Repurposing HIV Drugs in Cancer, Alzheimer's, and More

Introduction: Preventing Reverse Transcription

New human data shows what some medical scientists have long suspected: that certain HIV drugs (NRTIs) might be repurposed as a new and different kind of treatment for:

• some cancers (Mass General Cancer Center, 2022), (Rajurkar, 2022);
• prevention and maybe treatment of early Alzheimer's (Magagnoli, 2023), (Wahl, 2023), and more;
• and probably many other diseases as well. There are more than 10,000 known diseases, with at least 200 new ones described annually. Most are rare diseases; and only about 5% have known treatment options.
• Probably some of these diseases require reverse transcription, which could be detected by a simple blood test (not currently available to U.S. doctors) and treated if found. (Besides the research possibilities above, hepatitis B is a proven, well-known example - not a retrovirus, but it requires reverse transcription.>

The oldest class of HIV/AIDS drugs is the NRTIs (nucleoside rerverse transcriptase inhibitors). These drugs block reverse transcription, an abnormal process that HIV and other retroviruses use to reproduce. How many other non-retroviral diseases require reverse transcription for some step in their life cycle is unknown.

What is reverse transcription?

Normally the information in DNA is transcribed into RNA - which can then be translated into proteins, and also serve other function in the body.

But an abnormal enzyme called reverse transcriptase can translate RNA back into DNA. That DNA can then integrate at random places in the cell's DNA, damaging that cell. HIV uses this process to reproduce itself - integrating itself into the cell's DNA. The NRTI drugs were designed to block this reverse transcription, to stop HIV from reproducing.

Reverse transcription occurs in other illnesses as well - no retrovirus needed. The best known is hepatitis B, which is caused by a DNA virus, not a retrovirus. Certain NRTIs are used to treat hepatitis B, which happens to have a reverse transcription step that is required for its reproduction.

And reverse transcription can come from some human genes as well. Why would human genes evolve to produce an enzyme that is harmful to the individual? They didn't. These genes were inserted into the human genome by retroviral infections in the primate line, about 5,000,000 years ago. Evolution has not been able to snip them out, but has usually been able to silence them and prevent their activity. Also, many errors have accumulated from successive copying. But a few of the unwanted genes have survived and can still cause trouble - for example, when the silencing mechanisms weaken due to aging.

Suppressing Reverse Transcription

The opportunity here is that we already have several approved NRTI drugs, including lamivudine, with known safety and which are likely to be effective against a group of diseases that require reverse transcription as part of the disease process. And while viruses and cancer cells can develop resistance to drugs, the unhealthy human genes (resulting from prehistoric retroviral infections) probably will not, because (in the present day) there is only human DNA - no virus, cancer cell, or other agent that reproduces so there's, 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.

Cautions:

• Before prescribing lamivudine or other NRTIs, doctors should make sure that the patient does not have HIV or hepatitis B. If they do, they need appropriate treatment, and lamivudine alone would be harmful. (In most cases the appropriate treatment could include one or more NRTIs, so the patient will get that benefit anyway.)
• 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. Additionally, abacavir has been associated with about a doubling of the risk of heart attacks in people with HIV (Elion, 2019).
• For all NRTIs, be sure to check FDA warnings. For lamivudine, see the 34-page FDA “label” (FDA, 2019), especially the boxed warning on page 1 - and also the last 4 pages, which are intended to be given to the patient.
• All NRTIs can have serious side effects. These drugs should not be used for general health purposes, but might be tried for diseases like Alzheimer's, cancer, or possibly even aging, when the consequences of not treating are worse than the risk of side effects.
• For aging and diseases of aging, note that most of the experience with NRTIs has been for treating younger patients. Older patients might have more side effects.

Patients/Providers Movements Needed

The medical system fails to get lamivudine or other FDA-approved NRTIs tested for new uses in people, and into the standard of care if they are successful. Scientists keep doing lab and animal studies, but seldom have any workable way to do the first tests to see if patients can actually benefit. Meanwhile, doctors are understandably reluctant to suggest an unproven drug to their patients. So nothing happens to improve human treatment.

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. - but be careful, some pharmacies will charge more than ten times that much). Insurance seldom covers anything "experimental," but most people in rich countries could pay $2 per day out of pocket, if that brings actual relief. And once the treatment has been clearly found to work, government or philanthropic funding could be found for those who could not pay.

Many doctors will not prescribe "off label" - meaning an approved drug for a purpose not specifically approved by the FDA, even though such prescription is clearly legal (FDA, 2018). But about two million U.S. physicians can legally prescribe lamivudine or other NRTIs (none of which are controlled substances). The main problem is that most physicians have never used lamivudine or any other NRTI, and don't know anything about these drugs. Movements of patients and physicians can bring together willing patients, doctors, and the information they need to use the drugs safely.

Another way around the off-label problem is Truvada PrEP - an FDA-approved NRTI combination pill for people without HIV, to prevent HIV infection. Many people have at least some risk of HIV infection through sexual contact.

But long-term use of Truvada can cause bone and kidney problems, which you don't get with lamivudine. (An improved form of Truvada called Descovy reduces these problems, but Descovy is extremely expensive for patients (about $2,250 per month) - even with insurance, which often requires patients to pay 1/3 of the cost for very expensive drugs. It should become more affordable in 2025, but only for Medicare patients, whose out-of-pocket costs should be capped at $2,000. per year for all their "Part D" drugs together, due to new federal legislation.)

Cancer and Reverse Transcription

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 lamivudine (an NRTI) 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 patients had very advanced cancer and were being treated with a single drug, lamivudine alone; 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 other cancer treatments.

We use the future tense because in the more than 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 ever prescribe off-label - meaning to prescribe an FDA-approved drug for a use not currently approved, which is clearly legal in the U.S. (The FDA regulates the marketing of pharmaceuticals, not the practice of medicine.)

And getting additional FDA approval (so that using lamivudine in cancer treatment wouldn't be off-label anymore) is unlikely as 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 seemingly endless negotiation and paperwork that would be required, to get this approval added to the current lamivudine indications? Probably not the doctors, who are already overloaded with patient care plus insurance hassles and other paperless work. Not the scientists, who are busy with other research. We need system changes for getting this followup clinical testing done.

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. The cancer reduction compared to the HIV-negative population was almost 50% – even though most cancers, and cancer overall, increased in the patients in these studies, as in other patients with HIV.

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. 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 with this disease.

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. 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.

Therefore it seems likely that lamivudine or other NRTIs might show even better results in patients without HIV. The cancer effect of the drugs would not be reduced by the opposite effect of 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 some other kinds of cancer. For less common cancers, there isn'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/provider movements willing to work outside of dysfunctional systems, to bring neglected treatment opportunities to public attention.

Entecavir, a Better Lamivudine?

Entecavir is similar to lamivudine. It was designed to be better for treating hepatitis B, and it is; entecavir has replaced lamivudine as standard of care. It was not tested or developed for HIV. It might or might not be better for other uses (besides hepatitis B). It is being tested for repurposing to treat cancer (Lourenço, 2023). We haven't focused on entecavir in this article, because lamivudine has more human data and is better known to doctors. Also, entecavir was highly customized for hepatitis B, which might mean that it works less well for other uses.

Alzheimer’s and Reverse Transcription

New Human Data on Alzheimer's Prevention

A study of two large medical-insurance databases found that exposure to NRTIs (nucleoside reverse transcriptase inhibitors, the drug class that includes lamivudine) was associated with an almost 50% reduction in human Alzheimer’s diagnosis, 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 the first to our knowledge to report Alzheimer’s reduction in patients exposed to HIV drugs – and a big reduction. This study avoided the obstacles to early human trials for a new indication 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 drugs (for treatment of HIV or any other purpose) were about 50% less likely to develop Alzheimer’s than those who had never been treated with NRTIs.

To see the four Alzheimer's-free "survival" curves (meaning survival without Alzheimer's - in the two databases, each with and without adjustment by patient matching) scroll down to the Results section of the report (Magagnoli, 2023). Note that the scaling is not identical. But you can see a similar picture in all four graphs, when comparing the risk of Alzheimer's with vs. without exposure to NRTIs. 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 (and therefore receive NRTIs). 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 no longer live on their own. With the first HIV treatments (all of which were NRTIs, in the early days), AIDS dementia largely disappeared. But the other consequences of AIDS did not decrease as much. In retrospect it seems likely that the NRTIs targeted dementia specifically, not just by treating AIDS.

If this is true, NRTIs might be even more effective against dementia in people who don't have HIV.

The 10% annual reduction in Alzheimer's diagnosis (Magagnoli, 2023) cautions us not to expect immediate results.

An excellent recent article Wahl, 2023), made the case for trying lamivudine (3TC) for age-related cognitive decline, mostly based on mouse and C. Elegans data. But the research team could not do the most important study: trying lamivudine to prevent, slow or relieve aging-related cognitive decline in people.

At least three animal studies are relevant: (Vallés-Saiz, 2023), (Li, 2021) and (Martinez, 2022).

Three Small, Recent Clinical Trials Testing NRTIs for Alzheimer's

(Sullivan, 2024) "performed a 24-week phase 2a open-label clinical trial of the original HIV dose of 300 mg daily oral lamivudine (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" (which is good news since these patients had suspected Alzheimer's). And several blood markers suggested benefits. This study has reported results, published early on a preprint server before peer review (Sullivan, 2024). [Note: lamivudine is no longer for HIV, because entecavir is better.]

(Frost, 2023) is conducting a similar study using lamivudine (3TC), but for early onset Alzheimer's disease. It enrolled 12 patients and has now been completed. An early report of results indicated very little change in dementia severity (Frost, 2023-results tab).

(Riddle, 2024) Repurposing Nucleoside Reverse Transcriptase Inhibitors for Treatment of AD (LINE-AD). This double-blind, placebo-controlled study is recruiting 35 participants aged 50-85 with MCI (mild cognitive impairment) or mild to moderate Alzheimer's; 25 will get the drug, 10 will get placebo. There are many additional inclusion and exclusion criteria. This study is testing emtricitabine (brand name Emtriva, also called FTC), a drug similar to lamivudine. The only trial site is Butler Hospital, at Brown University in Providence, RI. It is currently recruiting, with an estimated completion date of 2025-03-31. So far (2024-09-02) no results have been posted.

New Basic Research Advance

A technical paper published October 2024 reported "widespread transposable element dysregulation," in donated brains of older people who had died with Alzheimer's (Feng, 2024). The researchers "identified 26,188 genome-wide significant TE expression QTLs" in these brains (TE means transposable elements; QTL is a concept widely used in genetics to help relate genes to physical characteristics).

Many transposable elements require reverse transcription in order to become active and do damage. This paper strengthens the case that shutting down reverse transcription (possible with NRTIs) may have promise in prevention or treatment of Alzheimer's disease. Hopefully this research will increase scientific and medical interest in the area.

ALS: AIDS Drugs Tested, Found NOT to Work

Notice:

In April 5, 2025 the Lighthouse II clinical trial was ended, after an interim analysis showed no survival benefit from Triumeq in treating ALS (also called MND, Motor Neuron Disease). A full analysis is now being done. For the record, we left our original article below.

Aging and Reverse Transcription

A dream as old as humanity is to live longer and healthier. Today we are much closer than ever before to developing medical technology to do so. Once dismissed unthinkingly, treatment of aging is getting renewed attention because governments want to reduce healthcare spending, much of it due to age-related conditions such as cancer and Alzheimer’s.

I started this site to report on aging. But it is very hard to tell if a drug or other intervention slows human aging, because of the long human lifespan. It could take decades to prove that a pharmaceutical increased the length of human life, at enormous expense - and then we would have the answer to a question that was decades old.

But looking at age-related diseases could get results quickly. And reducing major illnesses like cancer or Alzheimer's has value in itself (and would almost certainly increase lifespan and healthspan in any case).

Reducing age-related diseases by inhibiting reverse transcription is the most important anti-aging possibility we found from repurposing HIV treatments. And it has been widely ignored by the medical system - probably because of the importance of big money in moving treatments through research and into the standard of care. And there is no big money here, as the key pharmaceuticals are off-patent. That's why we need patient movements to push research and drugs through the system - as happened in AIDS, which was widely ignored in the early days for different reasons.

The theory of aging that most interests us now is that with aging, the body loses the ability it has evolved to silence harmful reverse transcriptase genes - which were inserted into our germline by retroviral infections millions of years ago. There are other causes of DNA damage also, but usually we don't have good drugs to stop them. With reverse transcription we do, since that's how the NRTIs work against HIV.

Here are a few references relevant to aging and reverse transcription. We will report on them later: (Wahl, 2023), (Brochard, 2023), (Gorbunova, 2022), (De Cecco, 2019), (Brown University, 2019), (Küry, 2018 [HERVs, ALS, and MS]), (Brown University, 2016), (Simon, 2019).

Meanwhile we note an observation by a colleague in San Francisco, which I also noticed when I lived there and published AIDS Treatment News. Gay men seemed to look younger than their age. At that time, many were being treated for HIV, with one or more NRTIs in their drug regimen. They looked younger despite HIV being widely believed to speed aging. This makes sense, if the NRTIs (which were the only treatments in the early days, and are still included in some of the newest regimens today) reduce reverse transcription, slowing one kind of the DNA damage that is a major cause of aging.

Rare and Mystery Diseases: New Hope?

Many people have chronic, sometimes lifelong diseases that are never diagnosed, or may be entirely unknown to current medical science. Could reverse transcription be causing some of these problems? There is a safe and easy way to screen large numbers of people with various illnesses to find out.

Testing for Reverse Transcriptase (RT) Activity

There are inexpensive tests for RT activity. They only need a blood sample; they do not need to give any drug to any patient. These tests are currently used for research, and may not be available at this time for medical practice in the U.S.; a doctor cannot order one for a patient. But a screening program to test this approach would be research, and it could use the tests.

Reverse transcriptase is abnormal in humans. If it is found, it is likely caused by a disease process (or by aging, which some don't consider a 'disease' - a seemingly trivial issue that has fatal real-life consequences). So those cases of positive test results could be treated with lamivudine or other NRTI, to see if the drug brings benefit. (Our guess is that the great majority of the tests on rare or mystery diseases will be negative - but those that are positive could lead to a new treatment, not just for one patient but for many, even if scientists still don't understand the disease or what caused it.)

The result might be a new treatment for many diseases – a medicine that works entirely differently from the treatments (if any) already in use for that condition.

There are over 10,000 known diseases, with 200 or more added annually, and only 5% have a known treatment option. How many currently untreatable diseases might be helped by inhibiting reverse transcriptase? No one knows, but NRTIs developed for treating retroviral diseases have long been approved for hepatitis B (which is not caused by a retrovirus). And there is human evidence suggesting benefit for important diseases discussed on this site: some cancers, some dementia.

Also, theory suggests possible benefits even for slowing aging, and for some autoimmune diseases (Mustelin and Ukadike, 2020).

Since only a blood test is needed, it would be feasible to screen many patients who currently cannot be treated, and every success from treating abnormal reverse transcription immediately provides affordable, effective treatment already on pharmacy shelves - and used long-term for other purposes by hundreds of thousands of people, so considerable safety information is known.

For information on one of the many blood tests for reverse transcriptase activity, see (Vermeire, 2012).

Covid

Long Covid Patient Experience With HIV and Other Drugs, December 2024

Why Do Some People Keep Testing Positive After Recovery from Covid?

A laboratory study at the Whitehead Institute for Biomedical Research found that reverse transcription can occur in Covid-infected cells, and the resulting DNA can integrate into the cells' DNA (Zhang, 2023).

This could be the cause when people with Covid keep testing positive, even after recovery from acute disease. Presumably fragments of the virus have become part of the DNA of some of the patient's cells - which might then keep generating copies of the viral fragments, causing positive tests even when patients cannot infect others. And these viral fragments might contribute to Long Covid as well, by provoking an ongoing immune response. (No patients were treated in this lab study.)

Covid viruses do not code for reverse transcriptase, so they cannot create it. But reverse transcriptase can be in the body from other causes, for example, de-repression of HERV-K, which is part of the human genome.

Milder Covid Disease in People Already on NRTIs

A study reported on 405 chronic hepatitis B patients treated with NRTIs who also caught Covid. Of the 405 patients, "No COVID-19 patient required hospitalization, intensive care unit admission, oxygen support or died" (Liao, 2023) - a remarkable outcome when over 400 Covid patients were treated. And all of them had chronic hepatitis B.

These patients were being treated for chronic hepatitis B with either entecavir or tenofovir DF - both of these drugs are NRTIs. Both were about equally effective in reducing the severity of Covid. (Entecavir was never tested or developed for HIV. Tenofovir was, and became a major HIV drug, usually used in a combination called Truvada.)

What we don't know is how early the treatment must start to make Covid milder. In the cases noted above, treatment often started long before Covid infection occurred. Would there be any benefit if patients diagnosed with Covid then started entecavir or tenofovir? No one knows, but it may be worth trying, especially if Paxlovid is not available or is prohibitively expensive.

Long Covid and NRTIs?

Now that we know that NRTIs can affect Covid (Liao, 2023), it might be worth trying them for Long Covid.

Entecavir is interesting, now that it appears to be active against Covid. For hepatitis B, entecavir is a much-improved lamivudine. It is effective in very small doses, about 1% of the lamivudine dose. It is off-patent and affordable.

Long Covid Brain Fog: Guanfacine and NAC?

These drugs are not NRTIs, but we think people should know about this possibility for relief.

Guanfacine is an FDA-approved drug for high blood pressure; an ER (extended release) version was later approved for ADHD in children and adolescents. It has also been used off-label for traumatic brain injury, and PTSD. Researchers at Yale School of Medicine tried it combined with NAC (N-acetylcysteine) for brain fog in Long Covid, in an open-label study with 12 patients. Eight who continued on the drug reported substantial relief, measurable on neurological tests (and the ability to return to a full schedule at work by at least one of the patients, a nurse). Two stopped treatment due to side effects of guanfacine, mainly low blood pressure and dizziness. The other two were lost to follow-up.

This is early research. But since there is no approved treatment for what can be a debilitating condition, patients with brain fog may want to try it to see if they get relief.

The published paper is (Fesharaki-Zadeh, 2023). For a quick explanation, see (Yale School of Medicine, 2022). Unfortunately the team at Yale School of Medicine had difficulty convincing other physicians to prescribe guanfacine off-label.

Note: The guanfacine dose used was 1 mg per day, going up to 2mg if tolerated. NAC is available online and at some health-food stores. The dose used was 600 mg per day. It might have some effect by itself.

NAC has been used as an "adjunct" HIV treatment (De Rosa, 2000). It was one of the most popular alternative/complementary HIV/AIDS treatments, especially in the early days before modern HIV drugs were available. It is one of several strategies for replacing the body's glutathione (the body's most important antioxidant), if it is deficient due to illness.

Drug Repurposing Organizations and Articles

Drug repurposing means finding new uses for approved, well-known drugs. Government and non-government programs are currently doing this. See:
(Critical Path Institute, 2024) - Conference Sept. 9-11, 2024 in Washington DC,
(Cures Within Reach, 2024),
(Morningside Center at Emory University, 2024),
(EveryCure, 2024),
(Cure Drug Repurposing Collaboratory, 2024) - will close August 31, 2024, due to lack of funding
(CURE ID) - recommended by Cure Drug Repurposing Collaboratory
(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, most of which have no FDA-approved treatment (Cure Drug Repurposing Collaboratory, 2024). With thousands of drugs, there are many millions of combinations; finding promising ones seems like finding needles in a haystack. And it's hard to test each one - due to placebo effects, and the general slowness of clinical research.

Here, blocking reverse transcription could have a major advantage in drug repurposing, because of the screening tests noted above: if substantial RT activity is found, then NRTI treatment might be worth trying. It would be worth testing people with known or unknown diseases to see if this approach might be relevant for them.

In other words, treating abnormal reverse transcription (if found by the blood test) might be a path to relieving some diseases, even if they cannot be diagnosed and are not understood by current science.

Clinical Trial Design for Repurposed Drugs

Here are some thoughts:

A drug already approved and in use has lots of safety information available. So instead of spending years on a separate safety trial, the main trial could be started immediately, perhaps with a special safety protocol for the first dozen or few dozen volunteers, to check for any unexpected concerns for this different patient population.

Many existing clinical trials have been designed to look for superiority or non-inferiority of a new drug compared to an existing drug. Interim results have to be kept secret, sometimes for years, and volunteers must be blinded to which treatment they are receiving, lest they switch to a regimen that looks good at the time. This design is dominant because it works for pharmaceutical companies trying to get FDA approval and then market their drugs. Much faster and less expensive trials may be appropriate for repurposing drugs already approved and widely used.

Consider a clinical trial of one or more treatment options, which uses standard ways to measure how well the volunteers are doing. Patients could be randomized to the different options, or they could be allowed to choose which treatment they wanted to receive; both approaches have advantages and disadvantages. (Randomization is usually necessary to prove causation. But sometimes a randomized trial is not feasible, and uniform logs of patients' experience can be useful.)

Recruiting could be helped by excluding volunteers only for safety reasons - not to get a more uniform population to prove drug superiority more economically, which limits most trials to a special sample of people not representative of those who will use the drug if the trial is successful.

Reporting of results could be instantaneous, by an algorithm that is re-run every time new data comes in, and updates the results on a public website. So once there is enough data for a meaningful report, results could always be up to the minute, based on all blood tests, physicians' findings, etc. Researchers and doctors can publish their interpretation of the interim results at any time. No more waiting for years to find out how the volunteers are doing with the treatment(s) being tested.

The assumption here is that doctors and patients could look at these results as they come in and use human judgment to decide how to proceed. And of course the presentation of the results would be designed with doctors and patients in mind.

These trials wouldn't need any termination point, but could run until the organizers or volunteers decide to do something else.

I've been in the room where early HIV clinical trials were designed, and the basic procedure was to take a trial that has already been run, and update its protocol as little as possible to name the new drugs, doses, side effects, etc. That copycat system can help with compatibility of results. But for drug repurposing, we need fresh starts.

How to PAY MUCH LESS for Generic Prescription Drugs

The U.S. pharmaceutical marketplace is a mess, and you can easily pay ten times too much for the same drug, depending on what pharmacy you choose. In the U.S., all these drugs are approved by the FDA and meet the same standards, so a pill is just as safe as the same drug priced 10 times higher. Most people don't realize that they need to compare prices for pharmaceuticals their doctor prescribed - opening doors for abuse and profiteering throughout the medical system.

All drug repurposing is "experimental" by definition, until proven by clinical trials which may not be done for years or decades. So insurers won't pay. Fortunately the NRTIs discussed in this article are off patent and can usually be purchased for around $1 or $2 per day in the U.S., less elsewhere. Most people can afford that, and the low price makes it easier to fund relief for those who cannot.

Here are three ways to get low-cost generic prescription drugs. You may need to check more than one, because these pharmacies don't have every generic. And none can help much for drugs still under patent, as the patent holder can set whatever price it wants in the U.S., usually astronomical if the patient pays out of pocket (probably much less for health-insurance companies, though we do not know because the real prices they pay, including various discounts and deals, are secret).

Three ways to greatly cut expenses for non-patented drugs (all of these require U.S. prescriptions and ship within the U.S. only):

• costplusdrugs.com
  We think this one is best most of the time. The prices we have checked have been lowest, and the site is well organized. Also, it is rapidly increasing the number of drugs available, as it negotiates deals with manufacturers. And it is planning to manufacture some drugs itself, especially those subject to shortages in the U.S.
• www.goodrx.com
  This is a coupon system, which lets you print coupons to take to your local pharmacy. Not all pharmacies accept them, but most do. The advantage here is that with luck you can get the medicine quickly, without having to wait for the mail.
• www.healthwarehouse.com
  This mail-order pharmacy has low prices on lots of products, including over-the-counter supplies. It also fills veterinary prescriptions for your pets.

Note that two of the above three pharmacies are mail-order. That doesn't work if you need to start right away, e.g. antibiotics for an infection.

Also, there are no Federal standards to protect drugs during shipment to the end user, from excessive heat in summer or cold in winter; states are in charge of this, but often do nothing. We don't know if shipment temperature is a problem with NRTIs.

Three NRTI Regimens

Using the same doses as with HIV may be a good starting point, as about 30 million people in the world are now being treated for HIV with antiretrovirals - and probably a large majority of them are receiving NRTIs indefinitely. Also, some combinations are available as fixed-dose pills, taken once a day by adults. So there is much experience using these doses for a long time, with reasonable safety.

But there are serious risks. All NRTIs have safety warnings of rare but severe side effects; see the warnings on the first page of the Full Prescribing Information that usually comes with each drug (or drug combination pill). These drugs should never be used for general health - only when possible benefits outweigh risks. That may be the case with major diseases such as Alzheimer's or cancer - where there is evidence that they might be helpful, but not conclusive proof at this time.

And patients should not use the regimens below if they have HIV or hepatitis B. Those need proper treatment (which often but not always includes NRTIs).

Here are three regimens worth considering - all are available at low cost, even if you have no health insurance at all:

* Lamivudine alone, 300 mg once per day. Its advantage is lesser side effects. See full prescribing information, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/
020564s039,020596s038lbl.pdf. Note: this might not be the latest information.

* Epzicom (which is Triumeq without the expensive integrase inhibitor that might be unnecessary as we explained above) is also one pill per day. Patients must be tested to make sure they are HLA-B*5701 negative - if they are positive they must not use Epzicom or Triumeq (or any other regimen containing abacavir). Sometimes the dangerous reaction can happen even if they test negative. If it does, the patient must stop any regimen containing abacavir and NEVER take any abacavir again. See full prescribing information, https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Epzicom/pdf/EPZICOM-PI-MG.PDF. Note that the International AIDS Society-USA Panel 2022 guidelines no longer recommend abacavir for most patients starting HIV treatment, due to this problem and also an association with cardiovascular events (IAS, 2023).

* Oral PrEP (pre-exposure prophylaxis, usually with generic Truvada, one pill per day). PrEP is given only to HIV-negative people at risk of contracting HIV; for sexual transmission it is about 99% effective in preventing HIV infections that would have occurred without it (when used consistently as directed), so public policy often favors PrEP, making it easier to get it prescribed.

With Truvada, bone density and kidney function need to be watched; many older people have bone-density problems and should get a DEXA scan before using Truvada, to check for this risk. See full prescribing information for Truvada PrEP, https://www.gilead.com/~/media/files/pdfs/medicines/hiv/truvada/truvada_pi.pdf. Note: Descovy PrEP reduces the bone and kidney problems of Truvada. But Descovy is very expensive in the U.S., about $2200. per month, until the patent doesn't expire for about eight years. Persons receiving drugs under Medicare Part D should get some relief, because their out-of-pocket cost for Part D (but not Part B) drugs will be capped at $2,000 per year starting in January 2025. Note that while Truvada PrEP is also approved for receptive vaginal sex, Descovy is not, because it was not tested in that population. We note this because insurance companies may use it to deny payment.

At CostPlusDrugs.com prices are very low (except for Descovy and most other drugs that are currently patented). For example, a three-month supply of Truvada PrEP currently costs $53.30 (which includes a $5 delivery charge) - even without any health insurance.

A problem in the U.S. at least is that many doctors are unwilling to prescribe off-label - even when the patient is well-informed and requests the drug. "Off-label prescribing is when a physician gives you a drug that the U.S. Food and Drug Administration (FDA) has approved to treat a condition different than your condition. This practice is legal and common. In fact, one in five prescriptions written today are for off-label use." (https://www.ahrq.gov/patients-consumers/patient-involvement/off-label-drug-usage.html, 2015). Prescribing lamivudine alone is off-label - as is prescribing Epzicom except as part of a combination treatment for someone with HIV.

But PrEP is always prescribed only for people who are HIV-negative (and are at risk of HIV infection). Many people have secret lives that they may not be willing to share with their doctor. If they say they need PrEP to prevent HIV, they do, and it's not off-label. It's what the FDA approved PrEP for.

Note: PrEP is also available as cabotegravir, a drug injected once every two months, or taken as tablets. But cabotegravir is not an NRTI.

Caution: NRTIs are not general health tonics. These false building blocks of DNA inhibit reverse transcription, but can also interfere with the body's normal construction of new DNA, especially mitochondrial DNA; see our Perplexity.ai search for recent articles (last 5 years) on nrti drugs and mitochondrial dna damage. All approved NRTIs can cause lactic acidosis, which can be life-threatening; patients should receive an information sheet that lists symptoms (you can print a copy from the last 4 pages of (FDA, 2019). These drugs should be used only when the alternative is worse. That is why we suggest considering this possibility for cancer, Alzheimer's, and possibly some serious rare and mystery diseases. There might be some other potential uses as well.

Needed: Patients' Initiative, and Movements

We need national and international patient activist movements to spread repurposing 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, as patients are told to wait for clinical trials that are not even being planned and may never be done.

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 allowed in the U.S.) might be expected to wait for or set up a new clinical trial, which could 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 off-label use, the patient is.

Almost 2,000,000 doctors in the U.S. can legally prescribe lamivudine or any other NRTI (although 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 get attention, early use, and research.

“N of 1” trial designs, or just 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.

But if we do nothing, then the early ACT UP slogan Silence = Death will apply again.

New potential uses of lamivudine and other NRTIs need more attention by researchers, doctors, and patient advocates. We hope this article explains these largely neglected possibilities, here and on pharmacy shelves today, to improve human life and health.

References

You don't need these references unless you are reading this article offline. That's because we link directly to the document, from the citation in the text.

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 some of the links below); there may be a delay before the published article appears in PMC.

Several of the following references have paywalls we could not get around; all are about ALS with HIV treatment, including a report of complete response more than two decades ago.

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