Better-tolerated Drugs Research Articles

Trilaciclib: A Novel Approach to Mitigate Chemotherapy-Induced Myelosuppression in Cancer Treatment

AbstractTrilaciclib, a novel cyclin-dependent kinase 4/6 inhibitor, has demonstrated the ability to protect bone marrow from chemotherapy toxicity, improving patients' quality of life (QoL). This review describes the mechanism of action, efficacy, and toxicity profile of trilaciclib. Trilaciclib halts retinoblastoma protein phosphorylation during the early G1 phase, preventing the transition from the G1/S phase and inducing the cell cycle arrest in the G1 phase, which protects the hematopoietic cell lineages. Trilaciclib is indicated by the United States Food and Drug Administration and National Comprehensive Cancer Network to decrease the incidence of chemotherapy-induced myelosuppression in adult patients before a platinum/etoposide or topotecan containing regimen for extensive stage small cell lung cancer. Its ease of administration as an intravenous infusion, given before starting chemotherapy, and the favorable side effect profile make it a better-tolerated drug, improving patient QoL.

Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Real-world effectiveness and tolerability of carbamazepine and oxcarbazepine in 354 patients with trigeminal neuralgia.

It is widely agreed that carbamazepine and oxcarbazepine are highly effective in the long-term treatment of trigeminal neuralgia. However, the tolerability of these drugs across the different aetiologies of trigeminal neuralgia is still undetermined. In this retrospective, real-world study, we assessed the effectiveness and tolerability of carbamazepine and oxcarbazepine in a large cohort of patients with classical (254 patients), secondary (60 patients) and idiopathic (40 patients) trigeminal neuralgia. We analysed data using a propensity score analysis to account for selection bias; frequencies of side effects associated with carbamazepine and oxcarbazepine were calculated by adjusting data with the inverse probability of treatment weighting. The initial proportion of responders was 88.3% with carbamazepine, and 90.9% with oxcarbazepine. The number of refractory patients was significantly higher in idiopathic (15%) and secondary forms (27%) than in classical trigeminal neuralgia (6%; p<.05). In 53 patients treated with carbamazepine (29.6%) and in 22 treated with oxcarbazepine (12.6%), major side effects caused treatment interruption or dosage reduction to an unsatisfactory level. Side effects occurred more frequently in patients treated with carbamazepine (43.6%) than with oxcarbazepine (30.3%, p<.0001). The frequency of treatment discontinuation was higher in patients with secondary and idiopathic forms than in those with classical trigeminal neuralgia (p<.05). Our real-world study shows that carbamazepine and oxcarbazepine are effective in most patients with trigeminal neuralgia; nevertheless, side effects are still a major issue, particularly in patients with secondary and idiopathic trigeminal neuralgia. Although carbamazepine and oxcarbazepine are effective in most patients with trigeminal neuralgia, their side effects are still a major issue, thus necessitating the development of better-tolerated drugs.

Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis

Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens. We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug. 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed. Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis. Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

Polymyxins and Their Potential Next Generation as Therapeutic Antibiotics.

The discovery of polymyxins, highly basic lipodecapeptides, was published independently by three laboratories in 1947. Their clinical use, however, was abandoned in the sixties because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were discovered. Now polymyxins have resurged as the last-resort drugs against extremely multi-resistant strains, even though their nephrotoxicity forces clinicians to administer them at doses that are lower than those required for optimal efficacy. As their therapeutic windows are very narrow, the use of polymyxins has received lots of justified criticism. To address this criticism, consensus guidelines for the optimal use of polymyxins have just been published. Quite obviously, too, improved polymyxins with increased efficacy and lowered nephrotoxicity would be more than welcome. Over the last few years, more than USD 40 million of public money has been used in programs that aim at the design of novel polymyxin derivatives. This perspective article points out that polymyxins do have potential for further development and that the novel derivatives already now at hand might offer major advantages over the old polymyxins.

Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics.

Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-negative bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clinical use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-negative bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivatives that are less toxic and/or more effective at tolerable doses are currently under preclinical development and their properties have recently been described in several extensive reviews. Other derivatives lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized “permeabilizer” derivatives, i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compound that recently successfully passed the clinical phase 1. Also, a few other permeabilizer compounds are brought up.

Current and Emerging Therapeutics for the Management of Endometriosis.

Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives (COCs) and progestins, available for multiple routes of administration, are effective first-line hormonal options. In fact, several randomized controlled trials (RCTs) demonstrated that they succeed in improving pain symptoms in the majority of patients, are well tolerated and not expensive. Second-line therapy is represented by gonadotropin-releasing hormone (GnRH) agonists. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). The use of danazol is limited by the large availability of other better-tolerated hormonal drugs. Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be administered only in women with symptoms refractory to other conventional therapies in a clinical research setting. Promising preliminary data have emerged from multicenter Phase III trials on elagolix, a new oral GnRH antagonist but non-inferiority RCT data are required to compare elagolix with first-line therapies for endometriosis.

Perinatally HIV-Infected Youths After Transition from Pediatric to Adult Care, a Single-Center Experience from Northern Italy.

With the development of combination antiretroviral therapy (cART), the first generation of perinatally HIV-infected children has reached young adulthood. A retrospective study was conducted on perinatally HIV-infected young adults after transition to adult care in Brescia (Northern Italy). Twenty-four patients were transferred to Infectious Disease outpatient Clinic from Pediatric Clinic between 2004 and 2016. Median age at transition was 18 years. 37.5% were male, and 75% were Italian. Median CD4+ T-cell count was 534 cell/μL, and 9/24 presented detectable HIV-RNA at the time of transition. At month 12 after transition, median CD4+ T-cell count was 626 cell/μL, and HIV-RNA was still detectable in 25% of patients. Nineteen patients were still in care at the end of follow-up (median of 52 months); 100% on cART, with undetectable HIV-RNA and a median CD4+ T-cell count of 716 cell/μL. After transition, cART regimen was modified in 14/19 patients (in 13 of them it was modified at least twice). Resistance testing is available for 13 patients showing resistance-associated mutations to at least one class of drugs in 9 patients. Transition to adult care is a critical point and youths present lower rates of viral suppression compared to adults. We observed 80% of viral suppression (5 young patients were lost to follow-up and considered as failures), notwithstanding social problems and resistance mutations. With the availability of more potent and better-tolerated drugs, optimization of cART is possible also in this previously difficult-to-treat group of patients. Novel tools to address adherence to cART in young adults and teenagers will also be needed.

Experimental and Clinical Treatment of Chagas Disease: A Review.

.Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed. Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.

Avelumab, an anti-PD-L1 monoclonal antibody, shows activity in various tumour types

During the past 5 years, immune checkpoint inhibitors have revolutionised the management and treatment of cancer, because they have been associated with striking improvements in clinical outcomes in patients with some tumour types. For example, the use of checkpoint inhibitors has changed the natural history of melanoma with a pronounced increase in patients' survival. 1 Robert C Long GV Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372: 320-330 Crossref PubMed Scopus (4060) Google Scholar , 2 Ribas A Puzanov I Dummer R et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015; 16: 908-918 Summary Full Text Full Text PDF PubMed Scopus (1230) Google Scholar These agents have also been tested in many other tumour types, such as renal cancer, urothelial cancer, and squamous cell cancer of the head and neck, with promising results and have subsequently gained approval from the regulatory authorities. In non-small-cell lung cancer (NSCLC), survival rates have improved in recent years, both as a result of advances in disease management—including the addition of new-generation agents to the therapeutic armamentarium—and supportive care. Indeed, the development of many active and better-tolerated drugs, such as bevacizumab, pemetrexed, nab-paclitaxel, and, more recently, nintedanib and ramucirumab, has increased the number of available treatment options for patients with NSCLC. Two anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, have already been approved for the treatment of NSCLC in the second-line setting or beyond, 3 Borghaei H Paz-Ares L Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015; 373: 1627-1639 Crossref PubMed Scopus (6826) Google Scholar , 4 Brahmer J Reckamp KL Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373: 123-135 Crossref PubMed Scopus (6294) Google Scholar , 5 Herbst RS Baas P Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016; 387: 1540-1550 Summary Full Text Full Text PDF PubMed Scopus (4591) Google Scholar as has the anti-PD-L1 antibody atezolizumab. 6 Rittmeyer A Barlesi F Waterkamp D et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017; 389: 255-265 Summary Full Text Full Text PDF PubMed Scopus (3203) Google Scholar Additionally, on Oct 24, 2016, pemrbolizumab also gained approval for the first-line treatment of NSCLC in a small subgroup of patients with high expression (>50%) of PD-L1. 7 Reck M Rodriguez-Abreu D Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016; 375: 1823-1833 Crossref PubMed Scopus (6306) Google Scholar Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trialAvelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. Full-Text PDF Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trialAvelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. Full-Text PDF Correction to Lancet Oncol 2017; 18: 556–57Kotsakis A, Georgoulias V. Avelumab, an anti-PD-L1 monoclonal antibody, shows activity in various tumour types. Lancet Oncol 2017; 18: 556–57—In this Comment, the term ‘immune-related’ should have read ‘infusion-related’ in two phrases. The two affected sentences should have read as follows: “However, an important finding from these two studies was that the frequency of infusion-related reactions exceeded 20%; infusion-related reactions are uncommon with the other approved immunotherapeutic agents, with an estimated frequency of about 1–2%” and “Once again, ongoing phase 3 trials ( NCT02395172 , NCT02576574 ) might shed light on the frequency, significance, and severity of infusion-related adverse events and how best to manage them.” These corrections have been made to the online version as of July 26, 2017. Full-Text PDF

Adverse systemic reaction to benznidazole

Benznidazole, drug of choice for Chagas disease (CD), has been associated with a high incidence of adverse reactions that can become serious, necessitating discontinuation of the drug. We describe the case of a Bolivian patient living in Spain for 9 years, who, following treatment with benznidazole for CD in indeterminate chronic phase, presented with fever, skin lesions, digestive symptoms, general malaise, and laboratory abnormalities. After the discontinuation of benznidazole and, the intake of antihistamines and systemic corticosteroids, the patient presented a complete resolution of the symptoms. Optimization of dose strategies and development of more effective, and better-tolerated drugs is advisable.

Antiepileptic Drugs Under Investigation for Treatment of Focal Epilepsy.

Despite optimal medical treatment, up to 30% of patients with epilepsy continue to experience recurrent seizures, and the challenge for new more efficacious and better-tolerated drugs is continuing. New antiepileptic drugs include the evolution of preexisting drugs and new compounds identified through the investigation of additional molecular targets, such as SV2A synaptic vesicle protein, voltage-gated potassium channels, ionotropic and metabotropic glutamate receptors, and gap junctions. We report the available data about different classes of molecules that are in the pipeline for treatment of focal epilepsy. We will present data available on drugs derived from the evolution of preexisting anticonvulsants. We will then report the results on clinical trials performed with new compounds identified through the investigation of additional molecular targets. The challenge for new, more efficacious, more specific, and better-tolerated drugs is continuing and a better knowledge of mechanisms underlying epilepsy should represent the guide for future research. The ultimate goal of treatment should be not only to render the patients seizure free but also to improve the quality of life and reduce costs of medical care.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Comment on “Hepatitis C and the Sex Trade”

We read with interest Dr. Shafran's editorial [1] on our study published in November/December 2015 issue of the journal providing a baseline assessment of engagement in the continuum of hepatitis C (HCV) care among sex workers in Vancouver [2]. Given the limited peer reviewed evidence available in this area, we believe that our research, which uses data from a large cohort of sex workers in Vancouver, makes a strong and unique contribution to start filling these gaps. Here, we address the main issues raised by the editorial. While we agree that globally injection drug use is the major driver of HCV transmission, other routes have also been documented. Particularly relevant to our study population is the potential for permucosal transmission of HCV in high-risk sexual practices and sharing of intranasal drug paraphernalia, especially in the context of multiple partners [3]. The editorial also appears to overlook the significant limitations of risk-based testing. Research demonstrates that certain risk exposures are frequently underreported due to stigma and fear of disclosing on the part of the clients [4] or failure of ascertainment by healthcare providers [5]. “Symptomatic testing” also has important limitations given that chronic HCV is frequently asymptomatic and that ALT levels are typically within normal range in up to 40% of people with chronic HCV [6]. Importantly, overreliance on risk-based or “symptomatic testing” strategies has resulted in a large proportion of underdiagnosis of HCV, which leads to missed opportunities for optimal treatment and prevention of HCV related morbidity, mortality, and onward transmission. Consequently, HCV testing guidelines are increasingly recommending additional population-based strategies [5]. As described in our paper, diagnosis of HCV infection was based on laboratory testing. Other data (e.g., engagement in the HCV cascade) relied on self-reported quantitative data collected through surveys conducted by experienced interviewers, as it is routinely done in epidemiological research and within public surveillance systems. In addition, although our study was not designed to evaluate barriers to HCV care, we discussed potential barriers, as well as potential strategies to overcome them and improve HCV care outcomes. These recommendations are informed by prior extensive research with sex workers and other marginalized populations in our setting that characterized gaps and successful strategies to improve healthcare access [4, 7]. The editorial also places a substantial amount of the responsibility for changes in health status to be the responsibility of individuals (“in the end, adult (sex workers) must want to have better health outcomes”) [1] and correspondingly places blame on individuals for whom health status does not improve. This ignores the well-established body of literature pointing to the limited agency of individuals from marginalized populations to enact change in the face of structural and socioeconomic inequities, regardless of their own desire to do so [4, 8]. Our research and many others globally have demonstrated over more than 10 years that failure by governments and policy-makers to address systemic barriers to care (e.g., extreme violence, police harassment) has pushed sex workers away from health access and in many cases forced sex workers to prioritize their immediate safety (e.g., protections from violence) over longer-term health risks [4]. Finally, the editorial suggests that HCV treatment should be discouraged among women involved in sex work. Although no data on HCV care among sex workers are available in the literature, multiple studies demonstrate that when appropriately supported other marginalized populations, such as people who inject drugs, achieve rates of sustained virological response comparable to those achieved in the general population [9]. Further, modeling studies suggest that expanding access to persons at increased risk for transmission has the potential to significantly reduce HCV incidence and prevalence, particularly when combined with other harm reduction strategies, and importantly that this strategy is likely to be cost-effective [9]. Withholding HCV treatment from populations with the highest burden of HCV is clearly against international HCV treatment guidelines, including those from the World Health Organization (WHO) and the American Association for the Study of Liver Disease (AASLD)/Infectious Diseases Society of America (IDSA) [9]. Shifting focus away from judgmental blanket assumptions about individuals' abilities to sustain treatment and personal health goals towards strategies that could best engage and support marginalized populations in long-term care would be a far more productive as well as ethical use of resources. Given increasing availability of highly efficacious, simpler, and better-tolerated HCV drugs there is now a real opportunity to control the HCV epidemic in Canada and abroad. Equitable access to early HCV treatment and care, coupled with innovative low threshold models of care, as well as social-structural interventions addressing the underlying factors continuing to fuel the HCV epidemic, will be critical to maximizing the individual and population benefits of HCV treatment and move us closer to the 90-90-90 HCV target proposed by the WHO in September 2015 [10].

Choice of antiretroviral drugs for postexposure prophylaxis for adults and adolescents: a systematic review.

The choice of preferred regimens for human immunodeficiency virus postexposure prophylaxis (PEP) has evolved over the last 2 decades as more data have become available regarding the safety and tolerability of newer antiretroviral drugs. We undertook a systematic review to assess the safety and efficacy of antiretroviral options for PEP to inform the World Health Organization guideline revision process. Four databases were searched up to 1 June 2014 for studies reporting outcomes associated with specific PEP regimens. Data on PEP completion and discontinuation due to adverse events was extracted and pooled estimates were obtained using random-effects meta-analyses. Fifteen studies (1830 PEP initiations) provided evaluable information on 2-drug regimens (zidovudine [ZDV]- or tenofovir [TDF]-based regimens), and 10 studies (1755 initiations) provided evaluable information on the third drug, which was usually a protease inhibitor. The overall quality of the evidence was rated as very low. For the 2-drug regimen, PEP completion rates were 78.4% (95% confidence interval [CI], 66.1%-90.7%) for people receiving a TDF-based regimen and 58.8% (95% CI, 47.2%-70.4%) for a ZDV-based regimen; the rate of PEP discontinuation due to an adverse event was lower among people taking TDF-based PEP (0.3%; 95% CI, 0%-1.1%) vs a ZDV-based regimen (3.2%; 95% CI, 1.5%-4.9%). For the 3-drug comparison, PEP completion rates were highest for the TDF-based regimens (TDF+emtricitabine [FTC]+lopinavir/ritonavir [LPV/r], 71.1%; 95% CI, 43.6%-98.6%; TDF+FTC+raltegravir [RAL], 74.7%; 95% CI, 41.4%-100%; TDF+FTC+ boosted darunavir [DRV/r], 93.9%; 95% CI, 90.2%-97.7%) and lowest for ZDV+ lamivudine [3TC]+LPV/r (59.1%; 95% CI, 36.2%-82.0%). Discontinuations due to adverse drug reactions were lowest for TDF+FTC+RAL (1.9%; 95% CI, 0%-3.8%) and highest for ZDV+3TC+boosted atazanavir (21.2%; 95% CI, 13.5%-30.0%). The findings of this review provide evidence supporting the use of coformulated TDF and 3TC/FTC as preferred backbone drugs for PEP. Choice of third drug will depend on setting; for resource-limited settings, LPV/r is a reasonable choice, pending the improved availability of better-tolerated drugs with less potential for drug-drug interactions.

Significant reduction in HIV virologic failure during a 15-year period in a setting with free healthcare access.

Calendar trends in virologic failure (VF) among human immunodeficiency virus (HIV)-infected patients can help to evaluate the performance of healthcare systems and the need for new antiretroviral therapy (ART). We examined the time trend in the rate of VF beyond 6 months of ART between 1997 and 2011 in France. We included patients from the French Hospital Database on HIV who received at least 6 months of ART. VF was defined as 2 consecutive plasma HIV-RNA values >500 copies/mL or as 1 value >500 copies/mL followed by a treatment switch. We adjusted for patients' characteristics by fitting a multivariable generalized estimating equation logistic regression model with an exchangeable covariance matrix. A total of 81 738 patients were enrolled, and median follow-up was 112.4 months. Median CD4 count was 333 cells/µL, and 23% of patients had HIV infection classified as Centers for Disease Control and Prevention stage C. Overall, 29.3% of patients received single/dual-drug ART initially, and 45.4% of patients experienced at least 1 episode of VF during follow-up. The percentage of patients with VF fell from 61.5% in 1997-1998 to 9.7% in 2009-2011 (P < .0001). Factors associated with the lower frequency of VF were recent calendar period, a higher contemporary CD4 cell count, and first-line regimens based on nonnucleoside reverse transcriptase inhibitors or integrase inhibitors. The proportion of HIV-infected patients experiencing VF during routine care fell markedly between 1997 and 2009-2011, to only 9.7%. This was attributed to the advent of fully active and better-tolerated antiretroviral drugs, and to national guidelines recommending rapid management of VF after mid-2000.

Toxic and therapeutic effects of Nifurtimox and Benznidazol on Trypanosoma cruzi ex vivo infection of human placental chorionic villi explants

Nifurtimox (Nfx) and Benznidazole (Bnz) are the only available drugs in use for the treatment of Chagas disease. These drugs are recommended but not fully validated in evidence-based medicine and reports about the differential toxicity of both drugs are controversial. Here, we evaluated the toxic and therapeutic effects of Nfx and Bnz on human placental chorionic villi explants (HPCVE) during ex vivo infection of Trypanosoma cruzi, performing histopathological, histochemical, immunohistochemical as well as immunofluorescence analysis of the tissue. Additionally, we determined the effect of both drugs on parasite load by real time PCR. Bnz prevents the parasite induced tissue damage in ex vivo infected HPCVE compared to Nfx, which is toxic per se. The presence of T. cruzi antigens and DNA in infected explants suggests that these drugs do not impair parasite invasion into the HPCVE. Additionally, our results confirm reports suggesting that Bnz is less toxic than Nfx and support the need for the development of more effective and better-tolerated drugs.

Incidence and risk factors for drug intolerance and association with incomplete treatment for tuberculosis: analysis of national case registers for England, Wales and Northern Ireland, 2001–2010

Anti-tuberculosis drug regimens are efficacious, but drug intolerance can be severe and may impact on treatment completion rates. The Enhanced Tuberculosis Surveillance (ETS) system is a case register of all...

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.