Antiviral Therapy

Herrmann, Eva; Neumann, Avidan U; Schmidt, Jürgen M; Zeuzem, Stefan

doi: 10.1177/135965350000500203pmid: N/A

The balance of virus production and clearance for untreated patients with chronic hepatitis C virus (HCV) results in a decline of viraemia when initiating active antiviral treatment. During the first phase of interferon-α therapy, after a delay of about 8–9 h, the kinetics of the viral load is characterized by a rapid dose-dependent decline. This early response can be observed for almost all patients treated with interferon-α. After about 24–48 h, the viral decline enters a second phase of relatively slow exponential decay during the following weeks of therapy. Non-responding patients, however, show constant viraemia or even a rebound during this second phase. The rate of the exponential decline of the viral load in responding patients in this second phase is less sensitive to the dose of interferon-α and varies considerably among patients. Furthermore, combination therapy with interferon-α plus ribavirin does not significantly improve the initial viral decay, although it may prevent more patients from rebounding. Mathematical modelling of viral dynamics reveals high turnover rates of pre-treatment viral production and clearance, and permits the estimation of in vivo half-lives of a few hours for free HCV virions and of 1–70 days for productively infected cells. Infected cell death rate, which determines the second phase decline slope, is predictive of response to treatment. Current models indicate that the early biphasic viral decline is explained if interferon-α partially blocks virion production from infected cells, yet they do not rule out additional antiviral or immunological effects. Therapeutic implications are the advisability of use of frequent (daily) and comparatively high initial doses. In conclusion, kinetic analysis of the viral decay during the first weeks of treatment permits the prediction of response at the end-of-therapy and might help to evaluate new drugs and to optimize therapy.

Degen, Olaf; Van Lunzen, Jan; Stellbrink, Hans-Jürgen

doi: 10.1177/135965350000500204pmid: N/A

Objective To investigate the antiviral activity of abacavir added to stable background therapy. Design: Retrospective analysis. Materials and Methods In 27 subjects with detectable plasma viraemia during stable treatment abacavir was added as the only agent. Patients were pre-treated for 180 weeks (mean) with regimens containing zidovudine (102 weeks) and lamivudine (88 weeks). Results were analysed in two groups: group 1, >400 HIV RNA copies/ml; group 2, 25–399 copies/ml. In 7/13 group 1 patients genotypic resistance analysis was performed prior to abacavir. Results Median follow-up was 28 weeks, median HIV RNA load at baseline 2.48 log10 copies/ml (3.52 and 1.66 log10 copies/ml in groups 1 and 2, respectively). Plasma viraemia was reduced to less than 400 HIV RNA copies/ml in 2/13 subjects in group 1 and 11/11 in group 2 (week 24). Only one patient in group 1 responded transiently to less than 25 HIV RNA copies/ml. In contrast, 10/14 and 11/11 in group 2 reached values below this threshold at weeks 12 and 24, respectively. Overall, 7/13 group 1 patients were found with ≥2 zidovudine resistance-associated mutations. The lamivudine resistance-associated mutation M184V was present in four of seven cases. All of these patients showed only a moderate and transient reduction of plasma viraemia (medium peak reduction of 0.73 log10 after 20 weeks). Conclusions The addition of abacavir during low-level treatment failure may restore or achieve suppression to levels below the cut-off of the ultrasensitive PCR.

Korba, Brent E; Cote, Paul; Hornbuckle, William; Schinazi, Raymond; Gangemi, J David; Tennant, Bud C; Gerin, John L

doi: 10.1177/135965350000500205pmid: N/A

Cell culture studies in our laboratory previously demonstrated synergistic antiviral activity for the combinations of lamivudine and a novel recombinant hybrid human alpha B/D interferon (rHuαB/D IFN) against hepatitis B virus (HBV) replication. Based on these results, a study was designed to determine if an enhanced antiviral effect with this drug combination could be demonstrated in vivo using the woodchuck hepatitis virus (WHV)/woodchuck experimental model of chronic HBV infection. Both antiviral agents have been shown to be effective against WHV replication in WHV chronic carriers during previous studies by our laboratories. Two combination treatment regimens were compared to matched monotherapies in a placebo-controlled trial. The first used simultaneous administration of rHuαB/D IFN and lamivudine for 24 weeks. The other combination treatment regimen used a staggered dosing schedule of 12 weeks of administration of lamivudine alone, followed by 12 weeks of simultaneous dosing with both drugs, followed by 12 weeks of therapy with rHuαB/D IFN alone. Both treatment regimens with combinations of lamivudine and rHuαB/D IFN were more effective at reducing WHV replication in chronically infected wood-chucks than the corresponding monotherapies. Both combination treatments produced antiviral effects that were at least equal to that expected for additive activity based on estimations generated by Bliss Independence calculations. The staggered treatment regimen reduced viraemia and intrahepatic WHV replication significantly more than that expected for additive interactions, indicating synergistic antiviral effects. These studies demonstrate that combination therapy of chronic WHV infection has enhanced antiviral benefit over corresponding monotherapies and indicate that combination treatment of chronic HBV infection can be superior to therapies using a single antiviral agent.

Miller, Veronica

doi: 10.1177/135965350000500201pmid: N/A

Mocroft, A; Miller, V; Chiesi, A; Blaxhult, A; Katlama, C; Clotet, B; Barton, S; Lundgren, Jens D

doi: 10.1177/135965350000500206pmid: N/A

Objectives To monitor the response to highly active anti-retroviral therapy (HAART) over time and the proportions of patients with poor virological control in order to help provide some insight into drug resistance. Design Analysis of data from the EuroSIDA study; an observational study initiated in 1994 of almost 8500 patients with HIV from across Europe. Methods Patients who initiated HAART, and had both a CD4 lymphocyte count and viral load measured in the 3 months prior to starting HAART, were included in analyses. The proportion of patients with a poor virological response (defined as a viral load of >10 000 copies/ml, using either a single measure or two consecutive measures) at 16 and 48 weeks was determined. Multivariate logistical regression was used to determine the factors associated with a poor virological response at both time points. Results Median CD4 cell count at starting HAART was 218 cells/mm3 [interquartile range (IQR), 113–327 cells/mm3] and median viral load was 4.36 log10 copies/ml (IQR, 3.57–5.04 log10 copies/ml). At 16 weeks, 16% had a viral load of >10 000 copies/ml based on a single viral load measure and 10% if the more stringent definition of two consecutive viral loads above this level was used. At 48 weeks these proportions were 19% and 13%, respectively. Compared with patients from Southern Europe, patients from both Central and Northern Europe had approximately half the chance of a poor virological response at 16 weeks (odds ratios 0.53 and 0.47, P=0.0015 and P<0.0001, respectively), while at 48 weeks both regions still had approximately a 25% reduced chance of a poor virological response, but this was no longer statistically significant (odds ratio 0.77 and 0.75, P=0.17 and P=0.13, respectively). Conclusions There were marked differences in virological response to HAART across regions of Europe, which may be partly explained by regional differences in access to HAART and utilisation. If drug resistance is closely related to virological failure, these results may help to provide an early insight into the potential problem of drug resistance across Europe. Continued follow-up is essential to monitor patients with poor virological control.

doi: 10.1177/135965350000500202pmid: N/A