Sterilizing activity of second-line regimens containing TMC207 in a murine model of tuberculosis

Rationale

The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model.

Objective and Methods

Swiss mice were intravenously inoculated with 6 log10 of Mycobacterium tuberculosis (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model).

Measurements

Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment.

Main Results

The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207, moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide.

Conclusions

In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18–24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside.     

Month 2 Culture Status and Treatment Duration as Predictors of Recurrence in Pulmonary Tuberculosis: Model Validation and Update

Background

New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated.

Methods

Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al.

Findings

The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions.

Interpretation

Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.     

Potential economic viability of two proposed rifapentine-based regimens for treatment of latent tuberculosis infection

Rationale

Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability.

Objectives

To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI).

Methods

We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/rifapentine daily for one month, isoniazid/rifapentine weekly for three months (self-administered and directly-observed), and isoniazid daily for nine months; a strategy of “no treatment” used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms.

Results

Both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily isoniazid/rifapentine for one month was the least expensive and most effective regimen.

Conclusions

Daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced, study designers should consider relaxing non-inferiority boundaries.     

Clinical Characteristics and Treatment Outcomes of Patients with Low- and High-Concentration Isoniazid-Monoresistant Tuberculosis

Background

Isoniazid (INH) resistance is now the most common type of tuberculosis (TB) infection resistance worldwide. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of patients with low- and high-concentration INH-monoresistant TB.

Methods

One hundred and thirty-four patients with culture-confirmed INH-monoresistant TB during 2006 January to 2007 December were retrospectively enrolled. INH resistance was classified as either low-concentration or high-concentration resistance according to the critical concentrations of 0.2 µg/mL or 1 µg/mL of INH, respectively. The patients’ clinical outcomes, treatment regimens, and treatment duration were analyzed.

Results

The treatment success rates between low- and high-concentration INH-resistant TB were similar (81.8% vs. 86.7%). The treatment regimens and treatment duration were similar between both groups. Only a minor percentage of the patients in both groups received 6-month treatment regimens (low vs. high concentration resistance, 9.1% vs. 13.3%; respectively, p = 0.447) The most common reason for treatment duration longer than 6 months was pyrazinamide given for less than 6 months, followed by a delay in clinical response to treatment. Multivariable analysis showed that prior tuberculosis treatment (Odds ratio, 2.82, 95% C.I., 1.02–7.77, p = 0.045) was the only independent risk factor for unsuccessful treatment outcome.

Conclusion

Different levels of INH resistance did not affect the treatment outcomes of patients with INH-monoresistant tuberculosis. Prolonged Rifampin-containing regimens may achieve those good outcomes in patients with low- and high-concentration INH-monoresistant TB.     

HIV Cure Strategies: How Good Must They Be to Improve on Current Antiretroviral Therapy?

Background

We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART).

Methods

We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY.

Results

For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving.

Conclusions

Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.     

Randomized Clinical Trial of Thrice-Weekly 4-Month Moxifloxacin or Gatifloxacin Containing Regimens in the Treatment of New Sputum Positive Pulmonary Tuberculosis Patients

Background

Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India.

Methods

Newly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens.

Results

Of 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification.

Conclusions

4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB.

Trial Registration

Clinical Trials Registry of India CTRI/2012/10/003060     

Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis

Background

Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes.

Methods and Findings

PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1–2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy.

Conclusions

TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy. Please see later in the article for the Editors'' Summary     

Determinants of Highly Active Antiretroviral Therapy Duration in HIV-1-Infected Children and Adolescents in Madrid,Spain, from 1996 to 2012

Objectives

To investigate the duration of sequential HAART regimens and predictors of first-line regimen discontinuation among HIV-1 vertically infected children and adolescents.

Design

Multicentre survey of antiretroviral-naïve patients enrolled in the HIV-Paediatric Cohor,t CoRISpeS-Madrid Cohort, Spain.

Methods

Patients with a follow-up of ≥1 month spent on HAART, with available baseline CD4 count and HIV-viral load (VL) were included. Time spent on sequential HAART regimens was estimated and multivariable regression was used to identify predictors of time to first-line regimen discontinuation.

Results

104 patients were followed for a median 8 years after starting HAART among 1996–2012; baseline %CD4 was 21.5 (12.3–34.0)and viral load was 5.1 (4.6–5.6) log₁₀ copies/mL. Patients received a mean of 1.9 regimens. Median time on first-line HAART (n = 104) was 64.5 months; second HAART (n = 56) 69.8 months; and third HAART (n = 21) 66.5 months. Eleven (11%) patients were lost to follow-up while on first-line HAART and 54% discontinued (cumulative incidence of 16% and 38% by 1 and 3-year, respectively). The main predictor of first-line regimen discontinuation was suboptimal adherence to antiretrovirals (AHR: 2.60; 95% CI: 1.44–4.70).

Conclusions

Adherence to therapy was the main determinant of the duration of the first-line HAART regimen in children. It is important to identify patients at high risk for non-adherence, such as very young children and adolescents, in provide special care and support to those patients.     

Relapse Rate and Associated-Factor of Recurrence after Stopping NUCs Therapy with Different Prolonged Consolidation Therapy in HBeAg Positive CHB Patients

Background

Many chronic hepatitis B (CHB) patients recur after off-therapy and have to accept prolonged consolidation therapy with NUCs. We investigated the rate of HBV relapse after stopping NUCs therapy with different time period of prolonged consolidation therapy in HBeAg positive CHB patients, and analyzed the associated-factor of recurrence.

Methods

We recruited 162 HBeAg-positive CHB patients who met the standard of stopping NUCs therapy recommended by the 2005 APASL. Patients in group A, without the prolonged consolidation therapy, were as controls. Patients in group B were divided into 3 subgroups (group B1, 7 (range 3–11) months of the prolonged consolidation therapy; group B2, 17 (range 13–20) months of the prolonged consolidation therapy; group B3, 28 (range 25–34) months of the prolonged consolidation therapy). Virologic relapse was defined as an increase in serum HBV DNA to >10³copies/ml after off-therapy.

Results

One hundred and thirty-six patients (group A, 40 patients; group B1, 54 patients; group B2, 23 patients; group B3, 19 patients) were eligible for this study. The cumulative rates of relapse in group B at 6 months and 48 months were 29.2%, 41.7% after off-therapy, respectively. The cumulative rates of relapse in group B were statistically lower than that in group A at the same time periods. The cumulative rate of relapse in group B3 or group B2 was statistically lower than that in group B1, respectively. On multivariate analysis by Cox’s proportional hazard model, age at off-therapy, baseline ALT and the different time period of the prolonged consolidation therapy were associated with the relapse of HBV after off-therapy.

Conclusions

Consolidation therapy with NUCs after HBeAg seroconversion should be further prolonged. Age at off-therapy, ALT at baseline and the time period of the prolonged consolidation therapy could provide information to direct anti-viral therapy.     

Effects of Length of Abstinence on Decision-Making and Craving in Methamphetamine Abusers

Rationale

The majority of drug abusers are incapable of sustaining abstinence over any length of time. Accumulating evidence has linked intense and involuntary craving, Impulsive decision-making and mood disturbances to risk for relapse. However, little is known about temporal changes of these neuropsychological functions in methamphetamine (METH)-dependent individuals.

Objectives

To investigate the effect of length of abstinence on decision-making, craving (baseline and cue-induced), and emotional state in METH-addicted individuals.

Methods

In this cross-sectional study, 183 adult METH-dependent patients at an addiction rehabilitation center who were abstinent for 6 days (n = 37), 14 days (n = 33), 1 month (n = 31), 3 months (n = 30), 6 months (n = 26), or 1 year (n = 30) and 39 healthy subjects were administered the Iowa Gambling Task (IGT) to assess decision-making performance. Depression, anxiety, and impulsivity were also examined. One hundred thirty-nine METH abusers who were abstinent for the aforementioned times then underwent a cue session, and subjective and physiological measures were assessed.

Results

METH dependent individuals who were abstinent for longer periods of time exhibited better decision-making than those who were abstinent for shorter periods of time. And self-reported emotional symptoms improved with abstinence. METH abusers’ ratings of craving decreased with the duration of abstinence, while cue-induced craving increased until 3 months of abstinence and decreased at 6 months and 1 year of abstinence.

Conclusions

We present time-dependent alterations in decision-making, emotional state, and the incubation of cue-induced craving in METH-dependent individuals, which might have significant clinical implications for the prevention of relapse.     

Genotyping of Plasmodium vivax reveals both short and long latency relapse patterns in Kolkata

Background

The Plasmodium vivax that was once prevalent in temperate climatic zones typically had an interval between primary infection and first relapse of 7–10 months, whereas in tropical areas P.vivax infections relapse frequently at intervals of 3–6 weeks. Defining the epidemiology of these two phenotypes from temporal patterns of illness in endemic areas is difficult or impossible, particularly if they overlap.

Methods

A prospective open label comparison of chloroquine (CQ) alone versus CQ plus unobserved primaquine for either 5 days or 14 days was conducted in patients presenting with acute vivax malaria in Kolkata. Patients were followed for 15 months and primary and recurrent infections were genotyped using three polymorphic antigen and up to 8 microsatellite markers.

Results

151 patients were enrolled of whom 47 (31%) had subsequent recurrent infections. Recurrence proportions were similar in the three treatment groups. Parasite genotyping revealed discrete temporal patterns of recurrence allowing differentiation of probable relapse from newly acquired infections. This suggested that 32 of the 47 recurrences were probable relapses of which 22 (69%) were genetically homologous. The majority (81%) of probable relapses occurred within three months (16 homologous, 10 heterologous) and six genetically homologous relapses (19%) were of the long latency (8–10 month interval) phenotype.

Conclusions

With long follow-up to assess temporal patterns of vivax malaria recurrence, genotyping of P.vivax can be used to assess relapse rates. A 14 day unobserved course of primaquine did not prevent relapse. Genotyping indicates that long latency P.vivax is prevalent in West Bengal, and that the first relapses after long latent periods are genetically homologous.

Trial Registration

Controlled-Trials.com ISRCTN14027467     

Poor Adherence to National and International Breastfeeding Duration Targets in an Australian Longitudinal Cohort

Objectives

To report on the proportion and characteristics of Australian infants who are fed, and mothers who feed, in accordance with the national and international breastfeeding duration targets of six, 12 and 24 months. Furthermore, to examine the longitudinal breastfeeding duration patterns for women with more than one child.

Methods

Breastfeeding duration data for 9773 children have been self-reported by a national sample of 5091 mothers aged 30–36 years in 2009, participating in the Australian Longitudinal Study on Women’s Health.

Results

Only 60% of infants received the minimum recommended 6 months of breast milk, irrespective of breastfeeding exclusivity. Less than 30% of infants received any breast milk at 12 months, and less than 3% were breastfed to the international target of 24 months. Young, less educated, unmarried or low-income women were at an increased risk of premature breastfeeding cessation. For women with three or more children, nearly 75% of women who breastfed their first child for at least six months reached this breastfeeding duration target for their next two children.

Conclusion

While national breastfeeding rates are typically evaluated in relation to the infant, a novel component of our study is that we have assessed maternal adherence to breastfeeding duration targets and the longitudinal feeding practices of women with more than one child. Separate evaluations of maternal and infant breastfeeding rates are important as they differ in their implications for public health policy and practice.     

Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis

Background

A standardized regimen recommended by the World Health Organization for retreatment of active tuberculosis (TB) is widely used, but treatment outcomes are suspected to be poor. We conducted a systematic review of published evidence of treatment of patients with a history of previous treatment or documented isoniazid mono-resistance.

Methods and Findings

PubMed, EMBASE, and the Cochrane Central database for clinical trials were searched for randomized trials in previously treated patients and/or those with with mono-resistance to isoniazid, published in English, French, or Spanish between 1965 and June 2008. The first two sources were also searched for cohort studies evaluating specifically the current retreatment regimen. In studies selected for inclusion, rifampin-containing regimens were used to treat patients with bacteriologically confirmed pulmonary TB, in whom bacteriologically confirmed failure and/or relapse had been reported. Pooled cumulative incidences and 95% CIs of treatment outcomes were computed with random effects meta-analyses and negative binomial regression. No randomized trials of the currently recommended retreatment regimen were identified. Only six cohort studies were identified, in which failure rates were 18%–44% in those with isoniazid resistance. In nine trials, using very different regimens in previously treated patients with mono-resistance to isoniazid, the combined failure and relapse rates ranged from 0% to over 75%. From pooled analysis of 33 trials in 1,907 patients with mono-resistance to isoniazid, lower failure, relapse, and acquired drug resistance rates were associated with longer duration of rifampin, use of streptomycin, daily therapy initially, and treatment with a greater number of effective drugs.

Conclusions

There are few published studies to support use of the current standardized retreatment regimen. Randomized trials of treatment of persons with isoniazid mono-resistance and/or a history of previous TB treatment are urgently needed. Please see later in the article for the Editors'' Summary     

Mycobacterium ulcerans Disease: Experience with Primary Oral Medical Therapy in an Australian Cohort

Background

Mycobacterium ulcerans (MU) is responsible for disfiguring skin lesions and is endemic on the Bellarine peninsula of southeastern Australia. Antibiotics have been shown to be highly effective in sterilizing lesions and preventing disease recurrences when used alone or in combination with surgery. Our practice has evolved to using primarily oral medical therapy.

Methods

From a prospective cohort of MU patients managed at Barwon Health, we describe those treated with primary medical therapy defined as treatment of a M. ulcerans lesion with antimicrobials either alone or in conjunction with limited surgical debridement.

Results

From 1/10/2010 through 31/12/11, 43 patients were treated with exclusive medical therapy, of which 5 (12%) also underwent limited surgical debridement. The median patient age was 50.2 years, and 86% had WHO category 1 and 91% ulcerative lesions. Rifampicin was combined with ciprofloxacin in 30 (70%) and clarithromycin in 12 (28%) patients. The median duration of antibiotic therapy was 56 days, with 7 (16%) receiving less than 56 days. Medication side effects requiring cessation of one or more antibiotics occurred in 7 (16%) patients. Forty-two (98%) patients healed without recurrence within 12 months, and 1 patient (2%) experienced a relapse 4 months after completion of 8 weeks of antimicrobial therapy.

Conclusion

Our experience demonstrates the efficacy and safety of primary oral medical management of MU infection with oral rifampicin-based regimens. Further research is required to determine the optimal and minimum durations of antibiotic therapy, and the most effective antibiotic dosages and formulations for young children.     

Is IL-6 an appropriate target to treat spondyloarthritis patients refractory to anti-TNF therapy? a multicentre retrospective observational study

Introduction

The aim of this study was to evaluate, under real-life conditions, the safety and efficacy of tocilizumab in patients having failed anti-TNFα therapy for spondyloarthritis.

Methods

French rheumatologists and internal-medicine practitioners registered on the Club Rhumatismes et Inflammations website were asked to report on patients given tocilizumab (4 or 8 mg/kg) to treat active disease meeting Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis, after anti-TNFα treatment failure. Safety and efficacy after 3 and 6 months were assessed retrospectively using standardised questionnaires.

Results

Data were obtained for 21 patients, 13 with axial spondyloarthritis (46% men; median age, 42 years; disease duration, 11 years; HLA-B27-positive, 92.3%) and eight with peripheral spondyloarthritis (25% men; median age, 40 years; disease duration, 10 years; HLA-B27-positive, 62.5%). No patients with axial disease had at least a 20 mm decrease in the BASDAI, nor a BASDAI50 response or major ASAS-endorsed disease activity score improvements after 3 or 6 months; an ASAS-endorsed disease activity score clinically important improvement was noted at month 3 in five of 13 patients and at month 6 in one of four patients. A good DAS28 response was achieved in four patients with peripheral disease, including one in EULAR remission at month 3. Four patients were still taking tocilizumab at month 6, including one in EULAR remission and one with a good DAS28 response. Tocilizumab was well tolerated, with no serious adverse events. Initially elevated acute-phase reactants declined during tocilizumab therapy.

Conclusion

In patients having failed anti-TNFα therapy, tocilizumab decreased acute-phase reactants but failed to substantially improve axial spondyloarthritis and was inconsistently effective in peripheral spondyloarthritis.     

Administration of triclabendazole is safe and effective in controlling fascioliasis in an endemic community of the bolivian altiplano

Background

The Bolivian northern Altiplano is characterized by a high prevalence of Fasciola hepatica infection. In order to assess the feasibility, safety and efficacy of large-scale administration of triclabendazole as an appropriate public health measure to control morbidity associated with fascioliasis, a pilot intervention was implemented in 2008.

Materials and Methods

Schoolchildren from an endemic community were screened for fascioliasis and treated with a single administration of triclabendazole (10 mg/kg). Interviews to assess the occurrence of adverse events were conducted on treatment day, one week later, and one month after treatment. Further parasitological screenings were performed three months after treatment and again two months later (following a further treatment) in order to evaluate the efficacy of the intervention.

Results

Ninety infected children were administered triclabendazole. Adverse events were infrequent and mild. No serious adverse events were reported. Observed cure rates were 77.8% after one treatment and 97.8% after two treatments, while egg reduction rates ranged between 74% and 90.3% after one treatment, and between 84.2% and 99.9% after two treatments. The proportion of high-intensity infections (≥400 epg) decreased from 7.8% to 1.1% after one treatment and to 0% after two treatments.

Conclusion

Administration of triclabendazole is a feasible, safe and efficacious public health intervention in an endemic community in the Bolivian Altiplano, suggesting that preventive chemotherapy can be applied to control of fascioliasis. Further investigations are needed to define the most appropriate frequency of treatment.     

The Dynamics of Natural Plasmodium falciparum Infections

Background

Natural immunity to Plasmodium falciparum has been widely studied, but its effects on parasite dynamics are poorly understood. Acquisition and clearance rates of untreated infections are key elements of the dynamics of malaria, but estimating these parameters is challenging because of frequent super-infection and imperfect detectability of parasites. Consequently, information on effects of host immune status or age on infection dynamics is fragmentary.

Methods

An age-stratified cohort of 347 individuals from Northern Ghana was sampled six times at 2 month intervals. High-throughput capillary electrophoresis was used to genotype the msp-2 locus of all P. falciparum infections detected by PCR. Force of infection (FOI) and duration were estimated for each age group using an immigration-death model that allows for imperfect detection of circulating parasites.

Results

Allowing for imperfect detection substantially increased estimates of FOI and duration. Effects of naturally acquired immunity on the FOI and duration would be reflected in age dependence in these indices, but in our cohort data FOI tended to increase with age in children. Persistence of individual parasite clones was characteristic of all age-groups. Duration peaked in 5–9 year old children (average duration 319 days, 95% confidence interval 318;320).

Conclusions

The main age-dependence is on parasite densities, with only small age-variations in the FOI and persistence of infections. This supports the hypothesis that acquired immunity controls transmission mainly by limiting blood-stage parasite densities rather than changing rates of acquisition or clearance of infections.     

Completion of Treatment for Latent Tuberculosis Infection with Monthly Drug Dispensation Directly through the Tuberculosis Clinic

Setting

An Australian metropolitan TB clinic where treatment for latent tuberculosis infection (LTBI) comprises six months of isoniazid, self-administered but dispensed monthly by the clinic.

Objective

To determine the proportion of patients who complete treatment for LTBI and to identify factors associated with non-completion.

Methods

Clinical files of all patients receiving treatment for LTBI between 01/2000 and 12/2010 were reviewed. The study population comprised all patients who were commenced on isoniazid as treatment for LTBI. Odds ratios (OR) for completing treatment were estimated by logistic regression.

Results

Of 216 patients who commenced isoniazid treatment for LTBI, 16 (75%) completed six months treatment. Fifty-three percent of the 53 patients who did not complete treatment dropped out after three months treatment. The mean (SD) age of the patients was 27 (16) years and 123 (57%) were female. The majority of patients (59%) were born overseas and 69% received treatment for LTBI because they were contacts of patients with TB. Patients'' sex, age, country of birth, time since immigration for overseas born people, health care worker status, TST conversion status, chest x-ray findings, language, employment status and the indication for which treatment of LTBI was prescribed were not significantly related to treatment completion.

Conclusion

In a setting where isoniazid is dispensed monthly by the TB clinic, a relatively high proportion of patients who commence treatment for LTBI complete the six month scheduled course of treatment. The study did not identify any patient characteristics that predicted treatment completion. Interventions to improve completion rates should extend over the whole duration of treatment.     

Characterization of Treatment Resistant Depression Episodes in a Cohort of Patients from a US Commercial Claims Database

Context

Treatment Resistant Depression (TRD) is a significant and burdensome health concern.

Objective

To characterize, compare and understand the difference between TRD and non-TRD patients and episodes in respect of their episode duration, treatment patterns and healthcare resource utilization.

Design and Setting

Patients between 18 and 64 years with a new diagnosis of major depressive disorder (MDD) and without a previous or comorbid diagnosis of schizophrenia or bipolar disease were included from PharMetrics Integrated Database, a claims database of commercial insurers in the US. Episodes of these patients in which there were at least two distinct failed regimens involving antidepressants and antipsychotics were classified as TRD.

Patients

82,742 MDD patients were included in the analysis; of these patients, 125,172 episodes were identified (47,654 of these were drug-treated episodes).

Main Outcome Measures

Comparison between TRD and non-TRD episodes in terms of their duration, number and duration of lines of treatment, comorbidities, and medical resource utilization.

Results

Of the treated episodes, 6.6% (N = 3,134) met the criteria for TRD. The median time to an episode becoming TRD was approximately one year. The mean duration of a TRD episode was 1,004 days (vs. 452 days for a non-TRD episode). More than 75% of TRD episodes had at least four lines of therapy; half of the treatment regimens included a combination of drugs. Average hospitalization costs were higher for TRD than non-TRD episodes: $6,464 vs. $1,734, as were all other health care utilization costs.

Conclusions

While this study was limited to relatively young and commercially covered patients, used a rigorous definition of TRD and did not analyze for cause or consequence, the results highlight high unmet medical need and burden of TRD on patients and health care resources.