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Journal of the International AIDS... Feb 2023Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a... (Review)
Review
INTRODUCTION
Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV.
METHODS
We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009-March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0-19 years.
RESULTS AND DISCUSSION
Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height- and age-adjusted) from baseline to 48 weeks was -0.12 (interquartile range [IQR] -0.46, 0.17) to 0.05 (IQR not reported) for spine, and -0.09 (IQR -0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks.
CONCLUSIONS
Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24-48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes.
Topics: Infant; Humans; Child; Adolescent; Tenofovir; HIV Infections; Anti-HIV Agents; HIV-1; Adenine; Emtricitabine
PubMed: 36823283
DOI: 10.1002/jia2.26037 -
PloS One 2023It is critical to select subsequent treatments for patients after the failure of trastuzumab therapy. Following the failure of standard trastuzumab therapy guidelines in... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
It is critical to select subsequent treatments for patients after the failure of trastuzumab therapy. Following the failure of standard trastuzumab therapy guidelines in the Chinese Society of Clinical Oncology, pyrotinib and capecitabine is a grade I recommended regimen for treating patients with HER2-positive metastatic breast cancer. Concurrently, in treating patients with HER2-positive metastatic breast cancer, lapatinib and capecitabine are also recommended regimens for those who have previously received taxanes, anthracyclines, and trastuzumab therapy. However, there is currently no systematic review and meta-analysis comparing pyrotinib with lapatinib among HER2+ MBC patients. Therefore, this study aims to perform a systematic review and meta-analysis and assess whether pyrotinib is superior to lapatinib in efficacy and safety.
METHODS
Relevant trials were searched in CNKI, Wanfang, VIP, PubMed, Embase, and Cochrane CENTRAL databases from inception until March 27th, 2022. The primary outcomes were PFS and OS, and the secondary outcomes were ORR and grade ≥3 AEs.
RESULTS
Five relevant studies were included in this study, including 2 RCTs and 3 retrospective cohort studies. Pyrotinib combined with chemotherapy is superior to lapatinib combined with chemotherapy among HER2+ metastatic breast cancer patients, with a significant improvement in PFS (prior trastuzumab therapy) (HR: 0.47, 95% CI: 0.39-0.57, p<0.001, I2 = 0%, FEM), PFS (trastuzumab resistance) (HR: 0.52, 95% CI: 0.39-0.68, p<0.001, I2 = 40%, FEM) and ORR (RR: 1.45, 95% CI: 1.26-1.67, p<0.001, I2 = 8%, FEM), but has higher grade ≥3 diarrhea incidence (RR: 2.68, 95% CI: 1.85-3.90, p<0.001, I2 = 44%, FEM).
CONCLUSIONS
The efficacy of pyrotinib combined with chemotherapy is superior to lapatinib combined with chemotherapy but has more safety risks.
Topics: Humans; Female; Breast Neoplasms; Lapatinib; Capecitabine; Retrospective Studies; Receptor, ErbB-2; Trastuzumab; Treatment Failure; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36602979
DOI: 10.1371/journal.pone.0279775 -
Multiple Sclerosis and Related Disorders Jan 2023Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and... (Review)
Review
BACKGROUND
Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT.
METHODS
Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question.
RESULTS
A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided.
CONCLUSIONS
RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated.
Topics: Humans; Cladribine; Multiple Sclerosis; Expert Testimony; Lymphocytes; Tablets; Recurrence; Immunosuppressive Agents
PubMed: 36565573
DOI: 10.1016/j.msard.2022.104459 -
International Journal of Infectious... Feb 2023Human monkeypox virus (MPXV) infection is a recently declared public health emergency of international concern by the World Health Organization. Besides, there is scant...
OBJECTIVES
Human monkeypox virus (MPXV) infection is a recently declared public health emergency of international concern by the World Health Organization. Besides, there is scant literature available on the use of antivirals in MPXV infection. This systematic review compiles all evidence of various antivirals used on their efficacy and safety and summarizes their mechanisms of action.
METHODS
A review was done of all original studies mentioning individual patient data on the use of antivirals in patients with MPXV infection.
RESULTS
Of the total 487 non-duplicate studies, 18 studies with 71 individuals were included. Tecovirimat was used in 61 individuals, followed by cidofovir in seven and brincidofovir (BCV) in three individuals. Topical trifluridine was used in four ophthalmic cases in addition to tecovirimat. Of the total, 59 (83.1%) were reported to have complete resolution of symptoms; one was experiencing waxing and waning of symptoms, only one (1.8%) had died, and the others were having a resolution of symptoms. The death was thought unrelated to tecovirimat. Elevated hepatic panels were reported among all individuals treated with BCV (leading to treatment discontinuation) and five treated with tecovirimat.
CONCLUSION
Tecovirimat is the most used and has proven beneficial in several aggravating cases. No major safety concerns were detected upon its use. Topical trifluridine was used as an adjuvant treatment option along with tecovirimat. BCV and cidofovir were seldom used, with the latter often being used due to the unavailability of tecovirimat. BCV was associated with treatment discontinuation due to adverse events.
Topics: Humans; Antiviral Agents; Benzamides; Cidofovir; Disease Outbreaks; Isoindoles; Mpox (monkeypox); Monkeypox virus; Trifluridine
PubMed: 36470502
DOI: 10.1016/j.ijid.2022.11.040 -
Neurologia I Neurochirurgia Polska 2022This study was performed to compare probabilities of SDI on the Expanded Disability Status Scale (EDSS) in patients with relapsing-remitting multiple sclerosis (RRMS),... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
This study was performed to compare probabilities of SDI on the Expanded Disability Status Scale (EDSS) in patients with relapsing-remitting multiple sclerosis (RRMS), treated with cladribine tablets (CT) or fingolimod (FTY), natalizumab (NAT), alemtuzumab (ALE) and ocrelizumab (OCR).
CLINICAL RATIONALE FOR THE STUDY
Progression of neurological disability as measured by the EDSS has been a common endpoint in multiple sclerosis (MS) trials. Novel therapies can not only slow this process, but in some patients even reverse it. This effect can be measured by the sustained disability improvement (SDI) - an endpoint that seems to continuously gain importance in clinical practice. Despite that, SDI has rarely been explored as an outcome in MS clinical studies, mostly as post-hoc analyses from randomised trials or as retrospective analyses based on patient registry records.
MATERIAL AND METHODS
A systematic review was conducted in Medline, Embase and Cochrane to identify clinical trials (RCT or non-RCT) evaluating 6-month SDI. An indirect comparison via network meta-analysis (NMA) was performed. Bayesian inference with Markov chains Monte Carlo methods were applied.
RESULTS
Eight trials presenting SDI results and applicable for NMA were included: six non-RCTs, with control groups selected by propensity score matching, and two RCTs. NMA results revealed that probability of achieving 6-month SDI with CT was significantly higher compared to all other high efficacy disease-modifying drugs with available data - HR (95% Crl - Bayesian Credibility Interval) vs. FTY: 4.98 (2.11-11.79); vs. NAT: 3.12 (1.31-7.27); vs. ALE: 9.29 (3.40-25.21). The main results were confirmed in the sensitivity analyses.
CONCLUSIONS
Of all considered therapies, treatment with cladribine tablets was associated with a higher probability of sustained disability improvement in RRMS patients. As this conclusion is based on available clinical data of limited quality, future studies, as well as real-world data, would be valuable to provide further evidence regarding the comparative effectiveness of RRMS therapies.
Topics: Humans; Cladribine; Multiple Sclerosis; Immunosuppressive Agents; Network Meta-Analysis; Retrospective Studies; Bayes Theorem; Multiple Sclerosis, Relapsing-Remitting; Tablets
PubMed: 36421066
DOI: 10.5603/PJNNS.a2022.0068 -
Expert Review of Anti-infective Therapy Jan 2023Current recommended antiretroviral regimens include a combination of two (dual; DT) or three (triple; TT) antiretroviral drugs. This study aims to determine whether the...
Comparison of the design and methodology of Phase 3 clinical trials of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir-based dual therapy (DTG) in HIV: a systematic review of the literature.
INTRODUCTION
Current recommended antiretroviral regimens include a combination of two (dual; DT) or three (triple; TT) antiretroviral drugs. This study aims to determine whether the quality of evidence from clinical trials of dolutegravir (dolutegravir/lamivudine [DTG/3TC] or dolutegravir/rilpivirine [DTG/RPV]) is methodologically comparable to that of clinical trials conducted with bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).
AREAS COVERED
A systematic review of the medical literature was carried out in PubMed without date or language restrictions, following the PRISMA guidelines. All aspects of the methodological design of phase 3 randomized clinical trials (RCTs) of DT and TT, evaluated by the European Medicines Agency (registration trials), were reviewed. The quality of clinical trials was assessed using the Jadad scale.
EXPERT OPINION
The search identified 5, 3 and 2 phase 3 RCTs with BIC/FTC/TAF, DTG/3TC and DTG/RPV, respectively, that met the inclusion criteria. The designs would not be comparable due to differences in pre-randomization losses, blinding, patient recruitment, as well as differences in methodological quality, with the average score of the RCTs conducted with BIC/FTC/TAF, DTG/3TC and DTG/RPV being 4.2 (high quality), 3.0 (medium quality) and 3.0 (medium quality), respectively. Due to methodological differences between the BIC/FTC/TAF, DTG/3TC and DTG/RPV RCTs, the results of these are not comparable.
Topics: Humans; HIV Infections; Anti-HIV Agents; Emtricitabine; Adenine; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings
PubMed: 36399521
DOI: 10.1080/14787210.2023.2149490 -
Multiple Sclerosis and Related Disorders Dec 2022The Coronavirus 19 pandemic has raised new relevant questions regarding the management of patients with multiple sclerosis (pwMS) treated with different... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The Coronavirus 19 pandemic has raised new relevant questions regarding the management of patients with multiple sclerosis (pwMS) treated with different immunosuppressive and immunomodulant drugs. In most COVID-19 outcomes analyses, due to the small available sample size, patients treated with cladribine were grouped with patients treated with other treatments.
METHODS
Three major databases (PubMed, Scopus and Web of Science) and the most recent MS congress libraries were searched for extracting original articles on COVID-19 and multiple sclerosis. The key inclusion criteria were the presence of data on pwMS treated with cladribine and with documented positivity for COVID-19. The quality of the included studies was evaluated using a modified version of the Dutch Cochrane center critical review checklist proposed by MOOSE. A common-effect meta-analysis was used for estimating the pooled proportion of patients with severe events (hospitalizations, pneumonia, ICU admissions and deaths) and heterogeneity was assessed by the I statistic.
RESULTS
13 articles were included in the analysis and the median quality of the articles reached a level of 4. The selected studies included 5138 patients with COVID-19, of whom 107 (2.1%) were treated with cladribine. Pooled estimates of hospitalization and death were 9.36% and 0% for patients treated with cladribine, 14.98% and 2.66% for pwMS under other treatments.
CONCLUSION
These results indicate that pwMS treated with cladribine are not at a greater risk of developing a severe form of COVID-19.
REGISTRATION
The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022329464).
Topics: Humans; Cladribine; Multiple Sclerosis; COVID-19; Pandemics; Immunosuppressive Agents
PubMed: 36137347
DOI: 10.1016/j.msard.2022.104156 -
European Review For Medical and... Sep 2022Multi-agent regimens such as Folfirinox and gemcitabine plus nab-paclitaxel have shown significant improvements compared with single-agent gemcitabine as neoadjuvant... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of neoadjuvant Folfirinox and Gemcitabine plus Nab-Paclitaxel for borderline resectable and locally advanced pancreatic cancer: a systematic review and meta-analysis.
OBJECTIVE
Multi-agent regimens such as Folfirinox and gemcitabine plus nab-paclitaxel have shown significant improvements compared with single-agent gemcitabine as neoadjuvant chemotherapy for patients with borderline resectable or locally advanced pancreatic cancer. However, the efficacy and safety of Folfirinox and GNP as NAC for BRPC and LAPC is still controversial.
MATERIALS AND METHODS
The eligible studies including prospective, retrospective, and randomized controlled trial related to Folfirinox and GNP as NAC for patients with BRPC or LAPC up to March 2022 were searched and assessed. Pooled analysis for chemotherapy response rate, resection rate, R0 resection rate, progress free survival, overall survival, and grade 3/4 events of toxicity were performed in the study.
RESULTS
Eight studies were included in this meta-analysis. Compared with GNP, Folfirinox had higher resection rate (HR=0.82; 95% CI 0.59-1.14) and R0 resection rate (HR=0.77; 95% CI 0.60-0.97), better PFS (HR=0.78; 95% CI 0.55-1.12) and OS (HR=0.68; 95% CI 0.46-0.99), and without increasing severe toxicity rate (HR=0.95; 95% CI 0.71-1.28). There are no differences in rate of stable disease (HR=1.06; 95% CI 0.92-1.22) and partial/complete regression (HR=0.85; 95% CI 0.59-1.23) between two groups.
CONCLUSIONS
Higher resection and R0 resection rate and better PFS and OS results were obtained in Folfirinox group compared with GNP group for patients with BRPC and LAPC. There was no increased severe toxicity rate for Folfirinox compared with GNP.
Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies; Gemcitabine
PubMed: 36111933
DOI: 10.26355/eurrev_202209_29656 -
The Lancet. Child & Adolescent Health Oct 2022Abacavir is a nucleoside reverse transcriptase inhibitor recommended in paediatric HIV care. We assessed the safety and efficacy profile of abacavir used in first,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Abacavir is a nucleoside reverse transcriptase inhibitor recommended in paediatric HIV care. We assessed the safety and efficacy profile of abacavir used in first, second, or subsequent lines of treatment for infants, children, and adolescents living with HIV to inform 2021 WHO paediatric ART recommendations.
METHODS
In this systematic review and meta-analysis, we included observational and experimental studies conducted in infants aged 0-1 year, children aged 1-10 years, and adolescents aged 10-19 years living with HIV; with data on safety or efficacy, or both, of abacavir-based antiretroviral therapy (ART); published in English or French between Jan 1, 2009, and Oct 1, 2020, plus an updated search to incorporate studies published between Oct 1, 2020, and May 15, 2022. Studies could be non-randomised or non-comparative and include patients who are treatment-naive or those who previously received abacavir (only if abacavir was combined with other ART). Case studies, studies in adults aged 18 years or older, and those assessing the effect of maternal ART exposure were excluded. We extracted data related to study identifier, study design, study period, setting, population characteristics, ART treatment, and safety (any hypersensitivity reaction, death, grade 3 or 4 adverse events, treatment discontinuation, any other morbidities, and serious adverse events), and efficacy outcomes (HIV viral load and CD4 counts reported at 6 and 12 months after ART initiation). Using random-effect models, we estimated weighted pooled incidence and relative risk (RR) of outcomes. The protocol is published in PROSPERO (CRD42022309230).
FINDINGS
Of 1777 records identified, 1475 (83%) were screened after removing duplicates and a further 1421 (96%) were excluded. Of 54 full-text articles assessed for eligibility, 33 (61%) were excluded. Four records were identified from grey literature plus one duplicate from database searching, resulting in 24 studies included (two randomised controlled trials, one single-arm trial, 12 prospective cohorts, seven retrospective cohorts, and two cross-sectional studies). 19 studies described safety data and 15 described efficacy data. 18 (75%) studies were conducted in ART-naive participants. The risk of bias was considered moderate to high for most studies, and all outcomes had significant between-study heterogeneity. Data from 24 265 participants were included, of whom 7236 (30%) received abacavir. Abacavir hypersensitivity reaction was reported in nine (38%) studies, with an incidence ranging from 0·00% to 8·26% (I=85%; p<0·0001). The incidence of death (reported in seven studies) following abacavir treatment varied from 0·00% to 5·49% (I=58%; p=0·026). Viral suppression (<400 copies per mL) varied from 50% to 70% at 6 months (I=92%, p<0·0001) and from 57% to 78% at 12 months (I=88%, p<0·0001).
INTERPRETATION
Toxic effects due to abacavir use remain rare and manageable. Despite scarce data on efficacy, this meta-analysis supports the use of abacavir as a preferred first-line regimen for infants and children living with HIV.
FUNDING
WHO.
Topics: Adolescent; Adult; Anti-HIV Agents; Child; Cross-Sectional Studies; Cyclopropanes; Dideoxyadenosine; HIV Infections; Humans; Infant; Nucleosides; Observational Studies as Topic; Prospective Studies; Retrospective Studies; Reverse Transcriptase Inhibitors
PubMed: 36058225
DOI: 10.1016/S2352-4642(22)00213-9 -
Frontiers in Endocrinology 2022Previous studies determined the therapeutic effects of capecitabine-based chemotherapy regimens on early-stage triple-negative breast cancer (TNBC). However, the optimal... (Meta-Analysis)
Meta-Analysis
Addition of Capecitabine to Adjuvant Chemotherapy May be the Most Effective Strategy for Patients With Early-Stage Triple-Negative Breast Cancer: A Network Meta-Analysis of 9 Randomized Controlled Trials.
BACKGROUND AND OBJECTIVE
Previous studies determined the therapeutic effects of capecitabine-based chemotherapy regimens on early-stage triple-negative breast cancer (TNBC). However, the optimal strategy of capecitabine-based chemotherapy remains uncertain. We conducted this network meta-analysis to address this issue.
METHODS
We systematically searched PubMed, Embase, and the Cochrane Registry of Controlled Trials (CENTRAL) to retrieve eligible studies published before September 2021. Two independent reviewers extracted information from eligible studies using a pre-designed data extraction sheet. The primary outcome included disease-free survival, and the second outcome showed overall survival and adverse events. Direct meta-analysis was performed using RevMan 5.4, and Bayesian network analysis was performed using R version 3.6.1 with the "gemtc" and "rjags" packages.
RESULTS
Nine studies involving 3661 TNBC patients met the selection criteria. The network meta-analysis suggested that the addition of capecitabine to adjuvant chemotherapy achieved a significantly longer disease-free (HR = 0.66, 95% CrI = 0.49 to 0.86) and overall survival time (HR = 0.60, 95% CrI = 0.43 to 0.83) than standard chemotherapy. All comparisons did not achieve statistical significance. The addition of capecitabine to adjuvant chemotherapy was the most effective treatment for improving disease-free (81.24%) and overall survival (78.46%) times, and the replacement of capecitabine to adjuvant chemotherapy was the safest regime.
CONCLUSIONS
Based on available evidence, capecitabine-based chemotherapy benefits TNBC patients, and the addition of capecitabine with adjuvant chemotherapy was the most effective regime. In contrast, the replacement of capecitabine to adjuvant chemotherapy was the safest regime. More studies of high quality and large scale are needed to confirm our findings.
Topics: Bayes Theorem; Capecitabine; Chemotherapy, Adjuvant; Humans; Network Meta-Analysis; Randomized Controlled Trials as Topic; Triple Negative Breast Neoplasms
PubMed: 35957836
DOI: 10.3389/fendo.2022.939048