Patients with severe schistosomiasis mekongi morbidity demonstrating ongoing transmission in Southern Lao People's Democratic Republic.

Chronic infection with Schistosoma mekongi may result in severe hepatosplenic morbidity. We report on eight patients with severe morbidity due to S. mekongi infection. The patients were diagnosed, treated and followed-up between 2007 and 2010 in Khong district, Southern Lao People's Democratic Republic (Lao PDR), eight years after the end of a control intervention. S. mekongi control programmes aimed to prevent morbidity and mortality associated with infection. The patients were visited and interviewed annually. In addition, clinical and abdominal ultrasound examinations were performed and faecal and blood samples were examined. The patients' ages ranged from 6 to 66 years. Of the eight patients, three were children and five were adults. The four youngest patients (aged 6-27 years) significantly improved after praziquantel treatment. One patient (age 46 years) worsened between 2007 and 2010. Two patients died due to bleeding of the oesophageal varices. One patient was lost to follow-up. The leading clinical signs were ascites, splenomegaly, collateral veins on the abdomen and a poor general nutrition status. Ultrasonography disclosed advanced liver fibrosis patterns in all patients; in seven patients, fibrosis pattern E or F was revealed, as per the Niamey protocol (pattern A normal, pattern B to F pathological with increasing severity). Stool microscopy revealed that five patients were co-infected with hookworm and Opisthorchis viverrini. The youngest patient (aged 6 years) was born after the schistosomiasis control program had ended. From her severe morbidity, we can conclude that S. mekongi transmission was on-going in Khong district, and that even in areas with low S. mekongi transmission intensities, severe morbidity from schistosomiasis can develop quickly. Early diagnosis and treatment are imperative, and close monitoring is required.

Efficacy and safety of tribendimidine versus praziquantel against Opisthorchis viverrini in Laos: an open-label, randomised, non-inferiority, phase 2 trial.

BACKGROUND: Praziquantel is the only option for treatment of the liver fluke infection Opisthorchis viverrini. Tribendimidine could be an alternative drug. We aimed to assess the efficacy and safety of a single, oral dose of tribendimidine, compared with praziquantel administered in two doses, in participants with O viverrini infection. METHOD: We did an open-label, randomised, non-inferiority, phase 2 trial in children (8-14 years) and adolescents and adults (≥15 years) in Champasack province, southern Laos. Participants infected with O viverrini were randomly assigned (1:1), via a computer-generated block-randomisation procedure (block sizes of two, four, and six), to receive a single, oral dose of tribendimidine (200 mg for children, 400 mg for adolescents and adults) or two oral doses of praziquantel (50 mg/kg bodyweight and 25 mg/kg bodyweight, 6 h apart). Physicians assessing adverse events and laboratory personnel were masked to treatment allocation, but the investigators administering treatment and the participants could have recognised the treatment group based on differences in the number, appearance, and odour of the tablets. The primary outcomes were cure rate, defined as no parasite eggs in stool at 3 weeks' follow-up, and egg reduction rate. We did available-case analysis of all participants with primary endpoint data. The non-inferiority margin for the difference in cure rates between the groups was pre-specified as -3 percentage points. Adverse events were monitored at 3 h and 24 h after treatment. This trial is registered, number ISRCTN96948551. FINDINGS: Between Feb 1, and April 30, 2014, we assigned 607 participants with confirmed O viverrini infection to receive tribendimidine (n=300) or praziquantel (n=307). 11 participants (five in the tribendimidine group and six in the praziquantel group) did not provide stool samples at 3 weeks' follow-up and were excluded from the available-case analysis. 276 (93·6%) of 295 participants in the tribendimidine group were cured compared with 293 (97·3%) of 301 participants in the praziquantel group. The difference in cure rates between the two groups was -3·8 percentage points (95% CI -7·1 to -0·4), thus the lower limit of the confidence interval exceeded the non-inferiority margin. In both treatment groups, egg reduction rates were 99·9%. Adverse events were of mild and moderate intensity and were more frequent in the praziquantel group than in the tribendimidine group (odds ratio 4·5, 95% CI 3·2-6·3; p<0·0001). The most frequent adverse events were headache, vertigo, nausea, and fatigue. INTERPRETATION: Tribendimidine has a slightly lower cure rate than praziquantel and non-inferiority was not shown. However, tribendimidine has a similar egg reduction rate to praziquantel and leads to fewer adverse events and thus might complement praziquantel in O viverrini control programmes, particularly in settings co-endemic for hookworm. FUNDING: Joint Global Health Trials scheme from the Wellcome Trust, Department for International Development, and Medical Research Council.

Efficacy and Safety of Praziquantel Against Light Infections of Opisthorchis viverrini: A Randomized Parallel Single-Blind Dose-Ranging Trial.

Background: The liver fluke Opisthorchis viverrini, highly prevalent in Southeast Asia, is an important public health burden, including a risk factor for developing an aggressive bile duct cancer, cholangiocarcinoma, in chronically infected patients. Praziquantel, administered at a single 40 mg/kg dose in preventive chemotherapy programs and 3 × 25 mg/kg for individual treatment, is the drug of choice, yet information on the nature of the dose-response relationship is lacking. Methods: We performed a randomized, parallel, single-blind dose-ranging phase 2 trial in the Lao People's Democratic Republic in O. viverrini­infected adults. Patients were randomly assigned to 30 mg/kg, 40 mg/kg, 50 mg/kg, or 3 × 25 mg/kg praziquantel or placebo. Adverse events were recorded at baseline, 3 hours, and 24 hours posttreatment. Cure rates (CRs) and egg reduction rates (ERRs) were estimated 3 weeks after drug administration using available case analysis. Dose-response curves were predicted using Emax models. Results: Two-hundred seventeen O. viverrini­infected patients were assigned to the 5 treatment arms. The majority (94.3%) of patients harbored light infections. The Emax model predicted a high efficacy among the observed dose range. We observed CRs ranging from 92.7% to 95.5% and ERRs >99.5% for all praziquantel treatment groups. Adverse events were mild but higher in the standard treatment group (3 × 25 mg/kg) than in the single-dose treatment arms. Conclusions: Single-dose praziquantel appears to be as efficacious as the standard 3 × 25 mg/kg regimen for the treatment of O. viverrini infections, while presenting fewer adverse events. Further studies are necessary in moderate and heavy O. viverrini infections. Clinical Trials Registration: Randomized Controlled Trials (ISRCTN77186750).

Subtle to severe hepatobiliary morbidity in Opisthorchis viverrini endemic settings in southern Laos.

Evidence of severe hepatobiliary morbidity associated with Opisthorchis viverrini liver fluke infection including cholangiocarcinoma (CCA) is scarce in Laos although O. viverrini infection is highly prevalent. We assessed hepatobiliary morbidity using abdominal ultrasonography (US) in O. viverrini adult patients in Saravan province, Southern Laos. A random sample of 431 O. viverrini patients from 10 villages underwent abdominal US. Mild, moderate and markedly advanced periductal fibrosis was diagnosed in 7.0%, 66.5%, and 17.0% of patients, respectively. Normal liver parenchyma was seen in only 9.5% of patients. Presence of gall stones (13.2%), sludge (1.4%), gall wall thickening (1.2%), bile duct dilatation (1.6%), fatty liver (12.0%), kidney stones (8.6%) and cysts (7.9%) were diagnosed in considerable frequencies. In five patients (1.2%) hepatobiliary lesions suggesting CCA were diagnosed. Tumour markers, i.e. Interleukin-6, plasminogen activator inhibitor and carbohydrate antigen 19-9 were within normal range. The number of CCA suspected liver masses and hepatobiliary morbidity diagnosed among clinically asymptomatic adult patients in O. viverrini endemic area presents a major public health concern in Laos. However, definitive diagnosis of Opisthorchis-related severe sequelae including CCA is urgently needed to gauge the burden of this deadly disease in Laos.

Perceived illness drives participation in mass deworming campaigns in Laos.

Multiple helminth infections are very common in communities of southern Laos. Preventive chemotherapy in combination with health education is the mainstay of control. We assessed the knowledge, perceptions and practices of rural communities related to endemic helminthiasis and their control during a mass drug administration (MDA) campaign. Short interviews with household heads (n=192), direct observations and discussions with attendees of MDAs, and in-depth interviews with local opinion leaders (n=21) were carried out. Quantitative and qualitative data analysis was performed. Results showed that opinion leaders and villagers were well aware of the importance of attending MDA. Leaders perceived the effectiveness of MDA against severe schistosomiasis and appreciated that it was provided for free and in their village. They encouraged villagers to attend it. Anticipated adverse events of praziquantel was a barrier for participation. A majority of leaders purchased deworming tablet (mebendazole, albendazole) in a local pharmacy for deworming when MDA is absent in their villages (19/21). Most leaders (20/21) had a good knowledge on severe schistosomiasis though only a few of them (5/21) described its cause correctly. They knew little about the disease consequences of liver fluke (3/21) and soil-transmitted helminth (4/21) infections but more about their causes. A high risk for worm infection was observed: consumption of raw or insufficiently cooked fish (100%), frequent physical contacts with Mekong River water (76.0%) and low number of latrines (14.5%). In conclusion, MDA is widely accepted in affected communities. Avoiding severe schistosomiasis was the main motivation to comply. Participation rates increased significantly with drugs provided free of charge in the villages. Better knowledge on the consequences of worm infections and on its modes of transmission will foster the distribution and acceptance of appropriate preventive treatment and other measures in helminth-endemic communities. Where multiple infections require several drugs for MDA, preceding health education and information about MDA and its benefits are a prior condition.

Efficacy of praziquantel against Schistosoma mekongi and Opisthorchis viverrini: a randomized, single-blinded dose-comparison trial.

BACKGROUND: Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ) is the drug of choice for morbidity control but few dose comparisons have been made. METHODOLOGY: Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for a PZQ dose-comparison trial. Prevalence and intensity of infections were determined by a rigorous diagnostic effort (3 stool specimens, each examined with triplicate Kato-Katz) before and 28-30 days after treatment. Ninety children with full baseline data were randomized to receive PZQ: the 40 mg/kg standard single dose (n = 45) or a 75 mg/kg total dose (50 mg/kg+25 mg/kg, 4 hours apart; n = 45). Adverse events were assessed at 3 and 24 hours posttreatment. PRINCIPAL FINDINGS: Baseline infection prevalence of S. mekongi and O. viverrini were 87.8% and 98.9%, respectively. S. mekongi cure rates were 75.0% (95% confidence interval (CI): 56.6-88.5%) and 80.8% (95% CI: 60.6-93.4%) for 40 mg/kg and 75 mg/kg PZQ, respectively (P = 0.60). O. viverrini cure rates were significantly different at 71.4% (95% CI: 53.4-84.4%) and 96.6% (95% CI: not defined), respectively (P = 0.009). Egg reduction rates (ERRs) against O. viverrini were very high for both doses (>99%), but slightly lower for S. mekongi at 40 mg/kg (96.4% vs. 98.1%) and not influenced by increasing diagnostic effort. O. viverrini cure rates would have been overestimated and no statistical difference between doses found if efficacy was based on a minimum sampling effort (single Kato-Katz before and after treatment). Adverse events were common (96%), mainly mild with no significant differences between the two treatment groups. CONCLUSIONS/SIGNIFICANCE: Cure rate from the 75 mg/kg PZQ dose was more efficacious than 40 mg/kg against O. viverrini but not against S. mekongi infections, while ERRs were similar for both doses. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN57714676.