Benedetta Massetto

Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): A multicentre, open-label, non-randomised, phase 3 study

BACKGROUND Although interferon-free regimens are approved for patients co-infected with HIV and genotype-2 or genotype-3 hepatitis C virus (HCV), interferon-based regimens are still an option for those co-infected with HIV and HCV genotypes 1 or 4. These regimens are limited by clinically significant toxic effects and drug interactions with antiretroviral therapy. We aimed to assess the efficacy and safety of an interferon-free, all-oral regimen of sofosbuvir plus ribavirin in patients with HIV and HCV co-infection. METHODS We did this open-label, non-randomised, uncontrolled, phase 3 study at 45 sites in seven European countries and Australia. We enrolled patients (aged ≥18 years) co-infected with stable HIV and chronic HCV genotypes 1-4, including those with compensated cirrhosis. Once-daily sofosbuvir (400 mg) plus twice-daily ribavirin (1000 mg in patients with bodyweights <75 kg and 1200 mg in those with weights ≥75 kg) was given for 24 weeks to all patients except treatment-naive patients with genotype-2 HCV, who received a 12-week regimen. The primary efficacy endpoint was sustained virological response 12 weeks after treatment. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01783678. FINDINGS Between Feb 7, 2013, and July 29, 2013, we enrolled 275 eligible patients, of whom 262 (95%) completed treatment; 274 patients were included in the final analysis. Overall rates of sustained virological response 12 weeks after treatment were 85% (95% CI 77-91) in patients with genotype-1 HCV, 88% (69-98) in patients with genotype-2 HCV, 89% (81-94) in patients with genotype-3 HCV, and 84% (66-95) in patients with genotype-4 HCV. Response rates in treatment-naive patients with HCV genotypes 2 or 3 (89% [95% CI 67-99] and 91% [81-97], respectively) were similar to those in treatment-experienced patients infected with those genotypes (83% [36-100] and 86% [73-94], respectively). There was no emergence of sofosbuvir-resistance mutations in patients with HCV viral relapse. Six (2%) patients discontinued treatment because of adverse events. The most common adverse events were fatigue, insomnia, asthenia, and headache. Four (1%) patients had serious adverse events regarded as related to study treatment. Additionally, four (1%) patients receiving antiretroviral treatment had a transient HIV viral breakthrough; however, none required changes in antiretroviral regimen. INTERPRETATION Sofosbuvir and ribavirin provided high rates of sustained virological response after 12 weeks of treatment in treatment-naive and treatment-experienced patients co-infected with HIV and HCV genotypes 1-4. The characteristics of this interferon-free combination regimen make sofosbuvir plus ribavirin a useful treatment option for this patient population. FUNDING Gilead Sciences.

Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a

BACKGROUND & AIMS It was recently demonstrated that none of the hepatitis B e antigen (HBeAg)-negative patients without any serum hepatitis B surface antigen (HBsAg) decline and with <2log hepatitis B virus (HBV) DNA decline at week 12 of a 48-week peginterferon alfa-2a (PEG-IFN) treatment course achieved a sustained response (SR). We aimed at validating this stopping rule in two independent trials. METHODS HBeAg-negative patients receiving 48 or 96 weeks of PEG-IFN in the phase III registration trial (N=85) and PegBeLiver study (N=75) were stratified according to the presence of any HBsAg decline and/or 2log HBV DNA decline at week 12. SR was defined as HBV DNA <2000IU/ml and normal alanine aminotransferase 24 weeks after treatment. RESULTS The original PARC trial included 102 patients (genotype A/D/other: 14/81/7), 25 (25%) had an SR. The validation dataset consisted of 160 patients (genotype A/B/C/D/other: 10/18/34/91/7), 57 (36%) achieved an SR. The stopping rule performed well across the two studies (p=0.001) and its negative predictive value [NPV] was 95% in the validation dataset harbouring genotypes A-D. Its performance was best for genotype D. Moreover, among the 34 patients treated for 96 weeks, none of the 7 (21%) without HBsAg decline and with <2log HBV DNA decline at week 12 achieved an SR (NPV 100%). CONCLUSIONS We confirmed in two independent studies that the combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients with a very low chance of SR to either 48 or 96 weeks of PEG-IFN therapy.

Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is active against lamivudine-resistant hepatitis B virus (HBV) infection, but data to support its clinical efficacy in this setting are limited. METHODS In a prospective, double-blind, 96-week trial, patients were randomly assigned (1:1) to groups given TDF (300 mg, n = 141) or a combination of emtricitabine (FTC, 200 mg; n = 139) and TDF (300 mg, FTC/TDF). Patients were hepatitis B e antigen (HBeAg)-positive or HBeAg-negative, with levels of HBV DNA ≥3 log10 IU/mL and lamivudine resistance mutations (HBV polymerase or reverse transcriptase amino acid substitutions rtM204I/V ± rtL180M by INNO-LiPA Multi-DR v3; Innogenetics, Inc, Alpharetta, GA). The primary end point was proportion with HBV DNA <69 IU/mL (Roche COBAS Taqman assay; Roche Molecular Systems, Inc, Pleasanton, CA). RESULTS Patient groups were well matched for demographic and disease characteristics, including region (60% from Europe), HBV genotype (45% genotype D), HBeAg status (47% HBeAg-positive), and duration of lamivudine treatment (mean, 3.8 years). At week 96 of treatment, 89.4% of patients in the TDF group and 86.3% in the FTC/TDF group had levels of HBV DNA <69 IU/mL (P = .43). HBeAg loss and seroconversion did not differ between groups; only 1 patient (0.7%) in the FTC/TDF group lost hepatitis B surface antigen. Treatment was well tolerated; confirmed renal events (creatinine increase of ≥0.5 mg/dL [>44 umol/L], creatinine clearance <50 mL/min, or level of PO4 <2 mg/dL [<0.65 mmol/L]) were generally mild and infrequent (<1%). Small reductions (<2%) in mean bone mineral density of hip and spine were detected by dual-energy x-ray absorptiometry in both groups. No TDF resistance developed through 96 weeks of treatment. CONCLUSIONS TDF alone is safe and effective for treatment of patients with lamivudine-resistant, chronic HBV infection. Clinical Trials.gov No, NCT00737568.

The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection

BACKGROUND & AIMS GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B. METHODS In two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha. RESULTS Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point. CONCLUSIONS Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.

Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry

BACKGROUND & AIMS We conducted an open-label phase 2 study to assess the efficacy and safety of the oral nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin in patients of Egyptian ancestry, chronically infected with genotype 4 hepatitis C virus (HCV). METHODS Treatment-naive and previously treated patients with genotype 4 HCV were randomly allocated in a 1:1 ratio to receive sofosbuvir 400mg and weight-based ribavirin, for 12 or 24 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response (HCV RNA <25IU/ml) 12 weeks after cessation of therapy (SVR12). RESULTS Thirty treatment-naive and thirty previously treated patients were enrolled and treated for 12 weeks (n=31) or 24 weeks (n=29). Overall, 23% of patients had cirrhosis and 38% had diabetes. 14% of treatment-naive patients were interferon ineligible and 63% of treatment-experienced patients had prior non-response. SVR12 was achieved by 68% of patients (95% CI, 49-83%) in the 12-week group, and by 93% of patients (95% CI, 77-99%) in the 24-week group. The most common adverse events were headache, insomnia, and fatigue. No patient discontinued treatment due to an adverse event. CONCLUSIONS The findings from the present study suggest that 24 weeks of sofosbuvir plus ribavirin is an efficacious and well tolerated treatment in patients with HCV genotype 4 infection.

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

BACKGROUND The novel prodrug tenofovir alafenamide delivers the nucleotide reverse transcriptase inhibitor tenofovir to target cells more efficiently at a lower dose than tenofovir disoproxil fumarate, thereby reducing systemic exposure. We compared the efficacy and safety of the two drugs in patients with HBeAg-negative chronic hepatitis B virus (HBV) infection in a non-inferiority study. METHODS In this ongoing randomised, double-blind, phase 3, non-inferiority study in 105 centres in 17 countries, patients with HBeAg-negative chronic HBV were randomly assigned (2:1) by a computer-generated allocation sequence (block size six), stratified by plasma HBV DNA concentration and previous treatment status, to receive once-daily oral doses of tenofovir alafenamide 25 mg or tenofovir disoproxil fumarate 300 mg, each with matching placebo. Participants, investigators, and those assessing outcomes were masked to group assignment. Eligible patients were aged at least 18 years with HBeAg-negative chronic HBV infection (with plasma HBV DNA concentrations of >20 000 IU/mL), serum alanine aminotransferase concentrations of greater than 60 U/L in men or greater than 38 U/L in women and at no more than ten times the upper limit of normal, and estimated creatinine clearance of at least 50 mL/min (by the Cockcroft-Gault method). The primary efficacy endpoint was the proportion of patients who had HBV DNA less than 29 IU/mL at week 48 in those who received at least one dose of study drug; the study was powered to show non-inferiority with a 10% efficacy margin of tenofovir alafenamide compared with tenofovir disoproxil fumarate. Bone and renal safety, and key secondary safety endpoints were assessed sequentially. The study will be conducted for a total of 3 years as a double-blind comparison to assess the longer term response to treatment. This study is registered with ClinicalTrials.gov, number NCT01940341. FINDINGS Between Sept 12, 2013, and Oct 31, 2014, 426 patients were randomly assigned (285 assigned to tenofovir alafenamide and 141 assigned to tenofovir disoproxil fumarate; one patient assigned to tenofovir disoproxil fumarate did not receive the treatment. 268 (94%) of 285 patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48 versus 130 (93%) of 140 patients receiving tenofovir disoproxil fumarate (difference 1·8% [95% CI -3·6 to 7·2]; p=0·47), which demonstrates non-inferiority. Patients receiving tenofovir alafenamide had significantly smaller mean percentage declines in bone mineral density than those receiving tenofovir disoproxil fumarate (hip -0·29% [95% CI -0·55 to -0·03] vs -2·16% [-2·53 to -1·79], adjusted percentage difference 1·87% [95% CI 1·42 to 2·32; p<0·0001]; spine -0·88% [-1·22 to -0·54] vs -2·51% [-3·09 to -1·94], adjusted percentage difference 1·64% [95% CI 1·01 to 2·27]; p<0·0001). At week 48, mean change in serum creatinine was small in both groups (tenofovir alafenamide 0·01 mg/dL [95% CI 0·00 to 0·02] vs tenofovir disoproxil fumarate 0·02 mg/dL [0·00 to 0·04], adjusted percentage difference -0·01 mg/dL [95% CI -0·03 to 0·01]; p=0·32), but patients receiving tenofovir alafenamide had a smaller reduction in creatinine clearance (median change in estimated glomerular filtration rate -1·8 mL/min [IQR -7·8 to 6·0] vs -4·8 mL/min [-12·0 to 3·0]; p=0·004). Most adverse events were mild to moderate in severity in the two treatment groups. The most common adverse events overall were headache (tenofovir alafenamide 40 [14%] patients vs tenofovir disoproxil fumarate 14 [10%] patients), nasopharyngitis (30 [11%] vs 15 [11%]), and upper respiratory tract infection (35 [12%] vs ten [7%]). 14 (5%) patients receiving tenofovir alafenamide and nine (6%) patients receiving tenofovir disoproxil fumarate had serious adverse events, none of which was deemed by investigators to be related to study treatment; one patient in the tenofovir disoproxil fumarate group died, but this was not deemed to be related to study treatment. INTERPRETATION In patients with HBeAg-negative chronic HBV, the efficacy of tenofovir alafenamide was non-inferior to that of tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING Gilead Sciences.

Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4

BACKGROUND & AIMS Egypt has the highest prevalence of chronic hepatitis C virus (HCV) infection in the world, and more than 90% of patients are infected with genotype 4 virus. We evaluated the efficacy and safety of the HCV polymerase inhibitor sofosbuvir in combination with ribavirin in HCV genotype 4 patients in Egypt. METHODS Treatment-naïve or treatment-experienced patients with genotype 4 HCV infection (n=103) were randomly assigned to receive either 12 or 24 weeks of sofosbuvir 400 mg and ribavirin 1000-1200 mg daily. Randomization was stratified by prior treatment experience and by presence or absence of cirrhosis. The primary endpoint was the percentage of patients with HCV RNA <25 IU/ml 12 weeks after therapy (SVR12). RESULTS Among all patients, 52% had received prior HCV treatment and 17% had cirrhosis at baseline. SVR12 rates were 90% (46/51) with 24 weeks and 77% (40/52) with 12 weeks of sofosbuvir and ribavirin therapy. Patients with cirrhosis at baseline had lower rates of SVR12 (63% 12 weeks, 78% 24 weeks) than those without cirrhosis (80% 12 weeks, 93% 24 weeks). The most common adverse events were fatigue, headache, insomnia, and anemia. Two patients experienced serious adverse events (cerebral ischemia, dyspnea). No adverse events resulted in treatment discontinuation. CONCLUSION Sofosbuvir plus ribavirin for 12 or 24 weeks is effective in treating both treatment-naïve and treatment-experienced Egyptian patients with genotype 4 HCV.

Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B

Objective Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population. Methods 128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 μg PegIFN for 48 weeks (group A, n=51), 180 μg PegIFN for 48 weeks followed by 135 μg weekly for an additional 48 weeks (group B, n=52) or 180 μg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 μg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (primary), HBV DNA <2000 IU/ml and HBsAg clearance at 48 weeks after treatment. Results Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA <2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg <10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events. Conclusions In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment. Trial registration number http://ClinicalTrials.gov registration number: NCT01095835.

Treatment With Ledipasvir–Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial

Nearly 10% of kidney transplant recipients in Western countries have chronic hepatitis C virus (HCV) infection (1). The higher HCV prevalence in kidney transplant recipients than in the general population is a direct consequence of the association between HCV infection and kidney impairment as well as an increased risk for HCV infection acquired during hemodialysis or from blood transfused before routine HCV screening (2, 3). Chronic HCV infection increases the risk for end-stage renal disease (47) and, in kidney transplant patients, is associated with higher graft loss and mortality rates (810). Treatment with interferon regimens has been limited because of the increased risk for interferon-mediated graft rejection and relatively low efficacy, resulting in an unacceptable riskbenefit ratio (8, 11). Direct-acting antiviral agents (DAAs) were developed that are highly effective against all HCV genotypes and seemed to be safe and effective in clinical trials as well as in studies of immunocompromised patients, such as orthotopic liver transplant recipients with HCV infection. Interest in using DAAs to treat HCV infection in kidney transplant patients has increased; however, data regarding their use in this population are very limited (3, 12, 13). In 2 small studies, treatment with a combination of DAAs for 12 weeks led to high rates of sustained virologic response (SVR) in kidney transplant recipients, with no significant adverse events or graft rejection noted (14, 15). In clinical trials, the fixed-dose combination of ledipasvir and sofosbuvir given for 12 or 24 weeks provided SVR rates ranging from 93% to 99% in treatment-naive and -experienced patients with HCV genotype 1, 4, 5, or 6 infection (1620). European and North American guidelines recommend as first-line options treatment with ledipasvirsofosbuvir for 12 weeks, along with ribavirin for patients without cirrhosis or with ribavirin for those with cirrhosis, or for 24 weeks without ribavirin in patients with cirrhosis who are intolerant or have a contraindication to ribavirin (21, 22). The high efficacy observed with fixed-dose ledipasvirsofosbuvir, even when not administered with ribavirin, represents a critical advantage for treating patients with impaired kidney function, avoiding the need for complicated ribavirin dosing strategies and assessment of ribavirin blood concentration. In addition, the lack of significant drugdrug interactions between ledipasvirsofosbuvir and immunosuppressant drugs and the absence of a clinically relevant effect of hepatic dysfunction on drug pharmacokinetics support its use in treating HCV recurrence after liver transplantation (23, 24). On the basis of these encouraging data, we conducted the first multinational, randomized, controlled study to make an exploratory comparison of the efficacy and safety of 12 and 24 weeks of ledipasvirsofosbuvir without ribavirin in kidney transplant patients with chronic HCV genotype 1 or 4 infection. Supplement. Study Protocol Methods Setting and Participants Patients were enrolled at 5 clinical sites in 4 European countries: Italy, France, Austria, and Germany. Eligible patients were aged 18 years or older; had chronic HCV genotype 1 or 4 infection, with plasma HCV RNA levels of 15 IU/mL or greater; and had received a kidney transplant at least 6 months before the baseline study visit. Patients with compensated cirrhosis were eligible, with cirrhosis defined as a METAVIR score of 4 or an Ishak score of 5 or greater by biopsy, a FibroScan (Echosens) value greater than 12.5 kPa, or a FibroTest (BioPredictive) score greater than 0.75 plus an aspartate aminotransferaseplatelet ratio index greater than 2. Patients were excluded from participation if they had a body mass index less than 18 kg/m2; decompensated liver disease (that is, presence of ascites, encephalopathy, or variceal hemorrhage); an electrocardiogram with clinically significant abnormalities; HIV infection; hepatitis B virus infection; creatinine clearance less than 40 mL/min, as calculated by the CockcroftGault equation; an albumin level lower than 30 g/L; an international normalized ratio greater than 1.5 times the upper limit of normal (unless the patient had hemophilia or was stable while receiving an anticoagulant regimen affecting international normalized ratio); a hemoglobin level lower than 100 g/L; a platelet level of 50109 cells/L or less; a direct bilirubin level greater than 1.5 times the upper limit of normal, except for patients with Gilbert syndrome; and an alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase level greater than 10 times the upper limit of normal. All patients provided written informed consent before undertaking any study-related procedures. Study Design Patients were randomly assigned 1:1 to receive either 12 or 24 weeks of treatment with a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily by means of an integrated Web response system (Bracket). A statistician employed by the sponsor generated the randomization code by using SAS version 9.2 (SAS Institute). Randomization was stratified by genotype, treatment history (treatment naive or experienced), and the presence or absence of cirrhosis. Investigators, patients, and trial personnel were not blinded to treatment assignment. The study protocol was approved by each institutions review board or ethics committee before study initiation. The study was conducted in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice Guidelines and the Declaration of Helsinki. All authors had access to the study data and reviewed and approved the final manuscript before journal submission. Study Assessments Plasma HCV RNA was analyzed by using the COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 (Roche Molecular Systems), with a lower limit of quantification (LLOQ) of 15 IU/mL. Hepatitis C virus genotype and subtype were determined by using the Versant HCV Genotype INNO-LiPA 2.0 assay (Siemens). An interleukin-28B genotype test was done through polymerase chain reaction amplification and sequencing of the rs12979860 single-nucleotide polymorphism. Plasma samples for viral sequencing were collected at the same time points as those for HCV RNA levels. Deep sequencing of the NS5A and NS5B regions of the HCV RNA with MiSeq technology (DDL Diagnostic Laboratory) was performed on samples collected from all patients at baseline and on posttreatment samples from all patients with virologic failure. The resulting sequences were compared with reference sequences to determine the prevalence of resistance-associated substitutions (RASs) and the association of RASs with virologic outcomes. Resistance-associated substitutions present at more than 15% of sequence reads are reported. Adverse events were recorded from day 1 of treatment until 30 days after the last dose; serious adverse events and adverse events related to protocol-mandated procedures were collected from screening through the last day of follow-up (posttreatment week 24) or 30 days after the last dose. The data included reported adverse events as well as the results of physical examinations and clinical laboratory tests, vital signs, and electrocardiogram recordings. Treatment-emergent clinical and laboratory adverse events were summarized by using the Medical Dictionary for Regulatory Activities (MedDRA), version 19.0 (the MedDRA trademark is owned by the International Federation of Pharmaceutical Manufacturers and Associations on behalf of the ICH). Virologic relapse was defined as HCV RNA at the LLOQ or higher during the posttreatment period in a patient who had HCV RNA less than the LLOQ at the end of treatment. End Points and Statistical Analysis The primary efficacy end point was the percentage of patients with HCV RNA less than the LLOQ 12 weeks after stopping the study drug (SVR12). In the primary efficacy analysis, the SVR12 rate was calculated with a 2-sided 95% exact CI by using the ClopperPearson method (25). Patients with missing HCV RNA values at posttreatment week 12 who had posttreatment HCV RNA values less than the LLOQ before and after the missing posttreatment week 12 value were assumed to have achieved SVR12. This study was exploratory in nature; no inferential statistics or statistical comparisons were planned. The primary safety end point was any adverse event leading to permanent discontinuation of the study drug. We used SAS, version 9.2, for all statistical analyses. Role of the Funding Source The sponsor designed and conducted the study in collaboration with the principal investigators, collected the data, and monitored the study conduct. Results Study Population Of 130 patients screened, 16 (12.3%) were excluded: 11 did not meet eligibility criteria, 2 withdrew consent, and 3 were excluded because of existing clinically significant medical conditions (atrial fibrillation, planned heart surgery, and hyponatremia with a urinary tract infection). A total of 114 patients were enrolled and treated at 5 sites in 4 European countries between 7 November 2014 and 16 June 2015 (Appendix Figure). Overall, 94% of the patients were white and 58% were male (Table 1). Most were treatment naive (69%), did not have cirrhosis (85%), and had genotype 1 infection (91%). Of the patients with genotype 1 infection, 75% had genotype 1b infection. Appendix Figure. Patient disposition. LDVSOF = ledipasvirsofosbuvir. Table 1. Demographic and Baseline Characteristics* Efficacy Ledipasvirsofosbuvir treatment resulted in rapid HCV RNA suppression (Table 2). By week 4, 102 of 114 patients (89%) had HCV RNA less than the LLOQ (with target not detectable in 68%). By week 8, all 113 evaluable patients (100% [excluding 1 patient in the 12-week group who discontinued study treatment at week 4 because of a serious adverse event]) had HCV RNA less than the LLOQ (with target not detectable in 112 of 113 [99%]). At the end of treatment, a

Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate

BACKGROUND & AIMS In a study of 266 chronic hepatitis B e antigen (HBeAg)-positive patients, 23 experienced hepatitis B surface antigen (HBsAg) loss with up to 5 years of tenofovir disoproxil fumarate (TDF) treatment. HBsAg kinetics in patients with and without HBsAg loss and predictors of HBsAg loss were evaluated. METHODS HBsAg levels were quantified every 12 weeks. A multivariable regression analysis, involving prespecified baseline characteristics and on-treatment response parameters, was performed; a stepwise procedure identified independent predictors of HBsAg loss. RESULTS Among patients with HBsAg loss, 14 (61%), 1 (4%), 0 and 7 (30%) were genotypes A through D, respectively; 1 (4%) was genotype F. HBsAg loss was preceded by viral suppression (HBV DNA <29 IU/ml; n=23) and HBeAg loss (n=19). Among treated patients the strongest independent predictors of HBsAg loss were Caucasian race with genotype A/D and ⩽4 years of infection (HR=14.3, 95% confidence interval [CI] 4.7-43.4; p<0.0001) and an HBsAg decline of ⩾1 log10 IU/ml at week 24 (HR=13.7, 95% CI 5.6-33.7; p<0.0001). Among TDF-treated patients, a reduction in HBsAg level of ⩾1-log10 by week 12 or 24 had a positive predictive value of 35%-45%, respectively, and a negative predictive value of 94%-97%, respectively. CONCLUSIONS HBsAg loss in HBeAg-positive patients receiving TDF involves a chronology of virologic and serologic responses; patients with HBV genotypes A or D and a rapid early decline in HBsAg are more likely to lose HBsAg.