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1.
Antimicrob Agents Chemother ; 68(5): e0009324, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38597636

RESUMO

Capillary samples offer practical benefits compared with venous samples for the measurement of drug concentrations, but the relationship between the two measures varies between different drugs. We measured the concentrations of lumefantrine, mefloquine, piperaquine in 270 pairs of venous plasma and concurrent capillary plasma samples collected from 270 pregnant women with uncomplicated falciparum or vivax malaria. The median and range of venous plasma concentrations included in this study were 447.5 ng/mL (8.81-3,370) for lumefantrine (day 7, n = 76, median total dose received 96.0 mg/kg), 17.9 ng/mL (1.72-181) for desbutyl-lumefantrine, 1,885 ng/mL (762-4,830) for mefloquine (days 3-21, n = 90, median total dose 24.9 mg/kg), 641 ng/mL (79.9-1,950) for carboxy-mefloquine, and 51.8 ng/mL (3.57-851) for piperaquine (days 3-21, n = 89, median total dose 52.2 mg/kg). Although venous and capillary plasma concentrations showed a high correlation (Pearson's correlation coefficient: 0.90-0.99) for all antimalarials and their primary metabolites, they were not directly interchangeable. Using the concurrent capillary plasma concentrations and other variables, the proportions of venous plasma samples predicted within a ±10% precision range was 34% (26/76) for lumefantrine, 36% (32/89) for desbutyl-lumefantrine, 74% (67/90) for mefloquine, 82% (74/90) for carboxy-mefloquine, and 24% (21/89) for piperaquine. Venous plasma concentrations of mefloquine, but not lumefantrine and piperaquine, could be predicted by capillary plasma samples with an acceptable level of agreement. Capillary plasma samples can be utilized for pharmacokinetic and clinical studies, but caution surrounding cut-off values is required at the individual level.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT01054248.


Assuntos
Antimaláricos , Lumefantrina , Malária Falciparum , Malária Vivax , Mefloquina , Piperazinas , Quinolinas , Humanos , Feminino , Mefloquina/sangue , Mefloquina/uso terapêutico , Mefloquina/farmacocinética , Antimaláricos/sangue , Antimaláricos/uso terapêutico , Antimaláricos/farmacocinética , Gravidez , Quinolinas/sangue , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Lumefantrina/uso terapêutico , Lumefantrina/sangue , Malária Falciparum/tratamento farmacológico , Malária Falciparum/sangue , Adulto , Malária Vivax/tratamento farmacológico , Malária Vivax/sangue , Adulto Jovem , Etanolaminas/sangue , Etanolaminas/farmacocinética , Etanolaminas/uso terapêutico , Fluorenos/sangue , Fluorenos/uso terapêutico , Fluorenos/farmacocinética , Adolescente
2.
Malar J ; 23(1): 40, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317164

RESUMO

BACKGROUND: Artemisinin-based combination therapy (ACT) has been effective in the supervised treatment of uncomplicated malaria in Ghana. Since ACT usage is primarily unsupervised, this study aimed to determine the effectiveness of artemether-lumefantrine (AL) for treating malaria patients in two transmission settings in Ghana. METHODS: Eighty-four individuals with uncomplicated Plasmodium falciparum malaria were recruited from Lekma Hospital (LH) in Accra (low-transmission area; N = 28), southern Ghana, and King's Medical Centre (KMC) in Kumbungu (high-transmission area; N = 56), northern Ghana. Participants were followed up for 28 days after unsupervised treatment with AL. The presence of asexual parasites was determined by microscopic examination of Giemsa-stained blood smears. Plasmodium species identification was confirmed using species-specific primers targeting the 18S rRNA gene. Parasite recrudescence or reinfection was determined by genotyping the Pfmsp 1 and Pfmsp 2 genes. RESULTS: After AL treatment, 3.6% (2/56) of the patients from KMC were parasitaemic on day 3 compared to none from the LH patients. One patient from KMC with delayed parasite clearance on day 3 remained parasite-positive by microscopy on day 7 but was parasite-free by day 14. While none of the patients from LH experienced parasite recurrence during the 28-day follow-up, three and two patients from KMC had recurrent parasitaemia on days 21 and 28, respectively. Percentage reduction in parasite densities from day 1, 2, and 3 for participants from the KMC was 63.2%, 89.5%, and 84.5%. Parasite densities for participants from the LH reduced from 98.2%, 99.8% on day 1, and 2 to 100% on day 3. The 28-day cumulative incidence rate of treatment failure for KMC was 12.8% (95% confidence interval: 1.9-23.7%), while the per-protocol effectiveness of AL in KMC was 89.47%. All recurrent cases were assigned to recrudescence after parasite genotyping by Pfmsp 1 and Pfmsp 2. CONCLUSION: While AL is efficacious in treating uncomplicated malaria in Ghana, when taken under unsupervised conditions, it showed an 89.4% PCR-corrected cure rate in northern Ghana, which is slightly below the WHO-defined threshold.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Humanos , Combinação Arteméter e Lumefantrina/uso terapêutico , Antimaláricos/uso terapêutico , Gana , Artemisininas/uso terapêutico , Combinação de Medicamentos , Artemeter/uso terapêutico , Malária Falciparum/tratamento farmacológico , Recidiva , Parasitemia/tratamento farmacológico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Plasmodium falciparum/genética
3.
Malar J ; 23(1): 261, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39210367

RESUMO

BACKGROUND: The burden of malaria persists in sub-Saharan Africa and the emergence of artemisinin resistance has introduced complexity to control efforts. Monitoring the efficacy of artemisinin-based treatment for malaria is crucial to address this challenge. This study assessed treatment efficacy of artemether-lumefantrine (AL) and genetic diversity of Plasmodium falciparum isolates in a Nigerian population. METHODS: Participants presenting with clinical symptoms of uncomplicated malaria at a health centre in Lagos, Nigeria, were screened for P. falciparum. Enrolled participants were treated with AL and monitored through scheduled check-up visits, clinical and laboratory examinations for 28 days. Parasite clearance and genetic diversity were assessed through polymerase chain reaction (PCR) analysis of merozoite surface proteins (msp1 and msp2). The prevalence of drug resistance mutations was assessed by P. falciparum multidrug resistance gene 1 (mdr1) genotyping followed by P. falciparum ubiquitin-specific protease 1 (ubp1) gene sequencing. RESULTS: The PCR-uncorrected treatment outcome revealed 94.4% adequate clinical and parasitological response (ACPR) and 5.6% late parasitological failure (LPF) rates. After PCR correction, no suspected LPF case was detected and ACPR 67/67 (100%) was achieved in all the individuals. Moreover, a high prevalence of wild-type alleles for mdr1 N86Y (93.7%), and mdr1 D1246Y (87.5%) was observed. Genetic diversity analysis revealed predominant K1 allelic family for msp1 (90.2%) and FC27 for msp2 (64.4%). Estimated multiplicity of infection (MOI) was 1.7, with the highest MOI observed in the 5-15 years age group. ubp1 sequence analysis identified one nonsynonymous E1528D polymorphism at a low frequency (1.6%). CONCLUSION: The study demonstrated sustained efficacy of AL for treating uncomplicated P. falciparum malaria. Genetic diversity analysis revealed various allelic types, suggesting occurrences of polyclonal infections. Nonetheless, the detection of a significant ubp1 polymorphism could have future implications for the epidemiology of anti-malarial drug resistance in the population.


Assuntos
Antimaláricos , Combinação Arteméter e Lumefantrina , Resistência a Medicamentos , Malária Falciparum , Plasmodium falciparum , Combinação Arteméter e Lumefantrina/uso terapêutico , Nigéria , Humanos , Plasmodium falciparum/genética , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/uso terapêutico , Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Feminino , Masculino , Criança , Pré-Escolar , Adolescente , Adulto , Adulto Jovem , Resistência a Medicamentos/genética , Pessoa de Meia-Idade , Lactente , Resultado do Tratamento , Artemisininas/uso terapêutico , Artemisininas/farmacologia , Variação Genética , Idoso , Proteínas de Protozoários/genética , Combinação de Medicamentos , Proteína 1 de Superfície de Merozoito/genética , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico
4.
Malar J ; 23(1): 125, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38685044

RESUMO

BACKGROUND: Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether-lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy. METHODS: Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR-RFLP. RESULTS: A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0-2666/µL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors. CONCLUSIONS: The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.


Assuntos
Antimaláricos , Combinação Arteméter e Lumefantrina , Artemisininas , Combinação de Medicamentos , Etanolaminas , Fluorenos , Humanos , Antimaláricos/uso terapêutico , Antimaláricos/farmacocinética , Combinação Arteméter e Lumefantrina/uso terapêutico , Feminino , Etanolaminas/uso terapêutico , Etanolaminas/farmacocinética , Adolescente , Fluorenos/uso terapêutico , Fluorenos/farmacocinética , Fluorenos/farmacologia , Artemisininas/uso terapêutico , Artemisininas/farmacocinética , Masculino , Gana , Adulto , Adulto Jovem , Criança , Pré-Escolar , Pessoa de Meia-Idade , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Medicamentos Genéricos/uso terapêutico , Resultado do Tratamento , Farmacogenética , Idoso , Lactente
5.
Malar J ; 23(1): 184, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867217

RESUMO

BACKGROUND: Malaria remains a major global health problem although there was a remarkable achievement between 2000 and 2015. Malaria drug resistance, along with several other factors, presents a significant challenge to malaria control and elimination efforts. Numerous countries in sub-Saharan Africa have documented the presence of confirmed or potential markers of partial resistance against artemisinin, the drug of choice for the treatment of uncomplicated Plasmodium falciparum malaria. The World Health Organization (WHO) recommends regular surveillance of artemisinin therapeutic efficacy to inform policy decisions. METHODS: This study aimed to evaluate the therapeutic efficacy of artemether-lumefantrine (AL), which is the first-line treatment for uncomplicated P. falciparum malaria in Ethiopia since 2004. Using a single-arm prospective evaluation design, the study assessed the clinical and parasitological responses of patients with uncomplicated P. falciparum malaria in Metehara Health Centre, central-east Ethiopia. Out of 2332 malaria suspects (1187 males, 1145 females) screened, 80 (50 males, 30 females) were enrolled, followed up for 28 days, and 73 (44 males, 29 females) completed the follow up. The study was conducted and data was analysed by employing the per-protocol and Kaplan-Meier analyses following the WHO Malaria Therapeutic Efficacy Evaluation Guidelines 2009. RESULTS: The results indicated rapid parasite clearance and resolution of clinical symptoms, with all patients achieving complete recovery from asexual parasitaemia and fever by day (D) 3. The prevalence of gametocytes decreased from 6.3% on D0 to 2.5% on D2, D3, D7, and ultimately achieving complete clearance afterward. CONCLUSION: The overall cure rate for AL treatment was 100%, demonstrating its high efficacy in effectively eliminating malaria parasites in patients. No serious adverse events related to AL treatment were reported during the study, suggesting its safety and tolerability among the participants. These findings confirm that AL remains a highly efficacious treatment for uncomplicated P. falciparum malaria in the study site after 20 years of its introduction in Ethiopia.


Assuntos
Antimaláricos , Combinação Arteméter e Lumefantrina , Malária Falciparum , Humanos , Etiópia , Malária Falciparum/tratamento farmacológico , Combinação Arteméter e Lumefantrina/uso terapêutico , Masculino , Feminino , Antimaláricos/uso terapêutico , Antimaláricos/efeitos adversos , Adulto , Adolescente , Adulto Jovem , Pré-Escolar , Criança , Estudos Prospectivos , Pessoa de Meia-Idade , Lactente , Artemisininas/uso terapêutico , Artemisininas/efeitos adversos , Fluorenos/uso terapêutico , Fluorenos/efeitos adversos , Resultado do Tratamento , Etanolaminas/uso terapêutico , Etanolaminas/efeitos adversos , Idoso , Combinação de Medicamentos , Plasmodium falciparum/efeitos dos fármacos
6.
Breast Cancer Res Treat ; 197(3): 489-501, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36459284

RESUMO

PURPOSE: To evaluate the efficacy and safety of pamiparib in patients with locally advanced or metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious germline BRCA1/2 mutations (gBRCA1/2 m). METHODS: In this open-label, phase II, multicenter study in China (NCT03575065), patients with triple-negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+/HER2- cohort) and ≤ 2 prior lines of chemotherapy received pamiparib 60 mg orally twice daily in 28-day, continuous cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee. RESULTS: In total, 88 patients were enrolled (TNBC cohort: 62; HR+/HER2- cohort: 26). Median age was 45.5 (range: 27-67) years, and 60 patients (68.2%) had received 1 or 2 prior lines of chemotherapy; 42 patients (47.7%) had previously received platinum chemotherapy. In the TNBC cohort, ORR was 38.2% (95% confidence interval [CI] 25.4-52.3) and median duration of response (DoR) was 7.0 months (95% CI 3.9-not estimable). In the HR+/HER2- cohort, ORR was 61.9% (95% CI 38.4-81.9) and median DoR was 7.5 months (95% CI 5.6-14.8). The most common treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and ≥ Grade 3 TEAEs were hematologic (including anemia, decreased neutrophil count, and decreased white blood cell count). Overall, 64.8% of patients had TEAEs leading to dose reduction and 2.3% had TEAEs leading to treatment discontinuation. CONCLUSION: Pamiparib showed encouraging efficacy and an acceptable safety profile in patients with locally advanced and metastatic HER2- breast cancer with gBRCA1/2 m. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03575065; July 2, 2018.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fluorenos/uso terapêutico , Células Germinativas/metabolismo , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
7.
Malar J ; 22(1): 32, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36707795

RESUMO

BACKGROUND: When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response. METHODS: Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ) or no prophylaxis. After diagnosis of uncomplicated Plasmodium falciparum malaria, a therapeutic efficacy monitoring was conducted with PCR-correction according to WHO guidelines. The plasma lumefantrine levels on day 7 in 100 episodes of uncomplicated malaria was measured. A frailty proportional hazards model with random effects models to account for clustering examined the relationship between participant characteristics and malaria treatment failure within 28 days. Pearson's Chi-squared test was used to compare lumefantrine concentrations among patients with treatment failure and adequate clinical and parasitological response (ACPR). RESULTS: 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008). CONCLUSION: Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.


Assuntos
Antimaláricos , Artemisininas , Infecções por HIV , Malária Falciparum , Malária , Humanos , Adulto , Antimaláricos/uso terapêutico , Malaui , Artemisininas/uso terapêutico , Artemeter/uso terapêutico , Combinação de Medicamentos , Combinação Arteméter e Lumefantrina/uso terapêutico , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Lumefantrina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Resultado do Tratamento , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico
8.
Dig Dis Sci ; 68(6): 2738-2746, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36811718

RESUMO

BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.


Assuntos
Hepatite C Crônica , Porfiria Cutânea Tardia , Porfirinas , Masculino , Humanos , Feminino , Sofosbuvir/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Antivirais/efeitos adversos , Porfiria Cutânea Tardia/diagnóstico , Porfiria Cutânea Tardia/tratamento farmacológico , Porfiria Cutânea Tardia/induzido quimicamente , Fluorenos/uso terapêutico , Hepacivirus/genética , Resultado do Tratamento , Quimioterapia Combinada , RNA , Genótipo , Porfirinas/farmacologia , Porfirinas/uso terapêutico
9.
Clin Infect Dis ; 74(10): 1831-1839, 2022 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-34410358

RESUMO

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). METHODS: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. CONCLUSIONS: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03334747).


Assuntos
Antimaláricos , Malária Falciparum , Adulto , África Subsaariana , Antimaláricos/efeitos adversos , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Humanos , Indóis , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Compostos de Espiro , Resultado do Tratamento
10.
Antimicrob Agents Chemother ; 66(1): e0158421, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34694880

RESUMO

Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.).


Assuntos
Antimaláricos , Malária Falciparum , Adolescente , Adulto , Antimaláricos/efeitos adversos , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Humanos , Lumefantrina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirazóis , Pirimidinas , Método Simples-Cego , Adulto Jovem
11.
Antimicrob Agents Chemother ; 66(9): e0000222, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-35993723

RESUMO

The emergence of artemisinin-resistant parasites in Africa has had a devastating impact, causing most malaria cases and related deaths reported on the continent. In Ethiopia, artemether-lumefantrine (AL) is the first-line drug for the treatment of uncomplicated falciparum malaria. This study is one of the earliest evaluations of artemether-lumefantrine (AL) efficacy in western Ethiopia, 17 years after the introduction of this drug in the study area. This study aimed at assessing PCR- corrected clinical and parasitological responses at 28 days following AL treatment. Sixty uncomplicated falciparum malaria patients were enrolled, treated with standard doses of AL, and monitored for 28 days with clinical and parasitological assessments from September 15 to December 15, 2020. Microscopy was used for patient recruitment and molecular diagnosis of P. falciparum was performed by Var gene acidic terminal sequence (varATS) real-time PCR on dried blood spots collected from each patient from day 0 and on follow-up days 1, 2, 3, 7, 14, 21, and 28. MspI and msp2 genotyping was done to confirm occurrence of recrudescence. Data entry and analysis were done by using the WHO-designed Excel spreadsheet and SPSS version 20 for Windows. A P value of less or equal to 0.05 was considered significant. From a total of 60 patients enrolled in this efficacy study, 10 were lost to follow-up; the results were analyzed for 50 patients. All the patients were fever-free on day 3. The asexual parasite positivity rate on day 3 was zero. However; 60% of the patients were PCR positive on day 3. PCR positivity on day 3 was more common among patients <15 years old as compared with those ≥15 years old (AOR = 6.44, P = 0.027). Only two patients met the case definition of treatment failure. These patients were classified as a late clinical failure as they showed symptoms of malaria and asexual stages of the parasite detected by microscopy on day 14 of their follow-ups. Hence, the Kaplan-Meier analysis of PCR- corrected adequate clinical and parasitological response (ACPR) rate of AL among study participants was 96% (95% CI: 84.9-99). In seven patients, the residual submicroscopic parasitemia persists from day 0 to day 28 of the follow-up. In addition, 16% (8/50) of patients were PCR- and then turned PCR+ after day 7 of the follow-up. AL remains efficacious for the treatment of uncomplicated falciparum malaria in the study area. However, the persistence of PCR-detected residual submicroscopic parasitemia following AL might compromise this treatment and need careful monitoring.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Malária , Adolescente , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Progressão da Doença , Etanolaminas/uso terapêutico , Etiópia , Fluorenos/uso terapêutico , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Parasitemia/tratamento farmacológico , Plasmodium falciparum/genética , Sudão , Resultado do Tratamento
12.
Antimicrob Agents Chemother ; 66(9): e0020722, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36036611

RESUMO

Antimalarial resistance threatens global malaria control efforts. The World Health Organization (WHO) recommends routine antimalarial efficacy monitoring through a standardized therapeutic efficacy study (TES) protocol. From June 2016 to March 2017, children with uncomplicated P. falciparum mono-infection in Siaya County, Kenya were enrolled into a standardized TES and randomized (1:1 ratio) to a 3-day course of artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP). Efficacy outcomes were measured at 28 and 42 days. A total of 340 children were enrolled. All but one child cleared parasites by day 3. PCR-corrected adequate clinical and parasitological response (ACPR) was 88.5% (95% CI: 80.9 to 93.3%) at day 28 for AL and 93.0% (95% CI: 86.9 to 96.4%) at day 42 for DP. There were 9.6 times (95% CI: 3.4 to 27.2) more reinfections in the AL arm compared to the DP arm at day 28, and 3.1 times (95% CI: 1.9 to 4.9) more reinfections at day 42. Both AL and DP were efficacious (per WHO 90% cutoff in the confidence interval) and well tolerated for the treatment of uncomplicated malaria in western Kenya, but AL efficacy appears to be waning. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended.


Assuntos
Antimaláricos , Artemisininas , Antagonistas do Ácido Fólico , Malária Falciparum , Malária , Quinolinas , Antimaláricos/efeitos adversos , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/efeitos adversos , Criança , Combinação de Medicamentos , Etanolaminas/efeitos adversos , Etanolaminas/uso terapêutico , Fluorenos/efeitos adversos , Fluorenos/uso terapêutico , Humanos , Lactente , Quênia , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Piperazinas , Plasmodium falciparum , Quinolinas/efeitos adversos , Reinfecção
13.
J Viral Hepat ; 29(9): 795-806, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35657133

RESUMO

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.


Assuntos
Hepatite C Crônica , Hepatite C , Amidas , Antivirais/uso terapêutico , Benzimidazóis , Benzofuranos , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Fadiga , Feminino , Fluorenos/uso terapêutico , Genótipo , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Imidazóis , Masculino , Pessoa de Meia-Idade , Náusea/tratamento farmacológico , Quinoxalinas , Sofosbuvir/uso terapêutico , Sulfonamidas
14.
J Med Virol ; 94(9): 4548-4553, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35595682

RESUMO

Data on sofosbuvir-based therapy for pregnant women and infants with severe chronic hepatitis C (CHC) are lacking. Two late pregnant women and one female infant with severe CHC were enrolled for treatment. Pregnant Women 1 and 2 and Infant 3 were 30, 33, and 1.2 years old, respectively; the gestational ages of pregnant Women 1 and 2 were 31 and 26 weeks, respectively. Notably, pregnant Women 1 and 2 and Infant 3 had hepatitis C virus (HCV) RNA levels of 139 000, 198 000, and 8 450 000 IU/ml; alanine aminotransferase levels of 420, 781, and 220 U/L; and received sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and sofosbuvir/ledipasvir for 12 weeks, respectively. All three patients were safely cured with favorable tolerance, and two newborns were both breastfeeding and were consistently negative for the anti-HCV antibody during the 1-year follow-up after birth. Additionally, two newborns and Infant 3 had normal growth parameters during the follow-up year one. In conclusion, this case series study found that sofosbuvir-based therapy for pregnant women and infants with severe CHC is safe and effective. The data may fill the gap and provide evidence of the use of sofosbuvir-based therapy as a reference when similar severe CHC situations are encountered during clinical practice.


Assuntos
Hepatite C Crônica , Sofosbuvir , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Fluorenos/uso terapêutico , Genótipo , Hepacivirus/genética , Humanos , Recém-Nascido , Gravidez , Gestantes , Sofosbuvir/uso terapêutico , Resultado do Tratamento
15.
Hepatology ; 74(3): 1645-1651, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33743550

RESUMO

HCV infections have increased in recent years due to injection drug use and the opioid epidemic. Simultaneously, HCV cure has become a reality, with the advent of direct-acting antivirals (DAAs) and expansion of treatment programs. As a result, HCV screening recommendations now include all adults, including pregnant individuals; and many countries have endorsed widespread DAA access as a strategy to achieve HCV eradication. However, almost universally, pregnant individuals have been systematically excluded from HCV clinical research and treatment programs. This omission runs counter to public health strategies focused on elimination of HCV but is consistent with a historical pattern of exclusion of pregnant individuals from research. Our systematic review of publications on HCV treatment with DAAs in pregnancy revealed only one interventional study, which evaluated sofosbuvir/ledipasvir in 8 pregnant individuals. Given the paucity of research on this issue of great public health importance, we aimed to appraise the current landscape of HCV research/treatment and analyze the ethical considerations for responsibly including pregnant individuals. We propose that pregnancy may be an opportune time to offer HCV treatment given improved access, motivation, and other health care monitoring occurring in the antenatal period. Moreover, treatment of pregnant individuals may support the goal of eliminating perinatal HCV transmission and overcome the established challenges with transitioning care after delivery. The exclusion of pregnant individuals without justification denies them and their offspring access to potential health benefits, raising justice concerns considering growing data on DAA safety and global efforts to promote equitable and comprehensive HCV eradication. Finally, we propose a path forward for research and treatment programs during pregnancy to help advance the goal of HCV elimination.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Benzimidazóis/uso terapêutico , Pesquisa Biomédica , Feminino , Fluorenos/uso terapêutico , Humanos , Gravidez , Sofosbuvir/uso terapêutico
16.
Malar J ; 21(1): 194, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35725411

RESUMO

We read with interest the publication on malaria treatment by Obonyo et al. (Malaria J 21:30, 2022). This commentary questions the methodology, especially the chosen time points of treatment outcome measures.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Malária , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Quinina/uso terapêutico , Resultado do Tratamento
17.
Dig Dis Sci ; 67(1): 100-120, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33528686

RESUMO

BACKGROUND: Patients' motivations for undergoing direct-acting antiviral (DAA) therapy for chronic hepatitis C may include anticipation of treatment benefits not well described in the literature. AIMS: Evaluate patients' anticipated and actualized improvements in several domains of functioning before and after viral cure. METHODS: Pre-post-study utilizing in-depth interviews with 28 patients prior to, and several months after, DAA therapy. Interviews were audio-recorded, transcribed, coded, and analyzed by two qualitative experts. RESULTS: Patients had a median age of 54 years, 43% were male, 57% white, 25% had cirrhosis, and 71% were treated with sofosbuvir/ledipasvir. Pre-treatment, patients hoped for improvements in several domains including psychological, emotional, physical, social, and occupational functioning. After viral cure, increased energy and less fear of transmission were pathways to better quality of life. Psychological and emotional improvements positively affected physical, social, and occupational functioning. Social improvements were due to better mood and motivation, fewer symptoms, and reduced fear of stigma and transmission. Occupational benefits were linked to increased stamina, self-confidence, and less pain, anxiety, and stigma. Reduced fear of stigma had a pervasive impact on all life improvements after cure. Patient characteristics such as the presence of cirrhosis or psychiatric issues influence treatment motivations. Qualitative data correspond with change in pre-post-survey scores. CONCLUSIONS: Tremendous hope is placed on the ability of DAA therapy to bring about substantial improvements in life functioning after viral cure. Highly interconnected effects on quality of life worked synergistically through improved physical and psychological well-being. Stakeholders should appreciate the multi-dimensional benefits that viral eradication bestows upon individuals and society.


Assuntos
Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica , Saúde Mental , Qualidade de Vida , Interação Social , Sofosbuvir/uso terapêutico , Antecipação Psicológica , Antivirais/uso terapêutico , Erradicação de Doenças , Transmissão de Doença Infecciosa/prevenção & controle , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Resultado do Tratamento
18.
Am J Gastroenterol ; 116(9): 1924-1928, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465694

RESUMO

INTRODUCTION: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. METHODS: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). RESULTS: Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. DISCUSSION: Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Falência Renal Crônica/terapia , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Esquema de Medicação , Feminino , Fluorenos/administração & dosagem , Hepatite C/complicações , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento
19.
J Antimicrob Chemother ; 76(5): 1269-1272, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33550391

RESUMO

BACKGROUND: In sub-Saharan Africa, artemisinin-containing therapies for malaria treatment are regularly co-administered with ART. Currently, dolutegravir-based regimens are recommended as first-line therapy for HIV across most of Africa. OBJECTIVES: To investigate the population pharmacokinetics of dolutegravir during co-administration with artemether/lumefantrine or artesunate/amodiaquine, two commonly used antimalarial therapies. METHODS: We developed a population pharmacokinetic model of dolutegravir with data from 26 healthy volunteers in two Phase 2 studies with a total of 403 dolutegravir plasma concentrations at steady state. Volunteers received 50 mg of dolutegravir once daily alone or in combination with standard treatment doses of artemether/lumefantrine (80/480 mg) or artesunate/amodiaquine (200/540 mg). RESULTS: A two-compartment model with first-order elimination and transit compartment absorption best described the concentration-time data of dolutegravir. Typical population estimates for clearance, absorption rate constant, central volume, peripheral volume and mean absorption transit time were 0.713 L/h, 1.68 h-1, 13.2 L, 5.73 L and 1.18 h, respectively. Co-administration of artemether/lumefantrine or artesunate/amodiaquine increased dolutegravir clearance by 10.6% (95% CI 4.09%-34.5%) and 26.4% (95% CI 14.3%-51.4%), respectively. Simulations showed that simulated trough concentrations of dolutegravir alone or in combination with artemether/lumefantrine or artesunate/amodiaquine are maintained above the dolutegravir protein-adjusted IC90 of 0.064 mg/L for more than 99% of the individuals. CONCLUSIONS: Dolutegravir dose adjustments are not necessary for patients who are taking standard 3 day treatment doses of artemether/lumefantrine or artesunate/amodiaquine.


Assuntos
Antimaláricos , Malária Falciparum , África , Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artesunato , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Compostos Heterocíclicos com 3 Anéis , Humanos , Malária Falciparum/tratamento farmacológico , Oxazinas , Piperazinas , Piridonas
20.
J Pediatr ; 233: 126-131, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33577805

RESUMO

OBJECTIVES: To assess the degree of liver stiffness using transient elastography in Egyptian children infected with hepatitis C virus (HCV) at baseline and 1 year after achievement of sustained virologic response (SVR) with direct acting antivirals. STUDY DESIGN: This prospective study included children infected with HCV who received treatment with sofosbuvir/ledipasvir and achieved SVR. At baseline and 1 year after achievement of SVR, the extent of hepatic fibrosis was assessed by transient elastography using FibroScan to measure liver stiffness, in addition to noninvasive markers including aspartate aminotransferase/platelet ratio index (APRI) and fibrosis-4 (FIB-4) index. RESULTS: The study included 23 cases that had variable degrees of fibrosis at baseline; their ages ranged between 10 and 18 years. At baseline, 13 patients had F1; 3 patients had F1-F2; 1 patient had F2; 3 patients had F3; 2 had F3-F4; and 2 patients with F4. One year after achievement of SVR, there was a statistically significant improvement in liver stiffness, APRI, and FIB-4 index (P = .03, <.001, .02, respectively). In 13 patients (56.5%), the liver stiffness improved; in 7 patients, it was stationary; and the remaining 3 patients showed mild increase in liver stiffness that was, however, associated with improvement in APRI and FIB-4 index. Comorbid conditions and previous treatment with interferon were not associated with increased liver stiffness 1 year after SVR. CONCLUSIONS: Egyptian children infected with HCV genotype 4 achieved significant regression in liver stiffness after treatment with direct acting antivirals.


Assuntos
Antivirais/uso terapêutico , Técnicas de Imagem por Elasticidade , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/diagnóstico por imagem , Adolescente , Aspartato Aminotransferases/sangue , Benzimidazóis/uso terapêutico , Criança , Feminino , Fluorenos/uso terapêutico , Genótipo , Hepatite C/genética , Humanos , Cirrose Hepática/classificação , Masculino , Estudos Prospectivos , Sofosbuvir/uso terapêutico
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