Terrault NA, Roland ME, Schiano T, Dove L, Wong MT, Poordad F, et al. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transplant 2012;18:716-726. (Reprinted with permission.)
Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)–infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV-coinfected patients and 2 control groups: 235 HCV-monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3-year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%-71%] and 53% (95% CI = 40%-64%) for the HCV/HIV patients and 79% (95% CI = 72%-84%) and 74% (95% CI = 66%-79%) for the HCV-infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney-liver transplantation (HR = 3.8), an anti-HCV–positive donor (HR = 2.5), and a body mass index <21 kg/m2 (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV-coinfected LT patients versus HCV-monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV-coinfected recipients versus HCV-infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes.
Since the advent of highly active antiretroviral therapy (HAART), the prognosis of infection due to human immunodeficiency virus (HIV) has improved dramatically. Thirty percent of HIV-infected patients are coinfected with hepatitis C virus (HCV), 10% are coinfected with hepatitis B virus (HBV), and a high number of HIV-infected patients die as a consequence of viral hepatitis. HIV infection was a contraindication to liver transplantation until early 2000.1 Then, several independent teams decided to offer liver transplantation to patients with controlled HIV infection and life-threatening liver disease.2 This major change in practice was related directly to the efficacy of HAART, which improved the survival of HIV-infected patients dramatically by controlling viral infection. In addition, many patients coinfected with HBV or HCV have poor survival due to progression of liver disease. Most studies have shown that combined prophylaxis with hepatitis B immune globulins plus nucleos(t)ides effective against HBV and HIV prevents HBV reinfection, avoids graft disease, and controls HIV infection with survival over 90%.3, 4
The 10-year experience in liver transplantation for HIV/HCV-infected patients reported from single and multicenter studies reflects poor overall posttransplant survival, challenging the use of liver transplantation in this population. The severity of HCV reinfection is the main cause of graft failure,5, 6 yet progression of HIV infection does not contribute to graft failure or death. However, the reason this population has a much poorer outcome than HCV-monoinfected patients has raised the unanswered question regarding the direct (viral interference) or indirect (immune response) impact of HIV on HCV infection.7 What has been observed is now well known: coinfected patients have a higher HCV viral load after transplantation, a higher rate of fibrosing cholestatic hepatitis (the most severe form of HCV recurrence) and overall a more rapid progression of fibrosis.5, 8 Although the pathogenesis of this severe form of HCV reinfection is unknown, several groups have tried to identify risk factors for HCV recurrence. In a recent multicenter study, Terrault et al. collected pre- and posttransplant data on 89 HIV/HCV-coinfected patients compared with 235 HCV-matched monoinfected patients.9 They showed an overall graft and patient survival of 60% and 53%, respectively, significantly lower than in the HCV-monoinfected group. More importantly, HIV infection was the sole independent factor associated with lower patient and graft survival. They also showed a higher rate of acute rejection in the HIV/HCV-coinfected group. In contrast to other studies, they did not show a more severe rate of fibrosis in the HIV/HCV-coinfected group, but a higher rate of death due to multiple organ failure and sepsis, yet there was no death directly attributed to HIV infection and no progression of the HIV disease after transplantation. Surprisingly, there was no improvement in survival in the more recent cohort of HIV/HCV-coinfected patients in comparison to the older cohort. In a more in-depth analysis, Terrault et al. identified several independent risk factors: HCV-positive graft donor, body mass index (BMI) <21 kg/m2, old donor, HCV infected donor, and combined liver and kidney transplantation. The authors identified a subgroup of 25 patients with a high-risk score identified by the association of three risk factors: BMI <21kg/m2, combined liver and kidney transplantation, and receipt of an HCV positive graft. These patients had a 3-year survival of only 29%. Therefore, the authors suggest that patients with this combination of risk factors are not well served by liver transplantation. In contrast, the group without these risk factors had a survival rate similar to patients older than 65 years in the Scientific Registry of Transplant Recipients database. The authors conclude that liver transplantation should still be offered to HIV/HCV-coinfected patients without the aforementioned risk factors. This study confirms one observation common to all studies: patients coinfected with HIV/HCV have a lower survival after liver transplantation than patients infected with HCV alone.5, 6, 8, 10 We are now at a point where a general sum up is mandatory. This study clearly has some limitations. First, the matched control HCV group was significantly different from the HIV/HCV-coinfected group: more patients in the HIV/HCV-coinfected group received HCV-positive grafts and grafts from non–heart-beating donors, two factors of graft selection known to be deleterious. Second, patients who received combined liver and kidney transplantation represent a marginal and heterogeneous group. Thus, the high-risk group includes only a single factor reflective of general health, liver disease, and HIV status: the BMI. Surprisingly, contrary to previous studies, graft fibrosis was not found to be more severe in the coinfected group.5, 6, 8 There may be some bias in the analysis of graft fibrosis progression, since the posttransplant management differed between the two groups and there were more early deaths in the HIV-HCV-coinfected group.
The experience of several centers2, 5, 6, 8-10 has identified risk factors including (1) pretransplant factors such as poor nutrition status, high Model for End-Stage Liver Disease score, CD4 count, and genotype 1 HCV; (2) donor factors such as HCV-positive grafts, older donor, and grafts with high donor risk index; (3) center experience in HIV/HCV-coinfected patients (<l per year); and (4) posttransplant factors such as high HCV viral load, severe infection, cytomegalovirus infection, acute rejection, and steroid boluses. Thus, a future high-risk score should prospectively include all these parameters (Fig. 1). In addition, we are entering a new era with potent direct antiviral agents against HCV. This population of HIV/HCV-coinfected patients will remain difficult to treat, with challenging drug-drug interactions between calcineurin inhibitors, protease inhibitors, and nucleos(t)ide analogues against HIV and direct antiviral anti-HCV agents.11 However, this will certainly open new possibilities to clear HCV either before or after transplantation and fortunately improve the outcome of liver transplantation dramatically for HIV/HCV-coinfected patients.