Introduction
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]. Médecins Sans Frontières (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*” OR “envenom*” 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.
Table 1. List of clinical trials investigating snake antivenom published in clinical trials registries.
Trial ID number | Title | Sponsor | Type of funding | Location | Year of trial registration | Recruitment status | Results published |
---|---|---|---|---|---|---|---|
NCT00303303 | The Efficacy of Crotaline Fab Antivenom for Copperhead Snake Envenomations | Carolinas Healthcare System | Government | United States | 2006 | Terminated | No |
NCT00636116 | Phase 3 Multicenter Comparative Study to Confirm Safety and Effectiveness of the F(ab)2 Antivenom Anavip | Instituto Bioclon S.A. de C.V. | Industry | US | 2008 | Completed | No |
NCT00639951 | Study to Evaluate the Efficacy of Two Treatment Schemes With Antivipmyn for the Treatment of Snake Bite Envenomation | Instituto Bioclon S.A. de C.V. | Industry | Mexico | 2008 | Recruiting | NA |
NCT00811239 | A Controlled Clinical Trial on The Use of a Specific Antivenom Against Envenoming by Bungarus Multicinctus | Hanoi Medical University | Government | Vietnam | 2008 | Completed | Yes [21] |
NCT00868309 | A Comparison of Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom (Anavip) and Crotalidae Polyvalent Immune Fab, Ovine Antivenom (CroFab) in the Treatment of Pit Viper Envenomation | Instituto Bioclon S.A. de C.V. | Industry | US | 2008 | Completed | Yes [22] |
ISRCTN01257358 | Clinical trial of two new anti-snake venoms for the treatment of patients bitten by poisonous snakes in Nigeria | Nigeria MoH | Unknown | Nigeria | 2009 | Completed | Yes [23] |
SLCTR/2010/006 | Low dose versus high dose of Indian polyvalent snake antivenom in reversing neurotoxic paralysis in common krait (Bungarus caeruleus) bites: an open labelled randomised controlled clinical trial in Sri Lanka | Individual researcher | None | Sri Lanka | 2010 | Not recruiting | No |
ACTRN12611000588998 | A randomised controlled trial of antivenom and corticosteroids for red-bellied black snake envenoming | Individual researcher | Government | Australia | 2011 | Not recruiting | No |
NCT01284855 | Comparison of Two Dose Regimens of Snake Antivenom for the Treatment of Snake Bites Envenoming in Nepal | University of Geneva | Government | Nepal | 2011 | Not recruiting | No |
NCT01337245 | Emergency Treatment of Coral Snake Envenomation With Antivenom | University of Arizona | Government | US | 2011 | Recruiting | NA |
ACTRN12612001062819 | A randomized controlled trial (RCT) of a new monovalent antivenom (ICP Papuan taipan antivenom) for the treatment of Papuan taipan (Oxyuranus scutellatus) envenoming in Papua New Guinea | University of Melbourne | Government | Papua New Guinea | 2012 | Recruiting | NA |
NCT01864200 | A Randomized, Double-Blind, Placebo-Controlled Study Comparing CroFab Versus Placebo With Rescue Treatment for Copperhead Snake Envenomation (Copperhead RCT) | BTG International Inc. | Industry | US | 2013 | Recruiting | NA |
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.
Table 2. List of antivenoms investigated in clinical trials published in peer-reviewed journals or on public registries.
Product name | Other name/product specifications | Manufacturer | Development stage 1 | Target region | Publications | Clinical trials registry number |
---|---|---|---|---|---|---|
CroFab | Polyvalent ovine antivenom (Fab) against Crotalid | Protherics | Phase III–IV | North America | [22,24,25] | NCT00303303 NCT00636116 NCT00868309 NCT01864200 |
Anavip | Polyvalent equine antivenom (Fab2) against Crotalinae (pit viper) | Instituto Bioclon S.A. | Terminated after Phase III | North America | [22] | NCT00868309 NCT00636116 |
Antivypmin | Polyvalent equine antivenom (Fab2) against Crotalinae (pit viper) | Instituto Bioclon S.A. | Phase III | North America | None | NCT00639951 |
NA | Polyvalent equine antivenom (Fab2) against North American Coral snakes (Micrurus) | University of Arizona | Phase III | North America | None | NCT01337245 |
Tiger snake antivenom | Monovalent equine (Fab) against Notechis scutatus | CSL | Phase III–IV | Australia | None | ACTRN12611000588998 |
Taipan antivenom | Monovalent equine (Fab) against Oxyuranus scutellatus | CSL | Phase I–II | Australia | None | ACTRN12612001062819 |
Antibotropico IVB | Instituto Vital Brazil | Phase II | Latin America | [26] | None | |
Antibotropico Butantan | Polyvalent equine antivenom against Bothrops species | Instituo Butantan | Phase II–III | Latin America | [26–29] | None |
Antibotropico FUNED | Fundação Ezequiel Dias | Terminated | Latin America | [26] | None | |
Antibotropico-laquetico Butantan | Bothrops-Lachesis polyvalent equine antivenom | Instituo Butantan | Phase II | Latin America | [30] | None |
Antiofiodico botropico polivalente | Polyvalent equine antivenom (IgG) against Bothrops asper, Bothrops atrox, and Bothrops xanthogrammus | Instituto Nacional de Higiene y Medicina Tropical "Leopoldo Izquieta Pérez" | Phase II–III | Latin America | [28] | None |
Monovalent B. atrox equine antivenom | Instituto Clodomiro Picado | Terminated | Latin America | [31,32] | None | |
Monovalent B. atrox equine antivenom | Instituto Nacional de Salud | Terminated | Latin America | [29] | None | |
B. atrox–Lachesis antivenom | Polyvalent equine antivenom (IgG) against B. atrox and Lachesis muta muta | Fundação Ezequiel Dias | Terminated | Latin America | [30] | None |
Polyvalent Antivenom | Polyvalent equine antivenom (IgG) against B. asper, Crotalus durissus, and L. muta | Instituto Nacional de Salud | ? | Latin America | [28] | None |
Polyvalent antivenom ICP | Polyvalent equine antivenom (IgG or Fab2) against B. asper, Crotalus simus, and Lachesis stenophrys | Instituto Clodomiro Picado (University of Costa Rica) | Phase II | Latin America | [31–34] | None |
EchiTab | Monovalent ovine antivenom (Fab) against Echis oscellatus | Therapeutic Antibodies/Micropharm | ? | Sub-Saharan Africa | [35] | None |
EchiTab Plus | Polyvalent equine antivenom against Bitis arietans, E. oscellatus, and Naja nigricollis | Instituto Clodomiro Picado (University of Costa Rica) | Phase I–II | Sub-Saharan Africa | [23,36] | ISRCTN01257358 |
EchiTab G | Monovalent antivenom (IgG) against E. oscellatus | Micropharm | Phase I–II | Sub-Saharan Africa | [23,36] | ISRCTN01257358 |
EgyVac antivenom | Equine polivalent antivenom against B. arietans, E. oscellatus, and N. nigricollis | Vacsera Ltd | Terminated after Phase I | Sub-Saharan Africa | [36] | None |
Ipser Africa Antivenom | Polyvalent equine (Fab2) antivenom against B. arietans, Bitis gabonica, Echis leucogaster, N. nigricollis, Naja haje, Naja melanoleuca, Dendroaspis viridis, Dendroaspis jamesoni, and Dendroaspis augisticeps | Institut Pasteur | ? | Sub-Saharan Africa | [35] | None |
Monospecific antivenom against E. oscellatus | Institut Pasteur | ? | Sub-Saharan Africa | [37,38] | None | |
SAIMR Echis antivenom | Monovalent equine antivenom (IgG or Fab2) against Echis carinatus / ocellatus | South African Vaccines Producer | ? | Sub-Saharan Africa | [38] | None |
North and West African polyvalent antivenom (Echis, Bitis, Naja) | Behningwerke | ? | Sub-Saharan Africa | [37,38] | None | |
Malayan pit viper antivenom | Monovalent equine antivenom against Calloselasma rhodostoma | Queen Saovabha Memorial Institute | Phase I–II | South East Asia | [11,39–41] | None |
Malayan pit viper antivenom | Monovalent caprine antivenom against C. rhodostoma | Twyford Pharmaceutical | Phase I–II | South East Asia | [39–41] | None |
Malayan pit viper antivenom | Monovalent equine antivenom against C. rhodostoma | Thai Government Pharmaceutical Organisation | Phase I–II | South East Asia | [39–41] | None |
Monocellate cobra antivenom | Monovalent equine antivenom against aja. kaouthia | Queen Saovabha Memorial Institute | ? | South East Asia | [42] | None |
Green pit viper antivenin (QSMI) | Polyvalent equine antivenom (Fab2) against green pit vipers | Queen Saovabha Memorial Institute | Phase I–II | South East Asia | [41,43] | None |
B. multicinctus and B. candidus antivenom | Polyvalent equine antivenom (Fab2) against Bungarus multicinctus and Bungarus candidus | Vietnam Poison Control Center, Hanoi Medical University | Phase I–II | South East Asia | [21] | NCT00811239 |
Monospecific antivenom against D. russelii | Myanmar Pharmaceutical Factory | ? | South East Asia | [44] | None | |
ProlongaTab | Monovalent ovine antivenom (Fab) against Daboia russelii | Therapeutic Antibodies Inc | Terminated | South Asia | [45,46] | None |
SII Polyvalent ASV IP | Polyvalent equine antivenom (Fab2) against Naja naja, E. carinatus, D. russelii and Bungarus caeruleus | India Serum Institute | ? | South Asia | [47–49] | None |
Snake antivenin IP | Polyvalent equine antivenom (Fab2) against N. naja, E. carinatus, D. russelii and B. caeruleus | Haffkine Biopharmaceutical Corporation Ltd | Phase II | South Asia | [45,46,50,51] | None |
Snake venom anti-serum | Polyvalent equine F(ab)2 against B. caeruleus, N. naja, D. russelii and E. carinatus | VINS bioproducts | Phase II | South Asia | None | SLCTR/2010/006 NCT01284855 |
Snake venom antiserum | Polyvalent equine F(ab)2 against B. caeruleus, N. naja, D. russelii and E. carinatus | Bharat Serum and Vaccines Ltd | Phase II | South Asia | None | SLCTR/2010/006 |
1 Not all publications mentioned the trial phase, and development status was established based on trial design, primary objectives, and number of subjects. This classification, though, bears some limitations, especially with regards to snake antivenoms development, in which Phase I with healthy volunteers are generally not conducted.
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 [15–17].
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].
Table 3. Available snake antivenom products in sub-Saharan Africa, as of September 2014.
Product | Company | Country of production |
---|---|---|
Antivipmyn-Africa | Instituto Bioclon/Silanes | Mexico |
ASNA-C | Bharat Serums and Vaccines | India |
ASNA-D | Bharat Serums and Vaccines | India |
EchiTabG | MicroPharm | United Kingdom |
EchiTabPlus | Instituto Clodomiro Picado | Costa Rica |
Fav-Afrique | Sanofi Pasteur | France |
Inoserp PanAfrica | Inosan | Spain |
SAIMR Boomslang antivenom | South African Vaccine Producers | South Africa |
SAIMR Echis antivenom | South African Vaccine Producers | South Africa |
SAIMR Polyvalent Snake antivenom | South African Vaccine Producers | South Africa |
Snake Venom Antiserum (Pan-African) | VINS Bioproducts | India |
Snake venom antiserum Echis ocellatus | VINS Bioproducts | India |
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 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.
Acknowledgments
We would like to thank Sarah Venis for her thorough review of the manuscript and Elisabeth Baudin for performing the cleaning and analysis of the data from Paoua, Central African Republic.
Funding Statement
The authors received no specific funding for this work.
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