Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks in patients with hepatitis C virus genotype 1 and slow virologic response.

UNLABELLED: The benefit of extending treatment duration with peginterferon (PEG-IFN) and ribavirin (RBV) from 48 weeks to 72 weeks for patients with chronic hepatitis C genotype 1 infection has not been well established. In this prospective, international, open-label, randomized, multicenter study, 1,428 treatment-naïve patients from 133 centers were treated with PEG-IFN alfa-2b (1.5 µg/kg/week) plus RBV (800-1,400 mg/day). Patients with detectable hepatitis C virus (HCV) RNA and a ≥2-log(10) drop in HCV RNA levels at week 12 (slow responders) were randomized 1:1 to receive 48 weeks (n = 86) or 72 weeks (n = 73) of treatment. Sustained virologic response (SVR) rates were 43% in slow responders treated for 48 weeks and 48% in slow responders treated for 72 weeks (P = 0.644). Relapse rates were similar in slow responders treated for 48 or 72 weeks (47% versus 33%, P = 0.169). The safety profile was similar in both treatment arms; serious adverse events leading to discontinuation of treatment were observed in 3.5% of slow responders treated for 48 weeks and 8.2% of those treated for 72 weeks. Among slow responders with a <2-log drop in HCV RNA at week 8, SVR was 39% in the 72-week arm and 19% in the 48-week arm. CONCLUSION: These data suggest that 48 weeks of therapy with PEG-IFN alfa-2b plus RBV (800-1,400 mg/day) should remain a standard-of-care treatment for treatment-naïve G1 slow responders.

Viral clearance or persistence after acute hepatitis C infection: interim results from a prospective study.

OBJECTIVE: Hepatitis C virus infection (HCV) has a high rate of chronic evolution; however, the underlying mechanisms remain to be elucidated. We investigated natural clinical, virological, and immunological course of acute HCV infection in order to identify possible prognostic factors of spontaneous resolution and to gain more understanding of early characteristics responsible for viral clearance or persistence. MATERIALS AND METHODS: Eight patients with acute symptomatic hepatitis C were prospectively followed up for more than 6 months (range, 8-14 months). None of the individuals received antiviral therapy during the study period. We analyzed biochemical, virological, and immunological parameters of these patients detected at different time-points of the follow-up. Plasma HCV RNA was quantitated using TaqMan real-time polymerase chain reaction. Virus-specific CD4(+) T cells were enumerated by interferon-gamma (IFN-gamma) ELISpot assay. RESULTS: Two of eight individuals resolved HCV spontaneously, while the remaining patients developed chronic HCV infection. HCV RNA became undetectable within 14 days of the study, followed by a rapid alanine aminotransferase normalization in patients with resolved infection. On the contrary, chronically infected subjects demonstrated persistent viremia or intermittently undetectable HCV-RNA, accompanied by polyphasic alanine aminotransferase profile throughout the study. Patients with self-limited hepatitis C displayed the strongest virus-specific CD4(+) T (IFN-gamma) cell reactivity within the first weeks of the follow-up, while persistently infected subjects initially showed a weak antiviral CD4(+) T (IFN-gamma) cell response. CONCLUSIONS: In most cases, acute hepatitis C progresses to chronic disease. Viral clearance within the first month after clinical presentation accompanied by monophasic alanine aminotransferase profile could predict recovery. Early and strong CD4(+)/Th1 immune response against HCV might play an important role in the disease resolution.

Rabies post-exposure prophylaxis vaccination with purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccine (PVRV) in a four-site intradermal schedule (4-0-2-0-1-1): an immunogenic, cost-effective and practical regimen.

Currently, two intradermal (ID) regimens for rabies post-exposure prophylaxis (PEP) are recommended by WHO and used in countries where approved by national authorities: the Thai Red Cross (TRC) two-site ID regimen and the eight-site ID regimen. Besides these WHO recommended schedules, a new economical four-site ID regimen was evaluated that reduces the cost of PEP by up to 80%, when compared with the standard intramuscular Essen regimen, reduces the number of visits required for the patients when compared with the TRC regimen, and is more convenient than the eight-site regimen. To determine the immunogenicity of the ID four-site PEP regimen (4-0-2-0-1-1), 180 healthy volunteers were randomized to receive 0.1 mL volumes of PCECV or PVRV administered ID over both left and right shoulders and both deltoid regions on day 0, both deltoid regions on day 7 and over one deltoid region on days 30 and 90. Regardless of the vaccine, every subject developed rabies virus neutralizing antibody (RVNA) titers above 0.5 IU/mL by day 14, as determined by rapid fluorescent focus inhibition test (RFFIT) using a homologous test system. Two weeks after the last dose of vaccine, RVNA titers were all above 0.5 IU/mL (day 104). Geometric mean titers were similar throughout the study period. Both vaccines were well tolerated. These results demonstrate that a new four-site ID PEP regimen is a cost-effective and convenient alternative to IM (Essen or Zagreb) or ID (TRC or eight-site) regimens, especially using a 1 mL vial of vaccine (PCECV).

Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.

BACKGROUND: Antiviral chemoprophylaxis effectiveness for influenza control has not been prospectively established for unvaccinated residents of long-term care facilities. This study evaluated the efficacy and tolerability of zanamivir against the standard of care (no intervention, ie, placebo) for influenza outbreak control in a largely unvaccinated institutionalized population. OBJECTIVE: To evaluate the efficacy and tolerability of zanamivir versus placebo for influenza outbreak control in long-term care facilities. METHODS: This double-blind, randomized, placebo-controlled study prospectively enrolled/followed residents of long-term care facilities (LTCF) at 12 centers for 1 to 3 influenza seasons (1997 to 2000). Following influenza outbreak declaration, asymptomatic subjects were randomized for prophylaxis to inhaled zanamivir 10 mg or inhaled placebo given once daily for 14 days. The proportion of randomized subjects who during prophylaxis developed symptomatic, laboratory-confirmed influenza (SLCI) was the primary end point. RESULTS: Influenza outbreaks were explosive. The attack rates varied from 9.5 to 14.8 per 100 residents. Of 1763 consents given and resulting in 494 randomizations, 49% received zanamivir and 51% placebo; 66% were elderly and 9% were vaccinated. SLCI occurred in 6% of zanamivir and 9% of placebo subjects (P = .355; protective efficacy for zanamivir = 29%, 95% confidence interval 31% to 62%), and symptomatic influenza confirmed by culture in 2% and 6%, respectively (P = .052; protective efficacy = 65%, 95% confidence interval 8.5% to 86%). Zanamivir use was also associated with a 70% (95% confidence interval 13% to 89%) reduction in laboratory-confirmed influenza with fever (2% vs 6%, P = .043). Influenza B was not detected. Zanamivir was well tolerated. No virus isolate demonstrated zanamivir resistance. CONCLUSIONS: The protective efficacy of zanamivir versus placebo for SLCI was marginal, for all laboratory confirmed illnesses, but significant against culture proven and febrile influenza, suggesting zanamivir can be effective for outbreak control and symptom reduction of unvaccinated institutionalized residents. Zanamivir had an acceptable safety profile in elderly, high-risk LTCF residents and was not associated with the emergence of resistant strains.

Hepatitis C virus RNA levels during initial induction or standard interferon therapy: influence of continued treatment on sustained response.

Hepatitis C virus (HCV) RNA kinetics were studied at baseline weeks 4, 8 and 12 during interferon-alpha (IFN) monotherapy in 65 patients (mean age 39 y, range 19-66 y) with chronic HCV infection. IFN treatment was given either as initial induction (n = 34) or as standard dosing 3 times a week (n = 31). Patients with genotypes 2 and 3 had a significantly steeper decline in HCV RNA levels than patients with genotype 1 at weeks 4, 8 and 12 (p < 0.001 at all points measured). The decline in viral load was more pronounced in patients with induction therapy than with standard therapy at weeks 4, 8 and 12 (p < 0.02, 0.054 and 0.01, respectively). Patients with a sustained viral response had a 3-log decline in viral levels at week 4, with few exceptions. Two patients with non-response at week 12 (1 each with genotype 1 and non-1) responded after supplementation with ribavirin.