Efficacy and safety of long term entecavir in chronic hepatitis B treatment naïve patients in clinical practice

Background and aims. Entecavir (ETV) is effective and safe in patients with chronic hepatitis B in the short term, but its long term efficacy and safety has not been established.Material and methods. We evaluated HBV DNA clearance, HBeAg/antiHBe and HBsAg/antiHBs seroconversion rates in HBeAg-positive and negative NUC naïve HBV patients treated with ETV for more than 6 months, and predictors of response.Results. A hundred and sixty nine consecutive patients were treated with ETV for a median of 181 weeks. 61% were HBeAg positive, 23% were cirrhotics, and mean HBV-DNA levels were 6,88 ± 1,74 log₁₀ lU/mL. Overall, 156 (92%) patients became HBV DNA undetectable, 92 (88%) HBeAg positive and 64 (98%) HBeAg negative patients. Seventy four (71%) patients cleared HBeAg after a median of 48 weeks of treatment, 23 (14%) patients cleared HBsAg (19 HBeAg positive and 4 HBeAg negative, p 0.025) after a median of 96 weeks of treatment, and 22 (13%) patients developed protective titers of anti-HBs. At the end of the study, 35 (20%) patients had discontinued therapy: 33 HBeAg positive and 2 HBeAg negative; 9 of them (26%) developed virological relapse after a median of 48 weeks of stopping treatment. None of the patients had primary non response and one patient developed breakthrough. Two patients developed HCC, three underwent liver transplantation and 3 deaths were attributable to liver-related events. No serious adverse events were reported.Conclusion. Long term ETV treatment showed high virological response rates, and a favorable safety profile for NUC-naive HBeAg-positive and negative patients treated in clinical practice.     

Antiviral therapy for treatment naïve patients with hepatitis C virus

This article focuses on the most recent therapies for patients with hepatitis C virus (HCV) who are na?ve to therapy. The primary end point for the treatment of na?ve HCV patients is viral eradication or a sustained virological response, which is defined as the absence of HCV in the serum, as detected by a sensitive polymerase chain reaction test, 24 weeks after stopping antiviral therapy. Recent data suggest that an SVR can be equated with a biochemical, virological,and histological response that is sustained for up to 5 years and is conceptually a cure of HCV in 90% of patients.     

Antiviral therapy for treatment naïve patients with hepatitis C virus

This article focuses on the most recent therapies for patients with hepatitis C virus (HCV) who are naive to therapy. The primary end point for the treatment of naive HCV patients is viral eradication or a sustained virological response, which is defined as the absence of HCV in the serum, as detected by a sensitive polymerase chain reaction test, 24 weeks after stopping antiviral therapy. Recent data suggest that an SVR can be equated with a biochemical,virological, and histological response that is sustained for up to 5 years and is conceptually a cure of HCV in 90% of patients.     

YMDD motif mutations in chronic hepatitis B antiviral treatment naïve patients: a multi-center study

ObjectiveThis study aimed to determine the natural prevalence of variants of tyrosinemethionine- aspartic acid-aspartic acid (YMDD) motif in patients with chronic hepatitis B (CHB), and to explore its relation with demographic and clinical features, hepatitis B virus (HBV) genotypes, and HBV DNA levels.MethodsA total of 1,042 antiviral treatment naïve CHB patients (including with lamivudine [LAM]) in the past year were recruited from outpatient and inpatient departments of six centers from December 2008 to June 2010. YMDD variants were analyzed using the HBV drug resistance line probe assay (Inno-Lipa HBV-DR). HBV genotypes were detected with polymerase chain reaction (PCR) microcosmic nucleic acid cross-ELISA, and HBV deoxyribonucleic acid (DNA) was quantitated with real-time PCR. All serum samples underwent tests for HBV, HCV, and HDV with ELISA.ResultsYMDD variants were detected in 23.3% (243/1042) of CHB patients. YMDD mutation was accompanied by L180M mutation in 154 (76.9%) patients. Both wild-type HBV and YMDD variant HBV were present in 231 of 243 patients. Interestingly, 12 patients had only YIDD and/or YVDD variants without wild YMDD motif. In addition, 27.2% (98/359) of HbeAg-positive patients had YMDD mutations, which was higher than that in HbeAg-negative patients (21.2%, 145/683). The incidence of YMDD varied among patients with different HBV genotypes, but the difference was not significant. Moreover, the incidence of YMDD in patients with high HBV DNA level was significantly higher than that in those with low HBV DNA level.ConclusionMutation of YMDD motif was detectable at a high rate in CHB patients in this study. The incidence of YMDD may be correlated with HBeAg and HBV DNA level.     

Clinical drivers in naïve patient eligibility for treatment of chronic hepatitis C

Hepatitis C virus (HCV) infection represents a major health problem, being a leading cause of cirrhosis and liver transplantation worldwide. Viral eradication achieved by Peginterferon and Ribavirin therapy is the only therapeutic option that can prevent fibrosis progression in chronic hepatitis and liver-related complications in cirrhotic patients. Unfortunately, the occurrence of potentially serious side effects argues against universal treatment of HCV-infected patients. Indeed most scientific societies suggest that eligibility for therapy be based on baseline factors, the so called clinical drivers for treatment eligibility. Current international guidelines recommend focusing on the severity of liver disease, likelihood of treatment response in terms of chances of sustained virological response (SVR) to antiviral therapy and risk of serious adverse events when making treatment decisions. However, evidence exists that treatment may benefit also patients with mild fibrosis and that baseline predictions of a SVR are inaccurate because of the key role of HCV kinetics while on-therapy. An extended treatment programme is further supported by the fact that an increase in the number of patients treated would ultimately result in a long-term reduction of liver-related deaths.     

Entecavir resistance is rare in nucleoside naïve patients with hepatitis B

Comprehensive monitoring of genotypic and phenotypic antiviral resistance was performed on 673 entecavir (ETV)-treated nucleoside na?ve hepatitis B virus (HBV) patients. ETV reduced HBV DNA levels to undetectable by PCR (<300 copies/mL, <57 IU/mL) in 91% of hepatitis B e antigen (HBeAg)-positive and -negative patients by Week 96. Thirteen percent (n = 88) of the comparator lamivudine (LVD)-treated patients experienced a virologic rebound (> or =1 log increase from nadir by PCR) in the first year, with 74% of these having LVD resistance (LVDr) substitutions evident. In contrast, only 3% (n = 22) of ETV-treated patients exhibited virologic rebound by Week 96. Three ETV rebounds were attributable to LVDr virus present at baseline, with one having a S202G ETV resistance (ETVr) substitution emerge at Week 48. None of the other rebounding patients had emerging genotypic resistance or loss of ETV susceptibility. Genotyping all additional ETV patients with PCR-detectable HBV DNA at Weeks 48, 96, or end of dosing identified seven additional patients with LVDr substitutions, including one with simultaneous emergence of LVDr/ETVr. Generally, ETV patients with LVDr were detectable at baseline (8/10) and most subsequently achieved undetectable HBV DNA levels on ETV therapy (7/10). No other emerging substitutions identified decreased ETV susceptibility. In conclusion, ETVr emergence in ETV-treated nucleoside na?ve patients over a 2-year period is rare, occurring in two patients with LVDr variants. These findings suggest that the rapid, sustained suppression of HBV replication, combined with a requirement for multiple substitutions, creates a high genetic barrier to ETVr in nucleoside na?ve patients.     

Interferon-alpha combined with ketoprofen as treatment of naïve patients with chronic hepatitis C: a randomized controlled trial

Summary. In this randomized controlled study, we evaluated the efficacy and safety of interferon-α combined with ketoprofen to that of interferon-α alone in naïve patients with chronic hepatitis C. Forty patients were randomized to receive Interferon-α_2a (3 million units three times a week) and ketoprofen (150 mg twice a day) and 40 to receive only interferon-α_2a at the same dose. Patients were treated for 6 months and followed up for 6 months. Response was defined by undetectable HCV-RNA in serum at the end-of-treatment and after 6 months from the completion of therapy (long term response). At the end of treatment the response was similar in the two group. However, combination treatment showed significantly higher efficacy than monotherapy in achieving long term response (10%vs 32.5%; P = 0.014). Overall adverse events were similar in the two groups. ‘Flu-like syndrome was significantly less common in the ketoprofen plus interferon group which experienced a significantly higher incidence of epigastric pain'. Our results indicate that the combination of ketoprofen plus interferon is significantly more effective than interferon alone in the tratment of naïve patients with chronic hepatitis C and is well tolerated. However this combined treatment appears to be less effective than the association of pegylated IFN and ribavirin which represent the current standard treatment. Thus, the role of ketoprofen in the treatment of chronic hepatitis C needs to be further evaluated against such a treatment.     

Serum HBsAg quantification in treatment-naïve Indian patients with chronic hepatitis B

Background and Aims

There is paucity of Indian data regarding serum HBsAg levels (qHBsAg) in treatment-naïve chronic hepatitis B (CHB). This study was done to determine correlation of qHBsAg with hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA levels and its ability to independently categorize subgroups of CHB.

Methods

We studied 131 treatment-naive CHB patients and initially classified them based on HBeAg status. The HBeAg-positive group was further classified into immune tolerance (IT) and immune clearance (IC) phases based on serum alanine aminotransferase. HBeAg-negative patients were classified into low replicators (LR) and HBeAg-negative chronic hepatitis (ENH) based on DNA levels. HBsAg quantification was performed using the Architect chemiluminescence system.

Results

HBeAg-positive patients had higher DNA (7.89 vs. 2.69 log₁₀?IU/mL) and higher qHBsAg (4.60 vs. 3.85 log₁₀?IU/mL) compared to the HBeAg-negative group. Good correlation between qHBsAg and DNA was seen in HBeAg-positive (ρ?=?0.6, p?<?0.001) but not in HBeAg-negative CHB (ρ?=?0.2). A qHBsAg level greater than 4.39 log₁₀?IU/mL predicted HBeAg-positive state with 81 % sensitivity and 85 % specificity. However, among HBeAg-negative CHB, qHBsAg failed to discriminate between LR and ENH.

Conclusions

A single point estimation of qHBsAg in treatment-naïve patients could predict replicative HBeAg-positive CHB, but was not helpful in defining replicative status in the HBeAg-negative CHB.     

Treatment of chronic hepatitis C with pegylated interferon plus ribavirin in treatment-naïve ‘real-life’ patients in India

Purpose/Aim

Results of treatment of chronic hepatitis C (CHC) with pegylated interferon plus ribavirin (PEG-RBV) are mainly available from well-designed clinical trials, and only few ‘real-life’ studies which give a true picture of success of therapy are available. Such data in Indian patients is scarce. This prospective study aimed to evaluate the efficacy, safety, and factors associated with sustained virological response (SVR) in Indian CHC patients treated with PEG-RBV in ‘real-life’ setting.

Material and Methods

All treatment-naïve patients with CHC/compensated cirrhosis treated with PEG-RBV between January 2004 and December 2010 were included.

Results

Of 592 patients started on treatment, 524 (88.5 %) completed therapy (mean?±?SD age—42.0?±?12.1 years; 74.3 % males). Genotype 3 (73.6 %) was the commonest, followed by genotype 1 (19.3 %). In intention to treat analysis, SVR rates for ‘all’ patients, genotype 1 and genotype 3 patients were 72.3 % (428/592), 57 % (65/114), and 78.2 % (341/436), respectively (in per-protocol analysis—81.7 %, 69.1 %, and 85.3 %, respectively). Noncirrhotics had better SVR rates compared to cirrhotics treated for the same duration. About 20 % patients had both low viral load and achieved rapid virological response (RVR). Factors significantly associated with SVR were age <40 years, absence of cirrhosis, RVR, and no reduction in interferon dose.

Conclusion

SVR rates in CHC patients treated in ‘real-life’ setting in India were better than those reported in western population. Therapy should be prolonged for patients with cirrhosis, while one-fifth of patients may qualify for abbreviated therapy. Factors significantly associated with SVR were age <40 years, absence of cirrhosis, RVR, and no reduction in interferon dose.     

The safety and tolerability of daily infergen plus ribavirin in the treatment of naíïve chronic hepatitis C patients

The treatment of chronic hepatitis C patients was enhanced when the combination of interferon alfa-2b and ribavirin was shown to be safe and more effective than interferon monotherapy. To date, no published reports have addressed the use of consensus interferon (CIFN) when combined with ribavirin. We conducted a pilot study to compare the safety and tolerability of daily CIFN plus ribavirin to CIFN monotherapy for the initial treatment of chronic hepatitis C patients. Forty subjects were randomized to two treatment groups; CIFN 9 microg daily, or CIFN 9 microg daily plus ribavirin 1000 or 1200 mg daily. All subjects received 48 weeks of therapy except for nongenotype 1 subjects in the combination treatment group who received only 24 weeks of therapy. The results show that at baseline, age, gender, risk factors, race, RNA titres, and liver histology were not different between the two groups. The proportion of subjects with genotype 1 infection was 50% (10/20) and 55% (11/20) for the monotherapy and combination therapy groups, respectively. Fifty (10/20) and sixty-five (13/20) per cent of subjects in the monotherapy and combination therapy groups exhibited a 2-log or greater decrease in viral titre at week 12 (P = NS). Using intent-to-treat analysis, 20% and 40% of enrolled subjects exhibited a sustained viral response in the monotherapy and combination therapy groups, respectively (P = NS). The proportion of subjects requiring dose reduction was 55% (11/20) and 65% (13/20), respectively. Study discontinuations for any reason were 25% (5/20) and 35% (7/20) for the monotherapy and combination groups, respectively. Discontinuations due to adverse events related to study drug were 20% (4/20) and 25% (5/20), respectively. A total of four serious adverse events occurred, two in each treatment group, only one of which was determined to be study-drug related. It is concluded that the safety and tolerability profiles of the two treatments were similar suggesting that daily dosing of CIFN may be difficult to tolerate resulting in discontinuation of therapy in a significant proportion of patients. The combination regimen resulted in a trend towards a higher viral response rate than monotherapy treatment. These data suggest that CIFN may be safely combined with ribavirin and may enhance the sustained response rate but is not well tolerated in US patients when given in a daily dosing regimen.     

Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: a randomized controlled trial

BACKGROUND/AIMS: We assessed the effectiveness and safety of an induction dose of peginterferon alfa-2b (PEG-IFN) plus ribavirin for initial treatment of patients with genotype 1 chronic HCV infection in a randomized, controlled, multicenter trial. METHODS: Three hundred and eleven na?ve patients infected with genotype 1 and chronic hepatitis were randomly assigned to 48-week treatment with PEG-IFN once weekly (80-100 micrograms depending on body weight for 8 weeks, followed by 50 micrograms for the next 40 weeks), or standard interferon alfa-2b (IFN) 6 million units on alternate days, both in combination with ribavirin (1000-1200 mg/day). RESULTS: PEG-IFN plus ribavirin significantly increased sustained virological response (SVR) compared with IFN plus ribavirin (41.1 vs. 29.3% respectively, P=0.030). Less patients discontinued PEG-IFN than IFN (19 vs. 31%, P=0.010). By logistic regression, SVR in the PEG-IFN group was independently associated with age <50 years, and mild fibrosis at liver biopsy. CONCLUSIONS: Combination therapy with an induction dose of PEG-IFN was a more effective and better tolerated treatment for na?ve patients with genotype 1 than combination therapy with high dose standard IFN. In patients aged less than 50 years with mild fibrosis this schedule achieves a very high rate of SVR.     

A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B

Purpose  

Clevudine and entecavir are currently available in Korea as antiviral drugs against chronic hepatitis B (CHB). We aimed to compare the efficacy of clevudine and entecavir therapy.     

Kinetics of hepatitis C virus RNA load during pegylated interferon alpha-2a and ribavirin treatment in naïve genotype 1 patients

Background

Pegylated interferon given for 24 or 48 weeks constitutes the most effective initial therapy for the treatment of chronic hepatitis C. It has been shown that viral load at week 2 appears the best time for predicting response to treatment. The objectives of this study were to assess whether the hepatitis C virus (HCV) RNA viral decline is predictive of sustained virological response (SVR) and to determine the best time for predicting complete response in our cohort of naïve patients treated with pegylated interferon alpha-2a (Peg-IFN alpha-2a) and ribavirin.

Results

Twenty patients treated with Peg-IFN alpha-2a and ribavirin for 48 weeks were studied. Six months after the end of treatment, a SVR (negative HCV RNA measured by PCR six months after the end of therapy) was obtained in 9 patients. Samples were obtained before and at week 2, 4, 8, and 12. At the end of week 2, viral load decreased more than 1.39 log in 8 out of the 9 patients with SVR and in 1 out of the 11 other patients. When we considered the viral load reduction from baseline to each week of treatment, week 2 appeared to be the best point time for predicting SVR, with a sensitivity of 91% (95%CI: 59;99), a specificity of 89% (52;98), a positive predictive value of 91% (59;99) and a negative predictive value of 89% (57;98).

Conclusion

During treatment with Peg-IFN alpha-2a plus ribavirin in genotype 1 patients, when the main objective of the treatment is viral eradication, viral kinetics showed that week 2 appeared to be the best time point for predicting SVR. Our results must be further confirmed on a larger cohort.

     

An a priori prediction model of response to peginterferon plus ribavirin dual therapy in naïve patients with genotype 1 chronic hepatitis C

BackgroundAim was to select naïve patients with genotype 1 chronic hepatitis C having a high probability of response to Peg-interferon + ribavirin therapy.MethodsIn 1073 patients (derivation cohort), predictors of rapid and sustained virological response were identified by logistic analysis; regression coefficients were used to generate prediction models for sustained virological response. Probabilities at baseline and treatment week 4 were utilized to develop a decision rule to select patients with high likelihood of response. The model was then validated in 423 patients (validation cohort).ResultsIn the derivation cohort, 257 achieved rapid virological response and 818 did not, with sustained virological response rates of 80.2% and 25.4%, respectively; interleukin-28B polymorphisms, fibrosis staging, gamma-glutamyl transferase, and viral load predicted sustained virological response. Assuming a <30% sustained virological response probability for not recommending Peg-interferon + ribavirin, 100 patients (25.6%) in the validation cohort were predicted a priori to fail this regimen. Assuming a ≥80% sustained virological response probability as a threshold to continue with Peg-interferon + ribavirin, 61 patients were predicted to obtain sustained virological response, and 55 of them (90.2%) eventually did.ConclusionsThis model uses easily determined variables for a personalized estimate of the probability of sustained virological response with Peg-interferon + ribavirin, allowing to identify patients who may benefit from conventional therapy.     

A randomized trial to assess the efficacy of interferon-alpha daily in combination with ribavirin in the treatment of naïve patients with chronic hepatitis C

Summary. A randomized trial was conducted to assess the efficacy of interferon-alpha (IFN) daily in combination with ribavirin in 301 naïve patients with chronic hepatitis C (CHC). Patients were randomized to receive ribavirin 1.2 g daily (QD) for 48 weeks with either IFN 5 MU (thrice weekly) TIW for 8 weeks followed by IFN 3 MU TIW for 40 weeks (IFN TIW, n  = 154) or IFN 5 MU QD for 8 weeks followed by IFN 3 MU QD for 16 weeks followed by IFN 3 MU TIW for 24 weeks (IFN QD, n  = 147). Treatment discontinuation rates, because of adverse events, were similar in the two arms (14.9% in IFN TIW and 14.3% in IFN QD, P  = 0.87). The proportion of patients with sustained virological response (SVR) was 27.9% for patients treated TIW and 38.8% for those treated QD ( P  = 0.046). According to logistic regression analysis, patients in the IFN QD arm had 1.7 times higher probability of achieving SVR, than those receiving IFN TIW ( P  = 0.038). Low baseline viral load ( P  = 0.017) and genotype non-1 ( P  = 0.036) were associated with higher SVR rates. Combination of IFN/ribavirin for 48 weeks is more effective when IFN is administered daily for the first 24 weeks in naïve patients with CHC.     

High sustained response to daily dosing of interferon with ribavirin in chronic hepatitis C patients naïve to therapy

Background : Viral kinetics suggests that daily administration of α‐interferon (IFN) will clear hepatitis C virus (HCV) RNA earlier and more frequently compared with standard t.i.w. To reduce the likelihood of viral replication, mutation and subsequent development of resistance, daily dosing with IFN may be appropriate. To determine the safety and efficacy of daily IFN with ribavirin in chronic HCV infection we performed a prospective study. Methods : Thirty‐five naïve adult HCV‐positive patients (25 male/10 female) were treated with IFN‐α2b; 5 MU daily for 2 weeks followed by 3 MU daily for 22 weeks and ribavirin 800–1200 mg/day depending on weight. Liver biopsy, performed in 25 patients, showed mild to moderate activity in 19 patients (76%) and severe activity in six patients (24%). Two patients showed staged IV fibrosis. Serotyping was performed in 29 patients by an enzyme immunoassay‐based Murex assay. Type 3 was the predominant serotype, present in 14 cases. Hepatitis C virus RNA was measured by the Chiron bDNA assay. Results : Mean baseline HCV‐RNA level was 14.2 ± 18.7 MEq/mL (median 6.09; range 0.2–92.5), which became undetectable in all but three patients at week 4. Normalization of alanine aminotransferase (ALT) at week 4 was seen in 27 patients. Three patients withdrew due to non‐compliance. Thirty‐two patients completed 24 weeks of therapy as per the protocol. At the end of treatment, the HCV‐RNA level was negative in 29 of 32 patients (90.6%) and ALT was normal in 31 of 32 patients (97%). Sustained viral response at 6 months follow up was seen in 28 of 32 patients (88%). The ALT level was normal in 28 of 32 patients (88%). Conclusion : Daily administration of IFN with ribavirin is well tolerated in the majority of patients. There is rapid elimination of virus with normalization of ALT and a significantly high sustained viral response. © 2002 Blackwell Publishing Asia Pty Ltd     

HIV-1 integrase sequence variability in antiretroviral naïve patients and in triple-class experienced patients subsequently treated with raltegravir

Viruses were sequenced from 75 antiretroviral therapy (ARV)-na?ve and from 75 ARV-treated patients who subsequently received a raltegravir-containing regimen. No major integrase inhibitor (INI)-resistance mutations were present in the 150 integrase (IN) sequences. Four ARV-na?ve (5.3%) and two ARV-treated patients (2.7%) had one of the following minor INI-resistance mutations: L74M, E157Q, G163R, and R263K but there was no association between baseline raltegravir genotype and subsequent response to raltegravir treatment. We also combined our sequences with 4170 previously published group M IN sequences from INI-na?ve patients to assess IN sequence variability and compared our findings with those of a study we performed in 2008 using data from 1563 patients. The number of polymorphic IN positions increased from 40% to 41% between the two studies. However, none of the major INI-resistance mutations was found to be polymorphic in either study and there were no significant changes in the prevalence of any of the minor INI-resistance mutations.