Safety of long-term nucleos(t)ide treatment in chronic hepatitis B

Abstract

Currently, five nucleos(t)ide analogs (NAs) are approved for the treatment of chronic hepatitis B (CHB) infection. They are lamivudine, adefovir dipivoxil, telbivudine, entecavir (ETV) and tenofovir disoproxil fumarate (TDF). Two of them, ETV and TDF, are recommended as first-line treatment options. Their main advantages include excellent tolerability, antiviral potency and a high genetic barrier to resistance within medium duration treatment periods (2 – 6 years). In most patients, NAs need to be administered on a long-term basis. Several studies suggest that NAs long-term administration have been associated with low rates of serious adverse events (AEs), including lactic acidosis, renal function impairment, osteopenia and osteoporosis. Discontinuations due to AEs tended to be low in published randomized clinical trial and in the experience in clinical practice. NAs long-term use appears to be safe and effective; and in patients with advanced liver disease, despite preliminary concerning reports, their short-term use also appears to be safe and effective. Although major AEs are infrequent, they can be initially clinically silent yet lead to serious medical problems, therefore, a proactive surveillance and their prompt management is recommended.

Keywords::

• chronic hepatitis B
• entecavir
• long-term
• nucleos(t)ide analogs
• safety
• tenofovir disoproxil fumarate
• therapy

Currently, five nucleos(t)ide analogs (NAs) are approved for the treatment of chronic hepatitis B (CHB) infection. They are lamivudine, adefovir dipivoxil, telbivudine, entecavir (ETV) and tenofovir disoproxil fumarate (TDF). Two of them, ETV and TDF, are recommended as first-line treatment options [1,2]. Their main advantages include excellent tolerability, antiviral potency and a high genetic barrier to resistance within medium duration treatment periods (2 – 6 years). There is a class warning for NAs regarding their potential to produce severe hepatomegaly with steatosis and lactic acidosis (LA), but these adverse events (AEs) are infrequently seen and have only been described in patients with advance liver disease. The main disadvantage of NAs therapy includes the need for extended or indefinite duration of therapy for the majority of patients, thus increasing the risk of adverse effects, lack of adherence and the emergence of escape mutants. Randomized controlled trials (RCT) demonstrated the efficacy and safety of short-term periods of ETV and TDF [3-7]. Data at a 5-year therapy period are still unknown; therefore, long-term safety studies are strongly recommended.

1. Entecavir

In the current issue of the Expert Opinion journal, Manns et al., reported safety and adherence results in a large group of CHB patients from the ETV-901 rollover study who were treated with ETV for at least a 5-year period [8]. Most of the reported AEs were mild to moderate, 19% were grade 3 – 4 events, with only 4% of them possibly related to ETV. These grade 3 – 4 AEs were myalgias (5%), neuropathy (hypoparesthesia and hyperparesthesia, polyneuropathy) (4%), increased lipase (2%), increased serum creatinine (SCr) (< 1%), increased serum lactate or decreased serum bicarbonate (< 1%), hypophosphatemia (< 1%), muscular weakness (< 1%), pancreatitis (< 1%) and creatinine phosphokinase elevation (< 1%). They did not report cases of LA, a serious complication of ETV treatment previously reported in patients with advanced liver disease [9]. They reported an overall discontinuation rate due to AEs was extremely low (< 1%).

Being an industry supported trial; it has the strength of an adequate follow-up and extensive data collection, which give us the opportunity to properly address long-term safety of ETV therapy. The most impressive findings of this study are the extremely low AE and discontinuation rates observed in a large population. ALT flares due to either escape mutants or immune clearance were identified in only 3% of the studied population. Disease progression was also seen in only a 3% of the patients, being the overall reported mortality rate of 2.5% (27/1051 patients), with a liver-related mortality of only 1.14% (12/1051). As per reported NAs preclinical data, a usual concern with the long-term administration is their potential carcinogenicity. After a 5-year period of ETV administration, only three cases of the de novo non-liver neoplasms were identified: two gastric and one pancreatic adenocarcinoma.

But industry sponsored trials also have some drawbacks. Patients from this study were treated with 1 mg qd dosing of ETV, not with the 0.5 mg qd recommended dose for naïve patients. As a controlled trial, patients have been carefully selected in order to be able to be included. Excluded patients usually have advanced liver diseases or comorbidities. The later commonly require administration of concomitant medications. The addition of different medications may have an important impact on study drug pharmacokinetics, efficacy and safety. The strict inclusion criteria of these studies, did not allow testing unexpected AEs due to drug to drug interactions, nor potential toxicity in patients with advance liver disease. For this reason, studies reporting results in ‘real life' are necessary to add information to controlled clinical trials reports.

ETV should be administered on an empty stomach (at least 2 h after a meal and 2 h before the next meal) and is generally well tolerated. The most commonly reported treatment-related AEs in Phase III clinical trials were headache, fatigue, dizziness and nausea at comparable rates with lamivudine [3,4]. Lampertico et al. reported an important field practice Italian experience with ETV: 418 NAs-naïve patients were treated with ETV 0.5 mg/day for 30 months. No serious AEs were reported. Mild increases in SCr occurred in 3% and hypophosphatemia in 1% [10]. In our small experience in routine clinical practice in a low endemicity country, no serious AEs were reported in naïve patients treated with ETV 0.5 mg/day for 110 weeks [11].

2. Tenofovir

The other first-line NA option for the treatment of CHB is TDF. In Phase III trials, the overall incidence of AEs was comparable in patients receiving tenofovir versus adefovir (ADV) [12]. The most common AEs in both studies included headache, nasopharyngitis, back pain, nausea and fatigue. Marcellin et al. reported the results over 96 weeks in two Phase III TDF studies: treatment-related AEs occurred in 6% of patients and grade 3/4 AEs in 5% of patients. Serious AEs occurred in 4% of patients and AEs resulting in discontinuation occurred in less than 1% of patients. Grade 3/4 laboratory abnormalities occurring in more than 1% of patients included glucosuria (3%), elevated serum amylase (2%) and elevated prothrombin time (2%) [13]. Continued follow-up of the same cohorts up to 240 weeks of treatment, found that less than 2% of patients discontinued TDF for an AE; 1.8% experienced a confirmed ≥ 0.5 mg/dl increase in SCr or confirmed decrease in creatinine clearance (CrCL) < 50 ml/min [14]. The use of tenofovir has been associated with greater loss of bone mineral density during the early months of therapy in HIV monoinfected patients, although no hepatitis B virus (HBV) monoinfected patient experienced bone fractures in these studies [13,14]. Recent data suggest that in HBV monoinfected patients, bone mineral loss might be related to vitamin D deficiency and not to TDF treatment [15]. Nevertheless, bone mineral density should be periodically evaluated in HBV patients taking TDF.

TDF has been associated with a small decline in renal function in HIV positive patients; however, large-scale clinical studies showed there is no evidence of impaired renal function with tenofovir in monoinfected CHB patients [7]. It has been associated with a dose-dependent but typically reversible proximal renal tubular toxicity and renal phosphate wasting. Patients who have preexisting renal impairment or are receiving other nephrotoxic agents are at an increased risk of nephrotoxicity. It is recommended that renal function be assessed before tenofovir therapy is initiated. In rare circumstances, LA, hepatomegaly and steatosis have also been reported in HIV coinfected and in HBV monoinfected patients treated with tenofovir.

As in the case of ETV, experience in the real world with TDF is also important. Lampertico et al. reported the European experience with TDF in the field practice: 302 NAs-naïve patients were treated with TDF for 21 months. When evaluating AEs, they found similar findings than those reported in pivotal studies. SCr increase greater than 0.5 mg/dl versus baseline occurred in 0.8% of the patients. Glomerular filtration rate (GFR) as estimated by MDRD (modification of diet in renal disease) formula was < 50 ml/min in 3% of the patients at baseline and declined below this level in five (2%) additional patients, three of whom with baseline GFR between 50 and 60. None of the patients had < 2.0 mg/dl blood phosphorus levels at both baseline and last visit assessment, and 1% showed proteinuria. Overall, TDF dosing was reduced or discontinued in 5% of the patients because of renal toxicity or other AEs [16].

3. Combination treatment

Clinicians should exercise caution in combining tenofovir or ETV with each other or other agents and remain alert for potential additive AEs. Till date, none of the combination therapies has been proven to be superior to monotherapy, and have not been recommended as first-line therapies [1,2]. However, there are some new data about safety and efficacy of combination treatment. Petersen et al. found no safety issues after 21 months of ETV plus TDF combination treatment in 57 CHB partial responders or multidrug-resistant patients [17]. Lok et al. also found no differences in AEs after 96 weeks of treatment, between combination and ETV monotherapy in 379 NAs-naïve CHB patients [18].

4. Decompensated liver disease

There are some safety concerns when using the newer NAs in CHB cirrhotic patients. LA with ETV was first reported in 2009. Five of 16 HBV cirrhotic patients treated with EVT developed LA. One of the patients died, and the other four recovered after treatment discontinuation. A significant correlation between the MELD (Model for End-Stage Liver Disease) score and the development of LA was observed (p = 0.002). The single components of the MELD score – bilirubin, INR (International normalized ratio) and creatinine – correlated as well with the development of LA (p = 0.003, 0.003 and 0.008, respectively). LA developed in patients with more severe liver dysfunction (MELD score > 20) [9]. These data suggested that ETV should be applied cautiously in patients with severe decompensated liver disease.

Fortunately, new data show that ETV and TDF can be safely used in CHB cirrhotic patients. One hundred and two patients with hepatic decompensation (Child–Turcotte–Pugh score ≥ 7) were treated with ETV for 108 weeks, and compared with 89 treated with ADV. The frequency of AEs, serious adverse events (SAEs) and grade 3 or 4 AEs was comparable between treatment groups. The rates of SCr increase > 0.5 mg/dl were also comparable across the two groups. Ten (11%) ETV-treated subjects and one (1%) ADV-treated subject had dose reduction for a change in renal function at one or more time points while on treatment. Seven (7%) ETV-treated subjects and five (6%) ADV-treated subjects discontinued study therapy due to AEs. Grade 2 LA was reported in one ETV-treated patient (MELD score 21); it required no treatment and resolved on continued ETV treatment [19]. For SAEs and grade 3 or 4 AEs, the majority of events were expected in this study population; the most frequently reported events were hepatic failure or a manifestation or secondary complication of decompensated cirrhosis. At the time of this analysis, 52 deaths were reported in treated subjects (ETV 23%; ADV 33%). The majority of deaths were due to a hepatic-related event [19].

A Phase II double-blind study randomized 112 patients with CHB and decompensated liver disease to receive either TDF (n = 45), emtricitabine (FTC)/TDF (n = 45) or ETV (n = 22). Eight patients (four TDF, three FTC/TDF and one ETV) had either a confirmed change from baseline in SCr of _0.5 mg/dl or phosphorus < 2.0 mg/dl during the first 48 weeks of the study. There were no reports of LA, although lactate levels were not mandated in the protocol. Seven discontinued the study drug because of an AE (two TDF, three FTC/TDF and one ETV). There were a total of six deaths (two TDF, two FTC/TDF and two ETV), and six received liver transplants. Five deaths were due to disease progression and occurred in patients with end-stage cirrhosis who were eligible to receive liver transplants. One death was attributed to septic shock. None of these AEs were considered related to study drug [20].

These data demonstrate the safety of these treatments through 48 – 108 weeks in patients with decompensated CHB. Long-term safety data are needed to confirm these results.

5. Expert opinion

Only two of the five NAs approved for the treatment of CHB infection are recommended as first-line treatment option: ETV and TDF. Their long-term use appears to be safe and effective, as demonstrated by Manns et al. in the case of ETV. In patients with advanced liver disease, despite preliminary concerning reports, their short-term use also appears to be safe and effective. Potentially severe AEs such as LA, worsening renal function and osteopenia (only in HIV monoinfected patients) have been reported with ETV and TDF. Although safety results from this study are encouraging, long-term follow-up studies in clinical practices are still needed. Although major AEs are infrequent, they can be initially clinically silent yet lead to serious medical problems, therefore, a proactive surveillance and their prompt management is recommended.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.