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Antiviral Therapy Apr 2022Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was... (Review)
Review
Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was limited to two therapeutic modalities, either interferon, which carried significant side effects and was efficacious in a minority of patients, or lamivudine which showed no durable effects with short-term use and a high rate of resistance with long-term use. Adefovir was found to be effective in suppressing viral replication and in resolving the hepatic inflammation associated with hepatitis B with only rare instances of resistance. In this article, we appreciate John Martin's contribution to science and medicine as we review the landmark trials of adefovir that brought forth a new era of treatment of Hepatitis B.
Topics: Adenine; Drug Resistance, Viral; Hepatitis B; Humans; Lamivudine; Organophosphonates
PubMed: 35499182
DOI: 10.1177/13596535211067605 -
The Brazilian Journal of Infectious... 2013The aim of this study was to conduct a cost-utility study of adefovir, entecavir, interferon alpha, pegylated interferon alpha, lamivudine and tenofovir for chronic... (Review)
Review
The aim of this study was to conduct a cost-utility study of adefovir, entecavir, interferon alpha, pegylated interferon alpha, lamivudine and tenofovir for chronic hepatitis B in the context of Brazilian Public Health Care System. A systematic review was carried out for efficacy and safety. Another review was performed to collect utility data and transition probabilities between health states. A Markov model was developed in a time horizon of 40 years with annual cycles for three groups of: HBeAg positive, HBeAg negative, and all patients. These strategies were compared to a fourth group that received no treatment. Discount rates of 5% were applied and sensitivity analyses were performed. Tenofovir offered the best cost-utility ratio for the three evaluated models: U$397, U$385 and U$384 (per QALY, respectively, for HBeAg positive, negative, and all patients). All other strategies were completely dominated because they showed higher costs and lower effectiveness than tenofovir. The sequence of cost-utility in the three models was: tenofovir, entecavir, lamivudine, adefovir, telbivudine, pegylated interferon alpha, and interferon alpha. In the sensitivity analysis, adefovir showed lower cost-utility than telbivudine in some situations. The study has some limitations, primarily related to the creation of scenarios and modeling. In this study, tenofovir presented the best cost-utility ratio. The results obtained in this study will be valuable in decision-making and in the review of the clinical protocol, mainly involving the allocation of available resources for health care.
Topics: Adenine; Antiviral Agents; Brazil; Cost-Benefit Analysis; Drug Therapy, Combination; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Male; Markov Chains; Organophosphonates; Polyethylene Glycols; Recombinant Proteins; Tenofovir
PubMed: 23849851
DOI: 10.1016/j.bjid.2012.12.005 -
Clinics in Liver Disease Aug 2019Chronic hepatitis B remains a significant cause of morbidity and mortality worldwide. Most hepatitis B virus (HBV)-infected individuals are neither diagnosed nor... (Review)
Review
Chronic hepatitis B remains a significant cause of morbidity and mortality worldwide. Most hepatitis B virus (HBV)-infected individuals are neither diagnosed nor treated. In those treated, nucleos(t)ide polymerase inhibitors persistently suppress viremia to the limits of quantitation; however, few achieve a "functional cure," defined as sustained off-treatment loss of detectable serum HBV DNA with or without loss of hepatitis B surface antigen. The low cure rate has been attributed to an inability to eliminate the viral reservoir of covalently closed circular DNA from hepatocytes. This review focuses on the diverse therapeutic approaches currently under development that may contribute to the goal of HBV cure.
Topics: Adenine; Antiviral Agents; DNA, Viral; Female; Forecasting; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Risk Assessment; Tenofovir; Treatment Outcome; Virus Replication
PubMed: 31266626
DOI: 10.1016/j.cld.2019.04.006 -
Journal of Pharmacy & Pharmaceutical... 2018Adefovir is an antiviral drug that exhibits high hydrophilic properties and negligible bioavailability (less than 12%). It is only applied in the form of the ester... (Review)
Review
PURPOSE
Adefovir is an antiviral drug that exhibits high hydrophilic properties and negligible bioavailability (less than 12%). It is only applied in the form of the ester prodrug adefovir dipivoxil (ADV). The oral bioavailability of ADV is limited (32% to 45%) by its low permeability (Class 3) and biological conversion of the prodrug to adefovir. Ion-pair formation is considered as an alternative approach to a covalent prodrug (ADV) to enhance intestinal permeation of adefovir.
METHODS
The effect of various counter-ions (anionic, cationic and two quaternary ammonium salts) on the lipophilicity of adefovir was investigated by means of the n-octanol/buffer partitioning system, an in vitro transport model (PAMPA) and a biological membrane (everted gut sac).
RESULTS
Quaternary ammonium salts, cetylpyridinium chloride (CPC) and cetrimide enhanced the lipophilicity of adefovir 136- and 87-fold, respectively. The apparent permeability of adefovir in combination with CPC (counter-ion) was 2.5-fold greater than ADV permeability in the PAMPA model. The apparent permeability of adefovir-CPC (counter-ion) was 1.3-fold greater than that of adefovir dipivoxil permeability in a biologic membrane (everted gut sac).
CONCLUSION
These results suggest that the adefovir-CPC ion-paired system has potential for improving the permeation of adefovir across the intestinal membrane. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Adenine; Animals; Antiviral Agents; Cell Membrane; Cetrimonium; Cetylpyridinium; Humans; Intestinal Mucosa; Ions; Organophosphonates; Prodrugs; Quaternary Ammonium Compounds
PubMed: 29789103
DOI: 10.18433/jpps29394 -
World Journal of Hepatology Feb 2017Oral nucleoside/nucleotide analogues (NAs) are currently the backbone of chronic hepatitis B (CHB) infection treatment. They are generally well-tolerated by patients and... (Review)
Review
Oral nucleoside/nucleotide analogues (NAs) are currently the backbone of chronic hepatitis B (CHB) infection treatment. They are generally well-tolerated by patients and safe to use. To date, a significant number of patients have been treated with NAs. Safety data has accumulated over the years. The aim of this article is to review and update the adverse effects of oral NAs. NAs can cause class adverse effects (., myopathy, neuropathy, lactic acidosis) and dissimilar adverse effects. All NAs carry a "Black Box" warning because of the potential risk for mitochondrial dysfunction. However, these adverse effects are rarely reported. The majority of cases are associated with lamivudine and telbivudine. Adefovir can lead to dose- and time-dependent nephrotoxicity, even at low doses. Tenofovir has significant renal and bone toxicity in patients with human immunodeficiency virus (HIV) infection. However, bone and renal toxicity in patients with CHB are not as prominent as in HIV infection. Entecavir and lamivudine are not generally associated with renal adverse events. Entecavir has been claimed to increase the risk of lactic acidosis in decompensated liver disease and high Model for End-Stage Liver Disease scores. However, current studies reported that entecavir could be safely used in decompensated cirrhosis. An increase in fetal adverse events has not been reported with lamivudine, telbivudine and tenofovir use in pregnant women, while there is no adequate data regarding entecavir and adefovir. Further long-term experience is required to highlight the adverse effects of NAs, especially in special patient populations, including pregnant women, elderly and patients with renal impairment.
PubMed: 28261380
DOI: 10.4254/wjh.v9.i5.227 -
Virology Journal Mar 2011Chronic viral hepatitis B remains a global public health concern. Currently, several drugs, such as tenofovir and adefovir, are recommended for treatment of patients... (Comparative Study)
Comparative Study Meta-Analysis Review
Chronic viral hepatitis B remains a global public health concern. Currently, several drugs, such as tenofovir and adefovir, are recommended for treatment of patients with chronic hepatitis B. tenofovir is a nucleoside analog with selective activity against hepatitis b virus and has been shown to be more potent in vitro than adefovir. But the results of trials comparing tenofovir and adefovir in the treatment of chronic hepatitis B were inconsistent. However, there was no systematic review on the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B. To evaluate the comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B we conducted a systematic review and meta-analysis of clinical trials. We searched PUBMED, Web of Science, EMBASE, CNKI, VIP database, WANFANG database, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Review. Finally six studies were left for analysis which involved 910 patients in total, of whom 576 were included in tenofovir groups and 334 were included in adefovir groups. At the end of 48-week treatment, tenofovir was superior to adefovir at the HBV-DNA suppression in patients[RR = 2.59; 95%CI(1.01-6.67), P = 0.05]. While there was no significant difference in the ALT normalization[RR = 1.15; 95%CI(0.96-1.37), P = 0.14], HBeAg seroconversion[RR = 1.32; 95%CI(1.00-1.75), P = 0.05] and HBsAg loss rate[RR = 1.19; 95%CI(0.74-1.91), P = 0.48]. More high-quality, well-designed, randomized controlled, multi-center trails are clearly needed to guide evolving standards of care for chronic hepatitis B.
Topics: Adenine; Antiviral Agents; Controlled Clinical Trials as Topic; Hepatitis B virus; Hepatitis B, Chronic; Humans; Organophosphonates; Tenofovir; Treatment Outcome
PubMed: 21388525
DOI: 10.1186/1743-422X-8-111 -
Viruses Sep 2022My collaboration with Prof. Antonín Holý, that spans a period of 3-4 decades (1976-2012), led to the discovery of several acyclic nucleoside phosphonates (ANPs) which...
My collaboration with Prof. Antonín Holý, that spans a period of 3-4 decades (1976-2012), led to the discovery of several acyclic nucleoside phosphonates (ANPs) which were clinically developed by Gilead Sciences: cidofovir, adefovir, and tenofovir. The latter was further converted to two orally bioavailable prodrug forms, TDF and TAF, and both TDF and TAF were further combined with other antiviral drugs, thus giving rise to a broad array of antiviral drug combinations for the treatment of HIV infections. TDF and TAF are both available for the treatment of hepatitis B virus (HBV) infections, and, in combination with emtricitabine, also applicable as Truvada and Descovy, respectively, for the prophylaxis of HIV infections.
Topics: Anniversaries and Special Events; Anti-HIV Agents; Antiviral Agents; Cidofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; Hepatitis B; Hepatitis B virus; Humans; Nucleosides; Organophosphonates; Prodrugs; Tenofovir
PubMed: 36146783
DOI: 10.3390/v14091978