Efficacy of Second Generation Direct-Acting Antiviral Agents for Treatment Na?ve Hepatitis C Genotype 1: A Systematic Review and Network Meta-Analysis

Background

The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs could improve the sustained virological response compared to pegylated interferon with ribavirin (PR). However, there has been no evidence from randomized controlled trials (RCTs) that directly compare the efficacy among the different regimens of DAAs.

Aim

Therefore, we performed a systematic review and network meta-analysis aiming to compare the treatment efficacy between different DAA regimens for treatment naïve HCV genotype 1.

Methods

Medline and Scopus were searched up to 25^th May 2015. RCTs investigating the efficacy of second generation DAA regimens for treatment naïve HCV genotype 1 were eligible for the review. Due to the lower efficacy and more side effects of first generation DAAs, this review included only second generation DAAs approved by the US or EU Food and Drug Administration, that comprised of simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD). Primary outcomes were sustained virological response at weeks 12 (SVR12) and 24 (SVR24) after the end of treatment and adverse drug events (i.e. serious adverse events, anemia, and fatigue). Efficacy of all treatment regimens were compared by applying a multivariate random effect meta-analysis. Incidence rates of SVR12 and SVR24, and adverse drug events of each treatment regimen were pooled using ‘pmeta’ command in STATA program.

Results

Overall, 869 studies were reviewed and 16 studies were eligible for this study. Compared with the PR regimen, SOF plus PR, SMV plus PR, and DVC plus PR regimens yielded significantly higher probability of having SVR24 with pooled risk ratios (RR) of 1.98 (95% CI 1.24, 3.14), 1.46 (95% CI: 1.22, 1.75), and 1.68 (95% CI: 1.14, 2.46), respectively. Pooled incidence rates of SVR12 and SVR24 in all treatment regimens without PR, i.e. SOF plus LDV with/without ribavirin, SOF plus SMV with/without ribavirin, SOF plus DCV with/without ribavirin, and PrOD with/without ribavirin, (pooled incidence of SVR12 ranging from 93% to 100%, and pooled incidence of SVR24 ranging from 89% to 96%) were much higher than the pooled incidence rates of SVR12 (51%) and SVR24 (48%) in PR alone. In comparing SOF plus LDV with ribavirin and SOF plus LDV without ribavirin, the chance of having SVR12 was not significantly different between these two regimens, with the pooled RR of 0.99 (95% CI: 0.97, 1.01). Regarding adverse drug events, risk of serious adverse drug events, anemia and fatigue were relatively higher in treatment regimens with PR than the treatment regimens without PR. The main limitation of our study is that a subgroup analysis according to dosages and duration of treatment could not be performed. Therefore, the dose and duration of recommended treatment have been suggested in range and not in definite value.

Conclusions

Both DAA plus PR and dual DAA regimens should be included in the first line drug for treatment naïve HCV genotype 1 because of the significant clinical benefits over PR alone. However, due to high drug costs, an economic evaluation should be conducted in order to assess the value of the investment when making coverage decisions.     

Health related quality of life among patients with tuberculosis and HIV in Thailand

Introduction

Health utilities of tuberculosis (TB) patients may be diminished by side effects from medication, prolonged treatment duration, physical effects of the disease itself, and social stigma attached to the disease.

Methods

We collected health utility data from Thai patients who were on TB treatment or had been successfully treated for TB for the purpose of economic modeling. Structured questionnaire and EuroQol (EQ-5D) and EuroQol visual analog scale (EQ-VAS) instruments were used as data collection tools. We compared utility of patients with two co-morbidities calculated using multiplicative model (U_CAL) with the direct measures and fitted Tobit regression models to examine factors predictive of health utility and to assess difference in health utilities of patients in various medical conditions.

Results

Of 222 patients analyzed, 138 (62%) were male; median age at enrollment was 40 years (interquartile range [IQR], 35–47). Median monthly household income was 6,000 Baht (187 US$; IQR, 4,000–15,000 Baht [125–469 US$]). Concordance correlation coefficient between utilities measured using EQ-5D and EQ-VAS (U_EQ-5D and U_VAS, respectively) was 0.6. U_CAL for HIV-infected TB patients was statistically different from the measured U_EQ-5D (p-value<0.01) and U_VAS (p-value<0.01). In tobit regression analysis, factors independently predictive of U_EQ-5D included age and monthly household income. Patients aged ≥40 years old rated U_EQ-5D significantly lower than younger persons. Higher U_EQ-5D was significantly associated with higher monthly household income in a dose response fashion. The median U_EQ-5D was highest among patients who had been successfully treated for TB and lowest among multi-drug resistant TB (MDR-TB) patients who were on treatment.

Conclusions

U_CAL of patients with two co-morbidities overestimated the measured utilities, warranting further research of how best to estimate utilities of patients with such conditions. TB and MDR-TB treatments impacted on patients'' self perceived health status. This effect diminished after successful treatment.     

Seasonal Influenza Vaccination for Children in Thailand: A Cost-Effectiveness Analysis

Background

Seasonal influenza is a major cause of mortality worldwide. Routine immunization of children has the potential to reduce this mortality through both direct and indirect protection, but has not been adopted by any low- or middle-income countries. We developed a framework to evaluate the cost-effectiveness of influenza vaccination policies in developing countries and used it to consider annual vaccination of school- and preschool-aged children with either trivalent inactivated influenza vaccine (TIV) or trivalent live-attenuated influenza vaccine (LAIV) in Thailand. We also compared these approaches with a policy of expanding TIV coverage in the elderly.

Methods and Findings

We developed an age-structured model to evaluate the cost-effectiveness of eight vaccination policies parameterized using country-level data from Thailand. For policies using LAIV, we considered five different age groups of children to vaccinate. We adopted a Bayesian evidence-synthesis framework, expressing uncertainty in parameters through probability distributions derived by fitting the model to prospectively collected laboratory-confirmed influenza data from 2005-2009, by meta-analysis of clinical trial data, and by using prior probability distributions derived from literature review and elicitation of expert opinion. We performed sensitivity analyses using alternative assumptions about prior immunity, contact patterns between age groups, the proportion of infections that are symptomatic, cost per unit vaccine, and vaccine effectiveness. Vaccination of children with LAIV was found to be highly cost-effective, with incremental cost-effectiveness ratios between about 2,000 and 5,000 international dollars per disability-adjusted life year averted, and was consistently preferred to TIV-based policies. These findings were robust to extensive sensitivity analyses. The optimal age group to vaccinate with LAIV, however, was sensitive both to the willingness to pay for health benefits and to assumptions about contact patterns between age groups.

Conclusions

Vaccinating school-aged children with LAIV is likely to be cost-effective in Thailand in the short term, though the long-term consequences of such a policy cannot be reliably predicted given current knowledge of influenza epidemiology and immunology. Our work provides a coherent framework that can be used for similar analyses in other low- and middle-income countries.     

An Economic Evaluation of Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Thailand

Background

Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand.

Method

A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years.

Results

The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years.

Conclusion

At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem.     

Systematic review of economic evaluations of preparedness strategies and interventions against influenza pandemics

Background

Although public health guidelines have implications for resource allocation, these issues were not explicitly considered in previous WHO pandemic preparedness and response guidance. In order to ensure a thorough and informed revision of this guidance following the H1N1 2009 pandemic, a systematic review of published and unpublished economic evaluations of preparedness strategies and interventions against influenza pandemics was conducted.

Methods

The search was performed in September 2011 using 10 electronic databases, 2 internet search engines, reference list screening, cited reference searching, and direct communication with relevant authors. Full and partial economic evaluations considering both costs and outcomes were included. Conversely, reviews, editorials, and studies on economic impact or complications were excluded. Studies were selected by 2 independent reviewers.

Results

44 studies were included. Although most complied with the cost effectiveness guidelines, the quality of evidence was limited. However, the data sources used were of higher quality in economic evaluations conducted after the 2009 H1N1 pandemic. Vaccination and drug regimens were varied. Pharmaceutical plus non-pharmaceutical interventions are relatively cost effective in comparison to vaccines and/or antivirals alone. Pharmaceutical interventions vary from cost saving to high cost effectiveness ratios. According to ceiling thresholds (Gross National Income per capita), the reduction of non-essential contacts and the use of pharmaceutical prophylaxis plus the closure of schools are amongst the cost effective strategies for all countries. However, quarantine for household contacts is not cost effective even for low and middle income countries.

Conclusion

The available evidence is generally inconclusive regarding the cost effectiveness of preparedness strategies and interventions against influenza pandemics. Studies on their effectiveness and cost effectiveness should be readily implemented in forthcoming events that also involve the developing world. Guidelines for assessing the impact of disease and interventions should be drawn up to facilitate these studies.     

Limonoids from seeds of Thai Xylocarpus moluccensis

A new andirobin, thaimoluccensin A (1), and two new phragmalin-type limonoids, thaimoluccensins B (2) and C (3), were isolated from seeds of a Thai mangrove plant, Xylocarpus moluccensis, together with eight known compounds. The structures of these compounds were elucidated on the basis of spectroscopic data. Only 7-deacetylgedunin (7), a gedunin-type limonoid, exhibited significant inhibitory activity against nitric oxide production from activated macrophages with IC₅₀ value less than 10 μM, suggesting that the compound has anti-inflammatory activity.     

Methodological Variation in Economic Evaluations Conducted in Low- and Middle-Income Countries: Information for Reference Case Development

Information generated from economic evaluation is increasingly being used to inform health resource allocation decisions globally, including in low- and middle- income countries. However, a crucial consideration for users of the information at a policy level, e.g. funding agencies, is whether the studies are comparable, provide sufficient detail to inform policy decision making, and incorporate inputs from data sources that are reliable and relevant to the context. This review was conducted to inform a methodological standardisation workstream at the Bill and Melinda Gates Foundation (BMGF) and assesses BMGF-funded cost-per-DALY economic evaluations in four programme areas (malaria, tuberculosis, HIV/AIDS and vaccines) in terms of variation in methodology, use of evidence, and quality of reporting. The findings suggest that there is room for improvement in the three areas of assessment, and support the case for the introduction of a standardised methodology or reference case by the BMGF. The findings are also instructive for all institutions that fund economic evaluations in LMICs and who have a desire to improve the ability of economic evaluations to inform resource allocation decisions.     

Overcoming doxorubicin-resistance in the NCI/ADR-RES model cancer cell line by novel anthracene-9,10-dione derivatives

Overcoming drug resistance with remarkable cytotoxic activity by anthracene-9,10-dione derivatives would offer a potential therapeutic strategy. In this study, we report the synthesis and the cytotoxicity of a novel set of anthraquninones. (4-(4-Aminobenzylamino)-9,10-dioxo-9,10-dihydroanthracen-1-yl-4-methylbenzenesulfonate) (3) has excellent in vitro cytotoxicity against doxorubicin-resistant cancer cell line (IC₅₀ = 0.8 μM), 20-fold higher than doxorubicin. The cytotoxic effect via G2/M arrest does not appear to be ROS.