Entecavir in decompensated HBV cirrhosis: The future is looking brighter

Practice guidelines recommend treatment of selected patients with chronic hepatitis B virus (HBV) infection who are at risk of developing progressive liver disease based upon their serum ALT and HBV DNA levels and/or liver histology [1], [2]. The seven approved medications for chronic HBV consistently lead to histological improvements in patients that suppress HBV replication during short-term treatment [3]. In addition, the rate of developing clinical outcomes and decompensation can be significantly reduced by using prolonged lamivudine therapy in patients with advanced but compensated fibrosis compared to no treatment [4]. However, the clinical and histological benefit with the oral nucleos(t)ide analogues is substantially reduced when drug-resistant variants of HBV emerge [3], [4]. As a result, the oral agents that most effectively suppress HBV replication with the lowest rate of drug resistance during prolonged use (entecavir, tenofovir) have emerged as preferred first line agents over the other available drugs (lamivudine, adefovir, telbivudine) [1], [2].

Practice guidelines also recommend prescribing an oral nucleos(t)ide analogue (but not the interferons) for patients with decompensated HBV cirrhosis independent of the patients serum ALT, HBV DNA level, and eAg status [1], [2]. These latter recommendations are largely based upon open-label studies of lamivudine and adefovir in decompensated HBV patients wherein antiviral therapy was associated with improved outcomes including a delay or prevention in the need for liver transplantation (Table 1) [5], [6], [7], [8]. For example, a prospective study of 154 decompensated HBV patients treated with lamivudine demonstrated improved laboratory and clinical parameters with treatment compared to baseline values. A biphasic survival pattern was also noted with most deaths occurring within the first 6months of treatment; patients with higher pretreatment bilirubin, creatinine, and HBV DNA levels were at greatest risk for early death while early suppression of HBV replication was not associated with more favorable outcomes [6]. Adefovir treatment in 226 patients with lamivudine refractory decompensated HBV also led to significant improvements in their CTP and MELD scores at 1-year compared to baseline [7], [8]. However, 14% still died within the first year and at least 33% required liver transplantation for long-term survival. Although antiviral drug resistance is substantially less common with adefovir monotherapy compared to lamivudine, concerns remain regarding the slow rate of suppressing HBV replication with adefovir as well as the potential for dose-dependent nephrotoxicity in decompensated HBV patients [9], [10].

Table 1. Oral nucleos(t)ide analogues in decompensated HBV cirrhosis.

	Study (reference)	Fontana [6]	Schiff [8]	Liaw [21]		Schiff [23]			Shima[16]
	Patients treated	154	226	191		112			70
				(100)	(91)	(45)	(45)	(22)
	Drug(s) used	LAM	ADV	ETV (1mg) vs. ADV		TDF	TVD	ETVc	ETV (0.5mg)
	% Lamivudine resistant at entry	0%	100%	34%		17%			0%
	Entry CTP Entry MELD	Median=9 NR	40%A 38%B 22%C NR	8.8+0.2 17.1+0 .5	8.3+0.2 15.3+0.5	7 11.0	7 13.0	7 10.5	8.4+1.8 11.5+3.9
	Entry HBV DNA (log10)	Median=8.0	7.0+1.6	7.5+0.2	8.2+0.2	5.7	6.3	5.9	7.2+1.2
	1-year efficacy and safety data
	% HBV DNA undetectable	>80%b	50%	57%	20 %	71%	88%	73%	89%
	% ↓CTP⩾2	NR	NR	35%	27%		NR		49%
	Mean MELD↓	NR	−2.0	−2.6	−1.7	−2.0	−2.0	−2.0	−2.2
	% 1-year patient survival	84%	86%	84%	83%	86%	93%	91%	87%
	Safety issues	Disease flare with LAM-R	Nephrotoxicityd	Nephrotoxi c ityd		Nephrotoxicityd			7% worsening liver disease
		HBV	6%	17%	24%	9%	7%	5%

ADV, adefovir; CTP, Child–Turcotte–Pugh score; ETV, entecavir; LAM, lamivudine; MELD, model for end stage liver disease; NR, not reported; TDF, tenofovir; TVD, tenofovir+emtricitabine.

a Efficacy data reported on 55 patients who survived 1-year. b bDNA assay with a lower limit of detection of 0.7×105genomes/ml. c ETV dose varied from 0.5 to 1.0mg per day depending upon pretreatment LAM-R. d Nephrotoxicity defined as ⇑ creatinine of >0.5mg/dl from baseline.

Entecavir suppresses HBV replication more rapidly and effectively than lamivudine in patients with compensated chronic HBV [11]. In addition, entecavir was a more potent and rapid suppressor of HBV replication compared to adefovir in compensated patients [12]. Furthermore, entecavir does not have any reported nephrotoxicity and the resistance profile at 5years in treatment naïve HBV patients has been excellent (i.e., ∼1%) [13]. Tenofovir is also a significantly more potent suppressor of HBV replication than adefovir and no drug-resistant variants have been reported with 3years of continuous treatment in compensated patients [14], [15]. Expanded use of these two newer drugs has been sought in difficult to treat patient populations, including hemodialysis patients and subjects with decompensated HBV cirrhosis. However, safety and efficacy data are very sparse to non-existent in these special patient populations and this is due to uncertainties in drug dosing and difficulties in conducting adequately powered prospective studies.

In this issue of the Journal, the effectiveness of entecavir (at a dose of 0.5mg per day) in a cohort of 70 consecutive Korean patients with decompensated HBV is reported [16]. The virological responses in the 55 decompensated HBV patients at 1year are also compared to 144 compensated patients treated with entecavir from the same center. Of note, none of these patients had previously been treated with an oral nucleos(t)ide analogue nor harbored drug-resistant variants of HBV. As expected, the mean MELD (11.5 vs. 7) and CTP scores (8.1 vs. 5.3) were significantly higher in the decompensated patients but the mean pretreatment HBV DNA levels (7.2 vs. 7.5log10) and proportion of HBeAg+patients (49.1% vs. 62.5%) was similar. Overall, the 1-year transplant-free survival rate was 87.1% in the decompensated patients. As previously reported with lamivudine, the majority of adverse outcomes occurred within the first 6months of treatment and these nine patients had more severe liver failure at entry compared to the others. However, the baseline HBV DNA levels and presence of HBeAg+ were similar in the non-survivors compared to the survivors. Similarly, the early response to antiviral therapy among those who died or underwent transplant was similar to the survivors. Nearly 50% of the entecavir treated patients had a clinically significant decrease in their CTP score of >2 points at 1-year. In addition, the rate of HBeAg loss in both the decompensated and compensated patients was remarkably high at 1year (48% and 41%, respectively). Finally, the kinetics of HBV DNA suppression were comparable in the decompensated and compensated patients.

Shim et al. are to be congratulated for providing important prospectively collected data on the utility of entecavir in a large group of patients with decompensated HBV cirrhosis. They convincingly show that entecavir at a dose of 0.5mg per day is effective in treating naïve decompensated HBV patients with nearly 90% achieving undetectable HBV DNA at month 12. In addition, suppression of HBV DNA was maintained during follow-up with no instances of viral rebound or entecavir-resistant HBV identified. However, the authors also note that not all decompensated patients improved with entecavir therapy and five patients developed HCC during follow-up. Furthermore, twelve subjects (22%) showed no change in their CTP score at 1-year; four subjects actually “experienced aggravation” of their liver disease with worsening CTP scores. Whether this “aggravation” was related to entecavir treatment or progression of their underlying liver disease is unclear.

All of the approved oral nucleos(t)ide analogues for HBV carry a BLACK-BOX warning in their labeling regarding potential mitochondrial toxicity that can manifest itself as lactic acidosis, myopathy, neuropathy, or even hepatotoxicity. Entecavir had the lowest risk of causing mitochondrial DNA depletion in an in vitro test system compared to the other oral antiviral agents [17], [18]. Nonetheless, a recent report from Germany showed that 5 of 16 hospitalized patients with decompensated HBV developed symptomatic lactic acidosis after receiving entecavir for 4–240days [19]. Although lactic acidosis resolved in four patients following entecavir discontinuation or dose reduction, one patient with fulminant HBV died. Whether these adverse events were due to direct mitochondrial toxicity or other causes in these patients who all had MELD scores>20 remains unclear. It is important to remember that mitochondrial toxicity can present as late as 1year after initiating oral nucleos(t)ide analogue therapy and that concomitant drugs, medical co-morbidities, and other host factors may alter drug pharmacokinetics in various tissues [18], [20]. Unfortunately, Shim et al. do not report upon entecavir dose adjustments during treatment nor serial renal, metabolic, or safety labs in their patients.

Preliminary reports from two other ongoing, multi-center studies also suggest that entecavir may be of benefit in selected patients with decompensated HBV (Table 1). In the first study, 195 patients with decompensated HBV were randomized to entecavir (1.0mg per day) or adefovir (10mg per day) [21]. In contrast to the Shim study, 34% of patients had lamivudine-resistant HBV. Interim results at week 48 demonstrate a significantly greater reduction in HBV DNA and serum ALT levels in the entecavir treated patients compared to the adefovir treated patients. In addition, 1-year mortality rates were similar in both treatment arms. These preliminary data confirm the superior antiviral efficacy of entecavir compared to adefovir in decompensated HBV patients. However, continued follow-up is needed since the rate of entecavir-resistant HBV can substantially increase over time in patients with lamivudine-resistant HBV and lead to potentially severe disease flares [13], [22].

A second ongoing, multi-center study set out to compare the safety and efficacy of tenofovir vs. tenofovir+emtricitabine vs. entecavir in 112 decompensated HBV patients [23]. In this study, the median pretreatment MELD and CTP scores of 10.5 and 7, respectively, were substantially lower than those reported in the other studies (Table 1). The frequency of undetectable HBV DNA at weeks 12, 24, and 48 was comparable in the three treatment groups. However, amongst the subjects with lamivudine-resistant HBV, 71% of the 18 patients in the tenofovir containing arms had undetectable HBV DNA at week 48 compared to 33% in the three entecavir treated patients. Improvements in CTP and MELD scores at week 48 were comparable between the three treatment arms but the rate of HBeAg seroconversion was 0% in the entecavir arm compared to 21% and 13% in the tenofovir and tenofovir/emtricitabine arms, respectively. Rates of nephrotoxicity, treatment “tolerability” and patient mortality were similar in the three treatment arms through week 48. Clearly, continued follow-up of these patients is needed to determine which of the newer antiviral agents can offer the best risk–benefit ratio in this challenging patient population. Although a tenofovir based regimen may be preferred in decompensated patients with lamivudine-resistant HBV, there are growing concerns regarding the long-term safety of tenofovir in some HBV patients including nephrotoxicity and metabolic bone disease [24], [25]. Furthermore, since patients with decompensated cirrhosis frequently are malnourished and may have low vitamin D levels, prospective studies of bone density and metabolic parameters during prolonged tenofovir treatment are warranted as well as potential calcium and vitamin D supplementation [26].

In summary, the study of Shim et al. and others (Table 1) are bright stars in the horizon for the management of decompensated HBV cirrhosis. The aggregate efficacy and safety data now support the use of entecavir as a first line treatment option for nucleos(t)ide naïve patients with decompensated HBV cirrhosis. However, continued follow-up from these ongoing studies including long-term efficacy, safety, and resistance data are needed. Further studies are also needed to identify the optimal agent(s) for patients with decompensated lamivudine-resistant HBV cirrhosis. In the meanwhile, decompensated HBV patients receiving oral nucleos(t)ide analogues must undergo frequent clinical and laboratory assessment to insure medication compliance and surveillance for virological and clinical response as well as drug side effects, drug resistance, and HCC. Finally, the data of Shim et al. confirm the importance of early liver transplant evaluation in decompensated HBV patients with high MELD scores at presentation due to our inability to reliably identify those patients with a poor short-term prognosis.