Progressive multifocal leukoencephalopathy in HIV-2 infection. Case ...

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To our knowledge, this is the first case of progressive multifocal leukoencephalopathy (PML) described in a HIV-2 infected patient born and living in Europe.

Journal of Clinical Virology 48 (2010) 215–217

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Case report

Progressive multifocal leukoencephalopathy in HIV-2 infection. Case report Vítor Duque a,∗ , Ana M. Matos b , J. Saraiva da Cunha a , A. Melic¸o-Sivestre a a b

Department of Infectious Diseases, University Hospital of Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal Laboratory of Microbiology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

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Article history: Received 25 December 2009 Received in revised form 2 April 2010 Accepted 10 April 2010 Keywords: Progressive multifocal leukoencephalopathy HIV-2 Female European White

1. Why this case is important To our knowledge, this is the first case of progressive multifocal leukoencephalopathy (PML) described in a HIV-2 infected patient born and living in Europe. It is also the second case described in a white person but the first described in a female. Our case shows us that HIV-2 infection is not only an infection of the African people. HIV-2 is also circulating in Europe were Portugal and France are the best examples. After the first imported cases from Africa, mostly immigrant black people the infection was probably transmitted to European natives. PML is not restricted to HIV-1 infection. Treating HIV-2 patients with PML could be very challenging and the difficult task is to find an efficient antiretroviral combination active on HIV-2 because optimal treatment strategies are currently unknown. Progression of PML in HIV-2 infected patients can be very rapid as observed in HIV-1 infected patients.

2. Case description A 51-year-old Caucasian female, was referred to our infectious diseases clinic for HIV-2 infection, recently diagnosed. She was born in Portugal, and divorced, with heterosexual risk behavior for HIV through unprotected sex with multiple partners. She denied intravenous drug abuse. No travel history was found.

∗ Corresponding author at: Rua José Castilho n◦ 12, 2◦ ESQ, 3030-301 Coimbra, Portugal. Tel.: +351 964944434; fax: +351 239400595. E-mail address: [email protected] (V. Duque). 1386-6532/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2010.04.006

HIV-2 infection was diagnosed in 1995. In that year, a total hysterectomy was performed because of invasive cervical cancer. The CD4+ T-cell count was 240 cells per ␮L. No viral load result for HIV-2 was available. Zidovudine and Didanosine was started in January 1996, after a drop in the CD4+ T-cell count to 204 cells per ␮L. She was asymptomatic. In October 1997, the CD4+ T-cell count was 80 cells per ␮L with a HIV-2 plasma viral load of 567 copies per mL. Triple combination therapy was started with zidovudine, lamivudine and indinavir. No virological or immunological response was observed but she was under constant medical care and antiretroviral therapy was maintained. In July 1998 she had a CD4+ T-cell count of 48 cells per ␮L with a plasma viral load of 262 HIV-2 RNA copies per mL. No other medication was taken at that time suggesting drug interaction. Incomplete adherence to therapy was confirmed by the pharmacy service where the medication was irregularly withdrawn. No resistance testing was available at the time. She remained asymptomatic until April 2001, when she presented in the emergency room of our hospital with pain when swallowing. Esophageal candidiasis was diagnosed by endoscopy and treated with fluconazole. In January 2002, a computed tomography of the brain, performed during the investigation of headaches showed no abnormalities. She was discharged asymptomatic. In April 2002, she was admitted to the infectious diseases ward because of complaints of slight weakness in the lower limbs. Neurologic examination showed left hemi paresis. No fever, aphasia or cognitive defects were observed.

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CD4+ T-cell count was 9 cells per ␮L and HIV-2 plasma viral load was 20,600 copies per mL. A brain magnetic resonance imaging (MRI), showed multiple and scattered white-matter lesions in the brain and cerebellum, hyperintense on T2-weighted sequences and hypointense on T1 predominating on the left. There was minimum and irregular contrast enhancement without edema, mass effect or displacement of normal structures. A lumbar puncture was performed that showed an elevated protein content (90 mg/dL) and a pleocytosis of 41 mononuclear cells. Glucose level was normal. Microbiological studies for mycobacteria and fungus were negative. A polymerase chain reaction was negative for HSV, VZV, CMV and EBV, but positive for JC virus. Progressive neurological deterioration was observed. On July 7th, 2002 she passed on, four months after clinical presentation. No autopsy was performed, being denied by the relatives. 3. Other similar and contrasting cases in the literature Previous reported cases of progressive multifocal leukoencephalopathy associated with HIV-2 infection were all from patients of African origin—Gambia,1,2 Guinea-Bissau3 and Cape Verde.4 All were immigrants living abroad, in Germany, France and United States, respectively. All were infected through heterosexual contact. In all these cases PML was the primary AIDS indicator condition leading to the diagnosis of HIV-2 infection. All but one4 had rapid progression of the disease with death ensuing in 3–4 months.2,3 Only one patient was still alive, whose clinical condition improved significantly after changing treatment from ritonavirboosted atazanavir to ritonavir-boosted lopinavir.4 An increased protein content in the cerebrospinal fluid (CSF) was described in two patients3,4 with values similar to our case. Multifocal brain lesions were identified on MRI including the cerebellum in two cases3,4 as happened in our case. JC virus was detected in the first described case1 , in extracts from the cerebellum in autopsy samples2 and in the CSF of a third case.3 PCR for JC virus was negative in one case4 of presumed PML. To our knowledge, we have described the fourth confirmed case of PML in a HIV-2 infected patient. 4. Discussion The original geographical heartlands of HIV-2 infection are identified as former Portuguese and French colonies in West and South Central Africa. As a result of traditional links with their former colonies, the main areas of infection in Europe are Portugal and France, which acted as diffusion nodes for the spread of the virus to other parts of Europe.5 Portugal is the European country with the highest prevalence of HIV-2 infection. At the beginning of the 1990s, HIV-2 infection accounted for 10–12% of the AIDS cases in Portugal but represents only 3.8% of AIDS cases, at present.6 In the south of Portugal, HIV-2 infected patients came from the epicenter of the HIV-2 epidemic and most are natives of GuineaBissau and the Cape Verde Islands, representing 42% and 15%, respectively.7 However, in the center and north of Portugal, HIV-2 infection was most probably introduced by Portuguese troops that were deployed in Guinea-Bissau, Cape Verde and Angola, during their independence wars.8 Data from a cohort study from the north of Portugal showed that 95% of their patients were white and of Portuguese origin, male (60%) and that only 5% were natives from Africa.8

The low transmissibility of HIV-2 and the behavior of these individuals explain the limited dissemination of the infection in the country. Infections are mainly acquired through unprotected heterosexual intercourse. Most of the cases remained confined to the spouses of the soldiers. Transmission through blood transfusions or its derivatives were described before 1986 when HIV-2 screening was not performed on a routine basis. Vertical transmission is a rare event in the country.6 HIV-2 replicates less efficiently than HIV-1, and viral load is significantly lower. Plasma viral load is generally detected in 74% of the patients with less than 200 CD+ T-cells per ␮L but a high viral load may be observed in advanced immunosuppression.4,9 In vitro, HIV-1 and HIV-2 exhibit comparable sensitivities to zidovudine and other nucleoside analog inhibitors.10 Saquinavir, indinavir and ritonavir were found to be equally active against HIV-1 and HIV-2 strains but little is known about the mutational pathways leading to resistance to these drugs or to the prevalence of primary resistance in naïve patients.11 In progressive multifocal leukoencephalopathy, JC virus primarily infects oligodendrocytes and is associated with failure to maintain myelination. In the immunocompromised host, the infection results in progressive neurological decline that begins with focal neurological deficits. Motor involvement with hemi paresis is usually the first sign followed by other focal neurological deficits that worsen with time and vary depending on the location of the lesion. The patient remains alert until the late stages. However, cognitive deficits and dementia may occur later in the disease, and generally follow motor, sensory and visual deficits.12 Before the introduction of triple combination therapy for HIV-1 infection, the median survival time after PML diagnosis was approximately 4 months for patients with less than 90 CD4+ T-cells at the time of presentation.13 PML was the primary cause of death in most of these patients. Our patient survived 4 months after the clinical presentation of PML as happened in the HIV-1 infected patients before the HAART (highly active antiretroviral therapy) era. A clear survival benefit can be observed in response to antiretroviral therapy and HAART must be considered the best successful therapy for HIV-1 associated PML.14 In our patient any immunological or virological benefit could not be observed primarily because of a lack of adherence to therapy. However, no regression of the lesions had been described after successful antiretroviral therapy in a HIV-2 infected patient.4 The survival rates after AIDS diagnosis in HIV-2 infected patients was 92% and 80%, at 1 and 3 years,12 and are significantly longer than in HIV-1 infected individuals. In our patient, AIDS was diagnosed in 1995 and PML was the terminal event. However, a shorter survival may be observed when PML is the AIDS presenting event in the HIV-2 infected patient. Data suggest that without the efficacy of combined antiretroviral therapy PML progression is very similar to that observed in HIV-1 infected patients in the pre-HAART era.11,15 Literature suggests that PML could be associated with HIV-2 infection in the same proportion as happens in HIV-1 infection. However, it could be less frequently diagnosed in Africa were most of the HIV-2 individuals are living. PML clinical evolution seems to be similar in HIV-1 and HIV-2 infected patients in the absence of efficacy of antiretroviral therapy. Conflict of interest statement There is no conflict of interests. References 1. Rubsamen-Waigman H, Adamski M, Von Briesen H. Lethal progressive multifocal leukoencephalopathy in an HIV 2 infected person as the only AIDS manifestation. AIDS Forschung 1987;2:572–5.

V. Duque et al. / Journal of Clinical Virology 48 (2010) 215–217 2. Stoner GL, Agostini HT, Ryschkewitsch CF, et al. Detection of JC virus in two African cases of progressive multifocal leukoencephalopathy including identification of JCV type 3 in a Gambian AIDS patient. J Med Microbiol 1998;47(8):733–42. 3. Bienaime A, Colson P, Moreau J, Zandotti C, Pellissier JF, Brouqui P. Progressive multifocal leukoencephalopathy in HIV-2-infected patient. AIDS 2006;20(9):1342–3. 4. Chan PA, Wakeman SE, Flanigan T, Cu-Uvin S, Kojic E, Kantor R. HIV-2 diagnosis and quantification in high-risk patients. AIDS Res Ther 2008;5:18. 5. Smallman-Raynor M, Cliff A. The spread of human immunodeficiency virus type 2 into Europe: a geographical analysis. Int J Epidemiol 1991;20(2):480–9. 6. INSA-Centro de Vigilância Epidemiológica das Doenc¸as Transmissíveis. A situac¸ão em Portugal a 30 de Junho de 2003. SIDA Informac¸ão 2003;130:2. 7. Gomes P, Abecasis A, Almeida M, Camacho R, Mansinho K. Transmission of HIV-2. Lancet Infect Dis 2003;3(11):683–4. 8. Mota-Miranda A, Gomes H, Serrão R, Araújo F. Transmission of HIV-2: another perspective. Lancet Infect Dis 2004;4(5):265–6. 9. Smith RA, Gottlieb GS, Anderson DJ, Pyrak CL, Preston BD. Human immunodeficiency virus types 1 and 2 exhibit comparable sensitivities to Zidovudine

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