Cognitive function measured with the Revised Hasegawa's Dementia Scale among elderly individuals in Lao PDR.

In Lao PDR, measurement of cognitive function has rarely been conducted among elderly individuals. This study aimed to investigate the cognitive function among elderly individuals who lived at their homes with family in Lao PDR. Participants were elderly individuals aged 60 years or over registered with the local government in urban (Vientiane capital; VC) and rural areas (Khammouane province; KP). Those with serious mental/physical diseases, those who could not walk by themselves, or those who could not speak the Lao language were excluded. The information was collected through interviews with the participants and their family members. A newly developed Lao version of the Revised Hasegawa's Dementia Scale (HDS-R) was applied to measure cognitive function. The participants were 414 elderly individuals (224 males and 190 females) aged 60 to 98 years. The average HDS-R score was 23.0 among 115 men in VC, 22.7 among 92 women in VC, 20.3 among 109 men in KP, and 17.5 among 98 women in KP. The main caregiver was a daughter (40.6%) followed by a spouse (31.4%). Among 414 elderly individuals, 42 (10.0%) stated the necessity of support. Those with HDS-R < 20 accounted for 38.8% in men and 48.9% in women. The adjusted odds ratio of HDS-R < 20 was significant for those in rural areas (3.83) relative to those in urban areas. Among superficially healthy elderly individuals residing with their families, those with reduced cognitive function were more common among women and in rural areas.

Efficacy and tolerability of triple drug therapy with albendazole, pyrantel pamoate, and oxantel pamoate compared with albendazole plus oxantel pamoate, pyrantel pamoate plus oxantel pamoate, and mebendazole plus pyrantel pamoate and oxantel pamoate against hookworm infections in school-aged children in Laos: a randomised, single-blind trial.

BACKGROUND: Albendazole and mebendazole are commonly used to control hookworm, but have shortcomings in their efficacy profiles. We assessed whether triple drug therapy (TDT) with albendazole, pyrantel pamoate, and oxantel pamoate was more effective than the co-administration of two drugs for the treatment of hookworm infections. METHODS: A randomised, single-blind trial was done from Sept 27 until Nov 17, 2017, in Laos. Children (6-15 years) from six schools were invited to participate. Hookworm-positive children were randomly assigned (2:2:1:1) by a computer stratified list (block sizes of six and 12) to TDT with albendazole (400 mg), pyrantel pamoate (20 mg/kg), and oxantel pamoate (20 mg/kg); albendazole plus oxantel pamoate; pyrantel pamoate plus oxantel pamoate; or mebendazole (500 mg) combined with both pyrantel pamoate and oxantel pamoate (used as proof of concept to compare the two TDTs). Two stool samples were collected at baseline and follow-up (17-30 days after treatment) and analysed with the Kato-Katz method. The primary outcome was the proportion of hookworm egg-negative children at follow-up in all Kato-Katz slides (cure rate [CR]) in the TDT with albendazole, pyrantel pamoate, and oxantel pamoate group compared with the albendazole plus oxantel pamoate and pyrantel pamoate plus oxantel pamoate groups. Secondary outcomes were tolerability 3 h and 24 h after treatment, egg reduction rates (ERRs) against hookworm, and efficacy against concomitant soil-transmitted helminth infections. Participating children and field and laboratory technicians were masked to treatment allocation. All children with follow-up data were included in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT03278431. FINDINGS: 1529 children were assessed for eligibility, of whom 533 provided complete baseline data and 414 provided complete outcome data. The CR was higher for the TDT albendazole, pyrantel pamoate, and oxantel pamoate (116 [84%] of 138) than with albendazole plus oxantel pamoate (73 [53%] of 138; odds ratio 4·7, 95% CI 2·7-8·3; p<0·0001) and pyrantel pamoate plus oxantel pamoate (36 [52%] of 69; 4·8, 2·5-9·3; p<0·0001). The geometric ERR of the TDT albendazole, pyrantel pamoate, and oxantel pamoate (99·9%) was higher than that for albendazole plus oxantel pamoate (99·0%; difference in ERR 0·9 percentage points, 95% CI 0·5-1·4), and pyrantel pamoate plus oxantel pamoate (99·2%; 0·7 percentage points, 0·3-1·3). Adverse events were reported by six (1%) children 3 h and none 24 h after treatment, without any difference across treatment groups. INTERPRETATION: TDT with albendazole, pyrantel pamoate, and oxantel pamoate could make a difference, in particular in the context of soil-transmitted helminth elimination. Pyrantel pamoate might be a useful alternative to prevent benzimidazole resistance; however, larger trials are needed to confirm this finding. FUNDING: Swiss National Science Foundation.

Evaluation of Two DNA Extraction Methods for Detection of Strongyloides stercoralis Infection.

Strongyloides stercoralis is present worldwide, but its prevalence is still uncertain, mainly due to the lack of sensitivity of diagnostic methods. Molecular techniques are under development, but a standardized protocol is still unavailable. We compared the sensitivity of real-time PCR, using two extraction protocols, with that of the Baermann technique. Samples were collected in the framework of the baseline screening of a randomized clinical trial evaluating moxidectin against S. stercoralis in Lao People's Democratic Republic. Two stool samples from each participant were processed by the Baermann method, and one subsample was processed by PCR. DNA was extracted using the QIAamp DNA stool minikit based on the standard protocol for the QIAamp DNA minikit (QIA) and using a modification of the QIA procedure (POL). Subsequently, all extracted samples were analyzed by real-time PCR. Overall, 95 samples were analyzed by the three diagnostic methods. Sixty-nine (72.6%) samples were positive according to the Baermann method, 25 (26.3%) by the QIA method, and 62 (65.3%) by the POL method. The sensitivities were 86% (95% confidence interval [CI], 76.7 to 92.9), 31.0% (95% CI, 21.3 to 42.6), and 78.0% (95% CI, 66.8 to 86.1) for the Baermann, QIA, and POL methods, respectively. The sensitivities calculated for each day of the Baermann method separately were 60% (48.4 to 70.8%) and 64% (52.2 to 74.2%) for days 1 and 2, respectively. In conclusion, the POL method revealed a good performance and was comparable to the Baermann test performed on two stool samples and superior to the Baermann method performed on one stool sample. Additional studies are needed to standardize a PCR protocol for S. stercoralis diagnosis.

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.

Lao language version of the Revised Hasegawa's Dementia Scale.

With the aging of society, the number of elderly with reduced cognitive function has been increasing worldwide. As a test to measure the cognitive function, the Revised Hasegawa's Dementia Scale (HDS-R) has been used in Japan, Korea, and China. Since there was no HDS-R version for Laotians, the questionnaire and manual were developed through the cooperation of Lao and Japanese researchers. Back-translation was conducted to confirm the accuracy of the translation. The score on the 9-item HDS-R ranges 0 to 30 points, and reduced cognitive function is usually defined as a score of 20 points or lower. After receiving explanation regarding the use of the tool and practicing its implementation, 3 female doctors interviewed 30 superficially healthy volunteers aged 31 to 84 years (12 males and 18 females) who lived with his/her family in Vientiane Capital, Lao PDR. Their score distributed from 4 to 30 points, with an average of 24.7 (standard deviation 5.4) points. Six (20.0%) participants scored 20 points or lower. The discussion before and after the pilot interviews revealed that the following changes needed to be made in accordance to the culture of Lao people; 1) order of date in Question 2, 2) words to be memorized in Questions 4 and 7, 3) objects to be memorized using pictures, not actual objects, in Question 8. Additionally, we introduced new two rules; a clear time definition for no reply (10 seconds), and repetition of questions twice for those with ear problems. The revised version of the HDS-R was thought to be an appropriate standard questionnaire for use in studies on cognitive function among Laotians.

Efficacy of Moxidectin Versus Ivermectin Against Strongyloides stercoralis Infections: A Randomized, Controlled Noninferiority Trial.

BACKGROUND: Infections with Strongyloides stercoralis are of considerable public health relevance. Moxidectin, a well-established drug in veterinary medicine under consideration for regulatory submission for the treatment of onchocerciasis, might serve as an alternative to the widely used ivermectin. METHODS: We conducted an exploratory, randomized, single-blind trial to evaluate the efficacy and safety of moxidectin (8 mg) vs ivermectin (200 µg/kg) against S. stercoralis infections. Cure rate (CR) against S. stercoralis was the primary outcome. Safety and efficacy against coinfections with soil-transmitted helminths and Opisthorchis viverrini were secondary outcomes. Noninferiority required the lower limit of the 95% confidence interval (CI) of the differences in CRs not exceed 7 percentage points. RESULTS: A total of 127 participants were enrolled and randomly assigned to the 2 treatments whereby 1 participant per arm was lost to follow-up. We observed a CR of 93.7% (59/63) for moxidectin compared to 95.2% (59/62) for ivermectin. Differences between CRs were estimated as -1.5% percentage points (95% CI, -9.6 to 6.5), thus the lower limit of the CI exceeds the noninferiority margin of 7 percentage points. No side effects were observed. CRs against hookworm infection were 57% (moxidectin) and 56% (ivermectin). Low efficacy for both drugs against O. viverrini was observed. CONCLUSIONS: Moxidectin might be a safe and efficacious alternative to ivermectin for the treatment of S. stercoralis infection, given that only slight differences in CRs were observed. However, noninferiority could not be demonstrated. Larger clinical trials should be conducted once the drug is marketed. CLINICAL TRIALS REGISTRATION: Current Controlled Trials: ISRCTN11983645.

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).

Efficacy and safety of tribendimidine against Opisthorchis viverrini: two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials.

BACKGROUND: Treatment of the liver fluke infection Opisthorchis viverrini relies exclusively on praziquantel. Tribendimidine could be an alternative treatment option. We aimed to assess the efficacy and safety of ascending single, oral doses of tribendimidine in patients with O viverrini infection. METHODS: We did two randomised, parallel-group, single-blind, dose-ranging, phase 2 trials in children (aged 8-14 years) and adults and adolescents (≥15 years) in three O viverrini endemic villages in Champasack province, southern Laos. Patients with O viverrini infection were randomly assigned, via a computer-generated central block-randomisation procedure, with block sizes of three (study 1) and four, eight, and 12 (study 2), to receive oral tribendimidine at doses of 200 mg, 400 mg, or 600 mg in a 1:1:1 ratio (adults and adolescents in study 1); 25 mg, 50 mg, 100 mg, or 200 mg (four 50 mg tablets) in a 1:1:1:1 ratio (adults and adolescents in study 2); or 100 mg, 200 mg, or 400 mg in a 1:1:1 ratio (children in study 1). One non-randomised group of children received tribendimidine 50 mg (study 2). Participants, investigators, and laboratory technicians doing the diagnostic assessments were masked to group assignment, but the investigator administering treatment could have recognised the treatment group based on the number of tablets. The primary objective was to estimate the dose-response relation in terms of cure rate and egg reduction rate. We did available-case analysis of all patients with primary endpoint data. We predicted dose-response associations with Emax models. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN96948551. FINDINGS: Between Oct 25, 2012, and Nov 5, 2013, 318 adolescents and adults were randomly assigned to seven tribendimidine dose groups: 200 mg (n=51), 400 mg (n=49), or 600 mg (n=47) in study 1, and 25 mg (n=39), 50 mg (n=47), 100 mg (n=44), or 200 mg (four 50 mg tablets; n=41) in study 2. 128 children were randomly assigned to receive tribendimidine 100 mg (n=44), 200 mg (n=40), or 400 mg (n=44) in study 1; 39 children were enrolled and received tribendimidine 50 mg in study 2. In adolescents and adults, the number of patients cured increased with increasing tribendimidine doses up to 100 mg: ten of 39 patients (25·6%, 95% CI 13·0-42·1) were cured in the 25 mg group, 20 of 47 patients (42·6%, 28·3-57·8) were cured in the 50 mg group, and 34 of 44 patients (77·3%, 62·2-88·5) were cured in the 100 mg group; geometric mean egg reduction rates were 86·9% (95% CI 74·8-93·4), 95·9% (92·7-97·7), and 99·1% (98·2-99·7), respectively. The 200 mg dose resulted in cure in 40 of 47 (83·0%, 69·2-92·5) adolescents and adults given the 200 mg tablet and 25 of 41 (61·0%, 95% CI 44·5-75·8) of those given four 50 mg tablets; the 400 mg dose resulted in cure in 43 of 47 patients (91·5%, 79·6-97·6) and the 600 mg dose resulted in cure in 36 of 45 patients (80·0%, 65·4-90·4). Corresponding egg reduction rates were 99·8% (95% CI 99·7-100·0) with one 200 mg tablet, 97·9% (95·9-99·2) with four 50 mg tablets, 99·9% (99·8-100·0) with 400 mg, and 99·8% (99·6-99·9) with 600 mg. The Emax model predicted an egg reduction rate of 99·0% (95% CI 95·7-99·8) at 111 mg in adolescents and adults. 50 mg tribendimidine had moderate efficacy in children, with cure recorded in 16 of 39 patients (41·0%, 95% CI 25·6-57·9). The 100 mg dose resulted in cure in 40 of 44 children (98·9%, 95% CI 78·3-97·5) and an egg reduction rate of 99·7% (95% CI 99·0-100·0), with no increased efficacy at higher doses. The Emax model predicted an egg reduction rate of 99·0% (95% CI 92·2-99·9) at 215 mg. Few adverse events were reported and were mostly mild, with few moderate and no serious events. The most common adverse events 3 h after treatment in adolescents and adults were vertigo (n=35 [11%]), headache (n=9 [3%]), nausea (n=6 [2%]), and fatigue (n=4 [1%]), and in children were headache (n=3 [2%]), vertigo (n=2 [1%]), and fatigue (n=2 [1%]). INTERPRETATION: Tribendimidine has excellent efficacy and tolerability at doses of 100 mg and above. Our study included mainly adults and children with low-intensity O viverrini infection; future studies should assess the efficacy of tribendimidine in patients with infections of moderate and high intensity. FUNDING: Department for International Development, Medical Research Council, Wellcome Trust Joint Global Health Trials Scheme.