Currently, we are pinning all our hopes on vaccines for return to normalcy, which in the case of new data from Moderna and Pfizer have been found not just to protect against severe disease and death but also infection. This is a positive development and the second-generation vaccines currently being developed will likely bring greater efficacy. Yet the question remains will vaccination alone be enough to contain the Covid-19 pandemic. Vaccines still pose a myriad of challenges in terms of vaccine hesitancy, the unknown length, and duration of protection, and their efficacy against the ever-mutating variants. Therefore, it is clear that only a multifaceted approach utilizing vaccines, drug treatments, and public health measures will prevent infections from spreading.
The good news is that Remdesivir and other cocktails of monoclonal antibodies have shown that prevention and early treatment with antiviral drugs do work to reduce disease. However, these drugs are currently administered via infusion and require hospitalization, which makes delivery challenging and inaccessible to mass populations.
This is why Pfizer’s announcement that they are developing an oral antiviral drug that could be used at the first sign of infection or exposure is such promising news. The drug is part of a class of medicines called protease inhibitors and works by inhibiting an enzyme that the virus needs to replicate in human cells. Protease inhibitors are used to treat other viral pathogens such as HIV and hepatitis C.
A virus takes over our cell’s RNA in order to produce viral proteins to make more copies of itself. Initially, the infected cell forms a single viral protein chain like a long string that is mostly non-functional. The protease enzyme cuts the protein chain in specific areas to produce fully-functional working subunits that are critical for the virus to replicate. Protease inhibitors are a class of antiviral drugs that shut down this protein-cutting process and stops a virus from multiplying.
Respiratory viruses like influenza, respiratory syncytial virus, and now Covid-19 are uniquely challenging to treat once symptoms arise. Because infections and symptoms for respiratory viruses are typically short-lived, the immune system quickly engages in viral replication suppression. This is why these protease inhibitor drugs are ideally used in congregate living situations such as long-term care facilities, workplaces, schools, prisons, and family homes. Once an infection is detected in those communities, everyone exposed can immediately start prophylactic (preventative) treatment by taking a pill while isolating, preventing the viral replication and the spread of infection in the greater community.
An antiviral used for Influenza, Xofluza demonstrates the success of this approach, with the drug reducing transmission by 80% in a close-quarter family context. By attacking the virus before it has a chance to replicate we have the opportunity to prevent the spread of infections and mutation of future variants.
Of course, for this strategy to be completely successful, it needs to be combined with a mass rapid antigen testing program to detect infections in their earliest stages. Many public health officials, including myself, have been calling for a program like this to stop the spread of infections since the early days of the pandemic, I have detailed what such a plan would look like in an earlier piece on containing Covid-19 within the U.S.
If successful, the Pfizer drug could also be used for those experiencing long Covid-19 in order to prevent long-term shedding of the virus and potential transmission to others. In a prior column for Forbes, I wrote about research demonstrating the fecal transmission of Covid-19. One study, conducted in Zhejiang, China, discovered viral RNA in the stool of 59 percent of Covid-19 patients tested, remaining at detectable levels for three weeks on average. Another study found that the virus persisted longer in fecal samples than even respiratory samples. Though the presence of viral RNA doesn’t necessarily indicate the presence of live, actively replicating virus, the latter has been isolated and cultured from fecal samples in the laboratory. Protease inhibitors have a long history of use, a good safety profile, and are generally well-tolerated so they could even be given to asymptomatic Covid-19 patients to eliminate this longer-term shedding and risk of potential transmission.
Egypt’s 100 Million Healthy Lives initiative provides an example of how we could accomplish this. Egypt previously had one of the highest rates of Hepatitis C in the world. In 2018, Egypt launched the 100 Million Healthy Lives program. The goal was to screen all Egyptians over the age of 12 for active hepatitis C virus replication along with other chronic conditions. Those who tested positive were treated with the antiviral medication Sovaldi (sofosbuvir) a nucleotide analogue that inhibits the polymerase enzyme of hepatitis C and blocks its replication. This program means that Egypt may soon be the first country to eliminate hepatitis C.
The research for this current Pfizer drug comes from a revived compound identified in 2003 as a potential treatment for the Severe Acute Respiratory Syndrome (SARS) epidemic in China. The Pfizer compound was developed to inhibit an enzyme called a protease. The revived compound is specific to the proteases produced by coronaviruses, which are responsible for causing SARS in 2003 and COVID-19 today.
It is a tragedy that the development of this drug and others like it were abandoned until recently. Had we seen this research to completion after SARS and MERS, governments could have stockpiled the drugs years in advance of this latest outbreak and administered one-day delivery to all locations where the virus has been detected or suspected. All patients, hospital workers and any other persons suspected of contact would have been treated to stop the epidemic in its tracks. We need to learn from this mistake and invest in producing multiple antiviral drugs to prevent and treat Covid-19 the same way we have for HIV/AIDS, as well as long acting prevention drugs. A study from China has also shown success in designing 32 new protease inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro in a mouse model. This shows the potential for how many antiviral drugs could be developed.
For the strongest possible defence against Covid-19 and mutations of the virus we should look at the approach used for treating AIDS known as combination therapy. The gold standard for AIDS treatment now is called antiretroviral therapy. This is when patients take a cocktail of at least three different drugs that attack the HIV virus in different ways. The strategy is based on earlier success we had in fighting cancer. In the late 1970s, I established a laboratory at Harvard University’s Dana-Farber Cancer Institute to develop new drugs to treat cancer patients. Cancers developed resistance over time to single drugs, but combinations of drugs were effective in slowing, stopping or killing the cancers. We took that same lesson of combination chemotherapy to HIV. By the early 1990s, the first combination AIDS treatments were saving the lives of people infected with HIV. Today an infection is far from the death sentence it used to be, patients can now live almost unaffected by HIV, with a relatively minimal impact on life expectancy.
If trials of the Pfizer drug are successful, we need to apply this same approach and combine the Pfizer drug with other antivirals like Molnupiravir to outsmart the shape-shifting Covid-19 virus. Developing a drug to treat Covid-19 is actually easier than with HIV/AIDS as the drug only needs to be tolerated for a short period of time, as opposed to HIV/AIDS drugs which need to be taken for a lifetime. Antiviral drugs will form an important part of our armamentarium, alongside vaccines and public health measures as we continue our fight against the Covid-19 pandemic.