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Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study - & Commentary....."long-term suppression of HBV can lead to regression of fibrosis and cirrhosis....."
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Download the PDF here
Download the PDF here
Download the PDF here
The Lancet, Early Online Publication, 10 December 2012
"In our study, the low rate of clinical events of disease progression, including hepatocellular carcinoma, was consistent with the benefits of antiviral suppression."
"Progression to cirrhosis, development of hepatocellular carcinoma, and liver-related mortality are associated with persistent replication of hepatitis B virus (HBV) and high plasma HBV DNA concentrations in patients chronically infected with the virus........Viral suppression by means of inhibitors of HBV polymerase/reverse transcriptase has achieved clinical benefits with a reduction in hepatic decompensation and lower rates of hepatocellular carcinoma in cirrhotic patients......little is known about progressive changes in liver histology with long-term antiviral therapy. Advanced liver fibrosis was previously thought to be irreversible, but evidence is accruing that cirrhosis can be reversed if the underlying cause of liver injury is addressed.6-19 The evidence of an association between suppression of HBV replication and regression of liver fibrosis has, however, come from small studies that were not controlled adequately for antiviral use or treatment duration......During the 5 years, the proportion of participants with necroinflammation decreased (figure 2A); the proportion with mild or no necroinflammation (Knodell range 0-3) increased from 8% (27/348) at baseline to 49% (171/348) at year 1 and 80% (278/348) at year 5 (p<0·0001). The distribution of Ishak scores (figure 2B) also indicated improved liver histology during the study as shown by a progressive increase in the proportion with mild disease and decreases in the proportion with severe disease (p<0·0001). At baseline, 39% (136/348) of participants had no or mild fibrosis; this proportion was 43% (149/344) at year 1 and 63% (219/348) at year 5 (figure 2B). Conversely, at baseline 38% (133/348) had Ishak scores of 4 or more (pronounced bridging fibrosis to cirrhosis), but this proportion declined to 28% (97/344) at year 1 and 12% (42/348) at year 5. Overall, regression of fibrosis was documented in 176/348 (51%) of patients and histological improvement in 304/348 (87%) of patients at year 5. Furthermore, the histological improvement rate was 91% or more for patients with Ishak scores greater than 2 at baseline, and patients with the highest liver injury scores showed the greatest degree of improvement (p<0·0001, figure 2C). Viral suppression (HBV DNA <400 copies per mL) was documented in 330 (99%) of the 334 patients maintained on long-term therapy for whom the measurement was available......Of the 96 patients with cirrhosis at baseline, all but one with regression had a reduction of at least 2 units in the Ishak score at year 5, and more than half (58%, 56 patients) had a decrease of 3 units or more"
"Seven deaths were reported (table 3), all from malignant disease (three hepatocellular carcinoma; one cholangiocellular carcinoma of liver; one lung cancer metastases; one cervical cancer metastases; one nasopharyngeal carcinoma).
.......Signs of decompensated liver disease (ascites, hepatic encephalopathy, or bleeding oesophageal varices) developed in two patients, both with hepatocellular carcinoma. Overall, in the 12 patients who developed hepatocellular carcinoma, 11 had been assigned tenofovir DF in the randomised trial, and seven had underlying cirrhosis. Four patients developed hepatocellular carcinoma early during the first year of treatment and eight after year 1 (appendix)." from Jules: in this study, 7 patients who developed HCC had cirrhosis at baseline & 5 did not have cirrhosis, they had stages 2, 3 or 4. In HCV if a patient already has cirrhosis when they begin HCV therapy even if they achieve an SVR they still must take an MRI every 6 months continuously because there is a small risk still for developing HCC so undue delaying of therapy has risks, over time the risk decreases.
COMMENTARY - Scar undone: long-term therapy of hepatitis B......"long-term therapy also leads to substantial histological improvements, including decreases in fibrosis and apparent regression of cirrhosis. Such effects of long-term antiviral therapy of hepatitis B (and C and D) have been reported previously, but no other report has been as large or convincing....Importantly, in patients without hepatocellular carcinoma, none developed hepatic compensation or died of end-stage liver disease. "
Michele M Tana, *Jay H Hoofnagle
Liver Diseases Branch, Division of Intramural Research,
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD 20892, USA
In recent years, substantial progress has been made in the prevention and control of hepatitis B, a major cause of chronic liver disease, cirrhosis, and liver cancer worldwide.1 A safe and effective hepatitis B virus vaccine was developed in the early 1980s, and its subsequent widespread use resulted in notable decreases in rates of hepatitis B, at least in countries that adopted universal hepatitis B vaccination.2 Therapies for hepatitis B were developed more recently and are only now showing an effect on the burden of this disease. Interferon alfa was approved for this indication in the USA in 1991, but had low efficacy and was not well tolerated.3 Oral antiviral agents with activity against hepatitis B were developed in the 1990s. The first three agents approved in the USA (lamivudine in 1998, adefovir in 2002, and telbivudine in 2006) were very well tolerated, and yielded good viral suppression and clinical responses in 1-2 year studies.4, 5 With more prolonged therapy, however, the efficacy of these agents was limited by antiviral resistance.6 These shortcomings seem to be overcome by two newer, more potent antiviral agents-entecavir (approved in 2005) and tenofovir disoproxil fumarate (approved in 2008)-both of which have a high barrier to antiviral resistance. These antiviral agents suppress serum hepatitis B virus DNA to near or below detectable levels, and result in high rates of improvement in both biochemical and histological evidence of disease.7 Studies show that their long-term use (3-5 years) maintains viral suppression and biochemical improvements.8, 9
In this issue of The Lancet, Patrick Marcellin and colleagues10 report that long-term therapy also leads to substantial histological improvements, including decreases in fibrosis and apparent regression of cirrhosis. Such effects of long-term antiviral therapy of hepatitis B (and C and D) have been reported previously, but no other report has been as large or convincing.8, 11, 12 In 489 patients with chronic hepatitis B treated with tenofovir for 4-5 years, 348 underwent repeat liver biopsy. Liver histology showed improvement in inflammation and necrosis in almost all patients and a decrease in fibrosis in 51% (176 of 348 patients). An impressive finding was an apparent regression of cirrhosis in 74% of those with cirrhosis on initial biopsy (71 of 96 patients). Patients without resolution of cirrhosis were more likely to be overweight or obese.
Regression of fibrosis, as shown by paired liver biopsies before and after 4 years of therapy, is a strong and convincing endpoint in support of treatment. Nevertheless, histological improvement is a surrogate endpoint for the clinical consequences of cirrhosis: clinical decompensation, death from end-stage liver disease, and hepatocellular carcinoma, the dreaded long-term complication of chronic hepatitis B. In the study from Marcellin and colleagues, these hard endpoints were apparently improved but less well documented than the histological changes. The rate of hepatocellular carcinoma was about 2% (12 cases). Importantly, in patients without hepatocellular carcinoma, none developed hepatic compensation or died of end-stage liver disease. The study did not include an untreated control group for obvious reasons, but historical controls would have predicted higher rates for both outcomes.13 This study and many others now support the recommendation that patients with chronic hepatitis B receive long-term treatment with a potent oral antiviral agent with a high barrier to resistance.
If long-term treatment is recommended, how long should it be continued for, and what criteria should be used to decide when to stop therapy? In patients with HBeAg-positive hepatitis B, guidelines recommend discontinuation of antiviral therapy 6 months after loss of HBeAg. Furthermore, in patients with HBeAg-negative disease, findings from case series have shown that treatment can be safely discontinued after 3-5 years of treatment in some patients.14 In Marcellin and colleagues' study,10 tenofovir was continued anyway. Certainly, the loss of HBsAg, either with or without development of anti-HBs, is a signal that treatment can be stopped (as was shown in the 12 patients who stopped treatment and continued in this study). However, this endpoint was not especially common, since it occurred in only 23 of the 489 patients after 5 years of treatment.
The possible disadvantages of long-term therapy must be considered. An important issue for our overburdened health-care systems is cost: the suggested wholesale prices of tenofovir and entecavir are US$11 304 and $13 212 every year for the drugs alone.
The safety of long-term nucleoside therapy is also a consideration. Multiple case reports and small case series have documented that tenofovir can cause renal proximal tubular dysfunction, similar to Fanconi syndrome.15 Abnormalities usually develop after several years of treatment and are characterised by phosphate-wasting nephropathy and mild renal insufficiency. Typically, serum phosphate (and uric acid) concentrations decrease, serum creatinine increases minimally (by 18-44 μmol/L), and mild proteinuria develops (mostly low-molecular-weight proteins such as ß-2-microglobulin). Complete renal failure is rare, but hypophosphataemia can be severe, symptomatic, and even life threatening. In severe cases, osteomalacia or renal tubular acidosis can occur.16
Thus, efficacious long-term therapy with potent oral antiviral agents is an important advance for the management of chronic hepatitis B, but challenges remain. Which patients should be treated, for how long, and to what clinical endpoint? How can the rate of HBsAg loss be increased and the persistent risk of hepatocellular carcinoma be reduced? What is the safety of long-term therapy and how should patients be monitored? Good clinical studies often pose more questions than they can answer, and the accompanying study by Marcellin and colleagues is no exception.
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Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study
Patrick Marcellin, Edward Gane, Maria Buti, Nezam Afdhal, William Sievert, Ira M Jacobson, Mary Kay Washington, George Germanidis, John F Flaherty, Raul Aguilar Schall, Jeff rey D Bornstein, Kathryn M Kitrinos, G Mani Subramanian, John G McHutchison, E Jenny Heathcote
Summary
Background
Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection.
Methods
After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (≥1 unit decrease by Ishak scoring system).
Findings
Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0·0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (≥1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0·0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug.
Interpretation
In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis.
Funding
Gilead Sciences.
Introduction
Progression to cirrhosis, development of hepatocellular carcinoma, and liver-related mortality are associated with persistent replication of hepatitis B virus (HBV) and high plasma HBV DNA concentrations in patients chronically infected with the virus.1-3 In an estimated 15-40% of patients with chronic HBV infection, progression to cirrhosis, liver failure, or hepatocellular carcinoma will occur.4 Worldwide, HBV infection accounts for about 50% of all cases of hepatocellular carcinoma, most of which (up to 80%) are in patients with cirrhosis.5 Viral suppression by means of inhibitors of HBV polymerase/reverse transcriptase has achieved clinical benefits with a reduction in hepatic decompensation and lower rates of hepatocellular carcinoma in cirrhotic patients.6-8 However, little is known about progressive changes in liver histology with long-term antiviral therapy. Advanced liver fibrosis was previously thought to be irreversible, but evidence is accruing that cirrhosis can be reversed if the underlying cause of liver injury is addressed.6-19 The evidence of an association between suppression of HBV replication and regression of liver fibrosis has, however, come from small studies that were not controlled adequately for antiviral use or treatment duration.6,8,17-23
Tenofovir disoproxil fumarate (DF), a nucleotide analogue and potent inhibitor of HBV polymerase/reverse transcriptase, is approved for the treatment of HIV-1 and chronic HBV infections.24 Two international, multicentre, randomised, double-blind phase 3 studies (NCT00117676 and NCT00116805) compared the efficacy and safety of once-daily tenofovir DF versus once-daily adefovir dipivoxil for 48 weeks.25 Tenofovir DF was more effective than adefovir in terms of viral suppression and relief of histological inflammation.25 After week 48, patients continued on open-label tenofovir DF or were switched from adefovir to open-label tenofovir DF for a planned 7 further years.26 Participants in the open-label phase were eligible for a prespecified third liver biopsy at week 240. We report here the effects of 5 years of viral suppression on histology in liver fibrosis and cirrhosis in 348 patients who had evaluable histology at baseline and week 240.
Discussion
Treatment for chronic HBV infection aims to maximise viral suppression with the objectives of controlling liver fibrosis and preventing progression to clinical complications associated with hepatic decompensation and hepatocellular carcinoma. Little evidence has been available on the effect of long-term HBV suppression on liver histology. Our study, of a large cohort of patients with baseline, year 1, and year 5 liver biopsy samples, has shown that up to 5 years of treatment with tenofovir DF is safe and effective; long-term suppression of HBV can lead to regression of fibrosis and cirrhosis.
In small subsets of patients, treatment of chronic HBV with older polymerase/reverse transcriptase inhibitors, lamivudine and adefovir, has been reported to reverse advanced fibrosis and cirrhosis; however, in long-term use these agents often lead to incomplete virological suppression, and resistance develops in 20-75% of patients, leading to poor clinical outcomes.6-8,17 Studies with entecavir showed low rates of resistance in treatment-naive patients, and clear reversal of fibrosis has been reported in patients who took part in an amended roll-over protocol after receiving a median of 6 years of therapy. Those conclusions, however, were based on a total of 57 patients (8% of the randomised and treated population), and only four of them had cirrhosis at entry.18, 19 Our study of 348 patients with sequential histology data obtained over 5 years included 96 patients with cirrhosis at baseline. Nearly all patients on tenofovir DF had undetectable HBV DNA, which was associated with prevention of fibrosis progression in 96% overall and regression of cirrhosis in 74% of patients.
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Panel
Research in context
Systematic review
For most patients with chronic hepatitis B, the standard of care is life-long oral antiviral therapy, to improve quality of life and survival by preventing disease progression. This treatment strategy is based on the widely held but unproven assumption that sustained suppression of HBV replication will result in a reduction in histological activity, which in turn will lessen the risk of progression and offer the potential for reversing liver fibrosis. We searched PubMed with the search terms "antiviral agents","hepatitis B, chronic/drug therapy", "liver cirrhosis/pathology", "tenofovir disoproxil fumarate", "adefovir dipivoxil", "lamivudine", and "entecavir" for randomised controlled trials and other long-term clinical trials published in English up to December, 2011. Long-term studies with oral antiviral agents, including lamivudine,6, 7 adefovir,8, 15, 17 and entecavir,18, 19 have suggested that cirrhosis regression is possible, but they were small, especially in terms of the numbers of patients with advanced fibrosis or cirrhosis, and used treatments of limited or variable duration. Furthermore, the wide variability (3-7 years) in the timing of repeat liver biopsies hampers assessment of any beneficial effect. Rigorous interpretation of fibrosis regression in trials of older agents is difficult since loss of histological benefit has been described in patients who developed resistance to these agents with long-term use.
Interpretation
Our study provides the first definitive evidence that long-term suppression of HBV can lead to significant regression of fibrosis and reversal of cirrhosis in a substantial proportion of treated patients. The results demonstrate a beneficial histological treatment effect, and the consistency of the effect in subgroup analyses suggests that these findings are representative of the millions of HBV-infected patients worldwide. Long-term suppression of HBV should now be the standard of care for all patients.
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In general, interpretation of histological findings should take into account potential limiting factors, including variability in interpretation between observers and sampling error associated with needle biopsy.30-32 In our study, an independent pathologist, unaware of treatment outcome, reviewed all biopsy samples, thereby minimising the potential for variability. Several factors mitigated the influence of sampling error on the overall results. We included a large number of patients and observed a substantial treatment effect, particularly in patients with cirrhosis at baseline; most showed improvements of at least 2 points in Ishak score. Histological improvements were observed across different subgroups of patients. Another consideration is the qualitative nature of fibrosis assessment and the non-linear relation between fibrosis stage and collagen content as measured by morphometry,32 which suggests that in patients whose liver fibrosis regresses by 2 units, the magnitude of collagen decrease is probably much greater in patients with cirrhosis than in those without cirrhosis at baseline.
The population included in this analysis is representative of the range of patients with chronic HBV infection in terms of demographic and disease characteristics, so the treatment responses we observed are broadly applicable. Furthermore, the relevance of our findings is not limited to chronic HBV infection. Previous studies have shown that successful removal of the stimulus for chronic liver injury results in regression of fibrosis from several causes including chronic infection with hepatitis C virus treated with interferon,9-11 biliary drainage for chronic common-bile-duct stenosis in chronic pancreatitis,12 hepatic schistosomiasis treated with praziquantel,13 and venesection therapy for genetic haemochromatosis.14 The association of lower BMI with higher rates of fibrosis regression merits further investigation. The co-existence of obesity-associated liver disease in our cohort has not been excluded, since high BMI is associated with more rapid progression of liver disease in patients with chronic hepatitis C,33 and with poor response to medical treatment of portal hypertension.34
The histological response and regression of fibrosis seen in this study are probably due to the potent viral suppression achieved with long-term use of tenofovir DF. In clinical practice, maintenance of viral suppression is feasible given the the overall favourable safety profile and the absence of treatment-limiting toxicity. Furthermore, no tenofovir DF resistance-associated variants were detected, providing evidence of a high genetic barrier to the development of resistance during 5 years of treatment. Fibrosis regression would be expected to translate into clinical benefits, as previously shown by Liaw and colleagues.7 They found that hepatocellular carcinoma incidence in advanced fibrosis was lower in patients treated with lamivudine than in placebo-treated patients; however, this benefit was somewhat offset by higher rates of resistance development over time.7 In our study, the low rate of clinical events of disease progression, including hepatocellular carcinoma, was consistent with the benefits of antiviral suppression.
Treatment with tenofovir DF for up to 5 years is safe and well tolerated and maintains viral suppression in the majority of HBeAg-negative and HBeAg-positive patients with chronic hepatitis B. The findings of this study draw attention to the liver's capacity for fibrosis regression, even when cirrhosis has developed, in hepatitis B when long-term viral suppression is attained. Moreover, the low frequency of adverse outcomes noted in this cohort reinforces the potential clinical benefits associated with regression of fibrosis, especially in patients with cirrhosis.
Results
Of 641 patients enrolled and treated in the randomised trial, 585 (91%) entered the open label phase. 489 (76%) remained in the study at year 5. 634 patients (99%) had evaluable liver biopsy samples at baseline, and 348 (54%) had both baseline and year 5 liver biopsy results (figure 1). Ishak scores were available at all three timepoints (baseline, year 1, and year 5) for 344 patients. At 5 years of treatment, 141 (22%) patients had no biopsy data available (figure 1), mainly because patients refused the procedure. Overall, 22 (3%) patients discontinued for reasons of safety, tolerability, or efficacy, and ten HBeAg-positive patients discontinued before year 5 after confirmed seroconversion (six HBsAg seroconversion, four HBeAg seroconversion).
During the 5 years, the proportion of participants with necroinflammation decreased (figure 2A); the proportion with mild or no necroinflammation (Knodell range 0-3) increased from 8% (27/348) at baseline to 49% (171/348) at year 1 and 80% (278/348) at year 5 (p<0·0001). The distribution of Ishak scores (figure 2B) also indicated improved liver histology during the study as shown by a progressive increase in the proportion with mild disease and decreases in the proportion with severe disease (p<0·0001). At baseline, 39% (136/348) of participants had no or mild fibrosis; this proportion was 43% (149/344) at year 1 and 63% (219/348) at year 5 (figure 2B). Conversely, at baseline 38% (133/348) had Ishak scores of 4 or more (pronounced bridging fibrosis to cirrhosis), but this proportion declined to 28% (97/344) at year 1 and 12% (42/348) at year 5. Overall, regression of fibrosis was documented in 176/348 (51%) of patients and histological improvement in 304/348 (87%) of patients at year 5. Furthermore, the histological improvement rate was 91% or more for patients with Ishak scores greater than 2 at baseline, and patients with the highest liver injury scores showed the greatest degree of improvement (p<0·0001, figure 2C). Viral suppression (HBV DNA <400 copies per mL) was documented in 330 (99%) of the 334 patients maintained on long-term therapy for whom the measurement was available (appendix).
96 patients (28%) had cirrhosis (Ishak score ≥5) at baseline; 71 (74%) of these had a reduction in fibrosis at year 5 and were no longer cirrhotic. The difference between the proportion of patients with cirrhosis regression and the proportion of non-cirrhotic participants progressing to cirrhosis (1%) was significant (p<0·0001). Of the 96 patients with cirrhosis at baseline, all but one with regression had a reduction of at least 2 units in the Ishak score at year 5, and more than half (58%, 56 patients) had a decrease of 3 units or more (figure 2D). Demographic characteristics and baseline disease and on-treatment response characteristics associated with reversal or non-reversal of cirrhosis at year 5 are summarised in table 1. Body-mass index, history of diabetes mellitus, normal concentration of alanine aminotransferase at year 5, and mild or absent necroinflammation (Knodell range 0-3) were associated with a higher likelihood of cirrhosis reversal (table 1). In the multivariable logistic regression model, body-mass index (BMI; <25 vs ≥25 kg/m2 based on the WHO classification of normal vs overweight or obese) was an independent predictor of cirrhosis regression (p=0·0044, odds ratio [OR] 7·4 [95% CI 1·87-29·41]). The influence of BMI on regression of cirrhosis was even more apparent (p=0·0005, OR 18·9 [3·57-99·95]) when the normal-weight category was compared with the obese group (≥30 kg/m2), or the overweight category (≥25 to <30 kg/m2) was compared with the obese (p=0·039, OR 3·9 [1·07-14·15]). Further details of the model are given in the appendix.
Because 141 patients had no biopsy data at year 5, we undertook additional analyses to confirm the robustness of our observations. Demographic characteristics, baseline disease, and on-treatment response characteristics were similar in those who did and did not undergo liver biopsy at year 5 (appendix). Furthermore, under the approach of modified last observation carried forward, which included 239 patients with baseline and year 1 biopsy data only (missing year 5), and 47 patients with only baseline biopsy data (missing both years 1 and 5), the difference between the proportion with cirrhosis regression (53%) and the proportion of non-cirrhotic patients progressing to cirrhosis (9%) at year 5 remained significant (p=0·0012).
85% of HBeAg-negative and 73% of HBeAg-positive patients had biochemical responses (table 2, appendix). Suppression of HBV DNA loads to less than 400 copies per mL was achieved in 83% of HBeAg-negative and 65% of HBeAg-positive patients (intention to treat); similar proportions (83% of HBeAg-negative, 64% HBeAg-positive) had loads below the assay limit of detection. Of patients on treatment, 99% of HBeAg-negative patients and 97% of HBeAg-positive patients achieved HBV DNA concentrations below 400 copies per mL and also less than 169 copies per mL at year 5 (table 2, appendix).
Overall, 58 patients qualified for genotypic analysis during the open-label period, but no tenofovir DF resistance-associated mutations were detected. 20 of these patients had confirmed virological breakthrough (19 had one episode, one had two non-sequential breakthrough episodes). Genotypic analysis showed no sequence change in 11 of the 20 episodes, unique polymorphic site changes in six, and conserved site changes in two; genotyping was unsuccessful in one patient. Phenotypic analysis on samples from 15 points of virological breakthrough in 14 patients (including both patients with conserved site changes) showed no evidence of reduced susceptibility to tenofovir DF in vitro.
Confirmed loss of HBeAg and seroconversion to anti-HBe occurred in 49% and 40% of patients, respectively (table 2, appendix). 23 HBeAg-positive patients had confirmed loss of HBsAg, and 18 showed seroconversion to anti-HBs (table 2). 96% of the patients with HBsAg loss had genotype A (61%) or D (35%) at baseline. Of the 23 patients with HBsAg loss or seroconversion, viral suppression continued during treatment-free follow-up for 5 years in 12 (the remainder did not discontinue tenofovir DF or stopped treatment briefly then restarted [four] or withdrew from the study early [seven]).
Tenofovir DF treatment was well tolerated (table 3). Nine (2%) patients experienced treatment-related serious adverse events (12 events: increase in alanine aminotransferase, three; increase in aspartate aminotransferase, two; increase in lactate dehydrogenase, one; osteoporosis, two; osteopenia, one; acute pancreatitis, one; facial spasm, one; and mild renal failure, one). Eight (1%) patients permanently discontinued tenofovir DF owing to an adverse event.
Seven deaths were reported (table 3), all from malignant disease (three hepatocellular carcinoma; one cholangiocellular carcinoma of liver; one lung cancer metastases; one cervical cancer metastases; one nasopharyngeal carcinoma).
Signs of decompensated liver disease (ascites, hepatic encephalopathy, or bleeding oesophageal varices) developed in two patients, both with hepatocellular carcinoma. Overall, in the 12 patients who developed hepatocellular carcinoma, 11 had been assigned tenofovir DF in the randomised trial, and seven had underlying cirrhosis. Four patients developed hepatocellular carcinoma early during the first year of treatment and eight after year 1 (appendix).
Few laboratory abnormalities occurred during the 5 years (table 3).
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