In this study, HCV-infected liver transplant recipients with HIV were found to have significantly lower graft and patient survival than HCV recipients without HIV. This is consistent with previously published studies.5,6
Importantly, however, our study uniquely evaluated predictors of poor outcomes, and provides, for the first time, insights into critical patient selection and management strategies to maximize good outcomes. The association of graft survival in HCV-HIV recipients with low BMI and need for combined kidney-liver transplantation suggests wait-listed patients who are more debilitated do less well, and the findings of higher graft losses in HCV-HIV recipients with older or anti-HCV positive donors highlights the importance of both careful recipient and donor selection to achieve optimal outcomes.
In HCV transplant recipients, donor age is strongly associated with an increased risk of recurrent HCV cirrhosis, reduced responsiveness to HCV treatment and higher rates of graft loss.18–20
Among the HCV-HIV patients, older donor age was also associated with higher rates of graft loss, as was use of anti-HCV positive donors. The latter finding is important, as use of anti-HCV positive organs in HCV-infected transplant recipients without HIV has not been associated with an increased risk of severe HCV disease progression or graft loss.21
Donor biopsy data are not available so it unknown whether greater severity of disease in anti-HCV positive donors in HCV-HIV versus HCV recipients accounts for this difference.
Graft and patient losses due to hepatitis C did not differ between HCV and HIV-HCV coinfected recipients. This contrasts with a prior study from France indicating more severe HCV disease in coinfected patients 5
. The rate of advanced fibrosis (F3-4) in the HCV-HIV coinfected French cohort was 25% (4/20) and 57% (8/14) at 1 and 2 years post-transplant compared with 17% and 27 % in our cohort. In addition to the recognized limitations of sample size in providing precise estimates of recurrence rates, donor, recipient and post-transplant factors including using of anti-HCV therapy likely vary from center to center and may account for differences between studies. Additionally, in our study, HCV-HIV coinfected patients had a higher rate of graft loss due to sepsis and multiorgan failure (albeit not significantly) and this may have contributed to a survivor bias in assessment of fibrosis severity. The higher frequency of sepsis/MOF in the coinfected recipients may be related to their greater level of debilitation pre-transplant, a higher rate of treated acute rejection, or the presence of underlying recurrent HCV disease.
Acute rejection treatment in HCV-infected liver transplant recipients is a well-recognized risk factor for recurrent cirrhosis and graft loss.12, 22
The finding of a significantly higher rate of acute rejection in HCV-HIV compared to HCV recipients is a critically important finding of our study, as prevention of acute rejection may offer a means of optimizing outcomes in HIV-HCV recipients. This higher rate of acute rejection may be due to a higher rate of misinterpretation of acute rejection (versus recurrent HCV or drug toxicity effects) in HCV-HIV recipients, an overly cautious use of immunosuppression due to concerns for exacerbating HIV or HCV related diseases, or a reflection of the difficulties in achieving adequate immunosuppression due to interactions between antiretroviral drugs and calcineurin inhibitors16, 23
and mirrors the experience in kidney transplant recipients.24
Our data suggest that HCV-HIV patients with acute rejection were “under-immunosuppressed”, as lower tacrolimus trough level was associated with higher rates of treated acute rejection in univariate model and prednisone use post-LT was protective in the multivariate model. Alternatively, it is also possible that higher rates of acute rejection in patients with HIV reflect an inherently enhanced immune response and dysregulation of the immune response.25
Prior infections with other viruses (e.g. CMV) lead to the generation of memory alloreactive T cells as a result of crossreactivity 26
. Other studies have shown that the homeostatic expansion of T cells in HIV infection is often coupled with the acquisition of memory phenotype, which in turn, is associated with increased responsiveness of the T cell and nonspecific enhancement of alloimmunity 27
. Studies investigating T cell responses in coinfected patients are ongoing and are expected to shed light on contributing mechanisms.
Similar to the kidney transplant experience24
, there was no evidence of accelerated HIV disease progression, as indicated by stable or improved CD4+ T-cell counts and control of HIV viremia. HIV-specific infections/neoplasms did not contribute to morbidity or mortality in coinfected transplant recipients, with follow-up periods up to ~3.5 years.
While this study represents the largest U.S. experience with transplantation of HIV-HCV coinfected patients, limitations include the lack of a uniform immunosuppressive regimen and standard antiretroviral therapy followed by all centers. Additional limitations include lack of prospective data collection and central biopsy reading in the HCV-mono-infected controls. To avoid potential biases in selection, the HCV mono-infected patients were carefully matched by center, year of transplant and key recipient factors. However, this may not completely mitigate potentially important differences in the HCV-HIV and HCV cohorts. Finally, to minimize error related to assessment of liver disease severity, we focused on advanced fibrosis (bridging fibrosis and cirrhosis) as the critical endpoint. However, liver biopsy adequacy was not assessed and thus underestimation of fibrosis in both HCV-HIV and HCV mono-infected patients with small biopsies may have occurred.28
However, any measurement bias related to assessment of fibrosis severity would be non-differential.
In summary, this study highlights that patient and graft survival are lower in HCV-infected patients with HIV compared to those without HIV, but that acceptable results are achievable in most coinfected patients. Importantly, our results indicate how recipient and donor selection and management of post-transplantation complications may be used potentially improved upon in order to maximize patient and graft survival. Firstly, recipient severity of illness, as reflected by low BMI and need for kidney transplant influences outcomes post-LT. Thus, early referral for consideration of transplantation and utilization of donor options (e.g. living donor) that shorten wait-list time are the best means of overcoming this potential barrier to transplantation. Second, donor selection is important. Older donors are already recognized as a risk for HCV-infected transplant recipients and coinfected patients have higher rates of graft loss with older donors also. Anti-HCV positive donors should be used cautiously given the significant association with graft loss in our study. Thirdly, cytomegalovirus infection was strongly associated with graft loss and we recommend use of universal prophylaxis to minimize any risk for this complication. Finally, reducing rates of early acute rejection are highly desirable, as treatment of rejection is associated with graft loss and more severe HCV disease. Vigilance for rejection and a low threshold to obtain a biopsy to evaluate abnormal liver tests is recommended. Although protease inhibitor and efavirenz use has not been shown to be associated with rejection, graft loss or death, we hypothesize that newer antiretroviral regimens that avoid the use of protease inhibitors and efavirenz may facilitate conventional immunosuppressive drug dosing with better drug exposure and potentially reduce rejection rates. Thus, while there remain many challenges, our results support the continued select use of this life-saving treatment in HCV-HIV coinfected patients.