ENS HOT TOPIC: JCV titres and PML risk

Hot topic of the ENS; PML risk is low in MSers with low titres of JCV antibody. #MSBlog #MSResearch

“The hot topic of the ENS is the following abstract and presentation of PML risk profiling based on your titre or level of antibody to JCV.”

Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics

Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.

“The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres or a low index may choose to stay on natalizumab rather than switch. What level of risk are you prepared to take? I assume your level of risk will be based on personal factors, e.g. how bad your MS was before you started natalizumab.”

CoI: multiple

21 thoughts on “ENS HOT TOPIC: JCV titres and PML risk”

  1. Prof G, I had a JCV test over 18 months ago which showed I was JCV + but there was no discussion of the level of antibodies found. Two questions : Would those test results indicate the level of JCV antibodies then present or would I need a new test ? Secondly, given the proportion of people who convert from sero negative to sero positive over time, should all Natalizumab MSers be tested periodically to check their JCV status, including antibody levels ?Thanks

    1. I assume if you have a high titre you will not need retesting. Those who have a low titre and stay on the drug will need to be retested every 6 months to see if their titre increases. An switch from low to high titre is clearly a risk factor for developing PML. Those who are JCV negative also need to be monitored every 6 months to see if they become positive; this with low titre will be at low risk and those at high titre at high risk.

    2. I'm not a doctor or a scientist, so I got a little lost when reading this study. I was diagnosed with RRMS in 2006. I've been taking Tysabri since 2007 (6.25 years). I am JCV + and my MS symptoms are very mild. I took part in a study, called STRATIFY, I think. Is the data in the study posted on this blog from that study? What I did take away is the following:1. Even if you are JCV+, the level of JCV antibodies varies among those who are JCV+.2. Extrapolating from the sample subjects, the higher your JCV antibodies, the higher your risk of getting PML.3. With this sample size, the other assumed risk factors of PML (length of time on Tysabri and prior IS use) had no impact on the level of JCV antibodies in your system.Is this accurate, and if so, why is the drug company not obligated to share this information with me? How do I find out my JCV antibody level? Until know, I thought the only things to consider were whether or not you were JCV+ (ignoring any consideration of AB levels), length of time on Tysabri, and prior IS use. If someone out there is sitting on data about me that suggests I have high JCV antibodies, and they aren't telling me, that's wrong. It's my right to know. And informing the patient is the right thing to do.

    3. ProfG may be best placed to answer but he tried to post each month on the the risks to tysabrians. See the the box at the top of the page. This information is supplied by Biogen who are activity monitoring the situation. The information on titres of antibodies has only just appeared and as the data matures then Biogen are showing the risks of PML, which Prof G posts

    4. Your doctor should be testing your blood approximately every 3 months, I think it should be every month but they don't. But your doctor knows these numbers and has to tell you if you ask. A good doctor , in my opinion, would share this info with you regularly allowing you to make decisions regarding your health, The patients know very little and needs to ask, I just became positive and I have sadly given up the drug. It is a wonderful drug and I am scared about my future,

  2. I stopped Tysabri 8 months ago as I was JC positive. Should I get retested? If I have a low index could I start it again? I am now on Gilenya and don't feel as well as I did on Tysabri.

    1. Anonymous 9.00 am June 11th.Can't comment on retesting for JCV virus as I'm not a clinician but you say you don't feel as well on Gilenya as you did on Tysabri. Is this increased fatigue or some other symptoms. As I've said before many MSers I've spoken to who've ben on Tysabri said one of the most strking things was their fatigue disappeared.

  3. I was JC positive before I started Tysabri, I have had 26 infusions and my tiger is 2.09. I really dont understand the tiger levels and if mine is high???

  4. Would a figure of double the reading, i.e over 3 mean the risk is even higher than the table suggests ?

  5. So if someone has a higher titer level than 1.5 the risks are 1/118 chance of developing PML, is that correct? If that is correct, than someone with a titer level of 3 could be classed as possibly being 1/59 chance of developing PML? At what level should a specialist advise someone to cease tysabri in regard to titer levels?

    1. Re: "JCV antibody levels or titres"The levels of JCV virus antibodies are not linear and cannot be used to extrapolate risk. Yes, MSers with higher levels probably have a higher risk of developing PML, but the risk cannot simply be doubled. All MSers who are JCV seropositive should be counselled about stopping natalizumab or not starting it. Being told by your neurologist to come off the drug and doing it is a different thing. Many MSers want to stay on the drug as they feel so well and don't want to take the risk of rebound.

  6. I asked for a JCV titer (I am + for JCV) and I got a JC Polyoma Virus DNA, QN with a result of <500 copies/ml (<500). So is this good???? I am so confused!

    1. Why was JCV DNA test done and in what body fluid? If it is in the urine or blood it does not mean anything, It is only meaningful if it is the CSF and is being tested for in the context of PML.

  7. I had to stop taking Tysabri (after many years on it, starting in the trials in late 2002) because of my high JCV titer: 2.54. I had gotten used to a normal of not feeling impeded. Four months later after trying Tecfidera (which was like taking nothing) and now Gilenya (meh – definitely not Tysabri), it has dropped to 2.06. I know it isn't supposed to do that. I am excitedly looking at anything with potentially anti-JCV properties…Because (surprise surprise), I want to go back on Tysabri. I liked a normal that was mostly feeling good! If my titer continues to drop, is there a point where I could consider myself safe enough to go back on with enough monitoring (regular titers and MRIs)? This is the conversation I'm having with my neurologist at this point. I don't want PML, but I do want my life back.

  8. As well, there are no good/clear-cut guidelines as to how long JCV Ab testing ought to be done after STOPPING the drug' as well, the so-called index is valid till 72 mo and after that it is anyone's guess as to what happens. What is the effect of age, race, gender, and co-morbid conditions ? When should testing be stopped in a JCV Ab positive patient ?

  9. I was taking Tysabi for 10 months,I had to stop because of the side effects. I never tapered out. Then I find out before I started I was JC + with 1.72.. Even though I have stopped should I have another JC test done and will I need to have that test done let's say a yrs later or 2 yrs later? Please help, I'm so confused!!

    1. If your no longer on Tysabri then there shouldn't be any need for a further JC test.

  10. Hello. I just came across this blog. I have a JCV index of 3.51. I was on Rebif for several years and stopped last year as it really wasn’t working well for me. I have been on nothing for the past year. My new neurologist wants me to start on a new medication and recommends either Vumerity or Ocrevus. Mayzent is out because I have genetic condition that affects my eyes and the macular edema found in Gilenya and Mayzent is just too risky. In reading over other comments about high JVC indexes, should I be steering clear of any of the new medications that have the PML warning due to my index of 3.51. I am terrified of developing PML. And although the risk is overall low for PML, that genetic condition I have is super rare too. What would be some other recommended medications? Besides Rebif, I have also taken Avonex and Copaxone.

    1. I am not a neuro there has been one case of unexplained PML on ocrelizumab, not sure about diroximel fumarate, but there were few cases with dimethyl fumarate

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