The RECOVERY trial have released a statement on the HIV antiviral drug lopinavir-ritonavir, reporting no clinical benefit hospitalised COVID-19 patients.
Dr Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said:
“It is naturally disappointing that the ant-HIV drugs lopinavir and ritonavir (‘Kaletra’) have been found not to provide any clinical benefit to patients hospitalised with SARS-CoV2 infection. However, once again the value of conducting definitive, large-scale randomised controlled clinical trials has been demonstrated, and the RECOVERY trial run by Profs Horby, Landray and colleagues sets a very high bar in this regard. This is important as conflicting data had emerged from smaller trials conducted earlier during the pandemic, with some of the earliest studies suggesting potential efficacy. Now, these definitive data will permit the focus of RECOVERY and other trials to centre upon other therapies with potential for reducing the severity of COVID19.
“Interestingly, comparatively few of the most severe COVID19 patients were included in the study due to difficulties administering the drugs to people on artificial ventilation. Thus, whilst it is not formally possible to say whether this group of patients might have benefitted from treatment, this seems unlikely as direct-acting antiviral drugs such as Kaletra are usually more effective when used earlier during the disease course. This is different to the scenario with low dose dexamethasone, which is thought primarily target the aberrant immune response in late disease stages. As Kaletra neither improved survival, nor progression to the more severe disease stages across all subgroups, the likelihood of these drugs being useful in the treatment of SARS-CoV2 infection appears negligible.
“Lopinavir/Ritonavir were designed to target the essential HIV protease enzyme, which acts to cleave larger proteins made by the virus into smaller functional components. However, it was quickly recognised that ritonavir plays a more important role in reducing the breakdown of other drugs, such as lopinavir, by the liver and some other tissues. This allows effective treatments at lower doses as a result. Coronaviruses also encode a ‘main protease’ (Mpro), which performs a similarly essential function to the HIV enzyme. Thus, Mpro is a promising drug target and both HIV- and hepatitis C virus (HCV) drugs targeting the protease have been explored as therapies for COVID as a result. Unfortunately, whilst functionally similar, Mpro exhibits marked differences in its molecular structure that likely explains why these drugs are so much less effective compared with against their cognate targets. Accordingly, the Denison and Baric laboratories showed that Kaletra was poorly effective in disease models of the related MERS coronavirus. Nevertheless, Mpro does represent an exciting drug target for SARS-CoV2, shown by recent papers from the Hilgenfeld and Liu laboratories, detailing remarkable progress in preclinical development of potential candidate therapies. Going forward, it will be essential to combine the repurposing of existing drugs with the development of new therapies to enable the long term pharmaceutical management of SARS-CoV2.”
Dr Jeffrey K Aronson, consultant physician and clinical pharmacologist, University of Oxford, said:
“Although we have yet to see the full results of this segment of the RECOVERY trial, this outcome is not surprising. Lopinavir and ritonavir are protease inhibitors, designed to treat HIV, which is structurally and mechanistically different from SAR-CoV-2, the virus that causes COVID-19. HIV is an RNA virus (technically a class VI ssRNA-RT virus) that replicates in the nucleus of human cells using a reverse transcriptase enzyme. SARS-CoV-2 is different type of RNA virus (technically a class IV (+)ssRNA virus) and it uses an RNA polymerase enzyme to replicate in the cytoplasm.”
Prof Fiona Watt, Executive Chair of the Medical Research Council, which helped fund the trial, said:
“It is very important that we test potential therapies in randomised clinical trials so that we can find out whether re-purposed drugs work or not. The UK’s RECOVERY trial is the world’s largest randomised trial of potential COVID-19 treatments and has worked with unprecedented speed to start delivering the answers we need. Whilst it is disappointing that lopinavir/ritonavir, like hydroxychloroquine, has been found to be ineffective, the earlier findings with dexamethasone were positive. Researchers and health professionals are now focusing their efforts, and patient care, on other promising drugs.”
All our previous output on this subject can be seen at this weblink:
Dr Stephen Griffin: “No conflicts.”
Dr Jeffrey K Aronson: “No COIs.”
Prof Fiona Watt: “The MRC is part of UKRI, which funded the trial with DHSC and NIHR.”