HIV and MS: Could a Link Lead to New MS Treatment?

heapsreal

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Two clinical trials are now underway that offer the first tests of an intriguing but still not widely accepted theory of multiple sclerosis -- that its trigger lies within a part of the human genome that medical research has largely ignored.

Some researchers in Great Britain and Europe now believe that MS results from activation of "human endogenous retroviruses," or HERVs -- remnants of retroviruses that infected humans eons ago and became incorporated into the germline, such as that it is now part of the human genome.

This theory has prompted a group in the U.K. to begin a trial of the HIV drug raltegravir (Isentress) in about 25 MS patients, to see if the drug affects brain lesions seen in MRI scans. The trial is expected to conclude this August, with results potentially reported before the year is out.

Separately, a Swedish company called GeNeuro Innovation, founded by Swiss researcher Herve Perron, PhD, has developed a monoclonal antibody called GNbAC1 targeting a specific HERV element; safety results from a phase II trial are slated for presentation next month at the American Academy of Neurology's annual meeting.

Background

When the first full sequences of the human genome were released, one of the biggest surprises was how much of the genome appeared to encode retroviral elements such as integrase and helicase enzymes. By one estimate, 8% of the entire genome was made up of such sequences.

At first, these were assumed to be nonfunctional. But subsequent research established that, under some circumstances, they can become activated to express proteins.

It has yet to be proven conclusively that these are pathogenic, as even the proponents of HERV theories of disease will admit. One of the leaders of the U.K. raltegravir trial, Julian Gold, MBBS, MD, of the Albion Street Centre in Sydney, Australia, told attendees at an MS conference last fall that current laboratory methods aren't currently able to provide such proof, at least not for MS.

But there is circumstantial evidence -- several laboratories have isolated HERV proteins from MS lesion samples, and Epstein-Barr virus (EBV), which has itself been a suspected environmental cause of MS, has been found to activate HERV expression in lab studies.

Gavin Giovannoni, MBBCh, of Barts and the London School of Medicine and Dentistry in London, who also helps lead the raltegravir trial with Gold, told MedPage Today that all herpes viruses, of which EBV is one, can trigger HERV expression. But, he said, "EBV is particularly effective in activating HERVs."

Also, according to Gold, HERV expression has been linked to activation of both the innate and adaptive immune systems, providing a connection to the well-documented immunological and inflammatory features of MS.

Although the HERV theory doesn't explain everything about MS, such as the gender imbalance, Giovannoni said the conventional autoimmune paradigm has "lots of holes" too.

"It doesn't explain everything about MS, and as part of a causation theory it should explain everything. It doesn't explain the epidemiology very well, it doesn't explain the sex ratio, it doesn't explain some of the responses to certain therapies," he said.

"That's a clue that we don't know the whole story."

The HIV Connection

Perhaps the most significant piece of evidence for the HERV theory of MS is even more indirect: People with HIV appear to be at vastly reduced risk for MS.

What does HIV status have to do with HERVs or MS? Because nowadays, essentially everyone with HIV in developed countries where broad-based epidemiological research can be conducted is treated with antiretroviral drugs.

Gold is an HIV specialist -- the Albion Street Centre, which he directs, is Australia's largest HIV outpatient clinic. His "aha" moment came when an HIV-positive patient who also had MS came under his care. This patient was first diagnosed with HIV infection in 1985 but managed to avoid developing AIDS before the advent of highly active antiretroviral therapy (HAART) in 1996.

In a 2011 letter published in the European Journal of Neurology, Gold and colleagues described what happened after HAART was begun in 1996:

"Within months of commencing HAART, all MS symptoms gradually improved. Within 2 years, his urinary incontinence was controlled to the extent that he stopped wearing pads and fecal incontinence resolved. He has had no MS relapses."

The disease was not completely eliminated, the researchers indicated, because gadolinium-enhanced MRI scans made in 2002 continued to show lesions consistent with MS, even though clinical symptoms had largely disappeared.

Large-scale epidemiological studies have supported the notion that anti-HIV therapy may suppress MS pathology. A Danish national registry study published in letter form last year inEpidemiology, comparing 5,018 HIV-positive patients with some 50,000 age- and sex-matched individuals from the general population, found that the rate of MS incidence was markedly lower in the HIV patients (3.1 versus 10.4 per 100,000). However, it was not statistically significant because only one HIV patient developed MS during the study period.

Gold and colleagues conducted a similar (but as yet unpublished) study using the much larger U.K. general practice database, which covers some 55 million Britons. At the European MS meeting where he spoke last fall, he reported on results from some 21,000 HIV-positive individuals and 6.7 million controls, followed for a mean of 7 years.

In addition to matching controls to HIV patients by age and sex, they were also matched by region within the country and by the week in which they first came into contact with the national health system.

The relative risk for MS in the HIV patients versus controls was 0.38 (95% CI 0.15-0.79,P=0.011), he reported. The relative risk was even lower, 0.22, when only MS diagnoses occurring more than 1 year after HIV diagnosis were counted (at which point HAART is presumably well established in British HIV patients).

The Clinical Trials

There is no animal model for HERVs in MS, and the ability to study HERVs even in cell culture is limited, Gold said. He argued that "their exact role will only be obtained following appropriate clinical trials. If we wait for the laboratory to give us the answer, we will all have been retired."

Raltegravir was chosen for the U.K. trial for several reasons. One is that it is an HIV integrase inhibitor. "The integrases across HERVs and HIV are quite conserved," Giovannoni said, so that it is likely to be more effective in suppressing HERV elements than other types of antiretroviral drugs. He said it was also unique among antiretrovirals in also showing some potency against members of the herpesvirus family (though only in vitro -- this effect hasn't been studied clinically).

And, its manufacturer was willing to support the small, short-term trial. Gold pointed out that no company that markets MS medications is active in HIV drug development, or vice versa. He and Giovannoni were able to persuade raltegravir's maker, Merck's European subsidiary, to fund the 25-patient study which includes just 3 months of drug treatment after a 3-month baseline observation period. Gold said a longer and larger study would have been preferable but it could not be arranged.

The GNbAC1 monoclonal antibody's sponsor GeNeuro appears to have more resources, with France's Institut Merieux as a major investor. It has already completed a phase I safety study with the agent in healthy volunteers; the results to be presented at the AAN meeting next month are from 10 MS patients.

According to the abstract, no safety problems were seen, and a larger efficacy study is warranted. However, GeNeuro has not said whether or when such a trial would be undertaken.

Caution Reigns

MS specialists in the U.S. contacted by MedPage Today were unanimous in urging caution about HERV theory, although some were warmer to it than others.

Alessandro Serra, MD, of University Hospitals Case Medical Center in Cleveland, toldMedPage Today that "many studies" had supported the association between HERV-expressed proteins and MS.

However, these proteins also appear "in patients with other neurological conditions, and even in a proportion of healthy individuals," Serra said.

He said the debate in the community was over "whether HERVs are just bystanders within the normal immune response of MS patients, perhaps unable to handle these viruses, or whether they actually represent a key component of the pathogenic process of MS and even have a causative role."

Jerry Wolinsky, MD, of the University of Texas Health Science Center in Houston, pointed out that the search for MS triggers has been going on for decades and wound up in many blind alleys. Viruses have long been a popular suspect, but "thus far not fruitful."

With regard to retroviruses lurking within the human genome, "to my knowledge there has been no consistently recovered retrovirus sequence associated with brain or other tissues from patients with multiple sclerosis," Wolinsky said.

"That does not mean that one might not be afoot, but the technology is well enough developed that it would be unusual to expect that one will be found in the future, given the failure to do so even with application of modern tools."

Wolinsky added that the 2011 case report from Gold and colleagues, of the HIV/MS patient whose neurological symptoms resolved with HAART, did not persuade him. "The course of MS is very unpredictable," he said, and the disappearance of symptoms may simply have been "serendipitous."

Other experts were also supportive of research while agnostic or skeptical about the HERV theory. For example, Robert Bermel, MD, head of the Cleveland Clinic's Mellen Center for Multiple Sclerosis, told MedPage Today that "It becomes difficult ... to separate the specific effect of antiretroviral therapy from the effect of altered immune status related to HIV, or from the natural tendency of MS disease activity to decline over time."

On the other hand, Anthony Reder, MD, of the University of Chicago, called the HERV theory "important" as well as plausible.

HERVs, he said, result from "hundreds of millions of years of battles with retroviruses. The residual DNA fragments do not produce complete viruses but DNA fragments and retrovirus proteins do leak out and are seen by the immune system."

Serra said he hoped that the two clinical trials wouldn't be taken as make-or-break for the HERV theory. "We need more rigorous models, especially animal models that have been lacking so far. I know there are groups that are looking into it."

In the meantime, everyone who spoke to MedPage Today emphasized that it would be premature for physicians or patients to try antiretroviral drugs on their own as MS therapies. Giovannoni said that some patients have told him that they had succeeded in obtaining raltegravir.

"That's a little premature and we wouldn't recommend it," he said.

http://www.medpagetoday.com/Neurology/MultipleSclerosis/44861
 

Ecoclimber

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Tuesday, 5 August 2014
HIV infection linked to lower multiple sclerosis risk

#MS research HIV infection linked to lower MS risk

Gold J, Raph Goldacre R, Hubert Maruszak, Giovannoni G, Yeates D, Goldacre M. HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database studyJ Neurol Neurosurg Psychiatry 2014;0:1–4. doi:10.1136/jnnp-2014-307932 1

Objectives: Even though multiple sclerosis (MS) and human immunodeficiency virus (HIV) infection are well-documented conditions in clinical medicine, there is only a single case report of a patient with MS and HIV treated with HIV anti-retroviral therapies.

In this report, the patient’s MS symptoms resolved completely after starting combination anti retroviral therapy and remain subsided for more than 12 years. Authors hypothesised that because the pathogenesis of MS has been linked to human endogenous retroviruses, anti-retroviral therapy for HIV may be coincidentally treating or preventing progression of MS.

This led researchers from Denmark to conduct an epidemiological study on the incidence of MS in a newly diagnosed HIV population (5018 HIV cases compared with 50 149 controls followed for 31 875 and 393 871 person-years, respectively). The incidence ratio for an HIV patient acquiring MS was low at 0.3 (95% CI 0.04 to 2.20) but did not reach statistical significance possibly due to the relatively small numbers in both groups.

Our study was designed to further investigate the possible association between HIV and MS. Methods We conducted a comparative cohort study accessing one of the world’s largest linked medical data sets with a cohort of 21 207 HIV-positive patients and 5 298 496 controls stratified by age, sex, year of first hospital admission, region of residence and socioeconomic status and ‘followed up’ by record linkage.

Results
Overall, the rate ratio of developing MS in people with HIV, relative to those without HIV, was 0.38 (95% CI 0.15 to 0.79).

Conclusions
HIV infection is associated with a significantly decreased risk of developing MS. Mechanisms of this observed possibly protective association may include immunosuppression induced by chronic HIV infection and anti-retroviral medications.



Following the case of an HIV positive man with MS, whose MS symptoms appeared to disappear for more than 12 years after anti-retroviral treatment for HIV, a Danish research team attempted to find out if anti-retroviral drugs might treat or slow the progression of MS. Their results suggested this might be a possibility, but the numbers were too small to reach statistical significance, prompting the ProfGs to carry out a much larger comparative study.
Team G paired up with Ben Goldarce's dad and they did this by looking at episodes of hospital care between 1999 and 2011 in England.

In all, more than 21,000 people infected with HIV were treated during this period as were almost 5.3 million people treated for minor conditions or injuries who were not infected with HIV. The development of MS was tracked in all the participants for an average of between 6.5 and 7.5 years, in the context of the actual number of cases versus the expected number of cases in the population.

Compared with those who did not have HIV, those who did were 62% less likely to develop MS, based on 7 actual diagnoses of MS during that period versus the 18 that would be expected to develop. The degree of protection seemingly conferred by HIV seemed to increase the more time elapsed between a diagnosis of HIV and one of MS.

After more than a year between the two, HIV positive patients were 75% less likely to develop MS, based on four actual diagnoses versus the 16 that would be expected; after more than five years this increased to 85%, based on one actual case versus the 6.5 that would be expected.

The findings back those of the Danish researchers, but with the crucial difference being that they are statistically significant.

These findings are speculative rather than definitive because the study is observational, added to which there is no information on whether the HIV positive participants had taken anti-retroviral drugs, or for how long. The demographics of HIV and MS in UK are not identical but this study does look at very big numbers of people.

Whilst we do not advocate unsafe sex or picking up the HIV virus in the off chance it does your MS good

ProfG Down Under said “If subsequent studies demonstrate there is a causal protective effect of HIV and/or its treatment, and if the magnitude of it proves to be similar this would be the largest protective effect of any factor yet observed in relation to the development of MS.”

HIV infection itself may stave off the development of MS or it could be that anti-retroviral drugs, prescribed to dampen down the proliferation of the virus may also have the same effect on MS.

So the ProfGs have put their mouth where Merck USA's money is and are investigating the effect of raltegrovir in early multiple sclerosis in the now fully recruited INSPIRE trial as part of the Charcot Project



Why not get it from the Horse's Mouth (or should this be the Kangeroo's mouth) and listen to ProfG Down Under on "Inside Health" (Get it ONLINE (This link will work in UK, elsewhere not sure) or on the radio) on Tuesday 5th August 2014


STOP PRESS!!
Inside Health is on BBC Radio 4 Tonight at 21.00 BST, repeated tomorrow at 15.30 BST.
Sorry for the confusion!!
The story has cropped up in unusual places
CoI
Members of TeamG are authors of this work.

Posted by MouseDoctor at 06:00
Reactions:

Labels: Charcot Project
22 comments:
  1. anon36.png

    AnonymousTuesday, August 05, 2014 7:10:00 am
    The risk is not as low as people who are EBV negative

    Tuesday, August 05, 2014 7:34:00 am
    Thanks for posting this story on Good News Tuesday. The real question is whether the drugs are having the effect. Thanks to Profs G, we may get some indication next year. Does this put. prof Mouse out of a job ie no more need for rEAE?

    MouseDoctorTuesday, August 05, 2014 9:49:00 am
    Lets wait and see if the trial works before we start with our UB40.

    If there is a cure for MS it is likely to aid the newly diagnosed the most and we will still have to think about can we turn back the clock for those with existing damage......

    Have the current crop of drugs..stopped EAE......not really, although we have not really worked on projects dealing with the peripheral immune response for the past 10 years or more.

    Will I hang up my boots..maybe....or maybe adapt and move on.....

    The question is what would pharma do?.

    No more need for beta interferon and copaxone etc....no more MS pharma, ECTRIMS becomes a little meeting in a nice place, with no free lunch...or anything free....would they adapt and move on.

  2. anon36.png

    AnonymousTuesday, August 05, 2014 11:09:00 am
    You'll find another job mouse. I see you working in a shop selling vinyl records or reconditioned electric guitars. No Prof G to boss you around. No mice cages to clean out.

  3. mousedoctorpic.JPG

    MouseDoctorTuesday, August 05, 2014 11:49:00 am
    Thanks for the tip..I'll get my pliers and lemon oil at the ready


    Tuesday, August 05, 2014 8:53:00 am
    Thanks for this - great to see the work being done in this area. hope to listen later courtesy of iplayer

    MouseDoctor2Tuesday, August 05, 2014 3:02:00 pm
    A quick note to say that Inside Health is on BBC Radio 4 tonight at 9pm BST not 3 pm as previously stated and repeated tomorrow at 3.30 pm.Tuesday, August 05, 2014 9:29:00 am
    The effect is not significant when controlled for ethnicity. What is the association seen in other diseases? Michael Goldacre says this is not seen just for MS.

    MouseDoctorTuesday, August 05, 2014 9:55:00 am
    Michael and his big mouth:), you will be able to see the effect in other conditions when the papers are published. Today's news is about MS.
    • anon36.png

      AnonymousThursday, August 07, 2014 8:37:00 am
      Indeed. Old news :). Caucasians have a higher risk of MS than other ethnicities, British HIV population is probably skewed towards MSM and ethnic minorities, both of which are maybe not the top candidates for MS. Control for those and ... yeah
    • anon36.png

      AnonymousSaturday, August 09, 2014 10:02:00 am
      anon 8:37, are 'caucasians' an ethnic group? social constructs aside, the research applies to UK HIV population - 'predominantly made up of caucasian men.' <:)¬}>
    Tuesday, August 05, 2014 9:45:00 am
    There is no mention of EBV in the article. I thought Prof G thought that EBV was the cause. Has he switched to HERVs? Couldn't you have done a survey of the main HIV treatment centres in the UK, Australia, Denmark and asked three questions: How many HIVers are being treated with antiretrovirals in your centre? How many of them have MS? How many had been diagnosed with MS before before starting antiretrovirals? This would give a feel for any impact antiretrovirals were having. Could also ask for any observations they have with regard to HIV infection / treatment / MS. I'm sure a charity like the Terence Higgins Trust would help.

    MouseDoctorTuesday, August 05, 2014 11:45:00 am
    Good comments

    ProfG Down-Under is an international expert on HIV from Australia. He is director of the World Health Organization (WHO) Collaborating Centre and Director of the Albion Street Centre in Sydney, Australia, a centre established to provide services for people with HIV.

    I believe he has trawled the world literature HIV centres etc and the answer is unusually few people with HIV have MS,

    If you trawl through the blood you may see how EBV may be a trans activator of HERV which lie silent in the human genome but can be re awkened to produce virus.

    jayjillTuesday, August 05, 2014 2:16:00 pm
    So, is raltegrovir an antiretroviral drug used to treat HIV? Don't we need to understand the different types of antiretroviral drugs and allow people with ms to try them, starting with the ones likely to have a lesser impact on the overall functioning of the immune system? Again, those of us who have this condition have a heightened sense of urgency. Thanks for yet another informative post. (Sorry about my lack of knowledge about medicines etc).

    steve sTuesday, August 05, 2014 5:13:00 pm
    http://www.jimmunol.org/content/193/4/1544.full.pdf?with-ds=yes
    HIV-1 infection increases HERV-K expression and the protein may be a target for an Ab vaccine. Much research has shown the relation between EBV infection and subsequent expression of HERV-W in MS leading to immune dysfunction. Using anti-retrovirals to limit HERV production is one possibility but has there been any research on Ab targeting of HERV-W Ag?
    MouseDoctorTuesday, August 05, 2014 7:07:00 pm
    Yes look up the name Perron-H and you will find..there are clinical studies ongoing

    Wednesday, August 06, 2014 8:29:00 am
    It was interesting reading the latest article about a person having HIV lowered the risk of getting MS. I said year ago to many people that the cure for MS is AIDS. The reason being the two diseases cannot coexist. AIDS suppresses the immune system. MS is a overactive immune system. The two working against each other AIDS would win out every single time. But who in their right mind would infect themselves with AIDS? Although research seems a lot closer to solving and treating AIDS than they do MS.

    I feel MS is a chronic infection triggered by a bacteria infection. But it could also be connected with a virus. Mainly EBV. Interesting to know that chronic infections can actually cause CCSVI! One thing I have always wondered about is leaky gut syndrome. And the bacteria that is living in the gut and it hides itself by creating biofilm. I do not believe MS is a autoimmune disease. The body does not attack itself for no reason. There is always a trigger. The body can see what we cannot. I am happy that people are you are helping. The MS society has let us down with their fixed ways and little hope. Keep up the good work.

    Signed a MS sufferer.

    Reply
 
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Ecoclimber

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PLOS ONE
Activation of MSRV-Type Endogenous Retroviruses during Infectious Mononucleosis and Epstein-Barr Virus Latency: The Missing Link with Multiple Sclerosis?


Giuseppe Mameli, Giordano Madeddu, Alessandra Mei, Elena Uleri, Luciana Poddighe, Lucia G. Delogu, Ivana Maida, Sergio Babudieri, Caterina Serra, Roberto Manetti, Maria S. Mura, Antonina Dole

Abstract
The etiology of multiple sclerosis (MS) is still unclear. The immuno-pathogenic phenomena leading to neurodegeneration are thought to be triggered by environmental (viral?) factors operating on predisposing genetic backgrounds.

Among the proposed co-factors are the Epstein Barr virus (EBV), and the potentially neuropathogenic HERV-W/MSRV/Syncytin-1 endogenous retroviruses.

The ascertained links between EBV and MS are history of late primary infection, possibly leading to infectious mononucleosis (IM), and high titers of pre-onset IgG against EBV nuclear antigens (anti-EBNA IgG).

During MS, there is no evidence of MS-specific EBV expression, while a continuous expression of HERV-Ws occurs, paralleling disease behaviour. We found repeatedly extracellular HERV-W/MSRV and MSRV-specific mRNA sequences in MS patients (in blood, spinal fluid, and brain samples), and MRSV presence/load strikingly paralleled MS stages and active/remission phases.

Aim of the study was to verify whether HERV-W might be activated in vivo, in hospitalized young adults with IM symptoms, that were analyzed with respect to expression of HERV-W/MSRV transcripts and proteins.

Healthy controls were either EBV-negative or latently EBV-infected with/without high titers of anti-EBNA-1 IgG. The results show that activation of HERV-W/MSRV occurs in blood mononuclear cells of IM patients (2Log10 increase of MSRV-type env mRNA accumulation with respect to EBV-negative controls).

When healthy controls are stratified for previous EBV infection (high and low, or no anti-EBNA-1 IgG titers), a direct correlation occurs with MSRV mRNA accumulation.

Flow cytometry data show increased percentages of cells exposing surface HERV-Wenv protein, that occur differently in specific cell subsets, and in acute disease and past infection.

Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titers) are paralleled by activation of the potentially neuropathogenic HERV-W/MSRV. These novel findings suggest HERV-W/MSRV activation as the missing link between EBV and MS, and may open new avenues of intervention.

In conclusion,
our data indicate that the two main links of EBV to MS (past IM and high anti-EBNA-1 IgG titers) are associated to the activation of potentially neuropathogenic HERV-W/MSRV, both at the mRNA and the protein levels. These novel findings reinforce our hypothesis of a possible involvement of both viruses in MS pathogenesis [13], with the possibility for MSRV of a direct role of effector of pathogenicity, and for EBV of an initial trigger of future MS, years later, and indicate the activation of HERV-W/MSRV as the possible missing link between EBV and MS. These findings may open new avenues of intervention against MS.

Eco comment:
It is interesting how both ME/CFS Patient Dr. Synderman and Dr. Deckoff-Jones improved on raltegrovir. Given, it is a small patient sample and ancedotal at best. But, it does raise questions that are very similar to the MS research with regards to EBV and HERVs. So perhaps this would be a good avenue for research if the results are positive with the Charcot Project and treatment show significant improvement. It was late at night and I had to stop my comments. This info got out before I was ready.

Here is why this is important. It could possible open the door just a crack for the ME/CFS patient community in exploring this treatment option though research and trials for treatment. Dr. Deckoff-Jones blogged about it here: X RX Blog Neverland and MS Light. It can cause a strong paradigm shift in the scientific research community which seems to have tunnel vision with regards to MS research and it is refreshing that a few leading experts are willing to buck the system and think outside the box and not exhibiting typical 'tunnel vision' of some researchers. I applaud Dr. Gavin Giovannoni and his staff for thier creative thinking as I probably know he is receiving a great deal of push back from the scientfic community.

Also there is another MS HERV- Fc1 that has not been discussed here. Most importantly, it also allows possibility in opening the door a bit for research dollars from private foundations to explore the possible association between the two diseases.

I believe as a hypothesis that a genetic pre-disposition is involved. As someone pointed out in a previous thread on the outbreaks, wouldn't all ME/CFS patients have all the same pre-disposition for the same outbreak, not necesarrily. It is possible if EBV and EBAN1 is the catalyst since they occur in the majority of the human population. Replication studies must be conducted for varification.

If this is a dead end, all it means that the scientific research community increase their knowledge on this destructive disease. After 70+ decades of research and few drugs for this vulnerable patient community, it is time to explore other possibilities. Thomas Edison was quoted as saying: 'I have not failed. I've just found 10000 ways that won't work. Failure taught him various ways to repeatedly innovate.

To date their has been no new squences posted to GENBACK that differs from xmrv, so if institutions or researchers who claimed they found HGRV sequences from their research at the WPI, then post them on GENBANK so other researchers can verify them. Otherwise, retract their statements under some conspiracy scenariothat they found HGRVs .
 
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heapsreal

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yes raltergrav/isentress i have read in a few things having direct activity to ebv/cmv etc but its more dam expensive then valcyte. Always waiting for these drugs to go generic.
 
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