Report 1

This was a 46-year-old male patient, regularly followed in our institution since 1995, when he was diagnosed with hepatitis C virus (HCV) and HIV infection. He reported a past history of injecting drug use, which was the likely exposure route to both viruses. He was started on highly active antiretroviral therapy (HAART) in June 1995, and during the next 13 years he was sequentially prescribed with five different HAART combinations due to virologic and immunologic failure. Accordingly, he had a poor adherence to antiretroviral medication. Treatment for HCV infection was not prescribed due to persistently low T CD4 cell count. In October 2008, his blood tests showed a T CD4 cell count of 152/mm³ and an HIV viral load of 21,867 copies/mm³. After tropism and genotyping tests in October 2008, his antiretroviral therapy was changed to tenofovir, lamivudine, darunavir/ritonavir, raltegravir, and enfuvirtide. Two months later, his HIV viral load was undetectable, as it remained in February 2009 when his T CD4 count had already increased to 401/mm³.

During 14 years of follow-up the patient denied illicit drug use. In April 2009 he relapsed to injection drug use.

The patient reported that during the past 48 weeks he had been handling needles because he was in charge of administering subcutaneous medication to his wife for her HCV treatment. No relapse had happened until subcutaneous medication was started for himself. He reported that the feeling of the needle stick brought about strong memories of the previous injecting drug experience, and those were the main triggers for relapsing. Additionally, the needles and syringes provided to the patient for enfuvirtide administration were used for the injecting drug relapse.

The patient was referred to psychiatric follow-up and enfuvirtide was suspended from his prescription, while the remaining antiretroviral drugs were maintained. Six months after interruption of enfuvirtide and psychiatric support, the patient was again abstinent to illicit drugs, and no HIV treatment failure was observed.

Case Report 2

This was a 46-year-old male patient, regularly followed in our institution since 1991 when he was diagnosed with HIV infection. He had a previous history of a heavy illicit intravenous and inhaled drug abuse. He was started on antiretrovirals in January 1997, and for the first 8 years of follow-up he continued illicit drugs and alcohol consumption, with a variable adherence to antiretroviral medication. Accordingly, genotyping tests confirmed he carried a multidrug-resistant HIV strain. In October 2009 he was started on a new genotype-based regimen containing abacavir, lamivudine, darunavir/ritonavir, raltegravir, and enfuvirtide. During the previous 4 years he had been completely abstinent from alcohol and illicit drugs, and was also taking his medications on a more regular basis.

Eighteen days after being started on the new regimen, the patient spontaneously sought our facility referring anxiety, aggressiveness, behavioral change, and headache. He was fully aware of his altered behavior, and also told us that since he was started on enfuvirtide he had been feeling a strong impulse to illicit drugs relapse. He reported that every time he adminstered enfuvirtide, handling the needles and syringes brought about memories of cocaine or heroin injection, although without the desired psychotropic effect. As an attempt to reduce the anxiety, he had already relapsed on marijuana, but denied any relapse of injecting drugs.

Brain computed tomography and cerebrospinal fluid examinations performed to rule out opportunistic infections were both normal.

Facing the risk of relapse on illicit drugs, enfuvirtide was interrupted, with gradual recovery to his normal behavioral status. His antiretroviral treatment was successfully maintained with the oral medications.

Relapse is a common event following abstinence from chronic alcohol and illicit drug abuse and remains a major challenge in the treatment of addiction. In the last decades, several psychological and psychobiological models have been developed as an effort to assess the nature and precipitants of drug relapse. ^7,8 In both human and animal studies, the exposure to situations previously associated with drug intake has been shown to provoke drug use relapse. ⁹

Clinicians involved in the care of HIV and AIDS patients have been concerned when prescribing enfuvirtide to antiretroviral-experienced patients due to its subcutaneous administration. While some patients may report uneasiness in self-injecting the medication or lower adherence rates, former drug addicts exposed to syringe and needle handling and self-injection may face strong memories associated with the addictive behavior, ultimately triggering relapse.

These case reports emphasize the potential role of enfuvirtide injection as a trigger to illicit drug relapse. Both patients clearly implicated the drug-associated context of the injecting activity as a trigger for relapse; the medication itself does not seem to have any role as an eliciting factor.

Although new and more potent medications are now available for antiretroviral-experienced HIV patients, enfuvirtide may still be essential for the conception of an active and long-lasting antiretroviral regimen. Whenever a former injection drug user may be exposed to enfuvirtide or other self-injecting medications, a careful evaluation and multidisciplinary follow-up should be performed. If possible, additional environmental cues or stressors should be removed or reduced. Self-injecting may be avoided through the administration by a relative or in an outpatient service. Patient should have easy access to psychiatric and medical care, and the risk of relapse should be continuously evaluated. Enfuvirtide should be replaced or withdrawn as soon as possible.