Postexposure prophylaxis for Lassa fever: Experience from a recent outbreak in Nigeria.

BACKGROUND: Secondary transmission of Lassa fever (LF) occurs in the community and in health-care facilities, and is associated with high fatality in Nigeria. We investigated the role of oral ribavirin postexposure prophylaxis (orPEP) in preventing LF among the primary contacts of confirmed cases from December 2015 to March 2016.
MATERIALS AND METHODS: Epidemiological and clinical data of LF contacts were prospectively collected. However, information regarding ribavirin adverse effects (AEs) were collected retrospectively through a telephone interview. High-risk contacts were clinically monitored ΁ orPEP.
RESULTS: Thirty-five (94.6%) out of the 37 individuals enrolled in the study were contacts of confirmed LF cases, and friends and family members (54%) constituted the largest group. However, only 29 (83%) individuals were classified as high-risk contacts. Twenty-one (60%) of contacts were prescribed ribavirin with 6 (28.6%) of them reporting AEs. Body weakness (33%) was the most frequent AE, but there was no incidence of treatment discontinuation due to AE. Furthermore, there were no reported cases of LF among all respondents (0%), whether they had orPEP or not.
CONCLUSION: Secondary transmission of LF seems uncommon and the benefit of orPEP is uncertain. Although AEs of ribavirin may not be uncommon, they are rarely serious enough to cause treatment interruption. More emphasis should be on supporting persons looking after LF cases adopt measures that minimize the risks of exposure.

INTRODUCTION

Lassa fever (LF) is a viral hemorrhagic disease transmitted by Mastomys natalensis, the primary rodent species that carries Lassa virus (LV).1 The modes of transmission include exposure of broken skin/mucous membranes to contaminated blood/body fluids.2 Published data suggest that 4-55% of individuals in West Africa have serological evidence of exposure to LV,13 with a prevalence of 21% in Nigeria.4 Imported cases have been documented in the United States and Europe, and there is global concern that LV can be weaponized.567 According to the World Health Organization, the overall mortality rate is 1%, but climbs to 15% among hospitalized patients,8 and rates exceeding 40% have been reported in Nigeria.910 While the Nigerian strains of LV may be more virulent,11 delays in instituting appropriate treatment could also account for the higher mortality.

Timely administration of intravenous ribavirin, a virustatic guanosine analogue, reduces mortality.12 However, questions regarding the efficacy and appropriate dosages of oral ribavirin as postexposure prophylaxis (orPEP) are unresolved.513 The minimum inhibitory concentration of ribavirin for LV from an in-vitro study is in the range of 4-40 μmol/L, but a mean peak plasma concentration of only 3.1 μmol/L (range: 1.2-9.6 μmol/L) was achieved with oral administration of 1 g/day in three divided doses for 10 days in humans.1415

Prescription practices for orPEP differ in Nigeria, and systematic studies on their efficacy or adverse effects (AEs) are lacking. In addition, the cost of a 10 day course varies from $42 to $1819, depending on the dose prescribed, the manufacturer and the period of purchase.13 Given the public health importance of LF and the need for better utilization of scarce resources, we investigated the role of orPEP in the prevention of secondary cases of LF.

MATERIALS AND METHODS

The study was carried out at the Jos University Teaching Hospital (JUTH) from December 2015 to March 2016. The hospital is a major referral center situated in Jos, the capital city of Plateau State.

Epidemiological and clinical data of respondents who had direct contact with suspected LF cases seen at JUTH were prospectively collected. Contact tracing and other aspects of the epidemic response were carried by officials of the State Ministry of Health and JUTH infectious diseases physicians. Contacts were categorized as high- or low-risk as defined by Bausch et al.13 In brief, high-risk exposure includes: (1) Needlestick injury (2) splashes on mucous membrane/broken skin (3) carrying out emergency procedures without the use of appropriate personal protective equipment (PPE) (4) continuous contact for hours in an enclosed space without the use of appropriate PPE. All contacts were advised to monitor their axillary temperature in the mornings and evenings for 21 days from the last day of exposure, and to report fever (≥38.0°C) for further evaluation. According to our usual practice, orPEP was offered to those with high-risk exposure, in whom ribavirin was not contra-indicated. LV-specific reverse-transcriptase polymerase chain reaction test for case confirmation was carried out at two Nigerian reference centers. Oral PEP was discontinued for those whose exposure source tested negative. High-risk contacts of positive cases who enrolled in the study were prescribed different regimens of oral ribavirin (LOT: 141102, Hubei Meibao Pharmaceutical, Tianzshan, China). Data on self-reported orPEP adherence and AEs were collected retrospectively in a telephone interview, approximately 4 weeks after orPEP prescription.

The main outcome measure was the proportion of primary contacts of confirmed LF cases who became ill with LF.

Ethical approval for this study was obtained from the JUTH Ethics Committee. The data set was anonymized by transcribing names into initials and serial numbers.

Statistical analysis was performed using SPSS (version 20, Chicago, IL, USA). Continuous variables were expressed as means ± standard deviations, or medians with interquartile range (IQR). Categorical variables were presented as proportions and compared using the Chi-squared tests or Fisher's exact test as appropriate. Means were compared using unpaired Student's t-tests. The value of P < 0.05 was considered statistically significant.

RESULTS

There were 45 primary contacts of suspected LF cases, but only 37 (82.2%) were identified for the study. Their mean age was 40.1 years (±10.9) and 18 (48.6%) were male. Friends and family members were the most exposed group (54.1%), and most were exposed while nursing the suspected cases. Whereas 35 (94.6%) of the 37 persons had contact with 10 confirmed LF cases, exposure was categorized as high-risk in only 29 (82.9%). Twenty-one individuals had orPEP and the self-reported adherence was 80.9% (17/21). The demographic and epidemiologic characteristics of all primary contacts are shown in Table 1.

Table 1

Demographic, epidemiologic and clinical characteristics of 37 respondents exposed to suspected/confirmed Lassa fever cases

The clinical characteristics and outcomes of contacts of confirmed LF cases who took orPEP compared with those who did not are shown in Table 2. There were no significant differences in age, sex, or exposure groups. Of the 21 contacts who were prescribed orPEP, 6 (28.6%) reported AEs during a median follow-up period of 30 (IQR: 29-35) days. While 3 (21.4%) of contacts not prescribed ribavirin also reported symptoms, there was no significant difference between the two groups (P = 0.58). None of the exposed individuals were diagnosed with LF.

Table 2

Comparison of clinical characteristics and ribavirin prophylaxis outcomes among 35 contacts of confirmed Lassa fever cases

There were 12 episodes of AEs attributed to orPEP. The median duration from exposure to initiating orPEP was 4 (IQR: 2-9) days while assessment of AEs was carried out 30 (IQR: 29-35) days after Ribavirin prescription. Body weakness was the most frequent AE 4 (33.3%), followed by insomnia 2 (16.7%) and dizziness 2 (16.7%). Diarrhea, malaise, dyspepsia, and palpitation were also reported once, each representing a proportion of 8.3%. Those prescribed 500 mg 4×/day for 10 days reported the most AEs 6 (50%). Curiously, there were no AEs with 2 g start, 1 g 3 × daily × 10 days prescription. Four (23.5%) individuals on orPEP had been regularly on antacids and hydrochlorothiazide/amiloride. None of those with AEs reported treatment interruption. The distribution of AEs and associated orPEP dosages is shown in Table 3.

Table 3

Adverse effects reported among contacts of confirmed Lassa fever cases who received oral ribavirin postexposure prophylaxis (N=6)

DISCUSSION

In this study, no secondary transmission of LF occurred with or without orPEP. AEs were reported in 6 (28.6%) individuals who took Ribavirin but curiously, none was reported among those prescribed the highest doses.

The absence of secondary cases of LF in this study suggests that person to person transmission may be uncommon. This is in agreement with a study in the United States in which there was no documented transmission among 188 contacts of an imported case; five of the contacts were considered high risk but were not prescribed ribavirin.5 Similarly, there was no secondary transmission, other than one probable asymptomatic infection in a physician, among 30 and 20 high-risk contacts in Germany16 and Nigeria, respectively.17 In these two studies, ribavirin prophylaxis was prescribed. However, there are reports of a seemingly secondary community transmission,18 and of nosocomial transmissions in Nigeria.218 The risk of transmission appears low even among nonimmune individuals residing in nonendemic regions.516 However, the effective use of convalescent human sera for treatment1920 indicates that acquisition of neutralizing antibodies from the previous infection could confer protection in some individuals, and may therefore account for differences in susceptibility in endemic regions. Another possible reason for reported differences in transmission is the severity of illness of the source cases at the time of exposure. Viremia increases as illness progresses, with the risk of transmission increasing in individuals exposed to LF cases with severe disease.716

In the current study, we also examined AEs associated with orPEP prescription. Several studies have described the AE profile of ribavirin and reports indicate that they are largely mild and reversible.131617 While the Nigerian Federal Ministry of Health recommends a 7 day course of 500 mg 4×/day (unpublished), variations in prescription may partly be a reflection of conflicting data regarding efficacy and AEs. Overall, 6/21 (28.6%) individuals reported AEs in our study, without those prescribed the highest doses. Iroezindu et al.17 reported 12/18 (66.7%) AEs using similarly high dose.17 They also reported fatigue and dizziness as the most common AEs, which is consistent with our own findings, as body weakness and fatigue may mean the same in Nigeria. The report of symptoms in our comparison group who were not on orPEP and in those concurrently on other medications [Table 2] suggest that psychosomatization, AEs from other medications and occurrence of illnesses unrelated to LF can all confound reports of AEs.17 Although laboratory evidence of Ribavirin AEs has been reported, including increased bilirubin and decreased hemoglobin, they are rarely significant enough to cause treatment interruption.1617

While our study is the largest evaluation of high-risk contacts of several confirmed LF cases during a single outbreak, it has important limitations. Since we did not assay for LV IgM or IgG antibodies, it was not possible to determine if asymptomatic infection occurred and if administration of ribavirin had any effect on the development of protective immunity in the short or long-term. Ribavirin adherence was self-reported, and as an observational study, we were unable to establish causality with reported AEs. Nonetheless, the inclusion of a control group, although few numbers, indicates that reported AEs can be due to reasons other than ribavirin. Laboratory evidence for AEs was not investigated. However, except perhaps for selected individuals, routine testing may not be necessary or even feasible in endemic regions due to resource constraints.

CONCLUSION

Symptomatic secondary transmission of LF is uncommon. Furthermore, AEs of ribavirin may not be uncommon, but they are rarely serious enough to cause treatment interruption. Although controlled studies for LF would be difficult to conduct, larger prospective studies could improve our understanding of the interactions between host immunity, the risk of infection and the cost-effectiveness of ribavirin prophylaxis. Meanwhile, all persons looking after LF cases, especially friends/relatives, should be supported to adopt measures that reduce the risks of exposure.

Financial support and sponsorship

The ribavirin caplets were provided by the Federal Ministry of Health, Abuja, Nigeria.

Conflicts of interest

There are no conflicts of interest.