Centro collaboratore OMS in Italia

Strongiloidosi ed infezioni parassitarie intestinali

Attività anno 2016

Responsabili:

dott. Zeno Bisoffi

dott.ssa Dora Buonfrate

01 dicembre 2017

www.salute.gov.it

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Rapporto di attività del centro per Terms of Reference (TOR),

come indicato da OMS

1. TOR 1: Valutare il burden globale della strongiloidosi

1 Il lavoro di stima globale del burden causato dalla strongiloidosi, finalizzato alla valutazione di

una possibile implementazione di campagne di controllo di tale parassita da parte dell’OMS, è

stato suddiviso in due aspetti principali: stima della prevalenza globale e stima della morbidità e

mortalità causati dalla strongiloidosi. Sono pertanto in corso due revisioni sistematiche della

letteratura: una sulla prevalenza globale della strongiloidosi, in collaborazione con il centro

collaboratore SWI-71, facente capo allo Swiss Tropical and Public Health Institute di Basilea,

l’altra incentrata sulla morbidità e mortalità causata dall'infezione da S. stercoralis. I risultati

delle revisioni sistematiche saranno combinati al fine di stimare il burden globale della

strongiloidosi.

2 È stato elaborato un protocollo di studio di bioequivalenza che confronta la formulazione

commerciale dell’ivermectina attualmente disponibile per uso umano, Stromectol, con un

prodotto generico contenente lo stesso principio attivo. Il cc è disponibile per iniziare questo

studio su volontari sani, una volta che un prodotto generico sia stato selezionato dal team di

prequalificazione dell'OMS.

3 Continua lo studio sulla prevalenza della strongiloidosi in diverse aree dell'Ecuador. Cinque

province sono state incluse nell'analisi sierologica della biobanca dell'Università Centrale di

Quito. L'indagine tra le comunità indigene Awa è stata completata con la raccolta di campioni

fecali, oltre ai campioni di siero.

2. TOR 2: Valutazione dell'accuratezza dei diversi metodi

diagnostici per la strongiloidosi

1. Sono stati pubblicati due studi diagnostici, valutando diversi metodi per la diagnosi di

strongiloidosi:

- Formenti F, Buonfrate D et al. Comparison of S. stercoralis serology performed on dried

blood spots and on conventional serum samples. Front Microbiol 2016; 7: 1778.

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Lo studio mette a confronto la sierologia per S. stercoralis eseguita come da routine, su

campione di siero, e la stessa metodica eseguita invece su sangue intero raccolto su carta

filtro. Lo studio ha dimostrato che le due metodiche presentano un’elevata concordanza: il

risvolto pratico è interessante soprattutto per studi svolti in paesi a basse risorse, dove la

validazione della sierologia eseguita tramite raccolta di una goccia di sangue su carta filtro

renderebbe possibile raccogliere e conservare più agevolmente i campioni.

- Buonfrate D, Perandin F, et al. A retrospective study comparing agar plate culture, indirect

immunofluorescence and real-time PCR for the diagnosis of Strongyloides stercoralis

infection. Parasitology 2017; 11:1-5. Lo studio confronta l’accuratezza di metodiche diverse

per la diagnosi di strongiloidosi. La real-time PCR, metodica di più recente introduzione

rispetto alle altre, dimostra una sensibilità lievemente maggiore rispetto alla coprocoltura,

mantenendo elevata specificità. E’ quindi una metodica alternativa alla coprocoltura come

test di conferma in caso di sierologia positiva.

2. E’ stata eseguita una revisione sistematica con una meta-analisi di studi diagnostici che valutano

l'accuratezza dei metodi molecolari per la diagnosi di infezione da S. stercoralis. Lo studio è

attualmente under review.

3. È in corso uno studio che confronta la sensibilità della real-time PCR per S. stercoralis nell'urina

rispetto alla metodica real-time PCR eseguita nelle feci, come da routine. Lo studio è in

collaborazione con la John Hopkins University di Baltimora, USA, centro che ha sviluppato la

metodica di PCR (convenzionale) per S. stercoralis nell'urina.

4. È stato elaborato un protocollo di studio per uno studio diagnostico longitudinale sulla

strongiloidosi, con il quale si intende confrontare tutti i principali metodi diagnostici disponibili. In

attesa di fondi, lo studio inizierà nel 2018.

3. TOR 3: Valutazione una possibile inclusione di strongiloidiasi in

campagne basate sulla “preventive chemotherapy” (PC) per il

controllo dei geoelminti

1. E’ stato pubblicato il seguente articolo: Barda B, Albonico M, et al. Side benefits of mass drug

administration for lymphatic filariasis on Strongyloides stercoralis prevalence on Pemba Island,

Tanzania. Am J Trop Med Hyg. 2017 Jun 19. doi: 10.4269 / ajtmh.17-0050. Il lavoro descrive

l'effetto della PC con ivermectina, somministrata nell’ambito del programma di eradicazione delle

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filariosi linfatiche, sulla prevalenza della strongiloidosi a Zanzibar. Si dimostra come tali interventi

di massa, ripetuti nel corso degli anni, abbiano portato al calo della prevalenza anche della

strongiloidosi. Tali dati forniscono un rilevante supporto alla valutazione dell’implementazione di

programmi di controllo per la strongiloidosi basati su campagne di distribuzione di massa di

ivermectina.

2. I risultati delle revisioni sistematiche descritte in TOR 1 saranno inclusi in un modello

matematico volto a stimare il fabbisogno globale di ivermectina per il controllo della strongiloidosi.

Tale stima ci è stata direttamente richiesta dal Dipartimento della OMS al quale facciamo capo, per

pianificare procedure e costi per un’eventuale programma di PC per S. stercoralis.

4. TOR 4 Promuovere il networking e lo scambio di informazioni tra

ricercatori

1. Il cc contribuisce regolarmente alla piattaforma di condivisione “Strongyloides Sharing Platform”

gestita assieme alla OMS, presentando revisioni della letteratura, promemoria e proposte di

collaborazioni.

2. Si è svolta una riunione del network internazionale “StrongNet” come riunione a margine durante

il Congresso Europeo di Medicina e Igiene Tropicale (ECTMIH) tenutosi ad Anversa. La riunione è

stata organizzata da questo cc, e l'ordine del giorno dell'incontro è stato inviato ai membri di

StrongNet attraverso la piattaforma di condivisione. Tema centrale del meeting è stata la

disponibilità dell’ivermectina, farmaco non registrato per uso umano in numerosi paesi (tra i quali

l’Italia). In allegato 1 il verbale della riunione.

3. Un convegno internazionale sui farmaci per le malattie tropicali si è tenuto a Verona nel

novembre 2017 (la locandina in figura 1). Filo conduttore del convegno è stata la ricerca di

possibilità per superare le difficoltà di approvvigionamento dei farmaci per le malattie tropicali

neglette in Italia, primo fra tutti l’ivermectina per la strongiloidosi.

5. TOR 5 Per valutare l'efficacia di diversi regimi di ivermectina per il

trattamento e il controllo della strongiloidosi

Gli arruolamenti di pazienti nello studio Strong Treat (studio clinico randomizzato per il confronto

di una singola dose di ivermectina rispetto a dosi multiple per il trattamento della strongiloidosi)

sono stati interrotti sulla base di un'analisi ad interim. I risultati finali dello studio dovrebbero essere

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disponibili entro la fine del 2018, alla fine di tutte le visite di controllo, previste ad un anno

dall’arruolamento del paziente. Lo studio è coordinato e promosso da questo centro collaboratore,

con la partecipazione di diversi centri in Europa (Italia, Spagna e Regno Unito).

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Allegato 1. STRONG-NET OPERATIONAL MEETING

Satellite symposium at 10th ECTMIH, Antwerp, Belgium

Flanders Meeting and Convention Center, Peacock room

23 October 2017, 5 - 6.30 pm

List of participants

Albonico Marco, CTD Negrar, Verona, Italy

Amor Arancha, Mundo Sano Foundation

Anegagrie Melaku, Mundo Sano Foundation

Arandes Antoni Soriano, Hospital Universitari Vall d’Hebron Pediatrics Dep – Infect Dis, Spain

Barda Beatrice, Swiss TPH, Basel, Switzerland

Bartoloni Alessandro, University of Florence, Italy

Bennis Issam, National School of Public Health, Morocco

Bisoffi Zeno CTD Negrar, Verona, Italy

Bottieau Emmanuel, Institute Tropical Medicine, Antwerp, Belgium

Buonfrate Dora, CTD Negrar, Verona, Italy

Camprubi Ferrer Daniel, ISGlobal, Barcelona, Spain

de los Santos Juan Jose, Mundo Sano Foundation

Dooms Eric, Bruxelles, Belgium

Foekje Stelma, Radboudamc, Nymegen, Netherlands

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Getaz Laurent, Hopital Cantonal, Geneva, Switzerland

Giordani Maria Teresa, S Bortolo Hospital, Vicenza, Italy

Gotuzzo Eduardo, Universitad Peruana Cayetano Heredia, Lima , Peru

Hammarstrom Helena, Sahlgrenska University Hospital, Goteborg, Sweden

Janzen Anita, Medical Mission Institute, Wuerzburg, Germany

Levecke Bruno, University of Gent, Belgium

Lier Tore, Norway/Sweden

Montresor Antonio, Department of Control of Neglected Tropical Diseases, WHO, Geneva, Switzerland

Mueller Andreas, Medical Mission Hospital Dept Tropical Medicine, Wuerzburg, Germany

Muñoz Jose, ISGlobal, Barcelona, Spain

Navarro Miriam, SEMTSI, Spain

Olliaro Piero, WHO/TDR, Geneva, Switzerland

Potet Julien, MSF Access Campaign

Salvador Fernando, PROSICS Barcelona, Spain

Shwab Jean-Marc, Geneva Hospitals, Switzerland

Spinicci Michele, University of Florence, Italy

Stejskal Frantisek, University Hospital Prague, Czech Rep

Strohmeyer Marianne, University of Florence, Italy

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Tamarozzi Francesca, CTD Negrar, Verona, Italy

van Lieshout Lisette, LUMC, Leiden, Netherlands

Verweij Jaco, Elisabeth Hospital, Tilburg, The Netherlands

Zammarchi Lorenzo , University of Florence, Italy

Minutes of the meeting

Emmanuel Bottieau and Marco Albonico, chairs of the meeting, welcome the participants. Marco

describes Strong Net activities and the role of the WHO Strongyloides Sharing Platform. He

resumes key points from the previous meeting of Strong Net (ECTMIH in Basel in 2015), that have

also been reported in a paper published in PloS NTD (Albonico et al., 2016).

1. Lisette Van Lieshout gives an overview of the last Australian Workshop on

strongyloidiasis (held on the 23rd September 2017). Epidemiology (mapping endemic

areas in Australia) and control of strongyloidiasis were among the main issues. From the

clinical point of view, presentations mostly focused on issues about management of

infections in children (possible dosages of ivermectin - IVM ) and pregnant women (safety

of IVM administration in pregnancy). For diagnosis, serology combined with molecular

techniques are seen as a good option until a single test in points of care will be available;

for epidemiology, the need of a better understanding of the role of dogs in the

transmission of S. stercoralis was raised.

Many participants confirm that IVM is safe in pregnant women, as it was observed in mass

treatment administration campaigns (IVM given to women who did not know they were

pregnant). In particular, Antonio Montresor reports of a study in Sri Lanka, where no additional

risk for the fetus was observed 9 months after drug distribution. Piero Olliaro says that TDR

manages a pregnancy registry, where data on safety after exposure to a wide range of drugs is

reported. This could be extended to areas where IVM is distributed for preventive chemotherapy.

Arancha Amor confirms that in Ethiopia IVM was administered also to children under 5 during an

outbreak of scabies, with no problems of tolerability. Zeno Bisoffi adds that one main study on

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scabies control with ivermectin was conducted in Australia (Romani L et al, New Engl J Med 2015).

Piero Olliaro says that one limitation to the use of IVM for scabies in the field is the need for giving

a second dose 2 weeks apart. Moxidectin might be a valid alternative for strongyloidiasis as well as

for scabies. Eduardo Gotuzzo highlights that HTLV1is a relevant risk factor for development of

severe strongyloidiasis; HTLV1 prevalence in Australia is the highest in the world. He also points

out that veterinary formulations have been used to treat cases of dissemination, but they are not

reliable for potentially severe side effects.Arancha Amor raises attention to diagnostic issues: in

her experience, PCR loses 20% of infections when used in studies on the field, while PCR in

combination with Baermann demonstrated to be the best screening strategy, if samples are

processed few hours after collection

2. Jose Muñoz presents a questionnaire on availability of IVM. Eurosurveillance, the journal

of ECDC, is going to publish guidelines on the screening of helminths (S. stercoralis and

Schistosoma spp) in migrants coming to Europe. If screening for those helminths is

recommended, then their specific treatments should be available. The questionnaire aims

at evaluating availability of IVM at different levels (hospitals, pharmacies…) in several

European countries. The results of the questionnaire will be used to design a map, showing

the countries where IVM is available.

3. Antonio Montresor illustrates possible initiatives to expand ivermectin availability, both

in endemic and non-endemic countries. He points out that IVM has been included in the

essential medicine list (EML) with indication of treatment for strongyloidiasis, and this

normally has a positive impact on registration /availability of a drug in several countries.

Also, IVM is now included in the EML for co-administration with albendazole in preventive

chemotherapy campaigns for STH. The indication for scabies has not been included yet, but

a dossier will be soon submitted. However, Merck is not willing to donate IVM outside

programs for the control of lymphatic filariasis and onchocerciasis, hence availability of a

generic drug could be relevant. Unfortunately, pre-qualification of IVM generic products

(essential pre-requisite to permit WHO to use the drug in different countries in preventive

chemotherapy control programs) at the moment has not raised much interest, because the

manufacturers do not see market perspectives. There are veterinary producers but there is

a need of certifying products for human use. An estimate of the global need of IVM is

essential to convince generic producers to pre-qualify their products. After pre-

qualification, a bioequivalence study is essential to complete the process for the use in

WHO campaigns. The Centre for Tropical Diseases (CTD) in Negrar, Verona (WHO

collaborating centre) is qualified to conduct bioequivalence studies and is available to test

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a pre-qualified generic drug in healthy volunteers. Finally, availability of IVM and other

drugs for NTDs is often an issue also in non-endemic areas. For instance, IVM is available in

pharmacies only in a few European countries.

Andreas Mueller adds that IVM is now available in the pharmacies in Germany. Antonio Montresor

explains that registration of the drug in a country has to be requested by the manufacturer, but

there is often a little interest from the producers to register drugs for which they do not see a

lucrative market.

4. Dora Buonfrate presents the progress on estimating the global need for ivermectin,

related to advocacy of public health strategies to control strongyloidiasis. Main method

relies on collecting evidence on the burden of strongyloidiasis. Hence, two systematic

reviews of literature have been planned in collaboration with the Swiss Tropical and Public

Health Institute (Swiss TPHI, WHO collaborating centre; unfortunately no representative of

the STPHI could take part to the meeting). The Swiss TPHI is in charge of coordinating an

update of the review of global prevalence of strongyloidiasis. The CTD is reviewing the

morbidity and mortality related to S. stercoralis; although the selection of full text papers

of possible inclusion is still ongoing, it seems that there are only very few studies that can

be used to evaluate this aspect of strongyloidiasis. Eventually, the results of the two

reviews will be combined and presented to the WHO experts, who will use them to

elaborate possible scenarios for the control of strongyloidiasis (for instance, administration

at community level, administration to school children…). Final aim is estimating how much

IVM (and its relative costs) would be needed for the most cost-effective control strategy.

Synergies with other groups interested in IVM mass administration (such as control of

scabies, malaria) would be important to show manufacturers that the market might be

appealing. Moreover, availability of a generic IVM would help to sustain the costs.

5. Zeno Bisoffi discusses how to estimate the risk of dissemination and whether a registry

of severe cases is possible. The risk associated to different risk factors (steroids,

immunosuppressant conditions…) that might lead to severe strongyloidiasis is not clear,

and an estimation is very difficult, also considering that only few cases are diagnosed and

reported. He suggests to create a Strongyloides Sharing Platform - based registry of severe

cases. Zeno shows the draft of a CRF that could be uploaded in the Sharing Platform, so

that Strong Net members can use it to report severe cases of strongyloidiasis. Emmanuel

Bottieau asks if cases of severe strongyloidiasis seen in centres different from the ones

included in the Sharing Platform (and of which one of the Strong Net member comes to

know about) should be reported. Zeno answers that it would be a good idea to increase

the amount of data.

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The plenary discussion focuses on possible strategies to improve availability of IVM and on

alternative drugs. Beatrice Barda is presenting at ECTMIH the results of a trial evaluating efficacy

and safety of different combinations of drugs, including moxidectin, for the control of T. trichiura

and other STH. The drugs seems a valid alternative to IVM also for the treatment of S. stercoralis

infection. . Piero Olliaro says that a dossier for registration of moxidectin for treatment of

onchocerciasis will be submitted to the FDA soon. The manufacturer (a no for profit company,

based in Australia) will then move to other indications (including scabies and strongyloidiasis). Also

other indications should be prospected to invite this and other producers. For instance, groups

working on the eradication of malaria might have an interest in IVM. Andreas Mueller confirms

that the effects of efficacy of IVM against An gambia is comparable to effects of preventive

chemotherapy with artemisinin derivatives. Hence, vector control strategies could include IVM.

Jose Muñoz asks if there is also evidence that moxidectin might have an action on mosquitoes, just

like IVM. Piero Olliaro answers that it seems to have very little efficacy. Jose Muñoz adds that

Chemo pharmaceutical is studying whether IVM might not be adjusted by weight and given in a

fixed dose combination with albendazole. Higher fixed doses might be safe. Another participant

adds that IVM has been tested to treat dengue, and researchers are moving to phase 3 studies.

Moreover, mechanisms alternative to donation should be explored. Julien Potet from the MSF

Access Campaign says that MSF would be particularly interested in exploring alternative ways.

Maria Teresa Giordani asks about screening tools/strategies for particular high-risk groups like

transplant patients. Zeno confirms that guidelines for the screening for Strongyloides in transplant

patients are available, indicating that serology should be used and different tests (including

commercial ones) are available.

Marco Albonico resumes the main key points of the meeting.

Conclusions and way forward:

- The two systematic reviews on prevalence and morbidity/mortality due to S. stercoralis will

pave the way to calculate the estimated needs of IVM.

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- The global need of IVM should foster generic producers to invest in a bio-equivalence study

in order to pre-qualify the drug product for public health interventions facilitated by WHO.

- A questionnaire on the availability of IVM will be developed and distributed to selected

Centers/Institution in European countries and map of (un)availability of IVM will be

produced.

- A draft CRF should be finalized and distributed through the Strongyloides share-point and

also to other centers in order to collect cases and set up a registry of severe cases of

strongyloidiasis.

- Synergies with scabies and malaria networks on the potential use of IVM will continue to

be explored

-New drugs for S. stercoralis: potential efficacy of moxidectin, but more data needed. Ongoing

process of registration

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Figura 1.