Effectiveness of early treatment of lopinavir–ritonavir in patients with severe COVID-19: a case series

Discussion

This retrospective report describes the clinical outcomes in a small cohort of COVID-19 patients who were treated with LPV/r no more than 12 days after the first onset of symptoms. Specifically, the in-hospital mortality was 5.26%, and 94.74% of patients have recovered and been discharged. The median hospital stay was 17 (range 11–45) days, and 68.42% of patients were virologically cured at day 6 from LPV/r therapy initiation and 84.22% of patients cured at day 12.

In a recent randomised controlled trial of LPV/r in adults hospitalised with severe COVID-19 conducted by Cao et al, the 28-day mortalities of the standard-care group treated within 12 days after the onset of symptom was 27.1%.¹ By way of comparison, the 5.26% mortality observed in this LPV/r use cohort is noteworthy since the age, oxygen-support category, and comorbidities between this LPV/r use cohort and the standard-care group of Cao et al's trial were comparable at admission. Moreover, in a cohort of patients hospitalised for severe COVID-19 who were treated with remdesivir, the mortality in patients receiving noninvasive oxygen support was 5.3%.¹⁰ This mortality rate is very close to our results of 5.26%. It is important to note that it was suggested that the use of remdesivir in patients with severe COVID-19 may have clinical benefit.¹⁰

Patients with clinical improvement and two consecutive negative PCR tests can be discharged according to national guidelines. However, a stricter policy followed in some hospitals, including ours, is that several days of observation is also required before COVID-19 patients are discharged. Therefore the length of stay in this cohort seems not to be directly comparable to those in other reports. Despite this, the hospital stays (median 17 days, range 11–45 days) of the discharged patients in this LPV/r use cohort is still encouraging, since Liu et al¹¹ reported a median length of stay of 25 (range 14–44) days, Zheng et al¹² a median length of stay of 35.97 days and Zhou et al¹³ a median time from illness onset to discharge of 40.0 (IQR 32.0–46.0) in severe COVID-19 patients.

The favourable evolution of our patients under an early LPV/r treatment paralleled a relatively rapid negative test for SARS-CoV-2. These data are important to compare with those in the literature, which shows that the median duration of viral shedding was 31 (IQR: 24–40) days from illness onset.¹³ There was also research reported that the number of days required for nCoV-RNA turning negative was 12.0 ± 0.82 in patients who were just treated with adjuvant medicine.⁵ However, the fall in culture positivity from the third day after the onset of LPV/r therapy is remarkable in our cohort and is one element suggesting the effectiveness of this treatment. A recent study showed that patients who initiated LPV/r treatment within 10 days from symptom onset, but not those who initiated treatment from day 11 onwards, had significantly shorter viral shedding duration compared with those without LPV/r treatment,¹⁴ which was consistent with our findings.

The results from the recently randomised evaluation of COVID-19 therapy (RECOVERY) trial showed that LPV/r was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.² This finding was contrast with our results. However, RECOVERY included patients who did not initiate LPV/r therapy until >12 days after the onset of symptoms. Therefore, the therapeutic window of LPV/r treatment could be an explanation for the contradictions. Direct acting antiviral drugs are usually more effective when used earlier during the disease course, corresponding to reports from the literature that early administration of LPV/r could prevent COVID-19.^3,14–16 Moreover, the course of treatment, clinical severity, the comorbidities of patients and the adjuvant drugs used may also influence the effects of LPV/r in different studies.

In this retrospective study, data on the safety and side-effects of LPV/r were not collected because attribution of the dysfunction to either LPV/r or the COVID-19 is challenging. Interpretation of the results in this descriptive pilot study is limited by the small size of the cohort, and we did not attempt an analytic approach to account for possible confounds. Nor did we evaluate the clinical relevance of the patients’ co-morbidities on the effects of LPV/r or he potential risk of drug–drug interactions between LPV/r and co-medications used for the management of other comorbidities in these patients. But for all this, the preliminary data in this cohort suggest that early intervention with LPV/r treatment in patients with severe COVID-19 could be effective and randomised controlled trials are urgently needed to further evaluate this strategy.