As a brutal second wave of Covid-19 infections rages on in India, more and more states are reporting critical shortages of ventilators and vaccines. The relative scarcity of these provisions means they’ll be difficult to wrangle in time to staunch further suffering and death. But there are drug therapies that could—in fact, they might be sitting on the shelves of physicians and pharmacists across the country.
Experts have known for some time that no single therapy will effectively prevent and treat Covid-19. What we need, especially now that highly infectious variants of SARS-CoV-2 are on the loose, is a veritable cocktail of drugs that overwhelms the virus through multiple lines of attack, giving it little opportunity to resist, evolve, or escape. The results of a new study, published in Cell magazine last month, suggest that a cocktail of one polymerase inhibitor—in this case remdesivir—and two hepatitis C drugs might do the trick.
The RNA-dependent RNA polymerase makes a good drug target because it is so essential to the replication strategy of SARS-CoV-2. Viewed in terms of the entire viral genome, this enzyme consists of three nonstructural proteins: nsp7, nsp8, and nsp12. Another exemplary target—what the seven different hepatitis C virus (HCV) drugs used in this study inhibit—are two proteases, enzymes that break down proteins into pieces a virus can use to copy itself.
The researchers behind the Cell study predicted that certain protease-inhibiting HCV drugs might inhibit also the main protease of SARS-CoV-2, known as nsp5. When they used a supercomputer to model and test their theory, all seven HCV drugs did indeed dock at nsp5. Interestingly enough, however, it was blockage of another protease, nsp3, that significantly boosted antiviral activity. Given that nsp3 precedes nsp5 in the virus’s replication strategy, it makes sense that blocking one has synergistic effects while the other is additive. But when combined with remdesivir, each of the four HCV drugs that inhibited nsp3 increased the potency of the treatment in cell cultures tenfold.
The tenfold increase in potency means the adverse effects of each drug can be mitigated using lower doses. If successful, these treatments should be effective not only at treating the disease, but very importantly preventing it in people who are likely to be exposed. This strategy is used routinely in malaria zones and even for HIV. No vaccine was ever invented for HIV, but high-risk individuals can still protect themselves from infection through a regimen known as pre-exposure prophylaxis (PrEP). India has the pharmaceutical research, development, and manufacturing capacity to produce large quantities of such a treatment and, more importantly, sell it to consumers at low cost, which is how generic drug prices in India are among the cheapest in the world. But for Covid-19, the choice of which treatment to scale up for mass consumption wasn’t easy or obvious—until now.
Of course, discovering a breakthrough product in the laboratory is one thing. Rolling it out with great haste is another. Before rush orders of the HCV drug and polymerase inhibitor combo can be placed, the therapy must be tested in animal models and clinical studies. At this stage, more convenient substitutes for remdesivir—which at present can only be administered intravenously in hospitals—should be considered and tested alongside it. One polymerase inhibitor, developed by Ridgeback Biotherapeutics LP and Merck & Co, that comes in pill form and has promising preliminary data behind it is molnupiravir. Pfizer is also developing an oral drug that should inhibit nsp5 as well, which would make it another viable addition to the cocktail.
Then comes the question of how to scale up production and distribution using existing infrastructure. Egypt did this with tremendous success with its 100 Million Healthy Lives program, which eliminated hepatitis C from the country in a matter of months by screening more than 60 million adults and providing free treatment to all who tested positive. The India-based multinational Cipla already manufactures HCV drugs en masse at low prices. In fact, they may have the capacity to produce the entire combination at scale. India has the added benefit of being able to supply its own active pharmaceutical ingredients (APIs). Hepatitis C treatments that cost US customers thousands of dollars cost only $25 to $35 in India. There is no good reason why Covid-19 combination therapy shouldn’t cost less than $5.
Were India to succeed at leveraging existing HCV drugs and pharmaceutical infrastructure alongside Covid-19-specific therapies, the strategy could have considerable import in countries facing similarly dire straits. It is impossible to know when the vaccine shortages plaguing not just India, but many countries around the world, will resolve. We also can’t expect new variants of SARS-CoV-2, many of which have learned to evade immune detection, to cease appearing in the meantime. Government and public health officials should take advantage of the opportunity to pump out combination drug therapies while they still can. Otherwise, many more countries may soon find themselves in circumstances not unlike India’s—overwhelmed to the point of paralysis. These drugs may be their only way out.