Interferon-gamma with peginterferon alpha-2a and ribavirin in nonresponder patients with chronic hepatitis C (ANRS HC16 GAMMATRI).

BACKGROUND AND AIM: Interferon-gamma-1b (IFN-γ-1b) improves alpha interferon (IFN-α) inhibition of hepatitis C virus (HCV) replication in replicon system. We described virological response after addition of IFN-γ to a combination of ribavirin/peginterferon (PEG-IFN)-α-2a or α-2b. METHODS: In this non-comparative, multicenter trial, patients chronically infected by HCV who were nonresponders to a previous treatment by PEG-IFN and ribavirin were restarted on a regimen of PEG-IFN-α-2a (180 µg/week) + ribavirin (1000-1200 mg/day) for 16 weeks. If HCV-RNA decreased less than 2 log(10) copies/mL (nonresponders), and if PEG-IFN-α-2a and ribavirin dosages were unchanged while tolerance was good, IFNγ-1b (100 µg three times per week) was added for the last 32 weeks of treatment. Virological response was evaluated at week 28 (12 weeks after initiation of IFN-γ-1b). RESULTS: Among the 48 patients started on dual therapy, 23 patients (47%) were nonresponders at week 12 and received IFN-γ-1b from week 16 onward. Their mean HCV-RNA (log(10) IU/mL) was 6.83 at baseline, 5.81 at week 12, and 5.63 at week 28. No patient reached undetectable HCV-RNA at week 28 (upper bound of 95% confidence interval: 14.8%); none had a decrease > 1 log(10) IU/mL. One case of grade 4 neutropenia was reported. CONCLUSION: Among the strictly selected nonresponders, IFN-γ-1b (at a dosage of 100 µg thrice a week) in combination with PEG-IFN-α-2a and ribavirin failed to show virological efficacy.

Neutralizing antibodies to interferon-α and circulating interferon in patients with chronic hepatitis C non-responding to pegylated interferon plus ribavirin re-treated by pegylated interferon-α-2a and ribavirin (ANRS HC16 GAMMATRI substudy).

A lack of antiviral response in patients with chronic hepatitis C treated with pegylated (PEG)-interferon (IFN)-α-2a + ribavirin (RIBA) may be explained by neutralizing antibodies to IFN-α-2a. The aim of this study was to assess neutralizing antibodies to IFN-α-2a and IFN levels in non-responder patients who were re-treated by PEG IFN-α-2a and RIBA for 12 weeks. Non-responders to a first-line treatment of PEG IFN-α-2a + RIBA were included for treatment with PEG IFN-α-2a (180 µg/week) + RIBA (1,000 mg/day if <75 kg, 1,200 mg otherwise) for 48 weeks. HCV RNA was measured at week 12. IFN levels and neutralizing antibodies to IFN-α-2a were measured retrospectively on stored sera at baseline and weeks 4 and 12, using a quantitative sandwich ELISA for neutralizing antibodies to IFN-α-2a. Twenty-three patients were non-responders and 19 patients were responders at week 12 of the initial phase of the second-line treatment. Non-responders and responders did not differ statistically: baseline age (median age 47 vs. 50 years), HCV RNA (median 6.8 vs. 6.4 log(10) copies/ml), gender (70% vs. 73% males), genotype (genotype 1: 91% vs. 80%). The median IFN-α-2a levels (pg/ml) at weeks 0, 4, and 12 (interquartile range) did not differ between the 19 responders to initial phase of second-line treatment and the 23 non-responders: <3.3 (<3.3-371.4), 1457.3 (106.8-3284.8), and 1,652 (90.8-5,000); 84.5 (3.3-277.4), 1407.4 (120.2-2443.4), and 1620.1 (120.2-2287.1), respectively. Among non-selected consecutive non-responder patients, re-treatment with PEG IFN-α-2a + RIBA is associated with virological response regardless of the presence of antibody-mediated resistance to conventional IFN treatment.

Phase I study of a candidate vaccine based on recombinant HIV-1 gp160 (MN/LAI) administered by the mucosal route to HIV-seronegative volunteers: the ANRS VAC14 study.

One goal of HIV vaccination is to achieve high mucosal levels of specific secretory IgA (SIgA). In order to elicit specific SIgA antibodies against human immunodeficiency virus type-1 (HIV-1), a vaccine must be administered by the mucosal route, to the nasal or vaginal mucosa for example. We report here the results of the first phase I, randomized, open-label trial designed to assess the mucosal tolerability and immunogenicity of a candidate vaccine (recombinant protein HIV-1 gp160MN/LAI with or without DC-Chol adjuvant) administered by the nasal or vaginal route. Thirty-four female volunteers with a mean age of 46 years were vaccinated. There were 465 adverse events, of which 65 were considered related to the vaccine. No severe adverse events were related to the vaccine, and no difference in terms of tolerability was observed between the sites of vaccination or between the vaccine formulations. None of the volunteers reported that study participation affected their intimate or broader social relationships. No anti-gp160 activity was found between week 4 and week 48 in serum, saliva, or cervicovaginal and nasal secretions. These results show that a mucosal HIV vaccine can be well tolerated when administered by the nasal or vaginal route.