PREVAIL IV: A Randomized, Double-Blind, 2-Phase, Phase 2 Trial of Remdesivir vs Placebo for Reduction of Ebola Virus RNA in the Semen of Male ...
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Clinical Infectious Diseases
Major Article
PREVAIL IV: A Randomized, Double-Blind, 2-Phase,
Phase 2 Trial of Remdesivir vs Placebo for Reduction of
Ebola Virus RNA in the Semen of Male Survivors
Elizabeth S. Higgs,1 Dehkontee Gayedyu-Dennis,2 William A. Fischer II,3,4 Martha Nason,1 Cavan Reilly,5 Abdoul Habib Beavogui,6,7 Jamila Aboulhab,1
Jacqueline Nordwall,5 Princess Lobbo,2 Ian Wachekwa,8 Huyen Cao,9 Tomas Cihlar,9 Lisa Hensley,1 and H. Clifford Lane1
1
Division of Clinical Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA; 2Duport Road Clinic, Paynesville, Liberia Partnership for Research on Ebola Virus
in Liberia, Monrovia, Liberia; 3Division of Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, North Carolina, USA; 4USA Institute of Global Health and Infectious
Diseases, University of North Carolina, Chapel Hill, North Carolina, USA; 5Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA; 6Centre National de Formation et de
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Recherche en Santé Rurale de Maferinyah, Forecariah, Guinea; 7Bioclinical and Fundamental Sciences Chair, Department of Medical Sciences, Faculty of Health Science and Techniques, Gamal
Abdel Nasser University of Conakry, Conakry, Guinea; 8John F. Kennedy Medical Center, Monrovia, Liberia; and 9Gilead Sciences, Foster City, California, USA
(See the Editorial Commentary by Cummins on pages 1857–9.)
Background. Ebola virus RNA persists in the semen of male Ebola survivors for months to years after the acute infection, and
male-to-female sexual transmission of the virus is well documented. We investigated whether remdesivir can safely reduce persist-
ence of seminal Ebola virus RNA.
Methods. We recruited men with persistent seminal Ebola RNA in Liberia and Guinea. Participants were randomized 1:1 to re-
ceive intravenous remdesivir (GS-5734; Gilead Sciences) or matching placebo administered once daily by intravenous infusion over
1 hour on 5 consecutive days. Stratification was by country and number of positive (1 or 2) preenrollment semen tests. We evaluated
the difference in mean assay negativity rate (ANR), that is, the proportion of negative tests for each participant in each group in the
treatment (days 1–28) and follow-up (months 2–6) phases on an intention-to-treat basis.
Results. We enrolled 38 men from July 2016 through June 2018. The mean treatment phase ANRs were 85% (standard deviation
[SD] = 24%) and 76% (SD = 30%) in the remdesivir and placebo arms, respectively (P = .270). The mean follow-up phase ANRs
were 96% (SD = 10%) and 81% (SD = 29%) in the remdesivir and placebo arms, respectively (P = .041). The 5-day remdesivir reg-
imen was well tolerated with no safety concerns.
Conclusions. In this small trial, remdesivir 100 mg/day for 5 days safely reduced the presence of Ebola virus RNA in the semen
of Ebola survivors 2 to 6 months after administration. A larger follow-up study is necessary to confirm results.
Clinical Trials Registration. NCT02818582.
Keywords. Ebola survivors; Ebola virus disease; post-Ebola syndrome; remdesivir; controlled clinical trial.
During the 2014–2016 West African Ebola outbreak, Ebola detection; a full year could elapse between detections with neg-
virus RNA was found to persist in the semen of the majority of ative tests in between, which could suggest that the virus was
male Ebola survivors after the end of acute illness and for years replicating intermittently. Persistence of Ebola virus RNA has
in a significant minority [1]. A longitudinal survivor study con- also been demonstrated in other immune-privileged sites, in-
ducted by the Partnership for Research on Infectious Diseases cluding the central nervous system and the eye [3, 4], including
and Vaccines in Liberia (PREVAIL III) demonstrated that even 1 case of meningoencephalitis relapse [3].
when sampling was begun 18 months after acute Ebola virus The persistence of Ebola virus RNA in survivors has impor-
disease (EVD), 30% of male survivors had detectable seminal tant public health implications. Male-to-female sexual transmis-
Ebola virus RNA; the longest period from onset of EVD to sion of Ebola virus is well documented and has caused cluster
Ebola RNA detection in semen was 40 months [2]. Longitudinal outbreaks with secondary and tertiary chains of transmission as
testing in PREVAIL III also revealed an intermittent pattern of long as 14 months after recovery [5]. A female, eventually de-
termined to be an Ebola survivor, was the index case in a small
cluster outbreak in Liberia; transmission to family members oc-
Received 5 October 2020; editorial decision 16 February 2021; published online 12 March 2021. curred in the post-partum period an estimated 15 months after
Correspondence: Elizabeth S. Higgs, MSC 9820, 5601 Fishers Lane, Division of Clinical
Research, National Institute of Allergy and Infectious Diseases, Rockville, MD, 20892-9820,
her presumed Ebola infection [6]. Sexual transmission is also
USA (ehiggs@niaid.nih.gov). thought to contribute to transmission during outbreaks [7].
Clinical Infectious Diseases® 2021;73(10):1849–56 In addition to viral persistence, Ebola survivors can suffer a
Published by Oxford University Press for the Infectious Diseases Society of America 2021. This
work is written by (a) US Government employee(s) and is in the public domain in the US.
constellation of signs and symptoms collectively known as post-
DOI: 10.1093/cid/ciab215 Ebola syndrome (PES) that linger long after recovery, including
Remdesivir for Persistent Ebola in Semen • cid 2021:73 (15 November) • 1849uveitis, musculoskeletal pain, memory difficulties, neurologic tests were conducted at each treatment or sample collection
abnormalities, fatigue, and headaches [2, 8]. The relationship visit, and the results were used to assess safety and the impact of
between seminal Ebola virus RNA and PES is not clear, although treatment on PES symptoms.
Ebola virus RNA in semen is associated with both the presence The trial was jointly designed by the US National Institute
of uveitis and higher levels of Ebola-specific antibodies [2]. for Allergy and Infectious Disease (NIAID) and the Ministry of
A safe, effective therapy that is capable of reducing or Health of Liberia under the PREVAIL umbrella. The US NIAID
eliminating persistent Ebola virus from semen could accelerate Institutional Review Board, the Liberian National Research
the end of outbreaks, prevent subsequent cluster outbreaks, and Ethics Board of Liberia, and the Guinean National Ethics
enable male survivors to resume normal sexual relations without Committee for Health Research approved the protocol.
fear of harming loved ones. If viral persistence is contributing
to PES, such a therapy might also reduce uveitis and other PES Outcomes
signs and symptoms. Two therapies that contain neutralizing Per protocol, the primary outcome for comparative changes in
monoclonal antibodies, Inmazeb (REGN-EB3) and Ebanga seminal Ebola virus RNA was each study arm’s mean ANR for both
phases. Secondary outcomes included differences in liver function
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(mAb114), are now licensed for treatment of acute Ebola virus
disease [9–11]. Remdesivir is a nucleotide analog prodrug with and coagulation tests and the rate of adverse events between the
broad-spectrum antiviral activity, including against Ebola and study arms (safety) and differences in the sustained negativity rate
other filoviruses [12], that directly impacts virus replication in the follow-up phase (efficacy). See the Supplementary Materials
through the inhibition of viral RNA polymerase. Unlike antibody for additional details on secondary outcomes.
therapies, however, remdesivir is a hydrophobic small molecule
that has been shown in preclinical studies to efficiently distribute Statistical Analyses
into immune privileged compartments including testes [12]. Per protocol, we recognized that an early reduction in ANR
The primary aim of the PREVAIL IV study was to assess the might not correlate with the more clinically meaningful longer-
effectiveness of a 5-day course of intravenous remdesivir in term reduction of viral RNA in the semen. Consequently, the
reducing seminal Ebola virus RNA during 2 distinct periods: 2 study phases were viewed independently with no adjustment
a short-term treatment phase (the 28 days after the initial in- for the multiplicity. Samples in phase 1 were not included in
fusion) and a longer-term follow-up phase (months 2–6). The the analysis for phase 2. Per protocol, the primary analysis used
secondary aims were to examine the safety and tolerability of Welch’s modified test, a 2-sample t test with unequal variance,
remdesivir treatment and assess its impact on the presence of as a test statistic to assess the difference in mean ANR between
PES symptoms and depression. the treatment and placebo arms; the permutation distribution
was used to compute a P value. Incidence of grade 1 or higher
and grade 2 or higher laboratory toxicities were compared
METHODS across arms using the Fisher exact test. A similar approach was
used to assess the incidence of adverse events for all grades, in-
Study Design
cluding serious adverse events. Differences in sustained nega-
Male Ebola survivors in Liberia and Guinea were screened for
tivity rate during the follow-up phase were evaluated using a
the presence of Ebola viral RNA in their semen. Criteria for in-
Mantel-Haenszel test. Estimates of the probability of resolution
clusion were age of at least 18 years, male sex, and evidence of
of post-Ebola sequelae noted at baseline used sample propor-
persistent Ebola virus RNA in semen, defined as at least 1 of
tions and the method of Clopper and Pearson to construct con-
a minimum of 2 semen samples positive for Ebola virus RNA
fidence intervals. Differences in resolution of symptoms were
by GeneXpert real-time polymerase chain reaction (RT-PCR)
conducted using the Fisher exact test.
within 42 days of enrollment, with at least 1 sample within
All analyses were conducted using SAS version 9.3 or R ver-
21 days. Exclusion criteria included history of kidney or liver
sion 3.6.0. The R packages gee and lme4cens were used for the
disease and abnormal kidney or liver test results.
secondary analyses. See the Supplementary Materials for fur-
Eligible volunteers were randomized to receive remdesivir
ther details on patient recruitment, exclusion criteria, random-
(GS-5734, Gilead Sciences, Foster City, CA) 100 mg/day or
ization, statistical power calculation, risk mitigation strategy,
matching placebo, administered as a 1-hour intravenous infu-
study procedures, and outcomes.
sion once daily for 5 days. Six semen samples were collected
during the “treatment phase” (days 4, 8, 11, 16, 24, and 28) and
RESULTS
5 during the 5-month “follow-up phase” (weeks 8, 12, 16, 20,
and 24). Samples were analyzed using RT-PCR (GeneXpert, From June 2016 through June 2018, 43 male EVD survivors
Cepheid, Sunnyvale, CA) as previously described [13]. The dif- with evidence of persistent Ebola virus RNA in their semen
ference in mean assay negativity rate (ANR) between arms was were screened for eligibility. Four were ineligible due to el-
evaluated for each trial phase. Clinical exams and laboratory evated hepatic transaminases or other abnormal laboratory
1850 • cid 2021:73 (15 November) • Higgs et alvalues, and 1 chose not to participate. One participant was re- the treatment phase. These results were not sensitive to adjust-
cruited in Guinea and the rest in Liberia. The study planned ment for baseline imbalances in age (see the Supplementary
to enroll 60–120 male Ebola survivors with persistent seminal Materials for further details). With stratification by number
Ebola virus RNA. However, the study team decided to stop re- of preenrollment positive tests, we found no statistical differ-
cruitment because additional eligible participants in Liberia ence in mean ANR between arms for the single-positive strata
and Guinea were unlikely to be found given the length of time in either the 28-day treatment phase or the 6-month follow-up
since the end of the Ebola outbreak. phase. In the double-positive strata, we found no significant
Twenty participants were randomized to remdesivir and difference in the treatment phase but we found a statistically
18 to placebo (Figure 1). Of the 38 randomized participants, 31 significant difference of 67 percentage points in the follow-up
had a single positive test in the preenrollment period and 7 had phase (P = .028). A secondary, prespecified efficacy analysis of
2 positive tests. The prerandomization mean screening cycle the unstratified sustained negativity rate, that is, the proportion
threshold values were nearly identical, 40.4 in the remdesivir of men who were negative on all tests in a given phase, found
group and 40.0 in the placebo group. Each participant was no significant differences between arms during the follow-up
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scheduled to provide 6 semen samples in the treatment phase phase (65% remdesivir, 61% placebo, P = .141).
and 5 in the follow-up phase, for a total of 418 planned semen No safety concerns were observed during the study. The drug
samples; only 12 of these samples were not collected. No partic- was well tolerated among study participants without any serious
ipant was lost to follow-up, and all were included in the analysis. adverse events; in fact, the untoward signs and symptoms pre-
Baseline characteristics of study participants are given in viously associated with remdesivir occurred more frequently in
Table 1. Participants enrolled an average of 2 years after onset the placebo group (Table 4). Only 1 dose reduction was ordered
of EVD symptoms. Demographics were well balanced between in the remdesivir group on day 2 for a grade 1 transaminase el-
groups, although participants in the placebo group tended to be evation; however, that reduction was based on a blood sample
older than those in the remdesivir arm (median 43 vs 36 years, drawn on day 1, before the drug was administered. In con-
respectively). At baseline, 95% (36 of 38) of participants had 1 trast, 5 dose reductions occurred in the placebo group during
or more signs and symptoms compatible with PES. With the ex- the drug administration period, all for grade 1 transaminase
ception of uveitis, these were well balanced between arms with elevations. The Data Safety Monitoring Board did not recom-
musculoskeletal, neurologic, and genitourinary symptoms re- mend any cohort-wide dose reductions. One participant in each
ported most frequently. Overall, 12 of 37 (32%) participants had arm had a grade 2 or higher alanine aminotransferase, and 2
uveitis (1 participant was not evaluated). participants in the remdesivir arm and 1 in the placebo arm
Ebola virus testing results for all 38 volunteers are shown in had a grade 2 or higher aspartate aminotransferase. Moreover,
Figure 2. The primary outcome results (mean ANR in treat- 1 participant in the placebo arm had a grade 2 creatinine and 2
ment vs placebo) are given in Tables 2 and 3. We found a statis- participants in the remdesivir arm had a grade 2 or higher pro-
tically significant decrease during the follow-up phase in mean thrombin time or partial thromboplastin time. Two participants
ANR in the remdesivir arm compared with placebo of 15 per- in the placebo arm had a grade 2 or higher total bilirubin. For
centage points (P = .041), but no significant difference during all participants, grade 3 or higher direct bilirubin was common
both at screening and over the course of the study. Using the
Wilcoxon rank sum test, a statistically significant difference in
the change in international normalized ratio (INR) levels be-
43 men > 18 with semen
sample with Ebola virus RNA tween the remdesivir and placebo arms was detected for days
detec on within 42 days
prior to randomiza on
3, 4, 5, and 8 with a return to no difference between arms on
day 11. However, there was no difference between groups in the
4 ineligible based on safety labs proportions experiencing a grade 2 or higher abnormality for
1 decided not to be randomized
INR. These prothrombin elevations were not considered clin-
ically significant.
38 randomized 1:1 within 4 strata The post-Ebola signs and symptoms noted at baseline de-
defined by country (Liberia or
Guinea) and whether one or two creased substantially among members of both the treatment
screening semen samples had
detectable Ebola virus RNA and placebo groups over the 6-month study period. The only
exception was uveitis, found in 12 participants (32%) at base-
line and 9 participants (24%) at week 24 (Table 5). Uveitis was
20 randomized to receive 100 mg 18 randomized to receive 100 mg
Remdesivir once daily by IV for 5 days placebo once daily by IV for 5 days more common in the placebo group (9 of 17, 53%) than in the
remdesivir group (3 of 20, 15%) at baseline (P = .023); how-
Figure 1. Partnership for Research on Infectious Diseases and Vaccines in Liberia
ever, no significant difference in uveitis incidence remained at
(PREVAIL) IV participant flow chart. the final visit. There was no observed difference in either the
Remdesivir for Persistent Ebola in Semen • cid 2021:73 (15 November) • 1851Table 1. Baseline Characteristics by Treatment Group
Characteristic Remdesivir Placebo Total
Demographics
Age (years) 36 (30–45) 43 (39–47) 40 (32–47)
Country of Enrollment
Liberia 20 (100.0) 17 (94.4) 37 (97.4)
Guinea 0 (0.0) 1 (5.6) 1 (2.6)
Years since Ebola virus disease diagnosis 2.0 (1.9–2.5) 2.0 (1.9–2.2) 2.0 (1.9–2.3)
Clinical information
Weight (kg) 68 (63–75) 68 (61–83) 68 (63–78)
Height (cm) 169 (166–174) 171 (168–173) 170 (167–174)
Body mass index (kg/m2) 24 (22–26) 24 (22–27) 24 (22–26)
Body temperature (°C) 37 (36–37) 37 (36–37) 37 (36–37)
Pulse (beats per minute) 58 (55–74) 66 (62–73) 64 (57–73)
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Systolic blood pressure (mm Hg) 125 (116–145) 121 (113–132) 124 (114–140)
Diastolic blood pressure (mm Hg) 81 (72–89) 78 (74–82) 79 (73–84)
Respiratory rate (breaths per minute) 19 (17–20) 19 (17–19) 19 (17–20)
Uveitis 3 (15.0) 9 (52.9) 12 (32.4)
Review of systems
Constitutional 2 (10.0) 6 (33.3) 8 (21.1)
Ears, nose, and throat 4 (20.0) 1 (5.6) 5 (13.2)
Cardiovascular 3 (15.0) 3 (16.7) 6 (15.8)
Respiratory 2 (10.0) 1 (5.6) 3 (7.9)
Gastrointestinal 5 (25.0) 9 (50.0) 14 (36.8)
Genitourinary 11 (55.0) 7 (38.9) 18 (47.4)
Male reproductive 7 (35.0) 3 (16.7) 10 (26.3)
Musculoskeletal 11 (55.0) 10 (55.6) 21 (55.3)
Neurological 8 (40.0) 13 (72.2) 21 (55.3)
Skin 6 (30.0) 5 (27.8) 11 (28.9)
Lymphatic 0 (0.0) 0 (0.0) 0 (0.0)
Number of participants randomized 20 18 38
Numbers are N (%) or median (interquartile range).
frequency of resolution of PES or d-dimer levels between the for treatment for acute EVD, whereas remdesivir did not [9].
study arms. However, antibodies are not expected to penetrate into immune-
At the end of each phase, all participants completed a sat- privileged sites, including the genital tract. We hypothesized that
isfaction survey and a depression assessment. Participant remdesivir, a potent small-molecule inhibitor of the Ebola virus
satisfaction with the study and study personnel was high RNA polymerase, would be effective because it can penetrate
(Supplementary Table 2). The depression assessment found immune-privileged sites in the body, including the testes com-
little evidence of depression among participants at baseline or partment, as indicated by animal preclinical studies [12]. We also
follow-up and no difference between study arms at the end of hypothesized that the drug would be most effective in the double-
the study (Supplementary Table 3). positive strata, reasoning that these men were more likely to have
actively replicating virus. Unfortunately, only 7 of 38 participants
were in the double-positive strata. Nonetheless, the trial reached
DISCUSSION
statistical significance for the primary end point, improvement in
This study demonstrates that a course of remdesivir at 100 mg mean ANR during the follow-up phase in both the entire study
per day for 5 days safely reduced the presence of Ebola virus population and the double-positive stratum.
RNA in the semen of male EVD survivors in the longer-term A 5-day course of remdesivir was safe and well tolerated. The
5-month follow-up period. This positive finding was driven primary concern from preclinical and phase 1 trial data was
primarily by the double-positive strata. No difference in mean transaminitis. During the trial, however, more transaminase
ANR was found in the single-positive strata or in the 28-day elevations and protocol-mandated dose reductions occurred in
treatment phase. the placebo arm than in the remdesivir arm. The study specif-
The Pamoja Tulinde Maisha (PALM) trial in the Democratic ically targeted adverse events previously reported to be asso-
Republic of Congo identified 2 monoclonal antibodies, mAb114 ciated with remdesivir and found no increase associated with
and REGN EB3, to improve survival when compared to Zmapp the drug.
1852 • cid 2021:73 (15 November) • Higgs et alTreatment phase (days) Follow-up phase (weeks)
Stratum 4 or 5 8 11 16 24 28 8 12 16 20 24
- - - - - - - - - - -
+ - - + - - - - - - -
+ - + - + - - - o - +
+ + - - - - - + + - -
- - - - - - + - + - +
- - - - - - - - - - -
- - - - - - - - - - -
Placebo, 1 pre-trial posi ve - - + - - + - - - - -
- - - - - - - - - - -
- - - - - - - - - - -
+ + - - - - - - - - +
- o o - o - o - - - -
- - - - - - - - - - -
- - - - - o - - - - -
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+ - - - + - - - - - -
+ + + + - + + + + + -
Placebo, 2 pre-trial posi ves o + + + + + + + - + +
- + - - - + - - + - +
- - - - o - - - - - -
- - - - - - - - - - -
- - - - - - - - - - -
- - - - - - - - - - -
+ - - - + - - - - - -
+ - - - - - - - - - -
- - - + - - - - + - -
- - - - - - - - - - -
Remdesivir, 1 pre-trial posi ve - + + - - + - + - - -
- - - - - - - - - - -
- o o - o - o - o - -
+ + + - + + + + - - -
- - - - - - - - - - -
- - + - - - - - - - -
- - - - - - - - - - -
- - - - - - - - - - -
- - - - - - - - - - -
- + + + - - - - - - -
Remdesivir, 2 pre-trial posi ves - + + - - - - - - - -
- - - o - o - - - - -
Figure 2. Semen testing results for the 38 participants. Red “+” indicates positive test, green “–“ indicates negative test, and white “o” indicates sample not collected.
We observed no difference in the frequency of resolution of higher than seen in PREVAIL III [2] at a similar time since
PES between the arms. A difference would have been difficult resolution of acute EVD in this larger survivor cohort (Table
to discern as all PES symptoms improved in both groups, ex- 5). This observation supports the hypothesis that persistent
cept for uveitis. Interestingly, with the exception of uveitis, the seminal RNA correlates with longer-lasting PES symptoms.
prevalence of signs and symptoms associated with PES among Although the mechanisms that underlie PES are not well un-
PREVAIL IV participants at their baseline was substantially derstood, one can extrapolate from other infections to hypoth-
esize that the presence of viral RNA drives immune activation
Table 2. Mean Assay Negativity Rate for Remdesivir and Placebo Arms that, in turn, contributes to fatigue, musculoskeletal pain, head-
in the Treatment and Follow-Up Phases aches, and other observed PES symptoms. Persistence of Ebola
virus RNA in semen is associated with uveitis and elevations in
Mean Assay
Phase Group N Negativity Rate P Value
Ebola-specific antibody titers [2].
The major limitation of this study was its small sample size, es-
Treatment (3–28 days) Remdesivir 20 0.85 .270
Placebo 18 0.76 pecially in the double-positive strata, a consequence of the study’s
Follow-up (2–6 months) Remdesivir 20 0.96 .041 late start relative to the end of the Ebola outbreak in West Africa.
Placebo 18 0.81 Though age is associated with Ebola virus RNA persistence and
Remdesivir for Persistent Ebola in Semen • cid 2021:73 (15 November) • 1853Table 3. Mean Assay Negativity Rate for Remdesivir and Placebo Arms
Phase Stratum Group N Mean Assay Negativity Rate P Value
Treatment (3–28 days) One baseline positive Remdesivir 16 0.86 .926
Placebo 15 0.86
Two baseline positives Remdesivir 4 0.79 .142
Placebo 3 0.28
Follow-up (2–6 months) One baseline positive Remdesivir 16 0.95 .429
Placebo 15 0.90
Two baseline positives Remdesivir 4 1.00 .028
Placebo 3 0.33
Results are stratified by the number of positive samples during the 42-day enrollment period.
there was a difference in age between treatment and placebo United States. These studies, as well as the safety results from
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arms, an analysis that controlled for age and other demographic the PALM study [9] and the first stage of the Adaptive COVID-
factors showed that these differences did not affect the results (see 19 Treatment Trial (ACTT-I) trial [14], led to licensure and
the Supplementary Materials). Strengths of this study are the re- widespread use of remdesivir in hospitalized coronavirus di-
peated testing of semen samples for Ebola virus RNA, collection sease 2019 patients. The extensive clinical experience with the
of 97% of planned semen samples, and no participants lost to drug in diverse patient populations supports consideration of a
follow-up. Each participant provided a total of 11 samples over modified treatment regimen, including use of a 200-mg loading
6 months. Repeat testing over time is necessary because persis- dose and/or extending the treatment course past 5 days.
tent seminal Ebola virus RNA, which tends to gradually decrease While the efficacy results of this study are encouraging, a larger
with time, is only intermittently detectable as less viral RNA is phase 2b/3 study is needed to reach a final conclusion about the
present in the semen. Whether intermittent detection is an indi- impact of remdesivir on persistence of Ebola virus RNA in semen.
cation of intermittent viral replication is not known. Participants in a study conducted closer to the time of acute
When our study began in July 2016, the US Food and Drug EVD would have a higher burden of persistent virus, be more
Administration (FDA) had restricted remdesivir use to popu- likely to consistently test positive before treatment (enriching the
lations with either EVD or evidence of persistent Ebola virus double-positive stratum), and perhaps be more likely to experi-
RNA. In June 2018, however, the Data Safety and Monitoring ence improvement in PES. Such a study, planned for the eastern
Board granted Gilead Sciences’ request that our unblinded Democratic Republic of Congo following the second largest
statistician provide safety data from the 38 participants in Ebola outbreak from 2018–2020, is on hold due to the Severe
PREVAIL IV to the FDA while keeping the study team blinded. Acute Respiratory Syndrome Coronavirus-2 pandemic.
The FDA then modified its partial clinical hold on remdesivir If efficacy is confirmed, a practice of acute EVD treatment
to allow additional phase 1 studies in healthy volunteers in the with monoclonal antibodies followed by maintenance treatment
Table 4. Presence of Targeted Signs and Symptoms (Any Grade) During and After Infusion Week
During Infusion Week After Infusion Week
Sign/Symptom Remdesivir Placebo Remdesivir Placebo
Dizziness 0 (0.0) 1 (5.6) 1 (5.0) 2 (11.1)
Dyspepsia 1 (5.0) 0 (0.0) 0 (0.0) 1 (5.6)
Tremor 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6)
Pruritis 1 (5.0) 0 (0.0) 3 (15.0) 4 (22.2)
Rash 0 (0.0) 0 (0.0) 0 (0.0) 4 (22.2)
Unexplained bleeding or bruising 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6)
Anorexia 1 (5.0) 4 (22.2) 0 (0.0) 5 (27.8)
Diarrhea 1 (5.0) 3 (16.7) 2 (10.0) 2 (11.1)
Nausea 4 (20.0) 3 (16.7) 1 (5.0) 1 (5.6)
Vomiting 1 (5.0) 1 (5.6) 0 (0.0) 0 (0.0)
Constipation 0 (0.0) 0 (0.0) 0 (0.0) 2 (11.1)
Headache 2 (10.0) 5 (27.8) 2 (10.0) 6 (33.3)
Infusion site pain 2 (10.0) 3 (16.7) 1 (5.0) 3 (16.7)
Any of above 10 (50.0) 10 (55.6) 7 (35.0) 12 (66.7)
Number of participants 20 18 20 18
1854 • cid 2021:73 (15 November) • Higgs et alTable 5. Reported Symptoms and Exam Abnormalities for Partnership for Research on Infectious Diseases and Vaccines in Liberia (PREVAIL) IV
Participants Approximately 2 Years and 2.5 Years After Acute Ebola Virus Disease (EVD) and for PREVAIL III Ebola Survivors Approximately 2 Years After
Acute EVD
PREVAIL IV (N = 38) PREVAIL III (N = 860)
Baseline (Approximately 2 Years Final Visit (Approximately 2.5
Symptom/Exam Abnormality Post-EVD) Years Post-EVD) 12-Month Visit (Approximately 2 Years Post-EVD)
Joint pain 18 47% 0 0% 28%
Headache 10 26% 0 0% 33%
Urinary frequency 9 24% 0 0% 2%
Memory loss 9 24% 0 0% 5%
Fatigue 7 18% 0 0% 5%
Muscle pain 7 18% 0 0% 8%
Uveitis 12 32% 9 24% 33%
Neurological 7 18% 1 3% 2%
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Chest 6 16% 1 3% 1%
Musculoskeletal 6 16% 1 3% 1%
Abdominal 5 13% 0 0% 5%
Joint 4 11% 1 3% 1%
Source: Sneller et al., Table 2.
Abbreviations: EVD, Ebola virus disease; PREVAIL, Partnership for Research on Infectious Diseases and Vaccines.
with remdesivir or other agents that penetrates into immune- submitted work. All remaining authors: No reported conflicts of interest.
All authors have submitted the ICMJE Form for Disclosure of Potential
privileged sites could help end outbreaks more quickly, and
Conflicts of Interest. Conflicts that the editors consider relevant to the con-
provide better long-term outcomes for Ebola survivors, and tent of the manuscript have been disclosed.
prevent future outbreaks from transmission from persistent PREVAIL IV Study Team members. Esther Akpa, Sara Albert, Nene
virus in survivors. Djiba Barry, Tomas Cihlar, Katherine Cone, Joseph Cooper, Bonnie
Dighero-Kemp, Jestina Doe-Anderson, Laurie Doepel, Alain DuChene,
Supplementary Data Vanessa Eccard-Koons, Risa Eckes, Julie Endee, Tolno Facely, Patrick Faley,
Betsey Herpin, Marie Hoover, Melvin Johnson, Kade Kallon, Hassan Kiawu,
Supplementary materials are available at Clinical Infectious Diseases online.
Matthew Kirchoff, David Valle, Alan Lifson, John McCullough, Laura
Consisting of data provided by the authors to benefit the reader, the posted
McNay, Wissedi Njoh, Jerome Pierson, Mary Smolskis, Debby Wentworth,
materials are not copyedited and are the sole responsibility of the authors, so
Barthalomew Wilson, David Wohl Elizabeth Elliott, Lawrence Fakoli,
questions or comments should be addressed to the corresponding author.
Catherine Freeman, Gregory Kocher, Janie Liang, Jonathan Marchand,
Lindsay Marron, James Pettitt, and Bode Shobayo.
Notes
Author Contributions. E. S. H. was the principal investigator at the US
National Institute of Allergy and Infectious Diseases, D. G. -D. was the prin-
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