Why lopinavir and hydroxychloroquine do not work on Covid-19
University of Basel
Lopinavir is a drug
against HIV, hydroxychloroquine is used to treat malaria and rheumatism. Until
recently, both drugs were regarded as potential agents in the fight against the
coronavirus SARS-CoV-2.
A research group from the University of Basel and the University Hospital Basel has now discovered that the concentration of the two drugs in the lungs of Covid-19 patients is not sufficient to fight the virus.
Lopinavir is a drug
against HIV, hydroxychloroquine is used to treat malaria and rheumatism. Until
recently, both drugs were regarded as potential agents in the fight against the
coronavirus SARS-CoV-2. A research group from the University of Basel and the University Hospital Basel has now discovered that the concentration of the two drugs in the lungs of Covid-19 patients is not sufficient to fight the virus.
In February 2020, a
Covid-19 patient cohort was established at the University and the University
Hospital in Basel to prospectively monitor a range of diagnostic means and
potential treatments for Covid-19, including the off-label use of
hydroxychloroquine and lopinavir/ritonavir.
A research group
monitored lopinavir plasma levels in Covid-19 patients. “Considering
that substantial inflammation was observed in these patients, and previous
studies have shown the inhibition of drug metabolism by systemic inflammation,
we had the rationale to investigate the effect of inflammation on lopinavir and
hydroxychloroquine plasma levels,” states Professor Catia Marzolini, first
author of the study and professor for experimental medicine at the University
of Basel.
The authors included
92 patients in their study. Professor Parham Sendi, who is the co-leader of
this study summarizes the main findings of the study as follows: First,
lopinavir plasma levels were more than two to threefold higher than typically
observed in HIV patients. Hydroxychloroquine levels were with normal range.
Second, there was a significant correlation between the inflammation marker levels in the blood and lopinavir plasma levels. And third, when the inflammation was blocked with the Interleukin-6 inhibitor Tocilizumab, lopinavir plasma levels were significantly lower than the ones in patients without Tozulizumab treatment.
Second, there was a significant correlation between the inflammation marker levels in the blood and lopinavir plasma levels. And third, when the inflammation was blocked with the Interleukin-6 inhibitor Tocilizumab, lopinavir plasma levels were significantly lower than the ones in patients without Tozulizumab treatment.
These results clearly indicate that drug metabolism enzymes (cytochrome P450 3A) are inhibited by systemic inflammation. “Caution is advised when prescribing CYP3A4 substrates such as Lopinavir/ritonavir or any other drug with a narrow therapeutic index to Covid-19 patients because of the risk of elevated drug levels and related toxicities,” the authors note.
Importantly, from the
lopinavir and hydroxychloroquine concentrations in the plasma, the study group
calculated the corresponding concentration in the lung compartment – the
anatomic site of SARS-CoV-2 infection. The results strongly suggest that it is
unlikely that both drugs reach sufficient concentrations to inhibit the virus
replication in the lung.
WHO accepted the
recommendation from the Solidarity Trial’s International Steering Committee to
discontinue the trial’s hydroxychloroquine and lopinavir/ritonavir arms on 4
July 2020.
Professor Manuel Battegay – the co-leader of this study and head of the Division of Infectious Diseases and Hospital Epidemiology at the University Hospital in Basel - mentioned that the results of this study provide important pharmacological and antiviral insights to the rationale of discontinuing the lopinavir/ritonavir arm.
In fact, they explain why hydroxychloroquine and lopinavir are not effective against the SARS-CoV-2.
Professor Manuel Battegay – the co-leader of this study and head of the Division of Infectious Diseases and Hospital Epidemiology at the University Hospital in Basel - mentioned that the results of this study provide important pharmacological and antiviral insights to the rationale of discontinuing the lopinavir/ritonavir arm.
In fact, they explain why hydroxychloroquine and lopinavir are not effective against the SARS-CoV-2.
Original source
Catia Marzolini et al.
Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
Antimicrobial Agents and Chemotherapy, published online July 8, 2020; doi: 10.1128/AAC.01177-20
Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
Antimicrobial Agents and Chemotherapy, published online July 8, 2020; doi: 10.1128/AAC.01177-20
Further information
Prof. Dr. Catia
Marzolini, University Hospital Basel, Infectology & Hospital Hygiene, phone
+41 61 265 21 14, email: catia.marzolini@usb.ch
Prof. Dr. Parham
Sendi, University Hospital Basel, Infectology & Hospital Hygiene, phone +41
61 265 51 26, email: parham.sendi@usb.ch