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  • 1
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    Age-dependent carriage of alleles and haplotypes of Plasmodium falciparum sera5, eba-175, and csp in a region of intense malaria transmission in Uganda
    Springer Science and Business Media LLC ; 2020
    In:  Malaria Journal Vol. 19, No. 1 ( 2020-12)
    Details
    In: Malaria Journal, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2020-12)
    Abstract: The development of malaria vaccines is constrained by genetic polymorphisms exhibited by Plasmodium falciparum antigens. The project the age-dependent distribution of alleles or haplotypes of three P. falciparum malaria vaccine candidates, Circumsporozoite Protein ( csp ), Erythrocyte Binding Antigen 175 (eba-175) and Serine Repeat Antigen 5 (sera5) in a region of intense malaria transmission in Uganda. Methods A cross-sectional study was carried out between August and November 2009 in which 250 study participants were selected from a population of 600. Finger prick blood samples were collected after informed consent from participants below 5 years, 5–10 years, and above 10 years of age. Blood was used for microscopy, RDT and dried blood spots. Plasmodium falciparum DNA was extracted by chelex method. Alleles of sera5 and eba-175 were determined by polymerase chain reaction (PCR) amplification followed by resolution of products by agarose gel electrophoresis. Allele calling was done using gel photographs from ethiduim bromide stained gels. Haplotypes of csp were identified by sequencing 63 PCR products using the P. falciparum 7G8 laboratory strain sequence as a reference. The data were analysed using SPSS 16, EQX for windows and Chi-square test was used to calculate associations (P-values), Excel was used to generate graphs. The BioEdit and NCBI blast software programs were used to analyse the sequences from which csp haplotypes map was constructed. Results Eba-175 FCR3 (48/178) and CAMP (16/178) alleles were observed, the FCR3 (24/67) allele being predominant among children aged below 5 years old while the CAMP (12/67) allele was predominant among older participants. Sera5 alleles ORI (6/204) and ORII (103/204) were observed in the population, ORII was more prevalent and was significantly associated with age (P values  〈  0.0001), parasite density (P-value  〈  0.0001) and clinical outcomes (P value = 0.018). There was marked csp diversity in the Th2/Th3 region. Out of 63 sequences, 16 conformed to the reference strain and one (1/16) was similar to a West African haplotype and the majority (14/16) of the haplotypes were unique to this study region. There was an age-dependent distribution of csp haplotypes with more haplotypes being harbored by children  〈  5-year of age, (10/16) compared to adults (2/16). Interestingly, the csp haplotype corresponding to 3D7 whose prototypical sequence is identical to the sequence of the leading malaria vaccine candidate RTS, S was not observed. Conclusion This data suggest that the eba-175 FCR3 allele , sera5 ORII allele , and csp haplotypes are targets of host immunity and under immune selection pressure in Apac District. These molecules could provide alternative malaria vaccine candidates as sub-unit vaccines .
    Type of Medium: Online Resource
    ISSN: 1475-2875
    URL: Article
    DOI: 10.1186/s12936-020-03432-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2091229-8
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  • 2
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    Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial
    Oxford University Press (OUP) ; 2023
    In:  Clinical Infectious Diseases Vol. 76, No. 3 ( 2023-02-08), p. e1177-e1185
    Details
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 76, No. 3 ( 2023-02-08), p. e1177-e1185
    Abstract: This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa. Methods An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months. Results Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], −6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, −0.3%; 97.5% CI, –7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug–related, and 1 death was SSG-related. Allometric dosing ensu red similar MF exposure in children ( & lt;12 years) and adults. Conclusions PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa. Clinical Trials Registration NCT03129646.
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Article
    DOI: 10.1093/cid/ciac643
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2002229-3
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  • 3
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    Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co‐infection
    Wiley ; 2020
    In:  Mycoses Vol. 63, No. 8 ( 2020-08), p. 840-853
    Details
    In: Mycoses, Wiley, Vol. 63, No. 8 ( 2020-08), p. 840-853
    Abstract: Cryptococcal meningitis remains one of the leading causes of death among HIV‐infected adults in the fourth decade of HIV era in sub‐Saharan Africa, contributing to 10%–20% of global HIV‐related deaths. Despite widespread use and early induction of ART among HIV‐infected adults, incidence of cryptococcosis remains significant in those with advanced HIV disease. Cryptococcus species that causes fatal infection follows systemic spread from initial environmental acquired infection in lungs to antigenaemia and fungaemia in circulation prior to establishment of often fatal disease, cryptococcal meningitis in the CNS. Cryptococcus person‐to‐person transmission is uncommon, and deaths related to blood infection without CNS involvement are rare. Keen to the persistent high mortality associated with HIV‐cryptococcal meningitis, seizures are common among a third of the patients, altered mental status is frequent, anaemia is prevalent with ensuing brain hypoxia and at autopsy, brain fibrosis and infarction are evident. In addition, fungal burden is 3‐to‐4‐fold higher in those with seizures. And high immune activation together with exacerbated inflammation and elevated PD‐1/PD‐L immune checkpoint expression is immunomodulated phenotypes elevated in CSF relative to blood. Lastly, though multiple Cryptococcus species cause disease in this setting, observations are mostly generalised to cryptococcal infection/meningitis or regional dominant species ( C neoformans or gattii complex ) that may limit our understanding of interspecies differences in infection, progression, treatment or recovery outcome. Together, these factors and underlying mechanisms are hypotheses generating for research to find targets to prevent infection or adequate therapy to prevent persistent high mortality with current optimal therapy.
    Type of Medium: Online Resource
    ISSN: 0933-7407 , 1439-0507
    URL: Issue
    URL: Article
    DOI: 10.1111/myc.v63.8
    DOI: 10.1111/myc.13122
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2020780-3
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  • 4
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    B Cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis
    American Society for Microbiology ; 2020
    In:  Infection and Immunity Vol. 88, No. 3 ( 2020-02-20)
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 88, No. 3 ( 2020-02-20)
    Abstract: Activated B cells modulate infection by differentiating into pathogen-specific antibody-producing effector plasmablasts/plasma cells, memory cells, and immune regulatory B cells. In this context, the B cell phenotypes that infiltrate the central nervous system during human immunodeficiency virus (HIV) and cryptococcal meningitis coinfection are ill defined. We characterized clinical parameters, mortality, and B cell phenotypes in blood and cerebrospinal fluid (CSF) by flow cytometry in HIV-infected adults with cryptococcal ( n  = 31) and noncryptococcal ( n  = 12) meningitis and in heathy control subjects with neither infection ( n  = 10). Activation of circulating B cells (CD21 low ) was significantly higher in the blood of subjects with HIV infection than in that of healthy controls and greater yet in matched CSF B cells ( P   〈  0.001). Among B cell subsets, elevated frequencies of memory and plasmablasts/plasma cells most clearly distinguished the CSF from blood compartments. With cryptococcal meningitis, lower frequencies of expression of the regulatory protein programmed death-1 (PD-1) on plasmablasts/plasma cells in blood (median, 7%) at presentation were associated with significantly decreased 28-day survival (29% [4/14 subjects]), whereas higher PD-1 expression (median, 46%) characterized subjects with higher survival (88% [14/16 subjects] ). With HIV infection, B cell differentiation and regulatory markers are discrete elements of the circulating and CSF compartments with clinical implications for cryptococcal disease outcome, potentially due to their effects on the fungus and other local immune cells.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.00779-19
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 1483247-1
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  • 5
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    Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis
    Oxford University Press (OUP) ; 2023
    In:  Journal of Antimicrobial Chemotherapy ( 2023-09-20)
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), ( 2023-09-20)
    Abstract: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response. Methods Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults. Results Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0–24h 187 (162–203) and 242 (217–328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0–28 517 (464–552) and 524 (456–567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25–28) and 30 (28–32) days, respectively] were comparable to previously observed values in adults. Conclusions Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure–response and exposure–toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkad286
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1467478-6
    SSG: 15,3
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  • 6
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    Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa
    Oxford University Press (OUP) ; 2020
    In:  Journal of Antimicrobial Chemotherapy Vol. 75, No. 11 ( 2020-11-01), p. 3260-3268
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 75, No. 11 ( 2020-11-01), p. 3260-3268
    Abstract: Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). Methods Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. Results A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. Conclusions Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkaa314
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1467478-6
    SSG: 15,3
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  • 7
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    Blood Parasite Load as an Early Marker to Predict Treatment Response in Visceral Leishmaniasis in Eastern Africa
    Oxford University Press (OUP) ; 2021
    In:  Clinical Infectious Diseases Vol. 73, No. 5 ( 2021-09-07), p. 775-782
    Details
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 73, No. 5 ( 2021-09-07), p. 775-782
    Abstract: To expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes. Methods Data from 3 clinical trials were combined in this study, in which Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative polymerase chain reaction (qPCR) before, during, and up to 6 months after treatment. The predictive performance of pharmacodynamic parameters for clinical relapse was evaluated using receiver-operating characteristic curves. Clinical trial simulations were performed to determine the power associated with the use of blood parasite load as a surrogate endpoint to predict clinical outcome at 6 months. Results The absolute parasite density on day 56 after start of treatment was found to be a highly sensitive predictor of relapse within 6 months of follow-up at a cutoff of 20 parasites/mL (area under the curve 0.92, specificity 0.91, sensitivity 0.89). Blood parasite loads correlated well with tissue parasite loads (ρ = 0.80) and with microscopy gradings of bone marrow and spleen aspirate smears. Clinical trial simulations indicated a & gt; 80% power to detect a difference in cure rate between treatment regimens if this difference was high ( & gt; 50%) and when minimally 30 patients were included per regimen. Conclusions Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities.
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Article
    DOI: 10.1093/cid/ciab124
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2002229-3
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