Ixazomib for relapsed or refractory multiple myeloma : review from an evidence review group on a NICE single technology appraisal

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment. Takeda estimated the cost effectiveness of IXA-LEN-DEX using a de-novo partitioned-survival model with three health states (pre-progression, post-progression, and dead). In their first submission, this model was used to estimate the cost effectiveness of IXA-LEN-DEX vs. bortezomib plus dexamethasone (BORT-DEX) in second-line treatment, and of IXA-LEN-DEX vs. LEN-DEX in third-line treatment. To estimate the relative clinical performance of IXA-LEN-DEX vs. BORT-DEX, Takeda conducted network meta-analyses for important outcomes. The network meta-analysis for overall survival was found to be flawed in several respects, but mainly because a hazard ratio input for one of the studies in the network had been inverted, resulting in a large inflation of the claimed superiority of IXA-LEN-DEX over BORT-DEX and a considerable overestimation of its cost effectiveness. In subsequent submissions, Takeda withdrew second-line treatment as an option for IXA-LEN-DEX. The manufacturer’s first submission comparing IXA-LEN-DEX with LEN-DEX for third-line therapy employed Tourmaline-MM1 data from third- and fourth-line patients as proxy for a third-line population. The appraisal committee did not consider this reasonable because randomization in Tourmaline-MM1 was stratified according to one previous treatment and two or more previous treatments. A further deficiency was considered to be the manufacturer’s use of interim survival data rather than the most mature data available. A second submission from the company focussed on IXA-LEN-DEX vs. LEN-DEX as third- or fourth-line treatment (the two or more previous lines population) and a new patient access scheme was introduced. Covariate modeling of survival outcomes was proposed using the most mature survival data. The Evidence Review Group’s main criticisms of the new evidence included: the utility associated with the pre-progression health state was overestimated, treatment costs of ixazomib were underestimated, survival models were still associated with great uncertainty, leading to clinically implausible anomalies and highly variable incremental cost-effectiveness ratio estimates, and the company had not explored a strong assumption that the survival benefit of IXA-LEN-DEX over LEN-DEX would be fully maintained for a further 22 years beyond the observed data, which encompassed only approximately 2.5 years of observation. The appraisal committee remained unconvinced that ixazomib represented a cost-effective use of National Health Service resources. Takeda’s third submission offered new base-case parametric models for survival outcomes, a new analysis of utilities, and proposed a commercial access agreement. In a brief critique of the third submission, the Evidence Review Group agreed that the selection of appropriate survival models was problematic and at the request of the National Institute for Health Care and Excellence investigated external sources of evidence regarding survival outcomes. The Evidence Review Group considered that some cost and utility estimates in the submission may have remained biased in favor of ixazomib. As a result of their third appraisal meeting, the committee judged that for the two to three prior therapies population, and at the price agreed in a commercial access agreement, ixazomib had the potential to be cost effective. It was referred to the Cancer Drugs Fund so that further data could accrue with the aim of diminishing the clinical uncertainties

A surveillance system to assess the need for updating systematic reviews.

BackgroundSystematic reviews (SRs) can become outdated as new evidence emerges over time. Organizations that produce SRs need a surveillance method to determine when reviews are likely to require updating. This report describes the development and initial results of a surveillance system to assess SRs produced by the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program.MethodsTwenty-four SRs were assessed using existing methods that incorporate limited literature searches, expert opinion, and quantitative methods for the presence of signals triggering the need for updating. The system was designed to begin surveillance six months after the release of the original review, and then ceforth every six months for any review not classified as being a high priority for updating. The outcome of each round of surveillance was a classification of the SR as being low, medium or high priority for updating.ResultsTwenty-four SRs underwent surveillance at least once, and ten underwent surveillance a second time during the 18 months of the program. Two SRs were classified as high, five as medium, and 17 as low priority for updating. The time lapse between the searches conducted for the original reports and the updated searches (search time lapse - STL) ranged from 11 months to 62 months: The STL for the high priority reports were 29 months and 54 months; those for medium priority reports ranged from 19 to 62 months; and those for low priority reports ranged from 11 to 33 months. Neither the STL nor the number of new relevant articles was perfectly associated with a signal for updating. Challenges of implementing the surveillance system included determining what constituted the actual conclusions of an SR that required assessing; and sometimes poor response rates of experts.ConclusionIn this system of regular surveillance of 24 systematic reviews on a variety of clinical interventions produced by a leading organization, about 70% of reviews were determined to have a low priority for updating. Evidence suggests that the time period for surveillance is yearly rather than the six months used in this project

Risk factors and algorithms to identify hepatitis C, hepatitis B, and HIV among Georgian tuberculosis patients

SummaryObjectivesTo determine prevalence, risk factors, and simple identification algorithms for HIV, hepatitis B, and hepatitis C co-infection; factors that may predispose for anti-tuberculosis therapy-induced hepatotoxicity.MethodsWe recruited 300 individuals at in-patient tuberculosis hospitals in three cities in Georgia, administered a behavioral questionnaire, and tested for antibody to HIV, hepatitis C (HCV), hepatitis B core antigen (anti-HBc), and the hepatitis B surface antigen (HBsAg).ResultsOf the individuals tested, 0.7% were HIV positive, 4.3% were HBsAg positive, 8.7% were anti-HBc positive, and 12.0% were HCV positive. In multivariable analysis, a history of blood transfusion, injection drug use, and prison were significant independent risk factors for HCV, while a history of blood transfusion, injection drug use, younger age at sexual debut, and a high number of sex partners were significant risk factors for HBV. Three-questionnaire item algorithms predicted HCV serostatus 74.1% of the time and HBV serostatus 85.2% of the time.ConclusionsTreatment of tuberculosis patients in resource-limited countries with concurrent epidemics of HCV, HBV, and HIV may be associated with significant hepatotoxicity. Serologic screening of tuberculosis patients for HBV, HCV, and HIV or using behavioral algorithms to identify patients in need of intensive monitoring during anti-tuberculosis therapy may reduce this risk

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

SYNTHESIS OF GOLD NANOPARTICLES BY BLUE-GREEN ALGAE Spirulina platensis

Kalabegishvili T. et al. E14-2012-31 Synthesis of Gold Nanoparticles by Blue-Green Algae Spirulina platensis The synthesis of gold nanoparticles by one of the many popular microorganisms Å blue-green algae Spirulina platensis was studied. The complex of optical and analytical methods was applied for investigation of experimental samples after exposure to chloroaurate (HAuCl4) solution at different doses and for different time intervals. To characterize formed gold nanoparticles UV-vis, TEM, SEM, EDAX, and XRD were used. It was shown that after 1.5Ä2 days of exposure the extracellular formation of nanoparticles of spherical form and the distribution peak within the interval of 20Ä30 nm took place. To determine gold concentrations in the Spirulina platensis biomass, neutron activation analysis (NAA) and atomic absorption spectrometry (AAS) were applied. The results obtained evidence that the concentration of gold accumulated by Spirulina biomass is rapidly growing in the beginning, followed by some increase for the next few days. The obtained substance of Spirulina biomass with gold nanoparticles may be used for medical, pharmaceutical, and technological purposes. The investigation has been performed a

Testosterone Replacement Therapy

Male hypogonadism (HG) can be defined according to its etiology as primary (pHG) when caused by any diseases affecting the testes, or as secondary (sHG) when due to a pituitary or hypothalamic dysfunction. Both fertility and testosterone (T) can be theoretically restored in sHG by removing the precipitating cause and/or by appropriate endocrine therapy. Conversely, only T treatment can be offered to patients with pHG. Symptoms and signs are quite similar independent of the underlying causes. Conversely, the phenotype of the hypogonadal patient is more often affected by the age of hypogonadism onset. Late-onset hypogonadism (LOH) that occurs in adulthood is probably the most common form of HG. In this chapter, the criteria defining LOH and the available T formulations along with their outcomes and main important side effects are analyzed in detail

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background: People who inject drugs (PWID) experience high rates of incarceration and may be at high risk of HIV and hepatitis C (HCV) virus infection during or after incarceration. We conducted a systematic review and meta-analysis to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID.Methods: MEDLINE, Embase and PsycINFO databases were searched for studies in any language published since 2000 assessing HIV or HCV incidence among PWID. Studies were included if they reported the association between recent (in last 3, 6 or 12 months or since last follow-up) or past incarceration and HIV or HCV (primary or reinfection) incidence. Authors of incidence studies not reporting these outcomes were contacted for data. Data were extracted and pooled using random-effects meta-analyses. Findings: Twenty published and 21 unpublished studies were included, originating from Australasia, Western and Eastern Europe, North and Latin America and East and Southeast Asia. Recent incarceration was associated with an 81% (rate ratio (RR):1.81, 95%CI: 1.40-2.34) and 62% (RR:1.62, 95%CI:1.28-2.05) increase in HIV and HCV acquisition risk, respectively. Past incarceration was associated with a 25% and 21% increase in HIV (RR:1.25, 95%CI:0.94-1.66) and HCV (RR:1.21, 95%CI:1.02-1.43) and acquisition risk, respectively.Interpretation: Incarceration is associated with substantial short-term HIV and HCV acquisition risk among PWID and could be a significant driver for HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV acquisition – including addressing structural risks associated with drug laws and excessive incarceration of PWID

LEXSIKO-COSEMANTIC GROUP “WILD ANIMALS” AS ONE OF FRAGMENTS OF LANGUAGE WORLD PICTURE (RUSSIAN, GEORGIAN, KAZAKH PARALLELS)

This article offers a linguacultural analysis of figurative meanings of words being denominations of wild animals in Russian, Georgian and Kazach languages. In the article reveals cultural similarities and differences in the figurative use of the same zoonym in the analyzed languages.The undertaken analysis makes a certain contribution to the reconstruction of the whole linguistic picture of the world, and also allows us to identify some features of the national perception of the worl

THE ZOONYMS "DOG", "PIG " IN RUSSIAN AND GEORGIAN LINGUOCULTURES

The article presents a comparative analysis of the images of a dog and a pig in Russian and Georgian linguocultures. Considers which qualities of an animal are reflected in the proverbs of the Russian and Georgian languages. Comparing the zoonyms in the proverbial utterance and the figurative meanings of the noun denoting the same animal, it is revealed that the images of animals in proverbs and sayings are wider and more diverse in comparison with the figurative meanings of the nouns naming these images