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 of Basel and the University Hospital in Basel that prospectively monitored a range of diagnostic means and potential treatments for COVID-19, including the off-label use of hydroxychloroquine and lopinavir/ritonavir.
Professor Catia Marzolini, first author of the study and professor for experimental medicine at the University of Basel, said, “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.”
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. The authors write, “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.”
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 either drug reaches sufficient concentrations to inhibit virus replication in the lung.
The WHO accepted the recommendation from the Solidarity Trial International Steering Committee to discontinue the trial’s hydroxychloroquine and lopinavir/ritonavir arms on 4 July 2020.
Professor Manuel Battegay, co-leader of the study and head of the Division of Infectious Diseases and Hospital Epidemiology at the University Hospital in Basel, said 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.
evere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak is a major epidemic threat that is spreading worldwide since January 2020 [1]. About one-third of patients with SARS-CoV-2 pneumonia hospitalized for acute respiratory failure will require admission to the intensive care unit (ICU), where mortality is high [2].
Up to date, no specific treatment has convincingly demonstrated its efficacy in this setting [3], pointing out the need for observational data that would help designing future randomized trials. Chloroquine is a widespread anti-malarial drug that is also associated with immunomodulatory effects [4, 5].
Hydroxychloroquine is an analog of chloroquine, widely used in the management of some diseases like systemic lupus, for which there are fewer concerns about clinical tolerance. Hydroxychloroquine has an in vitro anti-SARS-CoV-2 activity [6] and reduces viral load in asymptomatic patients and in those with a mild form of illness, without any benefit on clinical outcome [7, 8].
Likewise, lopinavir/ritonavir is a combination of protease inhibitor used in human immunodeficiency virus infection that has gained interest in the context of SARS-CoV-2 outbreak due to its in vitro inhibitory activity against SARS-CoV-1 [9].
A recent open-label controlled randomized trial failed to demonstrate any benefit of lopinavir/ritonavir beyond standard care [10], but the potential interest of the treatment has not been ruled out in the specific setting of the most seriously ill patients.
To date, no study has reported the potential impact of these antiviral therapies in critically ill patients despite the high mortality observed in this population [11, 12].
The present report took the opportunity of successive drug shortages and compassionate uses initiated before the start of randomized controlled trials. This observational report that is not a randomized controlled trial reflects the local experience of a national expert center since the beginning of the SARS-CoV-2 outbreak to compare the effects of lopinavir/ritonavir, hydroxychloroquine, and standard of care only on clinical outcomes and viral load reduction in patients with a severe SARS-CoV-2 pneumonia requiring ICU admission.
Discussion
The compassionate use of drugs and a supply shortage provided us with the opportunity to evaluate the association between hydroxychloroquine, lopinavir/ritonavir, or standard of care only and treatment escalation as defined by the need for intubation, ECMO and renal replacement therapy in critically ill patients presenting with SARS-CoV-2-related pneumonia.
It also evaluated virological outcomes. Our findings could not provide any definitive conclusion. However, it is noticeable that there was no significant difference in treatment escalation as well as on secondary clinical outcomes (ventilator-free days, mortality at day 14 and day 28) between groups.
In addition, there was no significant reduction in the respiratory tracts and plasma viral load between admission and day 7.
A recent study suggested that hydroxychloroquine could significantly reduce the viral load [7], but it was conducted in outpatients and a recent trial [10] performed in the ICU failed to demonstrate any benefit of lopinavir/ritonavir on clinical outcomes and viral load reduction.
The effects of hydroxychloroquine are not equivocal. In another setting that is the treatment of chikungunya infection, in spite of an inhibitory effect of chloroquine on the chikungunya virus in vitro, chloroquine’s immunomodulatory effects were associated with delayed immune responses, higher levels of viral replication, and worse illness [15, 16].
While hydroxychloroquine or lopinavir/ritonavir are largely available and cheap, the potential benefit of their administration in critically ill patients has not been evaluated so far and caution is needed before considering their broad use [17].
In our retrospective analysis conducted in the ICU, whether our patients did or did not receive a specific treatment (i.e., with either antiviral or immunomodulatory activity), a similar proportion of them needed treatment escalation (within the 24 h after the admission in the ICU).
Furthermore, there was a similar viral load reduction between groups. In addition, there was a similar proportion of patients with negative respiratory tract viral shedding on day 7 according to treatment allocation.
In line with this, our results cannot confirm or refute the conclusion of the Surviving Sepsis Campaign guidelines which suggest against the routine use of lopinavir/ritonavir and stated that there is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19-related pneumonia [18].
As compared to international guidelines [18], doses of hydroxychloroquine used in our patients were lower (200 mg twice a day versus a loading dose of 400 mg twice a day followed by 200 mg three times a day) which could explain the lack of beneficial effects of our strategy. Since no clear recommendations were available at the beginning of the outbreak, we conformed to our local disease control policies.
Up to date, a few studies have reported the 28-day mortality of critically ill patients with SARS-CoV-2 [10,11,12, 19, 20]. The larger study coming from China included 344 patients and reported a 28-day mortality of 39% [19]. The mortality rate at day 28 in our population is slightly lower (31%) but within the range of previous reports [10,11,12, 19].
It still remains a high mortality rate that requires efforts to improve management and to develop specific treatments. Currently, studies investigating the effects of drugs against SARS-CoV-2 on the prognosis of critically ill patients are scarce while there is a potential risk of cardiovascular adverse-drug-reactions as recently reported [21]. Therefore, further studies are needed to establish whether specific drugs have to be employed in this indication.
Strengths and weaknesses
This opportunistic retrospective analysis allows the first comparison of hydroxychloroquine and lopinavir/ritonavir versus standard of care only ever reported in the context of SARS-CoV-2 in critically ill patients.
The strength of our analysis was the efficacy evaluation combining virological data and clinical outcomes, which allows us to confront conclusions on the potential of hydroxychloroquine and lopinavir/ritonavir in our population.
Weaknesses are related to the monocentric and retrospective analysis. In addition, during the analyzed period, the management was obviously not blinded which may have influenced the clinical decision-making process.
Another limitation is the comparison of three successive periods of time during which experiences and skills of caregivers may have changed. Therefore, a trend toward lower mortality and better prognosis in the treatment groups should be taken with a lot of caution. Last, our findings were obtained in a seriously ill population and may not be generalized in less severe patients and sooner after the onset of the illness.
While our analysis was unpowered to demonstrate any beneficial or harmful effects of treatments on the prognosis of critically ill patients with SARS-CoV-2-related pneumonia, our findings may be useful in the conjunction of others in the perspective of individual meta-analysis to better investigate the potential interest of such drugs.
Very recently, preliminary unpublished data from the RECOVERY trial (NCT 04381936) reported no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98–1.26]; p = 0.10) between 1542 patients randomized to hydroxychloroquine compared with 3132 patients randomized to usual care alone [22]. Nevertheless, confirmation of these data is warranted before establishing definitive answers.
Conclusion
This retrospective observational analysis failed to demonstrate any benefit of hydroxychloroquine or lopinavir/ritonavir as compared to standard of care only on treatment escalation during the ICU stay. In addition, there was no significant difference of respiratory tracts and plasma SARS-CoV-2 load reduction between admission and day 7.
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More information: Catia Marzolini et al, 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
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