Addition Of Adefovir Research Articles

Development and Validation of an LC/MS/MS Method for the Determination of Tenofovir in Monkey Plasma

A simple, specific, sensitive LC/MS/MS method for the quantitation of tenofovir (TFV) in monkey plasma was developed and validated. After the addition of adefovir as an internal standard (IS), methanol was used to produce a protein-free extract. Isocratic chromatographic separation was performed on a reverse-phase Discovery C(18) column (4.6×250 mm, 5 µm). The mobile phase consisted of methanol-water-formic acid (20 : 80 : 0.5, v/v/v). Detection of TFV and the IS was achieved with electrospray ionization (ESI)-MS/MS in the positive ion mode using 288/176 and 274/162 transitions, respectively. The analytical range was set at 0.005-1.250 µg/ml using a 200 µl plasma sample. The intra- and inter-day precision values were less than 11.4%, and accuracy ranged from 0.4 to 2.9% in all quality control samples. The method was fully validated for its sensitivity, selectivity, accuracy and precision, matrix effect, recovery, and stability. Due to the high polarity of TFV, the major challenge was to circumvent ion suppression when quantitating the plasma concentration of TFV using the LC/MS/MS method. To avoid ion suppression, sufficient chromatographic separation was the most effective means for the present purposes. Moreover, it was found that the reconstitution solvents of the dried residue had a significant impact on LC peak shapes. The validated method was successfully applied to a bioequivalence study in 6 monkeys after the oral administration of two ester prodrugs of TFV (equivalent to TFV 20 mg/kg). The method permits laboratory scientists with access to the appropriate instrumentation to perform rapid TFV determination.

Eficácia do adefovir dipivoxil, entecavir e telbivudina para o tratamento da hepatite crônica B: revisão sistemática

Chronic hepatitis B is one of the most frequent infectious disease in the world and represents a serious problem of public health A systematic review of randomized clinical trials was conducted to evaluate the efficacy of the nucleoside/nucleotide analogues (adefovir, entecavir and telbivudine) used for the treatment of chronic hepatitis B. The databases PubMed and LILACS were consulted, among others Twenty nine articles published between January/1970 to December/2009 were selected All nucleoside/nucleotide analogues demonstrate upper or similar efficacy to lamivudine. The entecavir can be appropriate for patients with chronic hepatitis B, HBeAg positive and negative treatment-naive as alternative to lamivudine, considering its low potential of viral resistance. The addition of adefovir to lamivudine presented good results in lamivudine resistant patients. The use of entecavir and telbivudine in those patients presents risk of crossed resistance. TBV is one of the most recent antivirals available, but antiviral resistance already documented represents limitation to its use as therapeutic option to LAM. Adverse events of nucleoside/nucleotide analogues were similar in characteristics, gravity and incidence when compared to the lamivudina and placebo.

Current management of hepatitis B virus infection before and after liver transplantation

The progress in treatment against hepatitis B virus (HBV) has substantially improved the outcome of all HBV-infected patients. We systematically reviewed the existing data in the management of HBV transplant patients in order to assess the optimal regimen in the pretransplant setting, for post-transplant prophylaxis and for therapy of HBV recurrent infection. All data suggest that an effective pretransplant anti-HBV therapy prevents post-transplant HBV recurrence. Pretransplant therapy has been based on lamivudine with addition of adefovir upon lamivudine resistance, but the use of newer, potent high-genetic barrier agents is expected to improve long-term efficacy. Moreover, it may lead to improvement of liver function, which sometimes removes the need for transplantation, although more objective criteria for removal from waiting lists are required. After liver transplantation, the combination of HBV immunoglobulin and one nucleos(t)ide analogue, mostly lamivudine, is currently the best approach, almost eliminating the probability of HBV recurrence. Treatment of post-transplant HBV recurrence has been mainly studied with lamivudine, but it will be most effective with entecavir and tenofovir, which have a low risk of resistance. In conclusion, the newer anti-HBV agents improve the treatment of HBV both pretransplant and post-transplant. HBV immunoglobulin is still used in combination with an anti-HBV agent for post-transplant prophylaxis. Monoprophylaxis with one of the new anti-HBV agents might be possible, particularly in patients preselected as having a low risk of HBV recurrence, but further data are needed and strategies to ensure compliance must be used.

Liver transplantation for hepatitis B virus. Pre-emptive and peri-operative prophylaxis

In the past, reinfection of the graft by hepatitis B virus (HBV) after liver transplantation for HBV-related liver disease was often followed by severe liver damage and reduced survival. The long-term administration of hepatitis B immunoglobulin (HBIG) dramatically reduced this risk. However, this procedure was ineffective in most patients with active viral replication pre-transplant. The use of lamivudine in the pre-transplant setting partially solved this problem. The emergence of resistant mutants to lamivudine was also solved by the addition of adefovir. At present, combination therapy by oral antivirals pre-transplant and HBIG plus the same drugs post-transplant achieves nearly 100% of protection against graft reinfection. In a recent study, a new intravenous HBIG, Niuliva has shown high efficacy in achieving protective anti-HBs levels after liver transplantation for HBV-related liver diseases, as well as a good safety profile. Using combination therapies, the doses of HBIG can be reduced or even stopped after several weeks or months post-transplant, continuing with oral antivirals alone. The recently introduced antivirals achieve a very high antiviral potency and low risk of resistance. This may further increase the efficacy in preventing graft reinfection in the post-liver transplantation setting.

Evaluating anti‐viral drug selection and treatment duration in HBeAg‐negative chronic hepatitis B: a cost‐effectiveness analysis

Several anti-viral treatments are now available for HBeAg-negative chronic hepatitis B (CHB), but the clinical and economic outcomes of potential treatment strategies and durations are unclear. To examine the clinical and economic outcomes of potential treatment strategies and durations for HBeAg-negative CHB. We conducted a cost-utility analysis from a payer perspective over a lifetime time horizon. Disease progression probabilities, costs and quality of life data were derived from the literature. We evaluated 5-year, 10-year, lifetime and 5 on-1 off treatment durations. For each of these treatment durations, we evaluated initial therapy with entecavir, lamivudine or adefovir, with addition of adefovir or entecavir for patients who developed virological breakthrough because of resistance (12 strategies total). Increasing treatment duration improved quality-adjusted life-years (QALYs) and was generally cost-effective for all three drugs. However, a 5 on-1 off strategy was the most cost-effective: lifetime vs. 5 on-1 off entecavir had an ICER of $148,200/QALY. In probabilistic sensitivity analyses, entecavir 5 on-1 off was the preferred strategy over the range of commonly reimbursed cost-effectiveness thresholds. Lifetime treatment was preferred to a 5 on-1 off strategy, if treatment durability was < 10%. The results of our analysis suggest that in HBeAg-negative CHB infection, a 5 on-1 off treatment strategy with entecavir improves health outcomes in a cost-effective manner compared to alternative strategies.

Cost Effectiveness of Entecavir versus Lamivudine with Adefovir Salvage in HBeAg-Positive Chronic Hepatitis B

To evaluate the cost effectiveness of treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with entecavir compared with lamivudine with adefovir salvage, based primarily on the results of a recent 2-year, randomised, multicentre, clinical trial (n = 709). Previous economic analyses have been limited by the lack of comparative clinical data for entecavir and lamivudine beyond 1-year duration and for salvage therapy. We conducted a cost-utility analysis using a Markov model from a US-payer perspective over a lifetime time horizon. The hypothetical cohort was 35-year-old patients with HBeAg-positive CHB. We evaluated 2 years of treatment with entecavir 0.5mg/day versus lamivudine 100mg/day, plus addition of adefovir 10mg/day for patients who developed virologic breakthrough due to resistance to either drug. In a scenario analysis, we considered adefovir plus lamivudine combination therapy for treatment-naive patients. Clinical and economic inputs ($US, year 2006 values) were derived from publicly available data, and probabilistic sensitivity analyses were conducted to evaluate uncertainty in the results. The estimated 10-year cumulative incidence of cirrhosis for patients initiated on entecavir was 2.3% lower than for those on lamivudine (20.5% vs 22.8%). The discounted incremental cost per QALY gained was $US7600 in the base-case analysis, and the 95% central range from probabilistic sensitivity analysis was $US2500-$US19 100. Combination therapy for treatment-naive patients led to an increase in costs without improvement in patient outcomes compared with entecavir monotherapy. Our analysis suggests entecavir improves health outcomes in a cost-effective manner compared with lamivudine with adefovir salvage or combination therapy, and highlights the importance of using evidence-based effectiveness estimates in economic studies of CHB therapies.

Utilization of a Liver Allograft from a Hepatitis B Surface Antigen Positive Donor

With today's donor organ shortage, enhanced efforts must be made to utilize organs that previously would have been declined. We report a 26-year-old man with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection who received a liver transplant from an HBsAg-positive donor. HBV viremia (6,281,185 copies/ml) was seen early posttransplant despite lamivudine prophylaxis, but became negative with addition of adefovir. Virologic analysis revealed predominantly donor HBV strain immediately posttransplant. At 5 months there was an elevation of liver enzymes accompanied by histologic evidence of hepatitis. At this time, HCV-RNA was positive but HBV DNA was undetectable. Treatment with pegylated interferon and ribavirin resulted in sustained clearance of HCV RNA. Two years posttransplant, the patient has normal liver biochemistry and HCV and HBV viral load are undetectable with persistence of HBsAg. Our experience suggests that with effective antiviral therapy, the use of HBsAg seropositive donors is feasible in selected circumstances.

Sensitive assay for determining plasma tenofovir concentrations by LC/MS/MS

An LC/MS/MS assay for the determination of tenofovir (TNF) was developed and validated for use with the EDTA anticoagulated human plasma matrix. Heparin-treated plasma and serum matrices were also validated. After addition of adefovir as an internal standard, trifluoroacetic acid was used to produce a protein-free extract. Chromatographic separation was achieved with a Polar-RP Synergi, 2.0 mm x 150 mm, reversed-phase analytical column. The mobile phase was 3% acetonitrile/1% acetic acid, aq. Detection of TNF and the internal standard was achieved by ESI MS/MS in the positive ion mode using 288/176 and 274/162 transitions, respectively. The method was linear from 10 to 750 ng/ml with a minimum quantifiable limit of 10 ng/ml when 250 microl aliquots were analyzed. The usefulness of this LC/MS/MS method to routinely monitor plasma concentrations of TNF was demonstrated along with its ability to assist in the performance of pharmacokinetic studies.