Baseline Serum HCV-RNA Research Articles

Resistant-Associated Substitutions Do Not Affect HCV RNA and HCV Core Antigen Clearance During Direct-Acting Antiviral Agent Treatment in a Real-World Setting.

BackgroundSince oral direct-acting antiviral agents (DAAs) became available, the global hepatitis C treatment situation has undergone tremendous changes. However there are still many issues worthy of attention in treatment.MethodsWe selected 53 HCV-infected patients who were treated and followed up in the Peking University First Hospital from December 2017 to January 2021 to detect the RASs in HCV. Pearson correlation analysis was used to analyze HCV RNA and HCV cAg, the Fisher exact test and chi-square test was used to compare the effects of RASs on the rate of decline of HCV RNA and HCV core antigen (cAg) during DAA treatment.ResultsThe RASs and its prevalence on the NS3 are mainly Y56F 2.56% (1/39), Q80K 23.08% (9/39), S122G 71.79% (28/39), and V170I 38.46% (15/39). On the NS5A were R30Q 10.53% (4/38), P32A 5.26% (2/38), P58S 2.63% (1/39), and Y93H 21.05% (8/38). On NS5B were C316N 71.05% (27/38), C451H 2.63% (1/38), and I585C 2.63% (1/38). There was no significant correlation between the RASs (Y93H, V179I, Q80K, S122G, C316N) and HCV genotype (p > 0.05). The baseline serum HCV RNA and HCV cAg had a significant medium-degree correlation (r = 0.601, p = 0.002). After 1 week of DAA treatment was weak correlation (r = 0.413, p = 0.032). Q80K, S122G, V170I, Y93H, and C316N had no effect on the clearance of HCV RNA and HCV cAg within the first week of DAA treatment (p>0.05).ConclusionThe HCV genotype may have a limited impact on the presence of the five RASs (Y93H, V179I, Q80K, S122G, and C316N) as shown in this study. HCV RNA and HCV cAg have a correlation, especially at baseline is the highest; the appearance of some RASs has no effect on DAA treatment in most chronic hepatitis C patients.

High serum HCV RNA in chronic hepatitis C patients coinfected with HIV despite successful antiretroviral therapy.

Baseline serum HCV RNA predicts treatment success in chronic hepatitis C patients. Thresholds at 0.8, 2, 4 and 6 million IU/ml discriminate treatment outcomes using distinct antiviral regimens. Compared to the general population, immunosuppressed individuals exhibit greater viral load values. This has been confirmed in HIV-HCV-coinfected patients, although little is known about the influence of antiretroviral therapy. Serum HCV RNA results recorded from all chronic hepatitis C patients who consecutively attended at our clinic were analysed. A total of 813 patients with detectable HCV RNA were identified. HIV coinfection was present in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 467 (57%), 273 (34%), 170 (21%) and 127 (16%) had HCV RNA >0.8, >2, >4 and >6 million IU/ml, respectively. These high viral load values were found in 60%/36%/23%/18% of HIV-positive versus 47%/25%/11%/6% of HIV-negative individuals (P<0.01), respectively. In multivariate analysis, the greatest HCV RNA values were only significantly associated with HIV coinfection and HCV genotypes-1 or -4. Greater HCV RNA values were paradoxically found in HIV patients on than off antiretroviral therapy. Serum HCV RNA values above 0.8, 2, 4 and 6 million IU/ml are roughly seen in 47%, 25%, 11% and 6% of chronic hepatitis C monoinfected patients, respectively. Despite being on antiretroviral therapy, the corresponding figures are 1.3- to 3.0-fold greater in HIV-HCV-coinfected patients, who may benefit less frequently from shorter oral HCV treatment lengths.

726 Type 1 IFN-Alpha Receptor Expression by Peripheral Blood Monocytes During Triple Therapy Influences Rapid Virological Response in Genotype 1b-Infected Patients With Chronic Hepatitis C and High Viral Load

BACKGROUND/AIM: We previously reported that type I IFN receptor alpha-2 (INFAR-2) expression in peripheral blood monocytes (Mo) is related to early virological response (EVR) in patients with chronic hepatitis C (CHC) infected with genotype 1b and having high viral loads (Intervirology 53: 105-110, 2010). The aim of this study was to clarify whether IFNAR2 expression by peripheral blood Mo influences rapid virological response (RVR) in CHC patients infected with genotype 1b, having high viral loads and treated with triple therapy comprising teraprevir (TPV), pegylated (PEG)-interferon (IFN) and ribavirin (RBV). PATIENTS AND METHODS: Twenty-nine adult patients with biopsy-proven CHC were studied. Enrollment criteria included 26 to 82 (median: 58) years of age, baseline serum HCV-RNA quantified by RT-PCR between 5.2 and 7.2 log copies/ml, and infection with HCV genotype 1b. Twenty-four patients (15 males and 9 females) were treated with triple therapy. As a pilot study, TPV alone was administered to 5 patients (4 males and 1 female) for 7 days in order to investigate the effects of TPV for IFNAR-2 expression by peripheral blood Mo. A negative result for serum HCV-RNA on RT-PCR at 4 weeks after starting therapy was defined as RVR. IFNAR-2 expression by peripheral blood Mo was determined using flow cytometry by measuring the mean fluorescence intensity before and up to 14 days after starting triple therapy. IFNAR-2 expression was also determined before and up to 7 days after starting TPV alone. All 29 patients consented to genetic investigation for polymorphisms in the interleukin (IL)-28B gene at rs8099917. Twenty-four patients had genotype TT, 5 patients had genotype TG, and none had genotype GG. RESULTS: RVR was achieved in 19 patients (15 patients with genotype TT and 4 patients with genotype TG) and was not achieved in 5 patients (non-RVR) with genotype TT. Genotype at rs8099917 was not associated with RVR (P=0.65, by χ2 test). IFNAR-2 expression by peripheral blood Mo was not altered at 3 and 7 days after starting therapy, as compared to before therapy in patients receiving TPV alone (4 patients with genotype TT and 1 patient with genotype TG). IFNAR-2 expression by peripheral blood Mo before starting therapy did not differ between RVR patients and non-RVR patients. However, IFNAR-2 expression by peripheral blood Mo after starting therapy was always higher in RVR patients than in non-RVR patients, and IFNAR-2 expression by peripheral bloodMo 3 days after starting therapy was significantly (P , 0.05 on Mann-Whitney test) higher in RVR patients than in non-RVR patients. CONCLUSION: This study showed that IFNAR-2 expression by peripheral blood Mo at day 3 of triple therapy influences RVR in patients infected with genotype 1b and having high viral loads.

822 PRECLINICAL CHARACTERIZATION OF THE HEPATITIS C VIRUS NS5B POLYMERASE NON-NUCLEOSIDE INHIBITOR BI 207127

pharmacokinetics in a phase 1 study, when compared to the standard 500mg tablet. The aim of the current study was to evaluate the safety and efficacy of two doses of CR NTZ in combination with PegIFN plus RBV for treatment of CHC. Methods: In this phase 2 single-center (University of Tanta), double-blind, controlled study, 41 treatment-naive patients with CHC genotype 4 were randomized to receive placebo (n =8) versus CR NTZ 675 (n =17) or 1350mg (n =16) twice daily for 4 weeks followed by the same regimen plus PegIFN alfa-2a 180mg weekly and RBV 1000 to 1200mg daily for 48 weeks. In the three treatment groups, the mean (± SD) ages were 43±11, 36±9, and 32±11 years, and baseline serum HCVRNA levels 5.6±0.7, 5.3±0.6, and 5.6±0.5 log IU/mL, respectively. Results: Dose-dependent reductions in serum HCVRNA were observed 4 days after starting combination therapy. Median HCVRNA reduction of −4.74, −5.11 and −5.57 for the placebo, lowdose and high-dose groups, respectively, were observed at week 16. Virologic response rates are shown:

The Mutations in the Enhancer I/X Promoter and X Gene Region Increased Risk for Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Infection

BACKGROUND/AIM: Several reports have suggested that the number of amino acid (aa) mutations in the interferon sensitivity determining region (ISDR, aa 2209 2248) of the nonstructural protein 5A (NS5A) affects the response to IFN-based therapy in patients with chronic hepatitis C (CHC) with genotype 1 and high viral load. The aim of the present study was to clarify whether host immunity is influenced by the number of aa mutations in the ISDR. PATIENTS AND METHODS: Subjects included 44 consecutive patients with biopsy-proven CHC who were infected with genotype 1b (27 men and 17 women; age range, 29 to 70 (median: 58) years; baseline serum HCV-RNA levels, 100 to 850 (median: 480) KIU/ml, quantified by Amplicor Monitor Version 2.0 test). The number of aa mutations in the ISDR was retrospectively determined using stored serum samples taken immediately before starting therapy. All patients received interferon (IFN)-alpha 2b or pegylated-IFNalpha 2b and ribavirin. When serum HCV-RNA was negative at 12 weeks, the patient was defined as having early viral response (EVR). When serum HCV-RNA was negative at 24 weeks after the end of therapy, the patient was defined as having sustained viral response (SVR). Baseline liver test, and CD4-positive T cell subsets such as IFN-gamma (+)/IL-4 (−) (Th1) or IFN-gamma (−)/IL-4 (+) (Th2) cells in peripheral blood (PB) before and at 3, 7, 14, 28 and 56 days after starting therapy were analyzed. RESULTS: Rates of EVR and SVR were 14% (3/21) and 14% (3/21), respectively, in patients with one or fewer aa mutations in the ISDR (ISDR0-1), and 70% (17/23) and 53% (10/23), respectively, with two or more aa mutations in the ISDR (ISDR>2). Although the percentage of PB Th1 cells did not differ between the 2 groups during the study period, the percentage of PB Th2 cells was significantly lower in the ISDR0-1 group than in the ISDR>2 group at baseline and on days 3, 7, 14 and 28 of treatment. DISCUSSION: The number of aa mutations in the ISDR influenced PB Th2 cells before and at 3, 7, 14 and 28 days after the start of therapy, and was associated with higher EVR and SVR rates.

Influence of a Single Nucleotide Polymorphism at the Main Ribavirin Transporter Gene on the Rapid Virological Response to Pegylated Interferon–Ribavirin Therapy in Patients with Chronic Hepatitis C Virus Infection

The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the ENT1 gene may influence ribavirin activity as part of hepatitis C virus (HCV) therapy. A retrospective study was conducted in 109 human immunodeficiency virus (HIV)-infected patients who were infected with HCV genotypes 1 or 4 who had received pegylated interferon (pegIFN)-ribavirin. Single nucleotide polymorphisms (SNPs) at the ENT1 gene were examined using TaqMan 5'-nuclease assays. In the study population, allelic frequencies at rs760370 were as follows: A3 (43 [39%] of 109 patients), AG (50 [46%] of 109 patients), and GG (16 [15%] of 109 patients). Achievement of rapid virological response was more frequent in GG carriers than in AA/AG carriers (50% vs 17%, respectively; P = .007). In multivariate analysis, the GG genotype (odds ratio [OR], 15.9; 95% confidence interval [CI], 2.8-92.2; P < .002), a baseline serum HCV-RNA level <600,000 IU/mL (OR, 45.7; 95% CI, 8.7-240.5; P <.001) and a serum ribavirin trough concentration >2.5 μg/mL (OR, 4.8; 95% CI, 1.3-17.1; P < .016) were associated with rapid virological response. When 2 or more of these factors were present, positive and negative predictive values of rapid virological response were 65% and 91%, respectively. In summary, a SNP rs760370A→G at the ENT1 gene influences the chance of rapid virological response to pegIFN-ribavirin therapy in HIV-infected patients with chronic HCV infection due to HCV genotypes 1 or 4, most likely modulating intracellular ribavirin exposure within hepatocytes.

Treatment of chronic hepatitis C in HIV-infected patients with compensated liver cirrhosis

The greatest benefit of hepatitis C virus (HCV) therapy is seen in cirrhotics attaining sustained virological response (SVR). However, concerns about toxicity and poorer responses often discourage treatment of cirrhotics. This may be particularly relevant in HIV-HCV-coinfected patients, in whom progression of liver fibrosis is faster and treatment responses lower. This is a retrospective analysis of HIV-HCV-coinfected patients who had received peginterferon-ribavirin therapy at our institution. Individuals naïve for interferon in whom liver fibrosis had been assessed using elastometry within the year before being treated were chosen. Response rates and toxicities were compared in cirrhotics (>14.5 KPa) and noncirrhotics. Patients with previous liver decompensation were excluded. Overall, 41 cirrhotics and 190 noncirrhotics entered the study. Groups were similar in age, gender, HCV genotypes and baseline serum HCV-RNA. SVR occurred at similar rates in cirrhotic and noncirrhotics, either considered by intention-to-treat (39%vs 45%; P = 0.4) or as treated (50%vs 52%, P = 0.8). In multivariate analysis (odds ratio, 95% CI, P), SVR was associated with HCV genotypes 2-3 (5, 2.9-11, <0.01) and lower serum HCV-RNA (2, 1.4-3.03 for every log decrease, <0.01) but not with cirrhosis (1.2, 0.4-3.6, 0.6). Treatment discontinuations because of adverse events tended to be more common in cirrhotics than in noncirrhotics (17%vs 12%; P = 0.2), but only severe thrombocytopenia was more frequent in cirrhotics than in non-cirrhotics (20%vs 3% at week 24; P < 0.01). Response to peginterferon-ribavirin therapy is similar in HIV-HCV coinfected patients with and without liver cirrhosis. Therefore, treatment must be encouraged in all compensated cirrhotic patients, although closer monitoring and management of side effects, mainly thrombocytopenia, may be warranted.

758 CHARACTERIZATION OF RESISTANT MUTANTS SELECTED IN VITRO BY THE HCV NS3/4A PROTEASE INHIBITOR BI 201335

Background: MP-424 (telaprevir) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3–4A protease which is currently investigated in phase 3 trial in combination with peginterferon and ribavirin. We reported the first clinical study examining telaprevir monotherapy with an extended dosing period of 24 weeks in Japan (Ozeki I, et al: EASL 2009). After completing study drug therapy, patients were treated with peginterferon alfa-2b and ribavirin. Methods: Five naive patients were treated with telaprevir monotherapy at 750mg every 8 hours for up to 24 weeks. All patients, 48 to 68 years of age, had a chronic infection with HCV genotype 1b and their baseline serum HCVRNA levels were at least 1×105 IU/ml. Patients who met the definition of viral breakthrough (>2-log increase in HCVRNA above nadir) discontinued telaprevir dosing. RNA sequence was analyzed using the clonal sequencing method. After a withdrawal of MP-424, 4 of the 5 patients were enrolled in the off-study treatment with peginterferon alfa-2b and ribavirin within 4 weeks after the last administration of study drug. Results: At the initiation of off-study treatment, major NS3 protease variants in the patients were T54A, T54S+A156T, and A156V+V158I. All patients achieved undetectable HCVRNA levels by 12 weeks regardless of selected telaprevir-resistant variants. Sustained virologic response (SVR) was achieved in 2 patients who completed the assigned treatment for 48 weeks. The other 2 patients are now receiving peginterferon alfa-2b and ribavirin beyond 48 weeks for extended treatment period to 72 weeks. HCVRNA levels in these 2 patients continue to be undetectable. Conclusions: By the off-study treatment of standard peginterferon alfa-2b and ribavirin, all patients achieved complete EVR regardless of selected drug-resistant variants. Two patients who were typically treated for 48 weeks achieved an SVR. Updated results of this study will be presented.

759 COMBINATION OF TMC435 WITH TWO NOVEL NS5B INHIBITORS INCREASES ANTI HCV ACTIVITY AND RESULTS IN A HIGHER GENETIC BARRIER IN VITRO

Background: MP-424 (telaprevir) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3–4A protease which is currently investigated in phase 3 trial in combination with peginterferon and ribavirin. We reported the first clinical study examining telaprevir monotherapy with an extended dosing period of 24 weeks in Japan (Ozeki I, et al: EASL 2009). After completing study drug therapy, patients were treated with peginterferon alfa-2b and ribavirin. Methods: Five naive patients were treated with telaprevir monotherapy at 750mg every 8 hours for up to 24 weeks. All patients, 48 to 68 years of age, had a chronic infection with HCV genotype 1b and their baseline serum HCVRNA levels were at least 1×105 IU/ml. Patients who met the definition of viral breakthrough (>2-log increase in HCVRNA above nadir) discontinued telaprevir dosing. RNA sequence was analyzed using the clonal sequencing method. After a withdrawal of MP-424, 4 of the 5 patients were enrolled in the off-study treatment with peginterferon alfa-2b and ribavirin within 4 weeks after the last administration of study drug. Results: At the initiation of off-study treatment, major NS3 protease variants in the patients were T54A, T54S+A156T, and A156V+V158I. All patients achieved undetectable HCVRNA levels by 12 weeks regardless of selected telaprevir-resistant variants. Sustained virologic response (SVR) was achieved in 2 patients who completed the assigned treatment for 48 weeks. The other 2 patients are now receiving peginterferon alfa-2b and ribavirin beyond 48 weeks for extended treatment period to 72 weeks. HCVRNA levels in these 2 patients continue to be undetectable. Conclusions: By the off-study treatment of standard peginterferon alfa-2b and ribavirin, all patients achieved complete EVR regardless of selected drug-resistant variants. Two patients who were typically treated for 48 weeks achieved an SVR. Updated results of this study will be presented.

Pegylated Interferon‐α‐2a plus Ribavirin for Treatment‐Naive Asian Patients with Hepatitis C Virus Genotype 1 Infection: A Multicenter, Randomized Controlled Trial

Comparable sustained virologic response (SVR) rates have been documented between Asian patients who received 24 weeks of pegylated interferon (IFN) plus ribavirin and white patients who received 48 weeks of combination therapy for hepatitis C virus genotype 1 (HCV-1) infection. Whether a 48-week course of combination therapy shows a better SVR rate than a 24-week course of such therapy among Asian patients with HCV-1 infection has not been confirmed in multicenter, randomized studies. In this multicenter, randomized trial, 308 treatment-naive HCV-1-infected Asian patients were randomly assigned to receive either 24 or 48 weeks of pegylated IFN-alpha-2a (180 microg per week) plus ribavirin (1000-1200 mg/day) therapy. The primary end point was SVR, defined as an undetectable serum HCV RNA level 24 weeks after discontinuation of therapy. In addition, rapid virologic response (RVR) was defined as an undetectable serum HCV RNA level at week 4 of therapy, and complete early virologic response was defined as an undetectable serum HCV RNA level at 12 weeks of therapy in the absence of RVR. By intention-to-treat analysis, patients who received 48 weeks of therapy had a significantly higher SVR rate than did those who received 24 weeks of therapy (76% vs. 56%; P < .001). Among patients with a baseline serum HCV RNA level <800,000 IU/mL and RVR, SVR rates were comparable between 24- and 48-week courses of therapy (94% vs. 100%; P = .13). In contrast, 48 weeks of therapy was associated with a significantly higher SVR rate than was 24 weeks of therapy among patients without RVR (39% vs.16%; P = .01) and among those who achieved a complete early virologic response (44% vs. 20%; P = .02). In treatment-naive Asian patients with HCV-1 infection, 48 weeks of pegylated IFN-alpha-2a plus ribavirin therapy is associated with a higher SVR rate, compared with 24 weeks of such therapy. Patients with a baseline serum HCV RNA level <800,000 IU/mL and who have achieved an RVR can receive a 24-week course of therapy without compromising the SVR rates; however, those who have not achieved an RVR but who have achieved a complete early virologic response should receive a 48-week course of therapy.

Response to pegylated interferon plus ribavirin in HIV‐infected patients with chronic hepatitis C due to genotype 4

Hepatitis C virus (HCV) genotypes 1 and 4 respond less well to pegylated interferon (pegIFN) plus ribavirin (RBV) therapy. For this reason most studies merge these two genotypes when assessing virological response. However, in most trials the HCV genotype 4 population is rather small, and conclusions are mainly derived from what occurs in HCV-1 patients. All HCV-4 patients coinfected with HIV who received pegIFN plus RBV in two different multicentre studies, PRESCO and ROMANCE, conducted respectively in Spain and Italy, were retrospectively analyzed. Baseline plasma HCV-RNA, proportion of patients with HCV-RNA <10 IU / mL at week 4 (rapid virological response), and HCV-RNA declines >2 logs at week 12 (early virological response, EVR) were all assessed as predictors of sustained virological response (SVR). Overall, 75 patients (60 men) were evaluated. Median age was 40 years and median CD4 count 598 cells / mm(3); 49% had plasma HIV-RNA <50 copies / mL; 71% had elevated liver enzymes and 31% had advanced liver fibrosis (Metavir F3-F4). Median serum HCV-RNA was 5.7 log IU / mL. Rapid virological response was attained by 10 (20%) patients and EVR by 26 (42%). Using intention-to-treat and on-treatment (OT) analyses, SVR was achieved by 21 / 75 (28%) and 21 / 62 (34%) of HCV-4 patients, respectively. In the multivariate analysis (OT), baseline HCV-RNA (OR 0.09 for every log increment; 95% CI: 0.01-0.7) and EVR (OR: 7.08; 95% CI: 1.8-27.2) were significantly and independently associated with SVR. This is the largest series of HIV-infected patients with chronic hepatitis C due to HCV-4 treated with pegIFN plus RBV examined so far and the results show that HCV-4 behaves similarly to HCV-1. Therefore, these patients should be considered as difficult to treat population. Baseline serum HCV-RNA and EVR are the best predictors of SVR in HCV-4 / HIV-coinfected patients.

Clinical trial: randomized, double‐blind, placebo‐controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4

Nitazoxanide, licensed in the US for treatment of Cryptosporidium parvum and Giardia lamblia, inhibits hepatitis C virus replication in replicon systems. To evaluate the safety and efficacy of nitazoxanide monotherapy for the treatment of chronic hepatitis C. This multicentre, randomized, double-blind, placebo-controlled study randomized 50 adult patients with chronic hepatitis C genotype 4 at three centres in Egypt to nitazoxanide 500 mg tablet or placebo twice daily for 24 weeks. Patients were followed up every 4 weeks during treatment and for 24 weeks after therapy. Seven of 23 patients (30.4%) in the nitazoxanide group achieved undetectable serum HCV RNA compared to 0 of 24 in the placebo group during therapy (P = 0.004). Each of the seven responders had baseline HCV RNA levels < or =400 000 IU/mL. Six of the seven virological responders were followed up for 24 weeks after the end of treatment, and four patients (17.4% of 23 treated) had a sustained virological response. Adverse events were similar in the nitazoxanide and placebo groups. Nitazoxanide monotherapy is safe and effective in achieving sustained virological response in a modest number of patients with chronic hepatitis C genotype 4, particularly in patients with low baseline serum HCV RNA levels.

Mitochondrial DNA depletion in HIV-infected patients with chronic hepatitis C and effect of pegylated interferon plus ribavirin therapy

The metabolic stress derived from high levels of virus replication in both HIV and hepatitis C virus (HCV) infections results in mitochondrial DNA depletion, which seems to be enhanced in co-infected patients. The use of nucleoside analogues to treat HIV infection may further increase mtDNA depletion by inhibiting gamma DNA polymerase. Information on the impact of therapy with pegylated interferon (pegIFN) plus ribavirin on mtDNA is scarce and conflicting results have been reported. Fifty-nine HCV/HIV-co-infected patients (43 on and 16 off antiretroviral therapy) who initiated treatment with pegIFN plus ribavirin were retrospectively analysed. The amount of mtDNA in peripheral blood mononuclear cells (PBMC) was measured at baseline and at the end of HCV therapy. Mean baseline serum HCV-RNA was 5.8 log IU/ml and 56% of patients were infected by HCV genotype 1. An inverse correlation between serum HCV-RNA levels and PBMC mtDNA content was recognized at baseline (r = -0.370; P = 0.006). HCV-RNA suppression at the end of HCV therapy was associated with a significant increase in mtDNA, particularly in patients with baseline HCV-RNA levels greater than 6 log IU/ml (+61 mtDNA copies/cell) and in subjects not taking antiretroviral therapy (+133 mtDNA copies/cell). HCV replication correlates with the extent of mtDNA depletion in PBMC, and treatment of chronic hepatitis C is associated with a significant improvement in mtDNA content. This benefit, however, is not recognized when HCV medications are used along with antiretroviral therapy, probably because of a deleterious interaction of these drugs on mitochondria.

Sustained Virological Response Rate and Host Background in Chronic Hepatitis C Patients Receiving Various Interferon Therapies

BACKGROUND/AIM: To determine the sustained viral response (SVR) rate and to investigate the baseline host and viral characteristics of chronic hepatitis C (CHC) patients who achieved an SVR with interferon (IFN) alone or IFN plus ribavirin. PATIENTS AND METHODS: One hundred and forty-seven adults with CHC were studied. Baseline serum HCV-RNA was quantified by RT-PCR, and the HCV serotype was classified as S1 and S2. IFN therapy was selected according to the serum HCV-RNA load: IFN-alpha 2b plus ribavirin were given to 63 patients, while the other 84 patients were treated with IFN alone (53 patients received IFN-alpha or -alpha 2b, and 31 patients received consensus IFN). All IFNs were administered daily for 2 weeks, followed by the same dose thrice weekly for a median of 22 weeks (14-94 weeks). Twenty-four weeks after finishing therapy, SVR was defined as negative serum HCV-RNA by a qualitative PCR, and patients with any other outcome were defined as nonresponders. Peripheral blood CD4 positive T cell subsets (Th1 and Th2 cells), NK cells, serum cytokines, and standard liver function tests were measured before starting therapy. RESULTS: An SVR was achieved in 87 patients, while 60 patients were nonresponders. Multiple logistic regression analysis revealed that the serum log 10-transformed HCV-RNA load, serotype, and liver fibrosis were independent factors for SVR. According to univariate logistic regression analysis, serum Log IL-10 and peripheral blood Th1 cells were significant predictors of SVR. CONCLUSION: Our results suggest that an SVR is strongly associated with S2, serum HCV-RNA load, and mild fibrosis, even when therapy is chosen according the serum viral load and serotype. Rec.11/17/2006, Acc.11/27/2006, pp187-193

Pegylated Interferon Alfa-2b vs Standard Interferon Alfa-2b, Plus Ribavirin, for Chronic Hepatitis C in HIV-Infected Patients&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;

Treatment of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients is a growing concern. Most data on the virologic efficacy and safety of the combination of peginterferon alfa-2b and ribavirin in coinfected patients come from uncontrolled studies. To study the safety and efficacy of peginterferon alfa-2b plus ribavirin vs standard interferon alfa-2b plus ribavirin in HIV-HCV coinfected patients. A multicenter, randomized, parallel-group, open-label trial. Patients were enrolled from February 2000 to February 2002 and followed up for 72 weeks. Four hundred twelve HIV-HCV coinfected patients with detectable serum HCV-RNA, abnormal liver histology, a CD4 cell count of at least 200 x 10(6)/L, and stable plasma HIV-RNA. Treatment with ribavirin 400 mg twice a day, orally, plus either peginterferon alfa-2b (1.5 microg/kg subcutaneous injection once a week) or standard interferon alfa-2b (3 million units of subcutaneous injection 3 times a week) for 48 weeks. Sustained virologic response, defined by undetectable serum HCV-RNA at week 72. More patients had sustained virologic responses in the peginterferon group than in the standard interferon group (27% vs 20%, P = .047). This difference between the treatments was found in patients with HCV genotype 1 or 4 infection (17% for peginterferon vs 6% for standard interferon, P = .006) but was not found in patients with HCV genotype 2, 3, or 5 (44% for peginterferon vs 43% for standard interferon, P = .88). Together, a decline in HCV-RNA of less than 2 log10 from baseline and detectable serum HCV-RNA at week 12 predicted 99% of treatment failures. Histologic activity diminished and fibrosis stabilized in virologic responders. The 2 regimens showed similar tolerability although dose modifications for clinical and biological events were more frequent with peginterferon. Eleven cases of pancreatitis or symptomatic hyperlactatemia were observed, all in patients receiving didanosine-containing antiretroviral regimens. In combination with ribavirin, treatment with peginterferon alfa-2b is more effective than standard interferon alfa-2b for HCV infection in HIV-infected patients.

Combined treatment of relapse of chronic hepatitis C with high-dose α 2b interferon plus ribavirin for 6 or 12 months

Background/Aims: Retreatment of relapses of chronic hepatitis C with a standard regimen of interferon plus ribavirin for 6 months obtains a sustained response in a minority of patients with high viraemia and genotype 1b. We aimed to assess whether increasing the interferon dose and prolonging the time of combined treatment may enhance the effectiveness, and also to evaluate the tolerability, and to identify the determinants of sustained response. Methods: Fifty subjects with chronic hepatitis C who had relapsed after one or more courses of α-interferon monotherapy were randomised to receive α 2b interferon (6 MU tiw) plus ribavirin (1000–1200 mg daily) for 6 or 12 months. ALT normalisation and serum HCV-RNA clearance at the end of treatment and 6 months after stopping therapy were used as markers for sustained response. Results: End-of-treatment response was achieved in 48 patients (96%) and 27 (54%) had a complete sustained response. Patients treated for 12 months had a higher rate of sustained response (18/25, 72%; 95% C.I. 0.54–0.89) than those treated for 6 months (9/25, 36%; 95% C.I. 0.17–0.55, p=0.01). Twelve months of therapy was significantly more effective for patients with genotype 1b and baseline serum HCV-RNA greater than 450 000 copies/ml ( p=0.005). Seven subjects (14%) discontinued treatment because of side effects. Logistic regression analysis showed 12 months of therapy, young age and low pre-treatment serum HCV-RNA to be independent predictors of sustained response. Conclusions: Relapsers with genotype 1b and high levels of HCV-RNA will benefit from a 12-month course of 6 MU tiw interferon plus ribavirin, while subjects with genotype 1b and low levels of serum HCV-RNA or with genotype other than 1b may be treated for 6 months.

Biochemical and virological outcome of patients with chronic hepatitis C treated with interferon alfa-2b for 6 or 12 months: A 4-year follow-up of 211 patients

To compare two interferon (IFN) schedules for the treatment of chronic hepatitis C, we followed 211 patients who received 3 million units IFN-alpha2b thrice weekly for either 6 months (group 1; 85 patients) or 12 months (group 2; 126 patients), with a median follow-up of 3.4 (0.1- 8.4) and 4.2 (0.7-8.7) years, respectively. The biochemical and virological responses at the end of treatment were 34.1% and 16.5% versus 62.7% and 41.2% for the 6- and the 12-month regimens, respectively. Late biochemical responses (after the third month of treatment) occurred in 30.6% of responding patients, and they were not particularly associated with an adverse long-term treatment outcome. In a multivariate analysis, patients with a primary response were significantly more frequently infected with a non-1b HCV genotype (relative risk [RR]: 14.4), had been treated for 12 months (RR: 6.0), and had an early stage of liver fibrosis (RR: 5.2). Baseline serum HCV-RNA and ferritin levels also bore a significant, though weaker, association with a primary response. Using a set of pretreatment variables in a model of discriminant analysis, we could correctly predict the long-term virological outcome in 86.6% of the individual cases. At the end of follow-up, a biochemical and virological sustained response was observed in 14.1% and 11.8% versus 40.5% and 31% of groups 1 and 2, respectively. Significant predictors of a virological sustained response were a virological primary response (RR: 41.2) and the pretreatment level of serum HCV-RNA (RR: 10.3 per each 106-Eq/mL decrease). Patients with a "good treatment profile," including an early stage of liver fibrosis, a non-1b genotype and serum HCV-RNA <0.35 x 106 Eq/mL, had a 66.7% rate of observed virological SR, compared with a zero response for those with the opposite, a "bad treatment profile." We conclude that a 12-month IFN treatment, along with a non-1b genotype and the absence of advanced stage of fibrosis, are the main determinants for the induction of a virological primary response in chronic hepatitis C. Such response, along with a low pretreatment serum HCV-RNA level, are the main predictors for a 4-year virological response to IFN. (Hepatology 1997 Sep;26(3):734-9)

HCV-RNA SERUM LEVELS IN CHILDREN WITH CHRONIC HEPATITIS C AND RESPONSE TO INTERFERON THERAPY

Recently it has been reported that low baseline serum HCV-RNA levels and early loss of serum HCV-RNA on IFN therapy can predict a long-term response to IFN therapy in adults with chronic hepatitis C (CHC). Little information is available about viraemic changes during IFN therapy in children with CHC. Aim: to evaluate serum HCV-RNA levels before and during IFN therapy in children with CHC and compare virological and biochemical response rates. Methods: 25 consecutive children (13 males; mean age 7.9 yrs; range 3.6-11.5 yrs) affected by CHC were enroled to receive treatment with recombinant-alfa2b IFN (5MU/m2 t.i.w.) for 12 months. IFN therapy was suspended before time in case of severe side effects including hypertransaminasemia (>6 times the upper reference limit) or if no reduction of ALT after 6 months of therapy occurred. Patients' sera were tested for liver function tests and HCV-RNA serum levels by branched DNA signal amplification (b-DNA) assay (Chiron HCV-RNA 2.0; level of sensitivity 0.2 × 106 Eq/ml) at the following times: 2 and 1 week before IFN therapy, weekly for the first 3 weeks of treatment, and therafter monthly until the suspension of IFN. Results: At the present, 15 patients have completed the entire course of therapy, in remaning 10 patients IFN was suspended before time according to protocol. Before therapy, median HCV-RNA serum levels were 0.90 ×106 Eq/ml (range: 0.10-20.18), median ALT serum levels were 74 IU/L (range: 41-219; normal values <35 IU/L). At the end of treatment 8/25 were considered biochemical responders (BR) because ALT serum levels became normal during the treatment and persisted normal until the suspension, the remaining were biochemical nonresponders (NBR). In 11 patients (5 BR), viremia fell below the level of sensitivity already after the second dose of IFN. During the course of therapy, only 2 patients (both BR) showed undetectable levels of HCV-RNA levels for the whole period of treatment; 7 patients (all NBR) showed HCV-RNA levels persistently elevated; in the remaining patients viremia was fluctuating with phases of reduction below the level of sensitivity of the test. At the end of therapy, 12 patients (7 BR) had undetectable levels of serum HCV-RNA. Although no significant difference between pretreatment values of HCV-RNA serum levels between BR (median 0.29 ×106 Eq/ml; range: 0.10-1.62) and BNR (median 1.04 ×106 Eq/ml; range: 0.15-20.18) was found, none of BR had basal values of HCV-RNA >1.62 × 106 Eq/ml. Conclusions: an early reduction of serum HCV-RNA levels occurred in 44% of CHC patients treated with IFN, but only in 8% persisted for the entire course of therapy; persistent biochemical and virological responses may be predicted by low pretreatment HCV-RNA levels; the present study did not confirm the virological response rates observed in previous studies in whom a single evaluation of HCV-RNA levels was performed at the end of therapy.