Our analyses identified the 1941-1960 US birth cohort with HCV related disease as generating the greatest demand for LTx. Additionally, within this birth cohort of individuals with HCV related liver disease we found a dramatic increase in the rate of new registrants for LTx due to HCC. Interestingly, our observed and projected analyses suggest that older patients (≥60 years) with HCC will increasingly contribute to the proportion HCV infected liver transplant candidates, unless current patterns of care change dramatically.
Prior studies of HCV epidemiology and HCV age-specific mortality have identified that the peak prevalence of HCV and mortality associated with HCV occurs in the 1940 to 1965 US birth cohort. 5, 6
Our current study identifies a similar US birth cohort effect among LTx registrants with HCV related liver disease. Specifically, individuals born from 1941-1960 dominate the demand for LTx in the US. HCC is increasing in frequency in the US, and HCV infection is the leading contributing risk factor, implicated in up to 47% cases.7
The incidence rates of HCC in the US has more than doubled between calendar years 1985 and 1998 with point estimates increasing from 1.3 to 3.0 per 100,000 persons and reaching 4.1 per 100,000 persons in 2000. 9, 10
Adjusting for age, Kim et.al
found an increasing incidence of HCC in new registrants for liver transplantation with HCV. 11
Our study, using a birth cohort analysis confirms this finding and demonstrates that the increasing incidence of HCC is a significant contributor to an increase in the demand for LTx among the 1941 to 1960 birth cohort infected with HCV. Additionally, a recent study from Asahina et al
reported that increasing age in a cohort of patients treated for HCV had a strong independent association with the incidence of HCC, particularly in those over the age of 65. 12
In this context, as the 1941-1960 birth cohort observed in our study ages, the demand for LTx among patients with HCV and HCC is unlikely to decline until other age-specific comorbidities preclude transplantation.
When complications of end-stage liver disease occur in the setting of HCV there are two likely results, death or LTx. Unlike the analyses Wise et al
that used mortality with HCV as their measure of HCV disease burden in the US, we used listing for LTx as our HCV disease burden measure. These two HCV disease burden measures showed similar age-specific trends that we demonstrate are likely a birth cohort effect occurring in the US and previously attributed to HCV transmission due to injection drug use and unavailability of tests to adequately screen blood products for HCV during the years 1970-1990.5
In our study using listing for LTx as the HCV disease burden measure, we observed different birth cohort patterns in the rates of new registration LTx among individuals with HCV related disease depending on their HCC status. There are at least two potential epidemiologic explanations for this: 1) HCC incidence is higher in older patients; and 2) older patients with non-HCC indications for LTx (i.e
. ascites, hepatic encephalopathy or portal hypertensive bleeding) are less likely to be referred or listed for LTx. Our study is unable to determine which or to what degree these or other explanations resulted in our observations. Another potential influence on our findings is a possible ascertainment bias related to improved documentation of HCC after 2002 with the implementation of MELD based allocation that included additional priority of patients with HCC. Importantly, dependent on the knots in the natural cubic spline calculations, the projections of the observed data are largely based on data in the most recent 5-7 year period (ie since 2003-2005).
Characterization of observed trends and projected changes in the demographics of patients seeking liver transplantation in the US may allow for proactive planning by the US liver transplant community to adapt current treatment approaches and policies to future needs. Prior epidemiologic projections of HCV-related mortality and need for LTx predicted peak event rates in the 2014 and 2015 calendar years, respectively. 13
Using more contemporary data, our analyses demonstrate a steady rise in the demand for LTx in an increasingly older population with HCV infection driven primarily by patients with HCC. Absent an abrupt reversal of our observed rate of new registrants through 2010, the peak demand stemming from the 1941-1960 birth cohort is likely to extend beyond 2015, but increasing age and other age-related comorbidities may have a significant influence on liver transplant candidacy assessments in this birth cohort who will be 60 to 79 years old in 2020.14
The Center for Disease Control15-17
and others18, 19
are currently considering expansion of HCV screening to all persons in the 1945-1965 birth cohort in the US, an approach that may increase the HCV testing rate19, 20
. In the near term such a policy may increase HCV diagnosis rates and potentially HCC diagnosis rates but subsequently would be expected to reduce the occurrence of HCV-related liver disease19
and associated complications such as HCC. Additionally, advances in treatment of HCV or HCC which have the potential to alter the disease course could result in lower observed HCV related disease burden, particularly over longer time horizons and if the interventions have improved tolerability in elderly patients.
Although LTx can be performed safely in highly selected candidates who are over 70 years old, 21
alternative treatment strategies may be more appropriate particularly in patients infected with HCV. The strong adverse effect of donor age on graft and patient survival after LTx is amplified in HCV infected recipients.22, 23
But the practice of preferentially using younger donors for HCV recipients23-26
may not be appropriate in the elderly. For patients with HCV who develop HCC, local-regional therapies or surgical resection for compensated cirrhotics may be a more efficacious use of resources than LTx. 27-33
Over the coming decade, the projected increase in demand for LTx from an aging HCV infected population will challenge the liver transplant community to reconsider current treatment paradigms.