Jim Kling

February 24, 2015

SEATTLE — The experimental antiviral favipiravir improves survival in Ebola patients with a comparatively low viral load, but does not improve outcomes in more serious cases, according to a phase 2 study.

These results are preliminary, cautioned lead investigator Denis Malvy, MD, from the University of Bordeaux in France. "We decided to release data together with the data safety monitoring board because they found that these data had potential immediate consequences both for research and patient care issues," Dr Malvy told reporters attending a news conference held in advance of his presentation here at the Conference on Retroviruses and Opportunistic Infections 2015.

The JIKI trial is being conducted at four treatment units in Guinea run by Doctors Without Borders and The Alliance for International Medical Action. Jiki is the word for hope in Kissi, which is spoken in some West African countries. The official name of the trial is the Efficacy of Favipiravir in Reducing Mortality in Individuals With Ebola Virus Disease in Guinea.

The preliminary data being presented come from an analysis of 69 patients who were at least 14 years of age and who tested positive for the Ebola virus from two of four treatment units.

Patients were treated with oral favipiravir 6000 mg spread over 3 doses on day 1, and then 1200 mg twice a day for the next 9 days.

In the preliminary cohort, 64% of the 69 patients were women, mean age was 38 years, and the median duration of illness was 5 days.

Polymerase chain reaction was used to quantify viral load. At baseline, 42% of the patients had a cycle threshold below 20, indicating a higher viral load, and 58% had a threshold above 20, indicating a lower viral load.

Mortality outcomes in the study cohort were compared with outcomes at the same clinics in the 3 months before the trial began.

The overall mortality rate was lower in the treatment group than in the pretrial comparison group (48% vs 58%; P = .15). In patients with a higher viral load, the mortality rate was the same in the treatment and comparison groups (85% vs 85%; P = .26). However, in patients with a lower viral load, the mortality rate was lower in the treatment group than in the comparison group (15% vs 30%; P = .05).

When baseline creatinine levels were abnormal, the mortality rate was higher in patients with a higher viral load than in those with a lower viral load (100% vs 7%).

Table. Abnormal Creatinine Levels at Baseline

Creatinine Level Entire Cohort, % Patients With Higher Viral Load, % Patients With Lower Viral Load, %
>110 µmol/L 60 79 36
>300 µmol/L 27 43 10

 

The reduction in mortality in patients with a lower viral load — from 30% to 15% — is compelling, said Dr Malvy.

This drug could be "either a backbone or a partner in future therapeutic strategies, and it should be a part of future randomized studies," he told Medscape Medical News. "There is definitely a place for favipiravir in the care of Ebola patients."

Dr Malvy conceded that the drug likely has no value in patients with a higher viral load. "It is highly unlikely that favipiravir will ultimately be proven to reduce mortality in this population," he said.

However, there are concerns about the interpretation of the results because of the study design, said news conference moderator Scott Hammer, MD, from the Columbia University School of Medicine in New York City.

Challenge of Study Design During an Outbreak

The use of historic controls as a comparison group could be a problem because mortality rates can decline over the course of an epidemic. In fact, the pattern seen in this trial could have been an artifact of the passage of time, Dr Hammer pointed out.

Dr Malvy explained that such a decline was seen in the early months of the epidemic, but leveled off in August 2014. Patients in the pretrial comparison group were treated in September, October, and November of 2014.

A randomized placebo-controlled might provide more robust results, but such a study would be difficult, if not impossible, to conduct during an outbreak. "I have empathy for the investigators dealing with patients who are dying. There is a desire to do whatever you can for patients," Dr Hammer said.

The key is to gather more information as outbreaks continue. "I think that the mobilization to collaborate and try to get as much data as we can is what's important," he said.

"MSF considers this a positive preliminary result that needs further investigation before we can draw firmer conclusions," said Gilles Van  Cutsem, MD, medical coordinator for South Africa and Lesotho at Médecins Sans Frontières. "It is unfortunate that there seems to be very little impact on the most vulnerable patients," he added.

This study was funded by the European Union. Dr Malvy, Dr Hammer, and and Dr Van Cutsem have disclosed no relevant financial relationships.

Conference on Retroviruses and Opportunistic Infections (CROI) 2015: Abstract 103A. To be presented February 25, 2015.

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