NewHealthyAging.com
By John S. James, last updated 2024-04-26
The author founded AIDS Treatment News and published it for 20 years, 1986 to 2007. He is 82. He has no conflict of interest in any product or company discussed.
New human data shows what some scientists have long suspected: that some HIV drugs might be repurposed as a new and very different kind of treatment for:
These HIV drugs inhibit reverse transcription (explained below), so they are called NRTIs (nucleoside reverse transcriptase inhibitors). Several NRTIs are approved by the FDA for treating HIV. One of them, lamivudine (brand name Epivir, also called 3TC) is getting the most attention for repurposing because of its lower side effects.
And there's more good news. A blood test can tell how much reverse transcription is happening. So persons who are chronically ill but cannot be diagnosed, or maybe have an illness unknown to medicine, can easily be screened to tell if this treatment is likely to help them or not.
Unfortunately the U.S. medical system is not set up to use the new information effectively, so opportunities to improve health and life are being lost. If we don't want to waste a decade or more waiting for new treatment that might be here today, patients will need to take the initiative and build movements to push the system to move better and faster on drug repurposing, as patients pushed the system on AIDS.
Here we present evidence that repurposing lamivudine and/or other NRTI treatment (for conditions besides HIV and hepatitis B) deserves much more attention than it has received.
Normally, information from DNA is transcribed into RNA, which then produces proteins and also has other functions in the body. But sometimes an abnormal enzyme, reverse transcriptase, translates the RNA back into DNA – and that new DNA can insert itself into the cell's DNA at random places, damaging the cell. DNA damage is believed to be one cause of aging.
It is known that reverse transcription is not necessary for human health – since hundreds of thousands of people with HIV have taken reverse transcriptase inhibitors for decades without harm. But reverse transcription is necessary for some diseases, not just retroviruses like HIV (hepatitis B, caused by a DNA virus not a retrovirus, is the best-known example).
No viral or other infection is necessary to cause reverse transcription. That’s because some human genes can produce reverse transcriptase, the enzyme that makes reverse transcription possible. These genes did not evolve normally for any human survival purposes, but were placed in our DNA by retroviral infections in the pre-human primate line, millions of years ago. They still make up a large fraction of human DNA. Fortunately most of them are defective or have been silenced by human biology. But some can still cause trouble.
Fortunately there are low-cost blood tests for reverse transcriptase activity. Therse tests could screen patients with known or mystery diseases. If reverse transcriptase is found, then NRTI treatment might be tried to see if it brings relief; if it isn't found, then there is no reason to try a reverse-transcriptase inhibitor. Note that this strategy could work just as well even if the disease cannot be diagnosed - or is completely unknown to medicine.
The opportunity here is that we already have at least two approved NRTI drugs, lamivudine and/or abacavir, which are likely to be safe and effective against a group of illnesses that require reverse transcription as part of the disease process. And while viruses and probably cancer cells can develop resistance to drugs, the unhealthy human genes probably will not, because there is no virus or other agent that reproduces, no way for drug resistance to propagate and evolve. So we might already have a treatment for many diseases, one that works without drug resistance in some cases. (Note: abacavir [Ziagen] is an NRTI that is often combined with lamivudine. Abacavir requires a blood test before using it, as anyone who is HLA-B*5701 positive should never take abacavir because they are likely to have a dangerous hypersensitivity reaction to it. And abacavir might not be necessary; it was first approved in 1998, and the AIDS dementia problem had largely ended by then.)
Where the medical system fails is getting lamivudine or other FDA-approved NRTIs tested in people, so that doctors know whether they can help in treating particular illnesses. Scientists keep doing lab and animal studies, but have no workable way to do the first tests to see if patients benefit. Doctors are understandably reluctant to suggest an unproven drug to their patients.
But patients can take the initiative and ask for the drug if they want to try it. Lamivudine and other NRTIs are now off patent, so affordable generics are available (about $2 per day for lamivudine in the U.S., less elsewhere). Insurance won't cover anything "experimental," but most people could pay this price out of pocket. And once the treatment was known to work, government or philanthropic funding could be found for others.
All NRTIs require a prescription in the U.S., and a standard warning is given for all of them. Lamivudine does not cause serious side effects in most people, but medical supervision is necessary because it can cause dangerous reactions in a few, and dosage must be adjusted for patients with reduced kidney function. The 36-page FDA “label” for lamivudine (FDA, 2017) tells doctors what they need to know to use this drug safely. Note that the last 4 pages are written to be given to patients. (Also note: the lamivudine dose for HIV is twice the dose for hepatitis B. The higher HIV dose was used in the clinical studies discussed in this article.)
In April 2022 doctors and scientists at Mass General Cancer Center, one of the major cancer research institutions in the U.S. reported on the treatment of “32 patients with advanced metastatic colon cancer whose disease progressed despite four lines of previous cancer treatments” (Mass General Cancer Center, 2022), and (Rajurkar , 2022). Nine of the 32 had disease stability or mixed response on lamivudine alone, with no other cancer treatment at that time. Basically the doctors had no other conventional treatments to try, but they knew that "Many cancers exhibit high levels of the reverse transcriptase enzyme."
While 9 of 32 may seem disappointing, remember that these were very advanced patients being treated with a single drug at that time; this research provides proof of principle. In practice lamivudine will be used much earlier, and in combination with other cancer treatments. It will be one more tool for doctors, a well-tolerated drug that works very differently than all other cancer treatments.
We use the future tense because in the two years since this remarkable and easily usable result was published, it has been largely ignored by the medical community. Part of the problem is the refusal of many doctors to prescribe off-label. And getting additional FDA approval (so it won’t be off-label anymore) is unlikely since there is no commercial push for this drug since it is generic and cannot be sold for astronomical prices. Who will do the clinical trials, and the endless negotiation and paperwork required, to get this approval added to the current lamivudine “label”?
Additional supporting evidence came from earlier studies that showed a large decrease in certain cancers in patients with HIV - when an increase would have been expected (Coghill, 2018), also see (Hernández-Ramírez, 2017).
These studies reported an unexplained reduction in colorectal, breast, and prostate cancer among people in the U.S. being treated for HIV, between 1996 and 2012. Only about 50% of the expected cancers were found – even though most cancers, and cancer overall, increased in the patients being followed.
After trying and rejecting various possible explanations for the decrease in these cancers, the researchers basically gave up, and concluded that their findings “represent biological relationships requiring future investigation.”
At the time the registry data was collected, almost all HIV patients were being treated with NRTIs (plus other HIV drugs in many cases). So in view of the Mass General research, it seems likely that lamivudine and other NRTIs (not HIV) suppressed these cancers.
Don’t miss a subtle and important point here. It is likely that the cancer and the HIV treatment were pulling in opposite directions. The overall risk of cancer in all the patients studied was elevated 1.69 (in other words, a 69% increase in cancer in people with HIV vs. those without HIV). To illustrate with an extreme example, the risk of non-Hodgkin’s lymphoma was elevated almost 12 times (about a 1100% increase), so any decrease due to NRTIs would have been swamped. That means we don't know if the NRTIs helped or not.
So failure to get positive results on other cancers doesn’t mean that HIV treatment didn’t help – it means that we don’t know. The HIV treatment might have helped but been overpowered by a larger effect of HIV causing that cancer. In the case of colorectal, breast, and prostate cancers, the treatment won out, and prevented cancers that would have occurred without HIV treatment.
This means that lamivudine or other NRTIs might show even better results in patients without HIV.
So the benefit is not necessarily limited to the handful of cancers that showed up as underrepresented in patients being treated for HIV. Instead, the HIV drugs might be helping the treatment of other kinds of cancer. And for less common cancers, there wasn't enough data to tell. We just don’t know yet.
Two years have gone by with little progress toward using available knowledge to improve cancer treatment. The system discourages anyone from trying the approved HIV drug(s) for HIV-negative cancer patients, so little happens beyond more and more laboratory and animal testing.
We need patient movements willing to work outside of dysfunctional systems and do the right thing.
New human data on Alzheimer's prevention: Exposure to NRTIs (nucleoside reverse transcriptase inhibitors, the drug class that includes lamivudine) was associated with about a 50% reduction in human Alzheimer’s diagnosis, in two major medical-insurance databases, with over 200,000 patients meeting study criteria (Magagnoli, 2023). The reduction of Alzheimer’s was about 10% per year of exposure (suggesting that the Alzheimer’s reduction might have been more than 50% over a longer time).
This report is critical because it is first one to our knowledge to report Alzheimer’s reduction in patients exposed to HIV drugs – and a big reduction. This study evaded the obstacles to early human trials of an approved drug, by using database records of patients who had been treated in the past. Those who had been exposed to any NRTI drug (for treatment of HIV or of hepatitis B) were about 50% less likely to develop Alzheimer’s than those who had not been treated with NRTIs.
The paper may have other problems; it has not yet been published in a peer-reviewed journal. It is really two papers: one reporting human data from the two health-insurance databases, the other reporting mouse data with a different drug, Kamuvudine-9. But the critically important conclusion stands, as it’s hard to make a significant mistake when counting the patients with and without exposure to NRTIs, and with or without Alzheimer’s. The findings were much the same in both databases.
A standard criticism of such results is that correlation does not equal causation. But usually ideal data (from a large, randomized trial) is not available. In this case, we can develop scenarios that might explain away the association – and ask how plausible they are. For example, perhaps people who are not going to get Alzheimer’s anyway are more likely to get HIV. That doesn’t make sense.
What makes more sense is that the HIV treatment prevented Alzheimer’s. Consider the early history of AIDS. Before there was any treatment, many people with AIDS developed dementia. It was feared that facilities would be needed to hold thousands of patients who could not live on their own. With the first HIV treatments (all of which were NRTIs, in the early days), AIDS dementia largely disappeared.
The 10% annual reduction in Alzheimer's diagnosis cautions us not to expect results too soon.
An excellent recent paper (Wahl, 2023), made the case for trying NRTIs for treating or preventing human Alzheimer’s, mostly based on mouse and C. Elegans data. But then the research team could not do the most important study: trying lamivudine to prevent, slow or relieve Alzheimer’s in patients.
(Sullivan and 18 others, 2024) "performed a 24-week phase 2a open-label clinical trial of 300 mg daily oral 3TC (NCT04552795) in 12 participants aged 52–83 years with a diagnosis of mild cognitive impairment due to suspected Alzheimer’s disease." "Cognitive measures remained stable throughout the study," while several blood markers suggested benefit.
(Frost, 2023) conducted a similar study using lamivudine [3TC], titled Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer's Disease (ART-AD).
And two animal studies may be relevant: (Li, 2021) and (Martinez, 2022).
A major clinical trial in Australia and New Zealand is testing the AIDS combination treatment Triumeq against ALS, commonly known as Lou Gehrig’s disease (Lighthouse II. Macquarie University, Australia, 2023). It was motivated by the observation that ALS often progresses much more slowly in patients who also have HIV than in others (Satin, 2021) - probably because of their treatment, not because of HIV. Triumeq is a 3-drug combination pill; two of the drugs are NRTIs, lamivudine and abacavir. (The NRTIs are affordable, but Triumeq is expensive because the third drug is still under patent.) This phase 3 trial is known as Lighthouse II. An earlier trial, Lighthouse I, was phase 2. It was completed, and Lighthouse II is currently recruiting patient volunteers.
See other research reports on ALS: (Bowen, 2016), (Cone, 2002). And there are more.
There have been two theories to explain the slower progression seen with HIV. One is that there is a milder disease that only affects people with HIV, and that is indistinguishable from ALS except that it progresses more slowly and starts earlier in life, on average. The majority view seems to be that it is one disease.
If so, then it seems likely that HIV treatment makes ALS progress more slowly.
But why does ALS start earlier in life in patients with HIV? A likely reason is that before getting HIV treatment, those patients had untreated HIV. The immune damage it caused could have accelerated ALS. Then they got AIDS treatment, usually including NRTIs, greatly slowing ALS progression.
The results of Lighthouse II should show which theory is correct. Will the HIV treatment, which includes two NRTIs, help ALS patients who do not have HIV? Our guess is that it will help them even more than it helps ALS patients with HIV.
What would I do if I had ALS and wasn't in Australia or New Zealand? I would consider Triumeq if I were rich, and otherwise consider the two low-priced NRTIs in Triumeq (but only include abacavir if negative on the HLA-B*5701 blood test).
We will complete this section later. Here are some research reports we are looking at: (Gorbunova, 2022), (De Cecco, 2019), (Brown University, 2019), (Küry, 2018), (Brown University, 2016), (Simon, 2019).
Drug repurposing means finding new uses for approved, well-known drugs. Government and non-government programs are currently doing this, especially in Europe and the U.S. See (Cure Drug Repurposing Collaboratory, 2024), (Critical Path Institute, 2024), (Cures Within Reach, 2024), (Emory University Morningside Center, 2024), (EveryCure, 2024), (Jonker, 2024), and (Kulkarni, 2023). The goals are to save lives and improve health first, and also to reduce the cost of healthcare.
The drug repurposing movements have focused mainly on rare diseases, and on high-tech methods like artificial intelligence to find new treatments to try. There are about 10,000 diseases, three quarters of which have no FDA-approved treatment (Cure Drug Repurposing Collaboratory, 2024).
Blocking reverse transcription has a major practical advantage in drug repurposing. Fortunately there are affordable screening methods to discover which diseases might be helped by inhibiting reverse transcriptase. An inexpensive blood test can check for reverse transcriptase activity (Vermeire, 2012), without needing to give lamivudine or any other drug to the patient. Reverse transcriptase is abnormal in humans; if it is found, it is caused by a disease process, and it might be an essential step in the pathogenesis of the disease (as in the well-known case of hepatitis B). So inhibiting reverse transcriptase might be a new tool for controlling many diseases – a medicine that works entirely differently from the drugs already in use. And the doctors don't even need to have a diagnosis.
As far as we know these blood tests (there are several of them) are not currently available to doctors, as there has been no demand for routine medical use. They are sold in bulk for research and other uses, for example vaccine manufacturing. The wholesale price we have seen is $1,000 for 200 test kits ($5 each, plus lab expenses of course). Some of may be more accurate and less expensive than current commercial tests for measuring HIV viral load (Vermeire, 2012).
We need an international patient activist movement to spread information and push the medical system, like we had with AIDS - or we could wait another 20 years or more for the standard of care to catch up. Here is one way it could work.
Today, a doctor who takes the initiative and wants to try an approved drug for a use not currently approved (“off label” prescription, which is clearly legal in the U.S.) might be expected to set up a new clinical trial, which would be very expensive and take years just to get started. But if a well-informed patient takes the initiative, asks for the drug and insists on it, the doctor is not suggesting the unapproved use, the patient is. Almost 2,000,000 doctors in the U.S. can legally prescribe lamivudine or any other NRTIs (though it’s best if the doctor has experience with the drug). An activist movement can connect interested patients and doctors. And if an approved but off-label drug clearly improves the care of patients who are seriously ill, it will have the momentum it needs to catch on.
“N of 1” trial designs, or simply publishing case reports and case series, will be important. If successes and failures are not published, other researchers will not benefit from what was learned.
New potential uses of lamivudine and other NRTIs need more attention by scientists, doctors, and patient advocates. We hope this article focuses attention on a largely neglected opportunity, here today, to improve human health and life.
We always link to free full text when legally possible. Biomedical research that receives NIH funding (which is most of it) must deposit the accepted and peer-reviewed authors' manuscript, which goes into the free Pub Med Central database (you will see the 'PMC' in the links below). There may be an embargo of up to a year. If the journal's article has no paywall or other hassles, we link to their site. Only two of these references have paywalls we can't get around (they were published over two decades ago).
Bowen LN, Tyagi R, Li W, et al. HIV-associated motor neuron disease. Neurology. 2016;87(17):1756-1762. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089528/
Brown University. Brown to lead $9.7M grant to advance theory of aging. Brown University, 2016. Accessed April 21, 2024. https://www.brown.edu/news/2016-09-06/retrotransposition
Brown University. HIV drug could treat Alzheimer’s, age-associated disorders. Brown University press release, 2019. Accessed April 21, 2024. https://www.brown.edu/news/2019-02-06/aging
Chénais B. Transposable Elements and Human Diseases: Mechanisms and Implication in the Response to Environmental Pollutants. Int J Mol Sci. 2022;23(5):2551. https://doi.org/10.3390/ijms23052551
Coghill AE, Engels EA, Schymura MJ, Mahale P, Shiels MS. Risk of Breast, Prostate, and Colorectal Cancer Diagnoses Among HIV-Infected Individuals in the United States. J Natl Cancer Inst. 2018;110(9):959-966. https://doi.org/10.1093/jnci/djy010
Cone LA, Nazemi R, Cone MO. Reversible ALS-like disorder in HIV infection. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology. 2002;59(3):474; author reply 474-475. https://www.neurology.org/doi/10.1212/WNL.59.3.474. Sorry, paywall.
CURE Drug Repurposing Collaboratory. C-Path. Accessed April 21, 2024. https://c-path.org/program/cure-drug-repurposing-collaboratory/
Cures Within Reach. Current Repurposing Research Projects. Accessed April 21, 2024. https://www.cureswithinreach.org/programs/current-repurposing-research-projects/
De Cecco M, Ito T, Petrashen AP, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature. 2019;566(7742):73-78. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519963/
Critical Path Institute. Accessed April 26, 2024. https://c-path.org/
Emory University: The Morningside Center for Innovative and Affordable Medicine. Accessed April 21, 2024. https://morningsidecenter.emory.edu/.
Every Cure – Unlocking the hidden potential of existing drugs to save lives. Accessed April 21, 2024. https://everycure.org/
FDA, Label for EPIVIR (lamivudine). 1995. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020564s37_020596s036lbl.pdf. Accessed April 21, 2024.
Frost B. Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer’s Disease (ART-AD). Clinicaltrials.gov, 2023. Accessed December 31, 2023. https://clinicaltrials.gov/study/NCT04552795
Gorbunova V, Seluanov A, Mita P, et al. The role of retrotransposable elements in aging and age-associated diseases. Nature. 2021;596(7870):43-53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600649/
Hernández-Ramírez RU, Shiels MS, Dubrow R, Engels EA. Spectrum of cancer risk among HIV-infected people in the United States during the modern antiretroviral therapy era: a population-based registry linkage study. Lancet HIV. 2017;4(11):e495-e504. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669995/
(17)30125-X https://hsrc.himmelfarb.gwu.edu/gw_research_days/2019/SMHS/110
Jonker AH, O’Connor D, Cavaller-Bellaubi M, et al. Drug repurposing for rare: progress and opportunities for the rare disease community. Front Med. 2024;11. https://doi.org/10.3389/fmed.2024.1352803
Kulkarni VS, Alagarsamy V, Solomon VR, Jose PA, Murugesan S. Drug Repurposing: An Effective Tool in Modern Drug Discovery. Russ J Bioorg Chem. 2023;49(2):157-166. https://doi.org/10.1134/S1068162023020139
Küry P, Nath A, Créange A, et al. Human Endogenous Retroviruses in Neurological Diseases. Trends in Molecular Medicine. 2018;24(4):379-394. https://doi.org/10.1016/j.molmed.2018.02.007
Li M, Zhao J, Tang Q, et al. Lamivudine improves cognitive decline in SAMP8 mice: Integrating in vivo pharmacological evaluation and network pharmacology. Journal of Cellular and Molecular Medicine. 2021;25(17):8490-8503. https://doi.org/10.1111/jcmm.16811
Lighthouse II. Macquarie University, Australia. Randomised Double-Blind Placebo-Controlled Phase 3 Trial of Triumeq in Amyotrophic Lateral Sclerosis. https://clinicaltrials.gov/study/NCT05193994, Accessed December 31, 2023. Also see Lighthouse I, https://clinicaltrials.gov/study/NCT05193994.
MacGowan DJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology. 2001;57(6):1094-1097. https://doi.org/10.1212/wnl.57.6.1094
Magagnoli J, Yerramothu P, Ambati K, et al. Reduction of human Alzheimer’s disease risk and reversal of mouse model cognitive deficit with nucleoside analog use. Preprint published online March 20, 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055589/
Martinez de Lagran M, Elizalde-Torrent A, Paredes R et al. Lamivudine, a reverse transcriptase inhibitor, rescues cognitive deficits in a mouse model of down syndrome. Journal of Cellular and Molecular Medicine. 2022;26(15):4210-4215. https://doi.org/10.1111/jcmm.17411
Mass General Cancer Center. HIV drug stabilizes disease progression in metastatic colorectal cancer. Massachusetts General Hospital Cancer Center. Accessed April 21, 2024. https://www.massgeneral.org/news/press-release/hiv-drug-stabilizes-disease-progression-in-metastatic-colorectal-cancer
Rajurkar M, Parikh AR, Solovyov A, et al. Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer. Cancer Discovery. 2022;12(6):1462-1481. https://aacrjournals.org/cancerdiscovery/article/12/6/1462/699170/Reverse-Transcriptase-Inhibition-Disrupts-Repeat
Riddle M. Repurposing Nucleoside Reverse Transcriptase Inhibitors for Treatment of AD. clinicaltrials.gov; 2023. Accessed December 31, 2023. https://clinicaltrials.gov/study/NCT04500847 (Butler Hospital, Providence, Rhode Island.
Satin ZA, Bayat E. ALS-Like Disorder in Three HIV-Positive Patients: Case Series. Case Reports in Neurology 2021;13(1):59-64. https://doi.org/10.1159/000511203
Simon M, Meter MV, Ablaeva J, et al. LINE1 derepression in aged wild type and SIRT6 deficient mice drives inflammation. Cell Metab. 2019;29(4):871-885.e5. https://doi.org/10.1016/j.cmet.2019.02.014
Sullivan AC, Zuniga G, Ramirez P. et al. A Pilot Study to Investigate the Safety and Feasibility of AntiRetroviral Therapy for Alzheimer's Disease (ART-AD). MedRxiv [Preprint]. 2024 Feb 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10925371/. See also ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT04552795.
Vermeire J, Naessens E, Vanderstraeten H, et al. Quantification of Reverse Transcriptase Activity by Real-Time PCR as a Fast and Accurate Method for Titration of HIV, Lenti- and Retroviral Vectors. PLOS ONE. 2012;7(12):e50859. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050859
Wahl D, Smith ME, McEntee CM, et al. The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction. Aging Cell. 2023;22(5):e13798. https://doi.org/10.1111/acel.13798
To share this article, simply send the link, NewHealthyAging.com (.org works also).
For now the best way to reach me directly is FightDystopia@gmail.com
Comments: we will set up a system for publishing comments.
We do not use cookies. For statistics, we use the AWStats program which generates a report from the ISP's log files (how many users from what countries, for example). We do not make any effort to identify individuals. We do not sell or transfer personal data to anyone unless required by law.
This site was created by a writer, not a doctor, and does not provide medical advice. It is for information only, and is not a substitute for professional medical advice and treatment. People being treated for any serious condition should discuss all medication changes with their doctor.
NewHealthyAging.com by John S James is licensed under CC BY 4.0