Stevan A. Gonzalez

A Randomized Trial of Pegylated Interferon α-2b Plus Ribavirin in the Retreatment of Chronic Hepatitis C

OBJECTIVES:The efficacy of combination therapy with pegylated interferon (PEG IFN) α plus ribavirin (RBV) in the retreatment of chronic hepatitis C (CHC) in patients who previously failed combination standard IFN plus RBV or IFN monotherapy has not been well established.METHODS:Three hundred and twenty-one CHC patients including virologic nonresponders to combination IFN plus RBV (n = 219) or IFN monotherapy (n = 47), and relapsers to combination therapy (n = 55) were randomized to receive PEG IFN α-2b 1.5 μg/kg per wk plus RBV 800 mg per day (Regimen A, n = 160) or PEG IFN α-2b 1.0 μg/kg per wk plus RBV 1,000–1,200 mg per day (Regimen B, n = 161) for 48 wks.RESULTS:Sustained virologic response (SVR) occurred in 16% of the overall study population (Regimen A vs B, 18% vs 13%, p = 0.21), in 8% of the combination therapy nonresponders (10% vs 6%, p = 0.35), in 21% of the IFN monotherapy nonresponders (16% vs 27%, p = 0.35), and in 42% of the combination therapy relapsers (50% vs 32%, p = 0.18). In nonresponders to prior combination therapy, HCV ribonucleic acid levels <100,000 copies/mL at the end of the prior treatment course were associated with an increased SVR compared with levels ≥100,000 copies/mL (21% vs 5%, p = 0.002). In the overall study population, genotype 1 patients had lower SVR rates than others (14% vs 33%, p = 0.01), and African Americans had lower SVR than Caucasians (4% vs 18%, p = 0.01).CONCLUSION:Combination therapy with PEG IFN α-2b plus RBV is more effective in patients who relapsed after combination standard IFN plus RBV than in nonresponders to either combination therapy or IFN monotherapy. There was no significant effect of dosing regimen.

CD56+dim and CD56+bright cell activation and apoptosis in hepatitis C virus infection

CD3–CD56+dim natural killer (NK) cells, which are cytotoxic against virally infected cells, may be important in hepatitis C virus (HCV)‐infected patients who are successfully treated with pegylated interferon (PEG‐IFN)‐α. We used flow cytometry to enumerate activated (CD69+) and apoptotic (annexin‐V+) dim (CD3–CD56+dim) and bright (CD3–CD56+bright) NK cells obtained from HCV‐infected patients before treatment (n = 16) and healthy controls (n = 15) in the absence and presence of pegylated interferon (PEG‐IFN)‐α‐2b. A subset of HCV‐infected patients, subsequently treated with PEG‐IFN‐α‐2b in vivo, was determined to have a sustained virological response (SVR, n = 6) or to not respond (NR) to treatment (n = 5). In the absence of IFN, activated dim (CD3–CD56+dim CD69+) NK cells were significantly decreased (P = 0·04) while activated apoptotic dim (CD3–CD56+dimCD69+annexin‐V+) NK cells tended to be increased (P = 0·07) in SVR patients compared with NR patients. Activated bright (CD3–CD56+brightCD69+) and activated apoptotic bright (CD3–CD56+brightCD69+annexin‐V+) NK cells were significantly correlated (P = 0·02 and P = 0·01, respectively) with increasing hepatic inflammation. These findings suggest that in the absence of PEG‐IFN, activated dim (CD3–CD56+dimCD69+) NK cell turnover may be enhanced in SVR compared with NR patients and that activated bright (CD3–CD56+brightCD69+) NK cells may play a role in liver inflammation.

Hepatocyte proliferation in chronic hepatitis C: correlation with degree of liver disease and serum alpha-fetoprotein.

Abstract: Aims: Hepatocyte proliferation (HP) is an adaptive response to liver injury. The relationships between HP and necroinflammation, fibrosis, and serum α‐fetoprotein (AFP) levels in chronic hepatitis C virus (HCV) infection, however, are not well understood.

Hepatic inflammatory cytokine mRNA expression in hepatitis C virus-human immunodeficiency virus co-infection.

Summary.  Although epidemiologic studies have documented that hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co‐infected patients have accelerated fibrogenesis, especially those with CD4+ cell counts <200 cells/mm3, the pathogenic mechanisms are poorly understood. We investigated whether severe immunodeficiency in co‐infection is associated with changes in intrahepatic inflammatory cytokine mRNA levels. We measured interferon (IFN)‐γ, tumour necrosis factor‐α, transforming growth factor (TGF)‐β1, interleukin (IL)‐4, IL‐10, IL‐12p35 and IL‐12p40 mRNA levels by real‐time PCR performed on liver samples from HCV mono‐infected (n = 19) and HCV/HIV co‐infected (n = 24) patients. Co‐infected patients had decreased intrahepatic mRNA levels of IFN‐γ (P = 0.09), IL‐4 (P = 0.05) and IL‐12p35 (P = 0.04) compared with mono‐infected patients, while IL‐10 was increased (P = 0.07). In co‐infected patients, IFN‐γ mRNA levels increased linearly with increasing peripheral CD4+ cell counts by 1.23 times relative to the calibrator for every 100 CD4+ cells/mm3 increase (P = 0.02). No other cytokines were significantly associated with CD4+ cell counts. In conclusion, HIV‐induced lymphopenia may result in hepatic inflammatory cytokine suppression in HCV/HIV co‐infection. Intrahepatic IFN‐γ levels are significantly reduced in patients with advanced immunodeficiency. Further studies are needed to assess whether decreased IFN‐γ secretion by HCV‐specific CD4+ cells may account for accelerated fibrogenesis in these patients.

Medical and Behavioral Approaches to Engage People Who Inject Drugs Into Care for Hepatitis C Virus Infection

Direct-acting antivirals for hepatitis C virus infection may revolutionize treatment among persons with substance use disorders. Despite persons with substance use disorders having the highest hepatitis C virus prevalence and incidence, the vast majority have not engaged into care for the infection. Previously, interferon-based treatments, with substantial side effects and the propensity to exacerbate mental health conditions, were major disincentives to pursuit of care for the infection. Direct-acting antivirals with viral eradication rates of >90%, significantly improved side effect profiles, and shorter treatment duration are dramatic improvements over prior treatment regimens that should promote widespread hepatitis C virus care among persons with substance use disorders. The major unmet need is strategies to promote persons with substance use disorders engagement into care for hepatitis C virus. Although physical integration of treatment for substance use and co-occurring conditions has been widely advocated, it has been difficult to achieve. Telemedicine offers an opportunity for virtual integration of behavioral and medical treatments that could be supplemented by conventional interventions such as hepatitis C virus education, case management, and peer navigation. Furthermore, harm reduction and strategies to reduce viral transmission are important to cease reinfection among persons with substance use disorders. Widespread prescription of therapy for hepatitis C virus infection to substance users will be required to achieve the ultimate goal of global virus elimination. Combinations of medical and behavioral interventions should be used to promote persons with substance use disorders engagement into and adherence with direct-acting antiviral-based treatment approaches. Ultimately, either physical or virtual colocation of hepatitis C virus and substance use treatment has the potential to improve adherence and consequently treatment efficacy.