Alternative Therapies for Chronic Hepatitis B Patients With Partial Virological Response to Standard Entecavir Monotherapy Kevin T. Chaung, BS,* Connor O’Brien, MD,w Nghiem B. Ha, BS,zy Nghia H. Nguyen, BA,y8 Huy N. Trinh, MD,z# and Mindie H. Nguyen, MD, MAS, FAASLD, AGAFy Background: Entecavir (ETV) is a first-line, oral antinucleoside agent for the treatment of chronic hepatitis B patients. Despite its high potency, some patients may still be viremic after prolonged therapy with ETV monotherapy. Long-term outcome data com- paring maintained ETV monotherapy to alternative therapies in persistently viremic patients are limited. Our goal was to compare complete viral suppression (CVS) rates [hepatitis B DNA (HBV DNA) < 40 to 60 IU/mL] with alternative therapies to continued ETV monotherapy in ETV partial responders. Methods: This is a retrospective cohort study consisting of 86 consecutive treatment-naive, ETV = 0.5 mg partial responders (detectable HBV DNA after Z12 mo on ETV) who maintained ETV = 0.5 mg daily (n = 29) or switched to either ETV = 1.0 mg daily (n = 32) or ETV/tenofovir (TDF) = 0.5 mg/300 mg (n = 25) in 3 US GI/liver clinics from January 2005 to January 2012. Patients were identified by International Classification of Diseases, Ninth Revision query and data were collected by individual chart review. For those who remained on ETV = 0.5 mg, comparison at regimen “switch time” was done using values at 12 months from initial ETV therapy. Rates of CVS were evaluated using Kaplan- Meier methods. Multivariate Cox proportional hazard models were used to estimate hazard ratio (HR) relating to potential predictors to the desirable outcomes of CVS. Results: In all therapy groups, the majority of patients were Asian (93.1% to 100.0%), male (64.0% to 68.8%), and hepatitis B e antigen-positive (95.8% to 100.0%) and had similar baseline ala- nine aminotransferase (ALT) levels. However, baseline HBV DNA (7.0 vs. 7.9 vs. 7.8 log 10 IU/mL, P = 0.05) and HBV DNA at reg- imen switch point (2.9 vs. 3.7 vs. 3.6 log 10 IU/mL, P = 0.0014) were lower in the ETV = 0.5 mg cohort compared with those switched to ETV = 1.0 mg or ETV/TDF, respectively. The ETV = 0.5 mg cohort also had the shortest duration of ETV = 0.5 mg therapy before switch (11.8 vs. 13.5 vs. 19.2 mo, P < 0.0001). After the switch point, more patients on ETV/TDF achieved CVS compared with those on ETV = 0.5 mg or ETV = 1.0 mg at month 6 (77.3% vs. 13.8% vs. 9.4%), month 12 (86.4% vs. 40.5% vs. 25.0%), and month 18 (100% vs. 70.2% vs. 33.3%). Compared with the ETV = 0.5 mg and ETV = 1.0 mg groups, the ETV/TDF group also had higher rates of ALT normalization at month 6 (73.0% vs, 46.4% vs. 63.0%), month 12 (79.7% vs. 69.5% vs. 77.9%), and month 18 (100.0% vs. 69.5% vs. 86.8%), respectively. The multi- variate analyses, inclusive of baseline age and treatment duration on initial therapy with ETV = 0.5 mg, indicated that the ETV/TDF combination (HR = 12.19, P < 0.0001) was independently and positively associated with CVS, whereas high HBV DNA levels at baseline (HR = 0.77, P = 0.02) and at switch point (HR = 0.46, P = 0.002) were negatively associated with CVS. ETV = 1.0 mg dose was not a predictor for CVS compared with ETV = 0.5 mg. Conclusions: Following adjustments for HBV DNA levels and prior treatment duration, ETV/TDF combination therapy independently predicted superior viral suppression and ALT normalization in partial responders to ETV = 0.5 mg daily compared with ETV = 0.5 mg or ETV = 1.0 mg monotherapy. In patients who continued to be viremic after 12 months of ETV = 0.5 mg, one third were still viremic after another 18 months on the same therapy. Alternative therapies should be considered for these patients. Key Words: chronic hepatitis B, entecavir, tenofovir, partial viro- logic response, partial responders, recurrent viremia, complete viral suppression (J Clin Gastroenterol 2016;50:338–344) A ccording to the World Health Organization, approx- imately 240 million people globally are affected by chronic hepatitis B (CHB) and 780,000 people die annually due to acute or chronic complication of hepatitis B. 1 In the United States, it is estimated that excess of 1.25 million people are infected with CHB and 5000 patients die annually due to CHB complications. 2 If left untreated, approximately 15% to 40% of CHB patients have an increased risk of developing hepatic decompensation, cirrhosis, and/or hep- atocellular carcinoma (HCC), eventually leading to higher morbidity and mortality. 2–7 In addition, high serum hepatitis B DNA (HBV DNA) or viral load has been known to be associated with liver-related morbidity and mortality. 8–12 Therefore, the immediate primary goal of therapy for CHB patients is to achieve complete viral suppression (CVS) of HBV DNA. The long-term goal of oral antiviral therapy is Received for publication April 5, 2015; accepted October 23, 2015. From the *School of Medicine, Ross University, Miramar, FL; wDe- partment of Medicine; yDivision of Gastroenterology and Hep- atology, Stanford University Medical Center, Stanford; zSchool of Medicine, University of California at Davis, Sacramento; 8School of Medicine, University of California at San Diego, La Jolla; zSan Jose Gastroenterology; and #Pacific Health Foundation, San Jose, CA. K.T.C. and C.O.B. contributed equally. H.N.T. has served as advisory committee for Bristol-Myers Squibb, Gilead Sciences, and Vertex Pharmaceuticals; received research grant support from Bristol-Myers Squibb and Roche Pharma AG; and owns stocks and shares of Gilead Sciences. M.H.N. has con- sulted with Bristol-Myers Squibb, Gilead Sciences, and Bayer AG; and received research grant support from Bristol-Myers Squibb, Gilead Sciences, Novartis Pharmaceuticals, and Roche Pharma AG. The remaining authors declare that they have nothing to disclose. Reprints: Mindie H. Nguyen, MD, MAS, FAASLD, AGAF, Division of Gastroenterology and Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304 (e-mail: mindiehn@stanford.edu). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.jcge.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ORIGINAL ARTICLE 338 | www.jcge.com J Clin Gastroenterol  Volume 50, Number 4, April 2016 Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.