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.

A Randomized, Double-Blind, Multicenter Clinical Study Comparing the Efficacy and Safety of a Drug Combination of Lopinavir/Ritonavir-Azithromycin, Lopinavir/Ritonavir-Doxycycline, and Azithromycin-Hydroxychloroquine for Patients Diagnosed with Mild to Moderate COVID-19 Infections.

BACKGROUND: At the present time, COVID-19 vaccines are at the testing stage, and an effective treatment for COVID-19 incorporating appropriate safety measures remains the most significant obstacle to be overcome. A strategic countermeasure is, therefore, urgently required. AIM: This study aims to evaluate the efficacy and safety of a combination of lopinavir/ritonavir-azithromycin, lopinavir/ritonavir-doxycycline, and azithromycin-hydroxychloroquine used to treat patients with mild to moderate COVID-19 infections. Setting and Design. This study was conducted at four different clinical study sites in Indonesia. The subjects gave informed consent for their participation and were confirmed as being COVID-19-positive by means of an RT-PCR test. The present study constituted a randomized, double-blind, and multicenter clinical study of patients diagnosed with mild to moderate COVID-19 infection. MATERIALS AND METHODS: Six treatment groups participated in this study: a Control group administered with a 500 mg dose of azithromycin; Group A which received a 200/50 mg dose of lopinavir/ritonavir and 500 mg of azithromycin; Group B treated with a 200/50 mg dose of lopinavir/ritonavir and 200 mg of doxycycline; Group C administered with 200 mg of hydroxychloroquine and 500 mg of azithromycin; Group D which received a 400/100 mg dose of lopinavir/ritonavir and 500 mg of azithromycin; and Group E treated with a 400/100 mg dose of lopinavir/ritonavir and 200 mg of doxycycline. RESULTS: 754 subjects participated in this study: 694 patients (92.4%) who presented mild symptoms and 57 patients (7.6%) classified as suffering from a moderate case of COVID-19. On the third day after treatment, 91.7%-99.2% of the subjects in Groups A-E were confirmed negative by a PCR swab test compared to 26.9% in the Control group. Observation of all groups which experienced a significant decrease in virus load between day 1 and day 7 was undertaken. Other markers, such as CRP and IL-6, were significantly lower in all treatment groups (p < 0.05 and p < 0.0001) than in the Control group. Furthermore, IL-10 and TNF-α levels were significantly elevated in all treatment groups (p < 0.0001). The administration of azithromycin to the Control group increased CRP and IL-6 levels, while reduced IL-10 and TNF-α on day 7 (p < 0.0001) compared with day 1. Decreases in ALT and AST levels were observed in all groups (p < 0.0001). There was an increase in creatinine in the serum level of the Control, C, D, and E groups (p < 0.05), whereas the BUN level was elevated in all groups (p < 0.0001). CONCLUSIONS: The study findings suggest that the administration of lopinavir/ritonavir-doxycycline, lopinavir/ritonavir-azithromycin, and azithromycin-hydroxychloroquine as a dual drug combination produced a significantly rapid PCR conversion rate to negative in three-day treatment of mild to moderate COVID-19 cases. Further studies should involve observation of older patients with severe clinical symptoms in order to collate significant amounts of demographic data.

Transformation of infectious diseases and the Indonesian national military health research collaboration in supporting national health security.

Transformation of infectious diseases is a dynamic movement of the spread of disease that is largerly determined by the ability to understand geomedical maps, disease transmission and impacts on national security. Disease transformation is an order of infection that can be life threatening in a clinical perspective an outbreak at the community level. The involvement of the Indonesian National Military (Tentara Nasional Indonesia, TNI) in the transformation of infected diseases is a network that needs to be strengthened, considering that its role is very important to maintain health security as a gate for national security. Strength in dealing with the extraordinary event of infection requires on going collaboration, competence, networking and integration.

Adult-onset Still's Disease as a Differential Diagnosis in Prolonged Fever: Diagnosis and Treatment Experience.

Adult onset Still's disease is a rare systemic disease that may involve many organs and may mimick many disease such as infection, autoimmune disease, and also malignancy. The diagnostic approach and treatment strategies have not been well established due to its rarity; however, there are some diagnostic criteria that may help. We present a case of 36-year old man who experienced high prolonged fever which firstly thought as infection. He also had unilateral wrist and knee joint pain and maculopapular rash. Laboratory examination showed high leukocytes count with elevated polymorphonuclear neutrophil count, high platelet count, high ferritin level, and negative results of many infection markers (typhoid antibody, procalcitonin, malaria test, blood culture, urine culture, IgM pneumonia, ASTO, syphilis test, antiHIV, HBsAg, antiHCV, etc). Chest X-ray, joint X-ray, ultrasonography, and echocardiography showed normal result. The patient was then diagnosed with Adult-onset Still's disease and received intravenous methylprednisolone and the fever was disappeared in 3 days. Six months later the arthralgia appeared again, methotrexate was administered and the pain was then relieved.

Plasmodium ovale Infection After One Year Mefloquine Prophylaxis in A Young Indonesian Soldier: A Case Report.

Malaria chemoprevention using mefloquine has become the WHO standard regimen for military personnel who stay in the endemic area for an extended period of time. We reported a case of Plasmodium ovale infection in a young Indonesian Soldier following one year mefloquine prophylaxis 250 mg weekly. Typical fever and chills were experienced two weeks after returning from one year duty in Congo, West-Central Africa. The diagnosis of ovale malaria was made by peripheral blood smear, and 35/250 parasites in small microscopic view was found. Then, he recovered after dihydroartemisin and primaquine combination therapy. This was an unusual case of long-term prophylaxis failure since mefloquine has been recognized as the agent for malaria prevention, even multi-drug-resistance Plasmodium. Dormant stage of Plasmodium ovale, quinoline-resistance potential, and the efficacy of mefloquine itself are discussed as the cause of that phenomenon.

The Autoimmune Mechanism in Dengue Hemorrhagic Fever.

The immune response of dengue fever/dengue hemorrhagic fever is a series of immunopathogenesis processes starting from viral infection to the target on monocytes and macrophages. It may consequently cause a cascade of viremia in the circulation that stimulates the afferent, efferent, and effector mechanism by the interaction of the humoral and complement system. The cascade results in inflammatory substance that will affect capillary permeability and activate coagulation factors leading to further effects on endothelial level. The mechanism involving pathogenesis of DHF/DSS is still vague. So far, a theory of heterologous infection has been developed, which explains that on second infection, there is subneutralization that induce viral replication. The  autoimmune mechanism development leads to the better understanding of DHF. It also  explains the autoimmune response of the viral infection, which consists of molecular mimicry, bystander activation and viral persistence. The development of the autoimmune pathomechanism is related to the role of  autoantibody and endothelial dysfunction that may have role in worsening DHF.

Concurrent infections of dengue viruses serotype 2 and 3 in patient with severe dengue from Jakarta, Indonesia.

OBJECTIVE: To describe the clinical manifestation of patient with severe dengue, to identify the serotypes and genotypes of dengue viruses (DENV) which concurrently infecting the patient, and to explore the possible relationship of severe dengue with the concurrent infection of DENV. METHODS: Dengue diagnosis was performed using NS1 antigen detection and IgG/IgM ELISA. Standard clinical and laboratory examinations were performed to obtain the clinical and hematological data. DENV concurrent infections were detected and confirmed using RT-PCR and DENV Envelope gene sequencing. Phylogenetic analyses were performed to determine the genotypes of the viruses. RESULTS: The patient was classified as having severe dengue characterized by severe plasma leakage, hemorrhage, and organ damage involving lung, liver, and kidney. Concurrent infection of DENV serotype 2 and 3 was observed. The infecting DENV-2 virus was grouped into Cosmopolitan genotype while DENV-3 virus was classified into Genotype I. Both viruses were closely related to isolates that were endemic in Jakarta. Viremia measurement was conducted and revealed a significantly higher virus titer of DENV-3 compared to DENV-2. CONCLUSIONS: The occurrence of multi-serotype DENV infections was presented in a patient with severe clinical manifestation in Indonesia. The hyperendemicity of dengue in Indonesia may contribute to the DENV concurrent infections cases and may underlie the severity of the disease.

Septic Pulmonary Embolism Following Appendectomy Surgery.

Septic Pulmonary embolism is a rare condition where there were numerous pulmonary infarcts resulting from blood clot emboli that also contains microorganism. This disorder is insidious onset, Its clinical features usually unspecific and the diagnosis usually difficult to establish. A 43 old woman who underwent an appendicitis surgery, reentered the hospital at the sixth day after surgery presented with fever, pain at the surgical site, progressive severe dyspnea and chest tightness. From the physical examination finding there were tachycardia, tachypneu, wet rough basal rhonki on the right rear and tenderness at right lower region of the abdomen. The thorax-abdomen CT scan result was pleuropneumonial with minimal effusion in the right side. A CT angiography scan of the chest and abdomen showed intralumen emboli in medial lobe segmen of right pulmonary artery, right pleuropneumonia with segmental lession in segmen 10 right lobe and inflammation process along right lateral wall of the abdomen. Laboratory results that also supported diagnosis were D dimer 3442 ng/mL and culture result from surgical site pus showed E. Coli ESBL (+). Base on these findings, this case was established as a septic pulmonary embolism.