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

1. 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
2. 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
3. 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
4. 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
5. 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