To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM.

This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.

Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 ± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).

TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Approximately 400 million people worldwide are infected by the hepatitis B virus (HBV)[1]. Given that a significant portion of these patients receive treatment for management of chronic hepatitis B (CHB) over a long period of time[2-4], it is necessary to use new antivirals with potent action and an adequate long-term safety profile. Likewise, it is important that these medications possess a high genetic barrier that will lead to reduced HBV resistance rates[5]. The establishment of CHB treatment has, as its objective, the sustained suppression of virus replication to prevent disease progression and increase survival.

Sustained viral suppression with lamivudine (LAM) has been shown to reduce the progression of the disease, preventing the development of cirrhosis and the occurrence of complications, which include liver failure, hepatocellular carcinoma and liver-related mortality[6]. However, while LAM is an effective medication, its use has been limited due to the development of mutations in the polymerase region of HBV that promote resistance, causing loss of antiviral activity and its clinical benefit[7]. The rate of appearance of resistance is in the range of 15%-20% per year of treatment and may increase to up to 80% at 5 years after the start of treatment[8]. Management of LAM resistance has evolved in recent years. Initially, the recommended therapeutic option was to switch to adefovir dipivoxil (ADV)[9]. However, it was found that this strategy favoured the appearance of ADV resistance[10]. One randomized study demonstrated that the probability of developing ADV resistance at 3 years of treatment in patients with resistance to LAM was significantly higher in the patient group treated with ADV monotherapy than in the group receiving a combination of LAM plus ADV[11]. The Clinical Guidelines of the European Association for the Study of the Liver (EASL) recommend that patients with CHB and LAM resistance be changed to tenofovir disoproxil fumarate (TDF) or have ADV added if TDF is not available[12].

TDF, a prodrug of tenofovir, is a potent nucleotide analogue with high efficacy in CHB treatment[13]. Phase III clinical trials showed that TDF is superior to ADV in the suppression of viral replication and in histological improvement in both hepatitis B e antigen- (HBeAg-) positive and HBeAg-negative patients[5]. Furthermore, it is a drug with a high genetic barrier to resistance, with no reported cases of resistance during 6 years of treatment[14]. Additionally, the antiviral activity of TDF is maintained against HBV strains resistant to LAM[5,15,16].

The antiviral efficacy of TDF monotherapy has been demonstrated in patients with HBV infection and a partial prior response to ADV, including patients with a history of LAM resistance; its efficacy is similar to that of TDF in combination with emtricitabine (FTC) [17]. Based on these results and on the fact that, at the current time, there are no reports of TDF resistance, several authors have purposed TDF monotherapy treatment in patients with LAM resistance[12,18].

Patients who have previously failed LAM treatment and who have previously received combination treatment with LAM+ADV would be the ideal population to determine whether TDF monotherapy is equivalent to standard treatment (LAM+ADV) in maintaining a virologic response. As a result, the primary objective of the TENOSIMP-B study was to demonstrate the non-inferiority (with a limit of 15%) of TDF monotherapy in maintaining an undetectable viral load vs the combination LAM+ADV treatment in patients with CHB and prior failure of LAM. The secondary objectives of the study were to compare the safety profiles in each treatment group, especially the incidence of renal safety; to calculate adherence to treatment; and to determine the differences in hospital expenses for patients assigned to each of the treatment strategies.

TENOSIMP-B is a Phase IV open, randomized, controlled study of non-inferiority with 2 parallel arms (TDF and LAM+ADV) and prospective follow-up. The trial was performed in 14 Spanish public hospitals with the participation of adult patients with chronic HBV infection. The recruitment period was between August 2011 and January 2013. Patients were followed for 48 wk with intermediate visits during weeks 12, 24 and 36.

During the study period, patients were treated with the medication to be studied, and data were collected every 12 wk using an electronic case report form (eCRF). Variables collected included those related to the patient’s clinical data (HBV-DNA load and hepatitis B biochemical and serological parameters), information on possible adverse events (AEs) during study tracking and adherence to therapy using dispensation records provided by Hospital Pharmacy Services. In addition, through the use of a patient diary, information was compiled at each visit regarding the use of hospital resources by patients during the study period.

The randomization process was performed in blocks to ensure that each centre had a 1:1 ratio of patients with TDF (300 mg/d) or LAM (100 mg/d) plus ADV (10 mg/d). All drugs were administered orally.

The study was authorized by the Medication Research Ethics Committee (MREC) of the Hospital Universitario Central de Asturias (Oviedo, Asturias, Spain), which acted as the reference committee in coordination with committees from the other participating centres. The study was developed in accordance with the ethical principles stated in the Declaration of Helsinki and was consistent with the guidelines for good clinical practice and the applicable local regulatory requirements. All patients gave informed written consent for participation in the study.

LAM, the first nucleoside analogue that has been proven effective against HBV, was widely used during the 1990s in CHB treatment. As a consequence of its previous use and due to its low genetic barrier to resistance, a significant portion of patients with CHB who received this treatment have developed resistance[8]. For years, the addition of ADV to LAM has been the recommended regimen for the management of patients with LAM resistance[11]. A retrospective multi-centre study analysed the effectiveness of TDF monotherapy in patients who had failed treatment with LAM and/or ADV, noting a cumulative probability of virologic response of 79% after an average treatment duration of 23 mo. In this study, it was observed that the presence of LAM resistance did not influence the response to TDF monotherapy, whereas the presence of ADV resistance did influence the response[24]. In recent years, various randomized studies have shown that TDF monotherapy is as effective as a combined treatment with TDF and FTC or entecavir (ETV) in the rescue of patients with not only LAM resistance[25,26] but also resistance to other analogues such as ADV or ETV[27,28].

In the present study, the effectiveness and safety of a simplification of the therapeutic regimen consisting of TDF monotherapy was evaluated in patients who had failed treatment with LAM and who had been satisfactorily rescued with a combination of LAM+ADV. The simplification with TDF could, at least theoretically, encourage adherence to treatment, reduce adverse effects over the long term and decrease hospital expenses.

In this randomized study, it has been demonstrated that TDF monotherapy is as effective as the combination of LAM+ADV in maintaining a complete virologic response. During the 48 wk of the study, all patients maintained an undetectable HBV-DNA load. The preliminary results of a similar study carried out in Taiwan showed reappearance of HBV-DNA in 9.4% of patients assigned to TDF monotherapy and in 16.7% of those assigned to LAM+ADV, although in all cases the reappearance of viremia was transitory[29]. Another prospective study conducted in China demonstrated that TDF monotherapy was superior to a combination of LAM+ADV in achieving complete virologic response in patients with LAM resistance and suboptimal response to LAM+ADV[30]. Finally, a retrospective study carried out in the United States evaluated the strategy of simplifying treatment to TDF or ETV monotherapy in patients who had not completely responded to ETV and who had been satisfactorily rescued with the ETV+TDF combination[31]. In this study, it was observed that virologic rebound rates at 6 mo from the start of monotherapy were significantly higher (88%) in patients who received ETV than in those treated with TDF (39%). One of the factors associated in this report with the risk of presenting a virologic rebound was a duration of complete virologic response of less than 12 mo prior to simplification of treatment to monotherapy[31].

Regarding the biochemical response, in our study, we observed that ALT levels at the end of the study were similar to baseline levels and that there was no difference in ALT levels between patients who received monotherapy with TDF and those who continued combined treatment with LAM+ADV. On the other hand, during the 48 wk of the study, none of the patients lost HBsAg, an unsurprising finding given the reduced clearance rate of HBsAg in patients with HBeAg-negative CHB treated with nucleos(t)ide analogues, even when a potent analogue with a high generic barrier to resistance, such as TDF, is used[13].

In the safety evaluation, no serious adverse effects were observed during the study, and the rate of adverse effects was similar in the 2 study groups, with the most frequent adverse effect being the common cold. A patient from the TDF group presented with a drug-related adverse effect (digestive intolerance and muscle pains), which resulted in the interruption of treatment. As for renal safety, although both ADV and TDF can, on rare occasions, produce a Fanconi-like renal tubular acidosis, during the present study, no significant changes in the levels of serum phosphorus were observed in either of the 2 groups. Regarding kidney function, no differences were observed between the baseline visit and the end of treatment in either group, nor were there differences at the end of the study between patients who received TDF and those treated with LAM+ADV. Three patients, 2 in the LAM+ADV group and 1 in the TDF group, displayed mild and transitory deterioration in kidney function during the study, and 1 patient belonging to the LAM+ADV group moved from stage II at the start to stage IIIa at the end of the study. An observational study conducted in France in 214 patients who were treated with analogues for a median period of 2.4 years showed that kidney function decreased significantly in patients treated with ADV in monotherapy or combination therapy, whereas kidney function remained stable in those treated with LAM, TDF or ETV[32]. Although no differences were observed between the treatment groups in our study, likely due to its short duration and to the limited number of patients, it could be inferred that changing from the LAM+ADV combination to TDF may be beneficial for kidney function over the long term. Additionally, a new formulation of tenofovir, tenofovir alafenamide (TAF), has shown lower renal toxicity than TDF[33].

Another of the potential beneficial effects of treatment simplification may be greater treatment adherence. In our study, although adherence was greater in the TDF monotherapy group (95.3%) than in the combined treatment group (87.5%), the differences were not significant. It is possible that with a larger number of patients and a longer study period, these differences might have reached statistical significance.

Among the most relevant result of this study is the significant difference in average overall cost between the TDF-monotherapy group and the LAM+ADV group due to the reduction in drug costs. This finding may have a beneficial impact on the approach to this disease from the perspective of the health system.

On the other hand, the main limitations of the present study are the small number of patients included and the relatively short period of tracking the data.

Although in randomized studies, there is an established preference for analysis of a population using intention-to-treat (ITT) vs PPP due to a reduced risk of bias; given that our study is a non-inferiority study, the more restrictive analysis were chosen because ITT analysis tends to bias the results towards a lack of difference[34]. In this study, patient assignment was performed without blinding, a factor that may be related to selection bias[34], even though assignment without blinding is closer to routine clinical practice.

The results presented here in suggest that treatment simplification from the LAM+ADV combination to TDF monotherapy, in patients with HBeAg-negative CHB, LAM-treatment failure and complete virologic response under LAM+ADV treatment, is an efficient strategy. The current results are similar to the ones obtained with combined treatment in terms of effectiveness and safety. The treatment used was shown to decrease the cost of management of patients. It is likely that this simplification strategy would be equally efficient in patients with the same characteristics who are under LAM+TDF treatment.

The study’s authors would like to thank the medical department of Gilead Sciences SL for supplying the medications used in this study and its funding regardless of the study results; Miguel Ángel Casado, María Yébenes, Álvaro Muñoz, Fernando de Andrés, Eliazar Sabater and Araceli Casado of Pharmacoeconomics and Outcomes Research Iberia (PORIB) for management, coordination and monitoring of the study; Mireia Riera and Jordi Cantoni of BioClever for support and follow-up on the electronic case report forms; and the pharmacy services of the participating centres for their collaboration in obtaining dispensation records, with special thanks to University of Leon Hospital for its participation in the destruction of the study’s medications.

Research Group TENOSIMP-B: Principal researchers: Rodríguez M (Hospital Universitario de Central Asturias), Jorquera F (Complejo Asistencial Universitario de León), , Pascasio JM (Hospital Universitario Virgen del Rocío), Fraga E (Hospital Universitario Reina Sofía), Fuentes J (Hospital Universitario Miguel Servet), Prieto M (Hospital Universitari i Politècnic La Fe), Sánchez-Antolín G (Hospital Universitario Rio Hortega), Calleja JL (Hospital Universitario Puerta de Hierro de Majadahonda), Molina E (Hospital Clínico de Santiago de Compostela), García-Buey ML (Hospital Universitario de La Princesa), Blanco MÁ (Hospital General Universitario Gregorio Marañón), Salmerón J (Complejo Hospitalario de Granada), Bonet ML (Hospital Universitario Son Espases), Pons JA, (Hospital Universitario Virgen de la Arrixaca) and González JM (Hospital Clínico Universitario de Valladolid).

Collaborating researchers: González-Diéguez ML (Hospital Universitario Central de Asturias), Linares P, Olcoz JL (Complejo Asistencial Universitario de León), Cuaresma M, Ferrer MT, Giráldez A, Márquez JL, Ruiz R, Sousa JM (Hospital Universitario Virgen del Rocío), Aguilar P, Barrera P, Costan G, Mata M, Montero JL, Núñez F, Poyato A (Hospital Universitario Reina Sofía), Barrao E, Lázaro M (Hospital Universitario Miguel Servet), Aguilera V, Berenguer M, Casterá F, García M, Rubín A, Zaragoza A (Hospital Universitari i Politècnic La Fe), Almohalla C, García F (Hospital Universitario Rio Hortega), Pons F, Revilla J, Gómez M, Rodríguez LA (Hospital Universitario Puerta de Hierro de Majadahonda), Fernández J, Otero E, Martínez ST (University of Santiago Hospital Complex), Alonso MJ, Real Y (La Princesa University Hospital), Clemente G (Hospital General Universitario Gregorio Marañón), Gila A, Quintero D (Complejo Hospitalario de Granada), Aller R and Gómez S (Valladolid University Clinical Hospital).