A commentary on the Politicsweb site says that The Lancet has published the results of a clinical trial in Hong Kong comparing two drug regimens: interferon beta-1b, ribavirin and the anti-HIV drug lopinavir-ritonavir versus lopinavir-ritonavir alone. The study compared the time it took for the patients on each regimen, all with mild to moderate COVID-19, to test negative, in other words, be officially recovered. It took on average seven days for patients on the more intensive regimen versus 12 days for the lopinavir-ritonavir alone patients (from when they started treatment). None of the 127 trial participants died.
The commentary says as one South African pharmacologist has pointed out: this trial had no placebo arm nor a standard-of-care arm. Also, the endpoint was virological (PCR test result) rather than clinical (how well the patients were doing).
On the same day the outcome of a trial of lopinavir/ritonavir was published in the NEJM, and found no benefit (or harm). Here the endpoint was clinical, rather than virological improvement.
The commentary says taken together these two studies do suggest a very modest benefit to the three drug regimen. Whether there’s sufficient benefit for this regimen (or remdesivir) to become part of standard practice remains to be seen.
NEJM abstract
Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.
Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (SaO2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.
Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.
Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit.
The Lancet abstract
Background: Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin for treating patients with COVID-19.
Methods: This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.
Findings: Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination 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). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.
Interpretation: Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.
[link url="https://www.politicsweb.co.za/news-and-analysis/covid19-report-3-promising-new-tests-but-hydroxych?utm_source=Politicsweb+Daily+Headlines&utm_campaign=2d6644eabe-EMAIL_CAMPAIGN_2020_05_12_10_05&utm_medium=email&utm_term=0_a86f25db99-2d6644eabe-140250508"]Commentary on Politicsweb site[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa2001282"]NEJM abstract[/link]
[link url="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2820%2931042-4/fulltext"]The Lancet abstract[/link]