8. Lopinavir/Ritonavir

Like Voldemort at the end of The Goblet of Fire, lopinavir/ritonavir seems to have come back from the dead…maybe?

 

The background

SARS Open-label study showed improved clinical outcomes (combo of ARDS or death) with ribavirin plus lopinavir/ritonavir compared to ribavirin alone1 MERS Case reports suggest that triple-therapy with ribavirin, lopinavir/ritonavir, and interferon led to improved survival and viral clearance2 There is an ongoing clinical trial of combination therapy – stay tuned!3

 

LOTUS China trial4

Randomized open-label trial (no placebo) at a single hospital in China Methods 199 patients hospitalized with PCR-confirmed COVID-19 Had to have pulmonary involvement: positive chest imaging and hypoxia on room air: sats < 94% or P/F ratio < 300mmHg Randomized to lopinavir/ritonavir plus standard care vs standard care alone Primary endpoint: time to clinical improvement (7-point scale) Results No difference in the primary outcome of time to clinical improvement No difference in subgroup receiving treatment within 12 days of symptom onset No difference in 28-day mortality Note high mortality in both groups (19-25%) No difference in detectable viral RNA at various time points GI side effects were more common in the treatment group

 

Hung et al5

Multi-center prospective open-label phase II RCT at 6 hospitals in Hong Kong Methods Patients: 127 adults (>18yrs) with PCR-confirmed COVID, within 14 days of symptom onset, with NEWS2 scores of at least 1 Treatment: 14 days of lopinavir/ritonavir (BID) and ribavirin (BID) Plus up to 3 doses of interferon beta-1b every other day if within 7d of symptom onset* Control: lopinavir/ritonavir alone Primary outcome: time to a negative RT-PCR NP swab Secondary: time to resolution of symptoms, SOFA scores, hospital length of stay, 30-day mortality Interestingly, their power calculation was based on an estimated 26.4% (!!) improvement in mortality with triple-Tx group based on a prior study1 Results Patients: only very mildly ill Only 11% had dyspnea; and twice as many in control group as Tx group (sicker?) Only 13% required oxygen therapy during their admission Most of these people would NOT have been admitted to hospital here in Canada! Baseline viral load similar between groups Primary outcome: faster time to negative swab in the triple-therapy group (7 vs 12d) Secondary outcomes: many were also improved in the triple-therapy group Improved time to NEWS 0 (4 vs 8 days) Improved time to SOFA score 0 (3 vs 9 days) Shorter hospital length of stay (9 vs 14.5 days) No change in 30 day mortality (0% mortality in both groups)

 

Why the difference? Possible explanations:

Timing of medication administration: randomization occurred at median 13 days after symptom onset in LOTUS China Hung: 60% of patients presented within 7 days of symptom onset Subgroup who presented after 7 days: no difference Sicker patients in LOTUS China? Required to be hypoxemic on room air; vs only a small percentage of patients in Hung et al needed oxygen It’s the drugs! Maybe ribavirin or interferon are actually the effective agents? Is there something synergistic and magical about combination therapy?

 

The bottom line

This is promising! But… We need more studies With sicker patients: do these actually improve endpoints that we care about? To help tease out the effect of each drug If early administration is the key, we really need to think about how we might deploy this from a public health perspective

 

 

Sources

Chu CM. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. March 2004:252-256. doi:10.1136/thorax.2003.012658 Kim UJ, Won E-J, Kee S-J, Jung S-I, Jang H-C. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-α for Middle East respiratory syndrome. Antivir Ther, 2016; 21: 455-9. doi:10.3851/IMP3002 Arabi YM, Alothman A, Balkhy HH et al. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials 2018; 19: 81. doi:10.1186/s13063-019-3846-x Cao B, Wang Y, Wen D et al. A trial of lopinaviar/ritonavir in adults hospitalized with severe COVID-19. New Eng J Med, March 2020. doi:10.1056/NEJMoa2001282 Hung IF-N, Lung K-C, Tso EY-K et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet. May 2020. doi:10.1016/s0140-6736(20)31042-4