Review Article

Long-term Safety of Oral Anti-viral Treatment for Chronic Hepatitis B

G. L.-H. Wong; W.-K. Seto; V. W.-S. Wong; M.-F. Yuen; H. L.-Y. Chan

Disclosures

Aliment Pharmacol Ther. 2018;47(6):730-737. 

In This Article

Abstract and Introduction

Abstract

Background Safety profile of nucleos(t)ide analogues is an important issue in view of its widespread use for decades in patients with chronic hepatitis B (CHB).

Aim To review and evaluate the latest evidence on the safety profiles of the six approved nucleoside analogues.

Methods Relevant articles related to nucleoside analogue safety were selected for review following extensive language- and date-unrestricted, electronic searches of the literature.

Results Nephrotoxicity has been well reported in patients receiving older generations of nucleotide analogues, namely adefovir dipivoxil and tenofovir disoproxil fumarate (TDF). Yet risks of renal failure and renal replacement therapy were similar in patients treated with nucleoside analogues versus nucleotide analogues in real-life setting. Bone toxicity is closely related to nucleoside analogue effect on renal proximal tubular and phosphaturia. Real-life data demonstrated increased risk of hip fracture in patients receiving adefovir but not TDF. The newly approved tenofovir alafenamide (TAF) has improved renal and bone safety profiles compared to TDF. Long-term use of nucleoside analogues eg entecavir does not increase the risk of other cancers. Muscular toxicity may be seen in telbivudine-treated patients so regular monitoring is advised. Peripheral neuropathy and lactic acidosis are rare adverse events. Latest international guidelines support the use of TDF, telbivudine and lamivudine during pregnancy; breastfeeding is not contraindicated during TDF therapy.

Conclusions Long-term safety profile of nucleoside analogues is now better defined with more data from large real-life cohorts and clinical trials with long-term follow-up. The new nucleotide analogue, TAF is now available with favourable renal and bone safety profiles.

Introduction

The development of oral anti-viral treatment with nucleos(t)ide analogues (NAs) has revolutionised the management of chronic hepatitis B (CHB) in the last two decades.[1] At present, six NAs have been approved as anti-viral therapy for CHB. These agents are classified according to their chemical structures: the three nucleoside analogues include lamivudine, telbivudine and entecavir, whereas the two nucleotide analogues include adefovir dipivoxil, tenofovir disoproxil fumarate (TDF),[2] and the newly approved tenofovir alafenamide (TAF).[3,4]

NAs are well-known to effectively suppress hepatitis B virus (HBV) replication and reduce the risk of disease progression and hepatic events;[5] yet they cannot clear the replication template of HBV ie covalently closed circular DNA. Hence, hepatitis B surface antigen seroclearance rarely occurs during NA treatment.[6] As a result, most patients require long term, if not infinite, NA treatment.[7–9] This raises a small yet legitimate concern about the long-term safety of NA therapy. Although NAs are generally safe and relatively free of major side effects,[10] nephrotoxicity and bone toxicity may occur in a small yet significant proportion of patients receiving older generations of nucleotide analogues, for example, adefovir and TDF.[11] Early animal studies raised the concern of cancer risk of entecavir.[12] Muscle toxicity and peripheral neuropathy are unique adverse events reported in patients treated with telbivudine.[13,14] Other rarer side effects including lactic acidosis which may happen in very sick cirrhotic patients.[15] With the rising preemptive use of TDF to reduce mother-to-child transmission of HBV,[16] safety in pregnancy and breastfeeding has become an essential topic for both hepatologists and obstetricians. Given the eminent number of patients receiving NAs worldwide, even a small risk of any of these toxicities can be translated into a major medical issue. It is, however, reassuring from the results of a recent study in a 7-year real-life cohort that no patients discontinued entecavir because of the occurrence of drug-related side effects.[17] In this review article, the latest evidence on the safety profile of these six approved NAs is discussed concisely.

Nephrotoxicity

Chronic HBV infection per se is known to increase the risk of chronic kidney disease (CKD) such as membranous glomerulonephritis.[18] On the other hand, all NAs are renally excreted.[2] Older generations of nucleotide analogues, that is, adefovir dipivoxil and TDF, are known to be associated with a small but non-negligible risk of nephrotoxicity. Mechanisms of nucleotide analogue-associated nephrotoxicity include inhibition of tubular cell transport accumulation of endogenous compounds leads to toxicity in short term; and mitochondrial injury in long term. Adefovir and tenofovir are substrates of organic anion transporter (OAT)-1 and OAT-3; they are excreted by multidrug resistance protein (MRP)-4. Adefovir and tenofovir would be actively transported by MRP-4 to the proximal tubule; when MRP-4 is saturated, adefovir and tenofovir may accumulate in the intracellular environment leading to tubular damage (Figure 1).[19]

Figure 1.

Mechanism of nephrotoxicity related to nucleotide analogues. Nucleotide analogues (NtA), namely adefovir and tenofovir are substrates of organic anion transporter (OAT)-1 and OAT-3; they are excreted by multidrug resistance protein (MRP)-4. NtA is actively transported by MRP-4 to the proximal tubule; when MRP-4 is saturated, NtA may accumulate in the intracellular environment leading to tubular damage. (Modified from Rodriguez-Novoa et al19). MRP4, multidrug resistance protein 4, NtA, nucleotide analogues, OAT, organic anion transporter, P-gp, P-glycoprotein

Increased serum creatinine level of ≥0.5 mg/dL was found in 3% to 4% among patients receiving adefovir for up to 5 years, compared to none of the cases in the placebo group.[20] This similar degree of serum creatinine raise was observed in 1% of patients receiving TDF for 5 years.[21] Whether this degree of biochemical change would be translated to hard clinical outcome had not been established until recently. A large-scaled population-based study of 53 500 Chinese CHB subjects showed that NA treatment in general did not increase the risk of hard renal events including renal failure and renal replacement therapy (RRT); these events happened in 1.4% and 0.7%, respectively, in NA-treated patients at a median follow-up of 4.9 years.[22] Among NA-treated patients, the risk of both renal events were also similar in patients exposed or not exposed to nucleotide analogues.[22] The favourable renal safety profile was further confirmed by another two real-life cohort studies involving Caucasian CHB patients in Europe and in the USA.[23,24]

The above observations imply that with adequate monitoring of renal function coupled with proper dose adjustment of dosages of nucleotide analogues, nucleotide analogues can be used without increasing clinically significant renal events in CHB patients. This includes prompt detection of renal impairment so that the dose can be appropriately adjusted or even discontinued if necessary. Another recent study showed that even untreated CHB patients have substantial risk of CKD progression; the 5-year cumulative incidence of CKD progression was 48% in TDF-treated and 43% in untreated patients.[25] Furthermore, the incidence rates of RRT was significantly higher in both NA-treated and untreated CHB patients than in the general population.[26] Hence, regular monitoring of renal function should be offered not only to NA-treated patients but also untreated CHB patients. This is particularly important in subjects with well-recognised risk factors of nephrotoxicity, which include hypertension, diabetes mellitus, pre-existing renal impairment or concomitant nephrotoxic agents; estimated glomerular filtration rate (eGFR) and serum phosphate levels should be monitored regularly.[27] In a recent European multicenter, prospective, observational trial, serum phosphate and uric acid and urine alpha-1 microglobulin and glucose could be used to identify discrete tubular pathology in patients under NA treatment.[28]

There is an interesting observation that telbivudine can improve eGFR[29] and prevent nephrotoxicity in patients received adefovir.[30] There was an 8.5% increase in mean eGFR lasting for up to 6 years observed in the GLOBE study in which telbivudine was given for just 2 years.[31] Nonetheless there has not been solid clinical data showing telbivudine really reduces CKD and need of RRT; the population-based study was not able to demonstrate the impact of telbivudine on these renal outcomes as the number of patients using telbivudine was small.[22]

The issue of nephrotoxicity by TDF is going to fade out in the near future as a new generation of nucleotide analogue, TAF, has been approved in most parts of the world. The latest EASL practice guidelines for CHB recommend TAF as the one of the first line NAs; TAF is preferred over TDF if a patient has or is at risk of renal or bone disease.[7] With the similarly potent viral suppression,[32] TAF was shown to have better renal and bone safety profile compared to TDF.[3,4] At week 96 of two Phase three studies of total 1298 patients, TAF-treated patients had smaller declines in eGFR (−2.4 mL/min) than TDF-treated patients (−6.7 mL/min; P = 0.008).[33] Fewer TAF recipients experienced a decline in eGFR >25% (10% vs 18%; P = 0.002) or had a confirmed eGFR of <50 mL/min (0% vs 2%; P = 0.004).[32] Patients on TDF at risk of development and/or with underlying renal (as well as bone) disease should be considered for a switch to ETV or TAF, depending on previous lamivudine exposure.[7]

Bone Toxicity

Bone toxicity is another major concern as CHB by itself also affects the skeletal system.[34] Vitamin D deficiency, as evidence of a serum level of 25-hydroxycholecalciferol <32 ng/mL, was found in 82% of Chinese CHB patients.[35] In a global clinical trial including 737 CHB patients, 35% had insufficient and 58% had deficient vitamin D levels.[36] Asian patients are particularly at risk of bone problems in view of low body-mass index, low background bone mineral density (BMD) and high prevalence of osteoporosis.[37] It is believed that NAs do not have direct bone effect; instead their effect on renal proximal tubular can be associated with phosphaturia and bone loss (Figure 2).[38] Reduced BMD and even hypophosphatemic osteomalacia has been reported in patients receiving adefovir or TDF treatments, though the latter has only been reported in TDF-treated patients co-infected by human immunodeficiency virus (HIV).[39] In a population-based study in Hong Kong, NA-treated patients had similar risk of incident hip fracture, vertebral fracture and all fractures compared to untreated CHB patients; yet nucleotide analogue exposure increased the risk of hip fracture (but not vertebral fracture and all fractures).[22] Further detailed analysis revealed all fractures only happened in patients received adefovir but not TDF; besides the absolute event rate was low (0.7 per 1000 person-years).[22]

Figure 2.

Association between phosphate metabolism, phosphaturia and bone loss. The effect of nucleosides analogues on renal proximal tubules may lead to phosphaturia, which subsequently increase the activity of parathyroid hormone (PTH) and hence bone resorption. Fibroblast growth factor (FGF)-23 regulates urine phosphate excretion capacity. Vitamin D deficiency, which is common in patients with chronic hepatitis B, also contributes to hypophosphataemia. FGF, fibroblast growth factor, PTH, parathyroid hormone

Similar to the issue of nephrotoxicity, the availability of TAF will lessen concerns on bone toxicity. Pooled analysis of the two Phase 3 studies mentioned above showed that patients receiving TAF had smaller declines in BMD, particularly at the hip (−0.28%) than those receiving TDF (−2.16%; P<0.001).[33] Significantly fewer TAF than TDF recipients experienced a >3% reduction in spine (25% vs 45%) or hip (14% vs 39%) BMD over 96 weeks.[40] Furthermore, improved bone (as well as renal) safety was observed in patients who switched from TDF to TAF from week 96 onwards.[41] TAF may be the more ideal NA in CHB patients with underlying risk factors for osteoporotic fractures.

Cancer Risk

There were always some concerns about the effect of antiviral treatment on the risks of non-liver cancers, as entecavir shows potential carcinogenic effect in some early animal studies. Entecavir, one of the most commonly prescribed nucleoside analogues worldwide, increased lung adenomas and carcinomas, hepatocellular carcinoma (HCC) and vascular tumours in mice at a mega-dose of 4 mg/kg; whereas doses at 1.4 mg/kg to 2.6 mg/kg in rats increased the development of HCC, brain microglial tumours and skin fibroma.[12] These super-therapeutic dosages of entecavir in these animal studies were at least a 100-fold higher than what is used in humans. Fortunately, the cancer risk of patients receiving long-term entecavir has been recently elucidated.

A population-based study of 44 494 subjects in Hong Kong showed that NA-treated patients had similar risks of various common malignancies, in particular gastrointestinal, lung, urinary and renal malignancies, when compared to untreated patients (Table 1).[42] There was also no signal of drug-specific effect on cancer risk, as patients exposed to entecavir did not have increased risks of any of the malignancies. This was different from the observations in animal studies. As lung tumour development was preceded by pneumocyte proliferation in the lung of mice and the same did not happen in other animals (rats, dogs and monkeys), the carcinogenic effect is likely species-specific. Nevertheless, there seemed to be a slight increased risk colorectal cancer and possibly cervical cancer in NA-treated women shown in the subgroup analysis.[42] The absolute numbers of colorectal and cervical cancers in NA-treated cohort were just five and two of 1299 patients, respectively, which could be a biologically insignificant increase. More data would be needed to establish the exact risks of colorectal and cervical cancers in NA-treated female patients. Physicians should consider the relevant risk factors (eg family and sexual history, co-morbid conditions) and decide the need of colorectal and cervical cancer screening for women receiving NA treatment.

Muscle Toxicity

NAs may influence mitochondrial DNA replication via the inhibition of human DNA polymerase-γ, which may result in different clinical features of mitochondrial toxicity, including myopathy, peripheral neuropathy and lactic acidosis.[43] Such symptoms of mitochondrial toxicity were prominent among nucleoside/nucleotide reverse transcriptase inhibitors against HIV infection,[44] and were also observed in an early clinical trial involving fialuridine in CHB.[45] Myopathy was also frequently observed in an international phase III trial of clevudine which resulted in its early termination.[10]

In the registration trial of telbivudine, 7.1% of participants experienced a rise in creatine kinase to more than seven times the upper limit of normal after 1 year of treatment.[46] In a 4-year open-label study of 655 CHB patients, 71% of participants experienced any degree of rise in serum creatine kinase, although such elevations were usually transient and reversible, without the need to stop telbivudine. Myalgia was noted in 6.1%, of which three patients with clinical myopathy required telbivudine cessation.[47]

While clinical significant myopathy during telbivudine treatment is still uncommon with no reported cases of rhabdomyolysis or myocarditis,[14] it is still advisable to monitor creatine kinase for such patients and to monitor for symptoms of muscular toxicity. Otherwise, muscular toxicity is not a prominent feature among currently used NAs, with elevations of serum creatine kinase similar to corresponding comparative arms.[43]

Peripheral Neuropathy

As a presentation of mitochondrial dysfunction, peripheral neuropathy is similarly well-associated with antiretroviral therapy for HIV,[44] but not commonly observed during HBV-related NA treatment. It can however occur during the combination of telbivudine with pegylated interferon. A randomised open-label study compared the efficacy and safety of telbivudine and pegylated interferon alpha-2a combination therapy, telbivudine monotherapy and pegylated interferon alpha-2a monotherapy in hepatitis B e antigen (HBeAg)-positive CHB. This study was terminated prematurely when 14% of the combination group experienced peripheral neuropathy after a median exposure duration of 3.3 months. Clinical presentation ranged from peripheral sensory neuropathy to demyelinating polyneuropathy, with patients demonstrating an improvement of symptoms after cessation of treatment.[48] Peripheral neuropathy was otherwise not commonly experienced during telbivudine monotherapy,[46,48] and its occurrence was only sparingly reported among other NAs (lamivudine and entecavir).[49,50] Although the synergistic mechanism of neuropathy during concomitant telbivudine and pegylated interferon therapy remains unclear, and the combined use of the two drugs is not recommended.

Lactic Acidosis

The possible occurrence potentially fatal lactic acidosis is a labelled boxed warning of all NAs, mainly based on the well-established association between lactic acidosis and antiretroviral therapy for HIV.[51] There had been sporadic reports on lactic acidosis occurring during HBV treatment. Based on published cases related to TDF[52,53] and entecavir,[15,54] renal impairment seemed to be an important contributing factor, probably due to mitochondrial toxicity if renal dosage adjustments were not promptly enforced. The reported cases on entecavir all occurred in decompensated liver disease with high model of end-stage liver disease scores, including one patient who was prescribed entecavir 1 mg daily for lamivudine resistance.[15] Other contributing factors include the presence of severe sepsis[54] and immunosuppressive therapy.[55] Lactic acidosis had also been reported in patients receiving telbivudine[56] and adefovir[55] therapy.

From years of real-world experience, lactic acidosis during HBV treatment is likely a rare event. Nonetheless, a high degree of clinical awareness of its possibility is required, especially in patients with multiple co-morbidities, poor renal reserve and hepatic decompensation; fulminant liver disease itself is an established risk factor for lactic acidosis.[57] Prudent and timely adjustment of NA dosage with reference to renal function is essential.

Safety in Pregnancy and Breastfeeding

HBV is endemic in many Asian and African countries with high birth rates,[58] and hence any potential association of NAs with teratogenicity warrants special attention. The indications of NAs and especially TDF in pregnancy has also been expanded to the prophylaxis of maternal-to-foetal transmission in high-risk patients (HBeAg-positive and HBV DNA >200 000 IU/mL), as demonstrated by a randomised controlled trial comparing TDF plus standard-of-care versus standard-of-care only.[16] The safety of different NAs with regard to pregnancy and breastfeeding are depicted in Table 2.

TDF and telbivudine were previously categorised as Food and Drug Administration (FDA) pregnancy category B while entecavir, lamivudine and adefovir were category C, although the FDA pregnancy category is no longer in use as it oversimplified the risk-benefit profile of mother and fetus. Extensive safety data can be found in the Antiretroviral Pregnancy Registry for anti-virals, which provides safety information for over 100 000 live births. All six registered NAs relevant to HBV are included in the antiretroviral pregnancy registry, although at the time of writing, only TDF and lamivudine had adequate individual data for analysis.[59] There was no increase in risk of major birth defects among those with TDF or lamivudine exposure when compared to population-based controls.[60,61] A systematic review also found TDF, telbivudine and lamivudine to be safe in pregnancy with no increased adverse maternal or foetal outcomes.[62] The latest guidelines from the American Association for the Study of Liver Diseases support the use of TDF, telbivudine and lamivudine during pregnancy,[9] while the European Association for the Study of the Liver guidelines recommend only TDF due to its superior virological efficacy.[7]

Concerning breastfeeding, TDF is minimally excreted in breast milk, and absorption through the infant's gastrointestinal tract is negligible.[61] Studies involving breastfeeding HIV-infected mothers showed TDF not affecting infant growth up to 2 years, although longer term studies are lacking.[63] International recommendations generally state breastfeeding is not contraindicated during TDF therapy,[7,9] but such recommendations are not universally adopted.[64]

At the time of writing, human safety data of TAF during pregnancy is still lacking. Given its reduced systemic toxicity and superior safety profile when compared to TDF,[3,4] TAF should presumably be a suitable alternative for pregnant patients. Once such data emerge, TAF may be the ideal NA for pregnant women and breastfeeding mothers.

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