Hydroxychloroquine does not counter SARS-CoV-2 in hamsters, high dose of favipiravir does: study

Date:
October 9, 2020
Source:
KU Leuven
Summary:
Virologists have shown that a treatment with the anti-malaria drug
hydroxychloroquine does not limit SARS-CoV-2 coronavirus replication
in hamsters. A high dose of the anti-flu drug favipiravir, by
contrast, has an antiviral effect in the hamsters.



FULL STORY ========================================================================== Virologists from the KU Leuven Rega Institute in Belgium have shown
that a treatment with the anti-malaria drug hydroxychloroquine does not
limit SARS- CoV-2 coronavirus replication in hamsters. A high dose of
the anti-flu drug favipiravir, by contrast, has an antiviral effect in
the hamsters. The team published their findings in the Proceedings of
the National Academy of Sciences (PNAS).


========================================================================== Virologists at the KU Leuven Rega Institute have been working on two lines
of SARS-CoV-2 research: searching for a vaccine to prevent infection,
and testing existing drugs to see which one can reduce the amount of
virus in infected people.

To test the efficacy of the vaccine and antivirals preclinically, the researchers use hamsters. The rodents are particularly suitable for
SARS-CoV- 2 research because the virus replicates itself strongly in
hamsters after infection. Moreover, hamsters develop a lung pathology
similar to mild COVID-19 in humans. This is not the case with mice,
for example.

For this study, the team of Suzanne Kaptein (PhD), Joana Rocha-Pereira
(PhD), Professor Leen Delang, and Professor Johan Neyts gave the hamsters either hydroxychloroquine or favipiravir -- a broad-spectrum antiviral
drug used in Japan to treat influenza -- for four to five days. They
tested several doses of favipiravir. The hamsters were infected with the SARS-CoV-2 virus in two ways: by inserting a high dose of virus directly
into their noses or by putting a healthy hamster in a cage with an
infected hamster. Drug treatment was started one hour before the direct infection or one day before the exposure to an infected hamster. Four
days after infection or exposure, the researchers measured how much of
the virus was present in the hamsters.

Hydroxychloroquine versus favipiravir Treatment with hydroxychloroquine
had no impact: the virus levels did not decrease and the hamsters were
still infectious. "Despite the lack of clear evidence in animal models
or clinical studies, many COVID-19 patients have already been treated
with hydroxychloroquine," explains Joana Rocha-Pereira.

"Based on these results and the results of other teams, we advise
against further exploring the use of hydroxychloroquine as a treatment
against COVID- 19." A high dose of favipiravir, however, had a potent
effect. A few days after the infection, the virologists detected hardly
any infectious virus particles in the hamsters that received this dose
and that had been infected intranasally.

Moreover, hamsters that were in a cage with an infected hamster and had
been given the drug did not develop an obvious infection. Those that
had not received the drug all became infected after having shared a cage
with an infected hamster.



==========================================================================
A low dose of the drug favipiravir did not have this outcome. "Other
studies that used a lower dose had similar results," Professor Delang
notes. "The high dose is what makes the difference. That's important to
know, because several clinical trials have already been set up to test favipiravir on humans." Cautious optimism The researchers are cautiously optimistic about favipiravir. "Because we administered the drug shortly
before exposing the hamsters to the virus, we could establish that the
medicine can also be used prophylactically, so in prevention," Suzanne
Kaptein notes.

"If further research shows that the results are the same in humans, the
drug could be used right after someone from a high-risk group has come
into contact with an infected person. It may likely also be active during
the early stages of the disease." General preventive use is probably
not an option, however, because it is not known whether long-term use, especially at a high dose, has side effects.



==========================================================================
No panacea Further research will have to determine whether humans can
tolerate a high dose of favipiravir. "In the hamsters, we detected hardly
any side effects," says Delang. In the past, the drug has already been prescribed in high doses to Ebola patients, who appear to have tolerated
it well.

"Favipiravir is not a panacea," the researchers warn. This flu
drug, nor any other drug, has not been specifically developed against coronaviruses. As a result, the potency of favipiravir is to be considered moderate at best.

The study also highlights the importance of using small animals to test therapies against SARS-CoV-2 in vivo. "Our hamster model is ideally
suited to identify which new or existing drugs may be considered for
clinical studies," explains Professor Johan Neyts. "In the early days
of the pandemic, such a model was not yet available. At that time,
the only option was to explore in patients whether or not a drug such
as hydroxychloroquine could help them.

However, testing treatments on hamsters provides crucial information
that can prevent the loss of valuable time and energy with clinical
trials on drugs that don't work." Not all research models are equal
Kaptein, Rocha-Pereira, Delang and Neyts recently contributed to
a commentary in Nature Communications in which they give additional
context to the contradictory messages that have been circulating about (hydroxy)chloroquine.

In the early days of the pandemic, several studies were set up to test
these drugs in cell cultures. The results suggested that they could have
an antiviral effect. As a result, clinical trials were organised to test
the drugs on humans. However, cell cultures are not the best proxy for
the human body, and no conclusive effect was found in humans.

In their commentary, the authors describe several recent studies on
human organ-on-chip and other complex in vitro models, mice, hamsters,
and non-human primates. Each of these studies demonstrates that hydroxychloroquine and chloroquine do not have the efficacy suggested
by the studies in cell cultures.

Therefore, the authors conclude that these malaria drugs are very unlikely
to be effective in humans as a COVID-19 treatment.

More information The study "Favipiravir at high doses has potent antiviral activity in SARS-CoV- 2-infected hamsters, whereas hydroxychloroquine
lacks activity" by Suzanne Kaptein, Johan Neyts, Joana Rocha-Pereira,
Leen Delang et al. was published in PNAS.

The commentary "Emerging preclinical evidence does not support broad
use of hydroxychloroquine in COVID-19 patients" by Funnell et al. was
published in Nature Communications (open access).


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


========================================================================== Journal References:
1. Suzanne J. F. Kaptein, Sofie Jacobs, Lana Langendries, Laura
Seldeslachts, Sebastiaan ter Horst, Laurens Liesenborghs, Bart
Hens, Valentijn Vergote, Elisabeth Heylen, Karine Barthelemy,
Elke Maas, Carolien De Keyzer, Lindsey Bervoets, Jasper Rymenants,
Tina Van Buyten, Xin Zhang, Rana Abdelnabi, Juanita Pang, Rachel
Williams, Hendrik Jan Thibaut, Kai Dallmeier, Robbert Boudewijns,
Jens Wouters, Patrick Augustijns, Nick Verougstraete, Christopher
Cawthorne, Judith Breuer, Caroline Solas, Birgit Weynand, Pieter
Annaert, Isabel Spriet, Greetje Vande Velde, Johan Neyts, Joana
Rocha-Pereira, Leen Delang. Favipiravir at high doses has potent
antiviral activity in SARS-CoV-2-infected hamsters, whereas
hydroxychloroquine lacks activity. Proceedings of the National
Academy of Sciences, Oct. 9, 2020; DOI: 10.1073/pnas.2014441117
2. S. G. P. Funnell, W. E. Dowling, C. Mun~oz-Fontela, P.-S. Gsell,
D. E.

Ingber, G. A. Hamilton, L. Delang, J. Rocha-Pereira, S. Kaptein,
K. H.

Dallmeier, J. Neyts, K. Rosenke, E. de Wit, H. Feldmann,
P. Maisonnasse, R. Le Grand, M. B. Frieman, C. M. Coleman. Emerging
preclinical evidence does not support broad use of
hydroxychloroquine in COVID-19 patients.

Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-17907-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201009162432.htm

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