Three Analogies that Explain Broad-Spectrum Antiviral Drugs Against H5N1

                                                                 The Boxing Ring 

            In a boxing match, all any pugilist has to defend himself is the power of his two arms, his two fists, and his technique. To fight the next up-and-coming  pandemic opponent, H5N1 influenza, the therapeutic boxer has been gifted two fists and the power to propel them. One of the boxer’s fists consists of “specific” antiviral drugs that were developed to directly and specifically reduce replication of a particular virus. Specific antiviral drugs are effective against only one type of virus and are essentially useless against other viral infections. Currently, specific anti-influenza drugs primarily include oseltamivir, known as Tamiflu or OTV, and the newer baloxavir marboxil, known as Xofluza or BXM. Here I will refer to these two drugs as OTV and BXM.

            The flu fighter’s second fist consists of broad-spectrum antiviral drugs that are generally effective against most viruses, including influenza. They are effective against some viruses more than others. These are members of a larger class of anti-inflammatory, anti-viral drugs called NF-kappaB inhibitors or NF-kBIs for short. There are many different strengths of NF-kBI drugs and each works against certain viruses, some more than others. One important thing about NF-kBIs is they inhibit both viral replication and inflammation. That is because the NF-kB protein is a primary stimulant of most viruses, and it also increases inflammation.

            Although the Center for Disease Control (CDC) calls for using the specific drugs OTV and  BXM against the H5N1 opponent, the CDC fails to mention the second anti-flu arm, broad-spectrum antivirals that in the case of flu are best represented by aspirin (ASA), selenium (Se) and naproxen (NPX). Unlike specific antiviral drugs that target only one enzyme or immune factor that affects viral replication, based on an extensive review of the scientific literature, I have identified three broad-spectrum antiviral drugs that will be effective against H5N1. Each inhibits two or more factors, including the immune system’s response to flu infection.             

            Although the specific antiviral drugs OTV and BXM are initially effective, influenza viruses quickly develop resistance to them. Within five or seven days of OTV therapy, the virus has often mutated and become resistant. Then OTV is no longer effective – its proverbial punch loses all power. If the infected person then infects someone else, they pass on a virus that has already developed resistance to OTV. The same is true with BMX. Resistant virus begets resistant virus, so these specific drugs are no longer effective in people who are infected downstream with resistant mutated viruses. As an influenza pandemic continues, fewer and fewer people will be responsive to OTV-BXM therapy. The flu fighting boxer will lose all effectiveness from the punches it throws from the specific arm of its therapeutic boxing efforts.      

            With broad-spectrum antiviral medicines, the picture is completely different. ASA, Se, and NPX are all NF-kBIs that inhibit a human protein in cells that is the primary stimulant to both viral replication and inflammation. Thus, NF-kBI drugs kill at least two birds with one stone. Each of these three medicines also possesses one or more additional functions that inhibit viral replication or modulate the immune response.

            Aspirin inhibits platelet activation. Preventing platelet activation suppresses the flood of cytokine generating lymphocytes that would normally enter the lung to generate a cascade of immunologic events that ends with a cytokine storm, sepsis and multi-organ failure. Aspirin also helps prevent blood-clot forming distributed intervascular coagulation (DIC). DIC reduces blood flow to and through the organs and reduces both oxygen and nutrients getting to organs. That coagulation can lead to organ dysfunction and organ failure.

            Selenium provides a similar effect as aspirin in improving blood flow and reducing dangerous DIC, the cytokine storm, organ failure, sepsis, and death. Meanwhile, selenium works as the strongest immune booster because it is the strongest medicinal agent to increase CD4 lymphocyte count. CD4 cells have a major impact on the ability of the immune system to fight disease. Because selenium in the form of selenocysteine forms the basis of approximately 70-75% or more of all antioxidants in the body, Se also helps maintain the pro-oxidant versus antioxidant homeostasis, both within each cell and throughout the entire body.                    

            Naproxen works as both a specific inhibitor of influenza viral replication, and non-specifically as a broad-spectrum antiviral NF-kBI drug. The naproxen molecule fits “snuggly” into the viral groove of influenza A viruses, strongly blocking viral replication. The viral groove part of the virus is not subject to mutation and remains constant among influenza viruses. Therefore, flu viruses cannot develop resistance to naproxen. In a head-to-head comparison to Tamiflu/OTV, researchers showed that naproxen was 33% more effective in preventing mortality from an influenza A virus infection in mice than OTV was. Interestingly, naproxen/NPX is even more effective in inhibiting influenza B viruses (IVB) because it fits even more precisely into the IVB viral groove than in the IVA viral groove. ASA and NPX are non-steroid anti-inflammatory drugs (NSAIDs)

            Thus ASA, Se, and NPX all work directly through one or more mechanisms to inhibit influenza replication. Also they each work through one or more immune mechanisms to modify and improve the immune response to influenza A, including highly pathogenic avian influenza (HPAI) H5N1 influenza.                 

            As explained here, the scientifically based therapeutic antiviral boxer has two effective arms with two effective fists. After the specific antiviral fist quickly becomes almost useless because the virus rapidly develops resistance, the broad-spectrum antiviral arm and fist continues to be effective. In the long run, it is easy to see that the specific therapeutic arm is weaker, less resilient than the broad-spectrum arm. Therefore, one must question the logic of why the national response to the approaching H5N1 HPAI pandemic should be based solely on using two, resistance prone, specific antiviral therapies, while ignoring three broad-spectrum antiviral medicines that work as well or better than the specific drugs do. We should also consider that the specific drugs are much more expensive, and that broad-spectrum antiviral drugs can be used immediately, from the first moment a person discovers they are infected. H5N1 viral replication begins to decline about 48 hours after infection. That is before most patients even see a physician to get a prescription for OTV or BXM.  

            Any therapeutic boxer – or person infected with H5N1 - that enters the pandemic ring with their more powerful broad-spectrum antiviral arm tied behind their back is likely to forfeit their match. No enlightened, science-based therapeutic public policy should allow that. Why should Americans have to settle for that now?

                                                                        The Battlefield

            Historically there have been many famous battles. Who could forget Thermopylae, Yorktown, Waterloo, Gettysburg, the Battle of Britian, the Battle of the Bulge, Iwo Jima, or Diem Bien Phu? Now we are preparing to battle H5N1 HPAI. In many quarters battles against pandemic diseases have replaced military engagements. Casualties are much higher against novel viral enemies than against military ones. Victory in battle usually goes to the fighting force that has superior advanced armaments and the best strategy to use them. Americans are proud we have the most up to date military armaments and the best medical science. However, we sometimes play a strong hand poorly when it comes to the application of medicine. Just as in a boxing contest, if one fights with one arm tied behind their back, the side that fails to use all the resources it has at hand may be doomed to lose the battle. Now imagine a battle in an imaginary land called Fluviristan.

            The Homeland infantry was shipped off to war in Fluviristan with two types of weapons and told to win the war. One weapon was a rifle called the M1-OTV. The other was a bazooka designated the B2-BXM. In test trials both the M1-OTV and B2-BXM could hit the target and eliminate it. However, in a combat situation the target shapeshifts, quickly changing form. These changes caused the M1-OTV rifle to jam, becoming useless after about five days. Likewise, the B2-BXM bazooka is an excellent weapon, except it is hampered by the same jamming defect. Due to the shapeshifting mutational ability of the opponent, after a week or so under viral battlefield conditions, all the weapons are jammed, totally inoperable – the virus has become resistant. Then the Homeland viral defense forces are left with no effective defense whatsoever. They are defeated on the battlefield in the mythical land of Fluviristan with innumerable excess casualties. Little did the courageous Homeland soldiers on the frontline in Fluviristan know that Central Disease Command was holding back the secret weapons that could have saved their lives and won the war. Those were the C5-ASA artillery pieces, the AAH-Se attack helicopters, and the MX-NPX cruise missiles.

            The Homeland C5-ASA artillery pieces could have destroyed the effectiveness of the platelet land mines (PLMs) the enemy scatters across the battlefield. Normally, those PLMs burst into flames provoking a dangerous superinflammastorm that turns into a life-threatening sepsistorm. However, using just a little C5-ASA artillery suppressive fire can resolve that dangerous battlefield situation. If the troops had only known about them Homeland soldiers would have called the C5-ASA artillery a life saver. However, that special antiplatelet artillery was never used. Many more lives were lost.

            The Homeland antiviral troops also were kept in the dark about the AAH-Se attack helicopter. That helicopter had amazing capabilities. It could lay down a blanket of suppressive antioxidant firepower that could extinguish the superinflammastorm and the sepsistorm. Generating CD4 cell immune system generals to go to the scene of the battle to better gage what strategy and tactics to use, the AAH-Se attack helicopter was indeed a superweapon. If only Central Disease Command had deployed them when they had been needed most.  

            The MX-NPX cruise missile was also a remarkable achievement of advanced military-therapeutic development. The MX-NPX could be fired from afar and with incredible precision land within micrometers to fill the viroenemy’s groove chokepoint, preventing more Fluviristan soldiers from entering the battlefield. What a weapon! It could have saved the lives of so many brave Homeland warriors. Would have, should have, could have – but did not. Sadly for our troops, the MX-NPX was never deployed. Homeland mothers wept.

            Who were these generals at Central Disease Command that only provided their troops weapons that jammed but failed to supply the most modern scientifically advanced weapon systems they held in secret reserve? Why did they fail to deploy them when needed? What did they know and when did they know it? Why didn’t they know it? Central Command was supposed to be the experts. Viral warfare is not forgiving.

            As Benjamin Franklin, America’s most famous scientist and the most famous American in the world at the time of the American Revolution wrote in Poor Richard’s Almanac in 1758, quoting George Herbert’s poem from 1640: “For the want of a nail the shoe was lost. For the want of a shoe the horse was lost. For the want of the horse the rider was lost. For the want of a rider the message was lost. For the want of the message the battle was lost. For the loss of the battle the kingdom was lost. And all for the want of a horse’s shoe-nail.”   

            That was for the loss of one nail. What about the loss of three broad-spectrum antiviral drugs, each that work through multiple mechanisms? How many hundreds of thousands of pandemic lives might that cost?   

            What would scientist Franklin, or Hippocrates of Cos think of ignoring selenium, aspirin, and naproxen in the war against H5N1 HPAI influenza in 2025? Or Covid-19 in 2020? Would he be amazed how far American medical thinking or ethics had sunk from his day of can-do science? Or would he think this failure was caused by incompetence, or some kind of hidden corruption in the system? What would Franklin think? Franklin’s greatest regret in life was his failure to inoculate his son Francis who died as a child of smallpox.    

              Today, Franklin would obviously think we should deploy all five effective medications - all five weapons systems - against the approaching H5N1 flu pandemic - and all viral pandemics in the future.

            Would any military ever go to war and ignore its most valuable weapons? No. Never. Do public health officials consider wars against viral pandemics any less significant than military ones? More lives are lost in viral pandemics than in military engagements. Is our military intelligence that much superior to our public health intelligence? Why do we develop excellent military weapons systems and ignore excellent health weapons systems that have been repeatedly proven but are ignored, even though those proofs are found in medical journals?  

Fire in the Forest

Fires start small. Then they grow.

            Like most conscientious people I keep a fire extinguisher at home not far from the kitchen because there will always be some minutes delay in a fire department’s arrival if a fire starts. A similar problem exists with antiviral medications. Just as early therapy is the best therapy, early fire suppression is the best fire suppression. The same universal principle applies.

            Most viral diseases are highly inflammatory. Comparable to setting a house on fire, a virus like SARS-2 or H5N1 sparks the flame of infection. Soon the immune system responds with an ever-greater inflammatory reaction including fever, inflammation, swelling, platelet activation, and micro-clotting. In flu, the virus sparks the initial flame, but the immune reaction perpetuates the fiery inflammation that does the real damage. Novel viruses like SARS-CoV-2 (SARS-2) and H5N1 frequently generate an immune overreaction. One problem with specific antiviral drugs is they only directly target the virus that sparks the flame. They do not target the immune response of fever, inflammation, platelet activation, and clotting that actually causes the disease’s damage.

            After the virus ignites the initial fire, it continues to burn on its own. It is no accident that the word inflammation contains the word inflame. When the immune system is healthy and not overstressed or depressed due to handling too many other comorbidities, it can bring the fever and inflammation back under control by using its countervailing anti-inflammatory factors. It can act like an internal sprinkler system. However, when the immune system is older, overstressed by a plethora of other health conditions, or the viral assault is especially strong, as with a novel virus that the immune system has not established prior immunity to, the immune reaction can rage out of control. Then the disease spreads from its original site in the lungs - comparable to a house - to the rest of the body - comparable to the forest behind the house. Directly targeting the virus with specific antiviral drugs will have less impact on the disease – Covid or influenza – after it spreads beyond the original site of the lung where the virus sparked the original fire. Unusually however, with both Covid-19 and H5N1 HPAI, the virus infects not just lung tissue but also infects the other organs in the body. Additionally, H5N1 can infect neurons, the nervous system, and affect the brain, resulting in lethal encephalitis or blindness.

            Both SARS-2 and H5N1 replicate quite rapidly. Because RNA viruses have no ability to edit mistakes in genetic copying, they also mutate rapidly. Viral replication peaks about 48 hours into an infection and afterwards gradually decreases, petering out about 8 days post infection. However, most people do not see a physician until the third or fourth day after they are infected, so by the time they are prescribed either OTV, BXM or both, the initial viral spark is already in steep decline. Although specific antiviral drugs are beneficial in reducing the continual sparking of the illness, they are often too little too late to stop disease progression. The fire has already ravaged the original “house” of the lungs. The disease is now out of control in “the forest” of the body, well beyond its original site of infection. Specific antiviral drugs target the original spark and the declining viral spark, but they do not directly target the out-of-control immune system overreaction that causes the cellular damage, the cytokine storm, sepsis, DIC, multiple-organ-failure (MOF), septic shock, and mortality. The specific antivirals OTV and BXM target the cause of the disease. They do not target the disease itself, the destruction caused by the unmodulated, over-reactive response of the immune system. For that, one needs broad-spectrum antivirals and immune modulators. One needs selenium, aspirin and naproxen - SAN combination therapy.

            Selenium, aspirin, and naproxen are all anti-viral medicines that work through their action as NF-kB inhibitors. They also act as anti-inflammatory medicines via that same mechanism of action. While naproxen also works as a specific anti-viral against influenza A & B viruses, selenium and aspirin are both immunomodulators. Viruses including HIV, Ebola, SARS, influenza, and many more, genetically encode selenium-containing proteins as a component of their outer protective envelope. As viral replication increases, it drains cells and the immune system of the selenium they need to function properly and stay healthy. By inhibiting viral replication, antivirals help prevent the viral depletion of selenium, maintaining its contribution to the formation of cellular antioxidants and acting as an anti-inflammatory, calming the disease firestorm. Like aspirin, selenium helps prevent distributed intravascular coagulation, thus maintaining the flow of blood transporting oxygen and nutrients to the organs. In some viral diseases like AIDS, Ebola, and Covid-19, the level of selenium in the body is a measure of immune function. When total selenium levels fall below 80% of normal, the immune system becomes deficient, as in AIDS. When it drops below 70% of normal, mortality ensues. Thus, maintaining enough selenium in the body is as important for life as having enough water. Both excessive dehydration and deselenization can cause death.

            As for aspirin, the famous Dr. Robert Gallo once called aspirin “the greatest drug of all time”. Aspirin  therapy plays a critical role in the treatment of influenza and other respiratory diseases by preventing activation of platelets, thus reducing the trigger for the cytokine storm. Like selenium, aspirin can also increase CD4 white blood cell count, just not as sustainably long-term as selenium can. Aspirin also prevents clotting and DIC.  

            An important aspect of SAN combination therapy – Se, ASA, and NPX - is that a person can start SAN therapy the moment they realize they have a viral infection. Thus, SAN therapy can often prevent an initial infection from raging out of control. SAN therapy provides both antiviral and anti-inflammatory immune suppressing action via multiple mechanisms from the first moment treatment is required. The cost for a two-week course of SAN therapy is less than $20 and it is available over the counter at any pharmacy. All three components of SAN therapy can also be used prophylactically to reduce the chance of viral infection, disease severity, and “long H5N1”. Retrospective studies have shown that people who were already taking low-dose aspirin greatly improved their survival rates if they were infected with influenza or Covid-19.                       

            Selenium, aspirin, and naproxen are not contraindicated to OTV or BXM so they can all be used together in a four-way or five-way combination therapy against H5N1 HPAI. An old but durable rule of therapeutics is “early therapy is the best therapy.” That rule was violated during the Covid-19 pandemic and the world witnessed the result. When the house is on fire and it takes two or more days for the viral fire response team to write a prescription for specific antiviral drugs, the Hippocratic Oath should allow people to protect their own health with SAN combination therapy until physicians are able to prescribe additional specific antivirals to add to the broad-spectrum antivirals, anti-inflammatories, and immune modulators that patients can use as first aid viral fire extinguishers, even before they are able to visit their physicians. SAN early therapy will save lives.