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HepC Newsletter
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Dema-@aol.com
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Oct 31, 2009 16:24 PST
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NATAP http://natap.org/
_______________________________________________
Trends in Waiting List Registration for Liver Transplantation for Viral
Hepatitis in the United States
Gastroenterology Nov 2009
W. Ray KimCorresponding Author Informationemail address, Norah A. Terrault‡
, Rachel A. Pedersen§, Terry M. Therneau§, Erick Edwards∥, Andrew A.
Hindman¶, Carol L. Brosgart¶
Division of Gastroenterology and Hepatology, Mayo Clinic College of
Medicine, Rochester, Minnesota
‡ University of California-San Francisco, San Francisco, California
§ Division of Biostatistics, Mayo Clinic College of Medicine, Rochester,
Minnesota
∥ United Network for Organ Sharing, Richmond, Virginia
¶ Gilead Sciences, Inc, Foster City, California
"In conclusion, since the mid-1990s, a number of trends in the waiting
list registration have occurred, including an overall reduction in ESLD and
FLD over time, along with persistent increase in HCC. Whereas some of these
changes are attributable to the changes in the organ allocation system, the
trend seen with hepatitis B-related liver disease, namely a more rapid
decrease in ESLD and slower rise in HCC, was significantly more pronounced
compared with that with hepatitis C-related and non-viral liver disease. The
evidence to link this trend to antiviral therapy is indirect and
circumstantial; however, there are few other plausible explanations for this trend other
than a widespread application of antiviral therapy. The changes in ESLD in
other categories in the last few years, downward in those with HCV
infection and slightly upward in those with non-viral diseases, need to be
followed in the future."
'The last piece of circumstantial evidence for the causal role of HBV
antivirals in the reduction in the incidence of ESLD is the temporal
correlation and the rapidity with which the reduction occurred. Lamivudine became
available (for human immunodeficiency virus patients) in 1995 and was approved
by the US Food and Drug Administration for HBV in 1998. Adefovir dipivoxil
was approved in 2002, entecavir in 2005, and telbivudine in 2006. In
addition, tenofovir disoproxil fumarate, approved for HBV in 2008, had been used
in clinical practice “off-label” since its introduction in 2001 for the
human immunodeficiency virus indication.13 These medications rapidly and
potently suppress HBV replication, which has been associated not only with
reversal of fibrosis and, in some cases, of cirrhosis but also with prevention
and reversal of hepatic decompensation among those with advanced fibrosis
and cirrhosis.14, 16, 28 Although the impact of oral antivirals on the
incidence of HCC is less well established, it is probably smaller and delayed
compared with that on ESLD.14 One could hypothesize that the slower increase
in HCC registration in the HBV category, compared with others, may also be
related to the effect of antivirals.14"
ABSTRACT
Background & Aims
In the last decade, significant progress has been made in the treatment of
liver disease associated with chronic hepatitis, especially in patients
infected with the hepatitis B virus (HBV). To investigate whether the
population-wide application of antiviral therapies has impacted liver transplant
waiting list registration, we analyzed longitudinal trends in waiting list
registration for patients with hepatitis B and C and those with nonviral
liver disease.
Methods
This study represented a retrospective analysis of registry data
containing all US liver transplant centers. All adult, primary liver transplantation
candidates registered to the Organ Procurement and Transplantation Network
between 1985 and 2006 were included in the analysis. Standardized
incidence rates were calculated for waiting list registration for liver
transplantation by underlying disease (HBV and HCV infection and other) and by
indication for transplantation (fulminant liver disease, hepatocellular carcinoma
[HCC], and end-stage liver disease [ESLD]).
Results
Of 113,927 unique waiting list registrants, 4793 (4.2%) had HBV, and
40,923 (35.9%) had HCV infections; the remaining 68,211 (59.9%) had neither. The
incidence of waiting list registration for ESLD and fulminant liver
disease decreased, whereas that for HCC increased. The decrease in ESLD
registration was most pronounced, and the increase in HCC was least dramatic among
registrants with hepatitis B. The decrease in registration for ESLD
secondary to HCV infection was also significantly larger than that for ESLD
patients with nonviral etiologies.
Conclusions
The pattern of liver transplantation waiting list registration among
patients with hepatitis B suggests that the widespread application of oral
antiviral therapy for HBV contributed to the decreased incidence of
decompensated liver disease.
Chronic viral hepatitis resulting from chronic infection with hepatitis B
virus (HBV) and/or hepatitis C virus (HCV) is an important cause of liver
disease globally. In the United States, liver disease associated with
chronic HBV and HCV infection constitutes major indications for liver
transplantation (LTx) because chronic viral hepatitis not only causes liver failure
associated with end-stage liver disease (ESLD) but also hepatocellular
carcinoma (HCC).1 The burden of chronic HBV infection in the United States is
disproportionately among Americans that originate from other areas of the
world, particularly Asians and Pacific Islanders, a rapidly increasing
population group in the United States.2 The prevalence of chronic HCV infection is
the highest among middle-aged Americans (40–60 years of age).3 Given the
long disease span of chronic HCV infection from its acquisition to the
development of cirrhosis, it is feared that the burden of chronic HCV-related
liver disease will continue to increase.4 An example of such a trend may be the
increasing incidence, morbidity, and mortality associated with HCC, which
is commonly associated with chronic viral hepatitis.5, 6
In the past decade, much progress has been made in the therapy of chronic
viral hepatitis. For chronic HBV infection, the effectiveness of direct
antiviral agents (ie, oral nucleos(t)ide analogues) has been shown in terms of
sustained suppression of viral replication as well as biochemical and
histologic improvement.7, 8, 9, 10, 11, 12, 13 Although permanent viral
eradication is not expected because of the persistence of the intracellular
replicative intermediary (so-called covalently closed circular DNA), long-term
therapy is associated with significant clinical improvement, independent of
the stage of liver disease. In particular, in patients with advanced
fibrosis and cirrhosis, antivirals have been shown to prevent or reverse hepatic
decompensation.14, 15, 16
For chronic HCV infection, pegylated interferon α in combination with
ribavirin has been the mainstay of therapy.17, 18 Sustained virologic response,
namely, undetectable viral HCV RNA 6 months after discontinuation of
therapy, has been associated with cessation or reversal of fibrosis progression
and improved survival.19, 20 However, current antiviral therapy for chronic
HCV infection has limited effectiveness, depending on the genotype, which
is further reduced in patients with advanced fibrosis. Furthermore, it is
poorly tolerated and generally contraindicated in patients with hepatic
decompensation.21
Despite these advances in antiviral therapy against HBV and HCV, the
population-wide effects of antiviral therapy have not been evaluated. Following
a large increase in LTx activities for HBV-related liver disease in the
1990s when it became an accepted indication for LTx,22 anecdotal observations
have been made by clinicians that liver transplantation for ESLD associated
with chronic HBV infection has become less frequent. Accordingly, we
hypothesized that waiting list registration for LTx related to chronic HBV
infection has declined, whereas no such decrease would be found among patients
with nonviral liver disease. The aims of this work included (1) to describe
the longitudinal trend in LTx waiting list registration for viral and
nonviral liver disease in the United States and (2) to explore possible reasons
for the changes in the waiting list registrations.
Discussion
In this work, we clearly demonstrate that, recently, there has been a
significant decrease in waiting list registration for ESLD secondary to chronic
viral hepatitis, particularly HBV. This reduction was partly attributable
to a general trend in ESLD registration since implementation of the minimal
listing criteria in 1998 and MELD-based organ allocation in 2002.23, 24
However, the trend in HBV was much more pronounced and statistically
significantly different compared with that in the HCV and nonviral categories. In
contrast, against the backdrop of a general rise in the registration for
HCC, the rate of increase was significantly lower among HBV registrants
compared with HCV and Other diagnoses.
A decline in transplant waiting list registration for a particular
diagnosis may stem from a true reduction in the suitable candidates with the
condition and/or represent an artifact related to the changes in the listing
practice. The latter possibility may include (1) reclassification of patients
from ESLD to HCC, in light of the recent organ allocation system that has
given preferential priority to patients with HCC or (2) difference in the
timing of referral and waiting list registration in a subgroup of patients.
Although the OPTN data may not completely address these possibilities, the
following consideration suggests that neither of them is likely the main
reason for the trends being reported.
First, with regard to the possibility of reclassification of registrants,
it is likely that capture of the diagnosis of HCC in the OPTN data was more
complete in the recent era than previously. The change in liver allocation
system in 2002 ultimately had the impact of systematically increasing
priority given to patients with HCC.25 The diligence with which HCC is looked
for and reported to OPTN in an LTx candidate has consequently become much
greater and likely contributed to the trend of increased number of LTx
candidates with HCC at the expense of reduction in those with ESLD. However,
importantly, such reclassification should have affected all disease categories
and, thus, would not explain the larger decline in waiting list
registration seen in viral hepatitis. Furthermore, in the case of HBV, the increase in
the registration with HCC was slower than the other categories, making it
still less likely that reclassification from ESLD to HCC is the main reason
for the decline in ESLD registration.
Second, it may be possible that changes in waiting list registration
resulted from variability in the timing of referral or listing. For example,
because viral hepatitis tends to be more prevalent in minority groups, an
increasing delay in referral for LTx in those patients may lead to some patient
being too ill to be considered for LTx, resulting in a decrease in waiting
list registration. If this was the case, one would expect to see higher
MELD scores in those patients. In Figure 3, HBV patients were listed with
significantly higher MELD scores than the others, which does indicate that HBV
patients were indeed listed late. However, an important point is that the
listing MELD scores in HBV patients changed in parallel to those in other
patients while their registration was decreasing. If there was a bias unique
to HBV registrants, their listing MELD scores would have increased at a
greater rate than those of other groups.
These considerations point to a true reduction in the number of candidates
with ESLD secondary to chronic viral hepatitis. This trend, in turn, may
be a result of (1) a real change in disease epidemiology (ie, decreased
incidence in ESLD in the population) or (2) reduction in the proportion of
patients that are suitable candidates among patients developing ESLD. With
regard to epidemiology of HBV, available data indicate that the prevalence of
chronic HBV infection in the US population has been increasing as a result
of influx of immigrants from regions of the world endemic with HBV.26 Thus,
there is a dichotomy between increasing prevalence of chronic HBV infection
and decreasing incidence of ESLD associated with it. The most likely
explanation for this dichotomy is widespread use of effective antivirals that
have been shown to reduce the incidence of hepatic decompensation.14
The other plausible explanation may be that a decreasing proportion of
patients remain suitable candidates for LTx without a true decrease in the
number of patients who develop ESLD. We suspect that this scenario might turn
out to be the case, at least in part, with ESLD secondary to HCV for which
our data showed a decline in waiting list registration, while there is no
other epidemiologic evidence for a reduction in the incidence of ESLD.
Regardless of the incidence of ESLD secondary to HCV in the population, it is
possible that fewer patients are registered for LTx because an increasing
proportion of patients are unsuitable candidates. For example, as the average
age of HCV patients increase, many may become too old or have unacceptable
comorbid conditions such that LTx is no longer offered. In case of HBV,
however, Everhart and Ruhl recently demonstrated a decreasing trend in
mortality rate from HBV infection in the United States, essentially in parallel
with the reduction in waiting list registration shown in this analysis.27
These 2 corroborating analyses suggest that there has been true reduction in
the incidence of ESLD attributable to HBV.
The last piece of circumstantial evidence for the causal role of HBV
antivirals in the reduction in the incidence of ESLD is the temporal correlation
and the rapidity with which the reduction occurred. Lamivudine became
available (for human immunodeficiency virus patients) in 1995 and was approved
by the US Food and Drug Administration for HBV in 1998. Adefovir dipivoxil
was approved in 2002, entecavir in 2005, and telbivudine in 2006. In
addition, tenofovir disoproxil fumarate, approved for HBV in 2008, had been used
in clinical practice “off-label” since its introduction in 2001 for the
human immunodeficiency virus indication.13 These medications rapidly and
potently suppress HBV replication, which has been associated not only with
reversal of fibrosis and, in some cases, of cirrhosis but also with prevention
and reversal of hepatic decompensation among those with advanced fibrosis
and cirrhosis.14, 16, 28 Although the impact of oral antivirals on the
incidence of HCC is less well established, it is probably smaller and delayed
compared with that on ESLD.14 One could hypothesize that the slower increase
in HCC registration in the HBV category, compared with others, may also be
related to the effect of antivirals.14
Whether antiviral therapy played any role in the reduction in HCV
registration is much more difficult to assess. Population surveys have shown that,
as the cohort of Americans infected with HCV grows older, the number of
individuals with long-standing HCV infection is increasing.3, 29 On the other
hand, recent nationwide statistics indicate that mortality related to
chronic HCV infection may have reached a plateau.30 The effect of anti-HCV
therapy at the population level is likely to have a much longer lag period
compared with that for HBV, because the regimens available to date are not
uniformly effective, especially in patients with advanced fibrosis and cont
raindicated, by and large, in those with decompensated liver disease.21 Thus, it
is difficult to be confident that antiviral therapy has led to a decrease
in ESLD waiting list registration secondary to HCV. As previously stated,
the proportion of HCV patients with ESLD eligible for LTx may be decreasing,
independent of the incidence of ESLD related to HCV.
Last, we found that waiting list registration for FLD (“status 1”)
decreased over time in all 3 diagnosis groups. We believe there may be several
reasons for the observation. First, for HBV, it is likely that the pool of
susceptible individuals being exposed to the infection has decreased. There
has been a precipitous drop in the incidence of new HBV infection in the
United States since the mid-1990s as a result of a number of public health
interventions such as increasing coverage of the population with HBV vaccine
and widespread awareness of risks of parenteral transmission of human
immunodeficiency virus and other infectious diseases.31 Second, we believe that
there was a misclassification in the past of patients presenting with acute
deterioration of underlying chronic liver disease as FLD. This very likely
explains the trend seen in HCV registration. FLD presentation with acute
HCV infection is extremely rare, and the patients registered as status 1
previously probably represent misclassification, which has decreased over time.
Finally, acute non-viral liver disease showed the least amount of changes
over time, consistent with lack of epidemiologic data to indicate
meaningful changes in the incidence of FLD from nonviral etiologies in the United
States.32, 33
In conclusion, since the mid-1990s, a number of trends in the waiting list
registration have occurred, including an overall reduction in ESLD and FLD
over time, along with persistent increase in HCC. Whereas some of these
changes are attributable to the changes in the organ allocation system, the
trend seen with hepatitis B-related liver disease, namely a more rapid
decrease in ESLD and slower rise in HCC, was significantly more pronounced
compared with that with hepatitis C-related and non-viral liver disease. The
evidence to link this trend to antiviral therapy is indirect and
circumstantial; however, there are few other plausible explanations for this trend other
than a widespread application of antiviral therapy. The changes in ESLD in
other categories in the last few years, downward in those with HCV
infection and slightly upward in those with non-viral diseases, need to be
followed in the future.
Results
Between 1985 and 2006, there were 113,927 unique individuals registered to
the OPTN waiting list for liver transplantation. Of those, 4.2% (n = 4793)
met the criteria for HBV, whereas 35.9% (n = 40 923) were classified to
have HCV. The remaining 59.9% (n = 68 211) did not have either hepatitis
diagnosis and were grouped under “Other” diagnosis. The characteristics of
these candidates are summarized in Table 1. The 3 groups were similar in age,
whereas male sex predominated among patients with viral hepatitis,
especially those with HBV. With regard to racial distribution, the proportion of
non-white, non-AA subjects was much higher among those with HBV than the
other 2 categories. As expected, the proportion of HCC was higher with viral
hepatitis, particularly HBV, whereas status 1 registration for FLD was least
common with HCV. Among patients with ESLD, the median MELD score was 16 for
HBV, 14 for HCV, and 15 for Other (P < .01).
In Figure 1, the bars represent the total number of waiting list
registrants by diagnosis between 1985 and 2006. There was a linear increase in the
number of waiting list registrants in the 1980s and 1990s. The increase was
seen in all 3 diagnosis groups, although HCV was not diagnosed prior to the
introduction of anti-HCV testing in 1991. The number peaked at 8382 in
1999, followed by a substantial drop in 2002 (n = 7319), coincident with the
implementation of MELD-based organ allocation. Since then, the number of
registrants increased steadily to 8673 in 2006. The curve in Figure 1 depicts
the age- and sex-adjusted incidence rates for waiting list registration,
which showed a trend similar to the number of registrants. The incidence of
waiting list registration peaked in 1999, dipped in 2002, and then showed a
plateau at approximately 3.5 per 100 000 persons.
Figure 2 describes the incidence of waiting list registration for the 3
diagnosis groups. Figure 2A shows the incidence rate of waiting list
registration for ESLD, FLD, and HCC with HBV. The most noticeable trend is the
decline in waiting list registrations with ESLD since 1999—a 47% decrease over
the ensuing 7 years. In contrast, those with HCC increased by 72% during
the same period. Registrations with FLD decreased steadily after the initial
uptake in the mid-1990s. In Figure 2B, registrations for ESLD and HCV,
which increased rapidly during the 1990s, decreased since 1999, although the
magnitude of decrease (30%) was smaller than that in HBV. In contrast, those
with HCC increased by as much as 163% between 1999 and 2006. Finally,
Figure 2C shows that registrations for ESLD for nonviral liver disease also
reached a peak in 1999. It was followed by a small decrease and a plateau, such
that the reduction between 1999 and 2006 was only 14%. Registrations for
HCC in this category increased by 227% between 1999 and 2006.
Table 2 summarizes the results of multivariable Poisson regression model
to make formal comparisons for the trends seen in Figure 2. Compared with
era 2 (1998–2001), waiting list registration during era 1 (1994–1997) was
significantly lower except for HBV registrants with FLD, confirming the
substantial increase in overall registration during the 1990s. Between eras 2
and 3, for all 3 diagnosis groups, registrations for ESLD and FLD decreased,
whereas those for HCC increased. When the slopes of these changes were
compared across diagnosis, the reduction in ESLD registration for HBV was
significantly steeper than that for HCV (P < .01), which, in turn, was
significantly steeper than that for Other (P < .01). The rise in registration for
HCC was significantly lower for HBV (P < .01), compared with HCV or Other,
whereas the slopes in the latter 2 groups were comparable (P = .15). The
reduction in FLD with HCV was steeper than that with HBV (P = .02) or Other (P
< .01), whereas the slopes for the latter 2 were not significantly
different from each other (P = .15).
Figure 3 compares the mean MELD scores of patients with ESLD at waiting
list registration among the 3 diagnosis groups since MELD data started to be
routinely collected during 2001. There was a gradual increase in MELD
scores in all 3 groups. Consistent with data in Table 1, the MELD score among
HBV registrants was significantly higher than those with Other diagnosis,
which, in turn, was higher than that for HCV. However, the 3 curves moved
parallel to each other over time (P for difference in slope = .67).
Materials and Methods
Data Source and Elements
Data on all waiting list registrants in the United States were obtained
from the Organ Procurement and Transplantation Network (OPTN; currently
administered by the United Network for Organ Sharing), available as the Standard
Transplant Analysis and Research file as of May 1, 2007. Of a wide array
of information available in the database, elements necessary for the
analysis included demographic information (age, sex, and race), diagnostic codes
for underlying liver disease, presence of HCC, urgency status, and
laboratory data including viral serology and components of the Model for End-Stage
Liver Disease system (MELD).
Subjects included in the analysis were all primary LTx candidates newly
registered to OPTN between 1985 and 2006. Registration records in a given
subject were linked together using a deidentified subject code, even if the
subject was listed more than once at 1 or more listing centers. Thus, in a
given subject, only the very first registration was identified and included
in the analysis. Pediatric (<16 years of age) and repeat transplant
candidates were excluded, although in the latter group, waiting list registration
for their first LTx was included. Otherwise, candidates for multi-organ
transplantation were included.
Liver disease diagnosis was determined primarily by the diagnostic codes
(United Network for Organ Sharing codes 4102, 4106-7, 4202, 4206-7, and 4592
for HBV infection and 4103, 4104, 4106, 4204, 4206, 4216, and 4593 for HCV
infection). However, it was not uncommon for diagnostic information to be
written-in in the text fields available for supplemental comments.
Text-based searches were conducted in those fields for specific diagnoses, allowing
for typographical errors. Finally, results of serologic tests performed at
the time of LTx were used to identify records with viral hepatitis,
including hepatitis B surface antigen, hepatitis B e antigen, and immunoglobulin
M (IgM) type antibodies against hepatitis B core or hepatitis B virus DNA
for hepatitis B and antibodies against hepatitis C virus (anti-HCV) and
hepatitis C RNA for hepatitis C.
Statistical Analysis
Based on the diagnostic information, patients were classified into 3 main
diagnostic categories including HBV, HCV, and “Other” (non-HBV, non-HCV)
groups. The rare patients with concomitant HBV and HCV infection were
included in the HCV group. Within those groups, patients were further divided by
the indication for LTx, including fulminant liver disease (FLD), HCC, and
ESLD. FLD patients were identified by the status 1 designation. Patients who
had an HCC diagnosis (United Network for Organ Sharing codes 4400, 4401)
or an indication for HCC exception anytime prior to transplantation were
included as HCC. Candidates with neither FLD nor HCC diagnosis were classified
as ESLD.
Severity of liver disease at the time of waiting list registration was
assessed by laboratory components of the MELD score, namely, serum
concentrations of total bilirubin and creatinine as well as international normalized
ratio (INR) for prothrombin time. OPTN began collecting MELD score data in
2001. MELD score was calculated according to the standard formula of 11.2
loge(INR) + 9.57 loge(creatinine) + 3.78 loge(bilirubin) + 6.43; with a lower
limit of 1 for all variables, creatinine capped at 4, and creatinine set
to 4 in patients receiving renal replacement therapy. The MELD score
(rounded to the nearest integer) had a possible range of 6 to 40.
The main analysis included comparison of the longitudinal trend in waiting
list registration for HBV, HCV, and Other liver disease. The number of
registrants in the 3 diagnostic groups was enumerated for each calendar year.
The result was further divided into 3 indication categories, namely FLD,
HCC, and ESLD. We then computed the incidence of waiting list registration in
those categories, taking the entire adult US population as the denominator
population at risk. The incidence was adjusted according to the age and
sex distribution of the US census data. In estimating the variability of the
data, it was assumed that, given a fixed number of person-years, the number
of cases follows a Poisson distribution. This allowed the estimation of
standard errors and the calculation of 95% confidence intervals (95% CI) for
the incidence rates.
Temporal changes in waiting list registration were evaluated using the
generalized linear model assuming a Poisson error structure. Based on the
visually appreciable trends in waiting list registration, the Poisson model
considered 3 eras (1994–1997, 1998–2001, and 2003–2006) as the main
independent variable. Data prior to 1994 were not included in the analysis because
of lack of consistent diagnosis and documentation for HCV. Year 2002 was
omitted in the model because of the artificial reduction in the waiting list
registration associated with the implementation of MELD-based allocation.
Covariates considered in the Poisson model included the era, age (10-year
intervals), sex, and race (white, African American [AA], and other). Temporal
trends in the disease severity at the time of waiting list registration
were examined by using linear regression to model MELD with listing year and
diagnosis group.
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