Shorter viral shedding, symptom duration reported in patients treated early with mild to moderate disease

A triple antiviral cocktail of interferon beta-1b, lopinavir-ritonavir, and ribavirin significantly shortened the duration of viral shedding compared to lopinavir-ritonavir alone in patients with mild to moderate Covid-19 in early findings from a clinical trial conducted in Hong Kong.

The median time from treatment to negative viral shedding was 7 days in patients treated with the triple-combination therapy, compared to 12 days among patients treated with lopinavir-ritonavir alone.

Treatment with the triple therapy appeared to significantly shorten the duration of symptoms (average, 4 days versus 8 days) and hospitalization time (average, 9 days versus 14.5 days) among patients with mild to moderate symptoms who began treatment within 7 days of symptom onset.

The outcome improvements were not seen in patients who began treatment more than 7 days after symptom onset.

The phase II findings from the first randomized, controlled study of a triple antiviral therapy for the treatment of Covid-19 was published online May 8 in The Lancet. The study included 127 adult patients with mild to moderate Covid-19 symptoms treated at six public hospitals in Hong Kong.

Researchers stressed that larger, phase III studies are needed to determine if the triple antiviral therapy improves outcomes in critically ill patients. Eighty-six of the study participants received the triple-combination therapy.

“Our trial demonstrates that early treatment of mild to moderate Covid-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms and reduce the risk for health care workers by reducing the duration and quantity of viral shedding,” physician and principal investigator Kwok-Yung Yuen, of the University of Hong Kong, noted in a written press statement.

The combination of the combination HIV treatment lopinavir-ritonavir and the oral hepatitis C drug ribavirin was shown to improve outcomes in patients during the 2003 severe acute respiratory syndrome (SARS) outbreak, and interferon beta-1b was shown to improve lung function and reduce viral load in animal studies of Middle East respiratory syndrome (MERS) coronavirus.

“(Our) findings suggest that interferon beta-1b may be a key component of the combination treatment and is worth further investigation for the treatment of Covid-19,” said study co-author Jenny Lo, MD, of Ruttonjee Hospital, Hong Kong, in the press statement.

In commentary published with the study, Sarah Shalhoub, MD, of Western University, Ontario, Canada, wrote that despite the relatively small number of patients treated with the triple therapy, “this study provides much needed data on a potential therapeutic regimen for SARS-CoV-2.”

The combination of lopinavir-ritonavir, used as the control in the study by Yuen and colleagues, showed no benefit in patients with Covid-19 in an early study from Wuhan, China published March 18 in New England Journal of Medicine.

But Shalhoub wrote that this negative finding may have been due, in part, to the delayed time to treatment (median 14 days from symptom onset) in the patients included in the study.

Given this potential confounder, Shalhoub wrote that the “use of placebo as a control in the absence of proven effective therapy is therefore ideal.”

“Additionally, earlier enrollment to standardize the number of interferon beta-1b doses is important but might be impractical, particularly because patients might not present to hospitals earlier than 7 days, when symptoms typically worsen,” she added.

Patients in the open-label, randomized trial were assigned (2:1) to 14 days of treatment with lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million IU of interferon beta-1b on alternate days (triple-therapy group) or 14 days of treatment with oral lopinavir 400 mg and ritonavir 100 every 12 hours (control group).

The primary endpoint was time to negative RT-PCR result for SARS-CoV-2 on nasopharyngeal swab sample, and a secondary endpoint was time to symptom resolution, defined by a national early warning score 2 (NEWS2) of 0 maintained for 24 hours.

The study participants were recruited and began treatment between Feb. 10 and March 20, with 86 receiving the triple combination therapy and 41 assigned to the control group. The median patient age was 52 years (IQR, 32-62) and 54% were male. The median time to hospital admission from symptom onset was 5 days (IQR, 3-7).

Among the main findings:

  • The triple therapy group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [8–15]; hazard ratio 4.37; 95% CI 1.86–10.24, P=0.0010).
  • Among 76 patients who started treatment less than 7 days from symptoms onset, better clinical and virologic outcomes were seen in the triple-therapy group (n=52 patients) = median time to NEWS of 0 was 4 versus 8 days (P<0.001); median time to SOFA score of 0 was 3 versus 7 days, P=0.0010).
  • Adverse events included nausea and diarrhea with no significant difference reported between the two groups. One patient in the control group discontinued treatment due to biochemical hepatitis.

“Despite the concern of major side-effects arising from a combination of three drugs, no significant difference in incidence of adverse event between treatment groups were reported in our cohort of 127 patients,” the researchers wrote.

Study limitations cited by the researchers focused on the study design, which was “open-label, without a placebo group, and confounded by a subgroup omitting interferon beta-1b within the combination group, depending on time from treatment onset.”

“A subsequent phase 3 trial with interferon beta-1b as a backbone treatment with a placebo control group should be considered, because subgroup comparison suggested that interferon beta-1b appears to be a key component of our combination treatment. Our absence of critically ill patients did not allow the generalization of our findings to severe cases,” they added.

  1. A triple antiviral cocktail of interferon beta-1b, lopinavir-ritonavir, and ribavirin significantly shortened the duration of viral shedding compared to lopinavir-ritonavir alone in patients with mild to moderate Covid-19 in early findings from the first randomized trial of the triple combination treatment.

  2. Treatment with the triple therapy appeared to significantly shorten the duration of symptoms (average 4 days versus 8 days) and hospitalization time (average, 9 days versus 14.5 days) among patients with mild to moderate symptoms who began treatment within 7 days of symptom onset.

Salynn Boyles, Contributing Writer, BreakingMED™

This research was funded by the Department of Health of Hong Kong; the Research Grants Council, Hong Kong; the Health and Medical Research Fund, Hong Kong; and others.

The researchers declared no relevant relationships with industry related to this study.

Cat ID: 125

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