Secreted Phosphoprotein 1 Promoter Genetic Variants Are Associated with the Response to Pegylated Interferon α Plus Ribavirin Combination Therapy in Egyptian Patients with Chronic Hepatitis C Virus Infection

Background/Aims

The T-helper 1 (TH1) immune reaction is essential for the eradication of hepatitis C virus (HCV) during pegylated interferon α (PEG-IFN-α)- and ribavirin (RBV)-based therapy in chronic HCV patients. Secreted phosphoprotein 1 (SPP1) was shown to be a crucial cytokine for the initiation of a TH1 immune response. We aimed to investigate whether SPP1 single nucleotide polymorphisms (SNPs) may influence sustained virological response (SVR) rates.

Methods

Two SNPs in the promoter region of SPP1 at the −443 C>T and −1748 G>A loci were genotyped in 100 patients with chronic HCV genotype 4 infection using a TaqMan SNP genotyping assay.

Results

Sixty-seven patients achieved a SVR, and 33 patients showed no SVR. Patients carrying the T/T genotype at the −443 locus showed a significantly higher SVR rate than those carrying the C/T or C/C genotype (83.67% vs 50.98%, p<0.001). At the −1748 locus, the SVR rate was significantly higher in patients with the G/G genotype than in those with the A/A genotype (88.89% vs 52.63%, p=0.028) and in patients with the G/A genotype than in those with the A/A genotype (85.29% vs 52.63%, p=0.001).

Conclusions

SPP1 SNPs at −443 C>T and −1748 G>A loci may be useful markers for predicting the response to PEG-IFN-α-2b plus RBV therapy in Egyptian patients with chronic HCV genotype 4 infection.     

Prediction of a Null Response to Pegylated Interferon α-2b Plus Ribavirin in Patients with High Viral Load Genotype 1b Hepatitis C

Background/Aims

The present study aimed to clarify whether virological response within 2 weeks after therapy initiation can predict a null response to pegylated interferon α-2b plus ribavirin therapy in patients with high viral load genotype 1b hepatitis C.

Methods

The participants consisted of 72 patients with high viral load genotype 1b. The dynamics of viral load within 2 weeks were measured.

Results

Significant differences between null responders and nonnull responders were noted for interleukin (IL)-28B genotype, amino acid 70 substitution, α-fetoprotein, low-density lipoprotein cholesterol, hyaluronic acid, and viral response. The area under the curve (AUC) for the receiver operating characteristic curve of the hepatitis C virus (HCV) RNA level decline at 2 weeks (AUC=0.993) was the highest among the factors predicting the null response. When the cutoff value for the HCV RNA level decline at 2 weeks was set at 0.80 log, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting a null response were 82%, 96%, 82%, 96%, and 94%, respectively. In comparison, values for the non-TT and mutant type of amino acid 70 substitution were similar to those for HCV RNA level decline at 2 weeks.

Conclusions

Virological response at 2 weeks or the combination of IL-28B and amino acid 70 substitution are accurate predictors of a null response.     

Is Hepatitis C Virus Positivity a Contributing Factor to Occult Hepatitis B Virus Infection in Hemodialysis Patients?

Hepatitis B (HBV) infections continue to occur in adult hemodialysis units. Occult HBV infection (serum hepatitis B surface antigen [HBsAg] negative but HBV DNA positive) may be a contributing factor in these patients. This study was designed to (1) investigate the prevalence of occult HBV infection in hemodialysis patients and (2) compare the prevalence of occult HBV infection among hepatitis C (HCV)-positive and HCV-negative hemodialysis patients. The study included 138 patients on chronic hemodialysis. Eighty-four patients were HCV positive and 54 were HCV negative. HBV DNA testing was performed by polymerase chain reaction. We also recorded general characteristics of the patients, duration of hemodialysis, and serum alanine aminotransferase and aspartate aminotransferase levels. Twenty-one (15.2%) of the 138 hemodialysis patients were HBV DNA positive. Nine (16.6%) of the 54 anti-HCV antibody negative hemodialysis patients were HBV DNA positive. Twelve (14.2%) of the 84 anti-HCV antibody positive patients were HBV DNA positive. The prevalence in anti-HCV Ab positive and negative hemodialysis patients were same (P > .05). Hemodialysis duration, demographic features, and biochemical parameters were not significantly different in patients with and without occult HBV infection in both HCV-positive and -negative hemodialysis patients (P > .05). HCV positivity is not a contributing factor to occult HBV infection in hemodialysis patients. None of the parameters tested help to distinguish patients with occult HBV infection from those who are HBV DNA negative.     

Sustained Viral Response to Pegylated Interferon α-2b and Ribavirin in Chronic Hepatitis C Refractory to Prior Treatment

Hepatitis C virus (HCV) infection refractory to previous therapy is common. Treatment of patients with refractory disease is difficult and less studied. Pegylated interferon α-2b plus ribavirin is used for treatment of HCV patients naïve to therapy. We conducted a randomized study for refractory HCV patients using a high- vs. a low-dose pegylated interferon α-2b and ribavirin protocol. Our aim was (1) to determine the efficacy of pegylated interferon α-2b plus ribavirin to eradicate HCV in previously treated individuals and (2) to compare a low-dose to a high-dose regimen. One hundred fifty-two patients were initiated in the study, 112 (74%) were male and 40 (26%) female. Nineteen percent of patients obtained a sustained viral response (SVR) in the high-dose arm. Prior relapsers had the highest SVR rates: 50% in non-genotype 1 and 34% in genotype 1. The odds of achieving a SVR were six times higher in previous relapsers. The rate of SVR in genotype 1 patients who were nonresponders to prior therapy was only 8%. All patients who achieved a SVR had no detectable virus at week 24. However, only half of those who had undetectable viral titers at week 24 achieved a SVR. In conclusion, retreatment of patients with refractory hepatitis C infection with interferon α-2b and ribavirin combination therapy is well tolerated and gives modest response rates. The most important factor in predicting response to therapy is the manner of response to previous treatment. The likelihood of response to treatment can be predicted from the viral titers at 24 weeks.     

Diagnostic Value of Serum Level of Soluble Tumor Necrosis Factor Receptor IIα in Egyptian Patients With Chronic Hepatitis C Virus Infection and Hepatocellular Carcinoma

Background:

The prognosis of hepatocellular carcinoma (HCC) is unfavorable and needs serum markers that could detect it early to start therapy at a potentially curable phase.

Objectives:

The aim of this study was to determine the value of serum soluble tumor necrosis factor (TNF) receptor-IIα (sTNFR-IIα) in diagnosis of HCC in patients with chronic hepatitis C virus (HCV) infection.

Patients and Methods:

The study was performed on 110 subjects who were classified into five groups. Group I included 20 patients with chronic noncirrhotic HCV infection and persistently normal transaminases for ≥6 months. Group II included 20 patients with chronic noncirrhotic HCV infection and elevated transaminases. Group III included 20 patients with Chronic HCV infection and liver cirrhosis. Group IV included 20 patients with chronic HCV infection with liver cirrhosis and HCC. Group V included 30 healthy age and sex-matched controls. Medical history was taken from all participants and they underwent clinical examination and abdominal ultrasonography. in addition, the following laboratory tests were requested: liver function tests, complete blood count, HBsAg, anti-HCVAb, HCV-RNA by qualitative PCR, and serum levels of α-fetoprotein (AFP) and sTNFR-IIα.

Results:

The serum level of sTNFR-IIα was significantly higher in patients with HCC in comparison to the other groups. A positive correlation was found between the serum levels of sTNFR-IIα and AST and ALT in patients of group-II. Diagnosis of HCC among patients with HCV infection and cirrhosis could be ascertained when sTNFR-IIα is assessed at a cutoff value of ≥ 250 pg/mL.

Conclusions:

Serum sTNFR-IIα could be used as a potential serum marker in diagnosing HCC among patients with HCV infection.     

HBeAg-negative Patients with Chronic Hepatitis B Virus Infection and Normal Alanine Aminotransferase: Wait or Treat?

Alanine aminotransferase (ALT) is a common clinical indicator of liver inflammation. The current Chinese guidelines for the management of chronic hepatitis B (CHB) recommend antiviral treatment for patients with detectable hepatitis B virus (HBV) DNA and persistent ALT levels (ALTs) exceeding the upper limit of normal. However, it has been recently reported that patients with chronic HBV infection, especially HBeAg-negative patients with persistently normal ALTs, may have liver biopsy findings of significant inflammation and fibrosis. For HBeAg-negative patients with chronic HBV infection and normal ALTs, many controversial questions have been asked. To treat or not? When to initiate the treatment? Which drug is appropriate? In this review, we summarize the available data on the management of HBeAg-negative patients with chronic HBV infection and normal ALTs with the aim of improving the current clinical management.     

How Can We Make Decision for Patients With Chronic Hepatitis B According to Hepatitis B Virus (HBV) DNA Level?

Background:

HBeAg negative hepatitis B infection exerts both inactive carrier state and chronic active hepatitis, which are sometimes difficult to differentiate. Serial hepatitis B virus (HBV) DNA quantification, alanine transaminase (ALT) measurement, and liver histology assessment can help to differentiate these forms of hepatitis B infection.

Objectives:

We aimed to clarify the clinical and laboratory characteristics of HBeAg negative hepatitis B patients.

Patients and Methods:

Patients with hepatitis B, referred to Tehran Blood Transfusion Hepatitis Clinic from 2011 to 2013, were included and followed for one year. Laboratory assessments including liver function tests, HBV DNA quantification, and liver biopsy (for some cases) were performed.

Results:

Two hundred forty-three HBeAg negative hepatitis B patients were stratified into three groups based on to their HBV DNA level including group 1 (G1) with HBV DNA level < 2000 IU/mL, group 2 (G2) with HBV DNA level 2000-20000 IU/mL, and group 3 (G3) with HBV DNA level > 20000 IU/mL. The G2 had more similarity to G1 than G3 regarding their clinical characteristics.

Conclusions:

It is concluded that most HBeAg negative hepatitis B patients with serum HBV DNA level of 2000-20000 IU/mL, persistent normal ALT concentration, and no or mild liver damage on biopsy can be clinically managed as HBV inactive carriers.     

Pegylated Interferon-α Plus Ribavirin Therapy Improves Left Ventricular Diastolic Dysfunction in Patients With Chronic Hepatitis C Attaining Sustained Virological Response

Background

Pegylated interferon (pegIFN) in combination with ribavirin (RBV) has successfully improved the rate of sustained virological response (SVR) in chronic hepatitis C virus (HCV) infected individuals, which reduces the progression of the chronic liver disease. However, the influence of combination therapy (pegIFN/RBV) on cardiac function has yielded ambiguous results. The present study aimed to evaluate the effects of combination therapy with pegIFN/RBV on cardiac function of HCV-infected individuals with SVR.

Clinical Expression of ‘Silent’ Hepatitis B Virus Infection in a Patient with Visceral Leishmaniasis

A 69-year-old male was hospitalized in January 1999 because of viszeral leishmaniasis. He had also suffered from anti-hepatitis C virus (HCV)-positive chronic hepatitis for years. All serum hepatitis B virus (HBV) antigens and antibodies were negative except for anti-HBc. The patient was treated with amphotericin B cholesteryl sulfate (2 mg/kg twice a day for 7 days, iv). Fever disappeared on the 3rd day of treatment, the clinical condition improved rapidly and the patient recovered. In May 1999 the patient developed iteric HBsAg-negative acute hepatitis (aspartate aminotransferase 722 U/l; alanine aminotransferase 988 U/l). Anti-HBc IgM was positive and HBV-DNA was detected in serum by PCR. Anti-HAV IgM was negative. A serum sample obtained on presentation and stored at −80°C was retrospectively tested and found positive for HBV-DNA. In July 1999, complete remission of acute hepatitis and seroconversion to anti-HBs was observed. We suppose that a moderate depression of the immune system, probably associated with leishmaniasis, may have enhanced HBV replication in the patient who had an HBsAg-negative ‘silent’ HBV infection. Restoration of the immune system after successful antiprotozoan therapy might have induced cell-mediated necrosis of the HBV-infected hepatocytes and seroconversion to anti-HBs. Received: June 6, 2000 · Revision accepted: February 16, 2001     

High Predictability of a Sustained Virological Response (87%) in Chronic Hepatitis C Virus Genotype 1 Infection Treatment by Combined IL28B Genotype Analysis and γ-Glutamyltransferase/Alanine Aminotransferase Ratio: A Retrospective Single-Center Study

Background: Chronic hepatitis C virus genotype 1 (HCV-G1) infection is treated with pegylated interferon-α and ribavirin. Predictive factors for treatment success are even more important now as direct-acting antiviral agents are available. Methods: Clinical and laboratory parameters were analyzed by uni- and multivariate statistical means in 264 patients with HCV-G1 infections with regard to treatment outcome. Results: The overall sustained virological response (SVR) rate was 44%. Univariate analyses revealed SVRs to be associated with age, high alanine aminotransferase (ALT) and low γ-glutamyltransferase (γ-GT) serum activities, a low pretreatment γ-GT/ALT ratio, rapid virological response (RVR), and absence of steatosis. Multivariate analyses unveiled IL28B rs12979860 genotype (CC vs. CT: OR = 2.8, CI: 1.5-4.9, p = 0.001; CC vs. TT: OR = 7.1, CI: 3.1-16.7, p < 0.001), low pretreatment γ-GT/ALT ratio (OR = 2.5, CI: 1.7-3.3, p < 0.001), age (OR = 0.96, CI: 0.94-0.98, p = 0.001) and RVR (OR = 4.18, CI: 2.85-8.65, p < 0.001) to be significantly related to treatment outcome. Patients with the IL28B rs12979860 CC genotype and a low pretreatment γ-GT/ALT ratio achieved the highest rate of a SVR with the highest predictive values (OR = 26.7, 95% CI: 10-71.1, p < 0.0001). Conclusion: The pretreatment γ-GT/ALT ratio significantly enhances the predictability of the IL28B genotype. Employing this combination will help to identify patients who will most likely benefit from an interferon-α-based combination therapy in a nontriaged ordinary setting.     

Treatment Response and Tolerability of Pegylated Interferon-α Plus Ribavirin Combination Therapy in elderly Patients (≥ 65 years) With Chronic Hepatitis C in Korea

Background

The prevalence of hepatitis C virus (HCV) infections in elderly patients has been increasing in a number of countries. A few reports concerning pegylated interferon-α (PEG-IFN-α)-based combination treatment in elderly chronic hepatitis C (CHC) patients have been published, with slightly different treatment outcomes.

Objectives

We investigated the treatment response and safety of PEG-IFN-α plus ribavirin combination therapy in elderly patients with CHC.

Patients and Methods

Among a total of 181 treatment-naïve CHC patients (60 patients with genotype 1, 121 patients with genotype 2 or 3), 38 were aged ≥ 65 years (defined as the elderly group) and 143 were aged < 65 years (defined as the non-elderly group).

Results

The overall sustained virologic response (SVR) was lower in the elderly group than in the non-elderly group, but it was not significantly different (65.8 % vs. 76.2 %, P = 0.15). In a subgroup analysis, among patients with genotype 1, the elderly group had a significantly lower SVR rate than the non-elderly group (30.8 % vs. 66.0 %, P = 0.03). However, the SVR rate in patients with HCV genotype 2 or 3 was comparable between the two groups (84.0 % vs. 81.3 %, P = 0.85). HCV genotype was significantly associated with SVR in the elderly patients (genotype 1 vs. 2 or 3, odds ratio: 0.18, 95% confidence interval: 0.000-0.869, P = 0.03). The incidence of premature discontinuation of treatment (21.1 % vs. 9.1 %, P = 0.05) and dose modification (52.6 % vs. 31.5 %; P = 0.02) due mainly to adverse events or laboratory abnormalities, were higher in the elderly group than in the non-elderly group.

Conclusions

PEG-IFN-α plus ribavirin combination therapy might be considered for elderly CHC patients, especially for genotype 2 or 3, with vigilant monitoring of adverse events.     

Partial Response to Entecavir and Tenofovir in Na?ve Patients with Chronic Hepatitis B: Clinical Relevance and Management

Entecavir and tenofovir are the currently recommended first line analogues for treatment of na?ve patients with chronic hepatitis B. Despite their overall efficacy and high genetic barrier granting for a low risk of resistance, both regimens will fail to completely suppress HBV DNA at week 48 in 10% of HBeAg-negative and 30% of HBeAg-positive patients. A pre-treatment level >8 log₁₀ IU/mL HBV DNA and poor medication adherence were the most significant predictors of a partial virological response (PVR). While the clinical relevance of PVR is still poorly understood, nucleos(t)ide (NUC)-naive PVR patients who maintained detectable levels of viremia in follow up, were at risk of developing resistance to ETV. Patients with a suboptimal decline of viremia during the first 48?weeks of therapy with ETV and/or a residual viremia >1,000?IU/mL, can be protected by a rescue switch to TDF. Resistance to TDF has not been described so far, yet the long-term risk of PVR in TDF-treated patients remains unclear.     

Effectiveness of Sofosbuvir,Ribavirin and PEG-IFNα-2a in the Treatment of Naïve Egyptian Patients With Chronic Hepatitis C Virus Genotype 4

Background

Egypt is one of the largest epidemic areas of hepatitis C virus (HCV) in the world. Its prevalent genotype is 4 with a majority of subtype 4a. In 2013, the Food and Drug Administration approved a new direct-acting antiviral drug (sofosbuvir) to treat patients with chronic HCV infection. In Egypt, the patients are already being treated with sofosbuvir in conjunction with ribavirin and pegylated interferon alfa-2a (PEG-IFNα-2a) for 12 weeks since 2015. The present study was planned to explain the efficacy of this treatment regimen against the HCV genotype 4a in Egyptian patients and its pretreatment predictive factors of virological response.

Improved Efficacy of a Pegylated Interferon-α-2a Stepwise Optimization Treatment Strategy in the Treatment of Hepatitis B e Antigen-positive Chronic Hepatitis B Patients

Current pegylated interferon-α (PEG-IFN) treatment for chronic hepatitis B (CHB) e-antigen (HBeAg)-positive patients are suboptimal, and effective ways of improving PEG-IFN treatment efficacy are needed.This retrospective cohort study compared the efficacy of a PEG-IFN stepwise optimization treatment (PEG-IFN SOT) strategy with that of a 48-week PEG-IFN standard therapy (PEG-IFN ST) in HBeAg-positive CHB patients.A total of 110 patients were included in our study. Of these, 70 received the PEG-IFN SOT and 40 received the PEG-IFN ST (control group). We based the decision whether to add adefovir and/or extend the PEG-IFN–based treatment to 96 weeks on the patients’ 12-week or 24-week early virological response (12W EVR, at least a 2 log₁₀ reduction in HBV DNA copies/mL at week 12; 24W EVR, at least 1 log₁₀ reduction in HBsAg IU/mL or HBsAg <1500 IU/mL at week 24) and their 48-week partial response (48W PR, 1.0 ≤HBeAg ≤10.0 S/CO or HBeAg >10.0 S/CO but HBsAg <1000 IU/mL).The HBeAg seroconversion rate 24 weeks post-PEG-IFN treatment was significantly higher in the PEG-IFN SOT than the PEG-IFN ST group (50% vs 22.5%, P = 0.005). The HBsAg clearance rates in the PEG-IFN SOT and ST groups were 10% and 0% (P = 0.04), respectively. Receiving PEG-IFN SOT (OR = 0.26, P = 0.01), ALT × ULN at baseline (OR = 0.74, P = 0.003), and achieving 12 and 24W EVR (OR = 0.29, P = 0.03) were independent factors associated with HBeAg seroconversion.PEG-IFN SOT is a promising strategy for achieving high rates of serological response in HBeAg-positive CHB patients.