To date only ribavirin, a broad anti-RNA virus inhibitor, demonstrates
in vitro activity against CCHFV either in cell culture [
33,
34], or in mice models [
35,
36]. In the historical study conducted by Mardani
et al. in Iran during 1999-2001, the case fatality rate was 11.6% (8 of 69 patients) in the group treated with oral ribavirin compared with 58.3% (7 of 12 patients) in the untreated group, which corresponded to 80% efficacy (
P < 0.001) [
37]. This study constituted the basis for the World Health Organization (WHO) recommendations for treating CCHF patients with ribavirin. Promising results were also reported by others, and were mainly associated with early treatment [
38‐
40]. However, the use of ribavirin for CCHF treatment remains an issue of controversy since no difference in case fatality rates was found in other studies [
41‐
43], including the only randomized controlled trial published on this topic so far (6.3% among 64 ribavirin-treated patients versus 5.6% among 72 untreated patients;
P = 0.86) [
42]. Almost all data about ribavirin efficacy are limited to small observational studies and case series, and questions about methodological issues have been raised (for example no control for disease severity or day of initiation of treatment) [
17]. In a recent meta-analysis of 21 studies assessing the efficacy of ribavirin on CCHF outcome, the authors concluded that current evidence is insufficient to provide a clear answer [
44]. Currently, ribavirin is used in most endemic countries [
17], and ethical issues about using a placebo-control group have been raised. Given the high fatality rates associated with CCHF, a well-designed multi-center, randomized controlled trial taking into account severity criteria is urgently needed in order to provide evidence-based data about ribavirin efficacy.
Recombinant and natural interferons-α exhibit activity against CCHFV
in vitro, and might prove a promising treatment approach in the very early course of illness or as post-exposure prophylaxis, however no human studies have been conducted yet [
45]. The MxA protein, an interferon-induced protein of the superfamily of large GTPases, is a key component in the interferon-induced inhibition of replication of several viruses, including CCHFV [
46]. There are data suggesting that CCHFV possesses mechanisms to defeat the interferon-induced defense mechanisms by delaying IFN secretion for 48 hours post-infection [
47]. This may allow the rapid progression of illness rendering the infection almost IFN-insensitive, a phenomenon that may be linked to its pathogenicity [
47]. Specific laboratory findings may serve as prognostic factors for severe disease (for example severe thrombocytopenia, elevated transaminases, prolonged aPTT (activated partial thromboplastin time), decreased fibrinogen) with viral load and levels of specific cytokines playing an important factor affecting the course and the outcome of the disease [
24,
45,
48‐
51]. These factors may be useful as criteria for the construction of an algorithm about whether and when antiviral medications should be given.