What's new in HCV genotype 2 treatment

Genotype 2 (HCV-2) accounts for 8% of the patients with chronic hepatitis C virus in Europe. Because of the favourable response to interferon (IFN)-based treatment, this group is considered an 'easy-to-treat' genotype along with HCV-3. However, experimental and clinical data suggest possible differences between HCV-2 and -3. Recently, subtle differences in treatment efficacy have also been shown in response-guided treatment studies. In these studies, the duration of pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment was tailored according to treatment response. Although SVR rates were similar between HCV-2 and HCV-3 patients after a rapid virological response (RVR), in the absence of RVR, the rates were lower in HCV-3 than in HCV-2. The triple combination treatment, including direct-acting antivirals (DAA) that will be commercialized in the coming months might increase SVR rates in this particular subgroup of patients. According to existing results, telaprevir might be beneficial in HCV-2 but not in HCV-3 patients. A nucleotide analogue polymerase inhibitor, PSI-7977 by Pharmasett has been shown to be active against both. The role of the IL28B polymorphism as a predictor of response to the current standard of care (SoC), PEG-IFN and RBV treatment is the subject of debate, but this mainly seems to be because of the small size of the samples in the studies performed so far. Existing results suggest that the genetic evaluation of IL28B may be useful in patients with HCV-2 for predicting response in patients without RVR.     

HCV RNA decline in chronic HCV genotype 2 and 3 during standard of care treatment according to IL28B polymorphism

The IL28 gene is highly associated with sustained viral response (SVR) in patients infected with genotype 1 after standard of care (SOC) treatment with peg‐IFN and ribavirin. It is also associated with a steeper first phase HCV RNA decline during treatment. In genotype 2 and 3 infections, these correlations are less obvious. We studied the IL28B association to rapid viral response (RVR), SVR, first and second phase HCV RNA decline during treatment in 100 HCV mono‐infected and 13 HCV/HIV co‐infected patients. We found a significantly higher mean baseline HCV RNA level in IL28B SNP CC than non‐CC mono‐infected patients, 6.99 vs 6.30 log₁₀ IU/mL (P = 0.02), and a significantly larger median 1st phase decline in patients with CC than non‐CC genotype, 2.03 vs 1.37 log₁₀ IU/mL, respectively. The overall SVR rate in HCV mono‐infected patients was 87% vs 77% in HCV/HIV co‐infected patients, with no correlation to IL28B SNP. In mono‐infected patients with RVR, the SVR rate was high and independent of IL28B genotype. In mono‐infected patients who failed to achieve RVR who had IL28B CC and non‐CC genotype, 64% and 67% achieved SVR, respectively. In genotype 2 and 3 infected patients, the 1st phase HCV RNA decline was steeper in patients with IL28B CC vs non‐CC genotype during SOC treatment. This did not translate into a higher frequency of RVR or SVR. Hence, the clinical relevance of pretreatment analysis of IL28B polymorphisms in genotype 2 and 3 infected patients can be questioned in patients with expected high SVR rate.     

Effector and central memory T helper 2 cells respond differently to peptide immunotherapy

Peptide immunotherapy (PIT) offers realistic prospects for the treatment of allergic diseases, including allergic asthma. Much is understood of the behavior of naive T cells in response to PIT. However, treatment of patients with ongoing allergic disease requires detailed understanding of the responses of allergen-experienced T cells. CD62L expression by allergen-experienced T cells corresponds to effector/effector memory (CD62L^lo) and central memory (CD62L^hi) subsets, which vary with allergen exposure (e.g., during, or out with, pollen season). The efficacy of PIT on different T helper 2 (Th2) cell memory populations is unknown. We developed a murine model of PIT in allergic airway inflammation (AAI) driven by adoptively transferred, traceable ovalbumin-experienced Th2 cells. PIT effectively suppressed AAI driven by unfractionated Th2 cells. Selective transfer of CD62L^hi and CD62L^lo Th2 cells revealed that these two populations behaved differently from one another and from previously characterized (early deletional) responses of naive CD4⁺ T cells to PIT. Most notably, allergen-reactive CD62L^lo Th2 cells were long-lived within the lung after PIT, before allergen challenge, in contrast to CD62L^hi Th2 cells. Despite this, PIT was most potent against CD62L^lo Th2 cells in protecting from AAI, impairing their ability to produce Th2 cytokines, whereas this capacity was heightened in PIT-treated CD62L^hi Th2 cells. We conclude that Th2 cells do not undergo an early deletional form of tolerance after PIT. Moreover, memory Th2 subsets respond differently to PIT. These findings have implications for the clinical translation of PIT in different allergic scenarios.Specific immunotherapy involves therapeutic delivery of a disease-relevant antigen to induce tolerance (particularly of CD4⁺ T cells) toward that antigen (1, 2). It represents a realistic and potentially disease-modifying therapeutic approach for the treatment of allergic and autoimmune diseases with strong CD4⁺ T-cell components to their pathogenesis, such as allergic asthma (3–5). Traditional immunotherapy, using whole-protein antigens, is associated with the risk of severe allergic reactions, particularly anaphylaxis, in patients harboring allergen-reactive IgE (6, 7). Peptide immunotherapy (PIT) obviates this risk because it uses short synthetic peptides containing known T-cell epitopes, but not conformational antibody epitopes, thereby targeting disease-driving CD4⁺ T cells while avoiding IgE binding (8, 9).In animal studies, PIT can effectively reduce or prevent CD4⁺ T-cell–driven diseases (10–15). Encouraging findings have also been reported in allergic patients (16–20). However, reduced disease severity is not universal, and limitations in our understanding of the workings of PIT are impeding clinical translation. Mechanistic murine PIT studies have been advanced through the use of traceable populations of T-cell receptor (TCR) transgenic T cells. PIT is highly effective in silencing “naive” T cells whose first encounter with their cognate antigen is at the point of tolerogenic peptide application (21, 22). This is different from the clinical setting where established T-cell–driven pathology, by definition, presents with an increased frequency of antigen-experienced T cells (23). We, and others, have previously shown that application of tolerogenic peptide induces naive CD4⁺ T cells to enter a brief but abortive phase of proliferation that is followed by their wide-scale apoptotic deletion (21, 22, 24). This is most likely the result of insufficient costimulation from the antigen-presenting cell in the absence of innate immune triggers (21, 22, 24). However, several characteristics of antigen-experienced T cells hint that they may not necessarily respond to PIT in the same way. First, they have lower costimulation requirements (25, 26) that may make them less susceptible to deletion in response to costimulation deprivation in the tolerogenic setting. Antigen-experienced T cells can be phenotypically classified into effector and memory T-cell populations, the latter being subdivided into effector memory T cells (Tem) and central memory T cells (Tcm) (27, 28). Importantly, the phenotype and frequency of allergen-reactive T cells can vary, depending on the presence or absence of allergen exposure (e.g., perennial vs. seasonal allergy) (29–31). In addition, the phenotype of T cells in the end organ (e.g., the lung) may differ from those in peripheral blood (32–34). These complexities could have a major impact upon the clinical response to PIT and have not previously been addressed.Here, we developed a model to study the effects of PIT upon Th2-polarized TCR transgenic cells driving allergic airway inflammation (AAI). PIT effectively reduced AAI, despite the allergen-experienced nature of the eliciting Th2 cells. Furthermore, PIT was most potent against AAI driven by CD62L^lo Th2 cells (a phenotype associated with effector and Tem) compared with CD62L^hi Th2 cells (associated with Tcm) (27, 28). Importantly, CD62L^lo and CD62L^hi Th2 cells showed markedly distinct behavior in response to PIT, both in comparison with one another and compared with the known behavior of naive T cells. Notably, a sizeable population of PIT-treated CD62L^lo cells persisted long-term within the lung following PIT, in contrast to CD62L^hi cells. Whereas PIT led to diminished Th2 cytokine production at the time of airway challenge with allergen in CD62L^lo cells, this effect of PIT was not seen in CD62L^hi cells, which therefore retained pathogenic activity. The composition of Th2 cell subpopulations at the time of PIT is thus an important additional consideration in respect to clinical translation.     

Short interferon and ribavirin treatment for HCV genotype 2 or 3 infection: NORDynamIC trial and real-life experience

Objective: Interferon-free therapy for hepatitis C virus (HCV) infection is costly, and therefore patients with advanced fibrosis are prioritized. Although coupled with considerable side effects, a large proportion of genotype 2/3 infected patients achieve a sustained virological response (SVR) following interferon-based therapy. The present study evaluates experimental clinical trial and verifying real-life data with the aim of identifying patients with a high likelihood of favorable outcome following short interferon-based treatment. Material and methods: The impact of established response predictors, e.g. age, ITPA and IL28B genetic variants, IP-10, liver histopathology and early viral kinetics on outcome was evaluated among HCV genotype 2/3 infected patients enrolled in the NORDynamIC trial. Similarly outcome was evaluated among Finnish and Swedish real-life genotype 2/3 infected patients treated for 12–16 weeks in accordance with national guidelines. Results: In the NORDynamIC trial, age <40 years or achieving HCV RNA?<1000 IU/mL day 7 were highly predictive of favorable outcome following 12 weeks therapy. Among 255 Finnish real-life patients below the age of 40 years treated for 12 weeks with interferon and ribavirin, 87% of HCV genotype 2 and 79% of genotype 3 infected patients achieved SVR, and among 117 Swedish real-life patients treated for 12–16 weeks, 97% of HCV genotype 2 and 94% of genotype 3 infected achieved SVR. Conclusions: Short interferon-based therapy offers a high likelihood of achieving SVR for selected HCV genotype 2/3 infected patients, and is an acceptable option given that a thorough discussion of the side effects is provided prior to initiation.     

Normal and fibrotic liver parenchyma respond differently to irreversible electroporation

BackgroundThe safety and efficacy of irreversible electroporation (IRE) in treating hepatic, biliary, and pancreatic malignancies are active areas of clinical investigation. In addition, recent studies have shown that IRE may enable regenerative surgery and in vivo tissue engineering. To use IRE effectively in these clinical applications, it is important to understand how different tissue microenvironments impact the response to IRE. In this study, we characterize the electrical and histological properties of non-fibrotic and fibrotic liver parenchyma before and after IRE treatment.MethodsElectrical resistivity and histology of fibrotic liver from C57BL/6 mice fed a 0.1% 3,5-diethylcarbonyl-1,4-dihydrocollidine (DDC) diet were compared to those of non-fibrotic liver from matched control mice before and after IRE treatment.ResultsAt baseline, the electrical resistivity of fibrotic liver was lower than that of non-fibrotic liver. Post-IRE, resistivity of non-fibrotic liver declined and then recovered back to baseline with time, correlating with hepatocyte repopulation of the ablated parenchyma without deposition of fibrotic scar. In contrast, resistivity of fibrotic liver remained depressed after IRE treatment, correlating with persistent inflammation.ConclusionNon-fibrotic and fibrotic liver respond to IRE differently. The underlying tissue microenvironment is an important modifying factor to consider when designing IRE protocols for tissue ablation.     

Single and dual hormone secretors in GH3 cultures respond differently to hypothalamic factors.

Recent studies using both normal and tumoral pituitary cell cultures have demonstrated that growth hormone (GH) and prolactin (PRL) secreting populations contain cells which release either one or both of these hormones. In order to determine whether these two cell types can be differentially regulated by hypothalamic factors we performed the following study employing plaque assays for GH and PRL. Using cultures of GH3 cells, a rat tumor cell line which contains both of these cell types, we found that the hypothalamic factors vasoactive intestinal peptide (VIP) and thyrotropin releasing hormone (TRH) when used together had a greater influence on plaque formation than when each was used individually. This suggested that cells were present in culture that responded to one peptide but not the other. Estradiol-treated cultures (which contain only dual-secreting cells) were then evaluated for VIP and TRH responsiveness and found to respond to TRH but not VIP. Finally, we assessed the peptide sensitivity of cultures that were exposed to a conjugate of VIP and the A-chain of ricin (a potent cytotoxin). In addition to eliminating VIP-responsive cells, this treatment markedly reduced the proportions of cells secreting GH-only while having no appreciable influence on dual-hormone secretors. When taken together, our findings indicate that single and dual secretors respond differently to at least two hypothalamic secretagogues and suggest that regulatory differences between these cell types may be important in the control of GH and PRL secretion.     

Right-and left-sided colorectal cancers respond differently to traditional Chinese medicine

AIM To explore the differences in the responses of left-sided colorectal cancer(LSCRC) and right-sided colon cancer(RSCC) to traditional Chinese medicine(TCM).METHODS Patients with postoperative stage I-III colorectal cancer(CRC) were enrolled and divided into the LSCRC with or without TCM and RSCC with or without TCM groups depending on the primary tumor side and TCM administration. Patients in the TCM group were given TCM for at least 6 mo. Our research adopted diseasefree survival(DFS) as the primary endpoint. We applied a Cox proportional hazards regression model for the multivariate factor analysis using Stata 12.0 and SPSS 22.0 software for data analysis.RESULTS Of the 817 patients included in our study, 617 had LSCRC(TCM group, n = 404; Non-TCM group, n = 213), and 200 had RSCC(TCM group, n = 132; NonTCM group, n = 68). The 6-year DFS for patients with LSCRC was 56.95% in the TCM group and 41.50% in the Non-TCM group(P = 0.000). For patients with RSCC, the 6-year DFS was 52.92% in the TCM group and 37.19% in the Non-TCM group(P = 0.003). Differences between LSCRC and RSCC were not statistically significant regardless of TCM ingestion.CONCLUSION Patients with either LSCRC or RSCC and who took TCM experienced longer DFS; furthermore, patients with RSCC benefited more from TCM in DFS.     

Dual treatment of acute HCV infection in HIV co-infection: influence of HCV genotype upon treatment outcome

Purpose

With DAAs still only being licensed for chronic HCV infection, the ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal HCV treatment outcome.

Methods

303 HIV-infected patients from 4 European countries with diagnosed acute HCV infection were treated early with pegylated interferon (pegIFN) and ribavirin (RBV) (n = 273) or pegylated interferon alone (n = 30).

Results

All patients were male, median age was 39 years. Main routes of transmission were MSM (95 %) and IVDU (3 %). 69 % of patients were infected with HCV GT 1, 4.3 % with GT 2, 10.6 % with GT 3, 16.1 % with GT 4. Overall SVR rate was 69.3 % (210/303). RVR (p ≤ 0.001), 48-w treatment duration (p ≤ 0.001) and GT 2/3 (p = 0.024) were significantly associated with SVR. SVR rates were significantly higher in HCV GT 2/3 receiving pegIFN and RBV (33/35) when compared with pegIFN mono-therapy (6/10) (94 % vs. 60 % respectively; p = 0.016). In multivariate analysis, pegIFN/RBV combination therapy (p = 0.017) and rapid virological response (RVR) (p = 0.022) were significantly associated with SVR in HCV GT 2/3. In HCV GT 1/4, RVR (p ≤ 0.001) and 48-w treatment duration (p ≤ 0.001) were significantly associated with SVR.

Conclusions

Treatment of AHC GT 2 and 3 infections with pegIFN/RBV is associated with higher SVR rates suggesting different cure rates depending on HCV genotype similar to the genotype effects seen previously in chronic HCV under pegIFN/RBV. With pegIFN/RBV still being the gold standard of AHC treatment and in light of cost issues around DAAs and very limited licensed interferon-free DAA treatment options for chronic HCV GT 3 infection AHC GT 3 patients might benefit most from early interferon-containing treatment.

     

Optimal treatment duration for patients with HCV genotype 1 infection

The rapidity of viral disappearance on antiviral treatment of chronic hepatitis C with peginterferon/ribavirin correlates with the cure rate. The earlier the virus becomes undetectable, the higher are the response rates. This observation is the basis of response-guided therapy. Viral clearance within the first 4 weeks of treatment is called a rapid virologic response (RVR). The rate of RVR varies among various populations, with the highest one observed in Asian patients and the lowest in African-Americans. In patients infected with genotypes 1 and 4 who experience a RVR treatment with peginterferon/ribavirin can be shortened to just 24 weeks without losing efficacy (sustained virologic rate in RVR are >80%). In contrast, patients with a slow decline in viral load (> 2 log drop after 12 weeks with still detectable virus) may benefit from treatment extension to 72 weeks. Prolonged treatment reduces relapse rates but has no significant effect on cure rates. The data in patients with genotypes 2 and 3 are less clear, mostly because these genotypes are much easier to cure and a benefit is hard to detect. Nevertheless in patients with RVR and low baseline viral load treatment can be safely shortened to 16 weeks. The recently described polymorphism in the region of the IL28B gene may help to select patients for abbreviated or extended treatment schedules.