Randomized Trial of the Virologic Response during up to Two Years of Entecavir-Adefovir Combination Therapy in Multiple-Drug-Refractory Chronic Hepatitis B Virus Patients

Abstract

A 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple-drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine-resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group; P ‫؍‬ 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (؊2.8 log 10 IU/ml and ؊2.8 log 10 IU/ml, respectively; P ‫؍‬ 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P ‫؍‬ 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01023217.) A pproximately 400 million people worldwide are chronically infected with hepatitis B virus (HBV) (1, 2). The goal of HBV treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). A high serum HBV DNA level in patients with chronic hepatitis B (CHB) is an independent risk factor for disease progression to cirrhosis and HCC (3, 4). Reducing HBV DNA to very low or undetectable levels with nucleos(t)ide analogue (NUC) therapy is associated with reduced risks of disease progression (5-8).With the availability of potent NUCs, such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF), suppression of serum HBV DNA to levels undetectable by PCR assays is achievable in most NUC treatment-naive patients without selecting for drugresistant HBV mutants (9, 10). Until recently, however, many patients worldwide began antiviral treatment with the less potent NUCs, such as lamivudine (LAM) or adefovir (ADV), which also have a low genetic barrier to resistance.Add-on combination therapy with LAM and ADV has been the most common rescue therapy in patients with LAM-resistant HBV. However, in such patients, the continued use of LAM does not provide additional antiviral suppression (11). Consequently, a substantial proporti...

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial

“…These rates of virological response with TDF monotherapy are superior to those of combination therapies based on ADV, such as LAM plus ADV or ETV plus ADV, in multidrug-refractory patients 40–42. In a previous randomised trial at our institution,40 41 the proportion of patients with serum HBV DNA levels <60 IU/mL at 52 weeks was only 29% in the ETV plus ADV group. These findings suggest that TDF monotherapy would be a better treatment option than combination therapies based on ADV in multidrug-resistant patients.…”

Monotherapy with tenofovir disoproxil fumarate for multiple drug‐resistant chronic hepatitis B: 3‐year trial

“…Second, the predominant population had relatively low HBV DNA levels at baseline. This may be associated with the decreased replicative fitness of HBV with multiple mutations and the preceding partially effective combination therapies . However, the subgroup of patients with high viral load at baseline also showed persistent and significant decreases in HBV DNA over the study period.…”

Telbivudine protects renal function in patients with chronic hepatitisBinfection in conjunction with adefovir‐based combination therapy

“…In previous studies, antiviral effects of ADV‐based combination treatments such as ADV plus LAM, ADV plus LdT and ADV plus ETV were well elucidated for second‐line therapy for patients demonstrating LAM resistance or the primary failure of LAM therapy . Although combination antiviral therapy can be an effective rescue therapy, long‐term treatment against resistant HBV is also recommended for patients with chronic HBV infection or advanced liver disease, as well as for those treated with chronic immunosuppressive therapy .…”