New data from randomized trial dent HIV drug strategy against Covid-19
It’s not all good news coming out of the first round of clinical data investigating treatment options for Covid-19. In a new study published in the New England Journal of Medicine, researchers suggested that an HIV drug that had emerged as a promising candidate early on missed the clinical mark.
Adding lopinavir–ritonavir — a combo that AbbVie markets as Kaletra — to standard supportive care conferred “no benefit” to severely ill patients, they concluded, either in terms of clinical improvement or mortality. Furthermore, gastrointestinal adverse events were more common in the drug arm, although serious adverse events cropped up more in the standard care group. In the trial, 199 patients were randomized to the two cohorts.
While China began recommending Kaletra as a possible treatment for Covid-19 as early as January, scientists have cautioned against too much optimism with this mechanism. The new data suggest that the drug didn’t exert a strong antiviral effect against SARS-CoV-2.
“It’s probably a long shot to go for drug repurposing activity against the coronavirus using HIV drugs; these were protease inhibitors that were designed specifically for HIV,” George Painter, president of the Emory Institute for Drug Development, previously told Nature News.
Evercore ISI analyst Umer Raffat, though, argues that the authors of the paper made a mistake by looking at the overall results.
“This trial enrolled patients ~13 days post symptom onset (that’s VERY long … recall Tamiflu in flu setting has to be initiated in <2 days from symptom onset),” he wrote in a note. “As I’ve mentioned several times, it’s NOT about the overall trial … because we don’t (what’s) the time to peak viral load with COVID-19. Instead, it’s all about identifying the time point up until which an antiviral may work.”
If you zoom in on patients who received the drug relatively soon, such as those for whom treatment was initiated less than 12 days from symptoms, you see a 15% mortality rate versus 27% in the control arm, he said.
The overall 28-day mortality in the Kaletra group was 19.2% compared to 25% on standard care. In a modified intention-to-treat analysis, which excluded three patients with early death, the Kaletra group registered a 16.7% mortality rate.
The authors acknowledged that the difference in median time to clinical improvement between this modified ITT group and standard care group was “significant, albeit modest” (15 vs 16 days).
Several limitations could have influenced the results, they added:
In particular, the trial was not blinded, so it is possible that knowledge of the treatment assignment might have influenced clinical decision-making that could have affected the ordinal scale measurements we used. We will continue to follow these patients to evaluate their long-term prognosis. The characteristics of the patients at baseline were generally balanced across the two groups, but the somewhat higher throat viral loads in the lopinavir–ritonavir group raise the possibility that this group had more viral replication.
Other trials of Kaletra are ongoing, some involving combinations with interferons, guanosine-analog RNA synthesis inhibitors, reverse transcriptase inhibitors or influenza drugs. But even if they’re instructive, most readouts will likely be deemed unconclusive — a notion underlying the WHO’s decision to launch its own multiarm trial.
For Raffat, it presents a lesson for how to interpret the highly-anticipated data on Gilead’s remdesivir, which are expected in April: Look specifically for patients who initiated treatment fast enough.
“We shouldn’t expect overall remdesivir trial to look spectacular (especially also since the first author on this lopinavir trial is also running remdesivir trial – and he may present it the same way),” he wrote.
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