Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial.

BACKGROUND: There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option. METHODS: A multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption. RESULTS: 378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003). CONCLUSIONS: Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738. TRIAL REGISTRATION: ClinicalTrials.gov NCT01310738.

Asymptomatic carriers of Plasmodium spp. as infection source for malaria vector mosquitoes in the Brazilian Amazon.

We have described the existence of asymptomatic carriers of Plasmodium vivax and Plasmodium falciparum infections in native Amazon populations. Most of them had low parasitemias, detected only by polymerase chain reaction (PCR). Because they remain symptomless and untreated, we wanted to determine whether they could infect Anopheles darlingi Root, the main Brazilian vector, and act as disease reservoirs. Fifteen adult asymptomatic patients (PCR positive only) were selected, and experimental infections of mosquitoes were performed by direct feeding and by a membrane-feeding system. Seventeen adult symptomatic patients with high parasitemias were used as controls. We found an infection rate in An. darlingi of 1.2% for the asymptomatic carriers and 22% for the symptomatic carriers. Although the asymptomatic group infected mosquitoes at a much lower rate, these patients remain infective longer than treated, symptomatic patients. Also, the prevalence of asymptomatic infections is 4 to 5 times higher than symptomatic infections among natives. These results have implications for the malaria control program in Brazil, which focuses essentially on the treatment of symptomatic patients.

A reduced risk of infection with Plasmodium vivax and clinical protection against malaria are associated with antibodies against the N terminus but not the C terminus of merozoite surface protein 1.

Progress towards the development of a malaria vaccine against Plasmodium vivax, the most widely distributed human malaria parasite, will require a better understanding of the immune responses that confer clinical protection to patients in regions where malaria is endemic. The occurrence of clinical protection in P. vivax malaria in Brazil was first reported among residents of the riverine community of Portuchuelo, in Rondônia, western Amazon. We thus analyzed immune sera from this same human population to determine if naturally acquired humoral immune responses against the merozoite surface protein 1 of P. vivax, PvMSP1, could be associated with reduced risk of infection and/or clinical protection. Our results demonstrated that this association could be established with anti-PvMSP1 antibodies predominantly of the immunoglobulin G3 subclass directed against the N terminus but not against the C terminus, in spite of the latter being more immunogenic and capable of natural boosting. This is the first report of a prospective study of P. vivax malaria demonstrating an association of reduced risk of infection and clinical protection with antibodies against an antigen of this parasite.

Imunodeficiencia combinada severa / Severe combined immnodeficiency

As imunodeficiencias primarias (ID) sao classificadas em ID humorais, celulares, combinadas (humorais e combinadas), de fagocitos e complemento. A Sindrome de Imunodeficiencia Combinada Severa discutida na presente monografia, e uma doenca rara com comprometimento da imunidade celular e humoral, cuja heranca e auto-somica recessiva ou ligada ao cromossomo X. Sao varios os defeitos descritos que levam a SCID: bloqueio das "stem cells", bloqueio da maturacao das celulas T e anormalidades da membrana celular. As principais manifestacoes clinicas sao os processos infecciosos recorrentes associados alteracoes cutaneas, pulmonares, de trato digestivo, com evolucao grave (meningite, sepsis). Os exames laboratoriais mostram linfopenia (20 por cento), niveis de imonuglobulinas baixos e ausencia de resposta linfoproliferativa "in vitro". A terapeutica de reposicao de imunoglobulinas esta indicada e a correcao definitiva pode ser obtida atraves do transplante de medula ossea ou terapia genica (na deficiencia de Adenosina Deaminase)

Imunodeficiencia combinada severa: descricao de caso clinico / Severe combined immunodeficiency: description of clinical case

A imunodeficiencia combinada severa e uma doenca rara, cuja heranca e autossomica recessiva ou ligada ao cromossomo X. As manifestacoes clinicas expressam um defeito na resposta antigeno especifica. Os autores apresentam a avaliacao de uma crianca portadora de SCID, que apresentava processos infeciosos recorrentes, com multiplas internacoes. Foi realizada a avaliacao imunologica e descartada a deficiencia de adenosina-deaminase. O paciente foi submetido a herniorrafia de urgencia, evoluindo para obito no setimo dia pos-operatorio. O preparo para possivel transplante de medula ossea havia sido iniciado. Os achados anatomo-patologicos mostraram alteracoes em todo sistema imunologico. E discutida a importancia do diagnostico clinico e terapeutico precoces.