Faculty Bibliography

BACKGROUND: Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. METHODS: After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (>/=2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (>/=1 unit decrease by Ishak scoring system). FINDINGS: Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0.0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (>/=1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0.0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug. INTERPRETATION: In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. FUNDING: Gilead Sciences.

For patients treated with telaprevir, peginterferon, and ribavirin, futility rules have been developed to prevent needless drug exposure and minimize development of drug-resistant variants for patients who have little or no chance of achieving a sustained virologic response. We performed retrospective analyses of data from phase 3 trials and validated the current futility rule. All therapy should be stopped for treatment-naive and treatment-experienced patients if hepatitis C virus RNA levels are greater than 1000 IU/mL at weeks 4 or 12, or if hepatitis C virus RNA is detectable at week 24.

Telaprevir is a recently approved direct-acting antiviral against hepatitis C virus (HCV) that works through inhibition of the NS3/4A serine protease inhibitor. Phase 2b and 3 studies have shown marked increase in sustained virologic response rates in both treatment-naive and treatment-experienced patients with HCV genotype 1 treated with a telaprevir-containing regimen compared with pegylated interferon (Peg-IFN) and ribavirin alone. The most commonly observed side effects of telaprevir therapy are anemia to a greater degree than that observed with Peg-IFN/ribavirin alone; eczematous rash, which can be severe in a minority of patients; and anorectal discomfort.

Telaprevir is a recently approved direct-acting antiviral against hepatitis C virus (HCV) that works through inhibition of the NS3/4A serine protease inhibitor.Phase 2b and 3 studies have shown marked increase in sustained virological response rates in both treatment-naive and treatment-experienced patients with HCV genotype 1 treated with a telaprevir-containing regimen compared with pegylated interferon (PEG-IFN) and ribavirin alone. The most commonly observed side effects of telaprevir therapy are anaemia to a greater degree than that observed with PEG-IFN/ribavirin alone; eczematous rash, which can be severe in a minority of patients; and anorectal discomfort.

BACKGROUND & AIMS: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with boceprevir plus peginterferon alfa-2a-ribavirin (PEG2a/R) in patients with identical study entry criteria. METHODS: In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended. RESULTS: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P < .0001). Among patients with poor response to interferon therapy (<1-log(10) decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (>/=1-log(10) decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A >/=1-log(10) decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin <10.0 g/dL), compared with 27% in the PEG2a/R group; 43% vs 21%, respectively, developed neutropenia (neutrophil count <750/mm(3)). CONCLUSIONS: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065.

Resolution of chronic hepatitis C is considered when serum HCV RNA becomes repeatedly undetectable and liver enzymes normalize. However, long-term persistence of HCV following therapy with pegylated interferon-alpha/ribavirin (PegIFN/R) was reported when more sensitive assays and testing of serial plasma, lymphoid cells (PBMC) and/or liver biopsies was applied. Our aim was to reassess plasma and PBMCs collected during and after standard PegIFN/R therapy from individuals who became HCV RNA nonreactive by clinical testing. Of particular interest was to determine if HCV genome and its replication remain detectable during ongoing treatment with PegIFN/R when evaluated by more sensitive detection approaches. Plasma acquired before (n = 11), during (n = 25) and up to 12-88 weeks post-treatment (n = 20) from 9 patients and PBMC (n = 23) from 3 of them were reanalyzed for HCV RNA with sensitivity <2 IU/mL. Clone sequencing of the HCV 5'-untranslated region from plasma and PBMCs was done in 2 patients. HCV RNA was detected in 17/25 (68%) plasma and 8/10 (80%) PBMC samples collected from 8 of 9 patients during therapy, although only 5.4% plasma samples were positive by clinical assays. Among post-treatment HCV RNA-negative plasma samples, 9 of 20 (45.3%) were HCV reactive for up to 59 weeks post-treatment. Molecularly evident replication was found in 6/12 (50%) among PBMC reactive for virus RNA positive strand collected during or after treatment. Pre-treatment point mutations persisted in plasma and/or PBMC throughout therapy and follow-up. Therefore, HCV is not completely cleared during ongoing administration of PegIFN/R otherwise capable of ceasing progression of CHC and virus commonly persists at levels not detectable by the current clinical testing. The findings suggest the need for continued evaluation even after patients achieve undetectable HCV RNA post-treatment.

BACKGROUND: Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. METHODS: SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-alpha2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs). RESULTS: A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm. CONCLUSIONS: SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.

Background: Patients in P/R control arms of BOC Phase II/III studies who did not achieve SVR could receive BOC + P/R in PROVIDE. This interim analysis examines preliminary efficacy and safety of BOC + P/R in patients who failed prior P/R treatment. Methods: BOC (800 mg TID) was given with P 1.5 mcg/kg/week and weight-based R (600-1400 mg/ day) BID for up to 44 weeks. If > 2 weeks had elapsed since end of treatment (EOT) in the previous study, P/R was given for 4 weeks before adding BOC. Analyses included patients who received >=1 BOC dose. Denominators for on-treatment response included patients who reached the specific time point or discontinued, while those for SVR included all who reached end of follow-up, discontinued, or failed treatment. Results: 67% of 168 enrolled patients were male, 84% Caucasian, mean age 52 years, mean body mass index (BMI) 27.9 kg/m2, 77% high viral load (>800,000 IU/mL; mean log10 6.26); 10% cirrhotic; 61% HCV subtype 1a. SVR was achieved in 40% of prior null responders (<2 log10 decline in HCV RNA at TW12 in prior study) and 68% of partial responders/ relapsers; 78% (38/49) of prior null responders and 24% (26/107) of partial responders/relapsers had <1 log10 decline in HCV RNA after P/R lead in. Overall SVR was 47% in patients with <1 log10 decline with 36% SVR rates in prior null versus 65% partial responders/relapsers. 68% of patients with >=1 log decline achieved SVR (55% prior null; 70% prior partial responders/relapsers) and 7% discontinued due to adverse events. (Table Presented) Conclusions: BOC + P/R achieved high SVR rates regardless of prior response to P/R. Degree of interferon responsiveness after P/R lead in correlated with prior response and could help predict SVR for prior null responders. The safety profile was comparable to that previously reported for BOC + P/R