Network meta-analysis of direct-acting antivirals in combination with peginterferon-ribavirin for previously untreated patients with hepatitis C genotype 1 infection.

AIM: To conduct a network meta-analysis (NMA) to determine the comparative efficacy, as measured by sustained virological response (SVR), between boceprevir (BOC), telaprevir (TEL), faldaprevir (FAL), simeprevir (SIM) and sofosbuvir (SOF) in combination with peginterferon-ribavirin (PR) against a control of PR. DESIGN: A literature search was conducted to identify randomized controlled trials (RCTs) including adult patients with hepatitis C virus genotype 1 who were naive to any prior therapy. RCTs assessing standard duration therapy (SDT) or response-guided therapy (RGT) BOC, TEL, FAL, SIM or SOF in combination with PR against a control of PR were eligible for inclusion. All RCTs must have provided SVR at either 12 or 24 weeks post-therapy cessation. RESULTS: We included nine RCTs. All direct-acting antivirals (DAAs) were found to perform better than PR. Additionally, SDT FAL was found to be better than the 240 mg RGT FAL regimen with the PR lead-in. A sensitivity analysis excluding RCTs with only SVR at 12 weeks was consistent with the results of the primary analysis. A sensitivity analysis removing an RCT assessing SIM that reported SVR of >60% in the PR control group additionally found that RGT SIM was superior to the 240 mg RGT FAL regimen with the PR lead-in. DISCUSSION: Our analyses indicate that SDT and RGT regimens of DAAs plus PR do not differ greatly in terms of SVR among treatment-naive hepatitis C genotype 1 patients. More advanced Bayesian network meta-analyses are likely needed to incorporate a comprehensive evidence base, expanding beyond randomized clinical trials.

Antiretroviral therapy for initial human immunodeficiency virus/AIDS treatment: critical appraisal of the evidence from over 100 randomized trials and 400 systematic reviews and meta-analyses.

There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.

Direct-acting antiviral therapies for hepatitis C genotype 1 infection: a multiple treatment comparison meta-analysis.

BACKGROUND: New direct-acting antiviral agents for hepatitis C genotype 1 infection, boceprevir and telaprevir, offer enhanced sustained virologic response (SVR) among both treatment-naïve and treatment-experienced patients. AIM: To determine the relative efficacy of the new direct-acting antiviral agents by applying a multiple treatment comparison meta-analysis. DESIGN: We included published Phase II and III randomized controlled trials evaluating head-to-head comparisons between boceprevir, telaprevir, peg-interferon alpha-2a with ribavirin and peg-interferon alpha-2b with ribavirin in hepatitis C genotype 1 patients. We applied Bayesian multiple treatment comparison meta-analysis. RESULTS: We included data from four boceprevir, three telaprevir and six peg-interferon alpha-2a plus ribavirin vs. peg-interferon alpha-2b plus ribavirin randomized controlled trials. Both boceprevir and telaprevir offer statistically superior outcomes for SVR, relapse and discontinuation due to adverse events than either peg-interferons among both treatment-naïve and treatment-experienced patients. Among treatment-naïve patients, clinical outcomes were similar for boceprevir and telaprevir, for SVR [odds ratio (OR) 0.90, 95% credible interval (95% CrI) 0.41-1.91] and for relapse (OR 1.09, 95% CrI 0.19-4.84). Similarly, among treatment-experienced patients, clinical outcomes were similar for boceprevir and telaprevir and for SVR (OR 1.45, 95% CrI 0.70-3.08) and for relapse (OR 0.35, 95% CrI 0.13-1.02). For treatment-naïve patients receiving standard-duration therapy, telaprevir yielded lower rates of anemia and neutropenia, but higher rates of rash and pruritus. For treatment-experience patients, all adverse event rates were higher with telaprevir. DISCUSSION: Boceprevir and telaprevir exhibit similar effects among hepatitis C genotype 1 treatment-naïve and treatment-experienced patients.

Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis.

BACKGROUND: Statins are the most widely prescribed drug available. Due to this reason, it is important to understand the risks involved with the drug class and individual statins. AIM: We conducted a meta-analysis and employed indirect comparisons to identify differing risk effects across statins. DESIGN: We included any randomized clinical trial (RCT) of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin used for cardiovascular disease event prevention. The main outcome was adverse events [all-cause mortality, cancers, rhabdomylosis, diabetes, aspartate and alanine aminotransferase (AST/ALT), and creatinine kinase (CK) increases beyond the upper limit of normal]. In order to evaluate the relative effects of each drug on adverse events, we calculated adjusted indirect comparisons of the adverse-event outcomes. RESULTS: Seventy-two trials involving 159,458 patients met our inclusion criteria. Overall, statin treatments significantly increased the rate of diabetes when compared to controls (OR: 1.09; 95% CI: 1.02-1.16) and elevated AST (OR: 1.31; 95% CI: 1.04-1.66) and ALT (OR: 1.28; 95% CI: 1.11-1.48) levels when compared to controls. Using indirect comparisons, we also found that atorvastatin significantly elevated AST levels compared to pravastatin (OR: 2.21; 95% CI: 1.13-4.29) and simvastatin significantly increased CK levels when compared to rosuvastatin (OR: 4.39; 95% CI: 1.01-19.07). Higher dose studies had increased risk of AST elevations. DISCUSSION: Although statins are generally well tolerated, there are risks associated with almost all drugs. With few exceptions, statins appear to exert a similar risk across individual drugs.

Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials.

BACKGROUND: Statins represent the largest selling class of cardiovascular drug in the world. Previous randomized trials (RCTs) have demonstrated important clinical benefits with statin therapy. AIM: We combined evidence from all RCTs comparing a statin with placebo or usual care among patients with and without prior coronary heart disease (CHD) to determine clinical outcomes. DESIGN: We searched independently, in duplicate, 12 electronic databases (from inception to August 2010), including full text journal content databases, to identify all statin versus inert control RCTs. We included RCTs of any statin versus any non-drug control in any populations. We abstracted data in duplicate on reported major clinical events and adverse events. We performed a random-effects meta-analysis and meta-regression. We performed a mixed treatment comparison using Bayesian methods. RESULTS: We included a total of 76 RCTs involving 170,255 participants. There were a total of 14,878 deaths. Statin therapy reduced all-cause mortality, Relative Risk (RR) 0.90 [95% confidence interval (CI) 0.86-0.94, P ≤ 0.0001, I(2)=17%]; cardiovascular disease (CVD) mortality (RR 0.80, 95% CI 0.74-0.87, P<0.0001, I(2)=27%); fatal myocardial infarction (MI) (RR 0.82, 95% CI 0.75-0.91, P<0.0001, I(2)=21%); non-fatal MI (RR 0.74, 95% CI 0.67-0.81, P ≤ 0.001, I(2)=45%); revascularization (RR 0.76, 95% CI 0.70-0.81, P ≤ 0.0001); and a composite of fatal and non-fatal strokes (0.86, 95% CI 0.78-0.95, P=0.004, I(2)=41%). Adverse events were generally mild, but 17 RCTs reported on increased risk of development of incident diabetes [Odds Ratio (OR) 1.09; 95% CI 1.02-1.17, P=0.001, I(2)=11%]. Studies did not yield important differences across populations. We did not find any differing treatment effects between statins. DISCUSSION: Statin therapies offer clear benefits across broad populations. As generic formulations become more available efforts to expand access should be a priority.

Antiretroviral effects on HIV-1 RNA, CD4 cell count and progression to AIDS or death: a meta-regression analysis.

OBJECTIVE: Governments, clinicians and drug-licensing bodies have adopted changes in CD4 cell counts and HIV-1 RNA levels as evidence of effectiveness for new therapeutic interventions. We aimed to determine the strength of the association between the magnitude of the effect of changes in CD4 cell count and HIV-1 RNA and progression to AIDS or death in the highly active antiretroviral therapy (HAART) era. METHODS: We identified all randomized clinical trials (RCTs) evaluating the effect of HAART on both clinical and surrogate endpoints (1994 to September 2006). We performed a meta-regression and weighted linear regression. We additionally estimated potential RCT sample sizes that would be required to assess the effectiveness of new interventions in terms of clinical endpoints. RESULTS: We included data from 178 RCTs. We were unable to demonstrate a strong relationship at any time-point. Specifically, this was the case when CD4 T-cell change and clinical outcomes were examined at week 24 [coefficient -0.01, 95% confidence interval (CI) -0.03 to 0.001, P=0.54], week 48 (coefficient -0.01, 95% CI -0.02 to 0.001, P=0.83) and week 96 (coefficient 0.00, 95% CI -0.03 to 0.04, P=0.76). This was also the case when viral load was examined as a surrogate marker. Given the small number of clinical events occurring in new interventional RCTs, any RCT aiming to evaluate clinical endpoints within these time-points would require an exceptionally large sample size. CONCLUSIONS: Our findings indicate that, within short-term clinical trial settings, it is not possible to estimate the proportion of treatment effect associated with surrogate endpoints.

Immunocytochemical localization of insulin- and somatostatin-like material in human breast tumors.

Four types of human breast lesions and C3H mouse mammary adenocarcinomas (type A) were examined for the immunocytochemical localization of cells containing hormone-like substances. Insulin- or somatostatin-like immunoreactive material was observed in scattered single cells and nests of tumor cells in seven of eight infiltrating duct carcinomas, and in the majority of tumor cells from an anaplastic carcinoma. A few somatostatin-immunoreactive cells were observed in only one of seven fibroadenomas studied. No immunoreactive cells were observed in mouse adenocarcinomas or in human breast dysplasias. These results suggest that cells with hormone-like immunoreactivity may be a common feature in two types of malignant human breast tumors.

Changes in uterine morphology which accompany the development of preneoplastic and neoplastic mammary lesions in old mice.

Because of the accumulating evidence that anatomical and physiological changes occur in sites and systems removed from primary tumors, uterine morphology during the development of mammary tumors in C3H/HeJ mice was investigated. C3H/HeJ mice contain the mouse mammary tumor (MTV) virus in their milk and have a high incidence of mammary tumorigenesis. The C3HeB/FeJ mice, used as one set of controls, do not contain the mouse MTV virus in their milk and have a low incidence of mammary tumorigenesis. In young cycling animals without mammary lesions, no differences in uterine morphology were detected between the two strains. However, there were striking differences between the uteri of animals with mammary lesions (C3H/HeJ mice) and the uteri of animals with no mammary lesions. The age-matched control uteri ( 3HeB /FeJ) contained involuted uterine glands and quiescent endometrial stromal and epithelial tissue. The C3H/HeJ mice with mammary tumors contained cystic uterine glands, a stimulated endometrium, and extremely variable endometrial epithelial cells with pleomorphic microvilli. The uterine endometrium from C3H/HeJ mice with preneoplastic lesions also had a stimulated appearance. Some of the uteri of mice with preneoplastic lesions contained cells with cilia or stereocilia. The altered uterine morphology was correlated with preneoplastic and neoplastic mammary lesions and was not related to age or strain differences.

Fine structure analysis and surface characteristics of mouse mammary gland adenocarcinomas.

Mammary adenocarcinomas from C3H/HeJ mice carrying the mammary tumor virus were studied by means of light, transmission, and scanning electron microscopy. The histological appearance of the tumors was variable; however, 60% were classified as type B adenocarcinomas, while 20% were type A and 20% were composed of equal regions characteristic of both types. Four populations of tumor cells were observed with the TEM. The most abundant of these, primitive glandular cells, were characterized by large, regular, euchromatic nuclei and cytoplasm containing numerous free ribosomes, little rough endoplasmic reticulum, few mitochondria, small Golgi complex and a variable number of type A virus particles. Specialized glandular cells contained highly pleomorphic nuclei, many lysosomes, lipid droplets, multivesicular bodies, profiles of rough endoplasmic reticulum and granules resembling secretory proteins. Myoepithelial cells and dark glandular cells with abundant organelles, large Golgi complexes, dense cytoplasmic matrix and very heterochromatic nuclei were observed infrequently. The SEM revealed tumor cells to be variable in size, shape and surface characteristics. Most cells were rough in texture, displaying irregular ridges, small blebs and a few short microvilli. The contours of some cells were smooth, and a few cells had short, irregular microvilli on limited regions of their surfaces. Cells lining ducts within the tumor had microvilli on their apical surface, but the number, size, shape and distribution of microvilli varied considerably. Cells lining ducts from non-tumor-bearing animals displayed less variation in size, shape and surface morphology.

In vivo and in vitro measurement of tendon strain in the horse.

Strains gauges were applied to the superficial flexor tendon, deep flexor tendon, and suspensory ligament of sound adult horses. Maximum tendon strain occurred during full weight bearing while walking, when the forelimb was perpendicular to the group surface. There was decrease in tendon strain with increase in hoof angle for the deep digital flexor, but no change in tendon strain for the superficial digital flexor and suspensory ligament with changing hoof angle. At physiologic rates of strain, tendons were able to withstand large loads without yielding. Load strain curves developed in vitro indicated that during walking, the deep digital flexor was calculated to load to 416.8 kg; the superficial flexor tendon to 362.9 kg; and the suspensory ligament to 172.4 kg. This study shows that in the horse, strain in flexor tendons during walking was in excess of 5%, indicating strains within the visco-elastic range.

In vivo measurement of bone strain in the horse.

Strain gauges were successfully bonded in vivo to the cranial, caudal, medial, and lateral aspects of the equine radium and tibia and to the dorsal, palmar, or plantar, medial, the lateral aspects of the metacarpus and metatarsus--all in the mid-diaphyseal region. Various activities were investigated, including walking, trotting or pacing, and standing up from anesthesia. The strain patterns showed that each stride produced a characteristic deformation cycle. The strains were measured and the axial loads were calculated as the horse performed certain activities. The tension band side of each bone was predicted from the results. The tension band sides of the metacarpus and metatarsus were the dorsomedial and dorsolateral aspects; for the radius and tibia, the tension band sides were the cranial and craniolateral aspects, respectively.