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Viable strategies to facilitate liver
transplantation for HIV/HCV coinfection - Editorial
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Liver Transplantation Sept 2009
"The dismal rates of listing (14%) HIV-coinfected patients for transplant, as well as the extremely high death rates on the waiting list, are important observations in this prospective study and deserve further discussion......This underscores the importance of early referral of the HIV-coinfected patient.....Although the MELD score correlated with mortality in the Spanish series, the actual MELD score for HIV-positive candidates was associated with significantly higher mortality rates in comparison with HIV-negative candidates. This important finding underscores the necessity for liver transplantation at a lower MELD score for HIV-coinfected candidates. Because it remains unlikely that additional MELD points will be added for HIV-positive candidates on the wait list, the aggressive pursuit of high-infectious-risk donors and the use of living donors are currently the most viable strategies for facilitating liver transplantation at a lower MELD score."
Peter G. Stock 1 2 *, John Fung 1 2
1University of California San Francisco, San Francisco, CA
2Cleveland Clinic, Cleveland, OH
email: Peter G. Stock (stockp@surgery.ucsf.edu)
*Correspondence to Peter G. Stock, University of California San Francisco, Room M-884, 505 Parnassus Avenue, San Francisco, CA 94114
See Article on Page 1133
Article Text
The morbidity and mortality associated with human immunodeficiency virus (HIV) have dramatically decreased as a result of highly active antiretroviral therapy (HAART). Although people infected with HIV are no longer dying from the progression of HIV to acquired immune deficiency syndrome, end-stage liver disease secondary to the viral copathogens hepatitis B virus (HBV) and hepatitis C virus (HCV) has become a major cause of mortality in developed countries.[1] As infection with HIV has evolved into a chronic disease, an increasing number of coinfected people are being referred for liver transplantation in the United States and Europe. Although many transplant centers still consider HIV infection a relative contraindication to transplantation, those with early experience in coinfected recipients with well-controlled HIV have reported excellent results following liver transplantation for hepatitis B[2] and poorer but acceptable results following liver transplantation for hepatitis C.[3-5] At the same time, transplant centers that have been proceeding with liver transplantation in coinfected patients have reported significantly shorter pretransplantation survival in HIV-positive recipients listed for liver transplantation in comparison with HIV-negative subjects.[6] With this background, Murillas et al.[7] in this issue of Liver Transplantation report on the natural history and prognostic factors of end-stage liver disease in HIV-coinfected patients following their first clinical decompensation of liver disease.
Abbreviations
HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; HCC, hepatocellular cancer; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MELD, Model for End-Stage Liver Disease; NIH, National Institutes of Health.
The findings from this prospective study by Murillas et al.[7] are highly relevant and noteworthy, in that only 14% (15/104) of the coinfected patients in the Spanish cohort experiencing their first documented liver decompensation met the acceptance criteria for liver transplantation and were placed on a waiting list. Furthermore, only 33% (5/15) of the listed patients underwent liver transplantation, and the other 10 (67%) died while on the waiting list for a median survival time of 5 months. It is of equal importance that the Model for End-Stage Liver Disease (MELD) score and the inability to achieve an undetectable plasma HIV-1 RNA load were independent risk factors for death. For those patients listed for liver transplantation, the calculated mortality rate for a given MELD score in HIV-infected patients was similar to the mortality rate in non-HIV-infected patients with a MELD score that was roughly 10 points higher. Although the MELD score correlated with death on the waiting list for the HIV-infected patients, the absolute value of the MELD score was associated with poorer survival rates in comparison with HIV-negative monoinfected patients. The dismal rates of listing (14%) HIV-coinfected patients for transplant, as well as the extremely high death rates on the waiting list, are important observations in this prospective study and deserve further discussion.
A significant discrepancy between the US trials and this prospective Spanish trial is related to the inclusion trial for transplantation. Murillas et al.[7] report that a previous history of opportunistic infection (with the exception of tuberculosis) was an exclusion criterion for activation on the waiting list. This exclusion criterion was the reason that a very high percentage of patients (55/89) were precluded from the transplant list. Some of these patients may have done well with a liver transplant, and the overall outcome of the 104 coinfected patients referred after their first decompensation may have been improved. The US National Institutes of Health (NIH) multicenter trial evaluating the safety and efficacy of solid organ transplantation in people with HIV (http://www.hivtransplant.com) has similar requirements with respect to the CD4 requirements (>100 cells/L) as well as documentation that HIV can be suppressed with an antiviral regimen post-transplant in the event that HAART was not tolerated pre-transplant. However, the US trial does not exclude patients who have a history of an opportunistic infection as long as the opportunistic infection has been adequately treated. The US selection criteria for including patients with a history of opportunistic infections were liberalized after the initial experience during the pilot NIH trial, which demonstrated excellent infection control against opportunistic infections following reconstitution of the immune system with HAART. A history of opportunistic infections for which there is no reliable therapy continues to be an exclusion criterion in the current US multicenter trial; they include resistant fungal infections, chronic cryptosporidiosis, and progressive multifocal leukoencephalopathy. In those patients that have had successful eradication of an opportunistic infection (ie, cytomegalovirus or Pneumocystis pneumonia) following reconstitution of the immune system, the CD4 requirement for listing is increased to >200 cell/L. Liberalizing the inclusion criteria would potentially increase the number of eligible patients for transplantation in the Spanish experience and, on the basis of the early US experience, could be done without a penalty in terms of controlling opportunistic infections post-transplant. Increasing the number of eligible patients for transplant would give a significantly higher percentage of referred patients a chance for liver transplantation and hopefully improve the overall survival rates for coinfected patients with liver insufficiency.
A second important finding in the article by Murillas et al.[7] is related to the correlation of immune status and HAART with death in the coinfected patients following their first decompensation of liver function. A reduced CD4 count was associated with decreased survival, although this was not statistically significant. However, the patients that were not able to achieve an undetectable viral load during the follow-up had significantly decreased survival rates. As the authors suggest, some degree of this significance is related to a selection bias, in that patients with the most impaired liver function would be the least likely to tolerate HAART therapy. Nonetheless, this finding also highlights the importance of safe and effective antiretroviral therapy for the coinfected patients with liver insufficiency. Murillas et al. were unable to identify any particular HAART regimen with poorer outcomes, although the hepatotoxicity of the antiretroviral agents undoubtedly is in part responsible for the inability to tolerate the antiretroviral drugs and control the HIV viral load. The identification of antiretroviral regimens that are less toxic and hence more likely to achieve success are of paramount importance for coinfected patients who are not able to tolerate further insults by toxic agents. Although the Spanish series was not large enough to identify specific HAART regimens that were better than others, combining data sets with other large series will be an important strategy for ultimately identifying effective and better tolerated regimens. The identification of safe and effective regimens will facilitate better management of this challenging group of coinfected patients both before and after liver transplantation.
Perhaps the most important finding in the Spanish series was the significantly higher mortality rates for each category of MELD scores in HIV-infected patients in comparison with HIV-negative historic controls.[7] Even though MELD was predictive for death on the waiting list, the same MELD score in HIV-infected candidates for liver transplantation was associated with significantly higher death rates in comparison with HIV-negative candidates for liver transplants. Although the series was limited by the lack of a temporally related HIV-negative control group, these findings have important implications for HIV-positive coinfected patients on the waiting list. Murillas et al.[7] suggest that some prioritization for HIV-positive recipients might be indicated on the basis of these findings. In the US system, it is unlikely that additional MELD points for HIV-positive patients could become part of the standardized point system analogously to the additional points given for localized hepatocellular cancers (HCCs). Although these data may be useful in guiding regional review boards to consider additional points for coinfected candidates, a more likely strategy to decrease waiting list mortality and improve the chances for getting a liver transplant would be to pursue alternative sources of donor livers that would facilitate earlier transplantation. This underscores the importance of early referral of the HIV-coinfected patient. Although early referral has previously been impeded by confusion regarding the transplant candidacy of HIV-positive patients, increasing success following the transplantation of coinfected patients has gradually increased the awareness that successful liver transplantation can be accomplished in this medically complex and challenging group.
In the absence of additional MELD points to obtain liver transplants at the lower true MELD score, the ability to achieve an earlier transplant (at a lower MELD score) in a US center can generally be achieved by 3 strategies:
1 Utilization of living donor liver grafts, usually right lobes.
2 Utilization of higher infectious risk organs (serologically negative for HIV, HBV, and HCV) from deceased donors considered too high a risk for the potential transmission of undetected copathogens.
3 Utilization of deceased donor organs considered to be at a higher risk for early allograft dysfunction, such as older donors, donor livers with significant macrovesicular fat, and non-heart-beating donors.
On the basis of the poorer outcomes of HIV-coinfected patients with the last source of deceased donors (donors at a higher risk for early dysfunction), we are recommending the use of either living donors or high-infectious-risk deceased donors to expedite transplantation for coinfected patients at a lower MELD score. The poorer outcomes with extended criteria donors undoubtedly reflect the management complexities following transplantation in the coinfected recipients and their relative inability to tolerate the insult of early graft dysfunction. Ironically, many of the HIV/HCV-coinfected patients that are currently undergoing successful liver transplantation have obtained additional points based on HCC. Unlike the Spanish series, in which the presence of HCC was associated with poorer outcomes, the US experience is skewed in the other direction by the ability to provide liver transplants to coinfected patients with a lower true MELD score because of additional HCC points.
The use of living donor liver grafts (generally right lobes) is an important strategy allowing liver transplantation at a lower MELD score in the coinfected recipient. Clearly, the major advantage of providing a donor liver at a lower MELD score to the HIV-positive recipient must be weighed against the morbidity to the living donor as well as the increased risk of biliary tract complications and hepatic artery thrombosis in the recipient. In addition to the informed consent regarding the rates of morbidity and mortality associated with donating a right lobe, the donor should be informed of the current outcomes in HIV-coinfected patients. The requirement to inform potential donors of the recipient's HIV positivity has been controversial but remains a requirement of the US NIH multicenter trial (http//www.hivtransplant.com).
The other strategy that has resulted in successful transplantation at lower MELD scores in coinfected recipients has been the use of high-infectious-risk deceased donors. These are deceased donors that have a social history that puts them at a significant risk for viral infections but are serologically negative for HBV, HCV, and HIV. As the demand for deceased donors has increased, more HIV-negative patients are consenting to these otherwise high-quality donor organs, and this source of donors for HIV-positive recipients is becoming increasingly rare. Nonetheless, at the University of California San Francisco and the Cleveland Clinic, we continue to use 1 or 2 deceased donor livers per year that are at such a high risk for viral infection (despite negative serologies) that only HIV-positive recipients are willing to take the risk after receiving the full informed consent regarding the donor history. As the availability of serologically negative high-infectious-risk donors has decreased, there have been extensive discussions regarding the potential use of HIV-positive deceased donors for HIV-positive recipients. In South Africa, where there are an increasing number of patients with end-stage renal disease secondary to HIV-associated nephropathy and limited access to dialysis, 4 kidney transplants have been performed with kidneys from HIV-positive deceased donors (Elmi Muller, Groote Schuur Hospital, Cape Town) into recipients with HIV-associated nephropathy. This was not initially pursued in the United States because of concerns of superinfection with a more virulent or resistant strain in patients who had well-controlled HIV. There were some attempts at the state government level to change the current policies preventing the utilization of HIV-positive deceased donors, with the intent of providing a new source of scarce deceased donor organs for an increasing number of HIV-positive patients on both kidney and liver transplant waiting lists. However, current US Center for Disease Control regulations prohibit the use of HIV-positive organs, and utilization of organs derived from HIV-positive donors is considered a federal crime. Changes to this federal law are feasible but would require amendments to the current regulations. Nonetheless, the cautious use of HIV-positive deceased donors would be a potential alternative source of deceased donor livers that could be available to HIV-positive candidates at a lower MELD score. This strategy may warrant further consideration to deal with an increasing number of HIV-coinfected patients who would benefit from transplantation at a lower MELD score.
In summary, the findings by Murillas et al.[7] are highly relevant and confirm the extremely high mortality rates for HIV-coinfected patients following their first clinical decompensation of chronic liver disease. Only a small percentage of HIV-1 patients were considered adequate candidates for liver transplantation. Furthermore, for the few patients accepted for liver transplantation, a high mortality rate on the waiting list reduced the probability of receiving a transplant. These findings highlight the importance of early referral and multidisciplinary care to expand the number of HIV-positive patients with end-stage liver disease who could be candidates for successful liver transplantation and minimize the number of deaths on the waiting lists. Although the MELD score correlated with mortality in the Spanish series, the actual MELD score for HIV-positive candidates was associated with significantly higher mortality rates in comparison with HIV-negative candidates. This important finding underscores the necessity for liver transplantation at a lower MELD score for HIV-coinfected candidates. Because it remains unlikely that additional MELD points will be added for HIV-positive candidates on the wait list, the aggressive pursuit of high-infectious-risk donors and the use of living donors are currently the most viable strategies for facilitating liver transplantation at a lower MELD score.
References
1 Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, Snydman DR. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32: 492-497. Links
2 Terrault NA, Carter JT, Carlson L, Roland ME, Stock PG. Outcome of patients with hepatitis B virus and human immunodeficiency virus infections referred for liver transplantation. Liver Transpl 2006; 12: 801-807. Links
3 Ragni M, Belle S, Im K, Neff G, Roland M, Stock P, et al. Survival in HIV-infected liver transplant recipients. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 2003; Boston, MA.
4 Duclos-Vallee JC, Feray C, Sebagh M, Teicher E, Roque-Afonso AM, Roche B, et al. Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 2008; 47: 407-417. Links
5 Miro JM, Aguero F, Laguno M, Tuset M, Cervera C, Moreno A, et al. Liver transplantation in HIV/hepatitis co-infection. J HIV Ther 2007; 12: 24-35. Links
6 Ragni M, Eghtesad B, Schlesinger K, Dvorchik I, Fung J. Pre-transplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease. Liver Transpl 2005; 11: 1425-1430. Links
7 Murillas J, Rimola A, Laguno M, et al. MELD score is the best prognostic factor in HIV-1-infected patients with end-stage liver disease: a prospective cohort study. Liver Transpl 2009; 15: 1133-1141. Links
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