Monitoring the Response of AIDS-Related Progressive Multifocal Leukoencephalopathy to HAART and Cidofovir by PCR for JC Virus DNA in the CSF

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by the JC papovavirus [1]. Occasional remissions have been described with cytarabine, interferon α, zidovudine and camptothecin [2], but the prognosis of PML in AIDS patients with persisting severe immunosuppression has been dismal. Recently, a prospective randomized study has shown that intravenous or intrathecal cytarabine did not improve PML prognosis in AIDS patients receiving reverse transcriptase inhibitors [3]. Initiation of highly active antiretroviral treatment (HAART) improves survival of patients with PML, probably reflecting some immune reconstitution [4, 5, 6]. Andrei et al. [7]have reported that cidofovir, a cytidine nucleotide analogue used in the treatment of cytomegalovirus infection, emerged as the most selective antipolyomavirus agent. Recent reports described patients with PML who responded to a combination of HAART, cidofovir and in 1 case cytarabine [8, 9, 10]. We describe here a patient with PML who responded not only clinically and radiologically, but also microbiologically, as assessed by semiquantitative PCR for JC virus DNA in the CSF, to the addition of cidofovir to HAART.A 38-year-old female presented in the spring of 1997 with progressive difficulty to walk. She first came to medical attention in 1991 with oral thrush, chronic diarrhea and thrombocytopenia. HIV seropositivity was documented, and her CD4+ T cell count was 132/mm3. She was treated with fluconazole, zidovudine and Pneumocystis carinii prophylaxis. In November 1995, the CD4+ T cell count was 118/mm3 and viremia 31,059/ml. Lamivudine was prescribed and 1 month later, plasma HIV RNA was no longer detectable. Viremia and CD4+ T cells then rose slowly, reaching 6,088 copies/ml and 172/mm3, respectively, by February 1997. In between, in July 1996, she started complaining about unstable gait. The neurological examination was normal except for an abnormal labyrinthine test for falling (positive Romberg sign). The CSF examination and a cerebral MRI were normal. In February 1997, due to memory deficit, a repeat MRI showed two T2-hyperintense lesions involving the white matter of the right temporal lobe and the splenium corporis callosi, suggestive of PML. The CSF contained 2 WBC/mm3 and 265 mg/l of proteins. A positive PCR signal for JC virus was found in the CSF, corresponding to about 5,000 copies/ml, when the brightness of the PCR product band was compared to external standards amplified from known amounts of JC virus DNA. A diagnosis of PML was made, and HAART (stavudine, lamivudine, ritonavir) was initiated on February 24. Viremia became undetectable, but the CD4+ T cell count failed to increase. From February to May 1997, the neurological abnormalities progressed with the appearance of predominantly left kinetic ataxia, worsening static ataxia, lower limb choreo-athetotic movements and left arm hypoesthesia. A repeat MRI showed enlarging lesions (fig. 1A) while the CSF PCR tested again positive. A decision was made to add compassionate cidofovir to HAART. Cidofovir was administered from May 29 at a dosage of 5 mg/kg once a week for two doses and then biweekly until December 1997. No adverse effect was ascribed to cidofovir. In September, little neurological improvement was noticed, but the patient developed an apathetic mood with persisting memory deficit. Repeat CSF samples obtained 1, 2 and 3 months after the initiation of cidofovir tested negative for JC virus DNA (<200 copies/ml). In September 1997, a repeat MRI revealed regression in size and intensity of the splenium lesion and of the temporal subcortical lesion, with minor residual hyperintense signal along the ventricular trigonum collaterale (fig. 1B). When last seen in December 1997, the patient remained profoundly depressed, but the choreo-athetotic movements and ataxia had improved. Her CD4+ T cell count was 142/mm3.In short, this patient presented with a rapidly worsening PML, including 3 months after initiating HAART (which did not induce any CD4+ T cell increase). She then experienced a microbiological, neuroradiological and clinical response after the addition of cidofovir to her treatment, despite the absence of a CD4+ T cell increase. In this respect, she differs from recently reported patients [4, 5, 6, 11]who improved quickly upon initiating antiretroviral treatment, concomitantly with a CD4+ T cell response, probably reflecting functional immune reconstitution. While the respective role of HAART and cidofovir cannot be ascertained in our case, the response timing suggests that cidofovir might have afforded some benefit, a conclusion also reached by other investigators [8, 9]. The real value of adding cidofovir to HAART in the treatment of PML in AIDS patients will require a prospective randomized study. Our data demonstrate the potential of PCR detection of the JC virus DNA in the CSF to assist in the evaluation of the efficacy of antiviral regimens.Supported by grant No. 24 of the Association pour la collaboration Vaud/Genève. P.R.A.M. was also supported by grants No. 31-31955.91 and 31-36164.92 of the Swiss National Foundation for Scientific Research.