-
Clinical Gastroenterology and... Jul 2023Hepatitis C virus (HCV) eradication with direct-acting antivirals reduces hepatocellular carcinoma (HCC) risk. Pooled HCC incidence rates by cirrhosis status and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Hepatitis C virus (HCV) eradication with direct-acting antivirals reduces hepatocellular carcinoma (HCC) risk. Pooled HCC incidence rates by cirrhosis status and fibrosis stage have not been estimated using meta-analysis.
METHODS
We searched PubMed, Web of Science, Embase, and Cochrane Library from January 1, 2014 to December 31, 2020 to identify studies assessing HCC incidence or outcomes by cirrhosis status, in adults with HCV who achieved sustained virologic response (SVR) after direct-acting antivirals. Pooled estimates were obtained using random-effects modeling. Subgroup, sensitivity, and meta-regression analyses were performed to evaluate heterogeneity.
RESULTS
We included 31 studies involving 27,711 patients with cirrhosis (mean follow-up, 2.1 years) and 11 studies involving 32,123 patients without cirrhosis (mean follow-up, 2.6 years). HCC incidence was 2.99/100 person-years (95% confidence interval [CI], 2.52-3.54; I = 75%) in patients with cirrhosis, 0.47/100 person-years (95% CI, 0.32-0.70, I = 71%) in patients without cirrhosis, and 0.63/100 person-years (95% CI: 0.34-1.20, I = 0%) in stage 3 (F3) fibrosis. Among patients with cirrhosis, HCC incidence was highest in studies with <1 year of follow-up (6.17/100 person-years [95% CI, 3.73-10.19]) and progressively lower in studies with longer follow-up (1-2 years: 2.75/100 person-years [95% CI, 2.48-3.06]; 2-3 years: 2.90/100 person-years [95% CI, 1.90-4.44]; ≥3 years: 1.83/100 person-years [95% CI, 0.88-3.80]).
CONCLUSION
Pooled HCC incidence after SVR in patients with cirrhosis was very high (2.99/100 person-years) but may be declining as longer time accrues after SVR. In patients without cirrhosis, including F3 fibrosis, HCC incidence was lower than thresholds associated with cost-effective HCC screening. In patients with F3 fibrosis, the lack of between-study heterogeneity provides strong evidence that HCC screening may not be warranted.
Topics: Adult; Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Antiviral Agents; Incidence; Hepacivirus; Hepatitis C, Chronic; Hepatitis C; Liver Cirrhosis; Sustained Virologic Response
PubMed: 35525392
DOI: 10.1016/j.cgh.2022.04.013 -
BMC Gastroenterology Apr 2017The long-term clinical outcomes of antiviral therapy for patients with chronic hepatitis C are uncertain in terms of hepatitis C virus (HCV)-related morbidity and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The long-term clinical outcomes of antiviral therapy for patients with chronic hepatitis C are uncertain in terms of hepatitis C virus (HCV)-related morbidity and mortality according to the response to antiviral therapy. This study aimed to assess the impact of antiviral treatment on the development of HCC and mortality in patients with chronic HCV infection.
METHODS
A systematic review was conducted for studies that evaluated the antiviral efficacy for patients with chronic hepatitis C or assessed the development of HCC or mortality between SVR (sustained virologic response) and non-SVR patients. The methodological quality of the enrolled publications was evaluated using Risk of Bias table or Newcastle-Ottawa scale. Random-effect model meta-analyses and meta-regression were performed. Publication bias was assessed.
RESULTS
In total, 59 studies (4 RCTs, 15 prospective and 40 retrospective cohort studies) were included. Antiviral treatment was associated with reduced development of HCC (vs. no treatment; OR 0.392, 95% CI 0.275-0.557), and this effect was intensified when SVR was achieved (vs. no SVR, OR: 0.203, 95% CI 0.164-0.251). Antiviral treatment was associated with lower all-cause mortality (vs. no treatment; OR 0.380, 95% CI 0.295-0.489) and liver-specific mortality (OR 0.363, 95% CI 0.260-0.508). This rate was also intensified when SVR was achieved [all-cause mortality (vs. no SVR, OR 0.255, 95% CI 0.199-0.326), liver-specific mortality (OR 0.126, 95% CI 0.094-0.169)]. Sensitivity analyses revealed robust results, and a small study effect was minimal.
CONCLUSIONS
In patients with chronic hepatitis C, antiviral therapy can reduce the development of HCC and mortality, especially when SVR is achieved.
Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis C, Chronic; Humans; Liver Neoplasms; Mortality; Sustained Virologic Response; Treatment Outcome
PubMed: 28376711
DOI: 10.1186/s12876-017-0606-9 -
Survey of Ophthalmology 2022Cytomegalovirus (CMV) anterior uveitis is the most common form of ocular manifestation of CMV in immunocompetent individuals. The difficulty in diagnosing CMV anterior... (Meta-Analysis)
Meta-Analysis Review
Cytomegalovirus (CMV) anterior uveitis is the most common form of ocular manifestation of CMV in immunocompetent individuals. The difficulty in diagnosing CMV anterior uveitis may delay adequate treatment and affect outcomes. We sought to review systemically the overall clinical characteristics and compare treatment outcomes in CMV anterior uveitis and endotheliitis. A literature search was performed, and studies describing clinical characteristics, treatment regimens, and outcomes that included more than 5 treated eyes were included. In these 23 studies, acute CMV anterior uveitis commonly presented with high intraocular pressure (95.31%, 95% CI 90.45-98.60) and mild anterior chamber inflammation (cells >2+ = 3.18%, 95% CI 0.21-0.54). About two-thirds of CMV endotheliitis cases presented with high intraocular pressure and coin-shaped corneal lesions. Acute CMV anterior uveitis showed good clinical response to topical 0.15% ganciclovir (GCV) gel or oral valganciclovir (VGCV) (90%, 95% CI 74-100% and 95%, 95% CI 88-100%, respectively). For chronic CMV anterior uveitis, both topical GCV and oral VGCV yielded comparable results. Topical 0.5-2% GCV or a combination of topical and oral VGCV for CMV endotheliitis both resulted in good clinical response. Recurrence of inflammation was common after cessation of maintenance therapy. Overall, topical GCV resulted in an optimal outcome for CMV anterior uveitis. Escalated concentration and frequency of usage are needed for chronic CMV anterior uveitis and endotheliitis. Adequate induction and maintenance phases of anti-CMV treatment seem necessary to prevent recurrences.
Topics: Antiviral Agents; Aqueous Humor; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Eye Infections, Viral; Ganciclovir; Glaucoma; Humans; Inflammation; Treatment Outcome; Uveitis, Anterior; Valganciclovir
PubMed: 34954093
DOI: 10.1016/j.survophthal.2021.12.006 -
The Cochrane Database of Systematic... Oct 2014Hepatitis B vaccine has been recommended for use in people living with HIV (PLHIV) mostly because of the similarities in routes of infection and their prevalence in the... (Review)
Review
BACKGROUND
Hepatitis B vaccine has been recommended for use in people living with HIV (PLHIV) mostly because of the similarities in routes of infection and their prevalence in the same geographic areas. PLHIV may not develop sero-protection after receiving standard hepatitis B vaccine due to their compromised immune status.
OBJECTIVES
To evaluate the efficacy of hepatitis B virus vaccine in PLHIV compared to placebo or no vaccine.
SEARCH METHODS
We searched 6 English language databases in July 2012, and updated the search in June 2013 and August 2014. We searched the grey literature, conference proceedings, specialised web sites, and contacted experts in the field.
SELECTION CRITERIA
Randomised controlled trials of hepatitis B vaccine compared to placebo or no vaccine, evaluating relevant outcomes of efficacy and safety.
DATA COLLECTION AND ANALYSIS
Two review authors independently sought and extracted data on study design, participants, hepatitis B infection, hepatitis B related morbidity and mortality, anti-HBs immunogenicity and adverse effects related to vaccines from published articles or through correspondence with authors. Data were analysed qualitatively.
MAIN RESULTS
One double-blind randomised controlled trial with 26 participants who were on antiretroviral therapy (ART), comparing hepatitis B vaccine to placebo conducted in Spain met our eligibility criteria and was included in this review. The study ran for three years and participants were followed up on a monthly basis. The study reported adequate humoral response to vaccine at 12 months and no local or systematic side effects in both intervention and control groups. This humoral response was lost when the participants stopped taking ART. The sample size of the study was small and the study was conducted in a high income setting unlike the areas of highest burden of hepatitis B and HIV co-infections.
AUTHORS' CONCLUSIONS
The evidence from this study is insufficient to support any recommendations regarding the use of hepatitis B vaccine in PLHIV. Neither does this evidence demonstrate that hepatitis B vaccine is unsafe in PLHIV. Further randomised controlled trials in high prevalence areas are required to generate evidence on the long term efficacy and safety of hepatitis B vaccine in PLHIV with and without ART. Different regimens and routes of administration should also be explored.
Topics: Anti-HIV Agents; HIV Infections; Hepatitis B; Hepatitis B Vaccines; Humans; Randomized Controlled Trials as Topic; Vaccination
PubMed: 25300375
DOI: 10.1002/14651858.CD009886.pub2 -
Clinical NeuropharmacologyAcute traumatic brain injury is one of the most common causes of death and disability. Reduction in the level of consciousness is a significant complication that can...
OBJECTIVES
Acute traumatic brain injury is one of the most common causes of death and disability. Reduction in the level of consciousness is a significant complication that can impact morbidity. Glasgow Coma Scale (GCS) is the most widely used method of assessing the level of consciousness. Neurostimulants such as amantadine and modafinil are common pharmacologic agents that increase GCS in patients with brain trauma. This study aimed to compare the effectiveness of these 2 drugs.
METHODS
This systematic review obtained articles from Google Scholar, PubMed, Scopus, Embase, and MEDLINE databases. Extensive searches were conducted separately by 4 individuals in 3 stages. Ultimately, 16 clinical trials, cohort studies, case reports, and case series articles were obtained after reading the title, abstract, and full text and considering the exclusion criteria. The data of the final article were entered into the analysis table. This study was registered with PROSPERO (registration number CRD42022334409) and conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
RESULTS
Amantadine seems to be associated with a higher overall response rate. In contrast, modafinil is associated with the most remarkable change in GCS score during treatment. However, the number of clinical trials with high quality and sample size has not been satisfactory to compare the effectiveness of these 2 drugs and their potential side effects.
CONCLUSIONS
The authors recommend additional double-blind clinical trials are needed to be conducted with a larger sample size, comparing amantadine with modafinil to delineate the efficacy and adverse effects, both short and long term.
Topics: Humans; Modafinil; Consciousness; Brain Injuries, Traumatic; Amantadine; Brain Injuries; Randomized Controlled Trials as Topic
PubMed: 37962310
DOI: 10.1097/WNF.0000000000000577 -
Intervirology 2015We conducted a systematic review and meta-analysis of the influence of host and viral factors on the sustained virologic response (SVR) in hepatitis C virus genotype 6... (Meta-Analysis)
Meta-Analysis Review
Influence of Host and Viral Factors on Patients with Chronic Hepatitis C Virus Genotype 6 Treated with Pegylated Interferon and Ribavirin: A Systematic Review and Meta-Analysis.
OBJECTIVES
We conducted a systematic review and meta-analysis of the influence of host and viral factors on the sustained virologic response (SVR) in hepatitis C virus genotype 6 (HCV-6) patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV).
METHODS
Data were retrieved from Medline, Embase, PubMed and the Cochrane Library for 'genotype 6' studies published up to December 2014 and for abstracts from international scientific meetings. Inclusion criteria were efficacy of PEG-IFN+RBV based on SVR, 24- or 48-week therapy and treatment-naïve patients. Patients with hepatitis B, D and E and HIV coinfection or another concurrent liver disease were excluded. Pooled standard difference, odds ratio and confidence intervals (CIs) were calculated using a random-effect model with STATA 11.
RESULTS
Fourteen studies were included in the meta-analysis. The pooled SVR rate was 80% (95% CI: 0.78-0.83, p < 0.0001; I2 = 71.2%). SVR of the PEG-IFN+RBV-treated HCV-6 patients was markedly higher than that of HCV-1 patients (80.1 vs. 55.3%). The SVR rate was significantly higher for the 48- than the 24-week treatment, but not different among HCV-infected patients with rs12979860 and ss469415590 polymorphisms of the ILFN4 gene (80.6% CC vs. 66.7% non-CC, p = 0.593; 81.1% TT/TT vs. 60% non-TT/TT, p = 0.288). Gender and type of PEG-IFN did not affect SVR rates.
CONCLUSIONS
Treatment outcomes for HCV-6 patients are superior to those for HCV-1 patients and comparable to those of HCV-2 and HCV-3 patients, especially at 48 weeks. The level of fibrosis affects treatment outcome, but SVR rates are not significantly different between genders. IL28B and IFNL4 polymorphisms are not significantly associated with HCV-6 treatment outcome.
Topics: Antiviral Agents; Coinfection; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Immunologic Factors; Interferon-alpha; Polyethylene Glycols; Polymorphism, Genetic; Ribavirin; Treatment Outcome
PubMed: 27010195
DOI: 10.1159/000444366 -
Journal of Clinical Pharmacology Nov 2016During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully... (Review)
Review
During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean C and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.
Topics: Adult; Age Factors; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Discovery; Humans; Pharmaceutical Preparations; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 27040726
DOI: 10.1002/jcph.744 -
The Cochrane Database of Systematic... Aug 2015This is an updated version of a review first published in theCochrane Database of Systematic Reviews, Issue 4, in 2011. Vulval intraepithelial neoplasia (VIN) is a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of a review first published in theCochrane Database of Systematic Reviews, Issue 4, in 2011. Vulval intraepithelial neoplasia (VIN) is a pre-cancerous condition of the vulval skin and its incidence is increasing in women under 50 years. High-grade VIN (also called usual-type VIN (uVIN) or VIN 2/3 or high-grade vulval intraepithelial lesion) is associated with human papilloma virus (HPV) infection and may progress to vulval cancer, therefore is usually actively managed. There is no consensus on the optimal management of high-grade VIN; and the high morbidity and relapse rates associated with surgical interventions make less invasive interventions highly desirable.
OBJECTIVES
To evaluate the effectiveness and safety of medical (non-surgical) interventions for high-grade VIN.
SEARCH METHODS
We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 3), MEDLINE and EMBASE (up to 30 March 2015). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that assessed non-surgical interventions in women diagnosed with high-grade VIN.
DATA COLLECTION AND ANALYSIS
We used Cochrane methodology with two review authors independently abstracting data and assessing risk of bias. Where possible, we synthesised data in meta-analyses using random effects methods.
MAIN RESULTS
Five trials involving 297 women with high-grade VIN (defined by trial investigators as VIN 2/3 or VIN 3 or 'high-grade' lesions) met our inclusion criteria: three trials assessed the effectiveness of topical imiquimod versus placebo; one assessed topical cidofovir versus topical imiquimod; and one assessed low- versus high-dose indole-3-carbinol in similar types of participants. Three trials were at a moderate to low risk of bias, two were at a potentially high risk of bias.Meta-analysis of the three trials comparing topical imiquimod 5% cream to placebo found that women in the active treatment group were more likely to show an overall response (complete and partial response) to treatment at five to six months compared with the placebo group (Risk Ratio (RR) 11.95, 95% confidence interval (CI) 3.21 to 44.51; participants = 104; studies = 3; I(2) = 0%; high-quality evidence). A complete response at five to six months occurred in 36/62 (58%) and 0/42 (0%) participants in the active and placebo groups, respectively (RR 14.40, 95% CI 2.97 to 69.80; participants = 104; studies = 3; I(2) = 0%). A single trial reported 12-month follow-up, which revealed a sustained effect in overall response in favour of the active treatment arm at 12 months (RR 9.10, 95% CI 2.38 to 34.77; moderate-quality evidence), with 9/24 (38%) and 0/23 (0%) complete responses recorded in the active and placebo groups respectively. Progression to vulval cancer was also documented in this trial (one versus two participants in the active and placebo groups, respectively) and we assessed this evidence as low-quality. Only one trial reported adverse events, including erythema, erosion, pain and pruritis at the site of the lesion, which were more common in the imiquimod group. Dose reductions occurred more frequently in the active treatment group compared with the placebo group (19/47 versus 1/36 participants; RR 7.77, 95% CI 1.61 to 37.36; participants = 83; studies = 2; I(2) = 0%; high-quality evidence). Only one trial reported quality of life (QoL) and there were no significant differences between the imiquimod and placebo groups.For the imiquimod versus cidofovir trial, 180 women contributed data. The overall response at six months was similar for the imiquimod and cidofovir treatment groups with 52/91 (57%) versus 55/89 (62%) participants responding, respectively (RR 0.92, 95% CI 0.73 to 1.18). A complete response occurred in 41 women in each group (45% and 46%, respectively; RR 1.00, 95% CI 0.73 to 1.37). Although not statistically different, total adverse events were slightly more common in the imiquimod group of this trial with slightly more discontinuations occurring in this group. Longer term response data from this trial are expected.The small trial comparing two doses of indole-3-carbinol contributed limited data. We identified five ongoing randomised trials of various interventions for VIN.
AUTHORS' CONCLUSIONS
Topical imiquimod appears to be a safe and effective treatment for high-grade VIN (uVIN), even though local side-effects may necessitate dose reductions. However, longer term follow-up data are needed to corroborate the limited evidence that response to treatment is sustained, and to assess any effect on progression to vulval cancer. Available evidence suggests that topical cidofovir may be a good alternative to imiquimod; however, more evidence is needed, particularly regarding the relative effectiveness on longer term response and progression. We await the longer-term response data and the results of the five ongoing trials.
Topics: Administration, Topical; Adult; Aminoquinolines; Anticarcinogenic Agents; Antineoplastic Agents; Carcinoma in Situ; Cidofovir; Cytosine; Female; Humans; Imiquimod; Indoles; Organophosphonates; Randomized Controlled Trials as Topic; Vulvar Neoplasms
PubMed: 26284429
DOI: 10.1002/14651858.CD007924.pub3 -
AIDS and Behavior Mar 2017Although an increasing number of HIV infected people are accessing antiretroviral treatment, many do not achieve complete HIV viral suppression and remain at risk for... (Comparative Study)
Comparative Study Meta-Analysis Review
Although an increasing number of HIV infected people are accessing antiretroviral treatment, many do not achieve complete HIV viral suppression and remain at risk for AIDS and capable of HIV transmission. Food insecurity has been identified as a potential risk factor for poor virologic response, but the association between these factors has been inconsistently documented in the literature. We systematically searched five electronic databases and bibliographies of relevant studies through April 2015 and retrieved 11 studies that met our inclusion criteria, of which nine studies were conducted in North America and the remaining two studies were in Brazil and Uganda respectively. Meta-analyzed results indicated that experiencing food insecurity resulted in 29% lower odds of achieving complete HIV viral suppression (OR = 0.71, 95% CI 0.61-0.82) and this significant inverse association was consistently found regardless of study design, exposure measurement, and confounder adjustment methods. These findings suggest that food insecurity is a potential risk factor for incomplete HIV viral suppression in people living with HIV.
Topics: Anti-HIV Agents; Brazil; Cross-Cultural Comparison; Food Supply; HIV Infections; HIV-1; Humans; North America; Statistics as Topic; Uganda
PubMed: 27837425
DOI: 10.1007/s10461-016-1605-5 -
JAMA Aug 2014Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler... (Review)
Review
IMPORTANCE
Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler therapeutics using direct-acting antivirals that target various stages of the HCV life cycle are in development to eradicate HCV without concomitant interferon.
OBJECTIVES
To summarize published evidence on safety, efficacy (measured by a sustained virologic response [SVR], which is the treatment goal of undetectable plasma HCV RNA 12 or 24 weeks after therapy completion), and tolerability of current US Food and Drug Administration-approved interferon-based regimens and oral interferon-free regimens used for treating HCV infection and coinfection with human immunodeficiency virus (HIV) and HCV; to provide treatment recommendations for specialists and generalists based on published evidence.
EVIDENCE REVIEW
A literature search of Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister was conducted from January 1, 2009, to May 30, 2014. Publications describing phase 2, 3, and 4 studies evaluating the treatment of HCV were included. Forty-one studies involving 19,063 adult patients were included. Strength of clinical data and subsequent HCV treatment recommendations were graded according to the Oxford Centre for Evidence-Based Medicine.
FINDINGS
Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of SVR (89%-90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%-86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks' duration: 82%-93%; SVR for genotype 3, 24 weeks' duration, 80%-95%). Patients with HIV-HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients.
CONCLUSIONS AND RELEVANCE
New, short-duration, simpler therapies result in high SVR rates for HCV-infected patients. In conjunction with increased screening for HCV as suggested by recent Centers for Disease Control and Prevention guidelines, availability of new therapies may lead to the treatment of many more people with chronic HCV infection.
Topics: Antiviral Agents; Coinfection; Drug Therapy, Combination; Genotype; HIV Infections; Hepacivirus; Hepatitis C, Chronic; Humans; Life Cycle Stages; Liver Cirrhosis; Prevalence; United States
PubMed: 25117132
DOI: 10.1001/jama.2014.7085