Part 3, Lopinavir/Ritonavir (Kaletra)
It doesn’t come as a big surprise that an anti-viral drug used to fight HIV infection - and with that a retrovirus - made the shortlist for possible drugs for treatment of COVID-19 patients who are infected by SARS-CoV-19, also a retrovirus.
The drug, sold by Abbvie under the brand name Kaletra is actually a combination of the two protease inhibitors lopinavir and ritonavir. It was approved in September 2000 in the US and March 2001 in the EU. By now generic versions of the lopinavir/ritonavir combination have also been approved by the FDA.
Lopinavir/Ritonavir as Treatment for COVID-19
The lopinavir/ritonavir drug combination made it quickly onto the list of possible drugs to be used in the fight against the new coronavirus. Previous pre-clinical testing as well as treatment of a small number of patients suggested that the drug might be active against the closely related severe Acute Respiratory Virus coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS‐CoV)1.
All three viruses, SARS‐CoV, MERS‐CoV, and SARS-CoV-2 belong to the same genera of viruses and SARS‐CoV and SARS-CoV-2 share almost 80% of their genome. This close relationship combined with the initial encouraging results from previous studies gave rise to the hope that the combination of lopinavir and ritonavir might have anti-viral activity against SARS‐CoV-2.
However, the first clinical study on COVID-19 patients conducted in China and published in the New England Journal of Medicine in mid-March proved to be a disappointment. The study with 199 patients (99 on Kaletra, 100 in the control group) concluded that “no benefit was observed with lopinavir–ritonavir treatment beyond standard care.” A more detailed discussion of the outcomes of the study can be found in this article.
The story doesn’t end here for lopinavir/ritonavir. The first study was conducted under very difficult conditions in the middle of an outbreak, with few patients all of which were already severely ill by the time they received the drug. Administering the drug so late in the course of the disease could be responsible for the low efficacy. Whether patients who receive the drug earlier in their disease derive more clinical benefit from it remains to be studied.
Further investigation of lopinavir/ritonavir are ongoing, the drug is part of a WHO umbrella trial that evaluates four drugs or drug combinations, namely: remdesivir, lopinavir/ritonavir; lopinavir/ritonavir plus interferon beta and the anti-malarial chloroquine.
Mechanism of Action
Lopinavir/ritonavir are protease inhibitors which specifically interfere with the HIV protease that cleaves newly formed polyproteins into smaller subunits used to create the mature virion. Without the protease function only immature, noninfectious viral particles are formed. The drugs are combined because lopinavir is 3 to 4 times more effective against HIV than ritonavir but suffers from poor bioavailability. Combined with a low dose of ritonavir, the blood levels of lopinavir can be dramatically increased.
The list of adverse events includes diarrhea, nausea, asthenia, abdominal pain, vomiting, headache, rash and a host of others, but are generally mild to moderate. Lopinavir/ritonavir remains an effective drug for the treatment of HIV The following sections give you a great overview of the leading researchers, rising stars and preeminent institutions working on lopinavir/ritonavir.
Who is Who in Lopinavir/Ritonavir Research
Below is our Special TTL listing Lopinavir/Ritonavir experts and leading institutions.