Liver Transplantation for HIV/HCV Coinfection

Where Is the Controversy?

Emily Dannhorn; James P O'Beirne

Disclosures

Future Virology. 2013;8(7):639-648. 

In This Article

LT for HIV/HCV Coinfection

Why the Controversy? The Increasing Burden of Disease in the Face of Limited Organ Availability

LT has been recommended as a treatment for patients "where the risk of death without a liver transplant is greater than the risk of death from transplantation", and where "transplantation is likely to result in a 50% chance of a >5-year survival with a quality of life acceptable to the patient".[11] A significant disparity exists between the number of patients requiring LT and the number of donated human livers, which inevitably leads to deaths on the waiting list. Decisions regarding listing and allocation of organs for LT are complex. In most systems, organs are allocated to patients with the most medical need (the sickest first), but attention also needs to be paid to the concept of utility; that is to say, patients who are likely to have the best outcome should receive priority. At present in the UK patients are accepted onto the waiting list if the severity of their liver disease (measured using the UK Model for End-Stage Liver Disease [UKELD] score) meets a certain level, defining the point at which the risk of dying from complications of LT is less than the 1-year risk of mortality from their liver disease (minimal listing criteria).[12] Each LT center maintains its own list and can internally prioritize candidates and allocate organs according to the center's wishes. While it is generally accepted that patients with worse liver disease will be transplanted first, this center-based allocation allows some degree of donor–recipient matching in an attempt to optimize outcomes for all.

Due to the demand for organs, the waiting time for LT in the UK is increasing. In 2012 the total number of patients active on the liver transplant list was 553; an increase of 8% from 2011. Over the last 10 years, there has been a steady increase in the number of patients registered on the active transplant waiting list, which has not been reflected by a similar increase in the number of available organs, resulting in an increase in death on the waiting list, which now stands at approximately 15–20%.

The problem of the gap between the need for LT and available organs is not unique to the UK and many organ allocation systems have been developed to try and reduce the deaths on the waiting list. One such system is the Model for End-Stage Liver Disease (MELD) system, which was introduced in the USA in 2002 and more recently in parts of Europe.[13] The MELD system allocates organs purely on the severity of liver disease, and while there is no doubt that its application has resulted in less waiting list mortality, there are concerns that this approach of transplanting the 'sickest first' has reduced medium- and long-term post-LT survival, effectively reducing the utility of LT.[14,15] The perfect allocation system would minimize deaths on the waiting list while optimizing long-term graft outcomes. Currently, such an allocation system does not exist, but it is acknowledged that the optimal balance between justice and utility is dependent on a number of donor and recipient factors. One such factor is the etiology of the patient's liver disease, which can have a major impact on expected survival following LT (Figure 1). As can be seen from Figure 1, transplantation for HCV-related cirrhosis is associated with inferior 1- and 5-year survival compared with other indications.[16] The reason for this is recurrent HCV infection in the graft, which is universal and results in progression to cirrhosis in up to 30% of patients after 5 years of follow-up. Although outcomes for transplanted HCV-monoinfected individuals are worse than other indications, the 5-year survival remains well above 50% and therefore the indication appears to justify LT on the basis of utility and is not controversial. This is not the case for HIV/HCV-coinfected patients, where relatively recent series have shown 5-year survival rates barely above 50%. It is for this reason that LT for HIV/HCV coinfection is questioned. At first glance it would seem acceptable to deny LT to patients on the basis of such poor outcomes, but it must be remembered that the cutoff of 50% 5-year survival as the basis for utility is purely arbitrary, and from an ethical standpoint it is questionable to deny LT on this factor alone. Furthermore, to deny LT to such patients is to reject the opportunity to learn from past experience and apply those lessons for the benefit of future patients. It may well be that HIV/HCV-coinfected patients need different selection criteria or organ allocation systems in order to maximize benefit from LT. Successful progress in this regard rests on continuing to transplant coinfected patients in order to understand the differences between HCV-coinfected and -monoinfected patients with respect to both pre- and post-transplant variables in order to identify areas where patient selection, organ allocation or post-transplant treatment can be improved.

Figure 1.

The 1- and 5-year survival rates post-liver transplantation for common causes of cirrhosis.
Even in the absence of coinfection with HIV, the 5-year survival rate in patients with HCV is inferior due to recurrent disease.
Adapted with permission from [16].


Why is Coinfection Different From Monoinfection?

The exact effects of HIV on hepatitis C remain unclear, but it is accepted that HIV accelerates both HBV and HCV liver disease, more so with worsening of the HIV-associated immunodeficiency.[9] The combination of HIV/HCV coinfection is associated with a reduced rate of spontaneous HCV RNA clearance and therefore an increased likelihood of developing chronic HCV.[17] With established HCV infection, there follows a more rapid rate of fibrosis progression.[18] Predictors of fibrosis progression include detectable HIV viral loads, low CD4+ cell counts, the level of baseline necroinflammatory activity on liver biopsy and increased alcohol consumption (>50 g/day).[19] Compared with monoinfected patients, coinfected patients have a more rapid course of fibrosis. In paired liver biopsy studies, significant fibrosis progression was seen in 25% of coinfected patients over 3 years compared with 12% of monoinfected patients over a similar time period.[20] Following development of cirrhosis, the course of the liver disease is accelerated. Indeed, in coinfected patients with established cirrhosis, the median estimated survival time is only 13 months following the first decompensating event (e.g., bleeding varices, encephalopathy, renal failure). Interestingly, and very relevant for the issue of LT in HIV/HCV coinfection, the risk of death following decompensation may not be accurately reflected by the MELD score, which may disadvantage coinfected patients in organ allocation systems based on MELD.[21] HIV also increases the risk of development of HCC. Recent studies have shown that the incidence of HCC in predominantly HCV-coinfected patients is increasing, with studies from Spain and the USA showing a 10–23-fold increase in incidence over the last 10 years.[22–24]

It can be seen from the evidence above that liver disease in HIV/HCV-coinfected patients is a much more aggressive entity than that seen in monoinfected cohorts, with a more rapid clinical course, especially after the development of cirrhosis. Clearly, therefore, the best approach to this problem would be to identify and treat patients with HCV prior to the development of advanced fibrosis. There are a number of factors that would limit the success of this strategy. First, the majority of HCV infections in HIV-positive patients are HCV genotype 1 and therefore more difficult to treat.[10] With the current standard of care (pegylated interferon and ribavarin), sustained virological response rates are poor (15–30%) and treatment is difficult to tolerate. Additionally, HCV treatment uptake remains poor, especially among injecting drug users, which further reduces the number of patients who may benefit.[25,26] Second, while the advent of DAAs for HCV offers some hope for the future, only limited experience in coinfected patients has been published thus far. Current triple therapy regimens using the protease inhibitors telaprevir or boceprevir have been used in selected patients with coinfection in two Phase II trials.[27,28] Notwithstanding the potential for drug interactions with antiretrovirals, increased sustained virological response were seen compared with patients treated with standard of care (60–74 vs 26–44%), but it must be remembered that these patients were highly selected and therefore these results are unlikely to be applicable to the majority of patients with advanced fibrosis or cirrhosis.[26] Therefore, despite this advance in therapy, there is likely to be a need for LT in these patients for some time to come.

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