Assess the Efficacy of New HBV Treatments

雪绒花

Can Serum HBV-DNA Levels Serve As a Primary End Point to Assess the Efficacy of New HBV Treatments?


Three drugs have been approved by the US FDA for the treatment of chronic hepatitis B:?Intron A (interferon (IFN) alfa-2b), available since the early 1980s; Epivir-HBV (lamivudine; 3TC), a nucleoside analog introduced in the late 1990s; and the recently approved Hepsera (adefovir dipivoxil), a nucleotide analog with efficacy similar to lamivudine but with a more favorable resistance profile with efficacy against lamivudine-resistant HBV.

A number of other compounds are currently investigated in phase II/III clinical trials. Most are nucleos(t)ide analogs and include entecavir, emtricitabine, clevudine, beta-1 L-nucleoside, and other molecules. Other studies are assessing different ways of combining anti-HBV therapies (IFN and PEG-IFN plus lamivudine or adefovir, lamivudine plus adefovir, other nucleos(t)ide analogs combinations) with the hope of improving the effectiveness of monotherapy.
An article by Mommeja-Marin et. al.?/span>in the June 2003 issue of Hepatology argues in favor of using HBV DNA levels to assess the effectiveness of new HBV treatments. However, the July 2003 issue of Hepatology contains an editorial that argues such use of HBV DNA testing would be 損remature.?The editorial is written by Alfredo Alberti, MD, of the Venetian Institute of Molecular Medicine at the University of Padova in Padova, Italy. Selected sections of his commentary follow:

擣aced with [an] expanding armamentarium of potentially useful treatments, there is the need to identify parameters that accurately reflect their clinical efficacy. The final goal of therapy in chronic hepatitis B is to prevent cirrhosis and its complication, hepatocellular carcinoma, and HBV-related death.?
揑n clinical trials, it is unrealistic to assess for these 搕rue?end points due to the slow course of initially compensated chronic hepatitis B. Therefore, 搒urrogate?end points need to be used. However, identification of surrogates that adequately describe clinically significant events is not an easy task in chronic hepatitis B, due to the great virologic and clinical heterogeneity of the disease, its complex pathogenesis, and the type of response obtainable with therapy in most patients, i.e., short-term suppression rather than complete eradication of HBV.?/span>
揟he difficulties and uncertainties in proposing a well-defined parameter/time point as gold standard of response to antiviral therapy in chronic hepatitis B are reflected by the conclusions of the 2000 HBV Workshop organized by the National Institutes of Health and of the 2002 European Consensus Conference on Hepatitis B.?/span>
揟hese documents describe a number of types (virologic, biochemical, histologic, composite) and time points (early, end-of-therapy, maintained during long-term therapy, sustained after therapy) of response to be considered without indicating a specific type/time point to be adopted as a primary efficacy end point.?br>
擨n recent registration trials of nucleos(t)ide analogs, liver histology, defined as a decrease in histologic activity index (HAI) by 2 or more points with no worsening of fibrosis score, was adopted as the primary efficacy end point. This approach, however, has a number of limitations:
(1)     it requires an invasive procedure, to be performed twice, with the potential for bias when the percent of patients agreeing to a repeat biopsy is low;
(2)     it uses a poorly standardized semiquantitative assessment of a noncontinuous variable such as HAI;
(3)     it implies the unproven assumption that an HAI reduction of 2 points or more is clinically relevant and that improvement in liver histology after a certain duration (usually 1 year) of therapy can be maintained if treatment is stopped;
(4)     it does not allow early prediction of response; and (5) it is unsuitable in every day clinical practice.?/span>
揜ecently, highly sensitive polymerase chain reaction-based methods that measure serum HBV-DNA levels with a wide dynamic range have become available and can now be used to precisely assess and compare the potency of different anti-HBV treatments in suppressing HBV replication.?/span>
揝ince improvement of liver disease with antiviral therapies is thought to depend on suppression of HBV replication, can we consider serum HBV-DNA measurement a surrogate of clinically significant events and use it as a primary end point of efficacy in clinical trials, as in the case of antiviral therapy for chronic hepatitis C?
揟he use of virologic end points is fully justified in hepatitis C based on the high (>50%) rate of virus eradication that can be obtained with therapy,11-12 the demonstration that virus eradication can be accurately predicted by HCV-RNA testing at well-defined time points during therapy,13 the very high (>95%) rate of durability of sustained response, and the correlation between sustained virologic response and improvement in long-term clinical outcomes.?
揢nfortunately, this is not the case with hepatitis B. All types of anti-HBV treatments evaluated so far have resulted in long-term virus suppression with a finite course only in a small minority of patients. Virus eradication is rarely if ever achieved as the vast majority of patients remain hepatitis B surface antigen positive. Most cases need prolonged therapy to suppress liver disease activity and progression.?/span>
揢nfortunately, an initial response can be lost with time if drug resistance develops. If the virus cannot be completely eliminated, the question is to which levels and for how long its replication should be suppressed to ensure a significant benefit on clinical outcomes.

擳o propose HBV-DNA measurement as a primary end point of response to anti-HBV therapies, several criteria need to be fulfilled:
(1)     serum HBV-DNA changes should correlate with the end points for which surrogacy (i.e., improvement in clinical outcome) is proposed;
(2)     the extent and timing of 揷linically significant?HBV-DNA suppression should be precisely defined; and
(3)     HBV-DNA changes should predict changes in 搕rue?end points at the individual patient level, as assessed by the 損ercent of effect explained.?
(4)     Last but not least, HBV-DNA quantitative assays should be standardized as in the case of HCV-RNA assays. Unfortunately, most of these issues have not been yet solved.?
揑n conclusion, while serum HBV-DNA measurement by polymerase chain reaction-based assays is already a most useful tool to assess and compare the antiviral potency of different anti-HBV compounds and strategies, to monitor the virologic response in individual treated patients, and to identify cases with a reduced response or emergence of drug resistance, its implementation as the primary surrogate end point of efficacy in the assessment of new anti-HBV therapies appears premature.?/

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