A review into the Therapeutic Rationale for Use of Lopinavir/Ritonavir in COVID-19 Patients

Abstract

With the current outbreak of coronavirus disease (COVID 19) and no specific therapy for its management, varied drugs and drug combinations have been tried. This has led to repurposing of different drugs which have been in use for varied diseases e.g. Lopinavir/ritonavir which is used in Human Immunodeficiency Virus (HIV) management among other therapies. In this review we are keen to unravel some of the key features that make Lopinavir/ritonavir feasible as a treatment option for COVID-19. We do this through extensive review of literary materials especially clinical trial reports and case reports on use in COVID-19 patients.

There is still limited evidence with inconclusive evidence of benefit in use of Lopinavir/ritonavir in COVID-19 patients which calls for further studies in patients with severe COVID-19 before any substantive recommendation for use can be made.

Key words: Lopinavir/ritonavir, Clinical Trial, Efficacy, Coronavirus.

Background

Lopinavir is a novel protease inhibitor which was developed from ritonavir[1]. It is co-administered with low dose ritonavir as it improves the pharmacokinetic effects by enzyme inhibition of the cytochrome P450 3A4.Currently Lopinavir/ritonavir is used a co-formulated tablet that functions as an antiretroviral agent for the management of HIV type 1 infections.

Why was Lopinavir/Ritonavir considered as a possible treatment option for COVID19? Previous studies and clinical trials have shown a significant improvement in patients suffering from Severe Acute Respiratory Syndrome (SARS) which is in the family of coronaviruses. There was evidence of both in vitro and in vivo susceptibility of the virus. In an open label trial, 41 patients treated with a combination of Lopinavir/ritonavir and ribavirin showed a better clinical outcome i.e. lowered mortality and acute respiratory distress syndrome as compared to 111 patients on ribavirin alone which served as a historical control. The study pointed out other risks for adverse outcomes as old age and hepatitis B carrier status for which old age is a risk in SARS-CoV-2 as well.[2]

Mode of action Coronavirus disease (COVID-19) is caused by SARS-CoV-2 virus which is an RNA virus. During the viral lifecycle the virus employs the use of protease enzymes which cleave polyproteins to proteins necessary for viral replication. Lopinavir/ritonavir is protease enzyme inhibitor thus would potentially halt the viral replication process. The protease enzyme in question SARS-CoV-2 virus is 3-chymotrypsin-like cysteine protease (3CLpro) enzyme which appears to be conserved in the virus[3]. Though Lopinavir-ritonavir show activity in vitro against SARS-CoV-2 in vivo it is believed to have low selectivity thus higher concentrations may be required to exert therapeutic effects.[4]

Side effects, drug interactions and contraindications

It is common for a patient to experience gastrointestinal disturbances such as diarrhea among others. Asthenia, headaches and skin rash are also other side effects. Due to its mode of action, cytochrome enzymes 3A4 and isoenzyme 2D6 are inhibited; thus drugs which depend on these enzymes for clearance and for which high plasma concentrations are related with life threatening events are contraindicated. Such drugs include terfenadine, flecainide, astemizole and ergot derivatives such as cisapride. [1]

Evidence

The review involved review of multiple literature articles to ascertain the effectiveness of Lopinavir/ritonavir. One clinical trial was selected and a case study of a male patient was chosen.

Clinical Trial Findings

An open label clinical trial of Lopinavir-ritonavir in adults hospitalized at Wuhan, China with severe COVID 19 disease was undertaken[5]. These patients had oxygen saturation (SaO2) of less than 94% and were breathing ambient air. Patients were randomly assignedvto either receive Lopinavir/ritonavir (400mg and 100mg respectively) twice a day for 14days or receive the standard treatment at the hospital. The results showed that of the total 199 patients, 99 were assigned to Lopinavir/ritonavir and 100 to the standard care. There was lesser mortality rate in Lopinavir group at the 28th day (19.2% vs. 25.0% for Lopinavir/ritonavir vs. standard care treatment). Detectable viral RNA levels in patients were similar in both groups. It should be noted that gastrointestinal effects were common in the Lopinavir /ritonavir group but more severe adverse effects were noted in the standard care group. Patients in the Lopinavir/ritonavir group had a shorter stay at the ICU (6 days vs. 11 days) and shorter discharge time by one day. The study concluded that the efficacy of Lopinavir/ritonavir in comparison to standard treatment wasn’t substantial and to confirm or exclude possibility of treatment benefit further trials with severely ill patients would be needed.

Case Study Findings

A case study in South Korea focused on the index COVID-19 patient[6]. The patient presented initially with mild respiratory symptoms and intermittent fever which later on progressed to pneumonia by the sixth (6th) day of admission. On administration of Lopinavir/ritonavir on the 8th Day (Day 10 illness), a significant decline in viral load was noted on the second day and the titers continually declined to undetectable levels. The declines were attributed to either natural healing processes or to the drug or both. However, due to the brief stint before the decline in viral levels, it’s important to further study the effect of Lopinavir/ritonavir in these patients. Additionally, a major concern would be on the viral replication rate which would make it feasible that the viral replication was tapered within a day from drug administration. The study concluded that the decreased viral load was as a result of natural healing processes and the direct effect of Lopinavir/ritonavir couldn’t accurately be confirmed.

Conclusion The clinical efficacy and superiority of Lopinavir/ritonavir to standard care of COVID-19 patients is inconclusive and there is need for further study to unravel the probable preferential advantage. Current literature to this and evidence from trials especially those on compassionate use are still limited to give enable substantive recommendation for use in treatment of COVID-19. Additionally, the studies should look into the appropriate dosage in case efficacy is shown on use to ensure optimal treatment outcomes on use.

[1] Lopinavir/ritonavir: A review of its use in HIV infection: https://link.springer.com/article/10.2165/00003495-200363080-00004 [2] Role of Lopinavir /ritonavir in the treatment of SARS: initial virological and clinical finding: https://thorax.bmj.com/content/59/3/252.short [3] Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants: https://www.sciencedirect.com/science/article/pii/S2095177920301271 [4] Coronaviruses — drug discovery and therapeutic options: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097181/ [5] A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19: https://www.nejm.org/doi/full/10.1056/NEJMoa2001282 [6] Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR: https://www.jkms.org/DOIx.php?id=10.3346/jkms.2020.35.e79 Authors: Ms. Melissa Buttuk and Dr. Odhiambo David