Interferon combination therapy for HIV/hepatitis C virus coinfection

IFN-α has been the cornerstone of chronic hepatitis C virus (HCV) treatment for over a decade. Yet, rates of sustained virologic response of HCV infection to interferon-based therapy, particularly in difficult-to-treat populations, have been disappointingly low. This is particularly true in HIV/HCV coinfection, in which less than a third of patients typically respond to therapy. New HCV protease inhibitors, most of which will need to be administered with pegylated interferon, are in development, but comprehensive, long-term data for their use in coinfected patients is not yet available. Understanding the basis of this population's poor response to interferon-based therapy is crucial to future exploration of new therapeutic options, immunotherapy and prognosis in HIV/HCV-coinfected population.     

Predicting interferon therapy efficacy from hepatitis C virus genotype and RNA titer

We classified 53 Japanese patients with chronic hepatitis C who were treated with natural interferon- into genotypes and also tested the amounts of hepatitis C virus (HCV) RNA. The rate of the long-term complete response group, whose alanine aminotransferase levels remained within the normal range during the six months after therapy, was significantly higher (P<0.01) in the type-III patients (4/5, 80.0%) than in type-II patients (4/43, 9.3%). For these long-term complete responders, the amounts of HCV RNA was less than 10⁷ copies/ml serum in type-II patients, whereas two type-III patients with relatively high amounts of HCV RNA responded completely. These results confirm that the genotype of HCV is an important factor for predicting the response to interferon therapy. The amounts of HCV RNA can also predict its efficacy in type-II patients.This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan, and the Research Group of Intractable Hepatitis sponsored by the Ministry of Health and Welfare of Japan.     

Clearance of serum hepatitis C virus RNA after interferon therapy in relation to virus genotype

Abstract: The effect of recombinant interferon-alfa on serum HCV RNA levels in Japanese patients with chronic hepatitis C was investigated. At 24 weeks of treatment, 41 (32.5%) of 126 patients lost HCV RNA from serum, and aminotransferases were normalized in 31 (75.6%) of these 41 cases. HCV genotypes were categorized into four types (Type I, II, III, IV); the frequencies among the patients were: Type I: 0%, Type II: 70.6%, Type III: 20.6%, and Type IV: 6.3%. At the end of the 24-week treatment, HCV RNA levels were remarkably decreased in Type III patients and became undetectable in 18 (69.2%) of 26. In contrast, only 18 (20.2%) of 89 patients with Type II and two of eight with Type IV lost HCV RNA from sera. The relation between HCV genotype (Type III) and response to IFN therapy was also confirmed using a logistic regression model. HCV genotype seems to be an important factor in determining the response to IFN in patients with chronic hepatitis C.     

Hepatocellular carcinoma or interferon-based therapy history attenuates sofosbuvir/ribavirin for Japanese genotype 2 hepatitis C virus

AIM To investigate the real-world efficacy and safety of sofosbuvir/ribavirin(SOF/RBV) therapy for Japanese patients with genotype 2 hepatitis C virus(GT2-HCV).METHODS A total of 182 patients with GT2-HCV infection who received SOF/RBV therapy for 12 wk at our hospital were enrolled. The patients comprised 122 men and 60 women(age range: 17-84 years; mean age ± SD: 60.1 ± 12.1 years). Relationships between virological response and clinical data were examined by logistic regression analyses. RESULTS The proportions of patients with liver cirrhosis and history of hepatocellular carcinoma(HCC) were 29.0% and 17.3%, respectively. The proportion of patients with prior interferon(IFN)-based therapy was 25.6%. SOF/RBV therapy rapidly decreased HCV RNA levels. Several patients required RBV dose reduction because of anemia or fatigue. Four patients discontinued the therapy. The rates of sustained virological response at 12 wk after the end of treatment were 87.9%(intention to treat: 160/182) and 94.1%(per protocol: 159/169). Multivariate analyses showed that history of HCC or IFN-based therapy independently reduced the efficacy of SOF/RBV therapy. CONCLUSION SOF/RBV therapy for GT2-HCV is safe, highly tolerated, and effective. History of HCC or IFN-based therapy independently reduces the efficacy of this treatment.     

Optimizing hepatitis C therapy in HIV/hepatitis C virus (HCV) coinfected patients: Analysis of HCV viral kinetics on treatment

INTRODUCTION:

Hepatitis C virus (HCV) infection is potentially curable, but the sustained virological response (SVR) has been shown to be lower in patients coinfected HIV. A single-centre experience treating individuals with HCV and HIV coinfection is reported.

METHODS:

Twenty-one patients who received standard doses of pegylated interferon with weight-based dosing of ribavirin (mean 14.3 mg/kg) were retrospectively reviewed. Qualitative HCV polymerase chain reaction (PCR) was performed prospectively every four weeks if the patient remained HCV PCR positive. All patients with HCV genotype 1 were treated for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks and 32 weeks to 36 weeks if their HCV RNA level was undetectable after four weeks (RVR4) or eight weeks (RVR8) of therapy, respectively. If RVR8 was not achieved, the treatment was continued for 48 weeks.

RESULTS:

There were no dropouts or dose reductions within the first 12 weeks of treatment. SVR status was available for 20 patients and adequate serum for viral kinetics analyses was available for 17 patients. Eighty per cent of the patients achieved SVR (50% genotype 1; 100% genotypes 2 and 3). The week 8 viral load remained elevated for all genotype 1 nonresponders.

DISCUSSION:

High effectiveness rates were seen, particularly in patients with HCV genotype 2 and 3 who were treated for shorter durations. HCV viral loads after eight weeks of therapy helped distinguish patients with HCV genotype 1 who would respond to therapy.     

Early dynamics of hepatitis B virus in chimeric mice carrying human hepatocytes monoinfected or coinfected with genotype G

Of the 8 genotypes of HBV (genotypes A-H), genotype G is unique in that it has an insertion in the core gene and two stop codons in the precore region preventing the synthesis of hepatitis B e antigen. Most individuals with genotype G are coinfected with other genotypes, typically genotype A. Mice with severe combined immunodeficiency disease carrying human hepatocytes were infected with HBV particles propagated in Huh7 cells in culture. Mice monoinfected with genotype G did not raise detectable HBV DNA in serum, although products of the core gene emerged 4 to 8 weeks after inoculation. When they were superinfected with genotype A at week 10, however, HBV DNA of genotype A developed, which was replaced almost completely by that of genotype G within 10 weeks. Such a rapid takeover was also observed in mice initially infected with genotype A or C and superinfected with genotype G. Similar viral dynamics occurred in mice simultaneously coinfected with genotypes G and A. Takeover was markedly enhanced in mice inoculated with a serum passage containing genotype G with a trace of genotype A. Coinfection of mice with genotypes G and A induced abundant cellular steatosis along with increased fibrosis in the liver, which was not detected in mice monoinfected with genotype A or G. CONCLUSION: Genotype G can monoinfect chimeric mice at very low levels, and its replication increases maredly when coinfected with other genotypes. Coinfection with genotype G could enhance fibrosis under immunocompromised states.     

High uptake of hepatitis C virus treatment in HIV/hepatitis C virus co-infected patients attending an integrated HIV/hepatitis C virus clinic

Hepatitis C virus (HCV) is a major cause of liver disease in HIV-infected patients. The HCV treatment outcomes and barriers to HCV referral were examined in a centre with a HIV/HCV co-infection clinic. Patients who were antibody positive for both HIV and HCV between 1987 and January 2009 were identified. A retrospective chart review was undertaken. Multivariate analysis was performed to assess predictors of HCV clinic referral. Data were collected on 386 HIV/HCV patients; 202/386 had been referred to the co-infection clinic and 107/202 had HCV treatment. In addition, 29/202 were undergoing pretreatment work-up. Overall sustained virologic response (SVR) was 44%; SVR was equivalent in those who acquired HIV/HCV infection from intravenous drug use (IDU) and others. On multivariate analysis, patients who missed appointments, were younger, with active IDU and advanced HIV and who were not offered HCV treatment were less likely to be referred to the clinic. Patients attending the clinic were more likely to have been screened for hepatocellular carcinoma than those attending the general HIV service. Two-thirds of patients referred to the clinic had engaged with the HCV treatment programme. Dedicated co-infection clinics lower the threshold for treatment and improve management of liver disease in co-infected patients.     

Correlation between translation efficiency and outcome of combination therapy in chronic hepatitis C genotype 3

Combination therapy with interferon-alpha (IFN-alpha) and ribavirin (RBV) in chronic hepatitis C demonstrates the best responses against hepatitis C virus (HCV) of genotype 3. Still, it has proven to be ineffective in 20-30% of patients infected with this genotype. In the present study, we analysed the translation efficiency mediated by the internal ribosome entry site (IRES) region in HCV genotype 3 genomes isolated from sustained responders (SR) and non-responders (NR), assuming that this may influence the outcome of treatment. Pretreatment isolates of genotype 3 from 22 individuals (15 SR, seven NR) were selected for such analyses. The IRES region [nucleotide (nt) 1-407] was cloned into a dual luciferase vector and IRES activity assessed following transfection into various cell lines. Low relative translation efficiency was observed for IRES elements derived from SR patients, whereas those of NR patients showed significantly greater translation efficiency (29.7 +/- 13 vs 69.4 +/- 22; P < 0.01). Subsequently, the effect of IFN-alpha plus RBV on IRES-driven translation in vitro was determined. A greater suppressive effect was observed on IRES activity isolated from seven SR patients, when compared with seven NR patients. In conclusion, IRES efficiency in vitro correlated with treatment response for HCV genotype 3. Further studies are warranted to investigate whether IRES efficiency in vitro, or sequence motifs associated with IRES efficiency, will be worthwhile to explore as prognostic tools for other HCV genotypes in the treatment of chronic HCV infection.     

Individualizing treatment duration in hepatitis C virus genotype 2/3‐infected patients

The drugs currently licensed for the treatment of hepatitis C are Peg‐Interferon (PEG‐IFN) and ribavirin. In recent years, the recommendation to treat hepatitis C virus genotype 2‐ and 3‐infected patients with a fixed 800 mg/day dose of ribavirin in combination with PEG‐IFN and for just 24 weeks has been challenged by the concept of tailoring the length of therapy according to on‐treatment viral response. Therefore, the objective of the present review was to highlight the different designs of the studies on short treatment duration and the role of wk4‐R as a predictor of sustained virological response after an abbreviated course of treatment. The secondary aim was to verify whether we had enough evidence to support the implementation of a short treatment course in subsets of patients with genotype 2 and 3 infection. We will also focus on how drug dosing may have influenced the outcome of treatment. To clarify reasons for discrepant results in the studies so far published, the recently discovered genetic variant near the interleukin 28B gene will be presented and its predictive role will be discussed. Finally, we will face the debated issue of whether the subset of patients with genotype 2 or 3 requires an extended treatment duration.     

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

AIM: To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNA- dependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear. METHODS: HCV quasispecies were studied by clon- ing and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-α2b for 3 mo followed by IFN-α2b alone or com- bined IFN-R therapy for 9 additional months. Patients were categorized intro two groups based on their re- sponse to the treatments: 7 with sustained virological re- sponse (SVR) (quasispecies = 150) and 3 non-respond- ers (NR) to IFN-R (quasispecies = 106). RESULTS: Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispe- cies during therapy. Analysis of amino acids substitu- tions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate thetwo groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION: These results suggest that detailed mo- lecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.