Why lopinavir and hydroxychloroquine do not work on COVID-19

Date:
July 10, 2020
Source:
University of Basel
Summary:
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.

Researchers have now discovered that the concentration of the two
drugs in the lungs of Covid-19 patients is not sufficient to fight
the virus.



FULL STORY ========================================================================== 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
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 prospectively 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 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. 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 state.

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 -- 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 provide important pharmacological and antiviral insights
to the rationale of discontinuing the lopinavir/ritonavir arm. In fact,
they add scientific reasoning why hydroxychloroquine and lopinavir are
not effective against the SARS-CoV-2.


========================================================================== Story Source: Materials provided by University_of_Basel. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Catia Marzolini, Felix Stader, Marcel Stoeckle, Fabian Franzeck,
Adrian
Egli, Stefano Bassetti, Alexa Hollinger, Michael Osthoff, Maja
Weisser, Caroline E. Gebhard, Veronika Baettig, Julia Geenen, Nina
Khanna, Sarah Tschudin-Sutter, Daniel Mueller, Hans H. Hirsch,
Manuel Battegay, Parham Sendi. Effect of Systemic Inflammatory
Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma
Concentrations. Antimicrobial Agents and Chemotherapy, 2020; DOI:
10.1128/AAC.01177-20 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200710112108.htm

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