Antivenoms for Snakebite Envenoming: What Is in the Research Pipeline?

Of the 24 neglected tropical diseases (NTDs) and conditions listed by WHO, snakebite is among the top killers [1]. Tens of thousands of people die each year as a result of snakebite envenoming, with close to 50,000 deaths in India alone [2] and up to 32,000 in sub-Saharan Africa [3]. Yet there are few sources of effective, safe, and affordable antivenoms. The regions that bear the highest snakebite burden are especially underserved [4]. 
 
The Fav-Afrique antivenom, produced by Sanofi Pasteur (France), is considered safe and effective and is one of the few antivenoms to be approved by a Stringent Regulatory Authority (French National Regulatory Authority), although limited formal evidence has been published [5,6]. It is polyvalent, targeting most of the medically important snake species in sub-Saharan Africa. In particular, it is highly effective in treating envenoming by Echis ocellatus, the West African saw-scaled viper [5–7] that causes great morbidity and mortality throughout the West and Central African savannah. The venom of E. ocellatus may induce systemic haemorrhage, coagulopathy, and shock, as well as extensive local tissue damage. In the absence of treatment, the case fatality rate is 10%–20% [8]. Medecins Sans Frontieres (MSF) uses Fav-Afrique in its projects in sub-Saharan Africa, notably in Paoua in Central African Republic (CAR), where E. ocellatus envenoming is frequent [9]. Worryingly, MSF has been informed that the production of Fav-Afrique by Sanofi Aventis will be permanently discontinued. The last batch was released in January 2014, with an expiry date of June 2016. All the vials produced have already been sold by Sanofi Pasteur. 
 
Although several alternative antivenom products target a similar list of species as Fav-Afrique, there is currently no evidence of their safety and effectiveness. We aimed to review the evidence for the efficacy and safety of existing and in-development snake antivenoms, and to list the alternatives to Fav-Afrique in sub-Saharan Africa.


Search Strategy
We searched clinical trial registries (National Institutes of Health clinicaltrials.gov and WHO International Clinical Trial Registry Platform) and a publication database (EMBASE) to identify ongoing and completed clinical trials. The registries were searched by condition using the keywords "snakebite" OR "snake bite" OR "snake envenom Ã " OR "envenom Ã " OR "bite." Publication database search strategy was based on the Medical Subject Heading (MeSH) terms "clinical trial" AND "snake bites" AND "polyclonal antiserum OR snake venom antiserum OR venom antiserum." All terms were explored, and results were limited to studies conducted in humans. No time limits were imposed. Searches were conducted in September 2014 and included all records from the launch of the databases. Only those studies with a design compatible with that of a clinical trial (prospective, comparative, and interventional) and with the definition given by the CONSORT glossary were included. Prospective, single-arm cohorts were not considered as clinical trials.

Search Results
The registry searches yielded 29 records, four of which were observational studies. Among the interventional studies, 12 investigated antivenom as an intervention (eight were retrieved out of 176,201 records in clinicaltrials.gov and 12 out of 254,285 in ICTRP). Table 1 summarises the characteristics of the 12 trials. Four trials were sponsored by pharmaceutical companies and the remainder, by an individual researcher or academic institution. Four trials were open for recruitment and five were completed or terminated. A total of 11 different antivenoms were being investigated, most in only one trial.
The publication database search yielded 97 results (Fig 1). After cleaning, 82 records were retained, of which 30 had a design consistent with clinical trials. The remainder included 26 reviews or commentaries, 18 cohorts or cases series, four retrospective analyses of medical records, two case studies, one diagnostic study, and one cross-sectional survey. A search of references yielded an additional 11 reports of clinical trials. Of the 41 clinical trials thus identified, 32 investigated antivenom as an intervention. The locations of the 32 studies were Latin America (Brazil n = 3, Columbia n = 5, Ecuador n = 1); Asia (India n = 4, Thailand n = 5, Sri Lanka n = 3, Myanmar n = 1, Malaysia n = 1); Africa (Nigeria n = 5), and US (n = 4). 27 were sponsored by a public organization (e.g., university or public hospital). Most trials (n = 20) were conducted before 2000, the oldest dated from 1960 [10]. A total of 30 antivenoms were investigated; half were investigated in only one trial.

Urgent Need for More Research
Our results highlight the paucity of adequately conducted clinical trials and corroborate previous findings on the scarcity of safe, effective, and quality-assured snake antivenoms [4]. Comparison with dengue fever, which has a similar burden (11.97 Disability-Adjusted Life Years (DALYs) per 100,000 [4.99-20.46] versus venomous animal contacts 39.62 DALYs per 100,000 [22.46-69.74]) [13], is particularly revealing. In 2011, of 79 identified trials on dengue fever, 27 were recruiting patients, with six new products in development [14]. By contrast, the research pipeline for snakebite remains desperately dry, despite numerous calls for action [15][16][17].

Antivenoms in Sub-Saharan Africa
To determine how many antivenom products are currently available in sub-Saharan Africa, we searched WHO "Venomous snakes and antivenoms database" and held bilateral discussions with snakebite experts and pharmaceutical companies. We found that 12 antivenom products were commercially available in sub-Saharan countries as of September 2014 (Table 3), only three of which had been tested in at least one clinical trial, and many of which may lack efficacy [18].

Case study: The MSF experience in Central African Republic
The experience of MSF in CAR suggests that there are indeed significant variations in the efficacy of antivenoms against African snake venoms. MSF has been using Fav-Afrique to manage patients presenting with features of snakebite envenoming in Paoua, CAR, since 2008. In the first half of 2013, Fav-Afrique was temporarily unavailable, and an alternative product was   Table 2). Based on the trial design (Phase I to IV), ten products were considered still "under development," although development appears to have stalled for most of them. Our search strategy appears robust; a report conducted in 2010 identified a total of 43 randomized controlled trials on snakebite envenoming, 28 of which investigated antivenom properties [11]. We retrieved all except two of these trials [12,51]; the discrepancy could be due to differences in the criteria used to define clinical trials.
doi:10.1371/journal.pntd.0003896.g001  identified, directed against the venoms of 11 species of African snakes, including E. ocellatus. This antivenom was used for six months, with the same criteria for therapy as for Fav-Afrique. Although a methodologically sound study could not be conducted, a retrospective analysis of MSF medical records showed that the case fatality rate increased from 0.47% (three of 644 treated patients) with Fav-Afrique [9] to 10% (five of 50 treated patients) with the alternative antivenom. While more than 80% of patients were successfully treated with only one dose of Fav-Afrique, more than 60% treated with the alternative antivenom (31 of 50) required more than one dose to control envenoming. Worryingly, the first dose of the alternative antivenom was not able to alleviate spontaneous bleeding at admission in ten of 13 patients, and the administration of additional doses was required. These field data need cautious interpretation. However, they echo findings on the availability of ineffective and potentially harmful antivenoms in sub-Saharan Africa and support the conclusion that post-marketing surveillance is crucial [18]. They also call for a more robust and systematic evaluation of marketed products by regulatory authorities in the affected countries.

The Way Forward
Sanofi Pasteur urgently needs to disclose its plan to mitigate the negative impact of the decision to stop producing Fav-Afrique. Over the longer term, the multi-component strategy described by the Global Snakebite Initiative must be fully financed [19]; both innovations for better products and interventions and access to quality care need to be enhanced. The vast majority of the trials that we identified were sponsored by public organizations. The snakebite antivenom market so far appears poorly lucrative, unpredictable, and fragmented, hindering investment from pharmaceutical companies [4]. A major donor needs to step in, provide support, and, importantly, encourage existing global health initiatives, such as Drugs for Neglected Diseases initiative (DNDi), the Global Alliance for Vaccine and Immunization (GAVI)-Alliance, or the European and Developing Countries Clinical Trials Partnership (EDCTP), to extend their remits to life-saving treatments for snakebites. Finally, WHO should fully include snakebite envenoming in its list and programme of NTDs, support national regulatory authorities in performing adequate evaluations of existing antivenom products, and establish partnerships for access to existing and future antivenoms. Snakebite envenoming has been a most neglected disease for far too long.