Third-line Drugs Research Articles

Evaluation of the efficacy and safety of levetiracetam treatment for neonatal seizures in extremely preterm infants

Aim: Levetiracetam (LEV) is increasingly being used to treat seizures in the neonatal period. Data about using LEV in extremely preterm infants with seizures is insufficient and limited with only a handful studies. This study aimed to evaluate the efficacy and safety of LEV in the treatment of seizures in extremely preterm infants.Methods: This retrospective cohort study was conducted on extremely premature newborns, those who were born ≤28 weeks of gestational age, and took their first intravenous dose of levetiracetam due to neonatal seizure before their 44th gestational week between September 2017-February 2019. Loading and maintenance dosage of LEV, previously used antiepileptic medications, response to treatment and side effects of LEV were recorded.Results: Twenty extremely preterm neonates (9 males and 11 females) who received LEV were evaluated. Gestational ages ranged from 23 to 28 weeks, with a median of 26.5 weeks. Birth weights ranged from 520-1210 gr and 15 infants (75%) had extremely low birth weights. For the treatment of seizures, 12 patients (60 %) were initially started on levetiracetam as first-line therapy and eight patients (40%) were administered levetiracetam as a second or third-line antiepileptic drug. The efficiency of seizure control with LEV was 60 % (12/20) in all patients. The median LEV dose at the time seizure control was achieved was 40 mg/kg. No side effects were observed due to LEV treatment. Conclusion: This study shows that LEV can be efficient and safe for seizure management in extremely preterm infants. Seizure control was better achieved when LEV was given as the first-line antiepileptic medication in extremely preterm infants.

Pharmacoepidemiology of the antiglaucoma drugs in Brazil from 2012 to 2018

Abstract Purpose: To outline the epidemiological profile of clinical treatments for glaucoma provided by the Brazilian Unified Health System (SUS, acronym in Portuguese) between January 2012 and December 2018. Methods: A quantitative and descriptive study was conducted using available data based on the outpatient information system from SUS (SIA/SUS, acronym in Portuguese). The variables were monocular treatment with first, second, and third-line drugs; monocular treatment with combinations of two drugs and three drugs from different lines; binocular treatment with first, second, and third-line drugs; and binocular treatment with combinations of two drugs and three drugs from different lines. Results: During the analysis period, the prevalence of clinical therapies for glaucoma increased from 2012 to 2017 and decreased from 2017 to 2018. Of the clinically treated patients, 96% were carriers of binocular glaucoma. Among the regions of Brazil, the Northeast had the highest prevalence of binocular glaucoma (about 60% of the number of cases), and the most common therapy was combinations of two drugs from different lines. The Southeast region had the highest concentration of monocular glaucoma (53% of cases), and the predominant therapy was combinations of three drugs from different lines. The Midwest region had the lowest prevalence of monocular-treatments for glaucoma (less than 6%). Conclusion: In Brazil, the highest number of treatments offered by the public health system was in the Northeast and Southeast regions. There is a high national prevalence and potential for the morbidity of this disease. Therefore, it is necessary to strengthen programs aimed at early diagnosis and appropriate treatment to reduce adverse outcomes.

Third-line Life-prolonging Drug Treatment in a Real-world Metastatic Castration-resistant Prostate Cancer Population: Results from the Dutch Castration-resistant Prostate Cancer Registry

BackgroundEvidence concerning third-line life-prolonging drugs (LPDs) in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients is incomplete. ObjectiveTo evaluate third-line LPD outcomes in a real-world cohort of mCRPC patients, identify variables associated with overall survival (OS), and establish a prognostic model. Design, setting, and participantsPatients with mCRPC who were progressive on second-line LPD before July 1, 2017 were retrospectively identified from the Dutch Castration-resistant Prostate Cancer Registry (CAPRI) and followed until December 31, 2017. Outcome measurements and statistical analysisAssociation of potential risk factors with OS was tested by Cox proportional hazard models after multiple imputation of missing baseline characteristics. A predictive score was computed from the regression coefficient and used to classify patients into risk groups. Results and limitationsOf 1011 mCRPC patients progressive on second-line LPD, 602 (60%) received third-line LPD. Patients receiving third-line LPD had a more favorable prognostic profile at baseline and longer median OS than patients with best supportive care (10.4 vs 2.4 mo, p < 0.001). Eastern Cooperative Oncology Group performance status 1 and ≥2 (hazard ratio [HR] 1.51, p < 0.007 and HR 3.08, p < 0.001, respectively), opioid use (HR 1.55, p = 0.019), visceral metastases (HR 2.09, p < 0.001), hemoglobin <7 mmol/l (HR 1.44, p < 0.002), prostate-specific antigen ≥130 μg/l (HR 1.48, p = 0.001), alkaline phosphatase ≥170 U/l (HR 1.52, p < 0.001), and lactate dehydrogenase ≥250 U/l (HR 1.44; p = 0.015) were associated with shorter survival. Harrell’s C-index was 0.74. The median OS values for low-, low-intermediate-, high-intermediate-, and high-risk groups were 14, 7.7, 4.7, and 1.8 mo, respectively. Limitations include the retrospective design. ConclusionsWe developed a prognostic model and identified a subgroup of patients in whom third-line LPD treatment has no meaningful benefit. Our results need to be confirmed by prospective clinical trials. Patient summaryWe reported outcomes from third-line life-prolonging drugs in metastatic prostate cancer patients and developed a prognostic model that could be used to guide treatment decisions.

Predictors of outcome in refractory generalized convulsive status epilepticus.

ObjectiveRefractory status epilepticus is a serious condition in which seizure continues despite use of two antiepileptic medications. Retrospective studies have shown that 29%‐43% of SE patients progress into RSE despite treatment. Mortality following RSE is high. We aimed to evaluate the predictors of outcome in patients with RSE at a tertiary care center.MethodsSixty‐eight consecutive patients with RSE who presented to our hospital between February 2018 and January 2020 were evaluated for outcome.ResultIn our study 28(41.2%), patients who failed to respond to first‐ and second‐line antiepileptic drug responded to the third‐line antiepileptic drug thus avoiding mechanical ventilation and intravenous anesthesia. Low GCS at admission (P < .001), need for mechanical ventilation and intravenous anesthesia (P = .018), and long duration of RSE before recovery (P = .035) were strongly associated with worse outcome. Duration of RSE before starting treatment (P = .147), previous history of seizure (P = .717), and age of the patient (P = .319) did not influence the outcome.SignificanceIn our study, we prospectively evaluated patients with RSE and followed them for one month after discharge from the hospital. Unlike some of the previous studies, we identified an interesting finding whereby a significant proportion of the patients responded to the third‐line antiepileptic drug and thus avoiding the complications related to mechanical ventilation.

Weight-lowering Effects of Glucagon-like Peptide-1 Receptor Agonists and Detection of Breast Cancer Among Obese Women with Diabetes

It has been proposed that the weight loss associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may improve detection of breast cancer in patients undergoing this treatment. We aimed to determine whether the weight-lowering effects of GLP-1 RAs are associated with an increased detection of breast cancer among obese women with type 2 diabetes. Using the UK Clinical Practice Research Datalink, we conducted a propensity score-matched cohort study among female obese patients with type 2 diabetes newly treated with antidiabetic drugs between 1 January 2007 and 31 January 2018. New users of GLP-1 RAs (n = 5,510) were matched to new users of second- to third-line noninsulin antidiabetic drugs (n = 5,510). We used time-dependent Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with different GLP-1 RA maximal weight loss categories (<5%, 5%-10%, >10%). Breast cancer incidence gradually increased with GLP-1 RA maximal weight loss categories, with the highest HR observed for patients achieving at least 10% weight loss (HR = 1.8, 95% CI = 1.1, 2.8). In secondary analyses, the HR for >10% weight loss was highest in the 2-3 years since treatment initiation (HR = 2.9, 95% CI = 1.2, 6.9). In this population-based study, the detection of breast cancer gradually increased with GLP-1 RA weight loss categories, particularly among those achieving >10% weight loss. These results are consistent with the hypothesis that substantial weight loss with GLP-1 RAs may improve detection of breast cancer among obese patients with type 2 diabetes.

Incretin-based drugs and risk of lung cancer among individuals with type 2 diabetes.

To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation. A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships. In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

Third-Line Antidiabetic Therapy Intensification Patterns and Glycaemic Control in Patients with Type 2 Diabetes in the USA: A Real-World Study.

Third-line antidiabetic drug (ADD) intensification patterns and glycemic control post intensification in type 2 diabetes mellitus (T2DM) have not been thoroughly explored in a real-world setting. This study explored the patterns and risks of third-line ADD intensification post second-line ADDs and the probability of desirable glucose control over 12months by third-line ADD classes at the population level. We used the electronic medical records of 255,236 patients with T2DM in the USA initiating a second-line ADD post metformin from January 2013 to evaluate the rates and risks of third-line intensification and the probability of desirable glycemic control with different ADDs after addressing inherent heterogeneity using appropriate methodologies. Patients had a mean age of 60years and glycated hemoglobin (HbA1c) of 8.5% at second-line ADD. Over 209,136 person-years (PY) of follow-up, 40% had initiated a third-line ADD at HbA1c of 8.8%. Patients receiving dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as the second-line ADD had a 7% (95% hazard ratio [HR] confidence interval [CI] 1.05-1.10) and 28% (95% HR CI 1.24-1.33) higher adjusted risk of intensifying with a third-line ADD than did those receiving sulfonylureas as the second-line ADD. Those receiving sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as second-line ADD had a 17% (95% HR CI 0.80-0.87) lower risk. The adjusted probability of reducing HbA1c by ≥ 1% was similar in those receiving third-line sulfonylureas, thiazolidinediones, GLP-1 RAs, SGLT-2i, and insulin (minimum, maximum 95% CI of probability 0.61, 0.68), whereas those receiving DPP-4i had a significantly lower probability (0.58; 95% CI 0.56-0.59). Similarly, the probability of reducing HbA1c < 7.5% was similar in the sulfonylurea, GLP-1 RA, and SGLT-2i groups (minimum, maximum of 95% CI of probability 0.41, 0.49), whereas those receiving DPP-4i had a significantly lower probability of achieving an HbA1c < 7.5% (0.37; 95% CI 0.36-0.38). This study, based on a large representative cohort of patients with T2DM from the USA, suggests the need for revisiting real-world practices in choosing therapeutic intensification pathways and a more proactive strategy to tackle the persistent risk factor burden in patients with T2DM.

Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review

Background and Objectives: Distal symmetrical polyneuropathy (DSPN) is one of the most common chronic complications of diabetes mellitus. Although it is usually characterized by progressive sensory loss, some patients may develop chronic pain. Assessment of DSPN is not difficult, but the biggest challenge is making the correct diagnosis and choosing the right treatment. The treatment of DSPN has three primary objectives: glycemic control, pathogenic mechanisms, and pain management. The aim of this brief narrative review is to summarize the current pharmacological treatment of painful DSPN. It also summarizes knowledge on pathogenesis-oriented therapy, which is generally overlooked in many publications and guidelines. Materials and Methods: The present review reports the relevant information available on DSPN treatment. The search was performed on PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases, including among others the terms “distal symmetrical polyneuropathy”, “neuropathic pain treatment”, “diabetic neuropathy”, “diabetes complications”, ”glycaemic control”, “antidepressants”, “opioids”, and “anticonvulsants”. Results: First-line drugs include antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants) and pregabalin. Second- and third-line drugs include opioids and topical analgesics. While potentially effective in the treatment of neuropathic pain, opioids are not considered to be the first choice because of adverse reactions and addiction concerns. Conclusions: DSPN is a common complication in patients with diabetes, and severely affects the quality of life of these patients. Although multiple therapies are available, the guidelines and recommendations regarding the treatment of diabetic neuropathy have failed to offer a unitary consensus, which often hinders the therapeutic options in clinical practice.

Successful treatment of refractory status epileptics with a single dose of IV ketamine in a Saudi child - a case report

Background: Status epileptics are classically defined as seizures that are continuous for 30 minutes or longer or repetitive seizures between which the patient does not regain consciousness. This study reports a case of a boy with a 2-hour seizure. Case Presentation: We present the case of a 7-year-old boy, who is known to have tuberous sclerosis (TSC2 gene mutation). On the day of presentation, the seizure had started with aura (epigastric pain with weakness in the face), then started to seize in a form left focal jerky movement with generalization associated with rolling up of the eyes, and lasted for 5 minutes; it was aborted clinically by lorazepam 0.1 mg/kg IV. However, the electroencephalography (EEG) showed subclinical seizure. The patient received a loading dose of phenytoin, 20 mg/kg IV, with no changes in the EEG; then Keppra (three doses) with a total of 40 mg/kg IV was given, but subclinical seizure still persisted. The patient was given one dose of Ketamine IV of 1 mg/kg, which resulted in complete cessation of the seizure activity within 3 minutes after injection, which was confirmed by prolonged EEG monitoring. The total duration of the seizure was 2 hours. Conclusion: Ketamine can be considered as a third-line drug in refractory status epilepticus.

Therapeutic drug monitoring of levetiracetam in newborns

Neonatal seizures in full-term and preterm infants represent a common neurological syndrome. Levetiracetam (LEV) is one of the new and widely prescribed second- or third-line antiepileptic drug for the treatment of seizures. Routine therapeutic drug monitoring of LEV was not recommended due to its almost ideal pharmacokinetic profile: linear pharmacokinetics, predictable dose-concentration relationship, wide therapeutic index, favourable safety profile, and unlikely clinically significant drug-drug pharmacokinetic interactions. In newborns, drug pharmacokinetics may be under the influence of maturation process. LEV pharmacokinetics in newborns appears to be age (gestational, postnatal) dependent and highly variable within the age ranges. These aspects make therapeutic drug monitoring a useful procedure for therapy optimization in this specific patient population. In population modeling based on therapeutic drug monitoring and nonlinear mixed effects models, covariates were found that should significantly affect the LEV clearance and volume of distribution in newborns — creatinine clearance and total body weight. Using of these regression equations can help to adjust the LEV doses without the patient's measured concentration data. But the significant magnitudes of the interindividual variability remaining in these final regression models justify the need for therapeutic drug monitoring and Bayesian adaptive control for personalization of LEV dosage regimens in neonates.

Machine Learning Predicts Accurately Mycobacterium tuberculosis Drug Resistance From Whole Genome Sequencing Data.

Background: Tuberculosis disease, caused by Mycobacterium tuberculosis, is a major public health problem. The emergence of M. tuberculosis strains resistant to existing treatments threatens to derail control efforts. Resistance is mainly conferred by mutations in genes coding for drug targets or converting enzymes, but our knowledge of these mutations is incomplete. Whole genome sequencing (WGS) is an increasingly common approach to rapidly characterize isolates and identify mutations predicting antimicrobial resistance and thereby providing a diagnostic tool to assist clinical decision making.Methods: We applied machine learning approaches to 16,688 M. tuberculosis isolates that have undergone WGS and laboratory drug-susceptibility testing (DST) across 14 antituberculosis drugs, with 22.5% of samples being multidrug resistant and 2.1% being extensively drug resistant. We used non-parametric classification-tree and gradient-boosted-tree models to predict drug resistance and uncover any associated novel putative mutations. We fitted separate models for each drug, with and without “co-occurrent resistance” markers known to be causing resistance to drugs other than the one of interest. Predictive performance was measured using sensitivity, specificity, and the area under the receiver operating characteristic curve, assuming DST results as the gold standard.Results: The predictive performance was highest for resistance to first-line drugs, amikacin, kanamycin, ciprofloxacin, moxifloxacin, and multidrug-resistant tuberculosis (area under the receiver operating characteristic curve above 96%), and lowest for third-line drugs such as D-cycloserine and Para-aminosalisylic acid (area under the curve below 85%). The inclusion of co-occurrent resistance markers led to improved performance for some drugs and superior results when compared to similar models in other large-scale studies, which had smaller sample sizes. Overall, the gradient-boosted-tree models performed better than the classification-tree models. The mutation-rank analysis detected no new single nucleotide polymorphisms linked to drug resistance. Discordance between DST and genotypically inferred resistance may be explained by DST errors, novel rare mutations, hetero-resistance, and nongenomic drivers such as efflux-pump upregulation.Conclusion: Our work demonstrates the utility of machine learning as a flexible approach to drug resistance prediction that is able to accommodate a much larger number of predictors and to summarize their predictive ability, thus assisting clinical decision making and single nucleotide polymorphism detection in an era of increasing WGS data generation.

Comparative evaluation of the effects of synthetic disease-modifying antirheumatic drugs and biological agents on clinical course, the rate of development of destructive changes, and quality of life in patients with rheumatoid arthritis

There are few studies of the efficiency of therapy with disease-modifying antirheumatic drugs (DMARDs) and biological agents (BAs) in patients with early rheumatoid arthritis (eRA) as part of a treat-to-target strategy. Objective : to investigate the effects of DMARDs and BAs used in combination with methotrexate (MTX) on clinical course, quality of life (QoL), and the evolution of articular erosions and synovitis in patients with RA. Patients and methods . The investigation enrolled 151 patients with eRA. At the first stage, the patients received DMARDs. At the second stage, 101 patients with persistent moderate and high disease activity were prescribed MTX at a dose of 25 mg/week or 20 mg/week in combination with infliximab (INF), or 20 mg/week in combination with rituximab (RTX). At the third stage, 20patients with persistent high disease activity were switched to tocilizumab (TCZ) therapy. Results and discussion . At 12 months of DMARD therapy, a clinical remission was more often achieved in the MTX group. The use of INF or RTX significantly improved QoL in the patients. That of TCZ as a second- and third-line drug led to a significant decrease in DAS28-CRP. Conclusion . There were no statistically significant differences between the INF and RTMgroups with respect to the time course of changes in CRP, ESR, circulating immune complexes, and the indicators of X-ray progression, which confirms the possibility of switching from a first-line BA to its subsequent lines with an increasing clinical disease activity. TCZ can be a second- and third-line drug when the effect of therapy with other BAs escapes.

Neonatal hypotension survey: A South African perspective

Background. Neonatal hypotension remains one of the most controversial topics in neonatology. Various definitions are used but lack an evidence base. Owing to the variation in defining a low blood pressure (BP), significant differences in pharmacological manipulation of BP are evident. Objectives. The aim of the present research was to determine the diagnostic criteria for neonatal hypotension and management strategies for neonatal hypotension in South Africa. Methods. A 29-point questionnaire was designed to determine the criteria used by South African neonatologists and paediatricians to diagnose and manage neonatal hypotension. The survey was conducted at two different time points in 2017. Results. The combination of the two surveys resulted in a 9.3% (47/507) response rate. A BP below the gestational age (in weeks) was the most common definition used for neonatal hypotension (75%). Most clinicians (86%) administered fluid prior to initiating inotrope therapy. Dopamine, dobutamine and adrenaline were the most common first-, second- and third-line anti-hypotensive drugs used. Most clinicians (77%) did not use a hypotension management guideline. Conclusion. Neonatal hypotension definition and management in South Africa are similar to international patterns, despite a lack of evidence to support the diagnosis and management strategies.

The clinical application of fruquintinib on colorectal cancer

ABSTRACTIntroduction: Anti-angiogenetic agents are currently the most commonly used drugs for the treatment of colorectal cancer (CRC) patients, including various inhibitors targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptors (VEGFRs). Fruquintinib (HMPL-013), a highly selective and long-term small-molecule inhibitor of VEGFR (VEGFR1, 2, and 3) was recently approved in China for CRC treatment. Clinical studies have shown it has many advantages, such as low off-target toxicity, good drug tolerance, and strong effect.Areas covered: In the review, the molecular structure, mechanism of action, pharmacokinetics, clinical efficacy, and safety of fruquintinib are introduced in detail. The potential clinic application on non-small cell lung cancer (NSCLC) and gastric cancer is also discussed.Expert commentary: Fruquintinib was approved for patients with metastatic colorectal cancer (RAS wild type) who have previously received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and who have received or are not suitable for anti- VEGF therapy and anti- EGFR therapy. As a novel, therapeutic approach to CRC, Fruquintinib could be used as a third-line drug for the treatment of CRC patients. Due to drug resistance during the long-term therapy, the combination of fruquintinib with other targeted therapy drugs may be an effective option for CRC treatment.

Dipeptidyl Peptidase 4 Inhibitors and the Risk of Bullous Pemphigoid Among Patients With Type 2 Diabetes.

There are uncertainties regarding the association between dipeptidyl peptidase 4 (DPP-4) inhibitors and bullous pemphigoid (BP), a potentially severe autoimmune skin disease. Thus, we conducted a population-based study to determine whether use of DPP-4 inhibitors, when compared with other second- to third-line antidiabetic drugs, is associated with an increased risk of BP in patients with type 2 diabetes. Using the U.K. Clinical Practice Research Datalink, we conducted a cohort study among 168,774 patients initiating antidiabetic drugs between January 2007 and March 2018. Using time-dependent Cox proportional hazards models, we estimated adjusted hazard ratios (HRs) with 95% CIs of incident BP associated with current use of DPP-4 inhibitors, compared with current use of other second- to third-line antidiabetic drugs. We also conducted a propensity score-matched analysis to assess the impact of residual confounding. During 711,311 person-years of follow-up, 150 patients were newly diagnosed with BP (crude incidence rate, 21.1 per 100,000 person-years). Current use of DPP-4 inhibitors was associated with an increased risk of BP (47.3 vs. 20.0 per 100,000 person-years; HR 2.21 [95% CI 1.45-3.38]). HRs gradually increased with longer durations of use, reaching a peak after 20 months (HR 3.60 [95% CI 2.11-6.16]). Similar results were obtained in the propensity score-matched analysis (HR 2.40 [95% CI 1.13-4.66]). In this large population-based study, use of DPP-4 inhibitors was associated with an at least doubling of the risk of BP in patients with type 2 diabetes, albeit the absolute risk was low.

Time-dependent biases in observational studies of comparative effectiveness research in rheumatology. A methodological review

ObjectiveTo assess to what extent time-dependent biases (ie, immortal time bias (ITB) and time-lag bias (TLB)) occur in the latest rheumatology observational studies, describe their main mechanisms and increase the...

HIV-1 drug resistance testing at second-line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third-line.

The number of patients on second-line antiretroviral therapy is growing, but data on HIV drug resistance patterns at failure in resource-constrained settings are scarce. We aimed to describe drug resistance and investigate the factors associated with extensive resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), in patients failing second-line therapy in the HIV outpatient clinic at Arua Regional Referral Hospital, Uganda. We included patients who failed on second-line therapy (two consecutive viral loads ≥1000 copies/mm3 by SAMBA-1 point-of-care test) and who had a drug resistance test performed between September 2014 and March 2017. Logistic regression was used to investigate factors associated with NRTI genotypic sensitivity score (GSS) ≤1. Seventy-eight patients were included: 42% female, median age 31years and median time of 29months on second-line therapy. Among 70 cases with drug resistance test results, predominant subtypes were A (47%) and D (40%); 18.5% had ≥1 major protease inhibitor mutation; 82.8% had ≥1 NRTI mutation and 38.5% had extensive NRTI resistance (NRTI GSS ≤1). A nadir CD4 count ≤100/ml was associated with NRTI GSS ≤1 (OR 4.2, 95% CI [1.3-15.1]). Thirty (42.8%) patients were switched to third-line therapy, composed of integrase inhibitor and protease inhibitor (60% darunavir/r)+/-NRTI. A follow-up viral load was available for 19 third-line patients at 12months: 84.2% were undetectable. Our study highlights the need for access to drug resistance tests to avoid unnecessary switches to third-line therapy, but also for access to third-line drugs, in particular integrase inhibitors. Low nadir CD4 count might be an indicator of third-line drug requirement for patients failing second-line therapy.

Long term follow-up of multidrug resistant tuberculosis in a pubertal child

Increasing awareness of the rising global rates of multidrug-resistant tuberculosis (MDR-TB) has led to a concerted international effort to confront this disease. Nonetheless, despite cure rates &gt;80% in some programs, MDR-TB patients tend to have chronic disease and require prolonged therapy.1-3 Little is known about the long-term results and follow-up of patients with MDR-TB, include the recurrence rate and chronic disability in patients who have recovered from TB.4&#x0D; There are many side effects and adverse reactions to drugs can occur during MDR-TB treatment. These could be physical and or psychological, as well as reversible or irreversible. Treatment of MDR-TB requires a combination regimen, consists of second and third-line anti-tuberculosis drugs which more toxic than first-line drugs. Additionally, MDR-TB treatment requires a long duration of treatment (18-24 months) and causes discomfort in the patient.5 In a cohort of 60 patients treated for MDR-TB, the most common side effects included gastritis (100%), dermatological disorders (43%), and peripheral neuropathy (16.7).6 While in a cohort of 75 patients, the incidence of depression, anxiety, and psychosis for MDR-TB treatments was 13.3%, 12.0%, and 12.0%, respectively.7&#x0D; Aggressive and effective management are needed so the patient can tolerate the treatment and remain adhere the treatment.8 Long-term follow-up is required for the rehabilitation of disorders due to psychosocial sequelae. As such, psychosocial support can be benefit pediatric MDR-TB patients. &#x0D; Here, we present a case report on a two-year follow-up of a pubertal child with MDR-TB, focusing on medical aspects and her development.

SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management.

The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choosing a second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyperglycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.

Lamivudine monotherapy in children and adolescents: The devil is in the detail.

Although expanded access to antiretroviral therapy (ART), and starting lifelong ART as soon as possible after diagnosis of HIV, have dramatically improved survival and reduced morbidity in HIV-infected children and adolescents, ~20% of children will develop virological failure (VF). Children and adolescents may be at higher risk of VF and drug resistance for a number of reasons, including prevention of mother-to-child exposure, reliance on a caregiver to administer ART, poor palatability of paediatric drugs, tuberculosis/HIV co-treatment in protease inhibitor (PI) (mainly lopinavir/ritonavir)-based regimens, and adolescence being associated with poor adherence. In children with VF, if adherence issues are addressed and re-suppression is not achieved, a switch to second- or third-line drugs may be indicated, which is the gold standard in management. However, in the face of ongoing adherence challenges, with potential accumulation of resistance mutations, limited treatment options due to extensive resistance and limited approved paediatric formulations, other strategies have been used. These include continuing a failing PI regimen, switching to a holding regimen (one or more nucleoside reverse transcriptase inhibitors) or discontinuing ART. Lamivudine monotherapy is a common choice when holding regimens are used, on the premise that the lamivudine-associated M184V resistance mutation reduces viral replication and may maintain clinical and immunological stability compared with discontinuing treatment altogether. However, this strategy is generally associated with immunological, and in some cases clinical, decline after starting lamivudine monotherapy. We discuss the pros and cons of using this therapy in children. We also propose guidance for using lamivudine monotherapy, suggesting clinical and immunological criteria for its use. Close monitoring and adherence support are required with this approach. Given many new emerging ART drugs and strategies, lamivudine monotherapy should be administered temporarily, while efforts to improve adherence are implemented. It should not be considered a default option in children with VF.