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Kaletra—from HIV to SARS to COVID-19

One of the medicines that has been undergoing extensive testing in people with COVID-19 is a fixed-dose formulation of two drugs: lopinavir + ritonavir. In Canada and other countries this formulation is sold under the brand name Kaletra and is available in generic formulations. In some other countries it is sold under the name Aluvia.

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Lopinavir is the active antiviral drug in Kaletra. The relatively small dose of ritonavir is to delay the breakdown of lopinavir and to raise its levels in the body. This allows for once- or twice-daily dosing of Kaletra. The small dose of ritonavir has no antiviral activity.

For the first decade of the 21st century, Kaletra was a leading part of combination HIV treatment. However, Kaletra has been supplanted by better tolerated and more potent treatments for HIV. It is no longer a recommended treatment for the initial treatment of HIV today in Canada and many high-income countries.

In 2003 a new virus called SARS-CoV-1 (severe acute respiratory syndrome-coronavirus-1) first appeared in East Asia. This virus caused severe and in some cases, lethal pneumonia in infected people. Some doctors, encouraged by anecdotal reports at the time, repurposed Kaletra to treat cases of this viral infection. Unfortunately, based on the poor quality of studies hastily done in the time of SARS, definitive conclusions about the effectiveness of Kaletra could not be drawn. The subsequent disappearance of SARS meant that interest in this syndrome and funding for research on it dried up.

SARS-CoV-2

In late 2019 a new virus called SARS-CoV-2 appeared in China. Since the new virus was related to SARS-CoV-1, it made sense in a medical emergency to test potential treatments for the new virus even though doctors were uncertain precisely how it caused severe disease in some people.

On January 18, 2020, doctors in Beijing began a randomized controlled trial called Lotus. In Lotus, participants were given either Kaletra + standard care vs. standard care alone, both interventions for 14 consecutive days in people hospitalized with COVID-19. About 85% of participants required high-flow oxygen or non-mechanical ventilation.

Overall, researchers found no benefit of Kaletra on time to clinical improvement. After 28 days of monitoring, 19% of people who had taken Kaletra + standard care died vs. 25% who had been on standard care alone. This difference was not statistically significant.

Although these results are disappointing, it would be premature to dismiss Kaletra from further clinical trials of people who are at risk for SARS-CoV-2 infection or who have COVID-19.

Why didn’t Kaletra work in the Lotus study?

There are several potential reasons for the lack of significant clinical benefit of Kaletra in Lotus:

  • People enrolled in Lotus were very ill. The overall death rate in this study was 22%. This figure is much greater than what was generally reported in other hospitalized patients with COVID-19 in China (15%) during the early days of the pandemic.
  • People initiated Kaletra about 14 days after the onset of symptoms. This is relatively late in the course of COVID-19, perhaps too late for Kaletra to help them.
  • Lotus did not enroll sufficient people to demonstrate a statistically significant impact of Kaletra on endpoints (outcomes) such as survival.
  • The study was not placebo controlled. Due to the sudden emergence of COVID-19 and the need to rapidly conceive and implement a clinical trial, it was not possible to create placebo pills in time. Therefore, it is at least plausible that knowledge of which participants received Kaletra could have inadvertently biased the outcome and interpretation of some of the results.

Doctors who reviewed the data from Lotus commented in The New England Journal of Medicine, stating: “Lopinavir simply isn’t particularly potent against SARS-CoV-2. The concentration necessary to inhibit viral replication is relatively high as compared with historical data about the absorption and concentration of lopinavir. We currently know little about drug concentrations in the tissues where SARS-CoV-2 is replicating.”

The future of Kaletra in COVID-19

Despite the disappointing news from the Lotus study, it is still possible that Kaletra may be beneficial under the following circumstances, which require exploration in a clinical trial:

  • It is used by people who have been exposed to SARS-CoV-2 before symptoms of COVID-19 have appeared.
  • It is used early in the course of COVID-19.
  • It is used as part of an experimental combination therapy against COVID-19. Combining Kaletra with other potential treatments may enhance lopinavir’s antiviral activity. In some other viral infections, such as HIV and chronic hepatitis C virus, combination therapy is now the standard of care. Furthermore, preliminary data suggest that a combination of interferon-beta + Kaletra + ribavirin is more effective in facilitating recovery from COVID-19 than Kaletra alone. We have more information about this study next.

—Sean R. Hosein

REFERENCES:

  1. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-256.
  2. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine. 2020;382(19):1787-1799.
  3. Baden LR, Rubin EJ. Covid-19 - The search for effective therapy. New England Journal of Medicine. 2020;382(19):1851-1852.
  4. Cao B, Zhang D, Wang C. A trial of lopinavir-ritonavir in Covid-19. Reply. New England Journal of Medicine. 2020;382(21):e68.
  5. Doggrell SA. Does lopinavir measure up in the treatment of Covid-19? Expert Opinion in Investigational Drugs. 2020; in press.