This is some old material on lopinavir for COVID-19.  I've removed it from the main chapter because it doesn't appear to work.  For the sake of interest, here it is:  

general description

• This is a combination of antiviral agents used in treatment of HIV (including post-exposure prophylaxis following needle-stick injury).
• Compared to remdesivir, lopinavir/ritonavir has the advantage that it's widely available and has an established toxicity profile (it does have known side-effects and drug interactions, but these are generally tolerable).
• Lopinavir/ritonavir appears to work synergistically with ribavirin.  Available human data on SARS and MERS have combined these three agents together.  It's possible that a cocktail of all three drugs is required for efficacy (potentially explaining failures of any of these agents in isolation).  A recent very small study on lopinavir/ritonavir alone wasn't particularly impressive, suggesting that triple therapy with lopinavir/ritonavir/ribavirin might be necessary (Young 3/3/20).

mechanism of action

• Lopinavir and ritonavir are protease inhibitors, which block viral replication.
• Lopinavir seems to be the agent which actually acts on the virus.  Ritonavir is a CYP3A inhibitor which functions primarily to reduce metabolism of lopinavir, thereby boosting lopinavir levels.

in vitro data

• Lopinavir showed in vitro antiviral activity against SARS at concentration of 4 ug/ml.  However, when combined with ribavirin, lopinavir appears considerably more effective (with an inhibitory concentration of 1 ug/mL (Chu et al. 2004).
• For reference, the peak and trough serum concentrations of lopinavir are 10 and 5.5 ug/ml (Chu et al. 2004).

animal data

• Lopinavir/ritonavir was effective against MERS-CoV in a primate animal model (Chan 2015).

human data

• Chu et al. 2004:  Open-label before/after study on SARS.
  • 41 patients treated with lopinavir/ritonavir plus ribavirin were compared to 111 historical control patients treated with ribavirin alone.  Baseline imbalances did exist between groups (patients treated with lopinavir/ritonavir had lower initial lactate dehydrogenase (LDH) levels – so they weren't as sick).
  • Poor clinical outcomes (ARDS or death) were lower in treatment group (2.4% vs. 29%).  These differences persisted in multivariable models, which attempted to correct for baseline imbalances between the groups.
  • Use of lopinavir/ritonavir use correlated with a dramatic reduction in viral load.
  • All patients received concomitant ribavirin.  The dose was 4 grams oral loading dose followed by 1.2 grams PO q8hr (or 8 mg/kg IV q8hr) for 14 days.
• Chan et al. 2003:  Retrospective matched multi-center cohort study on SARS
  • 75 patients treated with lopinavir/ritonavir were compared with controls (matched on the basis of sex, age, comorbidities, lactate dehydrogenase level, and use of pulse-dose steroid).
  • Up-front treatment with lopinavir/ritonavir combined with ribavirin correlated with reduced mortality (2.3% versus 16%).  However, rescue therapy with lopinavir/ritonavir (often without concomitant ribavirin) didn't seem to make any difference.  The ribavirin dose was 2.4 grams loading dose, followed by 1.2 grams PO q8hr (or 8 mg/kg IV q8hr) for 10-14 days.
  • 👁 Image of viral load over time in Chan et al. here.
• Park et al. 2019:  Retrospective cohort study on post-exposure prophylaxis against MERS
  • This is a retrospective cohort study involving 22 patients with high-risk exposure to a single MERS patient (table below).  As a control group, four hospitals with outbreaks of MERS were selected.
  • Post-exposure prophylaxis consisted of a combination of lopinavir/ritonavir (400 mg / 100 mg BID for 11-13 days) plus ribavirin (2000 mg loading dose, then 1200 mg q8hr for four days, then 600 mg q8hr for 6-8 days).
  • MERS infections didn't occur in anyone treated with post-exposure prophylaxis.  However, the manner in which the control group was selected (retrospectively selecting hospitals with MERS outbreaks) likely biased the study in favor of showing a benefit of post-exposure prophylaxis.
  • Post-exposure therapy was generally well tolerated, although most patients reported some side-effects (most commonly nausea, diarrhea, stomatitis, or fever).  Laboratory evaluation shows frequent occurrence of anemia (45%), leukopenia (40%), and hyperbilirubinemia (100%).
  • 👁 Image of patient characteristics in Park et al. here.
• Young et al. 3/3/2020
  • Cohort study describing 16 COVID-19 patients in Singapore.  Among six patients with hypoxemia, five were treated with lopinavir/ritonavir (200 mg/100 mg BID, which is half of the usual dose of lopinavir).
  • Among the five patients, two patients deteriorated and had persistent nasopharyngeal virus carriage.
  • Possible reasons for these underwhelming results might include:  statistical underpowering, low dose of lopinavir/ritonavir, lack of synergistic ribavirin, and/or late initiation of therapy.  For further discussion see PulmCrit blog on this study here.
• Other evidence of lower quality:
  • Lopinavir/ritonavir has been used to treat one patient with COVID-19 (Kim 2020).
  • Lopinavir/ritonavir was reported to be effective in some case reports of MERS (Momattin 2019).
• Lopinavir/ritonavir is currently under investigation within multiple RCTs in China (but none in the United States).

dosing

• (1) Lopinavir/Ritonavir (Monograph from MedScape)
  • Standard dose (and dose used against coronaviruses) is 400 mg / 100 mg PO BID.
  • Generally no adjustment is made in renal dysfunction.
  • Crushing and administering tablets via a gastric tube may decrease absorption by ~50%.  Increased doses might be considered in this situation (Best et al. 2011).
• (2) Ribavirin (Monograph from MedScape)
  • Unknown whether synergistic ribavirin is useful.
  • The best validated regimen is probably Chu et al. 2004:  4 grams oral loading dose followed by 1.2 grams PO q8hr (or 8 mg/kg IV q8hr) for 14 days.

contraindications/cautions regarding Lopinavir/Ritonavir:  

• Serious adverse effects may include:
  • Hypersensitivity reaction, angioedema
  • Stevens-Johnson syndrome / Toxic epidermal necrolysis / Erythema multiforme
  • QT prolongation & Torsade de Pointes
  • AV block, PR prolongation
  • Hyperglycemia, hypertriglyceridemia
  • Renal failure
  • Anemia, leukopenia, neutropenia
  • Pancreatitis
  • Hepatotoxicity
• Common adverse reactions:
  • Nausea/vomiting, diarrhea
  • Insomnia, anxiety
• Contraindicated in:
  • Cardiac disease (ischemic heart disease, cardiomyopathy, structural heart disease, QT prolongation)
  • Liver disease
• Monitoring:  Transaminase levels
• Overall tolerability?
  • In Chu et al. 2004, 41 patients with SARS tolerated lopinavir/ritonavir reasonably well (one patient needed to discontinue due to doubling of transaminase levels).
  • In Chan 2003, 75 patients with SARS were treated with lopinavir/ritonavir without reports of severe adverse effects.

additional information: 

• PulmCrit Blog 3/19: Lopinavir is down and out
• PulmCrit blog 3/4 discussing the Young study and double vs. triple therapy.
• Further information on this is available in a recent review by Yao TT et al.