What are the role of the antivirals lopinavir/ritonavir and ivermectin in the treatment of coronavirus disease 2019 (COVID-19)?

Updated: Jun 25, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Answer

Lopinavir/ritonavir

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19. [343]

The Infectious Diseases Society of America (IDSA) guidelines recommend against the use of lopinavir/ritonavir. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition. [25]

The RECOVERY trial concluded no beneficial effect was observed in hospitalized patients with COVID-19 who were randomized to receive lopinavir/ritonavir (n = 1616) compared with those who received standard care (n = 3424). No significant difference for 28-day mortality was shown. Overall, 374 (23%) patients allocated to lopinavir/ritonavir and 767 (22%) patients allocated to usual care died within 28 days (p = 0.60). No evidence was found for beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. [344]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020.187 Interim results released mid-October 2020 found lopinavir/ritonavir (with or without interferon) appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. Death rate ratios were: lopinavir RR = 1.00 (0.79-1.25, p = 0.97; 148/1399 vs 146/1372) and lopinavir plus interferon RR=1.16 (0.96-1.39, p = 0.11; 243/2050 vs 216/2050). [135]

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO2 of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. [345] An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak. [346]

Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. [347]

A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Results showed that triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. [348]

Average wholesale price (AWP) for a course of lopinavir/ritonavir at this dose is $575. 

Ivermection

NIH COVID-19 guidelines for ivermectin provide analysis of several randomized trials and retrospective cohort studies of ivermectin use in patients with COVID-19. The guidelines concluded most of these studies had incomplete information and significant methodological limitations, which make it difficult to exclude common causes of bias.   Ivermectin has been shown to inhibit SAR-COV-2 in cell cultures; however, available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans. [349]     Chaccour and colleagues raised concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19. In addition, drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs. Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans. [350]  

A prospective study (n = 400) of adults with mild COVID-19 were randomized 1:1 to receive ivermectin 300 mcg/kg/day for 5 days or placebo. Use of ivermectin did not show a significantly shorten duration of symptoms compared with placebo (p = 0.53). [351]   

Table 4. Other therapies determined ineffective (Open Table in a new window)

Therapy Comment
Merimepodib (antiviral; BioSig Technologies) [352] Phase 2 trial in combination with remdesivir in advanced disease (NCT04410354). 
Acalabrutinib (Calquence; AstraZeneca) [353] Phase 2 trial (CALAVI US) of Bruton kinase inhibitor in hospitalized patients to ameliorate excessive inflammation (NCT04380688).
Ruxolitinib (Jakafi) [354] Data from the RUXCOVID study (n = 432) showed treatment with ruxolitinib plus standard-of-care did not prevent complications in patients with COVID-19 associated cytokine storm. 
Umifenovir (Arbidol){ref 376} [177] Antiviral drug that binds to hemagglutinin protein; it is used in China and Russia to treat influenza. In a structural and molecular dynamics study, Vankadari corroborated that the drug target for umifenovir is the spike glycoproteins of SARS-CoV-2, similar to that of H3N2. A retrospective study of non-ICU hospitalized patients (n = 81) with COVID-19 conducted in China did not show an improved prognosis or accelerated viral clearance. Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. 
Colchicine UK RECOVERY trial stopped the colchicine arm upon advice from its independent data monitoring committee for lack of efficacy in hospitalized patients with COVID-19. 

 


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