Evaluation of Single and Combination Therapies with Tenofovir Disoproxil Fumarate and Emtricitabine
            <i>In Vitro</i>
            and in a Robust Mouse Model Supporting High Levels of Hepatitis B Virus Replication

Schinazi, Raymond F.; Bassit, Leda; Clayton, Marcia M.; Sun, Bill; Kohler, James J.; Obikhod, Aleksandr; Arzumanyan, Alla; Feitelson, Mark A.

doi:10.1128/aac.01483-12

Cited by 11 publications

(12 citation statements)

References 46 publications

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“…Free FTC drug solution has been shown to have minimal cellular cytotoxicity (14). However, nanoformulation of FTC adds a new chemical entity requiring proper evaluation of FTC encapsulated nanoparticles for cytotoxicity prior to determining functionality.…”

Section: Characterization Of Npsmentioning

confidence: 99%

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

Mandal

Belshan

Holec

et al. 2017

Antimicrob Agents Chemother

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Among various FDA-approved combination antiretroviral drugs (cARVs), emtricitabine (FTC) has been a very effective nucleoside reverse transcriptase inhibitor. Thus far, FTC is the only deoxycytidine nucleoside analog. However, a major drawback of FTC is its large volume distribution (averaging 1.4 liters/kg) and short plasma half-life (8 to 10 h), necessitating a high daily dosage. Thus, we propose an innovative fabrication method of loading FTC in poly(lactic-co-glycolic acid) polymeric nanoparticles (FTC-NPs), potentially overcoming these drawbacks. Our nanoformulation demonstrated enhanced FTC loading (size of Ͻ200 nm and surface charge of Ϫ23 mV) and no to low cytotoxicity with improved biocompatibility compared to those with FTC solution. An ex vivo endosomal release assay illustrated that NP entrapment prolongs FTC release over a month. Intracellular retention studies demonstrate sustained FTC retention over time, with approximately 8% (24 h) to 68% (96 h) release with a mean retention of ϳ0.74 g of FTC/10 5 cells after 4 days. An in vitro HIV-1 inhibition study demonstrated that FTC-NP treatment results in a 50% inhibitory concentration (IC 50 ) ϳ43 times lower in TZM-bl cells (0.00043 g/ml) and ϳ3.7 times lower (0.009 g/ml) in peripheral blood mononuclear cells (PBMCs) than with FTC solution (TZM-bl cells, 0.01861, and PBMCs, 0.033 g/ml). Further, on primary PBMCs, FTC-NPs also illustrate an HIV-1 infection blocking efficacy comparable to that of FTC solution. All the above-described studies substantiate that FTC nanoformulation prolongs intracellular FTC concentration and inhibition of HIV infection. Therefore, FTC-NPs potentially could be a long-acting, stable formulation to ensure once-biweekly dosing to prevent or treat HIV infection.

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Section: Characterization Of Npsmentioning

confidence: 99%

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

Mandal

Belshan

Holec

et al. 2017

Antimicrob Agents Chemother

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“…These results indicate that DoG is useful as a hepadnaviral polymerase inhibitor. Nucleos(t)ide analogues are the only category of directacting antivirals approved by the FDA for chronic hepatitis B therapy (Schinazi et al 2012;Zoulim and Locarnini 2009). In vitro biochemical studies showed that nucleos(t)ide analogs act as chain terminators of viral DNA synthesis (Jones et al 2013;Staschke and Colacino 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Therapy with nucleoside analogues, such as 3TC, adefovir, entecavir, telbivudine, and tenofovir, is highly effective against HBV. However, their therapeutic value may be limited by the emergence of HBV-resistant mutants (Guo et al 2018;Schinazi et al 2012). For example, the single rtA181T mutation in HBV polymerase confers cross-resistance to 3TC, ADV, and LdT (Ahn et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistic studies demonstrated that nucleos(t)ide analogues inhibit HBV DNA replication by terminating DNA synthesis. However, drug-resistant mutants emerged after long-term treatment with nucleos(t)ide analogues have limited the wide application of these drugs (Guo et al 2018;Schinazi et al 2012;Zoulim and Locarnini 2009). For example, Meng et al (2017) recently reported that the 3TC resistance rate in China had gradually increased from 39.8% in 2010 to 56.6% in 2013 (Zhang et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Anti-hepatitis B Virus Activity of 2′,3′-Dideoxyguanosine

et al. 2018

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2 0 ,3 0-dideoxyguanosine (DoG) has been demonstrated to inhibit duck hepatitis B virus (DHBV) replication in vivo in a duck model of HBV infection. In the current study, the in vitro antiviral effects of DoG on human and animal hepadnaviruses were investigated. Our results showed that DoG effectively inhibited HBV, DHBV, and woodchuck hepatitis virus (WHV) replication in hepatocyte-derived cells in a dose-dependent manner, with 50% effective concentrations (EC 50) of 0.3 ± 0.05, 6.82 ± 0.25, and 23.0 ± 1.5 lmol/L, respectively. Similar to other hepadnaviral DNA polymerase inhibitors, DoG did not alter the levels of intracellular viral RNA but induced the accumulation of a less-than-full-length viral RNA species, which was recently demonstrated to be generated by RNase H cleavage of pgRNA. Furthermore, using a transient transfection assay, DoG showed similar antiviral activity against HBV wild-type, 3TC-resistant rtA181V, and adefovirresistant rtN236T mutants. Our results suggest that DoG has potential as a nucleoside analogue drug with anti-HBV activity.

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“…Despite the fact that TDF-based combination therapy is reported to provide more effective HBV suppression than therapy with each drug alone in vitro and in a robust mouse model [ 28 ], the results of our meta-analysis suggest that viral suppression occurring in monotherapy groups seemed to be similar to that in combination therapy groups (62.5% versus 70.9%, P = 0.086 at 24 weeks; 78.1% versus 83.7%, P = 0.118 at 48 weeks; 86.4% versus 87.9%, P = 0.626 at 96 weeks). Rates of undetectable HBV DNA were all higher in TDF combination therapy groups at the three time points but none of the three time points achieved statistical significance.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Tenofovir-Based Combination Therapy versus Tenofovir Monotherapy in Chronic Hepatitis B Patients Presenting with Suboptimal Responses to Pretreatment: A Meta-Analysis

Chen

Wang

Zhang

et al. 2016

Gastroenterology Research and Practice

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Background/Aims. It remains unclear whether tenofovir disoproxil fumarate- (TDF-) based combination therapy produces better outcomes than TDF monotherapy in chronic hepatitis B (CHB) patients. The aim of this study was to compare the efficacy of the two regimens by performing a meta-analysis. Methods. A comprehensive literature search was performed on the comparison of TDF-based combination therapy and monotherapy for CHB patients in the PubMed, Embase, Web of Science, and the Cochrane Libraries. Both dichotomous and continuous variables were extracted and pooled outcomes were expressed as risk ratio (RR) or standard mean difference (SMD). Results. Nine eligible studies (1089 subjects in total) were included in our analysis. The proportion of patients with undetectable HBV DNA at 24, 48, and 96 weeks were similar between the two comparable groups (62.5% versus 70.9%, P = 0.086; 78.1% versus 83.7%, P = 0.118; 86.4% versus 87.9%, P = 0.626, resp.). HBV DNA reduction, rates of ALT normalization, hepatitis B e antigen (HBeAg) loss, and HBeAg seroconversion were also similar between the two groups. Conclusions. On the current data, TDF-based combination therapy seemed to be no better than those achieved by monotherapy. Further studies are needed to verify this comparison.

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Evaluation of Single and Combination Therapies with Tenofovir Disoproxil Fumarate and Emtricitabine In Vitro and in a Robust Mouse Model Supporting High Levels of Hepatitis B Virus Replication

Cited by 11 publications

References 46 publications

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

In Vitro Anti-hepatitis B Virus Activity of 2′,3′-Dideoxyguanosine

Efficacy of Tenofovir-Based Combination Therapy versus Tenofovir Monotherapy in Chronic Hepatitis B Patients Presenting with Suboptimal Responses to Pretreatment: A Meta-Analysis

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