Drug combinations may be what helps us bridge the gap to an effective vaccine.
Vaccine development is slow. With questions surrounding the durability of immunity and availability of the vaccine, doctors on the front lines of health care are relying on available drug therapies to treat Covid-19. Most Covid-19 patients are often given a cocktail of available therapies, given that no one drug has been shown to be broadly effective against the virus. Several trials are ongoing looking at the effectiveness of drug combinations in the treatment of Covid-19. This may signal that drug combinations may be what carries us through the gap between now and an effective vaccine.
Viruses are difficult to treat. If you compare them to bacteria, most antibiotics function by blocking some biologic or metabolic process, whether it be DNA replication, protein synthesis or cell wall development. Those drugs effectively halt the growth and replication of the bacteria, two characteristics of living organisms. Viruses, on the other hand, do not have any of these mechanisms because viruses are not technically alive. This means that they have fewer potential drug targets. Still, there are dozens of antiviral medications on the market that work to inhibit these pathogens, many of which are used in combination with each other.
Drug Combinations Are Common in Viral Diseases
It is not uncommon to see viruses, particularly those for which there is not an effective vaccine, being treated with more than one drug. HIV is one example where patients are often on a cocktail of drugs, each targeted at one of the ways that HIV attacks the body. Again, this shows that there is neither a single effective drug therapy for HIV, nor an effective vaccine against HIV. It also highlights the complexity of HIV. The many steps involved in an HIV infection offer many targets for drug therapies.
Outside of social distancing, mask wearing and other public health measures, effective drug combinations may be the only weapon we have in the fight against this virus.
Covid-19, though not quite as complex as a virus like HIV, does have several demonstrated potential drug targets in its life cycle. This opens up the possibility that drug combinations may be a good option for treatment.
Drug Targets For SARS-CoV-2
The life cycle of SARS-CoV-2, the causative virus in Covid-19, can be broken down into a few phases. The first phase is binding and entry into the cell. This mechanism is well understood, involving the binding of the viral spike protein to the human ACE2 receptor, with the help of the human protease TMPRSS2. This mechanism allows the viral body to fuse with the human cell membrane and ultimately enter the cell.
There are a number of ways to block viral entry. Some researchers hope that antibodies against the SARS-CoV-2 spike antigen will be effective at blocking this initial binding event. Antibodies could be potentially derived from convalescent plasma, or administered directly into the respiratory system. A lab at UCSF has developed nanobodies — a similar, but much smaller cousin to the antibody — that can be nebulized into the lungs that appear to offer protection against Covid-19 infection in the lungs.
Another compound being investigated in hopes of blocking the entry phase of the virus is camostat mesylate, an inhibitor of the protease TMPRSS2 that is required for SARS-CoV-2 entry into the cell. TMPRSS2 cleaves the viral spike protein, readying it for binding to ACE2 and facilitating entry into the host system.
The second phase of infection involves the processing of viral RNA once inside the cytoplasm of the host cell. At this point, the SARS-CoV-2 viral body opens and releases viral RNA. At this point, the viral RNA molecules are translated — meaning RNA is turned into a protein — and the resulting products, called pp1a and pp1b, facilitate the mass replication of the viral genome.
A number of drugs exist that target these proteins directly. Lopinavir and ritonavir are both antiviral medications already on the market that are used in the treatment of HIV. The combination of the two drugs was investigated in Covid-19, but they were ultimately dropped because they showed little effect against the virus.
Remdesivir is another drug of interest in Covid-19. This antiviral is one of the few that has proceeded in clinical trials, and appears to be effective to some degree against the virus. Many people currently hospitalized with Covid-19 are put on remdesivir.
Remdesivir targets the replication of pp1a and pp1b, effectively halting the replication of the viral genome. Blocking this phase stops the viral life cycle in its tracks.
The final stage of the SARS-CoV-2 life cycle is assembly and release from the cell. At this point, the virus gathers its genome and forms within a new envelope with envelope proteins already studded in it. These new bodies — called virions — are released out of the host cell and go on to infect other cells in the body. This stage can potentially be blocked by drugs that inhibit the formation of the outer viral envelope. One compound under investigation for this function is an antiviral known as LJ001. This compound introduces oxygen into the newly formed envelope. This damage affects the functionality of the outer viral envelope.
Drug Combinations in Covid-19
We have seen a number of drug combinations come and go over the past many months. Perhaps the most memorable was the combination of the antimalarial hydroxychloroquine with the antibiotic azithromycin. This combination gained immediate attention as one of the first potential therapies in early 2020, but ultimately failed to produce any measurable effect against SARS-CoV-2.
Researchers have also developed drug combinations that not only target the viral life cycle, but also address the damaging symtpoms that result from SARS-CoV-2 infection. One combination involves remdesivir and the widely available anti-inflammatory dexamethasone. Dexamethasone is widely used steroid in a number of inflammatory conditions, but is capable of calming the vigorous immune reaction that occurs in Covid-19 — known as a cytokine storm. Remdesivir/Dexamethasone is currently one of the few approved treatments for Covid-19.
A new combination therapy is under investigation that couples remdesivir with the immune molecule beta-interferon (IFN-ß). Interferons are cytokines released by immune cells in response to infection. Certain interferons — so named for their ability to interfere with viral replication — not only show antiviral capacity, but are also capable of taming the immune response.
Remdesivir/INF-ß — now known as ACCT — is currently entering phase 3 trials this month. Remdesivir has shown some efficacy against Covid-19 and is being used under emergency authorization. IFN-ß is another approved compound with use in several diseases, but has not yet been tested against placebo for Covid-19. Should these results show promise, this drug combination could quickly go into use.
Drug combinations have a long history in the treatment of infectious diseases, including viral infections. Targeting more than one mechanism can create a potentially synergistic effect, and in some cases can dramatically slow the disease. Hospitals and critical care units are hopeful that these combinations will show effectiveness against Covid-19 because they offer quick and relatively low-cost treatment options to slow Covid-19, and lessen the chance of mortality.
Due to the challenges involved in vaccine development, many lingering questions cast doubt on whether a vaccine will be effective and produced in a timely manner. Effective drug combinations continue to be what allow hospitals to treat serious cases of Covid-19. Outside of social distancing, mask wearing and other public health measures, effective drug combinations may be the only weapon we have in the fight against this virus.