Triple therapy with interferon-beta + Kaletra + ribavirin

Individual drugs that are approved to treat a well-known virus and which are then repurposed to treat a new and sometimes unrelated virus will likely have only modest antiviral effects, particularly against SARS-CoV-2. However, when repurposed drugs are combined in an experimental regimen, they are likely to be more effective than just one drug alone (monotherapy). This was the concept underpinning the rationale for combining three drugs in this study (we also provide some information about how those drugs might work against SARS-CoV-2):

• interferon-beta – Interferons can have a number of roles in viral infections: they can reduce the ability of infected cells to produce copies of the virus; they can cause virus-infected cells to self-destruct; and they can cause uninfected cells to invoke an antiviral defence mechanism that protects them from infection. Preliminary information suggests that in some people SARS-CoV-2 is able to suppress the ability of cells in the lungs to produce interferon in the early stages of infection. Experiments with mice with viral pneumonia suggest that one form of interferon, interferon-beta, can reduce the formation of scar tissue in the lungs. Other preliminary information from laboratory studies suggests that interferon-beta has antiviral activity against cells infected with SARS-CoV-2.
• Kaletra (containing lopinavir-ritonavir) – Lopinavir may have some antiviral activity against SARS-CoV-2.
• ribavirin – This is an old antiviral drug with activity against a broad range of viruses in lab experiments with infected cells. It causes mutations in the production of copies of the virus. Many of these copies are defective.

Doctors in Hong Kong enrolled 127 hospitalized participants with COVID-19 and randomly assigned them to receive, in a 2:1 ratio, either triple therapy with the previously mentioned drugs or Kaletra monotherapy. All drugs were given for 14 days. Study drugs were dosed as follows:

• interferon-beta – Participants received a total of three doses of 8 million units per dose given on alternate days. This was injected just under the skin (subcutaneous injection).
• Kaletra – The standard dose of two tablets (400 mg lopinavir with 100 mg ritonavir) every 12 hours.
• ribavirin – 400 mg every 12 hours (this is a moderate dose of ribavirin).

At the start of the study, participants were about 52 years old, 54% men and 46% women. About 40% of participants had underlying conditions, including diabetes, higher-than-normal blood pressure and elevated levels of cholesterol.

Participants had mild-to-moderate disease—generally fever and cough for about five days—caused by SARS-CoV-2 infection.   

Results

Researchers found that there were significant differences in outcomes when comparing participants who received the two study regimens:

Reduction in the number of days producing virus

• triple therapy – seven days
• Kaletra alone – 12 days

Time to resolution of symptoms

• triple therapy – four days
• Kaletra alone – eight days

Length of time hospitalized

• triple therapy – nine days
• Kaletra alone – 15 days

These differences in the regimens were statistically significant.

About half of the participants reported side effects, including the following:

• diarrhea – 41%
• fever – 38%
• nausea – 34%
• elevated liver enzymes – 14%

There were no significant differences in the distribution or duration of these side effects by study regimen. The study team stated: “These side effects mostly resolved within three days after drug initiation.”

No serious side effects occurred in people who received triple therapy. One person who received Kaletra monotherapy developed liver injury graded as serious by doctors and had to prematurely stop taking this regimen.

Bear in mind

The results from this prospective phase II randomized study are promising for triple combination therapy. The study design is an improvement over the many retrospective studies that bedevil many COVID-19 clinical trials.

According to the study team, a larger phase III study with interferon-beta as the “backbone” of a combination regimen vs. placebo “should be considered.” Such a study should be able to yield a definitive answer about interferon-beta-based therapy for COVID-19.

—Sean R. Hosein

REFERENCES:

1. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395(10238):1695-1704.
2. Shalhoub S. Interferon beta-1b for COVID-19. Lancet. 2020;395(10238):1670-1671.
3. Clementi N, Farrarese R, Criscuolo E, et al. Interferon-beta inhibits SARS-CoV-2 in vitro when administered after virus infection. Journal of Infectious Diseases. 2020; in press.