High doses of favipiravir in two men survivors of Ebola virus disease carrying Ebola virus in semen in Guinea

BACKGROUND: Persistence of Ebola virus (EBOV) in semen remains of deep concern, as sexual transmission of EBOV seems plausible up to 6 months after acute phase of Ebola virus disease (EVD). Favipiravir, a broad spectrum antiviral product, has been evaluated in reducing EVD mortality in Guinea in 2014-2015 in the JIKI trial, the pharmacokinetic results of which suggest that an increase of dose might be necessary to achieve a therapeutically relevant exposure. In FORCE trial, we aimed at evaluating the tolerance and activity of high doses of favipiravir in male EVD survivors with EBOV RNA detection in semen in Guinea. CASE: In 2016, we launched a phase IIa open-labeled multicenter dose escalation study. Male survivors of EVD with EBOV RT-PCR positive on semen received a loading dose of 2400 mg BID of favipiravir on day 1 then a maintenance dose of 1800 mg BID from day 2-14. The primary outcome was the tolerance, assessed daily during period treatment and up to day 90. Unfortunately only two participants were included and the trial was stopped for lack of recruitment. No clinical adverse event of grade 3/4 was reported for both patients. One patient experienced a grade 3 hypocalcemia at day 10 and 14. CONCLUSIONS: High doses of favipiravir were well tolerated in these two participants. Better characterized tolerance and pharmacokinetics of high doses of favipiravir are of utmost importance considering that favipiravir is a candidate treatment for a variety of emerging severe viral diseases with poor prognosis

Molecular Diagnostics of Ebola Patient Samples by Institut Pasteur de Dakar Mobile Laboratory in Guinea 2014–2016

As part of the laboratory response to the Ebola virus outbreak in Guinea, the Institut Pasteur de Dakar mobile laboratory (IPD-ML) was set up in Donka hospital from 2014 to 2016. EBOV suspected samples collected at Ebola Treatment Centers (ETC) and from community deaths were sent daily to IPD-ML. Analysis was performed using dried oligonucleotide mixes for real-time RT-PCR designed for field diagnostic. From March 2014 to May 2015, a total of 6055 patient samples suspected for EBOV collected from seven regions of Guinea were tested by real-time RT-PCR. These patients’ clinical included serum samples (n = 2537 samples) and swabs (n = 3518 samples) with positivity rates of 36.74 and 6.88% respectively. Females were significantly more affected than males with positivity rates of 22.39 and 17.22% respectively (p-value = 5.721e-7). All age groups were exposed to the virus with significant difference (p-value <= 2.2e-16). The IPD-ML contributed significantly to the surveillance and patient management during the EBOV outbreak in Guinea. Furthermore, dried reagents adapted for field diagnostic of EVD suspect cases could be useful for future outbreak preparedness and response

Development and deployment of a rapid recombinase polymerase amplification Ebola virus detection assay in Guinea in 2015

In the absence of a vaccine or specific treatments for Ebola virus disease (EVD), early identification of cases is crucial for the control of EVD epidemics. We evaluated a new extraction kit (SpeedXtract (SE), Qiagen) on sera and swabs in combination with an improved diagnostic reverse transcription recombinase polymerase amplification assay for the detection of Ebola virus (EBOV-RT-RPA). The performance of combined extraction and detection was best for swabs. Sensitivity and specificity of the combined SE and EBOV-RT-RPA were tested in a mobile laboratory consisting of a mobile glovebox and a Diagnostics-in-a-Suitcase powered by a battery and solar panel, deployed to Matoto Conakry, Guinea as part of the reinforced surveillance strategy in April 2015 to reach the goal of zero cases. The EBOV-RT-RPA was evaluated in comparison to two real-time PCR assays. Of 928 post-mortem swabs, 120 tested positive, and the combined SE and EBOV-RT-RPA yielded a sensitivity and specificity of 100% in reference to one real-time RT-PCR assay. Another widely used real-time RT-PCR was much less sensitive than expected. Results were provided very fast within 30 to 60 min, and the field deployment of the mobile laboratory helped improve burial management and community engagement.Additional co-authors: Ali Mirazimi, Oliver Nentwich, Olaf Piepenburg, Matthias Niedrig, Amadou Alpha Sal

Use of Viremia to Evaluate the Baseline Case Fatality Ratio of Ebola Virus Disease and Inform Treatment Studies: A Retrospective Cohort Study.

BACKGROUND: The case fatality ratio (CFR) of Ebola virus disease (EVD) can vary over time and space for reasons that are not fully understood. This makes it difficult to define the baseline CFRs needed to evaluate treatments in the absence of randomized controls. Here, we investigate whether viremia in EVD patients may be used to evaluate baseline EVD CFRs. METHODS AND FINDINGS: We analyzed the laboratory and epidemiological records of patients with EVD confirmed by reverse transcription PCR hospitalized in the Conakry area, Guinea, between 1 March 2014 and 28 February 2015. We used viremia and other variables to model the CFR. Data for 699 EVD patients were analyzed. In the week following symptom onset, mean viremia remained stable, and the CFR increased with viremia, V, from 21% (95% CI 16%-27%) for low viremia (V < 104.4 copies/ml) to 53% (95% CI 44%-61%) for intermediate viremia (104.4 ≤ V < 105.2 copies/ml) and 81% (95% CI 75%-87%) for high viremia (V ≥ 105.2 copies/ml). Compared to adults (15-44 y old [y.o.]), the CFR was larger in young children (0-4 y.o.) (odds ratio [OR]: 2.44; 95% CI 1.02-5.86) and older adults (≥ 45 y.o.) (OR: 2.84; 95% CI 1.81-4.46) but lower in children (5-14 y.o.) (OR: 0.46; 95% CI 0.24-0.86). An order of magnitude increase in mean viremia in cases after July 2014 compared to those before coincided with a 14% increase in the CFR. Our findings come from a large hospital-based study in Conakry and may not be generalizable to settings with different case profiles, such as with individuals who never sought care. CONCLUSIONS: Viremia in EVD patients was a strong predictor of death that partly explained variations in CFR in the study population. This study provides baseline CFRs by viremia group, which allow appropriate adjustment when estimating efficacy in treatment studies. In randomized controlled trials, stratifying analysis on viremia groups could reduce sample size requirements by 25%. We hypothesize that monitoring the viremia of hospitalized patients may inform the ability of surveillance systems to detect EVD patients from the different severity strata

Use of Vibrio cholerae Vaccine in an Outbreak in Guinea

Producción CientíficaThe use of vaccines to prevent and control cholera is currently under debate. Shanchol is one of the two oral cholera vaccines prequalified by the World Health Organization; however, its effectiveness under field conditions and the protection it confers in the first months after administration remain unknown. The main objective of this study was to estimate the short-term effectiveness of two doses of Shanchol used as a part of the integrated response to a cholera outbreak in Africa. METHODS We conducted a matched case-control study in Guinea between May 20 and October 19, 2012. Suspected cholera cases were confirmed by means of a rapid test, and controls were selected among neighbors of the same age and sex as the case patients. The odds of vaccination were compared between case patients and controls in bivariate and adjusted conditional logistic-regression models. Vaccine effectiveness was calculated as (1-odds ratio) × 100. RESULTS Between June 8 and October 19, 2012, we enrolled 40 case patients and 160 controls in the study for the primary analysis. After adjustment for potentially confounding variables, vaccination with two complete doses was associated with significant protection against cholera (effectiveness, 86.6%; 95% confidence interval, 56.7 to 95.8; P=0.001). CONCLUSIONS In this study, Shanchol was effective when used in response to a cholera outbreak in Guinea. This study provides evidence supporting the addition of vaccination as part of the response to an outbreak. It also supports the ongoing efforts to establish a cholera vaccine stockpile for emergency use, which would enhance outbreak prevention and control strategies

Epidemiology of Epidemic Ebola Virus Disease in Conakry and Surrounding Prefectures, Guinea, 2014–2015

In 2014, Ebola virus disease (EVD) in West Africa was first reported during March in 3 southeastern prefectures in Guinea; from there, the disease rapidly spread across West Africa. We describe the epidemiology of EVD cases reported in Guinea’s capital, Conakry, and 4 surrounding prefectures (Coyah, Dubreka, Forecariah, and Kindia), encompassing a full year of the epidemic. A total of 1,355 EVD cases, representing ≈40% of cases reported in Guinea, originated from these areas. Overall, Forecariah had the highest cumulative incidence (4× higher than that in Conakry). Case-fatality percentage ranged from 40% in Conakry to 60% in Kindia. Cumulative incidence was slightly higher among male than female residents, although incidences by prefecture and commune differed by sex. Over the course of the year, Conakry and neighboring prefectures became the EVD epicenter in Guinea

Lessons learned for surveillance system strengthening through capacity building and partnership engagement in post-Ebola Guinea, 2015–2019

The 2014–2016 Ebola outbreak in Guinea revealed systematic weaknesses in the existing disease surveillance system, which contributed to delayed detection, underreporting of cases, widespread transmission in Guinea and cross-border transmission to neighboring Sierra Leone and Liberia, leading to the largest Ebola epidemic ever recorded. Efforts to understand the epidemic's scale and distribution were hindered by problems with data completeness, accuracy, and reliability. In 2017, recognizing the importance and usefulness of surveillance data in making evidence-based decisions for the control of epidemic-prone diseases, the Guinean Ministry of Health (MoH) included surveillance strengthening as a priority activity in their post-Ebola transition plan and requested the support of partners to attain its objectives. The U.S. Centers for Disease Control and Prevention (US CDC) and four of its implementing partners—International Medical Corps, the International Organization for Migration, RTI International, and the World Health Organization—worked in collaboration with the Government of Guinea to strengthen the country's surveillance capacity, in alignment with the Global Health Security Agenda and International Health Regulations 2005 objectives for surveillance and reporting. This paper describes the main surveillance activities supported by US CDC and its partners between 2015 and 2019 and provides information on the strategies used and the impact of activities. It also discusses lessons learned for building sustainable capacity and infrastructure for disease surveillance and reporting in similar resource-limited settings

Ebola virus disease in West Africa — the first 9 Months of the epidemic and forward projections

BACKGROUND On March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the epidemic to be a "public health emergency of international concern." METHODS By September 14, 2014, a total of 4507 probable and confirmed cases, including 2296 deaths from EVD (Zaire species) had been reported from five countries in West Africa - Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14. RESULTS The majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of EVD. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R-0) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5740 in Guinea, 9890 in Liberia, and 5000 in Sierra Leone, exceeding 20,000 in total. CONCLUSIONS These data indicate that without drastic improvements in control measures, the numbers of cases of and deaths from EVD are expected to continue increasing from hundreds to thousands per week in the coming months

Field investigation with real-time virus genetic characterisation support of a cluster of Ebola virus disease cases in Dubréka, Guinea, April to June 2015

On 11 May 2015, the Dubréka prefecture, Guinea, reported nine laboratory-confirmed cases of Ebola virus disease (EVD). None could be epidemiologically linked to cases previously reported in the prefecture. We describe the epidemiological and molecular investigations of this event. We used the Dubréka EVD registers and the Ebola treatment centre’s (ETC) records to characterise chains of transmission. Real-time field Ebola virus sequencing was employed to support epidemiological results. An epidemiological cluster of 32 cases was found, of which 27 were laboratory confirmed, 24 were isolated and 20 died. Real-time viral sequencing on 12 cases demonstrated SL3 lineage viruses with sequences differing by one to three nt inside a single phylogenetic cluster. For isolated cases, the average time between symptom onset and ETC referral was 2.8 days (interquartile range (IQR): 1–4). The average time between sample collection and molecular results’ availability was 3 days (IQR: 2–5). In an area with scarce resources, the genetic characterisation supported the outbreak investigations in real time, linking cases where epidemiological investigation was limited and reassuring that the responsible strain was already circulating in Guinea. We recommend coupling thorough epidemiological and genomic investigations to control EVD clusters.Peer Reviewe