Tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study.

BACKGROUND: Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin-piperaquine for the radical cure of P vivax malaria. METHODS: In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin-piperaquine alone, dihydroartemisinin-piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin-piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin-piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed. FINDINGS: Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4-22) in patients treated with dihydroartemisinin-piperaquine alone versus 21% (11-34) in patients treated with tafenoquine plus dihydroartemisinin-piperaquine (hazard ratio 0·44; 95% CI [0·29-0·69]) and 52% (37-65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin-piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin-piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin-piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively. INTERPRETATION: Although tafenoquine plus dihydroartemisinin-piperaquine was statistically superior to dihydroartemisinin-piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria. FUNDING: ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK. TRANSLATION: For the Indonesian translation of the abstract see Supplementary Materials section.

Bedaquiline Effect on QT Interval of Drugs-Resistant Tuberculosis Patients: Real World Data.

BACKGROUND: Bedaquiline (BDQ) is effective as part of treatment regimen for drug-resistant tuberculosis (DR-TB), but the cardiac safety profile of BDQ is not fully elucidated. This study aimed to analyse the cardiac safety of BDQ by examining its effect on the QT interval of DR-TB patients. METHODS: This is a retrospective study cohort conducted in two DR-TB referral hospitals in Indonesia. The QT interval before and after therapy using BDQ was measured manually and corrected using the Fridericia formula (QTcF). The QT interval profile was analysed over time during BDQ treatment. RESULTS: A total of 105 subjects participated in the study. The maximum mean difference (standard deviation) of QTcF after treatment with the baseline (∆QTcF) is 34,06 (52,92) ms after three months of therapy. During BDQ treatment, clinically significant QTcF prolongations was observed in 37.1% subjects with neither arrhythmia nor any other adverse cardiac event occurred. The interval QT prolongation led to BDQ discontinuation in 15.2% subjects temporarily and in 6.7% subjects permanently. There were seven deaths (6.7%) during the treatment. CONCLUSION: During BDQ treatment, maximum QT prolongation was observed after three months of BDQ therapy. Therefore, more intensive cardiac monitoring is recommended during this period and afterwards.

Outcomes of Daily Dose versus Part-daily Dose Treatment for Lung Tuberculosis: A Real-World Database Study in an Indonesian Hospital.

BACKGROUND: a meta-analysis of randomized control trials (RCTs) on category I pulmonary tuberculosis (PTB) treatments showed that either part-daily (2RHZE/4R3H3) or daily dose (2RHZE/4RH) had the same failure and recurrence rates. However, the World Health Organization (WHO) concluded that the part-daily dose had higher failure and recurrence rates. Therefore, this study was conducted to compare the treatment outcomes between both regimens, whether daily dose regimen has a better treatment outcome than part-daily dose regimen, and the adverse effects between both regimens. METHODS: this was an analytic cross-sectional study of patients at the Persahabatan General Hospital, over the period of January 2015-June 2018. Data were taken from medical records and supported by telephone interviews, each regimen group had 175 patients. RESULTS: there were no significant differences for success rates (p=0.470), lost to follow up rates (p=0.659), failure rates (p=1.000), death rates (p=1.000), and adverse effects in the continuation phase (p=0.324) between the groups. There were, however, significant differences in cure rates (p < 0.001) and complete treatment rates (p<0.001) between the groups. CONCLUSION: the cure rate and complete treatment rate were found to be better for the part-daily than the daily doses. The success rate of both regimens were the same as Indonesia's target (90%). In the continuation phase, there were no significant difference of adverse effects between both regimens.

TPMT Genetic Variability and Its Association with Hematotoxicity in Indonesian Children with Acute Lymphoblastic Leukemia in Maintenance Therapy.

PURPOSE: Hematotoxicity monitoring in children with acute lymphoblastic leukemia (ALL) is critical to preventing life-threatening infections and drug discontinuation. The primary drug that causes hematotoxicity in ALL children is 6-mercaptopurine (6-MP). Genetic variability of the drug-metabolizing enzymes of 6-MP, thiopurine S-methyltransferase (TPMT), is one factor that might increase the susceptibility of children to hematotoxicity. The present study aimed to determine the variability in TPMT genotypes and phenotypes and its association with the occurrence of hematotoxicity in ALL children in maintenance therapy. PATIENTS AND METHODS: A cross-sectional study was conducted at Cipto Mangunkusumo and Dharmais National Cancer Hospital, Jakarta, Indonesia, from June 2017 to October 2018. We included ALL patients, 1-18 years, who were receiving at least one month of 6-MP during maintenance therapy according to the Indonesian protocol for ALL 2013. Direct sequencing was used to determine TPMT*3A, *3B, and *3C genotypes, and LC-MS/MS analysis was performed to measure the plasma concentrations of 6-MP and its metabolites. Association analysis between the TPMT genotype and hematotoxicity was evaluated using the unpaired t-test or Mann-Whitney's test. RESULTS: The prevalence of neutropenia, anemia, and thrombocytopenia in ALL children during maintenance therapy was 51.9%, 44.3%, and 6.6%, respectively. We found a low frequency of TPMT*3C, which is 0.95%. No association was found between hematotoxicity and TPMT genotypes or age, nutritional status, serum albumin levels, risk stratification, the daily dose of 6-MP, and cotrimoxazole co-administration. However, hematotoxicity was associated with 6-methylmercaptopurine (6-MeMP) plasma concentrations and the ratio 6-MeMP/6-thioguanine (6-TGN). We also found no association between TPMT genotypes and TPMT phenotypes. CONCLUSION: The 6-MeMP/6-TGN ratio is associated with hematotoxicity in ALL children during maintenance therapy but is not strong enough to predict hematotoxicity.

Comparative Effectiveness of Tuberculosis Treatment Daily versus Intermittent Regimen in Indonesian TB-DM Patients: Real World Patient Database Study.

BACKGROUND: diabetes mellitus (DM) increases the risk of active TB by three times; there is no specific treatment strategy for tuberculosis-DM (TB-DM) patients. The 2017 WHO guidelines no longer recommended an intermittent regimen in the advanced phase of TB treatment due to higher risk of failure, relapse, and drug resistance compared to the daily regimen. This study aims to compare the effectiveness of treatment, in terms of clinical response and sputum conversion, of TB-DM patients in the advanced phase between the two-treatment delivery schedules. METHODS: a retrospective cohort study from the medical records of patients from 1 January 2015 to 31 December 2018 at Persahabatan Hospital, Jakarta. The inclusion criteria are TB-DM patients aged >18 years with non-reactive HIV test, who have entered the advanced phase of category 1 TB treatment with smear positive at the time of diagnosis. RESULTS: a total of 72 patients met the inclusion criteria. (75% male and 88.8% had at least 1+ smear results at the time of diagnosis). Thirty subjects still have positive smear at the beginning of the advance phase of treatment. After the advanced phase, 44.2% in the intermittent and 41.4% in the daily group were curedhaving sputum conversion. Seven subjects had side effects; but there were lots of dropouts and it is unclear whether they dropped because of side effects or not. CONCLUSION: there is no difference between sputum conversion profile and treatment success in advanced phase TB-DM treatment category 1 between the daily and intermittent regimen.ly for diabetic patients.

Association between C1236T Genetic Variant of ABCB1 Gene and Molecular Response to Imatinib in Indonesian Chronic Myeloid Patients.

OBJECTIVE: Imatinib is the first-line drug used for the treatment of chronic myeloid leukemia (CML) patients due to high molecular response and overall survival rate. However, some patients develop resistance to imatinib even after attaining a response. Mutation in ABCB1 efflux transporters is one of the known mechanisms of resistance to imatinib in chronic myeloid leukemia patients. This study was aimed to investigate the association of ABCB1 C1236T polymorphism in Indonesian chronic myeloid patients with molecular response to imatinib treatment. METHODS: We analyzed 120 samples from chronic myeloid leukemia patients in the chronic phase, who had been on imatinib treatment for at least 12 months. We analyzed the C1236T variant of the ABCB1 gene using PCR, followed by direct sequencing, and associate them with the achievement of major molecular response (MMR). RESULTS: The major molecular response was achieved in 28% of patients. The frequencies of the SNPs were CC (40%), CT (46%), and TT (14%). Our result showed that there was a lack of association between polymorphism of ABCB1 C1236T and imatinib response in Indonesian patients, with OR = 0.646 (95% CI: 0.283, 1.471; p>0.05). CONCLUSION: There was no association between ABCB1 C1236T variants with the major molecular response in Indonesian chronic myeloid leukemia patients receiving imatinib treatment.

Pharmacokinetic Profile of Curcumin and Nanocurcumin in Plasma, Ovary, and Other Tissues.

BACKGROUND: Curcumin is a natural diphenolic compound that is currently being investigated for various cancers, including ovarian cancer. Clinical application of curcumin has been limited due to its low solubility and bioavailability and rapid metabolism and degradation at physiological pH. Particle size is one factor that can affect the absorption process, which thus increases compound solubility and transport across the membrane. This study was conducted to determine the effects of modifying the particle size of curcumin on its pharmacokinetic parameters in blood and other organs. METHODS: Female Sprague Dawley rats were administered a single oral dose of 500 mg/kg curcumin or nanocurcumin. Blood samples were collected at 10, 15, 30, 45, 75, and 120 min, and ovaries, livers, kidneys, and colons were collected at 180 min. The levels of curcumin in plasma and organs were determined using UPLC-MS/MS, and the pharmacokinetic parameters were evaluated. RESULTS: Curcumin levels were detectable and measurable in plasma and organs of rats that were administered curcumin or nanocurcumin. Overall, no statistically significant differences were found in pharmacokinetic parameters between curcumin and nanocurcumin groups in both plasma and organs, except for ovaries. The curcumin levels in plasma, liver, kidney, and colon in the curcumin group were higher than those in the nanocurcumin group. However, curcumin concentrations in ovaries in the nanocurcumin group were 3.6 times higher than those in the curcumin group. CONCLUSION: Particle size reduction of curcumin did not increase the concentration of curcumin in the plasma but increased its distribution in the ovaries.