Oral Nucleoside Analogue Research Articles

Relationship between Phenotypic Changes of Dendritic Cell Subsets and the Onset of Plateau Phase during Intermittent Interferon Therapy in Patients with CHB*

ObjectiveThis study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40, CD80, CD83, and CD86. MethodThis was a cross-sectional study in which patients were divided into a natural history group (namely NH group), a long-term oral nucleoside analogs treatment group (namely NA group), and a plateau-arriving group (namely P group). The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer. ResultsIn total, 143 patients were enrolled (NH group, n = 49; NA group, n = 47; P group, n = 47). The results demonstrated that CD141/CD1c double negative myeloid dendritic cell (DNmDC)/lymphocytes and monocytes (%) in P group (0.041 [0.024, 0.069]) was significantly lower than that in NH group (0.270 [0.135, 0.407]) and NA group (0.273 [0.150, 0.443]), and CD86 mean fluorescence intensity of DNmDCs in P group (1832.0 [1484.0, 2793.0]) was significantly lower than that in NH group (4316.0 [2958.0, 5169.0]) and NA group (3299.0 [2534.0, 4371.0]), Adjusted P all < 0.001. ConclusionReduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B.

Deuremidevir and Simnotrelvir-Ritonavir for the Treatment of COVID-19.

Deuremidevir hydrobromide tablets and simnotrelvir tablets/ritonavir tablets (co-packaged) were approved by the Chinese National Medical Products Administration for the treatment of mild to moderate COVID-19 in January 2023. Both formulations contain small-molecule anti-SARS-CoV-2 agents. Deuremidevir, an oral nucleoside analog, is a broad-spectrum virus replication inhibitor targeting the highly conserved RNA-dependent RNA polymerase. Simnotrelvir-ritonavir is a co-packaged combination drug consisting of simnotrelvir tablets and ritonavir tablets. Simnotrelvir is an oral antiviral agent targeting the 3-chymotrypsin-like protease, which is essential for SARS-CoV-2 viral replication. Previous clinical trials revealed that both deuremidevir and simnotrelvir-ritonavir were effective and well tolerated in the treatment of COVID-19.

Abstract CT188: A phase Ib study of sapacitabine (sapa) and olaparib (ola) in patients (pts) with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer (MBC)

Abstract Background: PARP inhibitors (PARPi) are superior to chemotherapy in pts with BRCA1/2m MBC, with median PFS (mPFS) of 7 months with single-agent ola. Sapa is an oral nucleoside analog; the active metabolite, CNDAC, generates single-strand DNA breaks that are converted to double-strand breaks (DSB) during subsequent replication, resulting in cell death. CNDAC-induced DSB repair is dependent on homologous recombination. Sapa combined with ola may augment DNA damage compared to ola alone in BRCA1/2m tumors. Methods: We conducted a phase Ib study of sapa/ola in pts with BRCA1/2m HER2-negative MBC who were not previously PARPi-exposed. Primary objective was to determine the RP2D of sapa with ola. Secondary objectives included safety, tolerability and mPFS. RAD51 staining was performed on archival tissue. Serial blood samples were collected for circulating tumor DNA (ctDNA) analysis using low-pass WGS with targeted sequencing via the DDR Discovery Panel (Resolution Bioscience). Results: 10 women (median age 46) were enrolled before the study was terminated for hematologic toxicity. Germline BRCA1 and BRCA2 mutations were present in 3 and 7 pts, respectively. 4 pts had received prior platinum. All pts initially received standard dose ola (300 mg twice daily) with 100 mg (n = 3), 150 mg (n = 4), or 200 mg (n = 3) sapa once daily on days 1-5 and 8-12 of an every 28-day cycle. The RP2D was not determined. Hematologic AEs were common, including anemia (80%), neutropenia (80%), and thrombocytopenia (40%), with 1 DLT of G4 neutropenia lasting more than 7 days. The ORR was 50% (95% CI: 18.7% - 81.3%) with mPFS of 9.7 months (95% CI: 8.02 - NA). 3 pts had clinical benefit of 15+ months, exceeding expectations with olaparib alone, including 2 with PR, and 2 who remained on trial for 36+ months. 3 patients had confirmed PRs of short duration. Of the remaining patients, one withdrew consent early and the other 3 had non-CR/non-PD or SD of 4, 7 and 9 months. At progression, 2 pts had evidence of BRCA reversion mutation associated with an MMEJ signature; ctDNA also demonstrated MRE11 and PTEN amplifications in 1 of these pts, suggesting multiple resistance mechanisms. 3 pts had no evidence of reversion but had acquired putative non-reversion mechanisms of resistance, including changes suggesting enhanced MRN complex function, FANCD2 and ATR amplifications and PIK3CA mutation. The majority of tumors (6/10) were RAD51-negative. Other tumors with RAD51 foci demonstrated replication stress evidenced by high levels of pKAP1 and pRPA, suggesting benefit associated with sapa. Conclusions: Sapa/ola produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of 3+ years in 2 pts suggest possible combinatorial benefit. Further exploration with different sapa schedules or with substitution of a PARP1-selective inhibitor to decrease hematologic toxicity is warranted. Citation Format: Filipa Lynce, Noah Graham, Bose S. Kochupurakkal, Huy Nguyen, Philip D. Poorvu, Victoria Attaya, Raechel Davis, Kavita Garg, Lee P. Lim, Mark Li, Cloud P. Paweletz, Nabihah Tayob, Geoffrey I. Shapiro, Sara M. Tolaney. A phase Ib study of sapacitabine (sapa) and olaparib (ola) in patients (pts) with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT188.

A Systematic Review on Current Trends in the Treatment of Chronic Hepatitis B to Predict Disease Remission and Relapse.

Despite decreasing the prevalence of chronic hepatitis B (CHB), it is still a major health care challenge. Current antiviral regimens aim to suppress hepatitis B virus (HBV) deoxyribonucleic acid (DNA) activity to prevent the risk of hepatic decompensation, liver cirrhosis, and hepatocellular carcinoma (HCC). Currently, pegylated interferon (Peg-IFN) and nucleos(t)ide analogs (NA) are the first-line choices of drugs. Peg-IFN is now discontinued due to its mode of application and side effects. NA is used once daily to suppress HBV DNA activity but has little effect on covalently closed circular DNA (cccDNA), so continuous long-term therapy is required to suppress HBV DNA. Due to this effect, disease remission, relapse, and even clinical flare are common phenomena after the end of treatment (EOT). This review aimed to analyze the current regimens for treating chronic hepatitis B. Their mode of action, duration of treatment, and events after stopping therapy. The review was performed using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) 2020 guidelines. A search was undertaken in PubMed, PubMed Central, Google Scholar, and ScienceDirect. Screening of articles was carried out to find relevant and appropriate articles. Articles were then quality-checked before inclusion. Our analysis showed that long-term finite therapy with nucleoside analogs could improve clinical outcomes and suppress viral DNA activity. However, a functional cure, loss of hepatitis B surface antigen (HBsAg), is rarely achieved. The decision to end treatment depends on quantitative HBsAg level (qHBsAg), alanine aminotransferase (ALT), HBV DNA (deoxyribonucleic acid), hepatitis B e antigen (HBeAg), and fibrosis assessment. It is concluded that patients with HBeAg negative without cirrhosis can be easily withdrawn from treatment if they have long-term viral remission and a high HBsAg loss rate. However, patients with positive HBeAg should continue treatment because there is a high chance of disease relapse and even acute flare. To predict whether patients will benefit from EOT, some immunomodulatory markers are studied, including interleukin (IL-20, IL-8), fas ligand (FASGL), and IFN gamma. Although these factors are reliable, none pose an independent effect on disease remission. Combination therapy (IFN alpha + oral nucleoside analogs) is promising but has clinical shortcomings.

Sofosbuvir adsorption onto activated carbon derived from argan shell residue: Optimization, kinetic, thermodynamic and theoretical approaches

Activated carbon (AC) obtained from argan shell residue (ASR) was studied for the removal of the drug sofosbuvir from the liquid phase. The operating parameters including pH, adsorbent dosage, and sofosbuvir concentration were optimized with a Box Behnken design (B.B.D) using the response surface methodology (R.S.M.) approach. The results show a maximum removal at room temperaure of 54.5 mg.g−1 (99.63%) of sofosbuvir at pH 7, AC mass 0.5 g.L−1, and sofosbuvir concentration 0.1 mM. The adsorption investigation indicated that the process is well described by Freundlish isotherm model with R2 = 98.2%. Thermodynamic parameters, including ΔG°, ΔH°, and ΔS°, were also studied. The adsorption kinetics follows pseudo 2nd order. The produced AC was characterized by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and differential thermal analysis (DTA). To better understand the adsorption mechanism and dynamic behavior of sofosbuvir, an oral nucleoside analog and potent inhibitor of the hepatitis C virus, we applied the density functional theory (DFT) approach, Monte Carlo simulations, and molecular dynamics (MD) simulations to examine the impact of different adsorption sites, adsorption energy, and mechanism. The moisture content H(%), volatile matter Vm, and iodine value in AC were also evaluated. The results indicate that argan shell-based AC is a promising candidate for the adsorption procedure due to its low cost and higher adsorption capacity for sofosbuvir removal from the liquid phase.

Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice.

The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by therapeutic monoclonal antibodies, emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East Respiratory Syndrome CoV (MERS-CoV). The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral which has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19.

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

Variceal Bleeding in Patients with Initation of Sofosbuvir and Ribavirin – Case Reports

Abstract: Sofosbuvir is an oral nucleoside analogue and potent inhibitor of the Hepatitis C virus (HCV) RNA polymerase that is used in combination with other antiviral agents to treat chronic Hepatitis C Nevertheless, and for unknown reasons, successful antiviral therapy of Hepatitis C with Sofosbuvir and other direct acting agents in patients with cirrhosis is occasionally complicated by hepatic decompensation. Here we describe 2 case report of upper gi bleed at initial days of treatment with Sofosbuvir and Ribavirin. Keywords: Variceal bleeding , Sofosdbuvir, Ribavirin, Heptitis C, Nucleoside analogue, Antiviral.

Peginterferon Alfa-2a (40KD) Plus Lamivudine or Entecavir in Children With Immune-Tolerant Chronic Hepatitis B.

Treatment guidelines for chronic hepatitis B (CHB) do not recommend antiviral therapy for patients in the immune-tolerant phase of the disease, which generally occurs in children who acquire hepatitis B virus (HBV) vertically and may last for decades. On the basis of promising results of a pilot study, we conducted a randomized, controlled, multicenter study to evaluate the efficacy and safety of antiviral therapy in children and adolescents with immune-tolerant CHB. Fifty-nine children aged 3 to <18 years hepatitis B e antigen-positive with an HBV DNA titer >20,000 IU/mL and persistently normal alanine aminotransferase levels were randomized to 56 weeks of antiviral therapy with an oral nucleoside analogue [entecavir or lamivudine], combined with subcutaneous peginterferon alfa-2a from week 8, or 80 weeks of untreated observation. The primary efficacy outcome was hepatitis B surface antigen loss 24 weeks post-treatment in the antiviral therapy group or at the end of observation in the control group. Enrollment was terminated after the results of two similar studies showed that similar antiviral regimens were ineffective in children and adults with immune-tolerant CHB. At 24 weeks post-treatment, 1 of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group). No serious treatment-related adverse events were reported, and no patients discontinued treatment because of adverse events. The antiviral regimen evaluated in this trial had an acceptable tolerability profile, but was ineffective in children and adolescents with immune-tolerant CHB.

Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans.

Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.

Clinical observation of continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B

Objective: To observe continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B. Methods: Data of patients with active stage of chronic hepatitis B over the past 6 years were collected and analyzed retrospectively. The incidence of drug resistance mutation and related factors between patients taking LAM or ETV continuously and intermittently were compared with those taking LAM or ETV. Data comparison was performed using χ(2) test. Results: Patients with HBV DNA≥10(5) copies / ml at the time of initial treatment had higher resistance mutation rates than those with HBV DNA < 10(5) copies / ml at either continuous or intermittent treatment, and patients with intermittent treatment had higher resistance mutation rates than those with continuous treatment. Simultaneously, the incidence of drug resistance mutation in LAM and ETV in the first, second and third years were significantly higher in intermittent treatment than that of continuous treatment (P < 0.05). There was a positive correlation between the frequency of drug withdrawal and the rate of drug resistance mutation. There were no individual difference and drug difference between LAM and ETV. Conclusion: In the treatment of chronic hepatitis B with oral nucleoside analogues, drug resistance may occur in either continuous or intermittent treatment. When comparing continuous with intermittent treatment, it suggests that intermittent is more likely to cause viral resistance mutation.

Effects of continuous nursing intervention on WeChat on the compliance of oral nucleoside (acid) analogues in patients with chronic hepatitis B

Objective Continuous nursing intervention was conducted in patients with chronic hepatitis B by means of Weixin platform. The effect of this intervention on compliance of oral nucleoside (acid) analogues (NA) in patients with chronic hepatitis B was studied and analyzed. Methods A total of 240 patients with chronic hepatitis B treated in the Third People's Hospital of Guangyuan in Sichuan Province from October 2014 to December 2016 were recruited. According to the different nursing methods, all the research subjects were divided into experimental group (n=120) and control group (n=120) . For the experimental group, a nursing WeChat team and related WeChat group was established to provide professional counseling, authoritative scientific diagnostic information, appointment registration and other continuous nursing intervention for 6 months. Patients in the control group were given routine nursing. All patients were given oral NA treatment. The score of compliance after 6 months' intervention, the rate of review at 1st, 3rd and 6th month after discharge, and the recurrence rate at 12th month after discharge. Results The score of compliance of the control group was (52.37±7.65) , and experimental group (63.85±8.57) after intervention. The difference in compliance was statistically significant (t=10.947, P<0.05) . After intervention, the number of high compliance patients was 51 in the experimental group, which was higher than 29 in the control group, and the difference was statistically significant (χ2=9.075, P<0.05) . The rates of review at 1st, 3rd and 6th month after discharge of the experimental group were all 100.00%, which were higher than those of the control group (96.67%, 92.50% and 82.50%) . The recurrence rate at 12th month after discharge of the experimental group was 8.33%, which was lower than 20.00% of the control group, and the difference was statistically significant (P<0.05) . Conclusions With the help of WeChat platform, continuous nursing can significantly improve the compliance of oral NA, improve the degree of re-visit and reduce the recurrence rate after 1 years in patients with hepatitis B. Key words: Hepatitis, type B; WeChat platform media; Compliance; Continuous nursing

The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer

ABSTRACTIntroduction: TAS102 is an oral thymidine-based nucleoside analog that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy. The pivotal RECOURSE phase III trial demonstrated a significant improvement in disease control rate, progression-free survival (PFS), and overall survival (OS) as compared with placebo in patients with refractory mCRC.Areas covered: This manuscript aims to review the clinical development of TAS102 in CRC, with a particular focus on safety, and to provide some perspective regarding its role in clinical practice. A literature search was conducted of MEDLINE and EMBASE databases for published studies (January 2004–December 2016) using the search terms TAS102, trifluridine–tipiracil, metastatic or advanced CRC, clinical trial, toxicity, safety, pharmacology, pharmacokinetics, and therapy.Expert opinion: TAS102 significantly improves survival of patients with refractory mCRC and has manageable toxicity. An expanding role in the treatment of CRC is expected for TAS102 in the near future, as its favorable safety profile makes TAS102 a suitable drug to be combined with other cytotoxic and targeted agents.

Preliminary results from an ongoing phase 2a study of RX-3117, an oral nucleoside analogue to treat advanced urothelial cancer (aUC).

4543Background: RX-3117 is an oral small molecule nucleoside analogue (cyclopentyl pyrimidyl nucleoside) that is activated by uridine cytidine kinase 2. RX-3117 shows efficacy in various xenograft ...

Results of a Phase 3 Study of Elderly Patients with Newly Diagnosed AML Treated with Sapacitabine and Decitabine Administered in Alternating Cycles

Background: Sapacitabine is a novel oral nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading to production of double-strand DNA breaks and/or G2 cell cycle arrest. In AML cell lines, the active metabolite of sapacitabine, CNDAC, is synergistic with hypomethylating agents (HMAs) particularly when treated with HMAs first. In a pilot study, there were 6 CRs and 2 PRs in 25 patients treated with sapacitabine in alternating cycles with decitabine. This global randomized phase 3 study evaluated the survival benefit of this treatment strategy vs. decitabine monotherapy. Methods: Decitabine 20 mg/m2 was administered intravenously daily x 5 days of a 4-week cycle (for the control arm and odd cycles of the study arm) alternating with sapacitabine 300 mg p.o. b.i.d. x 3 days/week x 2 weeks of a 4-week cycle (even cycles of the study arm). The safety of these doses was further evaluated in the lead-in phase of the phase 3 study to confirm the findings from the pilot study. Eligible patients were ≥70 years with untreated AML and unsuitable for or unwilling to receive standard induction chemotherapy. Patients who had received HMAs for prior MDS or MPD were excluded. Results: For 482 patients randomized to receive decitabine/sapacitabine (n=241) vs. decitabine only (n=241), randomization was stratified by the presence of antecedent MDS or MPN, peripheral white blood cell count (WBC <10,000 vs. ≥10,000) and bone marrow blast percentage (≥50% vs. < 50%). Median age was 77 years (range 70-90), and 317 patients had de novo AML (66%), 165 secondary AML (34%). WBC was ≥10,000 in 161 patients (33%) and >40,000 in 59 patients (12%); 194 patients (40%) had unfavorable cytogenetic risk by SWOG criteria. Disease characteristics were well balanced in both arms. In total, 13.7% of patients achieved CR, more on the study arm vs. control (16.6% vs. 10.8%). A total of 37.3% treated patients received ≥5 cycles of treatment, similar on both arms, as were 30- and 60-day death rates. Median overall survival was 5.9 months on the study arm vs. 5.7 months on control arm, which did not reach a statistically significant difference. In the subgroup of patients with <10,000 WBC (n=321), median overall survival was higher on the study arm vs. control arm (8.0 months vs. 5.8 months), as was CR rate (21.5% vs. 8.6%). Grade 3 or higher adverse events (regardless of causality) that occurred in >10% patients were thrombocytopenia, anemia, neutropenia, pneumonia, febrile neutropenia, sepsis, and disease progression. Conclusion: The regimen of sapacitabine administered in alternating cycles with decitabine was active and well tolerated but it did not significantly improve overall survival as compared to decitabine monotherapy. Further analyses are being conducted to characterize the subgroups of patients who appeared to have benefited from this treatment regimen and the potential cost savings associated with the use of an oral drug. DisclosuresKantarjian:Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding. Goldberg:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; COTA: Employment, Equity Ownership; Pfizer: Honoraria; Ariad: Speakers Bureau; Jazz: Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Strickland:Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; CTI BioPharma: Consultancy; Tolero Pharmaceuticals: Consultancy; Sunesis Pharamaceuticals: Consultancy, Research Funding; Baxalta: Consultancy; Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria. Rubenstein:Alexion Pharmaceuticals: Speakers Bureau. Arellano:Cephalon Oncology: Research Funding. Schiller:bluebird bio: Research Funding; mateon therapeutics: Research Funding. Gaidano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Montesinos:Celgene Corporation: Honoraria, Research Funding. Rizzieri:Shire: Research Funding; Erytech: Research Funding. Subramanian:Boehringer-Ingelheim, Lilly, BMS, Astra-Zeneca, Pfizer, Biocept: Consultancy, Speakers Bureau. Buyse:IDDI: Employment, Equity Ownership. Chiao:Cyclacel LTD: Employment, Equity Ownership.

Constipation during Entecavir treatment in Chronic Hepatitis B patients: Two Cases Reports

Entecavir (ETV) is an oral nucleoside analog inhibitor of hepatitis B virus (HBV) DNA polymerase, which is widely used in patients with chronic hepatitis B (CHB). Despite the excellent safety data of this agent, the adverse events of headache, diarrhea, nausea and vomiting are recorded in the drug instruction of ETV.Here we report two CHB patients with ETV-associated constipation in whom symptom fully disappeared following ETV withdrawal.

Long‐term lamivudine therapy in chronic hepatitis B

One to 5years of therapy of chronic hepatitis B with oral nucleoside analogues result in significant clinical improvements, but effects of more prolonged therapy are not well defined. To describe outcomes of chronic hepatitis B with long-term lamivudine therapy. Forty-two patients with chronic hepatitis B treated with lamivudine were followed for 3.2-19.5 (median=16.1)years. Therapy was switched to other agents (n=16) if patients developed lamivudine resistance and relapse of disease. Among 22 HBeAg-positive patients, 17 (77%) became HBeAg negative, of whom 5 (23%) subsequently cleared HBsAg. Among 20 HBeAg-negative patients, 10 (50%) cleared HBsAg. The time to HBsAg clearance ranged from 0.9 to 16.8 (median=9.3) years. Lamivudine resistance arose in 24 patients (57%) of whom 6 (25%) lost HBsAg. HBsAg clearance was not always accompanied by seroconversion; anti-HBs appearing concurrently in only five patients (33%). Nevertheless, HBsAg loss allowed for stopping therapy in all patients, none re-developing HBsAg or suffering relapse; all having normal alanine aminotransferase levels and no (n=13) or unquantifiable HBV DNA levels (n=2) when last seen. In contrast, seven of 27 patients (26%) who remained HBsAg-positive died of liver disease or liver cancer or underwent liver transplantation, all of whom had cirrhosis. Long-term viral suppression with nucleoside analogues leads to HBsAg loss in a substantial proportion of patients, particularly if HBeAg-negative. Serious outcomes during the first 10-20years of treatment occur largely among patients with pre-existing cirrhosis who do not clear HBsAg with therapy.

Phase I study of sapacitabine and seliciclib in patients with advanced solid tumors.

2503Background: Sapacitabine is an oral nucleoside analogue; the active metabolite CNDAC generates ssDNA breaks that are converted to dsDNA breaks (DSB) during subsequent replication, resulting in cell death. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is an oral CDK2, 7 and 9 inhibitor, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation. This phase I study evaluates sequential and concomitant sapacitabine and seliciclib treatment. Methods: Dose escalation was conducted in patients with incurable solid tumors with sapacitabine b.i.d. x 7 consecutive days (d 1-7) followed by seliciclib b.i.d. x 3 consecutive days (d 8-10) or sapacitabine q.d. concomitantly with seliciclib q.d. x 5 days per week x 2 weeks (d 1-5, 8-12). MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine and seliciclib treatment. Res...

Cost-Effectiveness of Peg-Interferon, Interferon and Oral Nucleoside Analogues in the Treatment of Chronic Hepatitis B and D Infections in China

The cost-effectiveness of highly effective, but costly, peg-interferon (peg-IFN) treatment for chronic hepatitis B (CHB) infections in China is unknown. Endemic hepatitis D virus (HDV) may also modify the effectiveness of any HBV treatment option. The objective of this study is to determine the best antiviral treatment from a societal perspective in the Chinese population, which contains a mix of HBV and HDV infections. A Markov model is developed to simulate the clinical course of CHB and chronic hepatitis D (CHD) individuals. For a hypothetical Chinese cohort of 10,000 individuals aged 30-60years, cost-utility analysis is performed for therapies with: lamivudine, adefovir, telbivudine, entecavir, IFN and Peg-IFN. Costs and quality-adjusted life-years (QALYs) are discounted at 3% annually. A one-way sensitivity analysis is also conducted. Lamivudine, adefovir, telbivudine, and entecavir are all cost-effective treatments compared to palliative care at an incremental cost-effectiveness ratio (ICER) of -$418, -$197, -$443 and -$317 per QALY, respectively (2015 US dollars). Peg-IFN yields a maximum 156,000 QALYs with an ICER of $1149 per QALY while IFN results in the highest cumulative mortality of 48% along with the lowest QALY gained. Probabilistic sensitivity analyses confirm that only Peg-IFN and ETV are the only two cost-effective options at the current willingness-to-pay (WTP) of $12,000 in China. However, entecavir has a higher probability of being cost-effective than Peg-IFN at current WTP for all age groups. Peg-IFN generates maximum QALYs compared to lamivudine, adefovir, telbivudine and interferon, and presents itself as a cost-effective option at current WTP. Alternatively entecavir can be used in China, generating 10% lower QALYs than Peg-IFN but costing less than palliative care.

Use of telbivudine in kidney transplant recipients with chronic hepatitis B virus infection: A preliminary experience

Telbivudine is a relatively novel oral nucleoside analogue with favourable efficacy and tolerability in treatment-naïve chronic hepatitis B virus (HBV) infection, but its data in kidney transplant recipients (KTRs) was lacking. The efficacy and tolerability of telbivudine in four treatment-naïve HBsAg-positive KTRs were reviewed (treatment duration 54 (36-72) months) HBV DNA declined from 2.6 × 10(5) (7.8 × 10(3) -1.5 × 10(7) ) copies/mL at baseline to 170 (0.0-3.2 × 10(4) ) copies/mL at 12 months, and became undetectable at 24 and 36 months (P = 0.060, 0.118 and 0.005 compared with baseline). Alanine aminotransferase levels dropped from 46.5 (30-48) IU/mL at baseline to 28 (13-45) IU/mL, 34.5 (15-71) IU/mL and 26 (12-41) IU/mL at 12, 24 and 36 months, respectively (P = 0.109, 0.715 and 0.068 compared with baseline). Serum creatinine level and estimated glomerular filtration rate (eGFR) remained stable after 36 months of treatment (P all > 0.05 compared with baseline). No virological breakthrough, cirrhosis or hepatocellular carcinoma occurred. Our pilot data suggests that telbivudine has favourable efficacy and renal safety profiles in HBsAg-positive KTRs.