[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe,” is a longtime medical writer (not a doctor) who shares his thoughts with Gumshoe readers a couple times a month. He usually does not specifically cover investment ideas, and his words and opinions are his own — his past columns can be found here]
Lots of things will kill viruses. Out in the open, they’re not especially tough. If you get something on your hands that is contaminated with virus, washing your hands will do the trick. A mild disinfectant will take care of viruses on most surfaces. Even if you eat or drink something that contains viruses, chances are your stomach acids will dispose of the evil critters. And if they get past that obstacle, in many cases your immune system will recognize the “foe” signal and mount an attack.
The question is how to combat the virus once it has gained entry into your cells? That question is, unfortunately, considerably more complicated than it looks. It is true that there are some effective antiviral drugs – that is, quite effective as treatment for some specific viruses. However, at this time there are no broad-spectrum antivirals, although researchers are currently working to develop broad-spectrum antivirals (more about that further on in this piece). Clinicians need to be reasonably certain of the identity of the virus before they attack any viral infection with a drug. And even then, there are no drugs for many viral infections. Therefore, the first step in treating viral infections is arriving at an accurate diagnosis.
That’s not necessarily the case with bacterial infections. Lots – perhaps the majority – of bacterial infections are treated based on the clinician’s best guess as to the causative pathogen. This is known as “empiric” treatment – empiric because the clinician’s decision is grounded in experience rather than in specific data. The form of treatment based on a clear and positive identification of the specific pathogen responsible for the infection is called “definitive” treatment, and it’s obviously the ideal. The clinician takes dead aim at the culprit and eliminates that population of pathogens quickly and effectively, and – we hope! – without killing too many of the beneficial bacteria that colonize the gut, and also without creating resistance in the pathogenic bacteria. In order to accomplish that feat, however, the pathogen has to be identified, and this can take more time than is practical, especially since some pathogens are not quick to grow out in a culture; meantime the patient is not getting any better.
With empiric therapy, the clinician evaluates the symptoms and consults his/her own experience, as well as current knowledge of “what’s going around.” So, although the clinician may not be able to identify the specific pathogen with the greatest confidence, he/she chooses an agent that will hit the likeliest pathogen, but also a fairly wide variety of other pathogens that might also be involved – in other words, a broad-spectrum antibiotic. Many of the most widely used antibiotics, such as those in the beta-lactam class, which includes all the penicillin-related drugs, are broad-spectrum antibiotics. Empiric therapy with broad-spectrum antibiotics has obvious potential benefits for patients, to wit: patients receive treatment more quickly and probably recover more quickly. But there are downsides. This practice has certainly led to overuse of antibiotics and has contributed to the increase in antibiotic-resistant pathogens. A typical scenario, which I described in considerable detail in “How Worried Should We Be about Antibiotic Resistance” back in October of 2013, which you can see here, is when Clarence, a child with a cold, is prescribed an antibiotic because his mother is reluctant to take the doctor’s word for it that Clarence has a virus and will get over the cold in a couple of days.
That little imaginary case history emphasized that the antibiotic would not do one single solitary thing to help Clarence get over his cold. But it did not make the point which is relevant to our current discussion, namely, that there is no current antiviral drug that is effective against cold viruses. That does rather leave the doctor in a situation that is less than ideal. “Yes, Madam, little Clarence has an upper respiratory infection, also known as a cold. Yes, you quite correctly kept him out of school today, so that at the very least he would not infect the whole class with his cold – not that he hasn’t in all likelihood already passed on his cold to several of his little friends. But no, Madam, we have no medication that will cure his infection or make him recover any sooner. Take him home, make sure he gets plenty of rest and is well fed. Chicken soup might help him clear out the snot.”
The doctor, while confessing to the lack of an effective antiviral drug for the common cold, might suggest steps that would perhaps help Clarence get over his cold more quickly and might also alleviate the symptoms – antitussives (cough medicine), expectorants, decongestants, and the like, although some of these are not recommended for young children. Depending on the doctor’s inclination, he/she might recommend certain vitamins and/or micronutrients, not specifically as treatment for Clarence’s cold, but to bolster his overall immunity.
I am specifically not going to list the vitamins and micronutrients that may have an effect on immunity, because if I did that in each case I would have to go into considerable detail regarding such matters as what dose not to exceed, the putative effect of each vitamin or micronutrient, and the strength of the evidence about the effectiveness of those substances. The same thing goes for herbs and other supplements. And the list of micronutrients, vitamins, supplements, and herbs that have been suggested as immune-boosters is lengthy. Harvard Medical School publishes a sensible guide on boosting the immune system, which you can access here. In general, this is what they say helps the immune system:
- Don’t smoke.
- Eat a diet high in fruits, vegetables, and whole grains, and low in saturated fat.
- Exercise regularly.
- Maintain a healthy weight.
- Control your blood pressure.
- If you drink alcohol, drink only in moderation.
- Get adequate sleep.
- Take steps to avoid infection, such as washing your hands frequently and cooking meats thoroughly.
- Get regular medical screening tests for people in your age group and risk category.
“Many products on store shelves claim to boost or support immunity. But the concept of boosting immunity actually makes little sense scientifically. In fact, boosting the number of cells in your body — immune cells or others — is not necessarily a good thing. For example, athletes who engage in “blood doping” — pumping blood into their systems to boost their number of blood cells and enhance their performance — run the risk of strokes.
“Attempting to boost the cells of the immune system is especially complicated because there are so many different kinds of cells in the immune system that respond to so many different microbes in so many ways. Which cells should you boost, and to what number? So far, scientists do not know the answer. What is known is that the body is continually generating immune cells. Certainly it produces many more lymphocytes than it can possibly use. The extra cells remove themselves through a natural process of cell death called apoptosis — some before they see any action, some after the battle is won. No one knows how many cells or what kinds of cells the immune system needs to function at its optimum level.”
Diagnosing viral infections …
… is far from easy. Clarence’s doctor more or less knew that Clarence had a viral upper respiratory infection, but as to which specific cold virus, the doctor can’t do better than hazard a guess. The likeliest are the rhinoviruses, which, depending on the season, can cause up to 40% of colds. Or it could be the coronavirus, or the respiratory syncytial virus, or the parainfluenza virus. Or a couple of hundred others. In any case, it doesn’t much matter, because colds get better on their own, or, as the doctor would say, “resolve spontaneously.” At least, they resolve spontaneously in healthy people. And, unfortunately, there are no current antiviral agents that are effective against any of these viruses, although one agent, ribavirin has shown encouraging in vitro results against parainfluenza, and a combination of interferon alpha 2b and ribavirin can be used against a coronavirus variant that causes the notorious middle east respiratory syndrome (MERS), but not the common cold.
As to what to do when colds do not resolve spontaneously, as in people with immune systems that are not operating effectively, that’s when the likelihood of a secondary bacterial infection looms large. Those bacterial infections then require treatment with antibiotics – but not, we repeat, not prophylactically!
Some viral infections are particularly difficult to diagnose because the initial symptoms are mild and non-specific, and in some cases so mild as to be unnoticeable. Many people are infected with HIV without being aware of it, which is dangerous not only for the infected individual, but for other persons to whom the infected individual might pass on the infection, either through sexual contact or by some practice such as needle-sharing that transmits the blood of the infected person to another person. The characteristic symptoms of full-blown AIDS may not appear for a fairly long time, during which the virus can be transmitted.
Zika, a virus of much current interest, is not easy to spot quickly. Early symptoms include headache, fever, a rash, and sometimes conjunctivitis. The headache and fever, usually mild, disappear after two or three days, and the rash may last a week; in some cases no symptoms at all are manifest. Estimates as to how many people have become infected with Zika vary wildly. In Brazil, some estimates of the number of women who have been infected run as high as four million, and some health authorities have suggested that by the end of 2017, as much as three-quarters of the population of Puerto Rico may be infected with Zika. In Brazil, the great majority of infected persons have not sought medical attention, although with the more recent information regarding the link with microcephaly, the level of concern in the general public has greatly increased.
Zika is a member of the flavivirus family, related to dengue, yellow fever, West Nile, and others. Its genome has been sequenced, and it can be identified with accuracy by that method, which is exceedingly unlikely to be employed in the vast majority of cases. No currently known drug is effective against a Zika infection, and the accepted treatment protocol is rest.
By now, everyone must have learned that the CDC has pronounced that the cases of microcephaly that have been seen in Brazil are indeed due to Zika. I think that this is almost certainly correct, although the evidence is not rigorous. The pronouncement does not follow the famous Koch protocol, which holds that, first, the pathogen must be present in all investigated cases of the disease; second, that it must be able to be grown out in a culture; third, that the cultured pathogen should be able to cause the disease in a laboratory animal; and fourth, that the pathogen should be able to be isolated from the laboratory animal and be shown to be the same as the pathogen that was grown in the culture. That’s the standard for rigorous establishment of a cause-effect relationship between a pathogen and a disease condition.
But we can see that applying the Koch protocol to Zika-linked microcephaly would be nearly impossible. Instead, they employed a procedure called “Shepard’s criteria,” which state that if three out of seven criteria are met, the association can be ruled as established. Shepard’s criteria are commonly used to attempt to identify the causes of birth defects, and the Zika-microcephaly link did indeed meet three of the seven criteria, including the fact that exposure to Zika happened at a critical time in fetal development (the first and second trimesters), the fact that Zika-linked microcephaly is characterized by distinct damage on brain scans and other characteristic features such as extra skin on the scalp, eye damage, and joint distortion, and the fact that a rare exposure causes a rare outcome, namely that pregnant travelers who contracted Zika later gave birth to babies with microcephaly when they returned to a region where Zika was not known. And, finally, a few cases of Zika-linked microcephaly have been found in French Polynesia, and Zika virus has been isolated from the amniotic fluid of women bearing affected babies as well as in the brain tissue and spinal fluid of these babies.
All in all, that’s pretty convincing. I would maintain, however, that the driving force behind the CDC’s proclamation is that giving the Zika-microcephaly link the official seal of approval makes it more feasible to conduct a successful campaign to reduce the risk of damaged babies. The CDC is certainly not going so far as to tell women who are in at-risk areas that they should avoid pregnancy by whatever means lay at hand. I think their hope is that women will come to that conclusion on their own. And, indeed, the strong likelihood is that the epidemic will wane, so avoiding pregnancy for a year or two doesn’t have to be a profoundly life-altering decision.
Why do I think the epidemic is likely to wane? First, I seriously doubt that there will be anything resembling an epidemic in the US or, indeed, most of North America. Even if, as the CDC has announced, the evil Aedes aegypti mosquito finds a home in as many as 30 US states, those bugs aren’t going to find enough infected monkeys or humans to collect the virus from. So far, according to the CDC, about 700 people in the US have been infected with Zika, almost all of them importing the infection from other regions. There may be small pockets of infection, and in those areas we can expect mosquito control efforts to be operating at full throttle.
Second, in epidemic areas, mosquitoes are likely to run out of sources of virus. We don’t know exactly how long immunity lasts in a Zika patient, but there is evidence that the immune response when a person is infected with Zika includes robust increases in interferon. It’s the innate immune response that quells the Zika infection in most people as quickly as it does. So, without a viral reservoir, the epidemic will tend to be self-limiting.
But that still leaves the big question unanswered.
What kind of pharmaceutical treatment options are there for viral infections?
Let’s start with the upbeat fact that up until fairly recently there weren’t any effective antiviral drugs, and now at least there are quite a few. Antiviral drug developers did not start out with the immense advantage that the antibiotic developers had. Antibiotics are modeled after, and in some cases derived from, naturally-occurring substances that have emerged in the billion-year war between competing life-forms on our planet. I am not going to recap the story of Fleming’s discovery that led to penicillin and the whole category of beta-lactcam antibiotics, other than to emphasize that antibiotics, as a class, were out there, waiting to be discovered. The way it happened with antimicrobials was, essentially, “This stuff works! Don’t know exactly how or why, but let’s use it!” No such luck with antivirals.
Early efforts to develop antiviral drugs mostly followed the methods employed by antibiotic research, which was go grow cells in a culture, infect them with a virus, add various chemicals that might in some way stop the growth of the virus, and see if it worked. Mostly, it did not work. It was exceedingly difficult to identify a drug that would disable the virus without at the same time killing the host cell. That particular dilemma continued to plague antiviral drug development until the 1980s.
To come up with effective antivirals, researchers first had to puzzle out the viral life-cycle. This depended on X-ray diffraction, a technique that was instrumental in learning the structure of most of the building blocks of life. What researchers learned was that the viral replication cycle consisted of six steps. The first step is attachment, in which proteins on the outside of the virus (the capsid) bind to specific receptors on the surface of the host cell. Specific viruses bind to specific cells in the host. The binding action is determined by the laws of physical chemistry: certain atoms and molecules combine avidly, while others exhibit no mutual attraction. The binding forces between atoms determine the conformation of the molecules, which in turn determines how they interact. For example, HIV has a surface molecule, gp120, which combines with the CD4 molecule found on the surface of certain T cells, and since CD4 T-cells are key warriors in our immune response, HIV has the effect of crippling the response that normally protects us against viruses.
The next step is penetration, which is facilitated by changes in the host cell membrane during the process of attachment. Depending on the structure of the host cell wall, some viruses are able to propel their genetic material into the host cell while leaving the viral capsid outside.
When the entire virion enters the host cell, it sheds the capsid to release the genome, which can consist either of DNA or RNA; this process is called uncoating. When viruses inject their nucleic acid through the host cell wall, the capsid remains outside the cell. In either case, the capsid material is degraded.
Once the viral genome has gained entry to the host cell, it robs genetic building blocks from the host cells and creates duplicates of its own genome. This process is called replication.
After the initial replication of the viral genome has taken place, in some cases the virus emerges from the host cell by bursting or disrupting the cell membrane, killing the host cell. This step is termed release. In some cases, the virus undergoes further maturation or modification of the protein structure after release from the host cell. This step is usually called assembly. In some cases, however, the virus carries out the assembly phase before release from the host cell. And, also in some cases, the viral genome is incorporated into the host’s genome, such that each time the host divides, the viral genome is also replicated. As a general rule, this viral genome does not result in the propagation of active virus, but in some cases, new units of active virus can emerge from the host cells, usually killing the host cells.
Designing an agent that kills viruses or prevents viral replication also is dependent on understanding the nature of the viral genome. DNA viruses replicate in the host cell’s nucleus, taking over the host cell’s synthesizing capabilities. RNA viruses replicate in the host cell’s cytoplasm, employing their own enzymes to create copies of their genomes. Retroviruses use an enzyme called reverse transcriptase to convert host cell nucleic acid into viral genome. HIV, a retrovirus, introduces the genomic material formed by this process into the host cell’s genome.
HIV is a particularly difficult virus to deal with, because, as I’ve mentioned, the host cells that the virus targets are specifically those immune cells that protect us from viruses – the CD4 T-cells. But the way HIV enters cells and replicates has much in common with viral transmission and replication, and the way antiviral drugs attempt to control HIV is similar to the way they interact with other viruses.
The evolving anti-HIV drug arsenal
An agent that was accidentally found to inhibit the reverse transcriptase enzyme was azidothymidine (AZT, later called zidovudine, or Retrovir), which was initially developed as a possible anticancer drug. Understanding this process led to the development of other related drugs that inhibit reverse transcriptase, such as lamivudine (Epivir), and stavudine (Zerit). These drugs were the first to treat HIV infections with any degree of effectiveness.
The early reverse transcriptase inhibitors (RTIs) were largely superseded by tenofovir (Viread), one of the many anti-HIV agents developed by Gilead (GILD). (A brief digression: I do not want this piece to sound like a promotion for Gilead, but it’s impossible to write about drugs that treat HIV, or those that treat hepatitis C, without acknowledging Gilead’s near-dominance in the field. Full disclosure: we have owned Gilead stock for more than five years.) A couple of newer versions of tenofovir have emerged, the principal difference being equivalent efficacy at a much lower dose.
Tenofovir has been followed by a number of drugs with similar mechanisms. These include the nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside RTIs (NNRTIs). The most prominent among the newer NRTIs is emtricitabine (Emtriva, from Gilead), and among the NNRTIs, it’s efavirenz (Sustiva, from Bristol-Myers Squibb).
Two other mechanisms have been found to be effective in inhibiting viral replication. One is inhibition of the viral enzyme that cuts up the protein in the host cell so as to provide material for the replication of the viral genome. The viral enzyme that does this job is called “protease,” and the drugs that inhibit this enzyme are protease inhibitors. Cleaving host protein is a step in viral replication that precedes putting all the pieces together to make copies of the viral genome. A widely used protease inhibitor, ritonavir (Norvir, from AbbVie), was introduced in the mid 1990s and continues to be used today in HIV patients, most often in combination with other RTIs.
Another mechanism that inhibits viral replication relies on inhibiting yet another viral enzyme that is involved in that process. The enzyme has been dubbed “integrase.” In the process of viral replication, after the step in which reverse transcriptase has copied the viral genome into the host cell’s DNA, the modified DNA is then inserted into the host cell’s chromosomes with the aid of the viral enzyme integrase. Integrase inhibitors attempt to prevent this process. These are the most recent class of anti-HIV drugs. Elvitegravir (Vitekta, from Gilead) was approved in September of 2014 for treatment of “experienced” HIV patients, meaning patients who had already received treatment with other drugs. Elvitegravir is most often given in combination with a protease inhibitor such as ritonavir.
Ritonavir has a useful mechanism in addition to protease inhibition. It inhibits a liver enzyme that degrades some antiviral drugs, making it possible to employ those antivirals at lower doses. Another drug with a similar mechanism, cobicistat (Tybost, from Gilead) is used in several combination treatments.
In fact, combination treatment is the standard for HIV. The term of art is HAART, for “highly active anti-retroviral therapy,” and combinations in a single pill abound. There is a dual rationale for this form of treatment. It makes sense to attack the viral replication process at several points rather than aiming the attack at a single point in the process. And also, since no anti-HIV drug, nor any other anti-viral drug or any drug at all, is entirely free of side effects, it also makes sense to keep the individual doses at the minimum. So, if it’s possible to attain the same goal with smaller doses of two or three drugs, that may also have the benefit of minimizing adverse effects. Here are a few of the combos, with FDA-approval dates.
Combivir (1997) lamiduvine + zidovudine, generic, originally Glaxo Smith-Kline
Truvada (2004) emcitrabine + tenofovir, from Gilead
Atripla (2006) efavirenz + emtricitabine, from Bristol-Myers Squibb and Gilead
Complera (2011) emtricitabine + rilpivirine + tenofovir, from Gilead
Stribild (2012) cobicistat + elvitegravir + emtricitabine + tenofovir, from Gilead
Odefsey (2016) rilpivirine + emtricitabine + tenofovir, from Gilead
Descovy (2016) emtricitabine + tenofovir, from Gilead
Gemvoya (2015) elvitegravir + cobicistat + emtricitabine + tenofovir, from Gilead
(Although they have the same basic ingredients, Stribild and Gemvoya use different versions of tenofovir.)
In 2012, Truvada also received an FDA indication for prevention of HIV infection in individuals who are “at risk” for being infected with this virus. I suspect that this particular indication was granted mostly for political reasons; the FDA probably did not want to be seen to be denying protection to a vulnerable sector of the population. From my admittedly skeptical perspective, giving Truvada an indication for prophylaxis in a population characterized as being “at risk” would be like giving a similar indication to an anti-cancer prophylactic (if there were such a drug) for cigarette smokers. I do not know what share of Truvada’s prescriptions is for this prophylactic use, but I suspect it is small.
The effect of the many drugs and drug combinations used to treat HIV on the HIV death rate has been immense. The number of deaths in the US considered to be specifically due to HIV peaked at about 45,000 nationally in 1994 to 1995. Almost immediately, when the first effective agents became available, the number of deaths declined to about 15,000 per year in 1997. Thereafter, the annual death rate due to HIV has declined to about 5,000 per year and continues to decline, albeit slowly.
The chief reason that there continue to be deaths due to HIV in the US is not that the drugs are ineffective, but that many HIV-positive persons are undiagnosed, and many others are inadequately treated. HIV disproportionately affects minorities and economically disadvantaged persons. Their infection is likely to have progressed a great deal before it is diagnosed. They are likely to be treated at community health centers, and, although they are strongly urged to stick with the treatment, they are much less likely to be treatment-adherent.
Nonetheless, in the US today there are hundreds of thousands of persons whose treatment regimens for HIV have succeeded to the degree that they are able to lead essentially normal lives. Note that I qualified that statement: “essentially normal lives.” The effect of HAART frequently reduces the viral load to levels designated as “undetectable.” But that does not mean that there is no HIV present in those individuals. It’s there, but it’s hiding.
There has been considerable discussion regarding the possibility of discontinuing therapy in individuals whose viral loads reach the undetectable level. The current consensus is that therapy needs to continue, not only because the virus can and likely will emerge from its hiding place and go back to copying itself in host cells, but because there continues to be a risk of transmission of the virus to other persons. Therefore, the practices that facilitated the transmission of the virus in the first place – unprotected sex, needle sharing, etc – have to be avoided, and therapy needs to continue.
That’s in the United States of America, and other developed countries with robust health-care systems. In other parts of the world – Africa, much of Asia – diagnosis and treatment of HIV is an entirely different matter. The World Health Organization estimates that there currently are 40 million people worldwide infected with HIV, and that it has resulted in the deaths of about 25 million. So far. The big battle in those regions is not to improve treatment, but to prevent transmission, and among the weapons are condoms, circumcision, vasectomy, and drugs given immediately before childbirth to prevent perinatal transmission. Ebola and Zika make the headlines, but in the long run HIV/AIDS will be the killer.
* * * * * * *
I’ve gone on for longer than I intended about HIV and the drugs that treat it. But there are other viral illnesses, and there are other antiviral drugs, and they deserve some attention from Doc Gumshoe, so I will work up another piece to cover such matters as the drugs that treat such viruses as Herpes simplex and Varicella zoster, as well as flu, hepatitis C, and other viral ailments. And a topic of much potential: the long-sought broad-spectrum antiviral agents, which we said earlier didn’t exist. Fortunately, they may exist before too long.
Before I go back to further sleuthing on antiviral agents, there are some matters that I hope will pique the interest of Gumshoe Republic, so my next piece will take a look at those. Thanks to all for lively comments!