Chagas disease medical therapy: Difference between revisions

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{{Chagas disease}}
{{Chagas disease}}
{{CMG}} {{AE}} {{YD}}


{{CMG}}
==Overview==
[[Benznidazole]] and [[nifurtimox]] are the only [[antimicrobial]] [[therapies]] with proven efficacy against ''T. cruzi'' infection. Neither drug is [[FDA]]-approved, but can be obtained under investigational protocol. Either [[benznidazole]] or [[nifurtimox]] may be used to manage [[congenital]] infection, [[acute]] [[infection]], and [[chronic]] [[infection]] (only among young patients < 50-55 years) including those with early [[cardiomyopathy]].
 
==Medical Therapy==
*[[Benznidazole]] and [[nifurtimox]] are the only 2 [[antimicrobial]] agents that have demonstrated to be effective against ''T. cruzi'' [[infection]].
*Neither [[benznidazole]] nor [[nifurtimox]] is FDA-approved in the treatment of ''T. cruzi'', but are often used as investigational protocols.
 
===Acute Chagas Disease===
*Both benznizadole and [[nifurtimox]] are effective against acute ''T. cruzi'' [[infections]] with a [[cure]] rate that ranges from 80% to 90%.<ref name="pmid26222561">{{cite journal| author=Bern C| title=Chagas' Disease. | journal=N Engl J Med | year= 2015 | volume= 373 | issue= 5 | pages= 456-66 | pmid=26222561 | doi=10.1056/NEJMra1410150 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26222561  }} </ref>
 
===Chronic Chagas Disease===
*While it was thought that [[chronic]] Chagas disease cannot be managed by [[pharmacotherapy]], new evidence from randomized and non-randomized trials demonstrated that young patients (age < 50-55 years of age) with [[chronic]] Chagas disease, including those with early [[cardiomyopathy]], may be managed using long-term antitrypanosomal [[antimicrobial]] [[therapy]].<ref name="pmid8937280">{{cite journal| author=de Andrade AL, Zicker F, de Oliveira RM, Almeida Silva S, Luquetti A, Travassos LR et al.| title=Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. | journal=Lancet | year= 1996 | volume= 348 | issue= 9039 | pages= 1407-13 | pmid=8937280 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8937280  }} </ref><ref name="pmid9790423">{{cite journal| author=Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C| title=Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease. | journal=Am J Trop Med Hyg | year= 1998 | volume= 59 | issue= 4 | pages= 526-9 | pmid=9790423 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9790423  }} </ref>


==Overview==
*Seroconversion (seropositivity to seronegativity) may only occur several years following the beginning of antimicrobial therapy.<ref name="pmid26222561">{{cite journal| author=Bern C| title=Chagas' Disease. | journal=N Engl J Med | year= 2015 | volume= 373 | issue= 5 | pages= 456-66 | pmid=26222561 | doi=10.1056/NEJMra1410150 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26222561  }} </ref>


==Treatment==
===Congenital Chagas Disease===
There are two approaches to therapy, both of which can be life saving:  
*Similar to acute Chagas disease, both [[benznizadole]] and [[nifurtimox]] are effective against acute ''T. cruzi'' infections. When managed early, the cure rate of [[congenital]] Chagas disease ranges from 80% to 90%.<ref name="pmid26222561">{{cite journal| author=Bern C| title=Chagas' Disease. | journal=N Engl J Med | year= 2015 | volume= 373 | issue= 5 | pages= 456-66 | pmid=26222561 | doi=10.1056/NEJMra1410150 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26222561  }} </ref>


*'''Antiparasitic treatment''', to kill the parasite; and
==Antimicrobial Regimen==
*'''Symptomatic treatment''', to manage the symptoms and signs of infection.


Medication for Chagas' disease is usually only effective when given during the [[Acute (medical)|acute]] stage of infection. The drugs of choice are azole or nitroderivatives such as [[benznidazole]]<ref>Garcia S, Ramos CO, Senra JF, ''et al.'' "Treatment with benznidazole during the chronic phase of experimental Chagas disease decreases cardiac alterations." Antimicrob Agents Chemother. 2005 Apr;49(4):1521–8. PMID 15793134 [http://aac.asm.org/cgi/content/abstract/49/4/1521 Online]</ref> or [[nifurtimox]] (under an Investigational New Drug protocol from the [[Centers for Disease Control and Prevention|CDC]] Drug Service), but resistance to these drugs has already been reported.<ref>Buckner FS, Wilson AJ, White TC, Van Voorhis WC. "Induction of resistance to azole drugs in Trypanosoma cruzi." Antimicrob Agents Chemother. 1998 Dec;42(12):3245–50. PMID 9835521 [http://aac.asm.org/cgi/content/abstract/42/12/3245 Online]</ref> Furthermore, these agents are very toxic and have many [[adverse effect (medicine)|adverse effects]], and cannot be taken without medical supervision. The antifungal agent [[Amphotericin B]] has been proposed as a second-line drug, but cost and this drug's relatively high toxicity have limited its use. Moreover, 10-year study of chronic administration of drugs in Brazil has revealed that current chemotherapy does not totally remove [[parasitemia]].<ref>Lauria-Pires L, Braga MS, Vexenat AC, ''et al.'' "Progressive chronic Chagas heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives." Am J Trop Med Hyg. 2000 Sep-Oct;63(3-4):111-8. PMID 11388500 [http://www.ajtmh.org/cgi/reprint/63/3/111.pdf PDF Full text]</ref> Thus, the decision about whether to use [[antiparasitic]] therapy should be individualized in consultation with an expert.
:*'''Chagas disease'''<ref>{{Cite web | title =  Parasites - American Trypanosomiasis (also known as Chagas Disease) | url = http://www.cdc.gov/parasites/chagas/health_professionals/tx.html }}</ref>
::* 1. Preferred regimen(1):
:::* Patients of age < 12 years- [[Benznidazole]] 5-7.5 mg/kg/ day PO  bid for 60 days
:::* Patients of age 12 years or older- [[Benznidazole]] 5-7 mg/kg/day PO bid for 60 days
::* 2. Preferred regimen(2):
:::* Patients of age ≤ 10 years- [[Nifurtimox]] 15-20 mg/kg/day PO tid/ qid for 90 days
:::* Patients of age 11-16 years- [[Nifurtimox]] 12.5-15 mg/kg/day PO tid/ qid for 90 days
:::* Patients of age 17 years or older- [[Nifurtimox]]  8-10 mg/kg/day PO tid/ qid for 90 days
::* Note: In the United States, [[Nifurtimox]] and [[Benznidazole]] are not FDA approved and are available only from CDC under investigational protocols. <br />


In the [[chronic (medicine)|chronic]] stage, treatment involves managing the clinical manifestations of the disease, e.g., drugs and [[heart pacemaker]] for [[chronic heart failure]] and [[heart arryhthmia]]s; [[surgery]] for megaintestine, etc., but the disease per se is not curable in this phase. Chronic heart disease caused by Chagas' disease is now a common reason for [[heart transplantation]] surgery. Until recently, however, Chagas' disease was considered a [[contraindication]] for the procedure, since the heart damage could recur as the parasite was expected to seize the opportunity provided by the [[immunosuppression]] that follows surgery. The research that changed the indication of the transplant procedure for Chagas' disease patients was conducted by Dr. [[Adib Jatene]]'s group at the Heart Institute of the University of São Paulo, in São Paulo, Brazil.<ref>Bocchi EA, Bellotti G, Mocelin AO, Uip D, ''et al.'' "Heart transplantation for chronic Chagas' heart disease." Ann Thorac Surg. 1996 Jun;61(6):1727–33. PMID 8651775[http://ats.ctsnetjournals.org/cgi/content/abstract/61/6/1727 Online]</ref> The research noted that survival rates in Chagas' patients can be significantly improved by using lower dosages of the immunosuppressant drug [[cyclosporin]]. Recently, direct [[stem cell therapy]] of the heart muscle using [[bone marrow]] cell transplantation has been shown to dramatically reduce risks of heart failure in Chagas patients.<ref>Vilas-Boas F, Feitosa GS, Soares MB, Mota A, ''et al.'' "[Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas disease]." Arq Bras Cardiol. 2006 Aug;87(2):159-66. PMID 16951834 [http://publicacoes.cardiol.br/abc/2004/8202/8202010i.pdf PDF Full text.] [http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0066-782X2004000200010&tlng=en&lng=en&nrm=iso Also available here.]</ref> Patients have also been shown to benefit from the strict prevention of reinfection, though the reason for this is not yet clearly understood.
== Chagas heart disease ==


Some examples for the struggle for advances:
*In the past three decades, a consensus has emerged that parasite persistence is crucial to the development and progression of Chagas [[cardiomyopathy]]. It was believed that [[Antiparasitic]] treatment in the [[chronic]] phase of Chagas disease could prevent [[complications]] related to the [[disease]]. However, according to the results of the benefit trial, [[benznidazole]] seems to have no benefit for arresting [[disease]] progression in patients with [[chronic]] Chagas [[cardiomyopathy]].
*Use of oxidosqualene cyclase inhibitors and [[cysteine protease]] inhibitors has been found to cure experimental infections in animals.<ref>Engel JC, Doyle PS, Hsieh I, McKerrow JH. "Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection." J Exp Med. 1998 August 17;188(4):725-34. PMID 9705954[http://www.jem.org/cgi/content/abstract/188/4/725 Online.]</ref>
*[[Dermaseptin]]s from frog species ''Phyllomedusa oreades'' and ''P. distincta''. Anti-''Trypanosoma cruzi ''activity without [[cytotoxicity]] to mammalian cells.<ref>PMID 12379643</ref>
*Design of inhibitors to enzymes involved in [[trypanothione]] metabolism, which is unique to the kinetoplastid group of parasites.<ref>Fairlamb AH, Cerami A. "Metabolism and functions of trypanothione in the Kinetoplastida." Annu Rev Microbiol. 1992;46:695–729. PMID 1444271</ref>
*The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured epimastigotes of ''Trypanosoma cruzi''<ref>Brengio SD, Belmonte SA, Guerreiro E, ''et al.'' "The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured epimastigotes of Trypanosoma cruzi." J Parasitol. 2000 Apr;86(2):407-12. PMID 10780563</ref>
* The [[genome]] of Trypanosoma cruzi has been sequenced.<ref>El-Sayed NM, Myler PJ, Bartholomeu DC, ''et al.'' (2005). "The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease". Science 309 (5733): 409-15. PMID 16020725</ref> Proteins that are produced by the disease but not by humans have been identified as possible drug targets to defeat the disease.<ref>El-Sayed, ''et al.'', 2005</ref>


<br />
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
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Latest revision as of 20:52, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Overview

Benznidazole and nifurtimox are the only antimicrobial therapies with proven efficacy against T. cruzi infection. Neither drug is FDA-approved, but can be obtained under investigational protocol. Either benznidazole or nifurtimox may be used to manage congenital infection, acute infection, and chronic infection (only among young patients < 50-55 years) including those with early cardiomyopathy.

Medical Therapy

Acute Chagas Disease

Chronic Chagas Disease

  • While it was thought that chronic Chagas disease cannot be managed by pharmacotherapy, new evidence from randomized and non-randomized trials demonstrated that young patients (age < 50-55 years of age) with chronic Chagas disease, including those with early cardiomyopathy, may be managed using long-term antitrypanosomal antimicrobial therapy.[2][3]
  • Seroconversion (seropositivity to seronegativity) may only occur several years following the beginning of antimicrobial therapy.[1]

Congenital Chagas Disease

  • Similar to acute Chagas disease, both benznizadole and nifurtimox are effective against acute T. cruzi infections. When managed early, the cure rate of congenital Chagas disease ranges from 80% to 90%.[1]

Antimicrobial Regimen

  • Chagas disease[4]
  • 1. Preferred regimen(1):
  • Patients of age < 12 years- Benznidazole 5-7.5 mg/kg/ day PO bid for 60 days
  • Patients of age 12 years or older- Benznidazole 5-7 mg/kg/day PO bid for 60 days
  • 2. Preferred regimen(2):
  • Patients of age ≤ 10 years- Nifurtimox 15-20 mg/kg/day PO tid/ qid for 90 days
  • Patients of age 11-16 years- Nifurtimox 12.5-15 mg/kg/day PO tid/ qid for 90 days
  • Patients of age 17 years or older- Nifurtimox 8-10 mg/kg/day PO tid/ qid for 90 days
  • Note: In the United States, Nifurtimox and Benznidazole are not FDA approved and are available only from CDC under investigational protocols.

Chagas heart disease


References

  1. ↑ 1.0 1.1 1.2 Bern C (2015). "Chagas' Disease". N Engl J Med. 373 (5): 456–66. doi:10.1056/NEJMra1410150. PMID 26222561.
  2. ↑ de Andrade AL, Zicker F, de Oliveira RM, Almeida Silva S, Luquetti A, Travassos LR; et al. (1996). "Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection". Lancet. 348 (9039): 1407–13. PMID 8937280.
  3. ↑ Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C (1998). "Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease". Am J Trop Med Hyg. 59 (4): 526–9. PMID 9790423.
  4. ↑ "Parasites - American Trypanosomiasis (also known as Chagas Disease)".

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