Risk Assessment of Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis Patients during 1 Year of Ocrelizumab Treatment.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by the JC virus is the main limitation to the use of disease modifying therapies for treatment of multiple sclerosis (MS). METHODS: To assess the PML risk in course of ocrelizumab, urine and blood samples were collected from 42 MS patients at baseline (T0), at 6 (T2) and 12 months (T4) from the beginning of therapy. After JCPyV-DNA extraction, a quantitative-PCR (Q-PCR) was performed. Moreover, assessment of JCV-serostatus was obtained and arrangements' analysis of non-coding control region (NCCR) and of viral capsid protein 1 (VP1) was carried out. RESULTS: Q-PCR revealed JCPyV-DNA in urine at all selected time points, while JCPyV-DNA was detected in plasma at T4. From T0 to T4, JC viral load in urine was detected, increased in two logarithms and, significantly higher, compared to viremia. NCCR from urine was archetypal. Plasmatic NCCR displayed deletion, duplication, and point mutations. VP1 showed the S269F substitution involving the receptor-binding region. Anti-JCV index and IgM titer were found to statistically decrease during ocrelizumab treatment. CONCLUSIONS: Ocrelizumab in JCPyV-DNA positive patients is safe and did not determine PML cases. Combined monitoring of ocrelizumab's effects on JCPyV pathogenicity and on host immunity might offer a complete insight towards predicting PML risk.

Impact of JC virus antibody testing in patients with Crohn's disease with loss of response to infliximab: a Markov model.

BACKGROUND: The optimal treatment strategy for patients with Crohn's disease who have loss of response to the anti-tumor necrosis factor α medication infliximab is uncertain. Natalizumab has an alternative mechanism of action, but its use has been limited by the risk of progressive multifocal leukoencephalopathy. In this study, we performed a decision analysis assessing the impact of JC virus (JCV) antibody testing and natalizumab utilization for loss of response to infliximab. METHODS: We constructed a Markov model to assess the difference between unscreened natalizumab use (option 1), JCV antibody testing with natalizumab when appropriate (option 2), and second anti-tumor necrosis factor α use (option 3). The base case was a 35-year-old man with severe Crohn's disease with loss of response to infliximab. The time horizon was 3 years. Results are reported in quality-adjusted life years (QALYs). Deterministic and probabilistic analyses were conducted. Markov analysis using a cohort of 5000 individuals was performed. The impact of JCV antibody status on outcomes in this model was assessed. RESULTS: Option 2 was the preferred strategy (2.0880 QALYs), followed by option 1 (2.0875 QALYs) and option 3 (2.0808 QALYs). Patients in option 2 required fewer surgeries compared with option 3. Previous JCV infection was associated with reduced QALYs with all options that allowed for natalizumab use. CONCLUSIONS: JCV antibody testing and subsequent treatment selection yield improved outcomes over natalizumab without testing or using only a second anti-tumor necrosis factor α in all patients.

Topotecan and PML: the limits of pharmaceutical industry research.

AIDS: Topotecan, a drug typically used to treat cancer, has shown promising in vitro results against the JC virus. The JC virus causes progressive multifocal leukoencephalopathy (PML). SmithKline Beecham is planning to announce phase II placebo-controlled trials for PML. There is currently no known treatment for PML, although it sometimes responds to anti-HIV drugs, alpha-interferon, and peptide T. AIDS advocates are questioning why SmithKline Beecham did not perform animal and pre-clinical studies to see if topotecan would be effective and tolerable among HIV/AIDS patients. Topotecan treatment has resulted in minimum success fighting ovarian cancer, however, its toxic effects are dangerous and powerful. Advocates advise that any patient considering a trial of topotecan have their blood monitored very carefully, particularly for neutropenia. Participants should consider pre- and post-treatment with G-CSF (Neupogen) to boost white blood cells.^ieng

PML and a tale of two drug companies.

AIDS: PML is a rare disease that destroys myelin tissue in the central nervous system and causes lesions in the brain. Probably caused by the JC virus, the disorder can proceed rapidly. Currently there is no treatment for PML. However, Dr. Khalili at Thomas Jefferson University published research showing that topotecan, an analogue of campthotecin (derived from the bark of a chinese tree), suppresses the JC virus in the test tube at low doses. Although this is promising, it is unclear how well the drug crosses the blood-brain barrier or even if targeting the JC virus is the best way to stop PML. The drug is in phase II/III cancer trials. Although toxic, topotecan appears to inhibit the JC virus at lower doses than for cancer. SmithKline Beecham (SKB) owns the license to develop topotecan. SKB has had little interest in AIDS research since their protease inhibitor did not pan out. Responding to activists, SKB announced that they are pursuing topotecan as an anti-HIV drug, with studies opening this spring. There are other derivatives of campthotecin, 9-A-C and CPT-11 or irinotecan. 9-A-C does not work in the test tube; however, CPT-11, a cancer drug from Japan, is being studied by Upjohn. Upjohn supplied Dr. Khalili with CPT-11 and SN-38. Dr. Khalili found that both inhibited the JC virus in the test tube, and that SN-38 was a better JCV inhibitor than topotecan. Dr. Sidney Huff, Georgetown, has requested and received compassionate use for two PML patients.^ieng