Objective
To evaluate the efficacy of lenvatinib in the treatment of radioiodine‐refractory thyroid carcinoma.
Background
Thyroid carcinoma is one of the top ten carcinomas worldwide. Clinically, ...thyroid cancers are managed with resections and adjuvant therapy with radioiodine. However, radioiodine is not effective for radioiodine‐refractory (RR) thyroid carcinoma in some patients.
Lenvatinib is a multi‐kinase inhibitor for the treatment of RR thyroid carcinoma. Several clinical trials showed its efficacy in prolonging progression‐free survival (PFS) and overall survival (OS).
Design, patients and measurements
A systematic search was done on databases (PubMed, Embase, MEDLINE, Cochrane) on 8 June 2020. Search keywords were lenvatinib, thyroid carcinoma and randomized controlled trials. Clinical trials fulfilling the SELECT protocol were selected to evaluate the efficacy of lenvatinib in terms of prolongation of PFS, OS and objective response rate (ORR). The risk ratio and distribution of grade 3 or above adverse events were documented.
Results
Of the 3997 patients of mean age 62.5 years in fifteen selected studies, lenvatinib is associated with prolonged PFS (hazard ratio 0.24, 95% CI, 0.19‐0.31, p < .001) and OS (hazard ratio 0.65, 95% CI, 0.52‐0.81, p < .001). Compared with placebo, the risk ratio of ORR and incidence of grade 3 or above adverse events are 35.41 (95% CI, 19.42‐64.58, p < .001) and 8.25 (95% CI, 6.50‐10.46, p < .001), respectively. Subgroup analysis shows that lenvatinib is effective for all patients with RR thyroid carcinoma, regardless of age, histological subtypes, radiological subtypes and mutation status.
Conclusion
Lenvatinib is effective in the treatment of RR thyroid carcinoma. Close monitoring of serious adverse events is recommended.
Chronic hepatitis B (CHB) infection is the major cause of hepatocellular carcinoma (HCC). Primary prevention of hepatitis B infection by vaccination is effective in reducing the incidence of HCC. In ...persons with CHB infection, the two accepted treatment modalities are interferon alpha (IFN‐α) given subcutaneously for a limited period and nucleoside/nucleotide analogs given orally on a long‐term basis. These treatments are effective in suppressing viral activity and improving disease markers in short‐term studies. The long‐term effect on the development of liver cancers with these two forms of treatment appears to be different. However, there are no studies directly comparing IFN‐α and nucleoside/nucleotide analogs. Comparisons across studies are inevitably limited by differences in the baseline characteristics of the study cohorts. Long‐term follow‐up studies of IFN‐α therapy show inconsistent results. The beneficial effect in reducing the development of liver cancer is observed mainly in treatment responders who have preexisting cirrhosis of the liver. The long‐term studies of lamivudine (and adefovir) show a consistent reduction in the development of liver cancers in patients with, and without, cirrhosis. This beneficial effect is blunted by the development of resistance. The effects of the newer nucleoside/nucleotide analogs, with higher potency and minimal risk of resistance development, are, as yet, unknown. (HEPATOLOGY 2013)
The majority of people infected with SARS-CoV-2 fully recovered within a few weeks. However, a considerable number of patients of different ages still suffer from long-lasting problems similar to the ...multi-organ damage in its acute phase of infection, or experience symptoms continuously for a longer term after the recovery. The severity of the primary infection seems not to be associated with the possibility and severity of long-term symptoms. Various unresolved symptoms have been reported in COVID-19 survivors months after hospital discharge. Long COVID-19 Syndrome refers to survivors 4 months after initial symptoms onset. It is important to understand the systemic effects of Long COVID-19 Syndrome, its presentations, and the need for rehabilitations to restore functional recovery in survivors. Government, healthcare workers, and survivor groups should collaborate to establish a self-sustaining system to facilitate follow-up and rehabilitations, with prioritization of resources to more severely Long COVID-19 Syndrome survivors. This review looks into the systemic effects of Long COVID-19 Syndrome in various aspects: respiratory, cardiovascular, hematological, renal, gastrointestinal, neurological, and metabolic effects of Long COVID-19 Syndromes. Recommendations for follow-up and rehabilitations details have been explored to cope with the tremendous Long COVID-19 Syndrome patients.
Various strategies have been designed to contain the COVID-19 pandemic. Among them, vaccine development is high on the agenda in spite of the unknown duration of the protection time. Various vaccines ...have been under clinical trials with promising results in different countries. The protective efficacy and the short-term and long-term side effects of the vaccines are of major concern. Therefore, comparing the protective efficacy and risks of vaccination is essential for the global control of COVID-19 through herd immunity. This study reviews the most recent data of 12 vaccines to evaluate their efficacy, safety profile and usage in various populations.
Background and Aims
ARC‐520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral ...antigens and hepatitis B virus (HBV) DNA.
Approach and Results
We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC‐520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse‐transcriptase inhibitor (NUC)–experienced patients with hepatitis B early antigen (HBeAg)–negative (E‐neg) or HBeAg‐positive (E‐pos) disease. A total of 58 E‐neg and 32 E‐pos patients were enrolled and received four monthly doses of PBO (n = 20 E‐neg, 11 E‐pos), 1 mg/kg ARC‐520 (n = 17 E‐neg, 10 E‐pos), or 2 mg/kg ARC‐520 (n = 21 E‐neg, 11 E‐pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC‐520 dose were compared to PBO. Both E‐neg and E‐pos high‐dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E‐neg and E‐pos patients, respectively. The low‐dose groups did not reach statistical significance in either study. E‐pos patients showed a dose‐dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low‐dose and high dose ARC‐520 groups respectively. ARC‐520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed.
Conclusions
ARC‐520 was active in both E‐neg and E‐pos, NUC‐experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin.
Hepatocellular carcinoma (HCC) is the predominant primary liver cancer in many countries and is the third most common cause of cancer-related death in the Asia-Pacific region. The incidence of HCC is ...higher in men and in those over 40 years old. In the Asia-Pacific region, chronic hepatitis B virus and hepatitis C virus infections are the main etiological agents; in particular, chronic hepatitis B infection (CHB) is still the major cause in all Asia-Pacific countries except for Japan. Over the past two decades, the incidence of HCC has remained stable in countries in the region except for Singapore and Hong Kong, where the incidence for both sexes is currently decreasing. Chronic hepatitis C infection (CHC) is an important cause of HCC in Japan, representing 70% of HCCs. Over the past several decades, the prevalence of CHC has been increasing in many Asia-Pacific countries, including Australia, New Zealand, and India. Despite advancements in treatment, HCC is still an important health problem because of the associated substantial mortality. An effective surveillance program could offer early diagnosis and hence better treatment options. Antiviral treatment for both CHB and CHC is effective in reducing the incidence of HCC.
Background & Aims
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a key to viral persistence in chronic hepatitis B infection. Serum hepatitis B core‐related antigen (HBcrAg) is a ...novel marker for HBV disease. We aimed to determine whether HBcrAg could be a surrogate marker for intrahepatic cccDNA.
Methods
Three hundred and five liver biopsies and the corresponding sera collected from 138 nucleos(t)ide analogues‐treated patients were analysed. 124 patients had paired liver biopsies at baseline and 1‐year post‐treatment, and 43 patients had a third biopsy after 6‐12 years of treatment. Serum HBcrAg, HBV DNA and hepatitis B surface antigen (HBsAg), and intrahepatic HBV DNA and cccDNA were measured.
Results
HBcrAg strongly correlated with cccDNA (r=.70), intrahepatic total HBV DNA (r=.67) and serum HBV DNA (r=.69; all P<.0001). In the 130 samples with undetectable serum HBV DNA, HBcrAg was detectable in 101 (78%) samples, and HBcrAg levels still correlated positively with cccDNA (r=.42, P<.0001). At ≥6 years of therapy, the median logarithmic reduction in HBcrAg was 2.7 log kU/mL, which was comparable to the magnitude of reduction in cccDNA. Twenty‐one patients had undetectable cccDNA after ≥6 years of treatment, in whom 15 (71%) had detectable HBcrAg (range: 1.2‐537 kU/mL).
Conclusions
Serum HBcrAg is a reliable surrogate marker for intrahepatic cccDNA. HBcrAg could be a very sensitive marker to reflect the cccDNA content and persistence of disease even with the cccDNA levels below the detection limit of assays.
There has been a recent paradigm shift in the indications and endpoints of treatment for chronic hepatitis B (CHB). Hepatitis B e antigen (HBeAg)‐negative disease is being increasingly recognized. ...Antiviral treatment for both HBeAg‐positive and HBeAg‐negative patients should aim at long‐term suppression of HBV DNA, with the ultimate ideal endpoint of hepatitis B surface antigen (HBsAg) seroconversion. Conventional interferon alpha (IFN‐α), the only agent licensed in 1991, has been superseded by pegylated IFN‐α. HBeAg seroconversion using pegylated IFN‐α is 33%, with only 25% of HBeAg‐positive patients achieving undetectable HBV DNA by polymerase chain reaction (PCR) assay. Five nucleoside/nucleotide analogues have been licensed since 1998. Lamivudine, an L‐nucleoside, is limited by the development of resistance in 76% of patients after 5 years of therapy. Telbivudine, another L‐nucleoside, is more potent than lamivudine but resistance still develops in 25% of HBeAg‐positive and 11% HBeAg‐negative patients after 2 years. Adefovir, an acyclic phosphonate, is relatively weak, but is effective against lamivudine‐ and telbivudine‐ resistant mutations, for which it should be used in combination (add‐on therapy) rather than substituted. Resistance to adefovir develops slowly, rising to 29% for HBeAg‐negative patients by year 5, but more rapidly when used alone for lamivudine‐resistant HBV. Currently the two first line nucleoside/nucleotides are entecavir and tenofovir. Entecavir, a cyclopentane (D‐nucleoside), is very potent, with 94% of patients having undetectable HBV DNA after 5 years. Resistance develops in only 1.2% of treatment‐naïve patients. Tenofovir, another acyclic nucleotide, is more potent with less renal toxicity compared to adefovir. It is effective against lamivudine‐resistant mutations when used alone. No resistance to tenofovir has been described after its use for 3 years or longer, often for patients with human immunodeficiency virus/HBV co‐infection. With these current, potent antiviral agents associated with very low rates of resistance, long‐term HBV DNA suppression and possibly even reversal of cirrhosis can now be achieved in a proportion of patients. In addition, long‐term treatment with these antiviral agents is associated with a reduced risk of development of hepatocellular carcinoma.
•Advances in understanding the natural history of hepatitis B have led to new definitions of the major phases of infection.•New phases are high replicative, low inflammatory (formerly immune ...tolerant) and non-replicative (formerly inactive carrier).•The new concept of trained immunity may alter future hepatitis B treatment strategies.•The current goal of treatment for chronic hepatitis B is a functional cure.•Experimental therapies now under development target viral and host factors and previously inaccessible pathways.
The host immune system plays an important role in chronic hepatitis B (CHB), both in viral clearance and hepatocellular damage. Advances in our understanding of the natural history of the disease have led to redefining the major phases of infection, with the “high replicative, low inflammatory” phase now replacing what was formerly termed the “immune tolerant” phase, and the “nonreplicative phase” replacing what was formerly termed the “inactive carrier” phase. As opposed to the earlier view that HBV establishes chronic infection by exploiting the immaturity of the neonate’s immune system, new findings on trained immunity show that the host is already somewhat “matured” following birth, and is actually very capable of responding immunologically, potentially altering future hepatitis B treatment strategies. While existing therapies are effective in reducing viral load and necroinflammation, often restoring the patient to near-normal health, they do not lead to a cure except in very rare cases and, in many patients, viremia rebounds after cessation of treatment. Researchers are now challenged to devise therapies that will eliminate infection, with a particular focus on eliminating the persistence of viral cccDNA in the nuclei of hepatocytes. In the context of chronic hepatitis B, new definitions of ‘cure’ are emerging, such as ‘functional’ and ‘virological’ cure, defined by stable off-therapy suppression of viremia and antigenemia, and the normalization of serum ALT and other liver-related laboratory tests. Continued advances in the understanding of the complex biology of chronic hepatitis B have resulted in the development of new, experimental therapies targeting viral and host factors and pathways previously not accessible to therapy, approaches which may lead to virological cures in the near term and functional cures upon long term follow-up. This article forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”
One year of treatment with entecavir (0.5 mg daily) in nucleoside‐naive patients with hepatitis B e antigen (HBeAg)‐positive or HBeAg‐negative chronic hepatitis B (CHB) resulted in significantly ...improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long‐term rollover study and underwent long‐term liver biopsy were evaluated for improvements in histological appearance. Sixty‐nine patients 50 HBeAg‐positive and 19 HBeAg‐negative receiving entecavir therapy underwent long‐term liver biopsy (median time of biopsy = 6 years, range = 3‐7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ≥2, and adequate long‐term biopsy samples. At the time of long‐term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (≥2‐point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ≥1‐point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside‐naive patients with CHB who were treated with entecavir in this long‐term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010)
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