Triple combination therapy shows promise for COVID-19 patients with less severe illnesses

The trio of drugs include ribavirin, lopinavir-ritonavir and Interferon beta 1b.

May 8, 2020, 6:31 PM

As scientists scramble to find COVID-19 treatments among existing approved drugs, researchers in Hong Kong may have found a winning combination. Early data shows that a triple antiviral therapy may be safe and effective in treating patients with mild to moderate cases of COVID-19, according to a study published Friday in Lancet.

All three drugs used in the study are already approved to treat other illnesses. Interferon beta 1b is a drug commonly used to treat multiple sclerosis, lopinavir-ritonavir is an anti-retroviral medication used to treat HIV and ribavirin is commonly used to treat hepatitis C.

Researchers from six different hospitals in Hong Kong assigned over 120 patients to one of two treatment groups. They gave one group of patients suffering mild to moderate COVID-19 symptoms a cocktail of all three drugs, and gave the other group only lopinavir-ritonavir.

Doctors tested the amount of virus in samples taken from the patient's nose, saliva, back of the throat and stool on a machine that can detect the presence of viral genetic material.

When researchers compared the two groups, they found that the typical patient given the three drug-combo tested negative for the virus five days earlier than those who received just a single drug. In addition, the triple therapy treatment group had shorter hospital stays and reported that their symptoms disappeared much faster than the control group.

The study offers a promising sign that the drug cocktail helped their bodies beat back the virus faster.

PHOTO: Commuters wear masks while waiting for a bus as the outbreak of coronavirus continues in the Manhattan borough of New York City, on May 8, 2020.
Commuters wear masks while waiting for a bus as the outbreak of coronavirus continues in the Manhattan borough of New York City, on May 8, 2020.
Lucas Jackson/Reuters

Experts are cautiously optimistic about these results, but pointed out that more rigorous studies will be needed to know for sure if this drug combination works.

They believe that one of the driving factors in the success of the triple combination therapy groups was early treatment. Treatment was started within seven days of symptom onset for the majority of patients in both groups.

"The most important thing in treating any viral diseases is that you want to treat it early. If you don't treat it early, you're probably going to miss the window to treat it. And then you have to deal with its complications," said Dr. David Bernstein, vice chair of medicine for clinical trials and chief of hepatology and director of the Sandra Atlas Bass Center for Liver Diseases at Northwell Health.

Another welcome finding was the lack of significant negative side effects. The main negative side effects of the medications were nausea and diarrhea, but there was no difference between the two groups, and none of the patients in the study died.

"Patients often do not tolerate these medications terribly well," said Dr. Nathan Erdmann, an assistant professor in the division of infectious diseases at the University of Alabama at Birmingham.

Dr. Todd Ellerin, chief of infectious diseases at South Shore Health agreed: "Interferons have significant adverse side effects such as flu-like illness and have never really gained traction in and of themselves for the treatment of viral diseases."

Lopinavir-ritonavir appears to have caused most of the side effects, he said.

PHOTO: HIV drug treatments are seen on a table in Lome, Togo.
HIV drug treatments are seen on a table in Lome, Togo.
Bsip/Universal Images Group via Getty Images, FILE

However, there are some significant issues with the study. Experts say it was too small to draw any definitive conclusions.

"I will say, at this stage, I would not recommend rapid uptake of this treatment as standard therapy because of the limited sample size," said Erdmann.

Bernstein agreed, "This is a first study proving a concept, and now it has to be validated. And it has to be validated in large numbers."

An additional limitation of the study is that only patients with mild to moderate COVD-19 symptoms were examined. This triple combination therapy may not be as effective in people who are severely sick with COVID-19.

Experts also poked holes in the study's design, pointing out that it was not "blinded," meaning both participants and doctors knew which drugs were given, and their optimism about the triple combination treatment may have ultimately influenced the results.

"It's a severe limitation," said Bernstein. "We would like to see a double-blind, placebo-controlled trial."

In a double-blinded, placebo-controlled study neither the participants nor the doctors know which of the participants are given the real treatment or a placebo until the end of the study. This design better protects against researcher bias.

This brings up another concern, there was "no placebo arm," said Ellerin. "That may be the biggest issue."

Instead of testing the triple combination therapy against a placebo, the researchers tested it against lopinavir-ritonavir -- a drug that was already tested in patients with severe COVID-19 infection and didn't make a significant difference.

Nevertheless, despite its shortcomings the study may potentially fill an important gap in the slim number of COVID-19 treatments. In the U.S., doctors currently have nothing to offer patients with mild to moderate symptoms. They are generally sent home to rest and not admitted to the hospital unless they develop severe symptoms.

"This has the potential to be an outpatient treatment that can be used on patients with mild to moderate disease, but further testing is certainly required," said Bernstein. "I don't think you can go crazy over one particular small study, but let's see what happens and let's hope that there can be further investigation."

"Hopefully, future studies will provide more detail on which of the therapies are primarily responsible for the observed effect, or whether it is in fact the combination that drives the viral clearance," Erdmann said.

Ellerin added, "Whether this combination is as effective as other experimental therapies that are currently under investigation or whether there is a better combination out there that could lead to mortality benefits remains to be proven."

Angela N. Baldwin, M.D., M.P.H., is a pathology resident physician at Montefiore Health System in the Bronx and a contributor to the ABC News Medical Unit.

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