Lopinavir/Ritonavir (tradename KALETRA) is a combination of protease inhibitors typically used in HIV, including post-exposure prophylaxis (lopinavir is the actual antiviral agent, with ritonavir functioning to inhibit metabolism of lopinavir, thereby boosting levels of lopinavir). In vitro, Lopinavir/Ritonavir has activity against SARS-CoV-1 and functions synergistically with ribavirin (the addition of ribavirin increases Lopinavir's potency four-fold)(Chu et al. 2004).
Lopinavir/Ritonavir has appeared to be clinically effective against SARS-CoV-1 in two retrospective studies (Chu et al. 2004 and Chan 2003; more on these studies here). It also seemed to prevent MERS when used for post-exposure prophylaxis during a subsequent outbreak (Park 2019). So far, so good.
But there’s a catch! Aside from these studies being retrospective, there is another major problem with them. In all three cases, Lopinavir/Ritonavir was combined with Ribavirin. So, these studies should most accurately be regarded as trials of triple therapy with Lopinavir/Ritonavir/Ribavirin. In fact, the only group of patients treated with Lopinavir/Ritonavir alone among these three trials was a group of patients in Chan 2003 who received delayed salvage therapy with Lopinavir/Ritonavir – a treatment strategy that didn’t work.
Young et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore (JAMA 3/3/20)
This is a fresh cohort study describing 18 patients with COVID-19 in Singapore. Baseline clinical features appear similar to prior cohorts of COVID-19 patients (table below). Six of the eighteen patients required supplemental oxygen therapy. One interesting bit of information here is how well C-reactive protein seems to sort out the sicker patients (which is consistent with prior studies):
Five of the six hypoxemic patients were treated with Lopinavir/Ritonavir. The dose of Lopinavir/Ritonavir used was 200 mg/100 mg twice daily for up to 14 days, which is half of the Lopinavir dose used in all prior studies on SARS-CoV-1 and MERS referenced above (previous studies have used a dose of 400 mg/100 mg twice daily, which seems to be the standard recommended dose).
Outcomes overall were as might be expected for a cohort of patients this size. Most patients did very well (figure above). Two patients required admission to the ICU for supplemental oxygen, with one of these patients being intubated. No patients died. Nasopharyngeal viral load often persisted for scary long periods of time (for up to 24 days!), even in patients with mild disease who did well clinically:
Among the five patients with hypoxemia treated with lopinavir/ritonavir:
- Three patients had improved oxygenation. Among these, two patients had clearance of nasopharyngeal virus within two days of treatment.
- Two patients deteriorated, one of whom required intubation. These patients both experienced persistent ongoing nasopharyngeal viral carriage throughout their ICU stay.
- Four out of five patients experienced nausea, vomiting, and/or diarrhea. Three developed abnormal liver function tests.
There were no observable differences in the time course of nasopharyngeal virus clearance between patients receiving Lopinavir/Ritonavir and the untreated patients (figure above). This is a bit disappointing, compared to the stark effect of Lopinavir/Ritonavir/Ribavirin previously observed by Chu et al. 2004 (first figure above). There are numerous potential explanations for this:
- Selection bias caused Lopinavir/Ritonavir to be used in the sickest patients.
- Underpowering, due to the very low number of patients treated (n=5).
- Many patients received short courses of treatment, which may have been curtailed due to side-effects and/or clinical improvement (figure below).
- Many patients were treated over a week into their disease course, at a time-point which might be too late.
- The dose of Lopinavir/Ritonavir used may have been inadequate.
- Lopinavir/Ritonavir may be ineffective without synergistic Ribavirin.
- This cohort study describes 18 patients with COVID-19 who overall did well (with only one patient requiring intubation and no deaths).
- Five patients with hypoxemia were treated with Lopinavir/Ritonavir, at lower doses than usually recommended.
- The sample size is too small to use clinical endpoints for judging the effectiveness of Lopinavir/Ritonavir. However, based on some patients with clinical deterioration and persistent nasopharyngeal virus, the Lopinavir/Ritonavir might not have worked very well.
- Potential reasons for under-performance of Lopinavir/Ritonavir may include the low dose, or use without the synergism of Ribavirin (all three prior clinical studies demonstrating efficacy from Lopinavir/Ritonavir used it in combination with Ribavirin).
- Further trials are warranted evaluating standard doses of Lopinavir/Ritonavir, with or without Ribavirin.
- JAMA full text of Young et al. study (open access).
- IBCC chapter on COVID-19, section on lopinavir/ritonavir.
- (For more general links on COVID-19, see the bottom of the IBCC chapter).