Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels.

UNLABELLED: On-treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG-IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown limited external validity. We analyzed 803 HBeAg-positive patients treated with PEG-IFN in three global studies with available HBsAg measurements. A stopping-rule based on absence of a decline from baseline was compared to a prediction-rule that uses HBsAg levels of <1,500 IU/mL and >20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level <1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA <2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg >20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG-IFN monotherapy (n = 465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value [NPV]: 97%-100%), and in patients with genotypes B or C if HBsAg at week 12 was >20,000 IU/mL (NPV: 92%-98%). At week 24, nearly all patients with HBsAg >20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). CONCLUSION: HBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB. HBV genotype-specific stopping-rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype.

Telaprevir for previously treated chronic HCV infection.

BACKGROUND: Patients with genotype 1 hepatitis C virus (HCV) who do not have a sustained response to therapy with peginterferon alfa and ribavirin have a low likelihood of success with retreatment. METHODS: We randomly assigned patients with HCV genotype 1 who had not had a sustained virologic response after peginterferon alfa-ribavirin therapy to one of four treatment groups: 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 hours) for 12 weeks and peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 24 weeks; 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group); 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at the same doses as in the T12PR24 group); and 114 patients to the PR48 (or control) group, receiving peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group). The primary end point was sustained virologic response (undetectable HCV RNA levels 24 weeks after the last dose of study drugs). RESULTS: The rates of sustained virologic response in the three telaprevir groups--51% in the T12PR24 group, 53% in the T24PR48 group, and 24% in the T24P24 group--were significantly higher than the rate in the control group (14%; P<0.001, P<0.001, and P=0.02, respectively). Response rates were higher among patients who had previously had relapses than among nonresponders. One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of patients, with severe rash in 5%). Discontinuation of study drugs because of adverse events was more frequent in the telaprevir groups than in the control group (15% vs. 4%). CONCLUSIONS: In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirin was more effective than retreatment with peginterferon alfa-2a and ribavirin alone. (ClinicalTrials.gov number, NCT00420784.)

Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B.

UNLABELLED: Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN ± lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.

Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response.

UNLABELLED: Retreatment with peginterferon alpha and ribavirin (PR) offers a limited chance of sustained virologic response (SVR) in patients who did not achieve SVR with prior PR treatment. This study evaluated the safety and efficacy of telaprevir-based treatment in combination with PR in well-characterized patients who did not achieve SVR in the control arms of three Phase II clinical trials. Patients eligible to enroll in this open-label nonrandomized study either met on-treatment criteria for nonresponse or relapsed after 48 weeks of treatment in the control arm of the three Phase II PROVE studies. The initial protocol was a 24-week regimen: 12 weeks of telaprevir and PR followed by an additional 12 weeks of PR. During the study the protocol was amended to extend PR to 48 weeks for patients with previous null response. All other patients with undetectable hepatitis C virus (HCV) RNA at weeks 4 and 12 received 24 weeks of therapy. Those with detectable HCV RNA at weeks 4 or 12 received a total of 48 weeks of therapy. The overall SVR rate was 59% (69/117). SVR rates with T12PR were 37% (19/51) in prior null responders, 55% (16/29) in prior partial responders, 75% (6/8) in prior breakthroughs, and 97% (28/29) in prior relapsers. The overall relapse rate was 16% (13/83). Adverse events were similar to those in previous trials with telaprevir, with 9% of patients discontinuing due to an adverse event (most commonly rash and anemia). CONCLUSION: This study demonstrated the benefit of retreatment with a telaprevir-based regimen for patients with well-characterized nonresponse (null and partial) or relapse to a prior course of PR treatment.

FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program.

BACKGROUND & AIMS: EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. METHODS: Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. RESULTS: Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p ≤ 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p ≤ 0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). CONCLUSIONS: FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin.

Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy.

BACKGROUND & AIMS: Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. METHODS: This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 microg/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigator's request. RESULTS: Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (< or =600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. CONCLUSIONS: Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report.

Abstract Hepatitis C virus (HCV) genotypes 4, 5 and 6 represent >20% of all HCV cases worldwide. HCV-4 is mainly seen in Egypt, where it represents 90% of all HCV cases. Antischistosomal therapy was the main cause of contamination there, followed by procedures performed by informal providers and traditional healers such as dental care, wound treatment, circumcision, deliveries, excision and scarification. It is also highly prevalent in sub-Saharan Africa and in the Middle East. In Europe, its prevalence has recently increased particularly among intravenous drug users and in immigrants. HCV-5 is mainly found in South Africa, where it represents 40% of all HCV genotypes, but four pockets of HCV-5 were found in France, Spain, Syria and Belgium and sporadic cases were found elsewhere. The mode of transmission is mainly iatrogenic and transfusion. HCV-6 is found in Hong Kong, Vietnam, Thailand and Myanmar and also in American and Australian from Asian origin. The response to treatment in HCV-4 is intermediate between HCV-1 and HCV-2 and HCV-3. A sustained viral response is achieved in 43-70% with pegylated interferon and ribavirin. It is higher in Egyptians than Europeans and Africans and is negatively related to insulin resistance and to the severity of fibrosis. It increases to >80% with 24 weeks of therapy only if a rapid virological response is achieved. In HCV-5, a sustained virological response is achieved in >60% with 48 weeks of therapy. HCV-6 is also considered an easy-to-treat genotype, leading to a response in 60-85% of cases.

Early HBeAg loss during peginterferon alpha-2b therapy predicts HBsAg loss: results of a long-term follow-up study in chronic hepatitis B patients.

OBJECTIVES: Treatment with pegylated interferon (PEG-IFN) alpha-2b results in hepatitis B e antigen (HBeAg) loss in 36% of patients at 6 months post treatment. The aim of this study was to determine whether a long-term response to PEG-IFN is dependent on the timing of HBeAg loss. METHODS: A total of 91 patients treated with PEG-IFN alpha-2b alone (100 microg per week) and 81 patients treated with PEG-IFN alpha-2b and lamivudine (100 mg/day) for 52 weeks were enrolled in this study. Patients were initially followed up at 4-week intervals and had one additional long-term follow-up (LTFU) visit (mean: 3.03+/-0.77 years 26 weeks post treatment). RESULTS: Of the 172 patients included, 78 patients (46%) did not have loss of HBeAg, 47 (27%) lost HBeAg within 32 weeks, and 47 patients (27%) had loss of HBeAg after week 32. At LTFU, patients with HBeAg loss< or =32 weeks had hepatitis B virus DNA of <400 copies/ml significantly more often than did those who lost HBeAg after week 32 (47 vs. 21%, respectively; P=0.009). Hepatitis B surface antigen (HBsAg) negativity was also observed significantly more often in patients with early HBeAg loss (36 vs. 4%, respectively, P<0.001). Early HBeAg loss tended to occur more often in patients treated with PEG-IFN and lamivudine combination therapy than in those treated with PEG-IFN alone (35 vs. 21%; P=0.10), as did HBsAg loss (15 vs. 8%; P=0.14). CONCLUSIONS: Early PEG-IFN-induced HBeAg loss results in a high likelihood of HBsAg loss and may be associated with more profound viral suppression during the first 32 weeks of therapy in patients treated with lamivudine combinations.

Pharmacokinetics and response of obese patients with chronic hepatitis C treated with different doses of PEG-IFN alpha-2a (40KD) (PEGASYS).

AIMS: To evaluate whether higher doses of peginterferon alpha-2a (40KD) [PEG-IFN alpha-2a (40KD)] can compensate for lower exposure observed among obese patients with chronic hepatitis C (CHC) treated with the standard dose of PEG-IFN alpha-2a (40KD). METHODS: Noncirrhotic, obese (body mass index > or =30 kg m(-2)) patients with CHC participated in a single-centre, open-label study. Patients were randomized to 180 or 270 microg week(-1) PEG-IFN alpha-2a (40KD) + ribavirin (1000/1200 mg day(-1)) for 48 weeks. Blood samples were collected predose and up to 168 h after the first dose and at week 12 for pharmacokinetic analysis. Trough serum concentrations (C(trough)) were determined up to week 24. RESULTS: In the 180 microg week(-1) group mean +/- SD steady-state (week 12) estimates of AUC(0-168) (ng h(-1) ml(-1)), C(max) (ng ml(-1)) and CL/F (l h(-1)) were 2154 +/- 919, 13.8 +/- 6.7 and 0.102 +/- 0.051, respectively. In the 270 microg week(-1) group, estimates were 3374 +/- 1844, 23.4 +/- 10.7 and 0.090 +/- 0.042, respectively. The mean (range) C(trough) (ng ml(-1)) was 11.2 (4.4-18.5) in the 180 microg week(-1) group and 16.1 (0.4-44.2) in the 270 microg week(-1) group. Overall, 14 of 20 (70%) and 16 of 20 (80%) patients in the 180 microg week(-1) and 270 microg week(-1) groups were infected with hepatitis C virus genotype 1 or 4. In the 180 microg week(-1) and 270 microg week(-1) groups 14 of 20 (70%) and 15 of 19 (79%) patients, respectively, achieved a sustained viral response. Safety was similar between groups. CONCLUSIONS: Mean PEG-IFN alpha-2a (40KD) exposure was dose proportional from 180 to 270 microg week(-1). Increasing PEG-IFN alpha-2a (40KD) from 180 to 270 microg week(-1) achieves higher serum drug exposure in obese patients.

Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a.

BACKGROUND/AIMS: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha-2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). METHOD: The HBV studies included both hepatitis B e antigen (HBeAg)-positive (n=271) and HBeAg-negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 microg peginterferon alpha-2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health-related quality of life (HRQL) was assessed using the Short-Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24-week treatment-free follow-up period was also included. RESULTS: Differences (HBV vs HCV) were observed in the incidence of AEs (88-89 vs 96-100%), serious AEs (4-5 vs 7-16%) and treatment withdrawals (6-8 vs 17-33%). The frequency of depression-related events was lower in CHB patients (4 vs 22%, P<0.001), as was the impact of treatment on HRQL. CONCLUSIONS: The safety and tolerability of peginterferon alpha-2a in patients with CHB compares favourably with that observed in CHC patients, with a lower incidence of common interferon-related AEs and a significantly lower incidence of depression.

Peginterferon alpha-2a (40kD) [Pegasys] improves HR-QOL outcomes compared with unmodified interferon alpha-2a [Roferon-A]: in patients with chronic hepatitis C.

BACKGROUND: Use of unmodified interferon alpha-2a in chronic hepatitis C is associated with impaired health-related quality of life during therapy. Treatment with peginterferon alpha-2a (40kD) provides an improved sustained response over unmodified interferon alpha-2a. OBJECTIVES: To compare health-related quality of life during treatment for patients receiving peginterferon alpha-2a (40kD) [Pegasys] versus unmodified interferon alpha-2a [Roferon]. DESIGN: A randomised, international, multicentre, open-label, parallel group study. SETTING: 36 centres worldwide. PATIENTS: Interferon-naïve patients (n = 531) with chronic hepatitis C. INTERVENTIONS: Peginterferon alpha-2a (40kD) 180 mirog once a week (n = 267) for 48 weeks or unmodified interferon alpha-2a 6 million IU three times a week for 12 weeks followed by 36 weeks of 3 million IU three times a week (n = 264). MEASUREMENTS: Fatigue Severity Scale and 36-item Short-Form Health Survey (SF-36). RESULTS: At weeks 2 and 12, differences favouring peginterferon alpha-2a (40kD) were seen on seven of eight domains and both summary scores of the SF-36 (p < 0.05 to p < 0.01). At weeks 2, 12 and 24, patients receiving peginterferon alpha-2a (40kD) had less disabling fatigue (p < 0.01) than those receiving unmodified interferon alpha-2a. CONCLUSION: Treatment with peginterferon alpha-2a (40kD) is associated with less disabling fatigue and less impairment in patient functioning and well-being during treatment than unmodified interferon alpha-2a. In addition to safety and efficacy, the impact on health-related quality of life may be an important consideration for physicians when selecting an optimal treatment regimen.

Durable hepatitis B surface antigen decline in hepatitis B e antigen-positive chronic hepatitis B patients treated with pegylated interferon-α2b: relation to response and HBV genotype.

BACKGROUND: On-treatment decline of serum hepatitis B surface antigen (HBsAg) may reflect the immunomodulatory effect of pegylated interferon (PEG-IFN) for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). We compared HBsAg decline across HBV genotypes between combined responders (HBeAg loss and HBV DNA<10,000 copies/ml at week 78), HBeAg responders (HBeAg loss with HBV DNA>10,000 copies/ml) and non-responders. METHODS: HBsAg was measured at baseline, on-treatment and 6 months post-treatment in 221 HBeAg-positive CHB patients treated with PEG-IFN with or without lamivudine for 52 weeks, and in a representative subgroup of 142 patients at long-term follow-up (LTFU; mean 3.0 years). RESULTS: On-treatment HBsAg decline significantly varied according to HBV genotype (A and B more than C and D; P<0.001). On-treatment HBsAg decline also differed between patients with a combined response (n=43) and those without (n=178; 3.34 versus 0.69 log IU/ml decline at week 52; P<0.001). Among patients without a combined response, no difference was observed between HBeAg responders (n=41) versus non-responders (n=137). HBsAg decline was sustained in combined responders and progressed to 3.75 log IU/ml at LTFU. Patients with a combined response achieved pronounced HBsAg declines, irrespective of HBV genotype, and those who achieved HBsAg levels <1,000 IU/ml at week 78 had a high probability of a sustained response and HBsAg clearance through LTFU. CONCLUSIONS: On-treatment HBsAg decline during PEG-IFN therapy for HBeAg-positive CHB depends upon HBV genotype. Patients with a combined response to PEG-IFN achieve a pronounced HBsAg decline, irrespective of HBV genotype, which is sustained through 3 years of off-treatment follow-up.

Exploring differences in response to treatment with peginterferon alpha 2a (40kD) and ribavirin in chronic hepatitis C between genotypes 2 and 3.

Chronic hepatitis C virus (HCV) infections with genotype 2 or 3 are associated with favourable sustained virologic response (SVR) rates. However, genotype 3 may respond less well. We reassessed all treatment-naive patients with genotype 2 and 3 participating in a large expanded-access, non-randomized, open-label trial, evaluating 180microg pegylated interferon (peg-IFN) alpha-2a (40kD) once weekly and 800 mg/day ribavirin for 24-48 weeks. Factors measured prior to initiation of antiviral therapy were considered in the multiple logistic regression model for predicting SVR. In total, 180 patients were analysed of which 72 (40%) were infected by genotype 2 and 108 (60%) genotype 3. The baseline characteristics between patients infected by genotype 2 or 3 were no different including the distribution of hepatic fibrosis stages by METAVIR score. Overall SVR was lower in those patients infected with genotype 3. The significant multivariate predictors of lack of SVR were hepatic fibrosis (P = 0.014) and genotype 3 (P = 0.030). The negative impact of cirrhosis (METAVIR score F4) on treatment response was more evident among subjects with genotype 3 than those with genotype 2 (P = 0.027). There is significant interaction between cirrhosis and genotype 3 leading to a poor antiviral response in such patients requiring an alternate management strategy. This finding should be confirmed in a larger population.

Which patients with genotype 1 chronic hepatitis C can benefit from prolonged treatment with the 'accordion' regimen?

The on-treatment virological response to pegylated interferon plus ribavirin therapy is a useful tool in the management of patients with chronic hepatitis C. The time at which hepatitis C virus RNA becomes undetectable by a sensitive PCR assay has a huge impact on the probability of achieving a sustained virological response, particularly in genotype 1 patients, and may be useful in selecting patients for prolonged therapy. Indiscriminate extension of treatment in patients with hepatitis C virus genotype 1 is not beneficial. However, there is a subgroup of patients - the so-called 'slow responders' - who benefit from extending treatment from 48 to 72 weeks and can be readily identified after 4-12 weeks of combination therapy. Thus, it is important to distinguish slow responders from null responders. In the TeraVIC-4 study virological relapse rates were significantly lower, and sustained virological response rates were significantly higher, in those treated for 72 weeks with peginterferon alfa-2a (40 kDa) plus ribavirin (45% vs. 32% with 48 weeks, P=0.014). Patients are best served by quantitative determination of the hepatitis C virus RNA level at weeks 4, 12 and 24. The results of these determinations can then be used to tailor the length of therapy.

Successful treatment with peginterferon alfa-2b of HBeAg-positive HBV non-responders to standard interferon or lamivudine.

OBJECTIVES: Antiviral therapy leads to HBeAg seroconversion in 10-40% of the patients with HBeAg-positive chronic hepatitis B. Nonresponse may result in progression of liver disease and increased risk of hepatocellular carcinoma. As part of a global randomized controlled trial we investigated the efficacy (i.e., loss of HBeAg at the end of follow-up) of peginterferon alfa-2b (Peg-IFN alpha2b) in patients who failed to respond to previous courses of standard interferon (IFN) or lamivudine. METHODS: We analyzed a total of 76 previous nonresponders: 37 were nonresponders to standard IFN, 17 were nonresponders to lamivudine, and 22 were nonresponders to both therapies. All patients received a 52-wks course of 100 microg Peg-IFN alpha2b weekly combined with either 100 mg lamivudine daily or a placebo. After therapy patients were followed for 26 wks. RESULTS: Thirteen (35%) nonresponders to previous IFN, five (29%) nonresponders to previous lamivudine, and four (22%) nonresponders to both IFN and lamivudine responded to treatment with Peg-IFN alpha2b. No difference in response was found for those treated with Peg-IFN alpha2b alone or in combination with lamivudine. Nonresponders to prior IFN therapy with baseline ALT (alanine aminotransferase) > 4 x ULN (upper limit of normal) responded better to Peg-IFN alpha2b than those with ALT levels

Treatment considerations in patients with hepatitis C and cirrhosis.

Patients with cirrhosis due to hepatitis C have a high chance of dying from progressive liver disease and thus have much to gain from successful antiviral therapy. The highest sustained virologic responses in patients with cirrhosis have been achieved using pegylated interferon alfa plus Ribavirin; 43% or more remain with undetectable virus 6 months after the cessation of 48 weeks of treatment. In those who achieve a sustained virologic response, the degree of fibrosis is less as judged on posttreatment liver biopsy; cirrhosis may even regress. In those individuals with cirrhosis who achieve a sustained virologic response, the risk of developing hepatocellular carcinoma is significantly reduced and it is likely that their chance of developing liver failure is less. Patients who do not achieve sustained virologic response can still show histologic improvement as demonstrated on liver biopsy posttherapy as compared to baseline. Patients with compensated cirrhosis can benefit from therapy while those who are decompensated are prone to more safety issues. Thus, individuals with any evidence of hepatic decompensation should generally not be given interferon-based antiviral therapy, but treatment should be encouraged for those whose status is Child Class A.

Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data.

Multicenter randomized trials have shown that once-weekly pegylated interferon (peginterferon) alfa-2a is more efficacious than conventional interferon alfa-2a (IFN) in patients with chronic hepatitis C. We performed a meta-analysis of 1,013 previously untreated patients (from 3 randomized trials) with pretreatment and post-treatment liver biopsies to assess the differences between peginterferon alfa-2a and IFN in terms of their effects on liver histology. Reported values were standardized mean differences (SMD) between patients receiving peginterferon alfa-2a and those receiving IFN (post-treatment value minus baseline value for each group). We used a random-effects model to quantify the average effect of peginterferon alfa-2a on liver histology. Peginterferon alfa-2a significantly reduced fibrosis compared with IFN (SMD, -0.14; 95% CI: -0.27, -0.01; P =.04). A reduction in fibrosis was observed among sustained virologic responders (SMD, -0.59; 95% CI: -0.89, -0.30; P <.0001) and patients with recurrent disease (SMD, -0.34; 95% CI: -0.54, -0.14; P =.0007), whereas no significant reduction was observed among nonresponders (SMD, -0.13; 95% CI: -0.32, 0.05; P =.15). Logistic regression analysis indicated that patients with sustained virologic responses (SVRs) had an odds ratio (OR) of 1.61 (95% CI: 1.14, 2.29) for reduction in fibrosis compared with patients without SVRs, whereas obese patients (body mass index [BMI] > 30 kg/m(2)) had an OR of 0.56 (95% CI: 0.35, 0.90) compared with normal-weight (BMI < 25 kg/m(2)) and overweight patients (BMI, 25-30 kg/m(2)). In conclusion, in patients with chronic hepatitis C with or without cirrhosis, peginterferon alfa-2a (relative to IFN) significantly reduced fibrosis. The beneficial effects of peginterferon on liver histology are closely related to virologic response.

Twelve weeks of follow-up is sufficient for the determination of sustained virologic response in patients treated with interferon alpha for chronic hepatitis C.

BACKGROUND/AIMS: The current standard for the determination of sustained virologic response in patients treated for hepatitis C is undetectable hepatitis C virus (HCV) RNA 24 weeks following the completion of therapy. Sensitive molecular tests may permit earlier determination of sustained virologic response following the completion of therapy in end-of-treatment responders. METHODS: We examined this possibility in 1441 patients, who received 48 weeks of treatment with either standard or pegylated interferon alpha-2a. HCV RNA was determined by polymerase chain reaction assay (Amplicor HCV Monitor vs. 2.0) at baseline and monitored at 4-week intervals throughout the treatment and 24-week post-treatment follow-up periods. RESULTS: End-of-treatment and sustained response were achieved in 624 and 342 patients, respectively. For all treatments, relapse was most frequent at weeks 52 and 56 and became rare following week 60. Only six patients out of 348 patients (2%) became HCV RNA positive between weeks 60 and 72. Analysis of baseline characteristics failed to identify a specific set of parameters associated with early relapse. CONCLUSIONS: This finding suggests that determination of HCV RNA levels at 12 weeks of follow-up may be sufficient for making decisions related to the management of most patients treated with standard or pegylated interferon alpha.

Prognostic factors and early predictability of sustained viral response with peginterferon alfa-2a (40KD).

BACKGROUND/AIMS: Baseline factors and early decline in serum hepatitis C virus RNA are predictive of sustained virological response to interferon therapy in patients with chronic hepatitis C. We evaluated the prognostic value of baseline factors and early viral RNA among patients treated with peginterferon alfa-2a (40KD). METHODS: Data were pooled from three randomized trials involving 814 patients treated with peginterferon alfa-2a (40KD) (90, 135, or 180 mirog). Stepwise and multiple logistic regression identified independent baseline factors associated with response. Receiver operating characteristic curves for both absolute values and log(10) decline in viral RNA at 4, 8, 12 and 24 weeks of therapy were created. RESULTS: Independent prognostic factors for sustained virological response included viral genotype non-1, low pretreatment viral load, age (<40 years), no cirrhosis and body weight (<85 kg). In addition, alanine aminotransferase quotient (>3) and histological activity index score (>10) were also independently prognostic. Receiver operating characteristic curves showed that detectable or less than 2-log(10) decline in viral RNA at week 12 predicted sustained virological non-response (negative predictive value is 98%) . CONCLUSIONS: In patients with chronic hepatitis C treated with peginterferon alfa-2a (40KD), the decision to continue or stop treatment can be made as early as week 12.