Does adherence to hepatitis B antiviral treatment correlate with virological response and risk of breakthrough?
Authors: Marie Noelle Hilleret, Sylvie Larrat, Francoise Stanke-Labesque, Vincent Leroy
Journal: Journal of Hepatology (2011)

Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis BJournal of HepatologyVol. 54Issue 1PreviewLong-term treatment with nucleos(t)ide analogues (NUCs) is associated with increasing rates of antiviral drug resistance. Medication adherence is important in preventing drug resistance. This study aimed to determine, first, the persistence rates and the adherence rates to NUCs in patients with chronic hepatitis B (CHB), and second, the factors associated with adherence. Full-Text PDF Reply to: "Does adherence to hepatitis B antiviral treatment correlate with virological response and risk of breakthrough?"Journal of HepatologyVol. 55Issue 6PreviewWe are delighted that Dr. Hilleret and colleagues concur with our finding that in real life clinical practice, adherence to nucleos(t)ide analogs for hepatitis B is less than ideal and has a tendency to decline with time. We agree that the major limitation of our study [1] is the inability to correlate our findings with clinical data, but utilizing a nationwide pharmacy database enabled us to study a large number of patients in the community that are more representative than a small cohort of patients in a single tertiary referral center. Full-Text PDF Open Access We read with interest the study entitled "Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis B" by Chotiyaputta et al. [[1]Chotiyaputta W. Peterson C. Ditah F.A. Goodwin D. Lok A.S. Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis B.J Hepatol. 2010; 54: 12-18Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. This study is the first known report in "true life setting" of antiviral drug adherence of HBV patients. Using the US pharmacist providing system, data were collected from 11,100 patients taking HBV antiviral drugs. 55.3% of patients were taking more than 90% of their medication confirming that drug adherence might be better than that observed in HIV patient population [2Bangsberg D.R. Deeks S.G. Is average adherence to HIV antiretroviral therapy enough?.J Gen Intern Med. 2002; 17: 812-813Crossref PubMed Scopus (77) Google Scholar, 3Golin C.E. Liu H. Hays R.D. Miller L.G. Beck C.K. Ickovics J. et al.A prospective study of predictors of adherence to combination antiretroviral medication.J Gen Intern Med. 2002; 17: 756-765Crossref PubMed Scopus (385) Google Scholar]. This result could be explained by HBV antiviral therapy favourable profile for adherence, characterised by a once a day medication and quality of life not altered by side effects [[4]Reach G. Clinique de l'observance. L'exemple des diabètes. John Libbey EUROTEXT; 2006.Google Scholar]. However, authors pointed out the limitations of their findings, particularly the absence of virological monitoring regarding adherence status and the absence of correlation with breakthrough occurrence. Considering these limitations of Chotiyaputta's study, we report a series of 47 chronic hepatitis B patients either treated solely by adefovir therapy or in addition to lamivudine, for at least 3 years. Here, the adherence rate was assessed by a direct method, i.e., measurement of adefovir plasma levels, and was correlated with the virological response. Patients' characteristics were as follows: median age of 48 years, 81% male, 30% HBe(+) Ag, genotypes D 51%, A 38%, 75 percent had received prior treatment with nucleoside analogues. HBV DNA level (VL) was monitored by RT-PCR (sensitivity 12 IU/ml) every three months. Sequencing of HBV polymerase searching for known adefovir mutations (A181V, N236T and A181V/T + N236T) was performed in case of 0.5 log IU/L VL increase. Adefovir plasma levels were assessed by liquid chromatography tandem mass spectrometry in serum (lower limit of quantification: 1 ng/ml) every year (Y) and every time HBV DNA level increased by more than 0.5 log IU/ml. 14 patients (30%) had undetectable adefovir levels at least on one occasion during total treatment period. Among them, 6 (13%) had repeatedly undetectable adefovir levels per study observation period (one occasion n = 8, twice n = 2 and more than 2 times n = 4). Adefovir undetectability was observed at Y1 (15%), Y2 (11%), Y3 (17%), Y4 (8%). Those patients had 2.6 fold lower serum concentrations independently of weight on all time points from Y1 to Y4 (7.4 vs. 19.0 μg/L, p <0.0001). These were thus considered as being "poor adherent". They were significantly younger (39 vs. 52 years, p <0.001) and subsequently more frequently HBeAg+ (57% vs. 18%) with higher viral load (7.4 vs. 6.1 log IU/ml). As shown in Fig. 1, virological response was significantly better in adherent patients during the first year of treatment. At Y1, the mean viral load was significantly higher for poor adherent patients (4.37 log IU/ml vs. 2.96 log IU/ml; p = 0.001). At Y2, patients with poor adherence were less likely to achieve undetectable HBV DNA (21% vs. 42%, p <0.01), while there was a non-significant trend at year 4 (32% vs. 68%, p <0.07). Virological relapse was observed in 15 patients, mainly after two years of treatment. At the time of relapse, 9 patients demonstrated adefovir resistance mutations. 7 had undetectable adefovir levels, 2 patients only showing resistance mutation in this subgroup. Our study demonstrates that 30% of the patients were at least once "non adherent" to antiviral treatment, a scenario associated to lower adefovir concentrations in other time points. This suggests poor adherence over the treatment period. In Chotiyaputta's study, results were expressed in a different manner: 47% of the patients reached an adherence rate lower than 90% and were considered as having poor adherence. The higher rate of poor adherence reported in Chotiyaputta's study could be due to discrepancies in methods assessing adherence. Indeed, we used a very stringent criterion of poor adherence, defined by a dosage lower than the quantification lower limit that is certainly highly specific for detecting adherence failure but probably less sensitive than indirect methods. We found in our series similar results to Chotiyaputta et al. regarding the characteristics of poor adherent patients. Younger patients, respectively 39 year-old or less than 45 year-old in Chotiyaputta study, were less likely to have a good adherence rate. Chotiyaputta et al. underlined the first 6 months of therapy as a predicting factor of poor adherence. In our study, one third of patients had undetectable adefovir level among the first year of treatment. However, a linear progression of poor adherence rate throughout the 4 years of our study must be stressed. Similarly Chotiyaputta et al. found lamivudine as a predictor of poorer adherence, which could be a marker of longer treatment duration. Complementary to Chotiyaputta's study we clearly demonstrate a strong link between adherence rate and virological response. Adherence rate was a major factor for suboptimal response, which might even be of greater impact than resistance mutations. Regarding the current use of the new generation of nucleos/tide analogues such as tenofovir or entecavir, with a high genetic barrier, those conclusions enlighten the fact that assessment of patient adherence to antiviral treatment has to be addressed every time a suboptimal response is observed. In this setting, antiviral drug dosing should then be considered as a meaningful tool. Promoting persistence of on-therapeutic adherence motivation in this life long treatment setting is fundamental. As described with other chronic diseases, especially HIV, specific therapeutic educational programs are to be developed after a proper assessment of the true determinants of patient adherence. In order to perform adefovir dosage for the all patient cohort, the authors got a research fund from Gilead Sciences dedicated to this study. We would like to thank Dr. B. Beaupere and Gilead Sciences®, Inc. for their financial support.