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Undiagnosed Immunosuppression

Discussion in 'Immunological' started by undiagnosed, Mar 20, 2016.

  1. undiagnosed

    undiagnosed Senior Member

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    When you refer to NK cells, do you mean the NK cell function as associated with CFS? I haven't been able to get my NK cell function measured. I have had flow cytometry that showed elevated NK cells (CD3-/CD56+) at 20%.
     
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  2. TrixieStix

    TrixieStix Senior Member

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    @undiagnosed I thought of you when I came across an old thread where @Jonathan Edwards was answering questions about whether Immune System panels (Lymphocytes) like CD19, CD4, CD8, etc have much importance in the scheme of things. Here is a his reply. I've also posted a link to the thread so you can read the discussion if you like.

    Jonathan Edwards:

    "The numbers of these lymphocyte subsets in the blood are really not very important as long as they are reasonably near the standard range. Numbers of lymphocytes range hugely from person to person for reasons we do not know much about - particularly CD19 B cells and CD56 NK cells. If they are missing altogether that is another matter.

    In most major immune disorders the subset numbers are normal. Lupus can have low total lymphocytes. The clinical assay systems are mostly there because of AIDS where CD4 cells are very low.

    In other words, there is no such thing as 'optimal' here. These are just numbers of cells passing through the blood. They do not actually do anything in the bloodstream and some people seem to have faster throughput than others"

    http://forums.phoenixrising.me/inde...e-panel-lymphocyte-results.34533/#post-537990
     
  3. undiagnosed

    undiagnosed Senior Member

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    I basically agree and I'll repeat something I said in a previous post. For CD4 and CD8 counts in general, the values due to biological variation for any individual only span a small part of the reference range. The reference range is so wide because between individuals there is a large variety of biological homeostasis set points. Therefore, in order to really know if a count could indicate a problem, you would have to know what your homeostasis set point was. That's why I've been monitoring counts looking for changes over time. I suspect a specific disease process based on clinical history and am watching for statistically significant changes over time that support or reject my hypothesis.
     
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  4. Knockknock

    Knockknock Senior Member

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    Yes Sr,
    Both funtional and total Count.
    My onset started almsot 2 years ago, thanks god i was able to see a world class doctor in Cfs at NSU, they have a very high tech immunology lab, they test me for every aspect of my immune funtion.
    When the results came back we were stonished!!!
    My Nk cells were down to the floor both % wise and funtionality citotoxic to kill virurs and infected cells was totally diafuntional( deficiency).
    I want to make this clear, doctors like montoya, klimas etc when they diagnostic you with me/cfs, Cfids, they write clearly ( immune deficiency) i can take a pic of my diagnostic so you all can see it, for those who say its disfuntion not deficiency , is the diference with hiv they have deficiency, we have disfuntion.
    No Sr we have both disfuntion and deficiency!!!!
    Beside the Nk cells to be totally depleted, my entire immune system was collapsed, my Cd4 was at alsmost 400 with a little less i could of been diagnosted a none HIV/AIDS, the entire cd4/cd8 % was of the immnune was over active allost to the point of an auto immunity.
    My doctor told me what we all know, that somthing( unknow) cause my immune nk cells to be disfuntional the part of my immune system in charge of viral was deficiency this allow EBV and probably HHV6 to knock down my Cd and have my immune system so over active trying to clear infections from all angles.
    After a year of supplement and valtrex, and doxicycline antibiotic for mycoplaamas, i have recover 80/90%, of symtoms improved.
    Not yet the person i was before but for sure much better.
     
    Last edited: Feb 27, 2017
  5. Knockknock

    Knockknock Senior Member

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    I till have Mild cognitive issues some days, also some mild body aches like neurophaty kind, specially if i push myself to extra curriculum activities.
    My energy has improve from scale of 6 -7 when the onset to 8-9 at the moment.
    But the rest is what o mentioned.
    Since i have been now for a year on treatment, on my next visit my doctor is gona translate the comple gene report from 23me, looking for mutations Etc, she will also order a complete immune panel i including Nk cells.
    Ill keep you all of you guys update, if anything new Come up.
    I know many of you dont get to have access to this nind of test and to see Doctors with such a reputation and knwoledge in ME/CFS.
    Antthing new that i may find help full ill post it, so we can all benefic from it.
     
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  6. Knockknock

    Knockknock Senior Member

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    Undiagnosed,
    People can angue with me as much as they want this statement and ask for scientistic back up.
    My answere is this hard curcunstancial evidence is more than enough!!!!
    ''"" HIV alone do not cause immunosuppresion, hhv6 alone dont cause disease, Ebv alone dont cause disease, CMV alone dont cause disease, mycoplasma alone dont cause disease, hsv-1-2,hhv7-8 alone dont cause disease, we see it every day, people with healthy immune sustem over come this infections with no problem, most dont even know they had it and keep them latent inactive for life.
    For this illness to cause disease to turn into cronic illness you need to be immunosupressed, you need to have a pathogen causing immunosupresion, that is what happen in AIDS, most people dont progress to AIDS becouse they only have HIV, mean while other still progress and hiv enter the cell thru other receptors?? Why?? Its not understood, why some Hiv are diferent than others?? Do to mutations Is the answere scientistic have, but many scientistic belive other wise, belive that HIV alone done cause the immunosupression that we see on AIDS AND there has to be another retrovirus causing the illness to progress.
    This make sense to me why??
    Becouse thesame happen with HHV6
    Becouse thesame happen with EBV
    Thesame Happen with CMV.
    None of this virus cause illness unless you are immunosupressed.
    But why soooooo many peoole world wide are immunosupressed allowing this HARMLESS VIRUSES TO CAUSE CRONIC ILLNESS???
    Thesame thing happen to HIV.
    This will explain why most peoole dont progress to AIDS.

    All this and the so many similarities of CFS to AIDS are unrefusable facts.
    Even the fact that some of the nucleotide( NARTS) hiv retrovirals have a positive effect in CFS.
    My question is why so many people ignored this facts????
    Tired of been denied by other people? Shame, fear, skepticism?
    Missleaded by the medical stablishment??
    Why we ignore all this fact guys we are immunosupressed like AIDS, we have an overactive immune like AIDS, we have neurological neuroimflamatory cindition like AIDS, we have cd4/cd8 range like AIDS, viruses like hh6,cmv,ebv cause disease symptoms like AIDS.
    What else???
    Why so many people igonee this facts and keep looking for their answeres else were????
    Can some one tell me???
     
  7. undiagnosed

    undiagnosed Senior Member

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    @Lolinda, I've been working on updating my lab trend application and analyzing some of your data with it. The purpose of the tool is to more easily identify the most significant trends in analytes. I still need to do some verification to check for errors in the math and programming but wanted to show you what I have so far. The image below shows the tool loaded with some of your data.

    [​IMG]

    On the plot, there are a number of pieces of information shown. The two dashed horizontal lines show the reference range lower and upper limits. The data points are your actual lab value measurements. The error bars represent the uncertainty as a 95% confidence interval in the measurement which accounts for analytical and biological variability. The trendline is fit using linear regression.

    The table on the left shows each test type, the probability that the change is significant based on the Reference Change Value (RCV) method, and the R squared of the linear regression to gauge how well that model fits the data. With your data, the predictive power of the linear model will be limited as we only have three data points to work with. However, the significant time intervals between readings may help reduce some of the variablity. The program first creates a model using linear regression. Next, a one sided RCV is calculated using the first and last dates and associated predicted data from the linear model. Therefore, it is important that the linear model is good as the RCV calculation depends on it. If the model is poor, the RCV calculation will be inaccurate. Also, it is useful to look at the error bars on the plot to understand the uncertainty in the data and how that could affect the model. The table below shows highly significant trends found.

    >= 99% P_RCV, >= 99% Rsquared
    -----------------------------------------------

    [Test] [Trend] [Latest Result]
    ---------------------------------------------
    [MCHC] [Down] [Below Range]
    [CD4 Abs] [Down] [Below Range]
    [CD19 Abs] [Down] [In Range]
    [CD3+CD16+CD56+ Abs] [Up] [Above Range]
    [Platelets] [Down] [Below Range]
    [CD19 %] [Down] [In Range]

    The significance level could be lowered to include additional trends as well. It would be interesting to see if this signature of analytes changing could predict any particular disease states.

    Once I do some verification, I'll upload the program loaded with your data and post a link so you can mess around with it in your web browser if you want to.
     
    Last edited: Feb 28, 2017
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  8. undiagnosed

    undiagnosed Senior Member

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    @Lolinda, Here is the link to the version of the application referenced in my previous post. I haven't done any validation on it as I'm looking into more appropriate modeling techniques to improve it. This version does an ordinary least squares regression on the data and does Reference Change Value calculations on the first and last dates using the model values at those points. It's really just a quick hack and doesn't address possible issues such as autocorrelation of the data amongst other things. I'm looking into more robust modeling methods and allowing different time scales to be analyzed for future versions.

    You can sort the columns in the application by clicking the arrows next to RCV or RSquared. Also when you click on an item in the list, click it again to unselect it before selecting a new one.
     
  9. Lolinda

    Lolinda POTS + MCAS

    Hey @undiagnosed an @kangaSue thank you guys so much for your helpful comments! I just completed a marathon of doctor's appointments, that's why I didn't respond so far. :) In fact, I could use your comments to catch doctors' attention :) Thanks!! Now, I need to document all what I have learned, save and categorise my +100 open browser tabs and the dozens of scientific papers I hastily read .... and then in a few days I will be back with full energy to this thread. Talk to you guys soon!
     
  10. undiagnosed

    undiagnosed Senior Member

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    Hey @Lolinda, hope you got some useful information from your appointments. Looking forward to hearing more details.
     
  11. undiagnosed

    undiagnosed Senior Member

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    The following text describes my backup antiretroviral (ARV) treatment plan. It's a long read that outlines some of my thoughts and investigations. If anyone has any feedback on any part of it, let me know. I'm going to have some difficult decisions to make.

    My goal is and always has been to get a definitive diagnosis. I suspect based on evidence to date a retroviral infection is causing my symptoms, specifically some type of HIV. While clinically available tests I've taken have been negative, I have not been able to get access to less specific research assays that would be able to detect divergent virus. I've been pursuing multiple avenues including trying to work with researchers, contract research organizations, and even designing my own assays. However, this process has had many setbacks and is taking too long. I think ultimately I'm going to run out of time before I'm able to get a definitive diagnosis. Therefore, I am formulating a treatment plan that I can execute on my own if things get much worse.

    Based on my research, my ideal combination of ARVs would be Descovy (emtricitabine and tenofovir alafenamide) and Tivicay (dolutegravir). This combination contains two nucleoside reverse transcriptase inhibitors (NRTI) and an integrase strand transfer inhibitor (INSTI). It is a first line HIV-1 treatment and has some advantages over Genvoya which is another popular first line HIV-1 treatment. Descovy + Tivicay contains 3 drugs, one less than Genvoya which has a boosting agent that can interact with other medications.

    However, no generic version of Descovy exists so it is unaffordable without insurance coverage or other financial assistance. Since I cannot get a diagnosis, those options are off the table. Additionally, without a generic available, it would be more difficult to find a pharmacy willing to sell it without a prescription. The available alternative is Truvada (emtricitabine and tenofovir disoproxil fumarate) or one of the many Truvada generics that exist. This formulation is known to have more significant kidney and bone toxicity than Descovy, but is widely available at affordable prices. Tivicay now also has a generic version available in India that is affordable.

    For some cost comparisons, I looked at Descovy + Tivicay costs through online pharmacies vs. Tenvir-EM (Truvada generic) + Instgra (Tivicay generic). In the US, Truvada can be prescribed as Pre-exposure prophylaxis (PrEP) for people at risk for acquiring HIV, but the hassle involved would likely not be worth it in my case.

    Preferred ARVs
    Descovy
    30 pills (1 month) - $1112.36
    Canada Drugs

    Tivicay
    30 pills (1 month) - $771.44
    Canada Drugs

    Total per month
    $1883.80 + shipping (requires prescription)

    Generic ARVs
    Tenvir-EM
    30 pills (1 month) - $55.50 + $25.00 shipping = $80.50
    ALLDAYCHEMIST

    Instgra
    30 pills (1 month) - $60 + $30 shipping = $90.00
    IndiaMart Supplier

    Total per month
    $170.50

    The generic ARVs are an order of magnitude cheaper and within the realm of my financial constraints. However, there are a number of risks to consider if self-treatment with these ARVs is performed and I do not take them lightly.

    Risks

    1. Drug quality unknown, manufactured in India, sold by independent vendors

    The possible issues with drug quality include contamination, fake drugs (possibly dangerous), and not the correct levels of drug. Any of these issues could be very serious. Contamination or other unknown ingredients could be toxic and cause illness or even death in the most extreme case. Incorrect levels of the drug could lead to resistant virus which would be more difficult to treat and require possibly more toxic ARVs. It is therefore very important to have a high degree of confidence that the drug is legitimate and as claimed. This means that the manufacturer is producing a trustworthy drug and that the vendor is sourcing the drug directly from the manufacturer.

    The manufacturer of Tenvir-EM is Cipla, an Indian pharmaceutical company. Cipla got tentative approval from the FDA for Tenvir-EM in 2014. Tentative FDA approval is defined as follows:
    So there is good evidence that Tenvir-EM manufactured by Cipla is legitimate and safe. The next piece is to make sure that the vendor you purchase it from is sourcing it directly from the manufacturer. This is more difficult to establish. However, there is a group in the UK who have imported Tenvir-EM from particular vendors and performed Therapeutic drug monitoring (TDM) on themselves. This process measures medication concentrations in the blood. Testing showed adequate blood drug levels demonstrating that the drugs purchased were legitimate. So by ordering from one of the listed vendors, there is reasonable assurance that a legitimate drug will be received.

    The situation with dolutegravir is less certain. The only dolutegravir with tentative FDA approval to date is manufactured by Aurobindo Pharma. However, I was unable to find any vendors for this drug. The manufacturer for Instgra is Emcure. While Instgra does not have FDA tentative approval for dolutegravir, they have tentative approval for a number of other ARVs. However, Emcure has also been issued warnings from the FDA in the past for violations of good manufacturing processes. Cipla has also been warned along with many other Indian pharmaceutical manufacturers so it may not be too significant. The evidence is not as strong that Emcure is manufacturing a reliable drug, but unless an alternative can be found, it is currently the best option.

    With respect to vendors, there have been no third party tests as with Tenvir-EM which is used for PrEP. Therefore trust must be established with the vendor. The vendor I communicated with provided me with a number of documents claiming their legitimacy. However, ultimately there is some risk here as a high degree of trust cannot be established.

    2. Limited access to alternatives or other medications if significant sides effects are experienced

    Rarely there can be significant sides effects associated with starting antiretroviral therapy. For example immune reconstitution syndrome could be experienced which may require other medications to manage. Additionally it is possible that sides effects from the first line ARVs could be intolerable and would require switching to an alternative combination. It would be difficult to manage any serious problems on my own so the only real mitigation is that statistically the likelihood of such a scenario is relatively low.

    As of the end of 2015, more than 79,000 HIV- people at risk for acquiring HIV in the US take Truvada for PreP to prevent HIV infection. It is a generally well tolerated drug with minor short term side effects if any. Long term there are some known possible kidney and bone toxicities that need to be monitored. The drug has been deemed safe enough to be used for HIV prevention which is indicative of its relatively low toxicity.

    A number of people on the forums here have used older generation ARVs and experienced significant side effects but reports from members using newer generation drugs such as Truvada have been that relatively minor or no side effects have been experienced. The issues I've seen reported include @Daffodil who took AZT and RAL for a trial and reported significant lasting side effects presumably from the AZT. Another case was @PhoenixBurger who took a 30 day Post Exposure Prophylaxis (PEP) combination consisting of AZT, Lamuvidine, Ritonivir, and Lopinavir. @PhoenixBurger reported the onset of CFS symptoms after this course of medications. AZT and a hefty combination of other old NRTIs and protease inhibitors are known to have more significant side effects than newer class ARVs. @ScottTriGuy who has taken various ARVs for treatment of HIV has reported minor side effects from his newer ARVs, but issues including significant nausea when he was taking AZT early on. @cornwellsb has been taking Truvada for PrEP which has been well tolerated.

    Truvada includes 2 NRTIs and as previously described is generally well tolerated. I would also be adding 1 INSTI to complete the combination for treatment of HIV rather than PrEP. Dolutegravir is also generally well tolerated. Given the general tolerability, there is a decent chance of not needing to switch medications due to side effects or toxicities.

    3. Can't monitor viral load, have to use CD4 and clinical indications as markers

    This is a major sticking point. Since none of the clinically available viral load monitoring assays used to date have detected any viral load, ARV treatment monitoring cannot be performed optimally. The World Health Organization recommends use of clinical and/or immunological monitoring (CD4 count) if viral load testing is not available. This is typically done in resource-limited countries where viral load testing is not available. There are significant problems with this approach. It has been found that misclassifications of treatment failure has been as high as 50%. This means medications can be switched unnecessarily even though the viral load is suppressed or that significant resistance can be developed due to not knowing that the viral load is not suppressed.

    4. Don't know resistance profile, possible intrinsic resistance e.g. HIV-2

    Given that none of the common epidemic strains of HIV could be detected with clinically available tests taken to date, it is unknown what type could be implicated. However, some of the evidence makes HIV-2 look more likely. This is because more extensive testing for HIV-1 has been performed and the presence of some immune characteristics such as CD4/CD8 > 1, 6 years after infection. The main thing going against this is the low reported prevalence in the US. Another possibility is a recombinant or rare type of HIV-1.

    U.S. guidelines say that as long as you use an integrase inhibitor or protease inhibitor (rather than an NNRTI), you can start ART while waiting for the genotype results. This is one reason we can now consider “rapid starts,” sometimes on the day of diagnosis.

    Using 2 NRTIs and an INSTI are generally a good choice in accordance with the statement above for treating HIV-1 in the US. Therefore, the probability of having resistance to this combination off the bat is low.

    HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI). Only certain protease inhibitors have been effective against HIV-2 including saquinavir (SQV), lopinavir (LPV), and darunavir (DRV). There is evidence that 2 NRTIs and 1 INSTI is effective against HIV-2 but no trials have been completed to confirm this. There is currently a study underway using Stribild to treat HIV-2 infection. Stribild is similar to Truvada + Tivicay. The difference is that Stribild uses a different integrase inhibitor (elvitegravir) that requires a boosting agent. The study hypothesises that Stribild will be a safe and effective treatment for HIV-2. However, no results have been posted for the study yet so there is no definitive evidence yet.

    One study reported virological response of HIV-2 to dolutegravir. While the data is limited, it's at least a promising indication that dolutegravir has action against HIV-2.

    5. TDF - bone, kidney toxicity

    Initial and periodic laboratory testing will be required to monitor for adverse effects of ARV treatment. Generally, a number of baseline lab tests are done prior to treatment initiation. For TDF, regular monitoring of creatinine clearance and serum phosphate are needed to assess renal function.

    Additionally, it would be helpful to have baseline bone density testing done and to periodically monitor this to assess any treatment impact. I would rather minimize the possibility of both of these toxicities by using TAF instead of TDF but without access to it, I'd have to accept these TDF associated health risks.

    Harm if incorrect and treated unnecessarily
    • Drug toxicity related adverse events
    • Unecessary medication costs
    My quality of life is already fairly low. Certainly, it could be worse but having the opportunity to improve it and have the best chance for prolonged health is very appealing. Ultimately it comes down to the odds of a significant medication induced quality of life decline from my current state happening.

    Harm if correct and not treated
    • Continued decline of immune system and quality of life
    • Development of AIDS and lifethreating infections / cancers
    This is obviously an extremely harmful outcome. Given my trajectory, I believe an intervention will be needed to prevent this from occurring.

    Conclusion

    I would much rather go through the proper channels with access to the latest, least toxic drugs that I know are legitimate. It would be safer and I would have easier accessibility to other medications if the drugs are not tolerated well. I would also prefer to have access to a viral load assay that was able to detect the virus implicated so that ARV treatment monitoring could be performed properly. However, since I do not have those options and have no indication of having those options in the near future, I am left with trying to do the best I can with the resources available to me. Now it's a matter of deciding at what point it makes sense to take the risk, while trying to ensure it's prior to any major adverse health events due to disease progression.
     
    Last edited: Mar 17, 2017
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  12. Daffodil

    Daffodil Senior Member

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    @undiagnosed I am curious...if no test can show your retrovirus, why do you think it is some variation of HIV?
     
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  13. undiagnosed

    undiagnosed Senior Member

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    @Daffodil, primarily because I can't come up with any explanation that fits the evidence better. Obviously there is some evidence that does not support the HIV hypothesis, mainly the negative test results. If you are interested you can look at my previous post where I quantify my reasoning using Bayesian inference. My conclusion was that even in light of the negative test results, the probability of being HIV+ is high. No tests are perfect and HIV is a highly diverse and rapidly evolving virus so it's not unreasonable to question whether the tests are missing the infection in light of clinical and immunological evidence. I'm open to differential diagnoses, just haven't found anything as plausible.
     
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  14. Daffodil

    Daffodil Senior Member

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    @undiagnosed i guess i cannot blame you for this line of thinking..i have it sometimes myself.

    i wish you could see my doctor because i am so much better than i was before.
     
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  15. undiagnosed

    undiagnosed Senior Member

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    With respect to HIV or something else? Is the doctor you're referring to a general practitioner or some type of specialist?
     
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  16. Daffodil

    Daffodil Senior Member

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    CFS specialist
     
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  17. Knockknock

    Knockknock Senior Member

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    I dont even think is Hiv, a retrovirus yes, but not Hiv, actually think of this.
    Ok people with CFS that have active HHV-6 their CD4 lynphocytes are low many like me a very low count close to AIDS.. low 300's , so with this saif it proof you dont need hiv to have your CD4 lynphocytes depleted and to quialify for an AIDS diagnostic( you can find references of the hhv-6 all over onlie including hhv6 foundation.
    This may explain why many hiv carriers live a normal life with out progression.
    Also why hiv persist in the body and cant be cleear of the body( thesame thing that happen to herpes viruses, hhv-6 ,ebv, cmv, vzs.. either laten or active.
    Putting this facts together my hypotesis is that a person with HIV ( alone just hiv) is like a person with just hhv-6 or EBV or any of this herpes viruses that are laten abd cause no harm on healthy people.
    So an hiv person need to have another Retrovirus( tge retrovirus we have to progress to Aids, healty hiv carriers have all their body funtions normal, only aids has the problems we have, this also may explain why there is millions of none HIV-Aids cases around the world.
    The retrovirus we have is more potent virus( but slower replication) dependible in my factors, immune activation, horminal changes, other virus like cmv, ebv, hhv6?that are also know to give potency and help rapid replication on HIV as well.
    What undiagnosed said is very important( medicine should be able need another way of proving active viruses another way not just antibodys)
     
  18. undiagnosed

    undiagnosed Senior Member

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    @Knockknock, there is an overwhelming amount of evidence that contradicts your hypothesis. I do not want to derail this thread by discussing details here. If you want to have a deeper discussion on this topic, create a new thread. Repost your message and tag me in it. I will respond in more detail there. Thanks.
     
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  19. Daffodil

    Daffodil Senior Member

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    @Knockknock you said:

    "This may explain why many hiv carriers live a normal life with out progression."

    The only people who have HIV and live a normal life without progression with no medication, are elite controllers....and there aren't many of them, I don't think...
     
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  20. Knockknock

    Knockknock Senior Member

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    Well that is what you think and what i think, maybe reality is in between, there is no account of how many people live with hiv, for sure hiv is a virus easier to control, people infected with hiv can control the virus with none nucleotide retroviral drugs, most of hiv drugs dont work in viruses like MLV, XMRV, HTLV... etc only a very small amount like the ones tested before, raltegravir, tenafovir, azt( is use very little do to side effects and toxinity) .
    While hiv people have 30 drug of choice most dont work on this other viruses.
    Hiv is quick replication, this other RT are lowe replication, that is why we dont progress AIDS like HIV
     
    Last edited: Mar 22, 2017
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