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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 -
Multiple Sclerosis (Houndmills,... May 2023Multiple sclerosis patients experience 3-6 times more seizures than the general population, but observations vary among studies. Seizure risk in disease-modifying... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple sclerosis patients experience 3-6 times more seizures than the general population, but observations vary among studies. Seizure risk in disease-modifying therapy recipients remains unknown.
OBJECTIVE
The objective of this study was to compare seizure risk in multiple sclerosis patients receiving disease-modifying therapy versus placebo.
METHODS
MEDLINE(OVID), Embase, CINAHL, and ClinicalTrials.gov were searched from database inception until August 2021. Phase 2-3 randomized, placebo-controlled trials reporting efficacy and safety data for disease-modifying therapies were included. Network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using Bayesian random effects model for individual and pooled (by drug target) therapies. Main outcome was log seizure risk ratios [95% credible intervals]. Sensitivity analysis included meta-analysis of non-zero-event studies.
RESULTS
A total of 1993 citations and 331 full-texts were screened. Fifty-six included studies (29,388 patients-disease-modifying therapy = 18,909; placebo = 10,479) reported 60 seizures (therapy = 41; placebo = 19). No individual therapy was associated with altered seizure risk ratio. Exceptions were daclizumab (-17.90 [-65.31; -0.65]) and rituximab (-24.86 [-82.71; -1.37]) trending toward lower risk ratio; cladribine (25.78 [0.94; 4.65]) and pegylated interferon-beta-1a (25.40 [0.78; 85.47]) trended toward higher risk ratio. Observations had wide credible intervals. Sensitivity analysis of 16 non-zero-event studies revealed no difference in risk ratio for pooled therapies (l0.32 [-0.94; 0.29]).
CONCLUSION
No evidence of association was found between disease-modifying therapy and seizure risk-this informs seizure management in multiple sclerosis patients.
Topics: Humans; Multiple Sclerosis; Network Meta-Analysis; Bayes Theorem; Seizures; Cladribine; Anticonvulsants
PubMed: 36802988
DOI: 10.1177/13524585231151400 -
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 -
Oral Oncology Jan 2023Anti-PD1 antibody has emerged as a promising immunotherapeutic option in patients with recurrent and/or metastatic nasopharyngeal cancers (RM-NPC). We aim to summarise... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Anti-PD1 antibody has emerged as a promising immunotherapeutic option in patients with recurrent and/or metastatic nasopharyngeal cancers (RM-NPC). We aim to summarise existing evidence on the use of anti-PD1 antibodies in the treatment of these patients and compare its effectiveness with standard-of-care palliative chemotherapy. Our secondary aim is to explore potential combination therapies with anti-PD1 antibodies.
MATERIALS AND METHODS
PubMed, Embase and Cochrane databases were systematically searched for studies comparing the efficacy of various anti-PD1 antibodies in the treatment of RM-NPC (either as first or second line treatment) from inception to 2 September 2022. Meta-analyses were performed to correlate the various anti-PD1 antibodies with primary endpoints including overall response rate disease control rate (DCR), progression free survival (PFS) and overall survival (OS).
RESULTS
Eighteen studies with 1,887 patients met the inclusion criteria. The use of anti-PD1 antibody monotherapy as second-line treatment of RM-NPC revealed an ORR of 23 % (95 % CI = 19 %-28 %) and DCR of 51 % (95 % CI = 42 %-60 %). The ORRs for first-line as well as a combination of first and second-line treatments were 21 % (95 % CI = 15 % - 30 %) and 22 % (95 % CI = 6 % - 56 %, I = 75 %) respectively. The 12-month PFS and 12-month OS was also 27 % (95 % CI = 21 %-33 %) and 63 % (95 % CI = 53 %-72 %) respectively. ORR was much higher at 73 % (95 % CI = 32 %-94 %) when anti-PD1 antibodies were combined with Gemcitabine plus Cisplatin.
CONCLUSION
Anti-PD1 antibody demonstrate considerable activity in previously treated RM-NPC patients. Combining anti-PD1 antibodies with gemcitabine and cisplatin chemotherapy enhanced the efficacy of treatment.
Topics: Humans; Nasopharyngeal Neoplasms; Cisplatin; Neoplasm Recurrence, Local; Nasopharyngeal Carcinoma; Progression-Free Survival; Deoxycytidine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36413976
DOI: 10.1016/j.oraloncology.2022.106242 -
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 -
International Journal of Biometeorology Nov 2022Thermal stress has a direct effect on various types of DNA damage, which depends on the stage of the cell cycle when the cell is exposed to different climate conditions.... (Review)
Review
Thermal stress has a direct effect on various types of DNA damage, which depends on the stage of the cell cycle when the cell is exposed to different climate conditions. A literature review was conducted to systematically investigate and assess the overall effect of heat stress and DNA damage following heat exposure. In this study, electronic databases including PubMed, Scopus, and Web of Science were searched to find relevant literature on DNA damage in different ambient temperatures. Outcomes included (1) measurement of DNA damage in heat exposure, (2) three different quantification methods (comet assay, 8-hydroxy-2-deoxyguanosine (8-OHdG), and γ-H2AX), and (3) protocols used for moderate (31) and high temperatures (42). The evidence shows that long exposure and very high temperature can induce an increase in DNA damage through aggregate in natural proteins, ROS generation, cell death, and reproductive damage in hot-humid and hot-dry climate conditions. A substantial increase in DNA damage occurs following acute heat stress exposure, especially in tropical and subtropical climate conditions. The results of this systematic literature review showed a positive association between thermal stress exposure and inhibition of repair of DNA damage.
Topics: Humans; DNA Damage; 8-Hydroxy-2'-Deoxyguanosine; Heat Stress Disorders; Heat-Shock Response; Hot Temperature
PubMed: 36178536
DOI: 10.1007/s00484-022-02351-w -
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