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.     

Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection

Liver steatosis is highly prevalent in chronic hepatitis C virus (HCV) infection, especially in patients infected with genotype 3 virus, but its significance for the outcome of antiviral treatment is not fully understood. We have monitored steatosis in liver biopsies from 231 patients with chronic HCV infection who received pegylated recombinant interferon-alpha and ribavirin in a phase III study (DITTO trial). The degree of steatosis, along with relevant metabolic parameters, was correlated with the early disappearance of virus and with the final outcome of treatment. Our data suggest that the presence of steatosis impairs the early reduction of viral load during treatment in patients infected with HCV genotype 3 and non-3. Steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non-3 virus. Based on these findings, we propose that interventions aiming at reducing hepatic steatosis prior to the onset of antiviral therapy may be of benefit to patients infected with HCV of the non-3 genotypes. Patients infected with genotype 3, on the other hand, should be offered early antiviral treatment.     

HCV drug discovery aimed at viral eradication

Summary. Hepatitis C virus (HCV) causes significant morbidity and mortality worldwide with nearly 3% of the world population infected by this virus. Fortunately, this virus does not establish latency, and hence it may be possible to eradicate it. HCV is strongly associated with liver cirrhosis and hepatocellular carcinoma and is currently treated with pegylated interferon‐α (peg‐IFN‐α) and ribavirin. Unfortunately, these limited treatment options often produce significant side effects, and currently, complete eradication of virus with combined drug modalities has not yet been achieved for the majority of chronically HCV‐infected individuals. Restricted treatment options, lack of a universal cure for HCV and the link between chronic infection, liver cirrhosis and hepatocellular carcinoma necessitate design of novel drugs and treatment options. Understanding the relationship between the immune response, viral clearance and inhibition of viral replication with pharmacology‐based design can ultimately allow for complete eradication of HCV. This review focuses upon significant novel preclinical and clinical specifically targeted antiviral therapy (STAT‐C) drugs under development, highlights their mechanism of action, and discusses their impact on systemic viral loads and permanent clearance of infection.     

Absence of HCV viral recombination following superinfection

We sought evidence of viral recombination in five recently hepatitis C virus (HCV) infected young injection drug users who became superinfected with a distinguishable strain of HCV. The entire open reading frame of plasma HCV genomes was reverse transcribed, polymerase chain reaction amplified in two fragments, and directly sequenced. In two cases of same subtype (1a > 1a) superinfections the initial and later strains were both sequenced and compared for evidence of recombination. In three cases of superinfection with strains of different genotype/subtype (3a > 1a, 1a > 3a, 1b > 1a), the later time point HCV genomes were sequenced and compared with representative genomes of the initial genotype/subtype. No evidence of intra- or inter-genotype/subtype recombination was detected using six different programs for detecting recombination. We conclude that the generation of viable recombinant HCV genomes able to dominate in the viral quasispecies is a rare event.     

Hepatitis C viral kinetics

Abstract   Standard therapy with (pegylated) interferon-alfa and ribavirin still leads to sustained virologic response rates of 50–60%, only. Therefore, new therapeutic strategies are required. With the analysis of mathematical models of hepatitis C viral kinetics, individual kinetic rates as infected cell loss, clearance of free virus, and an efficiency factor on blocking viral production can be estimated. They can be used to summarize and quantify the initial response to antiviral therapy and, furthermore, allow the assessment of treatment mechanisms, prediction of treatment response, and the efficient identification of viral and host factors on treatment response. They may even be used for optimizing and individualizing therapy.     

Distribution of HCV genotypes and HCV RNA viral load in different regions of Mexico

Background and aim. To identify the geographic distribution of hepatitis C virus (HCV) genotypes and HCV RNA viral load in a large number of HCV-infected carriers in Mexico.Methods. Patients with chronic hepatitis C (n = 8,802) were studied to identify HCV genotype using an immune line probe assay in samples shown previously to be positive for viral RNA by an RT-PCR test. Baseline HCV RNA was also evaluated.Results. Genotype 1 accounted for 70.3%, genotype 2 for 21.8%, genotype 3 for 7.2%, genotype 4 for 0.3%, and genotype 5 for 0.1% of all cases; coinfection was present in 0.3%. Overall, Genotype 1 was the most prevalent Genotype. Regionally, genotype 1 occurred more frequently in the North-East, North, and Center-East regions of Mexico; genotype 2 was more prevalent in the South, East, and Peninsula regions; and genotype 3 was more prevalent in the North and North-West regions. Only 22.4% of patients with genotype 1 were classified in the low HCV RNA viral load category, and the distribution of this genotype did not differ significantly between regions.Conclusion. The prevalence of HCV genotypes and viral load in Mexico was 70.3% for genotype 1, but only 22.4% of these patients had a low HCV viral load. Distribution was not uniform in Mexico, with greater frequency of genotype 2 in South, East and Peninsula Regions and Genotype 3 in North and North-West Regions.     

HCV very late relapse following an atypical viral kinetics in a HIV patient treated for hepatitis C with direct-acting antivirals

Direct-acting antivirals (DAAs) for the treatment of HCV have dramatically increased the rate of sustained virological response: patients not achieving sustained virological response represent a challenge and rates of late recurrent viremia are very low. We describe here the first case of a very late HCV relapse, following an atypical kinetics (characterized by a spontaneous but transient HCV clearance after an early virological relapse), in a HIV co-infected patient treated with DAAs. Optimal adherence to the therapy was well documented and a phylogenetic analysis ruled out a possible reinfection from a different HCV strain. In conclusion, our case underlines the importance of a long follow-up (>?48 weeks) after DAAs therapies in HCV–HIV co-infected patients who might benefit the most from a very rigorous virological surveillance.     

Clinical implications of hepatitis C viral kinetics

Antiviral treatment of patients with chronic hepatitis C can perturb the steady-state of virus production and clearance. From serial measurements of changes in viremia, kinetic information on the dynamics of hepatitis C virus (HCV) replication can be obtained. After a delay of about 9 h due to interferon-a pharmacokinetics, the decline of viremia in patients treated with interferon-alpha is characterized by a concave shape. In the first phase (day 1) a rapid dose-dependent decline in viral load is observed. The second phase viral decline (> or =day 2) shows a much slower decline with no or less pronounced differences between the applied interferon-alpha schedules. While a first phase decline can be observed in almost all patients treated with interferon-alpha, non-responders typically reveal no further decline of viremia during the second phase. Kinetic analysis showed that combination therapy with interferon-alpha plus ribavirin has no direct synergistic antiviral effect in the initial 4 weeks of treatment of HCV-infected patients with 6 MU IFNalpha three times per week. Calculations revealed a minimum virus production and clearance per day in patients with chronic hepatitis C of approximately 10(10)-10(12) virions per day and an in vivo half-life of the virus in the order of a few hours. The high turnover rates of HCV explain the rapid generation of viral diversity and the opportunity for viral escape from the host immune surveillance and antiviral therapy. The implications derived from HCV kinetics comprise the consideration of more aggressive initial dosing regimens (especially daily doses), the possibility to optimize therapy individually not only according to pretreatment parameters but also according to the initial decline of viral load and the perception that eradication of the virus will rely on the half-life of infected cells.     

Hepatitis C viral kinetics in special populations

Mathematical models of hepatitis C viral kinetics provide a means of estimating the antiviral effectiveness of therapy, the rate of virion clearance, and the rate of loss of hepatitis C virus (HCV)-infected cells. They have also proved useful in evaluating the extrahepatic contribution to HCV plasma viremia and have suggested mechanisms of action for interferon-α and ribavirin. Viral kinetic models can explain the observed HCV RNA profiles under treatment—for example, flat partial response, biphasic and triphasic viral decay, and viral rebound. Current therapy with (pegylated) interferon-α and ribavirin has poorer success in patients with insulin resistance, hepatic fibrosis, African American ethnicity, HCV/HIV-coinfection, HCV genotype 1, or high baseline viral load. Mathematical modeling and statistical analysis of experimental data have been useful in understanding some of these treatment obstacles.     

The impact of fibrosis and steatosis on early viral kinetics in HCV genotype 1-infected patients treated with Peg-IFN-alfa-2a and ribavirin

Hepatitis C viral (HCV) kinetics after initiation of interferon-based therapy provide valuable insights for understanding virus pathogenesis, evaluating treatment antiviral effectiveness and predicting treatment outcome. Adverse effects of liver fibrosis and steatosis on sustained virological response have been frequently reported, yet their impacts on the early viral kinetics remain unclear. In this study, associations between histology status and early viral kinetics were assessed in 149 HCV genotype 1-infected patients treated with pegylated interferon alfa-2a and ribavirin (DITTO trial). In multivariate analyses adjusted for critical factors such as IL28B genotype and baseline viral load, presence of significant fibrosis (Ishak stage > 2) was found to independently reduce the odds of achieving an initial reduction (calculated from day 0 to day 4) in HCV RNA of ≥2 logIU/mL (adjusted OR 0.03, P = 0.004) but was not associated with the second-phase slope of viral decline (calculated from day 8 to day 29). On the contrary, presence of liver steatosis was an independent risk factor for not having a rapid second-phase slope, that is, ≥0.3 logIU/mL/week (adjusted OR 0.22, P = 0.012) but was not associated with the first-phase decline. Viral kinetic modelling theory suggests that significant fibrosis primarily impairs the treatment antiviral effectiveness in blocking viral production by infected cells, whereas the presence of steatosis is associated with a lower net loss of infected cells. Further studies will be necessary to identify the biological mechanisms underlain by these findings.