Toxoplasma encephalitis in an HIV-infected patient on highly active antiretroviral therapy despite sustained immune response

Introduction

Toxoplasma encephalitis (TE) is usually diagnosed in advanced stages of HIV infection (CD4+ T-cell counts <100–200 cells/µl).^1,2 In the era of highly active antiretroviral therapy (HAART), the incidence of TE has substantially declined. ³ Current guidelines recommend discontinuation of primary TE prophylaxis once the CD4+count is >200 cells/µl for >3 months and the patient is on HAART.^4,5 We present a rare case of TE in an HIV patient on HAART with persistent CD4+ count >200 cells/µl for more than a year.

Case report

A 55-year-old woman with a 20-year history of HIV/AIDS (CD4+ nadir 106 cells/μl, five years prior), well controlled on HAART (CD4+ range 291–312 cells/μl, 19–20% CD4+ cells) for >1 year, presented with acute onset of headache, nausea and vomiting. She had been on her current HAART (raltegravir, co-formulated emtricitabine/tenofovir and etravirine) for three years. Pneumocystis prophylaxis (trimethoprim-sulfamethoxazole) had been discontinued 10 months prior. She had a history of stage II (T3 N0) adenocarcinoma of the appendix, status post-appendectomy. Physical examination, including neurological examination was normal. Serum Toxoplasma IgG titer was >250 IU/ml. Plasma HIV viral load was 95 copies/ml. MRI revealed multiple ring-enhancing supra-tentorial and infra-tentorial parenchymal lesions with vasogenic oedema (Figure 1(a)–(d)). Since she had a history of stage II (T3 N0) adenocarcinoma of the appendix with appendectomy 1 year prior, metastatic brain disease was considered. TE and primary CNS lymphoma were considered but deemed unlikely given the relatively high CD4+ count near 300 cells/μl for over a year (CD4+ count had been > 200 cells/μl for 18 months and with lowest value in past 12 months being 260 cells/μl). Stereotactic brain biopsy of the right occipital lesion demonstrated Toxoplasma tachyzoites, confirmed by immunohistochemical studies (anti-Toxoplasma gondii rabbit polyclonal antibody, Biogenex, San Ramon, CA). There was no evidence of lymphoma or carcinoma (Figure 1(e) and (f)). A repeat MRI 17 days after induction therapy with sulfadiazine, pyrimethamine and leucovorin showed resolution of most of the cortical lesions. (Figure 1(g) and (h)) Maintenance therapy was continued after six weeks of induction treatment. OPEN IN VIEWER

Two weeks later the patient had recurrent symptoms. MRI brain with gadolinium showed significant progression of the caudate nucleus lesion with effacement into the right frontal horn and new choroid plexus lesions. Induction doses of the anti-toxoplasma regimen were restarted as failure of maintenance therapy was considered possible and she was subsequently switched to clindamycin and pyrimethamine/leucovorin due to intolerance of high-dose sulfadiazine. Recheck of her CD4+ count revealed 427 cells/μl (24% CD4+ cells). Repeat MRI two weeks after re-initiation of the treatment dose regimen revealed progression of the supra-tentorial lesions along with new hydrocephalus (Figure 1(i)).

Resistant toxoplasmosis or the presence of a new neurological process such as CNS lymphoma was considered. Lumbar puncture revealed a negative Epstein-Barr virus (EBV) polymerase chain reaction (PCR). Single-photon emission computed tomography (SPECT) imaging with thallium-201 showed increased uptake in the lesions, which was possibly consistent with CNS lymphoma. Dilated fundoscopic examination did not reveal any evidence of intraocular lymphoma. Given discordant results of negative CSF EBV PCR and positive SPECT, a brain biopsy was planned with the consideration of CNS lymphoma. However, the patient rapidly deteriorated in the presence of worsening hydrocephalus and died a few days later. No post-mortem examination was obtained.

Discussion

Although TE is a common occurrence in AIDS, it almost always presents with CD4+ counts less than 100 cells/μl. ⁶ While there are reports of patients (9 out of 64 in one study) who developed TE despite CD4+ > 200/μl, it is important to note that these were patients with first diagnoses of TE and were not on prophylaxis and or antiretroviral therapy. ⁶

Primary and secondary prophylaxis as well as appropriate discontinuation of prophylaxis has been the subject of several studies. Two randomized controlled studies have demonstrated no cases of TE during median follow-up of 409 person-years after discontinuation of prophylaxis 3–6 months after sustained immune response.^7,8 Of note, the median CD4+ cell count at discontinuation of prophylaxis was greater than 300 cells/μl in both studies and patients had either an undetectable viral load or low level viraemia.

The rationale for continuing prophylaxis for three to six months after improvement in CD4+ counts is that due to the pattern of step-wise immune reconstitution in patients beginning HAART, they may be susceptible to opportunistic infections for a short period. ⁹ TE as an Immune Reconstitution Inflammatory Syndrome (IRIS) has also been described. ¹⁰

Our patient had been on HAART for several years, with a CD4+ cell count approximately 300 cells/μl, and consistently low viral load; therefore, her presentation was unlikely to be a manifestation of IRIS, which is characterized by initial low CD4+ count (<100 cells/μl), and robust immunologic and virologic response to HAART.

To our knowledge, this is the first reported case of primary TE occurring following sustained immunological recovery on HAART. In an observational study of 358 patients discontinuing secondary prophylaxis, one case of TE relapse was noted in a patient on HAART and with CD4+ count >200 cells/μl, after interruption of maintenance therapy. ¹¹ It was postulated that the Toxoplasma gondii-specific immune response was defective. ¹¹ In vitro studies have demonstrated that up to 35% of patients do not demonstrate a lymphocyte proliferative response (LPR) to Toxoplasma gondii antigen, even 12 months after CD4+ recovery on HAART. ¹² Another study found that it might require 12–18 months for sustained in vitro responses to be seen, but this is still under investigation. ¹³ There are occasional reports of other opportunistic infections in a minority of AIDS patients on HAART, with sustained immunological response and apparent immune reconstitution.^14–18 Immunological studies in these patients have suggested that impaired CD4+ effector memory T-cell function and B-cell dysregulation might be manifestations of HIV-induced immune dysfunction independent of CD4+ T-cell counts.^19,20

We postulate that a possible mechanism by which our patient developed TE with CD4+ count ∼300 cells/μl on HAART is a similar functional immunological dysfunction. It is possible that in vitro testing would have revealed an impaired LPR despite being on HAART for 12–18 months with a sustained CD4+ count >200 cells/μl. The aetiology of the recurrent lesions remained unclear. Differentials included relapse of TE and less likely, concomitant CNS lymphoma (given high CD4+ cell count). Since a second brain biopsy was not performed, we could not completely exclude the possibility of metastatic lesions, Nocardia, pyogenic brain abscess or other causes of multifocal enhancing lesions, as AIDS patients may present with multiple opportunistic infections. ²¹ HIV clinicians should remain vigilant for atypical presentations or altered natural histories of classic opportunistic infections.