What is the evidence available for treatment of COVID-19 with lopinavir/ritonavir or remdesivir?

Background/Introduction

Coronavirus disease 2019 (COVID-19) is a respiratory disease resulting from exposure to a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]).1 Coronaviruses are large, enveloped RNA viruses and infect different types of living beings. Specifically, alpha and betacoronaviruses can exploit humans as hosts.2 The novel coronavirus is classified as a betacoronavirus, like past virulent pathogens: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).1,2 Animal-to-human spread of SARS-CoV-2 likely originated from a seafood and live animal market in Wuhan, Hubei Province, China.1

The first case of COVID-19 was reported to the World Health Organization (WHO) China office in December 2019.3 Once cases were seen throughout China and patients reported never coming in contact with animals, it became apparent that the disease was being spread between humans.1 Since then, COVID-19 has been reported in many countries throughout the world. The total number of cases is changing daily, however, as of March 31st, 2020, there have been 140,640 confirmed cases and 2398 deaths in the United States.4 Moreover, there have been 750,890 confirmed cases and 36,405 deaths attributed to COVID-19 globally. These numbers are changing rapidly and are updated daily on the WHO website which can be accessed here.

The clinical course of COVID-19 is not well understood and ranges from asymptomatic infection to life-threatening disease. After exposure to SARS-CoV-2, a patient may experience symptoms within approximately 4 to 5 days (interquartile range, 2 to 7 days); prior experience with coronaviruses suggest a likely incubation period of 2 to 14 days.5-7 Most common signs and symptoms of COVID-19 when patients have presented to the hospital are fever, cough, myalgia or fatigue, and shortness of breath.7 Severe illness is associated with acute respiratory distress syndrome (ARDS), septic shock, and multi-organ failure. People at highest risk for severe disease due to COVID-19 include elderly people and those with comorbities affecting the heart, lungs, and immune system.8

In general, only supportive care is recommended by the Centers for Disease Control and Prevention (CDC) for patients diagnosed with COVID-19 because possible treatments lack evidence of safety and efficacy.7 Two agents of initial interest in treating COVID-19 are lopinavir/ritonavir (LPV/r) and remdesivir due to previous in vitro and in vivo efficacy data against SARS- and MERS-CoV.9-12 Therefore, there is a need to examine current guideline recommendations and the little evidence available on the use of LPV/r and remdesivir as possible treatments.

Management Recommendations

New information about COVID-19 and its management are constantly being updated on the CDC website, therefore, it is important to keep monitoring the site for any changes.1,7 Although, the CDC is the main authority giving recommendations associated with COVID-19 in the United States, WHO and Sanford Guide share similar information.13,14  CDC interim guidance recommends that if a patient is experiencing mild symptoms, hospitalization may not be required; however, the patient should be monitored closely for potential worsening of disease during the second week after disease onset.7 Currently, only supportive care without the use of corticosteroids (unless indicated for additional reasons) is recommended as treatment for hospitalized patients with confirmed COVID-19. If needed, the patient should receive advanced organ support for respiratory failure, septic shock, and multi-organ failure. Further, there is no antiviral treatment for COVID-19 that is approved by the US Food and Drug Administration (FDA). The CDC does not recommend for or against the use of antivirals to treat or prevent COVID-19, but therapeutic options for COVID-19 patients are posted on the one of the pages of the CDC website.15

The Surviving Sepsis Campaign (SSC) issued a guideline on the management of critically ill adults with COVID-19.16 Following new unfavorable randomized controlled trial (RCT) results for use of LPV/r in COVID-19 (discussed below), SSC recommends against the routine use of LPV/r in critically ill COVID-19 patients and does say that it is a weak recommendation with low quality evidence. The guideline also warns for potential drug interations with LPV/r and directs readers to the University of Liverpool’s Prescribing Resources page for COVID-19. At this time, SSC states there is not enough evidence to recommend any other antivirals for critically ill patients, including remdesivir.

Discussion of lopinavir/ritonavir (LPV/r)

Lopinavir/ritonavir, an HIV-1 protease inhibitor combined with a boosting agent, was initially approved by the FDA in September 2000 to be used in combination with other antiviral agents for the treatment of HIV-1.17,18 Currently, LPV/r is available in the US in tablet and solution formulations.18 Although, LPV/r is only indicated for HIV-1, it has been studied in previous infections with highly pathogenic coronaviruses: SARS- and MERS-CoV.9-12 In a 2003 retrospective matched cohort study of patients with radiologically confirmed pneumonia, there were significantly lower rates of death and intubation between the cohort which used LPV/r as an initial treatment for SARS-CoV compared with the matched cohort receiving standard treatment (p<0.05).9 Animal data has demonstrated efficacy of LPV/r against MERS-CoV, and, a 2019 retrospective matched cohort study investigating the use of LPV/r plus ribavirin as post-exposure prophylaxis (PEP) for MERS in healthcare workers found that they were no cases of MERS-CoV infection in the group that received PEP (N=22) compared to 6 cases in the non-PEP group (N=21).10-12 These studies suggest efficacy of LPV/r in SARS- and MERS-CoV, however, more robust studies are needed to provide higher quality evidence.

Literature review of lopinavir/ritonavir

Evidence of LPV/r use as a treatment for COVID-19 patients is quite limited. One RCT, conducted in China, has been published which evaluated the safety and efficacy of LPV/r plus standard care versus standard care only in patients with severe COVID-19 (Table 1).19 The median patient age was 58 years old (interquartile range, 49 to 68 years), a majority of patients were male (60.3%), and randomization occurred a median of 13 days after symptom onset (interquartile range, 11 to 16 days). The investigators found no difference in time to clinical improvement in patients who received LPV/r versus those who did not for treatment of severe disease. Although investigators did not find a statistically significant difference in 28-day mortality between groups, the rate was 5.8% higher in the standard care group. Thirteen patients who received LPV/r stopped treatment early due to adverse events. However, this study had notable limitations: it was not blinded, the sample size was relatively small, patients recruited had severe disease, and patients in the LPV/r group had higher viral loads. In addition, the CDC has stated that the trial was underpowered.15

Completed retrospective cohort studies of LPV/r for COVID-19 treatment unfortunately did not result in high quality evidence so are excluded from Table 1. One retrospective cohort study evaluating clinical course and risk factors for mortality only had 41 of 191 patients (21%) that received LPV/r and found that LPV/r did not decrease the duration of viral shedding in the patients who received antiviral therapy.20 The other retrospective cohort study was not included because the purpose was to evaluate the efficacy of arbidol, a medication not available in the US, in combination with LPV/r compared to LPV/r alone in patients with COVID-19.21 More patients treated with the combination vs LPV/r alone had nasopharyngeal specimens that were negative for SARS-CoV-2 at days 7 and 14 after diagnosis. To conclude, there have been a handful of recent case reports, case series, and retrospective cohort studies conducted in Asia, from which conclusions about LPV/r use in COVID-19 could not be drawn.20-25

Table 1. Summary of evidence describing use of lopinavir/ritonavir in COVID-19.19
Study design and durationSubjects

 		InterventionsResultsConclusions
Cao 202023

Randomized, controlled, open-label, single-center trial

14 days		N=199 hospitalized non-pregnant adults with confirmed SARS-CoV-2 and radiologically confirmed pneumonia

SaO2 ≤ 94% on room air or a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) ≤ 300 mg Hg.		LPV/r (400/100 mg) twice daily + standard care (N=99)

Standard care (N=100) (supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and ECMO)		Primary:

·     Time to clinical improvement* was not different in the intention to treat population between the LPV/r group and standard care alone group (median, 16 days vs. 16 days; HR, 1.31; 95% CI, 0.95 to 1.85; p=0.09)

Secondary:

·     Mortality at 28 days was not different between LPV/r and standard care groups (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7)

·     Percentage of patients with detectable viral RNA was similar throughout the study time frame

Safety:

·     LPV/r-use was associated with more gastrointestinal adverse events

·     Standard care was associated with more serious adverse events

·     LPV/r was discontinued in 13 (13.8%) of patients due to adverse events		·    The addition of LPV/r to standard care was not associated with a decreased time to clinical improvement

·    More trials are needed to establish LPV/r treatment benefit in patients with severe COVID-19
*Clinical improvement was defined as the time from randomization to an improvement of two points on a seven-category ordinal scale or live discharge from the hospital, whichever came first.
Abbreviations: CI=confidence interval; ECMO= extracorporeal membrane oxygenation; HR=hazard ratio; LPV/r=lopinavir/ritonavir; SaO2=oxygen saturation.

Discussion of remdesivir

Remdesivir (GS-5734) is an investigational nucleotide analog, broad-spectrum antiviral, that is not approved by any regulatory agency in the world.12 It was available for compassionate use for treatment of COVID-19 upon request from its manufacturer, Gilead.26,27 As of March 22, 2020, because of overwhelming demand, Gilead has temporarily suspended its compassionate use program for remdesivir, with possible exceptions for pregnant women or children younger than 18 years old with confirmed, severe, COVID-19. Remedsivir is administered intravenously.28 Remdesivir was originally studied for use in Ebola infections and has shown efficacy against viruses SARS- and MERS-CoV in-vitro and in animal models.12 Human safety data for remdesivir has been captured in a randomized clinical trial investigating Ebola treatment, therefore, the initiation of current efficacy trials of remdesivir in the treatment of coronaviruses in humans is justified.12,29

Literature review of remdesivir

Safety and efficacy data for remdesivir are extremely lacking. There have been no RCTs published, however there are ongoing trials. Because of the lack of higher level data, available evidence for remdesivir as a case report is summarized. The patient was a 35-year-old non-smoking male (recently returned to the US from Wuhan, China) who presented with cough and fever of 4 days with a positive COVID-19 test.30 The patient had a negative chest X-ray for pneumonia, but lung auscultation revealed rhonchi upon arrivial to an urgent care clinic. On day 5 of hospitalization, the chest X-ray was positive for pneumonia and oxygen saturation decreased to 90% despite supportive care. Supportive therapy consisted of antipyretics acetaminophen and ibuprofen, guaifenesin for chest congestion, and normal saline. On day 6 of hospitalization, the patient was started on supplemental oxygen, vancomycin, and cefepime given his worsening condition. Remdesivir was started on day 7; vancomycin was discontinued on day 7, while cefepime and supplemental oxygen were discontinued on day 8. The patient’s oxygen saturation improved to 94 to 96% with ambient air on hospital day 8, chest X-ray abnormalities resolved, and appetite improved. No adverse events were observed with remdesivir. Although remdesivir was well-tolerated, stronger evidence in the form of RCTs are needed to assess safety and efficacy of remdesivir in COVID-19 patients.

Ongoing clinical trials

The WHO will be conducting a large, global, study called the SOLIDARITY trial.31,32 The promising agents to be included are remdesivir, chloroquine and hydroxychloroquine, LPV/r, and LPV/r plus interferon-beta. The WHO believes a large RCT conducted in different populations will generate evidence for the treatment recommendations needed in COVID-19. In addition, there are other ongoing clinical trials studying the use of LPV/r and remdesivir, against SARS-CoV-2. These trials are listed in Table 2.

Table 2. Recruiting clinical trials in COVID-19.33
LPV/rNCT04307693; NCT04276688; NCT04255017; NCT04251871
RemdesivirNCT04292899; NCT04292730; NCT04280705; NCT04257656; NCT04252664
Abbreviation: LPV/r: lopinavir/ritonavir.

Conclusion

Overall, there still needs to be more research completed before recommending use or avoidance of LPV/r and remdesivir as treatment options for COVID-19. Although a small RCT in China investigated LPV/r in COVID-19 patients and concluded with unfavorable results, the trial had limitations, which may be resolved in larger, blinded, trials. Remdesivir was associated with encouraging resolution of illness in a case report, which prompts the need for RCTs. However, at this moment the suspension of its compassionate use program is unfortunate to patients who may have potentially benefited from its use. As higher quality evidence becomes available, it will become clearer how to better fight SARS-CoV-2 and recommendations for use of antivirals will strengthen. For a list of updated resources, please check the FAQ on general information about COVID-19.

References

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Prepared by:
Victoria Kulbokas, PharmD Candidate Class of 2020
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2020

The information presented is current as March 24, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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