Prevalence and Therapeutic Significance of Anti-Interferon Antibodies in Hepatitis C Virus/hiv-Co-infected Patients

Chronic hepatitis C virus (HCV) infection is one of the leading causes of chronic liver disease worldwide. Pegylated interferon (peg-IFN) plus ribavirin is the treatment of choice for chronic HCV infection, but sustained responses are seen in less than two-thirds of patients [1,2]. This figure is significantly lower in HCV/HIV-co-infected patients [3,4], in whom anti-HCV therapy is unfortunately particularly needed because progression to liver cirrhosis occurs more rapidly [5]. Treatment with interferon has been associated occasionally with the development of neutralizing anti-interferon antibodies (anti-IFNAb) [6]. It is controversial as to whether it might eventually influence treatment outcomes, although it has been shown to be the case occasionally [7]. In order to explore whether the development of anti-IFNAb could explain the lower response to HCV therapy in co-infected patients, we examined a group of consecutive HIV-positive individuals who initiated peg-IFN plus ribavirin during the year 2005 at our institution. A total of 45 HCV/HIV-co-infected patients were identified; 33 had been exposed in the past to standard interferon and 12 were interferon-naive. All were treated with peg-IFN plus weight-based ribavirin doses for one year. Overall, 19 achieved a sustained virological response (negative serum HCV-RNA 24 weeks after completion of therapy), the remaining 26 being non-responders or relapsers. Specific anti-IFNAb were measured by an enzyme-linked immunosorbent assay (human anti-IFN-α; Bender MedSystems, Vienna, Austria) in serum specimens drawn at week 4 of HCV treatment. The lower limit of detection of this method is 1.38 ng/ml. The study population was mainly represented by men (64.4%), with a median age of 45 years (range 28–53). HCV genotype distribution was as follows: HCV-1 (53.3%), HCV-3 (35.6%) and HCV-4 (11.1%). None of the 19 sustained virological responders developed anti-IFNAb; in contrast, three (11.5%) out of 26 non-responders/relapsers developed anti-IFNAb (P = 0.25). One of these patients had been exposed to standard interferon plus 800 mg/day of ribavirin in the past. He was a 43-year-old man who had never been exposed to antiretroviral drugs; he was infected with HCV genotype 4, and failed to show a decline in serum HCV RNA greater than 2 logs at week 12 of re-treatment with peg-IFN plus weight-based ribavirin. His titre of anti-IFNAb was 6.98 ng/ml at week 4 of re-treatment. Although it was undetectable before initiating therapy, retrospective testing of a sample collected at the end of the previous course of HCV therapy 9 years earlier showed anti-HCVAb concentrations of 44.3 ng/ml. The other two co-infected patients who developed anti-IFNAb were interferon-naive and both were currently receiving antiretroviral drugs. One was a 44-year-old man infected with HCV genotype 1 who showed anti-IFNAb titres of 38.9 ng/ml at week 24 of HCV treatment; they were absent at week 4. The other patient was a 40-year-old man infected with HCV genotype 3, who showed anti-IFNAb titres of 2.93 ng/ml at week 4 of HCV therapy and greater than 200 ng/ml at week 24. Both patients failed to achieve undetectable HCV-RNA levels at week 24 of therapy. Several studies conducted in HIV-negative individuals have shown an association between anti-IFNAb formation and non-response, relapse or breakthrough to interferon therapy in patients with chronic viral hepatitis [6–12]. In contrast, other reports have not confirmed those findings [13–16]. In a recent study conducted in HCV-monoinfected patients, only a reduced proportion (8%) of them developed anti-IFNAb during treatment; however, none cleared HCV with interferon therapy [17]. A time relationship between the development of anti-IFNAb and viral breakthrough has been documented in only a few cases [15]. In agreement with these findings, in our study anti-IFNAb were identified in only three out of 45 HCV/HIV-co-infected patients (6.6%). All failed to achieve sustained virological response to peg-IFN plus ribavirin, including one subject infected with HCV genotype 3, which generally responds very well to HCV therapy. Although one of these three patients had been exposed to interferon therapy in the past, the other two were interferon naive. In contrast, none of 12 previous interferon failures nor of seven interferon-naive subjects who achieved sustained virological response with peg-IFN plus ribavirin developed anti-IFNAb. Altogether, these data do not support a critical role of anti-IFNAb as a cause of the lower response to HCV therapy seen in HCV/HIV-co-infected compared with HCV-monoinfected patients. Other factors, including those directly associated with HIV immune dysfunction, probably explain the poorest therapeutic outcome in the co-infected population. In a small subset of individuals, however, the development of anti-IFNAb could be responsible for virological failure. Sponsorship: This work was partly supported by grants from Fundación Investigación y Educación en SIDA (I.E.S.), Red de Investigación en SIDA (R.I.S.), the European VIRGIL Network, Agencia Lain Entralgo, and Fondo de Investigación Sanitaria (F.I.S.).