The Danger Of Covid-19 Monotherapy: Drug Resistance

(Posted on Monday, January 24, 2022)

The current protocol for Omicron infections dictates that patients are treated with either one monoclonal antibody preparation or one antiviral drug. This is not an optimal strategy but instead, one necessitated by current drug approvals. As welcome as these newly approved treatments are, they come with the potential of long-term dangers. Past experience demonstrates that the use of one drug rather than a combination of drugs means that viruses are very likely to develop resistance over time potentially leading to a pandemic fueled by drug resistant viruses. This is particularly true for immunosuppressed patients who are likely to be chronically infected. Drug-resistant mutations arise quickly in such and may persist for weeks or even months. Such events are speculated to have been the origin of some of the most troubling variants of concern.

We need to heed lessons from prior Influenza and HIV epidemics about drug resistance. Amantadine (sold under the brand name Gocovri) was an antiviral that was used for the prevention and treatment of influenza A in 1976. However, amantadine-resistant influenza viruses were first reported during the 1980 influenza A epidemic and the frequency of resistant viruses continued to rise into the early 2000s. The drug is no longer recommended for the treatment of flu viruses in the United States due to widespread resistance.

During the early days of HIV research, the drug azidothymidine, known as AZT was prescribed to HIV patients as monotherapy with initial positive results. However that approach quickly eventually led to resistance in individual patients and the transmission of an evolved virus. It was this experience that led to the development of the gold standard for HIV treatment; combination antiretroviral therapy.

The problem with drug resistance in HIV has become so severe it is strongly recommended that before antiretroviral treatment is initiated, the entire nucleotide sequence of the HIV genome be determined. Telltale mutations that would demonstrate resistance can be detected in the whole genome sequence allowing physicians to use a targeted cocktail of two or more drugs.

Clinical availability of rapid DNA and genome sequencing should be a high priority for research and development purposes. Not only for Covid-19 but for all other viral and bacterial diseases to combat another growing problem which is antibiotic drug resistance. We now have the opportunity for very rapid total DNA sequencing that can take less than half an hour. By using the latest methods, the entire human genome can be sequenced within five hours. This provides enough time and data for a physician to make a wise choice on what antiviral drugs could be used in a combination to combat resistance.

Presently there is no combination therapy approved for the treatment of Covid-19. As the virus continues to evolve and mutate to evade and suppress our acquired and innate immune systems, I recommend that we explore the use of combination therapy to combat drug resistance. Already the Covid-19 virus has evolved to create the Omicron variant, which is resistant to all FDA approved monoclonal antibodies except sotrovimab. However, recent data from Australia raises serious issues of sotrovimab as a stand-alone treatment.

In this study, the researchers determined the sequence of virus isolated from patients treated with sotrovimab from a cohort of 100 at a treatment center in New South Wales, Australia. The treatment was a single 500mg dose targeted at patients within five days of symptom onset thought to be at risk for severe disease progression. Of the initial 100 patients, 23 tested positive for SARS-CoV-2 infection at least 10 days post-infusion, and of these, the pre-and post-infusion respiratory tract samples of eight were collected. Of these eight, seven were hospitalized, six were partially vaccinated or unvaccinated, and four were given additional antibody treatment.

Viable virus samples obtained from four of the patients contained a mutation at amino acid E340 of the spike protein, either E340K, E340A, or E340V. The virus in one patient contained an additional mutation: the P337L mutation. These mutations are predicted to yield virus resistance to sotrovimab. Analyses of mutations in this region of the Spike, the receptor-binding domain, indicate that the observed mutations decrease sotrovimab neutralization by almost 300 fold.

The Australian researchers note that prior to the advent of sotrovimab clinical trials, mutations at amino acid 340 that confer resistance were extremely rare. They comment that the incidence of such 340 mutations is rising in virus isolates from around the world. Whether that is the result of sotrovimab induced mutation or to the greatly increased number of infected persons due to Omicron is an open question.

We need to follow the strategies used for HIV and create combinations of powerful, long-acting drugs that target a broad range of functions with a high therapeutic index. There are still many unexplored targets for SARS-CoV-2 drug development. I suggest that we expand our range of targets for drug development far beyond the common protease to the many enzymes and regulatory proteins specific to SARS-CoV-2 that do not exist in humans. As soon as is practical we need to begin testing combination therapy and conducting rapid sequencing of the virus infecting each patient to determine the best course of therapy. We need to closely monitor viable virus present in treated patients for drug resistance as well.

Read the full article on Forbes.