Clozapine,HIV and neutropenia: a case report

Abstract

There is paucity of information on the use of clozapine in patients with HIV. Ethnicity, co-prescribed medications and possible drug-drug interactions are important considerations in evaluating risk of blood dyscrasias during clozapine treatment. Individuals with HIV should not be denied access to the most effective antipsychotic, but a multidisciplinary approach is essential for optimal outcome in such complex patients.

Introduction

Schizophrenia and human immunodeficiency virus (HIV) infection are two of the most serious medical conditions affecting man and their occurrence together appears to be associated with greater morbidity and mortality than would be expected with either illness alone. ¹ There is a higher risk of HIV among individuals with severe mental illness. ² Another study in the Medicaid population in Philadelphia estimated that patients with schizophrenia were 1.5-times more likely to have a diagnosis of HIV infection. ³

Despite the high comorbidity, there is paucity of information regarding the treatment of patients with these complex co-occurring conditions. Individuals with HIV are more sensitive to extrapyramidal side effects (EPSEs) of typical antipsychotics ⁴ and hence atypical antipsychotics are used as the first line, with risperidone the most widely used agent. Published information and clinical experience on the use of clozapine in patients with HIV is rather limited. For example, in a retrospective, cross-sectional study that examined metabolic outcomes in 2229 antiretroviral-treated, HIV-infected adults, of the 258 prescribed second generation antipsychotics, only 1% was prescribed clozapine. ⁵

Clozapine is associated with a risk of neutropenia and agranulocytosis. The risk of neutropenia during clozapine treatment is 3% while the risk of the more severe agranulocytosis is about 0.8%. Factors that potentially increase the risk of blood dyscrasias with clozapine include age, sex, ethnicity, and some concurrent medications such as valproate.^{6 –8}

When neutropenia, defined by normative data in White populations, occurs in individuals of other ethnic groups who are otherwise healthy and who do not have repeated or severe infections, the condition may be referred to as benign ethnic neutropenia (BEN). ⁹ BEN which is highly prevalent among Black patients may account for the greater apparent risk of neutropenia among African-Caribbean patients during clozapine treatment. ¹⁰

Correspondingly, anemia, thrombocytopenia and leucopenia are among the most common hematological aberrations identified in patients with HIV infection. ¹¹ Neutropenia has been estimated to occur in between 10–50% of HIV cases. ¹² Various mechanisms by which HIV affects hematopoiesis have been proposed. Furthermore, some drugs used in the treatment of HIV such as zidovudine are clearly associated with neutropenia.

Despite the shared ability to cause neutropenia, it is not known if patients with HIV have a higher risk of agranulocytosis or neutropenia during clozapine treatment than other patients. ¹³

In this case report, we present the complex case of a 44-year old, HIV positive, African gentleman with a diagnosis of treatment refractory schizophrenia who developed neutropenia while on treatment with clozapine. After failed treatment with various antipsychotics, he was successfully rechallenged with clozapine. We obtained a signed written informed consent from the patient, XX, for the publication of patient information in the present case report.

Background

Patient XX came into contact with Mental Health Services in April 2003. On admission he presented with command auditory hallucinations, passivity phenomenon and bouts of violence and unpredictable assaultive behaviors. He had been diagnosed with HIV for 2 years before this time and was treated with antiretrovirals, although he was known to be noncompliant with the medication regimen. During the admission, he underwent a thorough neuropsychiatric assessment. He was treated with various antipsychotics including risperidone oral and depot, zuclopenthixol and pipothiazine long acting injections, to which there was limited response. Due to the poor response to antipsychotic treatment, clozapine was commenced in August 2005. This was effective: at discharge in August 2006, his brief psychiatric rating scale score had improved from 98 to 46. On discharge, he was on a dose of clozapine 100 mg twice daily (bd) with a clozapine level of 0.5 mg/l that was deemed in the therapeutic range. Although he still had residual symptoms, he was much improved. His medications on discharge included clozapine, Omacor^®, gliclazide, metformin, lactulose, citalopram, atazanavir, ritonavir, tenofovir and zidovudine.

Over the next 3 years (2006–2009), changes were made to his medications. In May 2007, zidovudine was changed to abacavir for reasons that are unclear. In July of the same year, sodium valproate was initiated for seizure prophylaxis upon the finding of a clozapine plasma level of 0.68 mg/l. In 2008, tests revealed HIV mutations that show resistance to some of the commonly used antiretroviral agents. In 2009, it was decided to intensify the HIV treatment because the viral load had been detectable at low levels (100–200 copies/ml) through 2008. Tenofovir and atazanavir were replaced with darunavir and Truvada (emtricitabine + tenofovir) while maintaining ritonavir.

By June 2010, he was stabilized on sodium valproate 500 mg bd, citalopram 20 mg once daily (od), darunavir 600 mg bd, Truvada^® 1 od, ritonavir 100 mg bd and clozapine 450 mg daily. At this time, his mental state was reasonably stable. His HIV was controlled with a viral load less than 20 copies/ml with a good CD4 response. He was living in supported accommodation and able to manage his finances.

In May 2012, XX’s blood test showed a neutrophil count of 1.3 × 10⁹/l (a first neutropenic ‘red result’ episode on clozapine, defined as neutrophils less than 1.5 × 10⁹/l or a white blood cell count less than 3.0 × 10⁹/l) necessitating clozapine cessation. This followed repeated episodes of ‘amber’ results defined as neutrophils ranging from 1.5 to 2.0 × 10⁹/l. Following withdrawal of the clozapine, neutropenia improved, but within 2 weeks he was admitted to hospital because of a significant relapse of his mental state when he became threatening, abusive, uncooperative and increasingly agitated. He was initiated on olanzapine but due to poor response, this was switched to depot flupenthixol. He developed severe EPSEs (a shuffling gait, slurred speech and without any improvement in his mental state). He required a period in psychiatric intensive care because of the deterioration in mental health, violence and aggression. Because of a lack of response and significant adverse effects, XX was switched back to olanzapine.

The olanzapine dose was gradually increased to 20 mg daily with limited response. A trial of high dose olanzapine up to 40 mg daily as well as the combination of olanzapine and amisulpride also failed to improve symptoms. Parkinsonian symptoms worsened with the combination of high dose olanzapine and amisulpride. After almost 1 year off clozapine trying different pharmacological approaches without much success, his case was presented before a tertiary panel of psychiatrists, psychopharmacologists, pharmacists and psychologists with expertise in the management of patients with treatment refractory illness. A recommendation for a clozapine rechallenge was made. The risks and benefits were discussed with his family, particularly his sister with whom the unit worked closely with throughout the admission.

Following this, a hematology referral was made to review the possibility of a clozapine rechallenge. The hematology view was that the neutropenia was unlikely to be due to clozapine but the HIV medications and the valproate may possibly be implicated. A recommendation for a cautious clozapine rechallenge was therefore supported and if necessary, adjunctive treatment with granulocyte colony stimulating factor (GCSF). ¹⁴ A diagnosis of BEN was considered by hematology but XX was deemed not to have fulfilled the criteria. Nevertheless, an off-label agreement was reached with Zaponex Treatment Access System, the clozapine registry, to use a lower neutrophil threshold and monitor his clozapine treatment according to the BEN criteria. Any prescribed medication with hematological adverse effects that could potentially affect the outcome with clozapine was reviewed. Sodium valproate and olanzapine were gradually withdrawn. No changes were made to the HIV medications. Clozapine was reintroduced in October 2013, and over the following weeks, both amisulpride and olanzapine were gradually withdrawn while clozapine dose was increased. After an initial exacerbation of symptoms, a gradual improvement was noted. The contingency plan in case of neutropenia was to consider the use of lithium or GCSF. There was no need to resort to the use of remedial measures. XX continued to improve in mental state and by the end of 2014, he was sufficiently improved for discharge. Psychiatric medication on discharge was clozapine 400 mg daily with a clozapine level of 0.49 mg/l and norclozapine level of 0.37 mg/l. His HIV medications remained the same as on admission, darunavir, Truvada^® and ritonavir.

At 3 years follow up, there have been no further episodes of neutropenia. XX remains mentally stable and compliant with both his clozapine treatment and antiretroviral regimen. He lives in a 24-hour supported housing. He has not had a further admission and his functioning has returned to his previous level prior to the severe relapse. He is able to travel independently to attend various activities in the community including art, music, exercise and an HIV support group.

Discussion

Published information on the use of clozapine in patients with HIV is very limited. A report by Dettling and colleagues ¹⁵ describes the use of clozapine in the treatment of HIV-associated psychosis in a 34 year old male. During clozapine treatment, the patient developed neutropenia apparently associated with lamivudine and zidovudine, that required discontinuation of the combination. Substitution with stavudine/lamivudine enabled successful continuation with clozapine treatment. Another study ¹⁶ examined clozapine in patients with HIV-associated psychosis in patients who had experienced moderate parkinsonism with typical antipsychotic drugs. The average dose in this study was a relatively low dose of 27 mg/day in which substantial improvement was noted both in psychotic symptoms and extrapyramidal symptoms. In 2009, Nejad and colleagues ¹⁷ published a report describing the successful use of clozapine in two patients with HIV and schizophrenia in which one of the patients developed neutropenia and was successfully rechallenged.

This report describes the case of a HIV patient who developed neutropenia 6 years after clozapine initiation and was successfully rechallenged following nonresponse to nonclozapine antipsychotics. It is unclear what caused the initial neutropenia. Was it related to clozapine, to his HIV or HIV treatment? Was it related to sodium valproate or did his ethnicity play a role? Did drug–drug interactions play a part in the development of neutropenia, or more likely, was it a combination of factors?

Whatever the cause of the neutropenia, the case highlights several potential and clinically significant pharmacokinetic and pharmacodynamic interactions. Ritonavir is a potent inhibitor of cytochrome (CYP)450 3A4 and, at higher doses also inhibits CYP2D6. It may also induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolized by these pathways. ¹⁸ According to the UK manufacturers, the use of clozapine is contraindicated with ritonavir because co-administration is likely to result in increased plasma concentrations of clozapine. ¹⁸ However, clozapine is metabolized primarily via CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6. Because of both the inhibitory and inducing properties of ritonavir, according to Stockley, ¹⁹ the overriding direction and magnitude of any resulting effect on clozapine concentrations, and therefore its clinical relevance, is unclear. Cobicistat, a newer pharmacokinetic enhancer is a structural analogue of ritonavir. It is a more selective CYP inhibitor than ritonavir and is devoid of enzyme-inducing properties and thus, is less likely to be involved in other drug–drug interactions. ²⁰

The interaction between ritonavir and clozapine could have led to an increase in clozapine levels which then necessitated the addition of sodium valproate for seizure prophylaxis. A recent case-control study demonstrated a strong association between clozapine and sodium valproate use and neutropenia risk. ²¹ The risk of neutropenia with valproate was found to be dependent on dose. Our patient developed neutropenia 5 years after initiation of the sodium valproate.

Worsening HIV disease parameters such as lower CD4 counts and higher viral load are associated with the development of neutropenia. At the time our patient developed neutropenia, his HIV was well controlled with a viral load less than 20 copies/ml with good CD4 response. As regards the risk of neutropenia with antiretrovirals, many of these agents can cause neutropenia but the risk appears greatest with zidovudine containing regimes. ¹² Zidovudine was discontinued in our patient in 2007 possibly due to this risk.

BEN was considered in our patient because of his ethnicity, but as his baseline blood counts prior to clozapine initiation were well within normal limits, this possibility was ruled out.

It remains unknown whether patients with HIV are at higher risk of developing neutropenia or agranulocytosis during clozapine treatment.

Conclusion

Patients with HIV and co-occurring refractory psychotic disorders should not be denied the most effective medication. Treatment of patients with HIV using clozapine requires a multidisciplinary approach involving psychiatrists, specialist pharmacists, HIV specialists and hematologists with careful assessment of risk factors for hematological disorders. In particular, careful attention is required with the use of concurrent medications that increase the risk of blood dyscrasias.