Olav Dalgard

Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: A pilot study

The aim of this study was to determine the efficacy of 14 weeks of treatment in patients infected with hepatitis C virus (HCV) genotype 2 or 3 who achieve early virological response (EVR). In a noncontrolled multicenter trial, 122 treatment‐naive patients received 1.5 μg/kg pegylated interferon alfa‐2b subcutaneously once weekly and 800 to 1,400 mg/d ribavirin based on body weight. Treatment was stopped at week 14 in patients with EVR, defined as undetectable HCV RNA at weeks 4 and 8. Patients without EVR were assigned to 24 weeks of treatment. The primary end point was sustained virological response (SVR), defined as undetectable HCV RNA 24 weeks after end of treatment. Among the 122 patients, 95 (78%) had EVR and received 14 weeks of treatment. The remaining 27 (22%) were treated for 24 weeks. SVR was obtained in 85 (90%) of 95 patients in the 14‐week treatment group and 15 of (56%) 27 in the 24‐week treatment group. Altogether, SVR was obtained in 100 of 122 patients (82%; 95% CI, 75%‐89%). SVR after 14 weeks of treatment was achieved more frequently among genotype 3a patients with low viral load compared with high viral load (98% vs. 79%; P = .019). Logistic regression analysis showed that absence of bridging fibrosis/cirrhosis was the only independent predictor of SVR. In conclusion, patients with genotype 2 or 3 and EVR obtained a high SVR after 14 weeks of treatment. The results need to be confirmed in a randomized, controlled study before this treatment approach can be recommended, particularly for patients with genotype 3 and high viral load or severe fibrosis. (HEPATOLOGY 2004;40: 1260–1265.)

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel

Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country‐specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel.

CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients.

Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA‐E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C+CD56dim NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi‐color flow cytometry revealed that the expanded NKG2C+CD56dim NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN‐γ, and TNF‐α) to stimulation with antibody‐coated as well as HLA‐E expressing target cells but not when stimulated with IL‐12/IL‐18. More importantly, NKG2C+CD56dim NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin‐like receptors (KIRs) specific for self‐HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C‐mediated activation suggesting that such biased expression of self‐specific KIRs may preserve self‐tolerance and limit immune‐pathology during viral infection. Together, these findings shed new light on how the human NK‐cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells.

Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response

A recent nonrandomized pilot trial showed that hepatitis C virus (HCV) patients with genotype 2/3 and rapid virological response (RVR) had a 90% sustained virological response (SVR) rate after 14 weeks of treatment. We aimed to assess this concept in a randomized controlled trial. In the trial, 428 treatment‐naïve HCV RNA–positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon α‐2b (1.5 μg/kg) subcutaneously weekly and ribavirin (800‐1400 mg) orally daily. The noninferiority margin was set to be 10% between the two groups with a one‐sided 2.5% significance level. RVR was obtained in 302 of 428 (71%), and 298 of these were randomized to group A (n = 148) or group B (n = 150). In the intention‐to‐treat analysis, SVR rates were 120 of 148 (81.1%) in group A and 136 of 150 (90.7%) in group B (difference, 9.6%; 95% confidence interval, 1.7‐17.7). Among patients with an HCV RNA test 24 weeks after the end of treatment, 120 of 139 (86.3%) patients in group A achieved SVR compared with 136 of 146 (93.2%) in group B (difference, 6.9%; 95% confidence interval, −0.1 to +13.9). Conclusion: We cannot formally claim that 14 weeks of treatment is noninferior to 24 weeks of treatment. However, the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks. (HEPATOLOGY 2007.)

Treatment of Chronic Hepatitis C in Injecting Drug Users: 5 Years’ Follow-Up

Aim of the Study: To assess the long-term hepatitis C (HCV) treatment outcome in former injecting drug users (IDUs). Materials and Methods: A long-term follow-up of 27 former IDUs who had been successfully treated for chronic hepatitis C was performed. These patients represented all IDUs who had obtained a sustained virological response in a Norwegian HCV treatment trial. The patients had been treated with interferon-α alone or in combination with ribavirin. At 5 years’ follow-up the 27 IDUs were retested for HCV RNA and risk behaviour for HCV transmission after treatment was assessed. In the control group all 18 non-IDUs who had obtained a sustained virological response in the same treatment trial were included. Results: At follow-up 13–82 months (median 64) after the end of treatment only one case of probable reinfection was seen among the 27 IUDs. No reoccurrence of HCV was observed in the control group. The IDU who was HCV RNA positive at follow-up had continued injecting drugs and reported frequent needle sharing. At follow-up HCV of genotype 1a was detected in contrast to genotype 1b before treatment indicating that this patient was reinfected with HCV. A return to injecting drug use occurred in 9 (33%) of 27 IDUs. Conclusion: The long-term outcome of HCV treatment in former IDUs was excellent. Despite frequent reinitiation of drug injection all but 1 remained HCV RNA negative.

IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection

Polymorphisms near the IL28B gene, which code for interferon (IFN)‐λ3, predict response to pegylated interferon‐α (PEG‐IFN) and ribavirin treatment in hepatitis C virus (HCV) genotype 1 infected patients. Follow‐up studies of the effect of IL28B gene in HCV non–genotype 1 infected patients have almost always used predominantly HCV genotype 2–infected or mixed genotype 2/3–infected cohorts with results partly conflicting with HCV genotype 1. We performed a retrospective analysis of 281 patients infected with HCV genotype 3 for association of response to therapy with IL28B polymorphisms. We found that the HCV genotype 1 responder genotypes at rs12979860 and rs8099917 did not associate with sustained virological response to PEG‐IFN/ribavirin therapy. However, the responder genotypes of both SNPs showed association with rapid viral response measured at 4 weeks (rs12979860, P = 3 × 10−5; rs8099917, P = 3 × 10−4). In multivariate analysis, age (<40 years), baseline viral load (<4 × 105 IU/mL) and the responder genotypes of SNPs rs12979860 or rs8099917 remained significant independent predictors of rapid viral response to therapy. Furthermore, we show that IL28B polymorphisms are associated with relapse in patients who achieve rapid viral response to PEG‐IFN/ribavirin therapy. The responder genotypes also showed association with markers of stage and activity of liver disease, namely high aspartate aminotransferase platelet ratio index (APRI, rs12979860, P = 0.018; rs8099917, not significant) and high alanine aminotransferase (ALT, rs12979860, P = 0.002; rs8099917, P = 0.001), in addition to a high baseline viral load (rs12979860, P = 1.4 × 10−5; rs8099917, P = 7.3 × 10−6). Conclusion: Polymorphisms near the IL28B gene show association with rapid viral response but not sustained viral response to PEG‐IFN/ribavirin therapy in HCV genotype 3‐infected patients. (HEPATOLOGY 2011;)

Recommendations for the management of hepatitis C virus infection among people who inject drugs

In high income countries, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). In many low and middle income countries large HCV epidemics have also emerged among PWID populations. The burden of HCV-related liver disease among PWID is increasing, but treatment uptake remains extremely low. There are a number of barriers to care which should be considered and systematically addressed, but should not exclude PWID from HCV treatment. The rapid development of interferon-free direct-acting antiviral (DAA) therapy for HCV infection has brought considerable optimism to the HCV sector, with the realistic hope that therapeutic intervention will soon provide near optimal efficacy with well-tolerated, short duration, all oral regimens. Further, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provide a framework for HCV assessment and care. Further research is needed to evaluate strategies to enhance testing, linkage to care, treatment, adherence, viral cure, and prevent HCV reinfection among PWID, particularly as new interferon-free DAA treatments for HCV infection become available.

Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy a randomized trial

Background Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). Objective To evaluate elbasvir-grazoprevir in treating HCV infection in PWID. Design Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688). Setting Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. Patients 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT). Intervention The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks. Measurements The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. Results The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. Limitation These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Conclusion Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Primary Funding Source Merck & Co.

Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C

HCV infects approximately 2–3% of the global population and is a leading cause of end-stage liver disease and hepatocellular carcinoma. Treatment of HCV infection with Peg-IFN in combination with ribavirin can eradicate HCV infection in 40–90% of patients; however, a major barrier to treatment uptake and delivery is the association of this therapy with frequent and, at times, serious adverse effects. Recognition and effective management of these adverse effects are critical components of the successful treatment of chronic HCV infection. In clinical trials, approximately 10–15% of patients discontinue Peg-IFN and ribavirin therapy due to adverse effects; however, in clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The off-target effect of Peg-IFN and ribavirin impacts most, if not all, organ systems; the most common adverse effects are hematologic, dermatologic, neurologic, immunologic, gastrointestinal, pulmonary, cardiovascular, and ocular. Regional and global variability exists in the nature of these adverse effects and the strategies employed to ameliorate their impact. This article provides a comprehensive literature review that systematically describes the adverse effects of Peg-IFN-α and ribavirin on various organ systems and, more importantly, recommends consensus approaches to managing those effects.

Recommendations for the Management of Hepatitis C Virus Infection Among People Who Inject Drugs

In the developed world, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). The burden of HCV-related liver disease in this group is increasing, but treatment uptake among PWID remains low. Among PWID, there are a number of barriers to care that should be considered and systematically addressed, but these barriers should not exclude PWID from HCV treatment. Furthermore, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provides a framework for HCV assessment, management, and treatment. Further research is needed to evaluate strategies to enhance assessment, adherence, and SVR among PWID, particularly as new treatments for HCV infection become available.