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Clinical Trial Watch: Reports from the Liver Meeting®, AASLD, San Francisco, November 2015

2016; Elsevier BV; Volume: 64; Issue: 6 Linguagem: Inglês

10.1016/j.jhep.2016.02.020

1600-0641

Johannes Wiegand, Florian van Bömmel, Andrés Duarte‐Rojo, José Altamirano, Juan G. Abraldeṣ, Augusto Villanueva, Thomas Berg,

Liver Disease Diagnosis and Treatment

The Liver Meeting® brought exciting news for all different genotypes of chronic hepatitis C virus infection. Data are presented according to genotypes and approved and experimental direct antiviral agents. They include relevant details for easy to treat patients and for so far difficult to cure populations like patients with end stage renal disease or drug abuse. Different real-life cohorts investigate post market approval data of different direct antiviral agents. The multinational real-life target-cohort presented data on current daily practice of sofosbuvir and ledipasvir [[1]Terrault N. Zeuzem S. DiBisceglie A. Lim J.K. Pockros P.J. Frazier L.M. et al.Treatment outcomes with 8, 12 and 24 weeks regimens of ledipasvir/sofosbuvir for the treatment of hepatitis C infection: analysis of a multicenter prospective observational study.Hepatology. 2015; 61: 256AGoogle Scholar]. According to the label, sofosbuvir and ledipasvir can be used for eight weeks in case of treatment naïve patients without cirrhosis and a baseline HCV-RNA viral load <6 Mio. IU/ml. However, the target investigators showed that physicians do not necessarily trust in the short treatment period and prefer 12 weeks of therapy instead, because only 40% of cases qualifying for eight weeks of therapy were treated according to the label. Shortening treatment duration to eight weeks was not inferior to the longer treatment period as both regimens achieved sustained virological response (SVR)12 rates of 97%. Viral kinetics at week 4 of therapy did not predict treatment outcome: Even if HCV-RNA was detectable, SVR12 results were not impaired after eight weeks of therapy. That sofosbuvir/ledipasvir treatment can be safely shortened to eight weeks in the appropriate patient population without jeopardizing efficacy was also confirmed by German investigators who reported 100% treatment success in a large single center experience [[2]Buggisch P. Wursthorn K. Stoehr A. Gauthier A. Atanasov P.K. Petersen J. Real world effectiveness of ledipasvir/sofosbuvir 8 weeks chronic hepatitis C treatment.Hepatology. 2015; 62: 806AGoogle Scholar]. Thus, the eight weeks sofosbuvir/ledipasvir treatment regimen should be more often used in daily practice if the three major baseline criteria of a naïve treatment status, absence of cirrhosis, and HCV-RNA <6 Mio. IU/ml are fulfilled. Shorter courses of therapy may improve adherence, affordability, and accessibility of direct antiviral agents. Therefore, a pilot trial in 26 non-cirrhotic HCV-genotype 1b infected Chinese patients evaluated SVR rates after only three weeks of therapy in patients who achieved plasma HCV-RNA levels <500 IU/ml after two days of treatment within a response guided therapy approach of different all oral antiviral triple combinations [[3]Lau G.K. Benhamou Y. Chen G. Li J. Shao Q. Ji D. et al.Complete cure after three weeks of all oral triple direct acting antiviral (DAA) regimens in non-cirrhotic chronic hepatitis C genotype 1b Chinese subjects (SODAPI study).Hepatology. 2015; 62: 1394AGoogle Scholar]. Patients were treated in three groups either with sofosbuvir, ledipasvir, and asunaprevir or sofosbuvir, daclatasvir, and simeprevir or sofosbuvir, daclatasvir, and asunaprevir, respectively. All 18 individuals with HCV-RNA levels 9 points was present in nine cases. Patients were treated for 24 weeks with sofosbuvir and daclatasvir, while ribavirin was added at the discretion of the investigator. Overall, the 24 week regimen without ribavirin was not inferior to the triple therapy and achieved SVR12 rates of 100% in patients with Child-Pugh class A cirrhosis or 15 MELD points were 75% and 80% after 24 weeks of sofosbuvir/daclatasvir and numerically inferior to the triple therapy regimen, however, low absolute patient numbers in these categories prevent further interpretation between treatment arms. Treatment of patients with direct-acting antiviral (DAA) failure represents a major challenge for future treatment strategies, especially in the context of high replication competent NS5A resistant variants which have shown long-term persistence. Several studies investigated re-treatment strategies with interferon-free antiviral therapies of failures after regimens with direct antiviral agents. In general, data were limited to patients with HCV-genotype 1 infection except few individual cases with HCV-genotype 4 and by small patient numbers. Re-treatment of patients after (mainly) failure of the 3D-regimen consisting of paritraprevir/ritonavir, ombitasvir, and dasabuvir were re-treated with the same regimen plus an add-on of sofosbuvir (n = 22, including n = 20 HCV-subtype 1a-infected patients) [[7]Poordad F. Bennett M. Sepe T.E. Cohen E. Reindollar R. Everson G.T. et al.Retreatment of HCV genotype 1 DAA-failures with ombitasvir/paritraprevir/r, dasabuvir, and sofosbuvir.Hepatology. 2015; 62: 1392AGoogle Scholar]. Treatment duration was 12 weeks for genotype 1a patients without cirrhosis (n = 14) and for genotype 1b patients (n = 2), while genotype 1a patients with compensated cirrhosis (n = 6) were treated for 24 weeks. In addition, all genotype 1a patients received weight-based ribavirin. SVR12 rates of patients treated for 12 weeks were 93% (n = 14/15), while SVR12 rates for genotype 1a patients with cirrhosis were still pending, but at least SVR4 was achieved in all of them. Failures of early daclatasvir and peginterferon based regimens ± asunaprevir (n = 16, including n = 9 cases with cirrhosis and n = 4 patients with HCV-genotype 4) were re-treated for 12 weeks with sofosbuvir plus simeprevir and achieved SVR12 rates of 87% [[8]Hezode C. Chevaliez S. Scoazec G. Soulier A. Varaut A. Bouvier-Alias M. et al.Retreatment with sofosbuvir and simeprevir of patients who previously failed on an HCV NS5A inhibitor-containing regimen.Hepatology. 2015; 62: 763AAbstract Full Text Full Text PDF Scopus (30) Google Scholar]. The pattern of baseline resistance associated variants (RAVs) significantly influenced the likelihood of sustained response which was 83% in 12 cases with NS5A associated RAVs and 75% in the eight cases with NS3 associated RAVs. HCV-genotype 1 failures of sofosbuvir/simeprevir regimens were re-treated after 7–55 weeks with sofosbuvir/ledipasvir either with or without ribavirin for 12 or 24 weeks (n = 42) [[9]Pungpapong S. Leise M.D. Watt K.D. Vargas H.E. Keavney A.P. Aqel B.A. Multicenter experience using sofosbuvir/ledipasvir with or without ribavirin to treat hepatitis C genotype 1 relapsers after simeprevir and sofosbuvir treatment.Hepatology. 2015; 62: 716AGoogle Scholar]. Results were stratified according to different treatment durations and the additional application of ribavirin. Due to different treatment durations and treatment regimens final solid conclusions about the optimal sofosbuvir/ledipasvir regimen in sofosbuvir/simeprevir failures cannot be drawn yet. Treatment options in special populations were presented for HCV-infected patients with end stage renal disease, drug abuse, HCV-genotype 4 infection, or decompensated cirrhosis. Sofosbuvir which is part of most DAA combination regimen is not licensed for patients with end stage renal disease and a glomerular filtration rate <30 ml/min/1.73 m2 and therefore alternative treatment options are eagerly awaited in this patient population. Pockros et al. presented final SVR12 data of the Ruby-I study investigating 12 weeks of paritraprevir/ritonavir, ombitasvir, and dasabuvir (3D regimen) in 20 treatment naïve HCV-genotype 1 infected patients with a glomerular filtration rate of 15–30 ml/min/1.73 m2 (n = 6) and <15 ml/min/1.73 m2 (n = 14) [[10]Pockros P.J. Reddy K.R. Mantry P.S. Cohen E. Bennett M. Sulkowski M.S. et al.RUBY-I: ombitasvir/paritraprevir/ritonavir + dasabuvir +/- ribavirin in non-cirrhotic HCV genotype 1 infected patients with severe renal impairment or end stage renal disease.Hepatology. 2015; 62: 716AGoogle Scholar]. 13 individuals with HCV-genotype 1a received additional ribavirin (200 mg per day). Overall SVR12 rates were 95%. Clinical relevant side effects were mainly related to ribavirin induced anemia. 69% of ribavirin treated patients required a ribavirin dose reduction, four cases received erythropoietin, while blood transfusions were not given in any of the patients. Thus, the 3D regimen seems to be a safe and highly effective treatment option for naïve genotype 1 infected individuals with grade 4 or 5 renal insufficiency. Alternative treatment strategies for patients with end stage renal disease and individuals on hemodialysis will become available soon with market approval of the NS3-/NS5A-inhibitor combination grazoprevir/elbasvir. This treatment option will allow for a 12 weeks treatment duration without ribavirin hereby eliminating the challenge of appropriate ribavirin dosing in impaired renal function [[11]Roth D. Nelson D.R. Bruchfeld A. Liapakis A. Silva M. Monsour Jr, H. et al.Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.Lancet. 2015; 386: 1537-1545Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar]. Patients with drug abuse are the population with the highest rate of HCV infection and this risk factor will be one of the major sources of the future HCV epidemiology. However, these individuals were excluded from all major phase III trials so far. At the Liver Meeting, for the first time controlled study data were presented on the use of direct antiviral agents in patients with drug abuse [[12]Dore G. Altice F. Litwin A.H. Dalgard O. Gane E.J. Shibolet O. et al.C-EDGE CO-STAR: efficacy of grazoprevir and elbasvir in persons who inject drugs (PWID) receiving opioid agonist therapy.Hepatology. 2015; 62: 227AGoogle Scholar]. Chronically HCV-genotype 1, 4, or 6 infected individuals on opioid substitution therapy were treated with grazoprevir plus elbasvir for 12 weeks. Notably, in 61% of cases concomitant drug abuse was detected by positive urine drug screen at baseline and throughout the study period (opiates, benzodiazepines, cocaine, amphetamines). However, in the full analysis set, 184/201 (91%) individuals achieved SVR12. SVR12 results in genotype 6 patients were only 20%, however, only five genotype 6 patients were recruited into the study. Only few patients were lost to follow-up. Five individuals suffered from a re-infection after an initial end of treatment response. These reinfections were observed at follow-up week 8. These data for the first time indicate that treatment with direct antiviral agents of individuals with drug abuse and chronic HCV infection is possible, although treatment settings have to be further evaluated and specified, before a wider use of similar treatment approaches may be recommended in the future. Moreover, concomitant preventive programs to decrease the risk of re-exposure and re-infection should be part of an integrated treatment concept. For patients with chronic HCV-genotype 4 infection, interim results of the so far largest controlled study in this population were presented by Esmat et al. [[13]Esmat G. El Raziky M. Gomaa A. Elbaz T. Abouelkhair M.M. Sabry A. et al.High virologic response rate in Egyptian HCV-genotype 4 patients treated with ravidasvir (PPI-668) and sofosbuvir: results of a large multicenter phase 3 registrational trial.Hepatology. 2015; 62: 1381AGoogle Scholar]. Patients were either treatment naïve or interferon (IFN)-experienced and were treated with sofosbuvir plus a second generation NS5A inhibitor ravidasvir (PPI-668) with or without ribavirin. In HCV-genotype 4 individuals without cirrhosis (n = 170), all cases achieved SVR12 after a treatment period of 12 weeks if they had not prematurely finished therapy due to events not related to the study drugs. In cases with cirrhosis (n = 130) treatment durations of 12 weeks and of 16 weeks for individuals with prior IFN-based therapy were evaluated. In the latter group, all patients achieved SVR12, whereas in the 12 weeks treatment arms, SVR12 results were in the range between 86–93%. Final study data have to be awaited in the future, however, the combination sofosbuvir/ravidasvir seems to be a promising treatment option for HCV-genotype 4 infected individuals. Several abstracts analyzed efficacy and safety of direct antiviral agents in patients with decompensated liver cirrhosis and evaluated consequences on the wait-list for liver transplantation (rate of delisting). In general, it is increasingly possible to treat and cure individuals with advanced HCV-induced liver disease. Shortly after market access of direct antiviral agents, the number of cases listed for liver transplantation due to HCV-induced liver cirrhosis is already declining [[14]Perumpail R.B. Wong R.J. Jayasekera C.R. Gonzalez S.A. Glenn J.S. Younossi Z.M. et al.Decline in hepatitis C virus related liver transplantation waitlist registrations among patients without hepatocellular carcinoma: early effect of direct acting antivirals?.Hepatology. 2015; 62: 1397AGoogle Scholar]. The MELD score lowering capacity of these therapies was analyzed on an individual patient data level of five clinical trials recruiting cases with decompensated cirrhosis by Munoz et al. [[15]Munoz S.J. Reich D.J. Rothstein K.D. Xiao G.S. Patel V. McNulty G.L. et al.Curing decompensated wait listed HCV patients with the new DAAs: the potential significant impact on liver transplant wait list and organ allocation.Hepatology. 2015; 62: 311AAbstract Full Text Full Text PDF Scopus (12) Google Scholar]. A MELD score reduction in response to DAA therapy was observed in 212 patients (56%). The extent of MELD reduction in these patients was 2.86 points after 12 weeks of therapy. The time interval to achieve a MELD score 35. A mathematical model of continued MELD reduction induced by DAA predicted that 993 patients would achieve a MELD below the threshold of transplant benefit (MELD 15) during the first 12 months after DAA therapy, leading to 515 donor livers becoming available for re-distribution to other listed patients during the same period of time. Correct timing of antiviral therapy in patients with decompensated HCV-induced cirrhosis on the waiting list for liver transplantation is of major importance. Data from France and Australia indicate that a major clinical improvement was observed in a minority of patients with MELD score ⩾20 points, suggesting that antiviral treatment might be postponed after liver transplantation in this population [16Coilly A. Pageaux P.G. Housel-Debry P. Duvoux C. Radenne S. De Ledinghen V. et al.Improving liver function and delisting of patients awaiting liver transplantation for HCV cirrhosis: do we ask too much to DAA?.Hepatology. 2015; 62: 257AAbstract Full Text Full Text PDF Scopus (2) Google Scholar, 17McCaughan G. Roberts S.K. Strasser S.I. Gow P. Wigg A.J. Tallis C. et al.The TOSCAR study: sofosbuvir and daclatasvir therapy for decompensated HCV cirrhosis with MELD scores > 15: what is the point of no return?.Hepatology. 2015; 62: 738AGoogle Scholar]. The phase III Astral study program investigated sofosbuvir plus velpatasvir as a pan genotypic once daily single tablet regimen for 12 weeks. Velpatasvir is a second generation NS5A inhibitor with improved resistance profile and antiviral activity against all HCV-genotypes 1–6. All data presented at the Liver Meeting in abstract form are in the meanwhile available as full publications [18Feld J.J. Jacobson I.M. Hezode C. Asselah T. Ruane P.J. Gruener N. et al.Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.N Engl J Med. 2015; 373: 2599-2607Crossref PubMed Scopus (804) Google Scholar, 19Foster G.R. Afdhal N. Roberts S.K. Brau N. Gane E.J. Pianko S. et al.Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.N Engl J Med. 2015; 373: 2608-2617Crossref PubMed Scopus (650) Google Scholar, 20Curry M.P. O’Leary J.G. Bzowej N. Muir A.J. Korenblat K.M. Fenkel J.M. et al.Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.N Engl J Med. 2015; 373: 2618-2628Crossref PubMed Scopus (597) Google Scholar]. In the pivotal trial for HCV-genotypes 1, 2, 4, 5, and 6, SVR12 results were 99%. At baseline, the study population included 19% with compensated cirrhosis and 32% with different prior IFN-based therapies including individuals treated with first generation protease inhibitors [[18]Feld J.J. Jacobson I.M. Hezode C. Asselah T. Ruane P.J. Gruener N. et al.Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.N Engl J Med. 2015; 373: 2599-2607Crossref PubMed Scopus (804) Google Scholar]. In the phase III Astral-3 program for HCV-genotypes 2 and 3, sofosbuvir/velpatasvir was compared to the standard therapy sofosbuvir plus ribavirin [[19]Foster G.R. Afdhal N. Roberts S.K. Brau N. Gane E.J. Pianko S. et al.Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.N Engl J Med. 2015; 373: 2608-2617Crossref PubMed Scopus (650) Google Scholar]. In HCV-genotype 2, sofosbuvir/velpatasvir achieved SVR12 results of 99% compared to 94% after 12 weeks of sofosbuvir/ribavirin. In HCV-genotype 3, 12 weeks sofosbuvir/velpatasvir achieved SVR12 results of 95% compared to 80% after 24 weeks of sofosbuvir/ribavirin. Importantly, the regimen was also highly effective in HCV-genotype 3 patients with cirrhosis who achieved SVR12 rates of 93% and 89% if being treatment naïve or experienced, respectively. Thus, 12 weeks of sofosbuvir/velpatasvir will become a very attractive treatment option for difficult to treat HCV-genotype 3 patients with cirrhosis which will be independent of ribavirin. Finally, sofosbuvir/velpatasvir was also applied in patients with decompensated cirrhosis (Astral-4 study) for either 12 or 24 weeks with or without ribavirin. However, it has to be noted that only 13 patients had a baseline MELD score ⩾16 points and patient numbers of HCV-genotypes 2, 4, and 6 were rather small. Overall, SVR12 rates were 83% after 12 weeks of therapy. HCV-genotype 3 patients with decompensated cirrhosis seem to profit from the addition of ribavirin, because SVR12 results could be improved from 50% to 85%. In patients with HCV-genotype 1a and 1b, addition of ribavirin increased SVR12 rates from 88% to 94% and 89% to 100%, respectively. [[20]Curry M.P. O’Leary J.G. Bzowej N. Muir A.J. Korenblat K.M. Fenkel J.M. et al.Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.N Engl J Med. 2015; 373: 2618-2628Crossref PubMed Scopus (597) Google Scholar]. Extension of treatment duration to 24 weeks did not show any significant benefit in any of the different patient groups. In summary, sofosbuvir/velpatasvir is a pan genotypic once daily single tablet regimen with high antiviral efficacy in many treatment scenarios. It was developed for a treatment duration of 12 weeks, however, it was not analyzed whether shorter treatment durations in easy to treat patients (i.e. in non-cirrhotic treatment naïve HCV-genotype 1 or 2 patients) would have been equally effective. Phase II study programs with second generation DAAs investigated the use of the protease inhibitor ABT-493 and the NS5A-inhibitor ABT-530 in non-cirrhotic genotype 1 and 2 patients or the use of an eight week triple regimen with grazoprevir plus MK-3682 (NS5B polymerase inhibitor) in combination with either elbasvir or MK-8408 (NS5A-inhibbitor) in HCV-genotypes 1–3 [21Poordad F. Felitarza F. Asatryan A. Hassanein T. Aguilar H.I. Lalezari J.P. et al.98%-100% SVR4 in HCV genotype 1 non-cirrhotic treatment-naive or pegylated interferon/ribavirin null responders with the combination of the next generation NS3/4A protease inhibitor ABT-493 and NS5A inhibitor ABT-530 (Surveyor-1).Hepatology. 2015; 62: 228AGoogle Scholar, 22Wyles D. Sulkowski M. Wang S. Bennett M. Vargas H.E. Overcash J.S. et al.High SVR4 rates achieved with the next generation NS3/4A protease inhibbitor ABT-493 and NS5A inhibitor ABT-530 in non-cirrhotic treatment-naive and treatment-experienced patients with HCV-genotype 2 infection (Surveyor-2).Hepatology. 2015; 62: 339AGoogle Scholar, 23Gane E.J. Pianko S. Roberts S.K. Thompson A.J. Zeuzem S. Zuckerman E. et al.Phase 2, randomized, open-label clinical trials of the efficacy and safety of grazoprevir and MK-3682 (NS5B polymerase inhibitor) with either elbasvir or MK-8408 (NS5A inhibitor) in patients with chronic HCV GT1, 2 or 3 infection (Part A of C-Crest 1 & 2).Hepatology. 2015; 62: 1389AGoogle Scholar]. The ABT-493/ABT-530 regimen achieved SVR12 rates of 98–100% after 12 weeks of therapy and will be further investigated for a shorter treatment duration of eight weeks and in patients with cirrhosis or with sofosbuvir/ribavirin failure [21Poordad F. Felitarza F. Asatryan A. Hassanein T. Aguilar H.I. Lalezari J.P. et al.98%-100% SVR4 in HCV genotype 1 non-cirrhotic treatment-naive or pegylated interferon/ribavirin null responders with the combination of the next generation NS3/4A protease inhibitor ABT-493 and NS5A inhibitor ABT-530 (Surveyor-1).Hepatology. 2015; 62: 228AGoogle Scholar, 22Wyles D. Sulkowski M. Wang S. Bennett M. Vargas H.E. Overcash J.S. et al.High SVR4 rates achieved with the next generation NS3/4A protease inhibbitor ABT-493 and NS5A inhibitor ABT-530 in non-cirrhotic treatment-naive and treatment-experienced patients with HCV-genotype 2 infection (Surveyor-2).Hepatology. 2015; 62: 339AGoogle Scholar]. The grazoprevir based triple regimens achieved SVR12 rates >90% in treatment naïve non-cirrhotic patients and will be further studied in additional genotypes, patients with prior treatment, cirrhosis, or HCV/HIV co-infection [[23]Gane E.J. Pianko S. Roberts S.K. Thompson A.J. Zeuzem S. Zuckerman E. et al.Phase 2, randomized, open-label clinical trials of the efficacy and safety of grazoprevir and MK-3682 (NS5B polymerase inhibitor) with either elbasvir or MK-8408 (NS5A inhibitor) in patients with chronic HCV GT1, 2 or 3 infection (Part A of C-Crest 1 & 2).Hepatology. 2015; 62: 1389AGoogle Scholar]. RG-101 is an oligonucleotide inhibitor of the micro RNA-122 (miR-122) linked to GalNAc carbohydrate, which was applied at a dosage of 2 mg/kg or 4 mg/kg as single subcutaneous injection in 28 patients with HCV-genotype 1, 3, or 4 infection in a phase I study (Fig. 1). Interestingly, a single injection induced HCV-RNA negativity lasting for 28 weeks in six out of the 28 individuals [[24]Van der Ree M.H. Vree J.M.D. Stelma F. Willemse S. van der Valk M. Rietdijk S. et al.A single dose of RG-101, a GalNAc-conjugated oligonucleotide targeting miR-122, results in undetactable HCV-RNA levels in chronic hepatitis C patients at week 28 of follow-up.Hepatology. 2015; 62: 315AGoogle Scholar]. RG-101 will be further developed in combination with different marketed direct antiviral agents, and further results will be presented in the year 2016. Actual treatment strategies for chronic hepatitis B virus (HBV) infections are based on long-term treatment with pegylated IFN (PegIFN) for 48 weeks or treatment with nucleosite/nucleotide analogs (NAs). By those drugs, durable suppression of HBV replication is possible for almost all patients, however, loss of HBsAg can only be achieved in a minority of patients (∼10%) and a decrease of HBV covalently closed circular (ccc)DNA, which is the matrix for HBV replication located in the nucleus of infected hepatocytes, is out of reach. In the recent 2015 Liver Meeting, results of a number of studies from pre-clinical and from early clinical phases assessing new compounds against HBV aiming at providing a more profound suppression of HBV replication were presented, but also interesting new approaches how to improve treatment outcome with currently available for HBV infections (Fig. 2). In the study GS-US-174-121 280 patients with lamivudine resistance were randomized 1:1 to receive either tenofovir (TDF) as monotherapy or in combination with emtricitabine. The results after five years of treatment were presented by Fung and co-workers [[25]Fung S. Hann H.W. Elkhashab M. Berg T. Fabri M.J. Horban A. et al.Long term efficacy and safety of tenofovir DF (TDF) in chronic hepatitis B patients (CHB) with documented lamivudine resistance (LAM-R): 5 year results from a randomized, controlled trial.Hepatology. 2015; 62: 1184AGoogle Scholar]. At this time point, 121 (86%) and 118 (85%) of the patients receiving the two treatment regimens were still under observation showing a suppression of HBV DNA to levels <69 IU/ml in 99.2% and 99.1%, respectively. Thus, study confirms findings in treatment naïve patients that the combination of a nucleoside plus nucleotide analog is not superior to the monotherapy with TDF. Of note, HBeAg seroconversion rates were 12% and 10% and HBsAg loss rates at 1% and 4%, respectively, and thus lower as in previously reported long-term trials [[26]Marcellin P. Gane E.J. Flisiak R. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials.Hepatology. 2014; 60: 313AAbstract Full Text Full Text PDF Scopus (44) Google Scholar]. Mean total bone mass density losses of 3% and 1% were seen at week 240 in hip and spine, respectively. Comprehensive resistance analysis throughout the five treatment years were presented by Berg et al. and demonstrated persistence of Lam resistance variant in in 3 of 7 patients with detectable HBV DNA in the combination arm and in none of 4 patients receiving TDF monotherapy, but there was no evidence of emergent TDF resistance [[27]Berg T. Gane E.J. Jablkowski M.S. Urbanek P. Corsa A.C. Liu Y. No detectable resistance to tenofovir disoproxil fumarate (TDF) when given alone or in combination with emtricitabine (FTC) in chronic hepatitis B (CHB) patients with documented resistance to lamivudine (LAM): final 5 year results.Hepatology. 2015; 62: 1027AGoogle Scholar]. Chan et al. presented an analysis of early HBsAg kinetics in a large open-label study assessing the efficacy of combination treatment with TDF and PegIFN-α2a. A total of 740 participants were randomly assigned to receive either TDF + PegIFN for 48 weeks, TDF + PegIFN for 16 weeks and then continuing on TDF alone through week 48, to TDF monotherapy for 120 weeks or to PegIFN monotherapy for 48 weeks [[28]Chan H.L. Ahn S.H. Chuang W.L. Tabak F. Mehta R. Petersen J. Early decline in serum HBsAg at week 4 and 12 of therapy with tenofovir disoproxil fumarate and pegylated interferon is predictive of HBsAg loss.Hepatology. 2015; 62: 333AGoogle Scholar]. In the present analysis it was shown that alanine aminotransferase (ALT) flares induced by combination TDF + PegIFN for 48 weeks led to profound HBsAg decline in the HBeAg positive and negative group, in contrast to the other PegIFN containing treatment arms where ALT flares were only associated with HBsAg decline in HBeAg positive patients. Among patients treatment with combination of TDF + PegIFN, sixteen patients experienced HBsAg loss by week 72,