Do we need more nucleos(t)ide analogs for the treatment of chronic hepatitis B?
Authors: Jorg Petersen
Journal: Journal of Hepatology (2014)

Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infectionJournal of HepatologyVol. 62Issue 3PreviewTenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures. Full-Text PDF Two-year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecavir: Results from a multicentre studyJournal of HepatologyVol. 62Issue 3PreviewWe aimed to compare the viral suppression, safety and rate of drug resistance between besifovir (a new acyclic nucleotide analogue) and entecavir. Full-Text PDF Currently available antiviral treatment for chronic hepatitis B (CHB) infection can be divided into two classes of therapeutic agents: pegylated interferon alpha (PegIFN) and nucleos(t)ide analogues (NAs). The advantages of PegIFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. However, PegIFN carries numerous side effects and the treatment is successful in only 30–40% of patients. The advantages of NAs are excellent tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. New oral NAs such as entecavir and tenofovir effectively suppress hepatitis B virus (HBV) with minimal risk of drug resistance. But for most patients, NA therapy remains a long-term therapy, especially in Hepatitis B e Antigen (HBeAg) negative patients, and there is a high rate of virologic relapse after cessation of oral therapy. Due to the long-term therapy, safety of oral drugs is of utmost importance. Nevertheless, most HBV investigators agree that NAs are largely safe. No specific side effects have been associated with lamivudine and entecavir. Adefovir may damage renal tubular cells and cause nephrotoxicity [[1]Izzedine H. Hulot J.S. Launay-Vacher V. et al.Adefovir Dipivoxil International 437 and 438 Study GroupsRenal safety of Adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies.Kidney Int. 2004; 66: 1153-1158Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. Tenofovir treatment has been reported to cause some loss in bone mineral density in patients infected with Human Immunodeficiency Virus (HIV) [[2]Stellbrinck H.J. Orkin C. Arribas J.R. et al.ASSERT study groupComparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study.Clin Infect Dis. 2010; 51: 963-972Crossref PubMed Scopus (347) Google Scholar]. In two other recent reports [3Fung J. Seto W.K. Lai C.L. Yuen M.F. Extrahepatic effects of nucleoside and nucleotide analogues in chronic hepatitis B treatment.J Gastroenterol Hepatol. 2014; 29: 428-434Crossref PubMed Scopus (75) Google Scholar, 4Fung S. Kwan P. Fabri M. Horban A. Pelemis M. Hann H.W. et al.Randomized comparison of tenofovir disoproxil fumarate vs. emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B.Gastroenterology. 2014; 146: 980-988Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar], Tenofovir in combination with or without emtricitabine was shown to reveal a small decrease (mean <2%) in both spine and hip bone mineral density, although clinically not relevant without increased fracture risk. Other studies have shown excellent long-term safety with very low numbers of side-effects [5Chang T.T. Lai C.L. Kew Y.S. Lee S.S. Coelho H.S. Carrilho F.J. et al.Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.Hepatology. 2010; 51: 422-430Crossref PubMed Scopus (487) Google Scholar, 6Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1270) Google Scholar] in mono-infected HBV patients. Therefore, the induction of renal tubular damage for tenofovir and its consequences have been regarded as controversial in HBV mono-infected patients over the last years [7Gara N. Zhao X. Collins M.T. Chong W.H. Kleiner D.E. Jake Liang T. et al.Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B.Aliment Pharmacol Ther. 2012; 35: 1317-1325Crossref PubMed Scopus (123) Google Scholar, 8Gish R.G. Clark M.D. Kane S.D. Shaw R.E. Mangahas M.F. Baqai S. Similar risk of renal events among patients treated with tenofovir or entecavir for chronic hepatitis B.Clin Gastroenterol Hepatol. 2012; 10: 941-946Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. Induction of rise of serum creatinine levels greater than 0.5 mg/dl or hypophosphatemia were rare events in the registration trials too. Finally, an initial report of a higher risk of lactic acidosis for entecavir-treated patients [[9]Lange C.M. Bojunga J. Hofmann W.P. Wunder K. Mihm U. Zeuzem S. et al.Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function.Hepatology. 2009; 50: 2001-2006Crossref PubMed Scopus (226) Google Scholar] in a retrospective analysis could not be confirmed in a prospective trial from the same group of investigators. In this issue of the Journal Hepatology, two studies of novel NAs in different stages of clinical development have been published. In the first study, Yuen et al., [[10]Yuen M.F. Ahn S.H. Lee K.S. et al.Two year treatment outcome of chronic hepatitis B infection treated with Besifovir vs. Entecavir: results from a multicentre study.J Hepatol. 2015; 62: 526-532Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] report about a two-year treatment outcome of chronic hepatitis B infection with besifovir, a new acyclic nucleotide analog, and compared the results to entecavir treatment. In a roll-over study to 96 weeks from a Phase IIb open-labelled, multicenter randomized study, the antiviral efficacy and safety of besifovir 90 mg daily, 150 mg daily, and entecavir 0.5 mg daily was studied in treatment naïve CHB patients. Overall, there was no significant difference in amount of HBV-DNA decline, ALT normalization, and loss of HBeAg in two treatment arms receiving besifovir 90 or 150 mg, compared to the entecavir 0.5 mg arm. Limitations for this study were a small sample size after week 48, missing bone density scans and no quantification of HBsAg levels. In respect to safety analysis, there was no difference in SAEs reported, but the most common side effect related to besifovir was carnitine depletion. Therefore, carnitine supplementation had to be provided to 84–100% of patients in the besifovir arms. With supplementation, no patient experienced clinical symptoms of carnitine deficiency, e.g., hypoglycemia, hypoketosis, or even encephalopathy. During follow-up, carnitine levels normalized again. A potential advantage of besifovir could be a better resistance profile for lamivudine pretreated patients compared to entecavir, but larger scale studies are required to demonstrate such a theoretical advantage. In the second study [[11]Agarwal K. Fung S.K. Nguyen T.T. et al.Twenty eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection.J Hepatol. 2015; 62: 533-540Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar], Agarwal et al., report about the 28-day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide (TAF), a phosphonate prodrug of tenofovir disoproxil (tenofovir). Data have been collected in a Phase 1b trial. The proposal to perform this study was the idea of an improved safety margin of TAF compared to tenofovir, enabling achievement of high levels of tenofovir diphosphate within HBV infected hepatocytes when given at lower doses. The resultant lower systemic exposures of tenofovir are hypothesized to translate into improved safety margin for TAF. Although early proof of concept studies had shown greater viral suppression of TAF in vitro against HIV compared to tenofovir, in this HBV study there was no difference in antiviral efficacy after 28 days in the TAF and tenofovir group. There was a higher mean ALT in both TAF groups compared to the tenofovir arm, with the 40 mg of TAF with a higher mean ALT compared to 8 mg of TAF. TAF in the 25 mg application appeared to be as safe as tenofovir, while at higher concentrations of TAF, there was a rising incidence of AEs. No difference in creatinine clearance, serum phosphate levels or other markers of bone formation such as bsAP was observed in TAF versus tenofovir treatment groups. What do we take home from these two studies? With entecavir and tenofovir, we do have already two NAs of different subclasses at hands with extensive real world experience for up to 9 years after licensing for entecavir and up to 7 years for tenofovir. Both drugs are acting as reliable "working horses" in our daily clinical practice. Treating patients with chronic hepatitis B, >90% of adherent patients will become HBV-DNA undetectable within the first year of treatment with these drugs, together with normalization of transaminases. Furthermore, there are negligible rates of development of drug resistant variants for both compounds, e.g., for entecavir there are only patients at risk that have been pretreated with lamivudine, for tenofovir there is still after eight years of reported clinical studies not a single patient with a confirmed viral resistance so far. Moreover, many different patient subgroups have been treated in real-life that might be prone to drug-related safety concerns (e.g., patients of advanced age, with comorbidities such as diabetes mellitus and arterial hypertension, suffering from renal insufficiency, or with Child Pugh B cirrhosis). Finally, there is convenient drug dosing with only one pill per day. The important remaining aspect of long-term NA therapy is clearly long-term safety. From the results shown in both studies here, it appears that we are still far from a proof of concept that one of those drugs in clinical development, besifovir or tenofovir alafenamide, might be clinically safer and/or more efficient in the long-term application compared to entecavir or tenofovir. Moreover, the supplementation of carnitine for besifovir-treated patients to prevent from carnitine deficiency associated symptoms, is a clear disadvantage for this drug, not only requiring another tablet per day in the long-term treatment, but also making clinical surveillance in the long-term more complicated and costly. For TAF, the biggest theoretical advantage might be in HIV patients on several co-medications, where the majority of safety signals for tenofovir, kidney and bones, were detected. In HIV patients, studies with an equivalent TAF drug concentration are currently in Phase III. Phase II studies in HIV patients detected a reduced impact on kidney function and BMD [[12]Sax P.E. Zolopa A. Brar I. Elion R. Ortiz R. Post F. et al.Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study.J Acquir Immune Defic Syndr. 2014; 67: 52-58https://doi.org/10.1097/QAI.0000000000000225Crossref PubMed Scopus (184) Google Scholar]. The safety findings from on-going trials in HIV patients comparing TAF with tenofovir might then be of relevance for further HBV development, where the 25 mg TAF regimen is currently studied in phase III clinical trials. For HBV mono-infected patients, the yet theoretical advantage needs to be further clarified with strict observation of bone scans and kidney function tests, which will require large scale long-term studies. Moreover, within the next years, entecavir and tenofovir will lose their patent protection with the result that these drugs might be available on a global scale to a more reasonable price especially in health-care systems that are suffering from budget restrictions, where, on the other hand, the demand for reliable drugs against chronic hepatitis B might be the highest. We have just experienced in the Hepatitis C world that novel drugs are not coming for penny stocks, so that a safety advantage of novel drugs needs to be really significant to justify probably higher costs for these drugs in the real world setting. In summary, is there really an urgent need to search for other NAs while we are eagerly awaiting the development of novel anti-HBV drugs with different modes of action against novel targets in the HBV replication cycle? Is our existing anti-HBV NA armamentarium not strong enough yet? The development of novel targets aiming at higher percentages of HBsAg loss, clinical cure, or even cccDNA silencing in the future should be our main target in pharmaceutical development. With this, we might be able to reach a real break-through in getting closer to clinical cure for our HBV infected patients with a finite course of treatment. In the meantime, even combining our two existing forces against HBV, PegIFN and NAs, in a smarter way to gain more HBsAg loss to be able to stop antiviral therapy in a larger number of patients might be of higher clinical relevance. As an example at The Liver Meeting® 2014, the combination of PegIFN and tenofovir led to a significant higher rate of HBsAg loss at 72 weeks compared to either mono-therapies and reached the primary endpoint of that study [[13]Marcellin P. Marcellin P. Ahn S.H. Ma X. et al.HBsAg loss with tenofovir disoproxil fumarate (TDF) plus peginterferon alfa-2a (PEG) in chronic hepatitis B (CHB): results of a global randomized controlled trial.Hepatology. 2014; 60: 294AGoogle Scholar]. It might be worthy to study in greater detail the possibilities of add-on or switch therapies in this respect to limit duration of antiviral therapies. Therefore, EASL considers combination therapy in chronic hepatitis B to be an area requiring further research and supports further assessment of the safety and efficacy of the combination of PegIFN with potent NAs to increase anti-HBe or anti-HBs seroconversion rates [[14]EASL Clinical Practice Guidelines Management of chronic hepatitis B virus infection. European Association for the Study of the Liver.J Hepatol. 2012; 57: 167-185Abstract Full Text Full Text PDF PubMed Scopus (2716) Google Scholar]. The two HBV-studies presented in this issue of the Journal of Hepatology, although clinically very meaningful and important, will not help us in developing more effective HBV treatments and long-term safety issues need to be demonstrated with these drugs before we will put back on the shelf our working horses entecavir and tenofovir. •Grant/Research Support: BMS, Novartis, Roche.•Clinical studies: AbbVie, BMS, Boehringer, Gilead, Janssen, Merck, MSD, Roche, Siemens, Vertex.•Consultant/Advisor: Abbott, AbbVie, BMS, Boehringer, GSK, Kedrion, Janssen, Merck, MSD, Novartis, Roche.•Sponsored lectures: Abbott, BMS, Boehringer, Gilead, Kedrion, Janssen, Merck, MSD, Novartis, Roche.