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:
- 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).
- Lopinavir/ritonavir was effective against MERS-CoV in a primate animal model (Chan 2015).
- 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 is currently under investigation within multiple RCTs in China (but none in the United States).
- (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
- 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?