Comparative study of mefloquine and sulphadoxine-pyrimethamine for malaria prevention among pregnant women with HIV in southwest Nigeria.

OBJECTIVE: To compare the effectiveness of mefloquine and sulphadoxine-pyrimethamine as intermittent preventive therapy for malaria among pregnant women with HIV. METHODS: The present randomized, controlled, prospective, open-label study enrolled women with HIV who had reached at least 16 weeks of pregnancy attending prenatal clinics at secondary and tertiary health facilities in South West Nigeria between January 1 and August 31, 2016. Block randomization was used to assign patients to treatment with mefloquine or sulphadoxine-pyrimethamine for malaria prophylaxis. The primary outcome was malaria parasitemia at delivery. Data were compared with the χ2 and t tests on a per-protocol basis. RESULTS: Of 142 women enrolled and randomized equally to each group, 131 (92.3%) completed the study (64 in the mefloquine group and 67 in the sulphadoxine-pyrimethamine group). Blood-sample malaria parasites were isolated from 6 (9%) and 5 (7%) patients in the mefloquine and sulphadoxine-pyrimethamine groups, respectively, at enrolment, and 6 (9%) and 9 (13%) patients in the mefloquine and sulphadoxine-pyrimethamine groups, respectively, at delivery; the differences between the groups was not significant at enrolment (P=0.693) or delivery (P=0.466). CONCLUSION: Outcomes following prophylactic use of mefloquine for intermittent preventive therapy for malaria among pregnant women with HIV were comparable to sulphadoxine-pyrimethamine treatment; mefloquine is a feasible alternative therapy. ClinicalTrials.gov: NCT02524444.

Role of LRV1 and RNAi in the Pathogenesis of Leishmania.

The recent paper by Brettmann et al. provides insight as to how an RNA virus can persistently coexist in a protozoan with RNAi activity and how these two entities work to maintain balance. The authors were also able to successfully remove the virus and examine the role of the virus in parasitemia and the pathogenesis of leishmaniasis.

Microbial translocation induces an intense proinflammatory response in patients with visceral leishmaniasis and HIV type 1 coinfection.

BACKGROUND: Leishmania infection is a cofactor in the heightened cellular activation observed in patients with American visceral leishmaniasis and human immunodeficiency virus type 1 (HIV) infection, with or without progression to AIDS (AVL/HIV). Thus, the persistence of a high parasite load despite antileishmanial therapy could be responsible for the continued immune stimulation. METHODS: CD8(+) T cells expressing CD38, parasite load, lipopolysaccharide (LPS), soluble CD14, macrophage migration inhibitory factor (MIF), intestinal fatty acid-binding protein (IFABP), and proinflammatory cytokines (interleukin 1ß, interleukin 6, interleukin 8, interleukin 17, interferon γ, and tumor necrosis factor) were measured in 17 patients with AVL/HIV, 16 with HIV, and 14 healthy subjects (HS). RESULTS: Lower Leishmania parasitemia was observed after antileishmanial and antiretroviral therapies. However, higher levels of CD38(+) on CD8(+) T cells were observed in both clinical phases of leishmaniasis, compared with HIV cases. AVL/HIV and HIV patients showed higher levels of LPS and IFABP than HS. Proinflammatory cytokine levels were significantly augmented in patients with active coinfection, as well as those with remission of Leishmania infection. LPS levels and Leishmania infection were positively correlated with CD38 expression on CD8(+) T cells and with IL-6 and IL-8 levels. CONCLUSIONS: LPS levels along with the immune consequences of Leishmania infection were associated with elevated cellular activation in coinfected patients. As a consequence, secondary chemoprophylaxis for leishmaniasis or even the use of antiinflammatory drugs or antibiotics may be considered for improving the prognosis of AVL/HIV.

Prevalence of parasitemia and associated immunodeficiency among HIV-malaria co-infected adult patients with highly active antiretroviral therapy.

OBJECTIVE: To investigate the malaria parasitemia, CD4(+) cell counts and some haematological indices among HIV-malaria co-infected adult patients with highly active antiretroviral therapy (HAART). METHODS: A total of 342 adult HIV positive subjects were recruited at the consultant outpatient HIV/AIDS clinic, University of Benin Teaching Hospital, Benin City, Nigeria between June 2011 to November 2011. Blood samples were taken for malaria parasite count, CD4(+) cell count and other haematological counts. RESULTS: Out of the 342 adult HIV positive subjects a total of 254 patients (74.3%) were found to have malaria parasitemia. The incidence of malaria parasitemia increased with advancing clinical stage of HIV infection and this was statistically significant (P=0.002). There was no statistical significance when gender was compared with the HIV-malaria status (P >0.05). Of the 254 co-infected patients, 134 (52.8%) had high parasitemia (>1.25 × 10(9)/L). Sixty patients were found to be hyperparasitemic (>2.5 parasites/L). There was a significant association between CD4(+) cell count and having significant parasitemia (P < 0.000 1). About half (50.8%) of co-infected patients had CD4(+) cell count ≤ 200/µL, and majority (44.9%) of this population also had significant parasitemia. Anaemia and thrombocytopenia were not significantly associated with HIV-malaria co-infection (P > 0.05). CONCLUSIONS: The prevalence of parasitemia is high among the HIV/AIDS infected patients.

Diagnosis, clinical presentation, and in-hospital mortality of severe malaria in HIV-coinfected children and adults in Mozambique.

BACKGROUND: Severe falciparum malaria with human immunodeficiency virus (HIV) coinfection is common in settings with a high prevalence of both diseases, but there is little information on whether HIV affects the clinical presentation and outcome of severe malaria. METHODS: HIV status was assessed prospectively in hospitalized parasitemic adults and children with severe malaria in Beira, Mozambique, as part of a clinical trial comparing parenteral artesunate versus quinine (ISRCTN50258054). Clinical signs, comorbidity, complications, and disease outcome were compared according to HIV status. RESULTS: HIV-1 seroprevalence was 11% (74/655) in children under 15 years and 72% (49/68) in adults with severe malaria. Children with HIV coinfection presented with more severe acidosis, anemia, and respiratory distress, and higher peripheral blood parasitemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). During hospitalization, deterioration in coma score, convulsions, respiratory distress, and pneumonia were more common in HIV-coinfected children, and mortality was 26% (19/74) versus 9% (53/581) in uninfected children (P < .001). In an age- and antimalarial treatment-adjusted logistic regression model, significant, independent predictors for death were renal impairment, acidosis, parasitemia, and plasma PfHRP2 concentration. CONCLUSIONS: Severe malaria in HIV-coinfected patients presents with higher parasite burden, more complications, and comorbidity, and carries a higher case fatality rate. Early identification of HIV coinfection is important for the clinical management of severe malaria.

Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma.

BACKGROUND: Infection with Epstein-Barr virus (EBV) early in life and repeated malaria exposure have been proposed as risk factors for endemic Burkitt lymphoma (eBL). METHODS: Infants were enrolled from 2 rural sites in Kenya: the Kisumu District, where malaria transmission is holoendemic and risk for eBL is high, and the Nandi District, where malaria transmission is limited and the risk for eBL is low. Blood samples were taken from infants through 2 years of age to measure EBV viral load, EBV antibodies, and malaria parasitemia. RESULTS: We observed a significantly younger age at time of primary EBV infection in children from Kisumu compared with children from Nandi (mean age, 7.28 months [±0.33 SEM] in Kisumu vs 8.39 months [±0.26 SEM] in Nandi), with 35.3% of children in Kisumu infected before 6 months of age. To analyze how different predictors affected EBV viral load over time, we performed multilevel mixed modeling. This modeling revealed that residence in Kisumu and younger age at first EBV infection were significant predictors for having a higher EBV viral load throughout the period of observation. CONCLUSIONS: Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy.

Effects of homeopathy in mice experimentally infected with Trypanosoma cruzi.

AIM: The aim of this study was to evaluate the action of homeopathic treatment on mice experimentally infected with Trypanosoma cruzi. METHODS: Eighty adult male C57BL/6 inbred mice were randomly allocated to five groups treated with biotherapy (nosode) of T. cruzi 12dH (12x) pre- and post-infection; Phosphorus 12dH post-infection; infected control treated with control solution and uninfected control. The biotherapy was prepared by the Costa method from the blood of mice experimentally infected with the Y strain of T. cruzi. Phosphorus was used because of its clinical and reportorial similarity to Chagas disease. T. cruzi (10(4)) sanguineous forms were inoculated intraperitoneally per animal. Parasitaemia was monitored, leukocyte and serological responses were evaluated at 0, 7, 14 and 42 days after infection. The prepatent and patent periods of parasitaemia, maximum of parasitaemia, day of maximum parasitaemia and mortality rates were compared between groups. RESULTS: A significantly shorter period of patent parasitaemia was observed in the group treated with the biotherapy before infection (p<0.05) than in the other groups. This group also had the lowest parasitaemias values at 9, 13, 15 (p<0.05), 17 (p<0.05), 22, 24 and 28 days, a lower rate of mortality and a significant increase of lymphocytes compared to the infected control group. The Phosphorus group had the longest period of patent parasitaemia, higher maximum parasitaemia, and a significant reduction of lymphocyte numbers, but no mortality. The infected control group had the highest mortality rate (not statistically significant), and the highest IgG titres at 42 days post-infection (p<0.05). CONCLUSIONS: The results suggest that pre-treatment with biotherapy modulates host immune response to T. cruzi, mainly during the acute phase of the infection. Phosphorus shows an action on the pathogenicity by T. cruzi infection. Homeopathic treatment of T. cruzi infection should be further investigated.

Malaria treatment efficacy among people living with HIV: the role of host and parasite factors.

Identification of an effect of HIV-associated immunosuppression on response to antimalarial therapy would help guide management of malaria infection in areas of high HIV prevalence. Therefore, we conducted an observational study of people living with HIV infection in Blantyre, Malawi. Participants who developed malaria were treated with sulfadoxine-pyrimethamine (SP) and followed for 28 days. Molecular markers for SP resistance were measured. One hundred seventy-eight episodes of malaria were assessed. The 28-day cumulative treatment failure rate was 29.1%. In univariate analysis, CD4 cell count was not associated with treatment failure (hazard ratio 0.6, 95% confidence interval 0.3-1.2). Among children, the risk of treatment failure increased with infection with SP-resistant parasites and anemia. Decreased CD4 cell count was not associated with impaired response to antimalarial therapy or diminished ability to clear SP-resistant parasites, suggesting that acquired immunity to malaria is retained in the face of HIV-associated immunosuppression.

Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.

BACKGROUND: Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. METHODS AND FINDINGS: Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0-6h were observed. CONCLUSIONS: The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.

The blood parasites of anurans from Costa Rica with reflections on the taxonomy of their trypanosomes.

During May 1997, specimens of 7 species of anurans, that included 5 Phrynohyas venulosa Laurenti, 5 Rana forreri Boulenger, 7 Rana vaillanti Brucchi, 6 Eleutherodactylus fitzingeri Schimdt, 4 Smilisca baudinii Duméril and Bibron, 1 Leptodactylus melanonotus, and 3 Bufo marinus Linneaus, from the Guanacaste Conservation Area, Costa Rica were examined for blood parasites. Their hematozoan fauna included intraerythrocytic and intraleukocytic icosahedral viruses, a rickettsia (Aegyptianella sp.), 2 species of Hepatozoon, Lankesterella minima, 2 unknown species of apicomplexans, 9 morphologically distinct types of trypanosomes, and 2 species of microfilariae. Rana vaillanti, the most aquatic species of frog, harbored the most species of parasites. Recent evidence indicates that morphological changes in the highly pleomorphic trypanosomes of anurans from different geographical regions have not kept pace with biochemical (isozyme) and molecular (DNA sequence) changes. Describing new species based solely on bloodstream trypomastigotes is discouraged. Additional criteria described herein should be applied when naming new species of anuran trypanosomes.

Malaria infection induces virus expression in human immunodeficiency virus transgenic mice by CD4 T cell-dependent immune activation.

To test the capacity of malaria parasites to trigger virus expression in vivo, human immunodeficiency virus (HIV) transgenic mice were infected with Plasmodium chabaudi chabaudi clone AS. Splenocytes recovered during peak parasitemia showed a dramatic elevation in viral p24 production that returned to baseline by day 15 and failed to rebound at recrudescence or after reinfection. The major sources of virus expression were antigen-presenting cells (APCs) rather than T lymphocytes. Nevertheless, T cells from infected mice stimulated with plasmodial antigen triggered 5-10-fold increases in p24 production from dendritic cells in vitro, which suggests that viral induction stems from interaction of malaria-specific T lymphocytes with HIV-expressing APCs. Indeed, depletion of CD4 T cells resulted in a 70% reduction in the p24 response stimulated by malaria in vivo. These findings demonstrate the ability of Plasmodium species to immunologically activate latently integrated HIV in vivo but suggest that this process may be restricted to acute infection.

Dual host infections: enhanced infectivity of eastern equine encephalitis virus to Aedes mosquitoes mediated by Brugia microfilariae.

When mosquitoes feed on a vertebrate host that is infected concurrently with virus and microfilariae (mf), both pathogens are ingested. If mf penetrate the mosquito midgut, a small portion of the ingested virus may disseminate directly into the mosquito hemocoel. This phenomenon, termed microfilarial enhancement of arboviral transmission, has the potential to enhance the infectivity of arboviruses to mosquitoes. We investigated whether concurrent ingestion of Brugia mf and eastern equine encephalitis virus would enhance the infectivity and subsequent transmissibility of the virus by Aedes mosquitoes. Trials with Ae. triseriatus and B. pahangi mf indicated that microfilarial enhancement was dose dependent. Both a sufficient number of penetrating mf and a sufficient viremia were required for enhancement to occur. Furthermore, studies with B. malayi and three species of Aedes indicated that under comparable conditions of host viremia and microfilaremia, microfilarial enhancement occurred in some mosquito species (i.e., Ae. aegypti and Ae. taeniorhynchus) but not in others (Ae. triseriatus). We suggest that certain key parameters determine whether dual virus/mf host infections will enhance arboviral infectivity to mosquitoes. These include species differences in the capacity of mf to penetrate the mosquito midgut, the amount of virus passing into the hemocoel during mf penetration, and the innate susceptibility of mosquitoes to hemocoelomically introduced virus.