Presented in part at the 16th Conference on Retroviruses and Opportunistic Infections, Montreal (Canada) in February 8–11, 2009. Abstract No. 833.
Outcome of HCV/HIV-Coinfected Liver Transplant Recipients: A Prospective and Multicenter Cohort Study
Article first published online: 4 APR 2012
© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 12, Issue 7, pages 1866–1876, July 2012
How to Cite
Miro, J. M., Montejo, M., Castells, L., Rafecas, A., Moreno, S., Agüero, F., Abradelo, M., Miralles, P., Torre-Cisneros, J., Pedreira, J. D., Cordero, E., de la Rosa, G., Moyano, B., Moreno, A., Perez, I., Rimola, A. and the Spanish OLT in HIV-Infected Patients Working Group investigators (2012), Outcome of HCV/HIV-Coinfected Liver Transplant Recipients: A Prospective and Multicenter Cohort Study. American Journal of Transplantation, 12: 1866–1876. doi: 10.1111/j.1600-6143.2012.04028.x
- Issue published online: 28 JUN 2012
- Article first published online: 4 APR 2012
- Received 3 August 2011, revised 31 January 2012 and accepted for publication 2 February 2012
- HCV infection;
- HIV infection;
- Liver Transplantation;
Eighty-four HCV/HIV-coinfected and 252-matched HCV-monoinfected liver transplant recipients were included in a prospective multicenter study. Thirty-six (43%) HCV/HIV-coinfected and 75 (30%) HCV-monoinfected patients died, with a survival rate at 5 years of 54% (95% CI, 42–64) and 71% (95% CI, 66 to 77; p = 0.008), respectively. When both groups were considered together, HIV infection was an independent predictor of mortality (HR, 2.202; 95% CI, 1.420–3.413 [p < 0.001]). Multivariate analysis of only the HCV/HIV-coinfected recipients, revealed HCV genotype 1 (HR, 2.98; 95% CI, 1.32–6.76), donor risk index (HR, 9.48; 95% CI, 2.75–32.73) and negative plasma HCV RNA (HR, 0.14; 95% CI, 0.03–0.62) to be associated with mortality. When this analysis was restricted to pretransplant variables, we identified three independent factors (HCV genotype 1, pretransplant MELD score and centers with <1 liver transplantation/year in HIV-infected patients) that allowed us to identify a subset of 60 (71%) patients with a similar 5-year prognosis (69%[95% CI, 54–80]) to that of HCV-monoinfected recipients. In conclusion, 5-year survival in HCV/HIV-coinfected liver recipients was lower than in HCV-monoinfected recipients, although an important subset with a favorable prognosis was identified in the former.
acquired immunodeficiency syndrome
highly active combined antiretroviral therapy
Spanish Foundation for the Investigation and Prevention of Acquired Immunodeficiency Syndrome
Spanish Group for the Study of Acquired Immunodeficiency Syndrome
hepatitis B virus
hepatitis C virus
human immunodeficiency virus
orthotopic liver transplantation
Model for End Stage Liver Disease
men who have sex with men
nucleoside reverse transcriptase inhibitor
sustained virological response
The life expectancy of patients infected by the human immunodeficiency virus type-1 (HIV) has improved dramatically since the introduction of combined antiretroviral treatment (cART) in 1996 (1). However, HIV-infected patients are currently dying of non–AIDS-defining events, especially liver disease related mainly to hepatitis C virus (HCV) infection (2–4). Consequently, orthotopic liver transplantation (OLT) is increasingly necessary in this population (5). At present, HIV-infection is not an absolute contraindication for OLT (6), and this life-saving intervention is performed in most developed countries in selected HIV-infected patients with end-stage liver disease.
In the cART era, excellent results have been achieved with OLT in HIV-infected patients with liver diseases not related to HCV (7–9); however, results in HCV/HIV-coinfected patients are poorer than those obtained in HCV-monoinfected patients (9–11). Published studies usually analyze small case series from single institutions and have relatively short follow-up periods. Cohort studies involving large series are in progress in several European countries and the United States.
In Spain, the first OLT in an HIV-infected patient was performed in 2002 (12). Since then, most Spanish liver transplant units have been performing OLT in this group, leading to the creation of a sizeable cohort, on which this study is based. Our objectives were to compare post-OLT survival between HCV/HIV-coinfected patients and HCV-monoinfected patients and to identify prognostic factors in HCV/HIV-coinfected patients.
This is a prospective, multicenter cohort study including 84 consecutive HCV/HIV-coinfected patients who underwent OLT between 2002 and 2006 in 17 centers in Spain and who were followed until July 2010. HIV-infected recipients were matched with 252 HCV-monoinfected patients (1:3 ratio) who underwent OLT during the same period at the same sites. Other matched criteria were calendar year (±1 year), age (±12 years), gender, presence of HBV coinfection and presence of hepatocellular carcinoma (HCC). The study was approved by the Institutional Review Boards of all the participating sites. All patients signed the informed consent form.
Definitions, data collection, data entry and data management
For each patient, pre-, peri- and post-OLT variables listed in Table 1 were collected. The donor risk index, a score derived from seven donor variables (Table 2) that helps to estimate the influence of donor characteristics on patient and graft outcome after transplantation, was calculated according to the criteria of Feng et al. (13). All variables were collected at each site using a standardized case report form. Information for each patient was recorded at registration on the OLT waiting list, every 3 months until OLT, and at OLT. After OLT data were recorded at 1, 3, 6, 9, 12, 15, 18, 24, 30, 36 months and annually thereafter for up to 10 years. Patient information was sent every 6 months to the coordinating center and entered into the FIPSE OLT-HIV-05-GESIDA 45–05 database (available at https://www.seif88.com/gesida/asp/login.asp). Two data entries were made per patient, and queries and missing data were sent periodically to local investigators for resolution. An audit was performed at all participating sites by checking information from patients selected at random. Overall, the error and missing data rates were less than 5% per site.
|No. of cases||84||48||36|
|Age (year)1||42 (39;45)||42 (39;45)||41 (39;46)||0.8191|
|Male recipients, n (%)||64 (76%)||36 (75%)||28 (78%)||0.5431|
|Caucasian race, n (%)||82 (98%)||47 (98%)||35 (97%)||0.9059|
|Body mass index||24 (22;26)||24 (22;27)||23 (21;26)||0.4487|
|HIV-1 risk factors, n (%)||0.5367|
|Drug use||63 (75%)||37 (77%)||26 (72%)|
|MSM||2 (2%)||1 (2%)||1 (3%)|
|Heterosexual relations||10 (12%)||3 (6%)||7 (19%)|
|Hemophilia||4 (5%)||3 (6%)||1 (3%)|
|Other||4 (4%)||3 (6%)||1(3%)|
|Duration of HIV-1 infection (mo)||157 (116;200)||164 (121;208)||139 (108;191)||0.9165|
|AIDS-defining events2, n (%)||17 (20%)||8 (17%)||9 (25%)||0.4813|
|Fulfill HIV inclusion criteria3, n (%)||74 (88%)||43 (90%)||31 (86%)||0.6925|
|HBV coinfection, n (%)||13 (15%)||12 (25%)||1 (3%)||0.0419|
|Duration of HCV infection (mo)||97 (52;181)||91 (50;181)||99 (65;172)||0.9165|
|HCV genotype, n (%)||0.0681|
|1||46 (55%)||20 (42%)||26 (72%)|
|2||3 (4%)||1 (2%)||2 (6%)|
|3||16 (19%)||12 (25%)||4 (11%)|
|4||12 (14%)||8 (17%)||4 (11%)|
|Other||3 (4%)||3 (6%)|
|Nontypable/others||4 (5%)||4 (8%)|
|Plasma HCV RNA viral load U × 106/mL||5.67(5.16;6.20)||5.52 (4.36;5.91)||5.85 (5.50;6.30)||0.007|
|Negative plasma HCV RNA viral load before OLT, n (%)||7 (8%)||6 (13%)||1 (3%)||0.2497|
|Hepatocellular carcinoma, n (%)||15 (18%)||9 (19%)||6 (17%)||0.9152|
|Child-Turcotte-Pugh class at listing, n (%)||0.0344|
|A||10 (12%)||8 (17%)||2 (6%)|
|B||38 (45%)||25 (52%)||13 (36%)|
|C||35 (42%)||14 (29%)||21 (58%)|
|MELD score at listing4||15 (11;18)||14 (11;16)||17 (12;20)||0.0259|
|MELD score before OLT4||16 (12;19)||14 (11;17)||18 (13;21)||0.0072|
|Delta MELD||0(1; -2)||0 (2; -2)||−0.5 (0.5;-4)||0.2147|
|Type of cART, n (%)||0.8210|
|NRTI-based||11 (13%)||6 (13%)||5 (14%)|
|PI-based||21 (25%)||13 (27%)||8 (22%)|
|Efavirenz-based||37 (44%)||20 (42%)||17 (47%)|
|Other regimens||15 (18%)||9 (19%)||6 (17%)|
|Plasma HIV-1 RNA below 200 copies/mL at listing, n (%)||80 (95%)||46 (96%)||34 (94%)||0.9025|
|CD4 cell count at listing||296 (200;420)||262 (193;424)||309 (208;408)||0.5651|
|Time on waiting list (mo)||4 (2;7)||4 (2;7)||5 (2;7)||0.9245|
|Transplants in centers with < 1 OLT in HIV-infected patients/year, n (%)||13 (15%)||4 (8%)||9 (25%)||0.0039|
|Donor characteristics and other peritransplant variables|
|Donor risk index||1.40 (1.17;1.77)||1.35 (1.03;1.55)||1.53 (1.37;1.78)||0.0019|
|Age (year)||52 (40;68)||48 (34;62)||61 (43;71)||0.0197|
|Male gender, n (%)||48 (57%)||29 (60%)||19 (53%)||0.5814|
|Caucasian race, n (%)||77 (92%)||45 (94%)||32 (89%)||0.5814|
|Cause of donor brain death, n (%)||0.0367|
|Vascular||44 (52%)||20 (42%)||24 (67%)|
|Cranial trauma||25 (30%)||20 (42%)||5 (14%)|
|Other||16 (19%)||8 (17%)||7 (19%)|
|Donor type, n (%)||0.3728|
|Deceased||81 (98%)||46 (96%)||35 (97%)|
|Living-donor||2(1%)||1 (2%)||1 (3%)|
|Domino||1 (1%)||1 (2%)|
|Cold ischemia time (min)||390 (310;535)||378 (297;535)||420 (333;455)||0.7738|
|Peri-operative transfusion requirements (units)5||3 (1;6)||2 (0;5)||4 (3;7)||0.0015|
|Length of follow-up (year)||3.63 (1.41;4.68)||4.44 (3.73;6.00)||1.38 (0.79;2.38)||NA|
|Initial immunosuppression, n (%)||0.9418|
|Cyclosporine-based||26 (31%)||15 (31%)||11 (31%)|
|Tacrolimus-based||49 (58%)||29 (60%)||20 (56%)|
|Other regimens||9 (11%)||4 (8%)||5 (14%)|
|Time to re-start cART (d)||9 (5;17)||9 (4;16)||10 (7;24)||0.1152|
|Type of cART, n (%)||0.8210|
|NRTI-based||11 (13%)||6 (13%)||5 (14%)|
|PI-based||21 (25%)||13 (27%)||8 (22%)|
|Efavirenz-based||37 (44%)||20 (42%)||17 (47%)|
|Others||15 (18%)||9 (19%)||6 (17%)|
|Acute rejection, n (%)||32 (38%)||18 (38%)||14 (39%)||0.9893|
|Chronic rejection, n (%)||2 (2%)||–||2 (6%)||0.0865|
|Peak plasma HCV RNA viral load increase after transplantation (log10)||6.66 (5.88;7.17)||6.48 (5.70;7.02)||6.89 (6.16;7.37)||0.059|
|Anti-HCV treatment, n (%)||47 (56%)||26 (54%)||21 (58%)||0.825|
|SVR to anti-HCV treatment, n (%)||13/47 (28%)||12/26 (46%)||1/21 (5%)||0.013|
|At least one infection, n (%)||58 (69%)||29 (60%)||29 (81%)||0.077|
|Severe infection, n (%)||39 (46%)||16 (33%)||23 (64%)||0.006|
|Invasive fungal infection6, n (%)||6 (7%)||1 (2%)||5 (14%)||0.008|
|CMV disease, n (%)||2 (2%)||1 (2%)||1 (3%)||1.000|
|Tuberculosis, n (%)||2 (2%)||1 (2%)||1 (3%)||1.000|
|Re-transplantation7, n (%)||4 (5%)||2 (4%)||2 (6%)||0.201|
|HCV/HIV coinfection||HCV monoinfection||p-Value|
|No. of cases||84||252|
|Matching recipient variables:|
|Age (year)1||42 (39;45)||47 (43;53)|
|Male gender||20 (76%)||63 (74%)|
|HBV coinfection||13 (15%)||13 (5%)|
|Hepatocellular carcinoma||15 (18%)||40(16%)|
|Other recipient variables:|
|Pre-OLT MELD score1||15 (11;18)||15 (13;18)||0.363|
|Delta MELD1||0 (-1;2)||0 (-2;2)||0.593|
|HCV genotype 1||46 (55%)||173 (69%)||<0.001|
|RNA—before OLT||7 (8%)||25 (10%)||0.830|
|SVR/No. treated after OLT||13/47 (28%)||39/117 (33%)||0.603|
|Donor age > 60 years||23 (27%)||74 (29%)||0.781|
|Donor brain death by trauma||25 (30%)||90 (36%)||0.388|
|Caucasian race||77(92%)||235 (93%)||0.629|
|Donation after cardiac death||1 (1.2%)||1 (0.4%)||0.440|
|Height (cm)1||170 (160;170)||170 (161;175)||0.104|
|Local donation||78 (93%)||251 (99%)||0.046|
|Cold ischemia time (minutes)1||388 (320;535)||377 (300;486)||0.412|
|Donor risk index1||1.40 (1.17;177)||1.38 (1.11;1.65)||0.134|
|Follow-up (year)1||3.63 (1.41;4.68)||4.68 (3.00;5.96)|
|Acute rejection2||32 (38%)||50 (20%)||0.001|
|FCH||9 (11%)||10 (4%)||0.029|
|Stage F3/F4 fibrosis||30/65 (46%)||54/187 (29%)||0.014|
|Severe graft fibrosis4||37/72 (51%)||62/193 (32%)||0.004|
|Retransplantation5||4 (5%)||17 (7%)||0.611|
|Mortality||36 (43%)||75 (30%)||0.033|
|Causes of death6|
|HCV recurrence||18 (21%)||31 (12%)||0.049|
|Infection||7 (8%)||15 (6%)||0.612|
|Tumors||3 (4%)||4 (2%)||0.373|
|Technical problems||–||6 (2%)||0.343|
|Other causes||8 (10%)||19 (8%)||0.643|
The definitions of HIV, HCV and HBV infections, AIDS-defining events (14) and bacterial, fungal and viral infectious and other posttransplant complications were based on standard criteria (15,16). Severe infections were defined as follows: any bacterial infection with bacteremia, pneumonia, intraabdominal and/or central nervous system involvement, invasive fungal infection, cytomegalovirus disease, any invasive viral infection and mycobacterial disease. As habitually in the setting of liver transplantation, the transplant activity of the participating centers was based on the number of transplants performed per year in HIV-infected patients and was considered low if the center performed less than 1 per year.
Data for HIV-negative recipients were obtained from the Spanish Liver Transplant Registry. Variables not included in the registry were collected at the participating sites according to a common protocol. Data were managed and analyzed blind at the coordinating center.
HIV-infected patients had to fulfill the following criteria according to their infection status (17): no AIDS-defining events except tuberculosis, esophageal candidiasis, or Pneumocystis jiroveci pneumonia, CD4+ T cell count >100 cells/μL (>200 cells/μL in cases with a history of opportunistic infection) and a plasma HIV-RNA viral load that was undetectable or suppressible with cART. Former intravenous drug users had to have abstained from heroin or cocaine use for more than 2 years. The minimum period of abstinence for alcohol was 6 months. As for liver disease, the criteria for accepting HIV-infected patients for transplantation were the same as those followed in Spain for HIV-negative patients: a minimum Child-Turcotte-Pugh score of 7 for patients with cirrhosis, and, for patients with HCC, 1 tumor of <5 cm or 2–3 tumors of <3 cm in the absence of hepatic macrovascular tumoral invasion and extrahepatic metastases.
Combined antiretroviral therapy was administered until the day of surgery and resumed once the patient was stable and oral intake was reintroduced. Antiretroviral drugs were administered according to national guidelines (18).
HIV-infected recipients received the same immunosuppressive regimens as HIV-negative patients according to local protocols. Rejection was diagnosed according to the Banff criteria (19). Post-OLT and HIV infection antimicrobial prophylaxis were administered according to national guidelines (20,21).
During follow-up, liver biopsies were performed according to the protocols of each center and were mostly annual or biannual. Fibrosing cholestatic hepatitis (FCH) was defined according to standard histologic criteria (22). In chronic hepatitis, fibrosis stage was established according to the METAVIR system (23). Severe graft fibrosis was defined as the development of FCH or stage F3/F4 fibrosis as assessed by the METAVIR score. HCV recurrence was treated with pegylated interferon α-2a or α-2b and ribavirin and was based on the same criteria for HCV monoinfected OLT recipients according to local protocols. Sustained virological response (SVR) was defined as a persistently negative plasma HCV-RNA viral load at 24 weeks of follow-up after the end of treatment.
Variables are expressed as the mean and standard deviation, median and interquartile range (IQR), or as proportions, as appropriate. Patient and graft survival and time to severe graft fibrosis were analyzed with the date of transplantation as the start date. Survival time from OLT was estimated using the Kaplan-Meier product-limit method; the curves obtained in different groups were compared using the generalized log-rank test (univariate Cox model analysis). Predictors associated with a p value <0.10 in the univariate analysis were considered as candidate predictors for the multivariate analyses. We used both forward stepwise and backward elimination subset selection methods to identify variables that predicted survival. The significance level for entering effects was <0.1 and the significance level for removing effects was 0.05. The hazard ratio (HR) and the associated 95% confidence interval (CI) for each predictor were calculated. Statistical significance was defined as a bilateral p value <0.05. All statistical analyses were carried out using the Stata package (release 9.2).
The annual distribution of OLT in HCV/HIV-coinfected patients and the number of cases per center are depicted in Figures 1(A) and (B). Pre-, peri- and postoperative variables in HCV/HIV-coinfected recipients and characteristics of their donors are shown in Table 1. Donors were HIV, HCV and HBV negative. No patients underwent combined liver–kidney transplantation. Median (IQR) follow-up was 3.63 (1.41; 4.68) years and no patients were lost to follow-up. No recurrences of HBV infection were recorded.
Post-OLT survival in HCV/HIV-coinfected patients and HCV-monoinfected patients
Table 2 shows the main characteristics of both cohorts. HCV/HIV-coinfected patients underwent the procedure in the same institutions and calendar year and, as matched criteria, they had a similar age and similar proportions of male gender, HBV coinfection and HCC as HCV-monoinfected recipients. Patients exposed and nonexposed to HIV had a similar MELD score. HIV-infected patients had a lower rate of HCV genotype 1 (p = 0.001), although the rates of sustained virological response after anti-HCV therapy were similar in both groups. Donor risk index was the same in both cohorts. The rate of acute rejection was almost two times higher in HIV-infected patients (38% vs. 20%; p = 0.001). CD4+ T-cell count remained stable in HIV-infected patients in most cases between 200 cells/μL and 300 cells/μL and most patients (>90%) remained virologically suppressed on cART during the post-OLT study period (Table 3). Four coinfected patients (5%) and 17 monoinfected patients (7%) underwent a second transplant.
|CD4+ T-cell counts1||Plasma HIV-1 RNA viral load <200 copies/mL|
|At listing (N = 84)||296 (200;420)||80 (95%)|
|At one month (N = 81)||296 (200;420)||73 (90%)|
|At 6 months (N = 77)||268 (175;395)||73 (95%)|
|At 1 year (N = 73)||269 (178;333)||68 (96%)|
|At 2 years (N = 60)||294 (189;387)||59 (98%)|
|At 3 years (N = 49)||334 (229;478)||47 (96%)|
|At 4 years (N = 35)||309 (246;475)||33 (94%)|
|At 5 years (N = 23)||344 (257;528)||22 (96%)|
Mortality was significantly higher among HCV/HIV-coinfected recipients. Thirty-six (43%) HCV/HIV-coinfected patients and 75 (30%) HCV-monoinfected patients died (p = 0.033) during a median (IQR) of 3.63 (1.41; 4.68) and 4.68 (3.00; 5.96) years of follow-up, respectively. As shown in Table 2, HCV recurrence was the most important cause of death—21% and 12% of cases (p = 0.049), respectively—but was more frequent in HIV-infected patients (p = 0.049).
Figures 2(A),(B) and Table 4 show patient and graft survival in HCV-infected liver recipients according to their HIV status. Patient survival (95% CI) rates at 1, 3 and 5 years for HCV/HIV-coinfected and HCV-monoinfected patients were 88% (79–93) versus 90% (86–93), 62% (51–72) versus 76% (70–80) and 54% (42–64) versus 71% (66–77), respectively (overall, p = 0.008). Similar differences were observed in graft survival (p = 0.042).
|HCV/HIV coinfection||HCV monoinfection||p-Value|
|No. of cases||N = 84||N = 252|
|Patient survival at||p = 0.008|
|1 year||88% (79%–93%)||90% (86%–93%)|
|2 years||71% (60%–79%)||81% (75%–85%)|
|3 years||62% (51%–72%)||76% (70%–80%)|
|4 years||60% (47%–69%)||73% (67%–78%)|
|5 years||54% (42%–64%)||71% (66%–77%)|
|Graft survival at||p = 0.042|
|1 year||86% (76%–92%)||85% (80%–89%)|
|2 years||69% (57%–78%)||74% (68%–79%)|
|3 years||60% (48%–70%)||69% (63%–74%)|
|4 years||54% (41%–65%)||65% (59%–71%)|
|5 years||45% (31%–58%)||64% (58%–70%)|
The multivariate analysis adjusted for the variables included in Table 2 that yielded a p-value <0.10 showed that HIV infection was an independent predictor of post-OLT mortality (HR, 2.20; 95% CI, 1.42–3.41; p < 0.001). HCV genotype 1 (HR, 2.14; 95% CI, 1.24–3.41; p = 0.006) and donor risk index (HR, 3.03; 95% CI, 1.57–5.83; p < 0.001) were also independently associated with death. A negative HCV RNA viral load before or after OLT was a protective factor (HR, 0.23; 95% CI, 0.10–0.49; p< 0.001).
Severity of HCV recurrence after OLT in HCV/HIV-coinfected patients and HCV-monoinfected patients
Coinfected patients had a higher rate of FCH than monoinfected patients (11% vs. 4%; p = 0.029) and a higher rate of stage F3/F4 fibrosis (46%vs. 29%, p = 0.014; Table 2). Severe graft fibrosis was also more frequent in coinfected patients (Table 2). Figure 3 shows the probability of severe graft fibrosis in patients according to their HIV status. The probability (95% CI) of remaining free from severe graft fibrosis at 1, 3 and 5 years for HCV/HIV-coinfected and HCV-monoinfected patients was 84% (73–91) versus 90% (85–94), 42% (27–54) versus 66% (56–73) and 24% (12–39) versus 49% (38–59), respectively (overall, p < 0.001).
Predictive factors of mortality among HCV/HIV-coinfected patients
The results of the univariate analysis of prognostic factors in HCV/HIV-coinfected liver recipients are shown in Table 5. A multivariate analysis including all variables reaching a p value ≤ 0.1 in the univariate analysis revealed the following independent risk factors for death: HCV genotype 1 (HR, 2.98; 95% CI, 1.32–6.76; p = 0.008), donor risk index (HR, 9.48; 95% CI, 2.75–32.73; p < 0.001) and a negative HCV RNA viral load before or after OLT (HR, 0.14; 95% CI, 0.03–0.62; p = 0.009). When we included pretransplant variables only, MELD score (HR, 1.06; 95% CI, 1.01–1.11; p = 0.023), transplant at a center with less than 1 OLT per year in HIV-infected patients (HR, 2.82; 95% CI, 1.30–6.94, p = 0.009) and HCV genotype 1 (HR 2.27; 95% CI, 1.09–4.76; p = 0.029) were independently associated with death.
|Hazard ratio (95% confidence interval)||p-Value|
|HCV genotype 1||2.55 (1.22;5.29)||0.012|
|Plasma HCV RNA viral load above the median (400,000 units)||1.89 (0.97;3.67)||0.061|
|HBV coinfection||0.13 (0.02;0.97)||0.042|
|MELD score at listing (1-unit increase)||1.06 (1.01;1.12)||0.026|
|MELD score pre-OLT (1-unit increase)||1.07 (1.01;1.12)||0.007|
|Child-Turcotte-Pugh C stage at listing||2.38 (1.22;4.62)||0.011|
|Center with <1 liver transplants in HIV-infected patients/year||3.08 (1.43;6.67)||0.004|
|Donor age ≥60 years||2.51 (1.29;4.90)||0.007|
|Noncranial trauma as cause of donor brain death||3.17 (1.23;8.16)||0.017|
|Peri-operative red blood cell transfusion ≥3 units||2.73 (1.47;6.25)||0.004|
|Donor risk index||6.35 (1.98;20.39)||0.002|
|Negative plasma HCV RNA viral load at any time (before or after OLT)||0.14 (0.03;0.58)||0.007|
|Peak plasma HCV RNA viral load increase after OLT (1 log10 increase)||1.53 (1.00;2.34)||0.048|
|Chronic rejection||3.57 (0.83;15.28)||0.086|
|Severe infection||2.61 (1.32;5.19)||0.006|
|Invasive fungal infection||3.73 (1.42;9.81)||0.008|
As pretransplant variables may be helpful in the selection of HCV/HIV-coinfected OLT candidates, we calculated a risk score for mortality taking into account the three variables identified in the multivariate analysis and their respective regression coefficients (24). The individual risk of mortality of the 84 recipients was calculated with the formula “Exp ([(0.81966* if genotype = 1]+[0.05748* MELD pre-OLT]+[1.03540 if center <1 OLT in HIV-infected patients/year])”. A risk score cut-off of 1.07795 classified the 84 recipients as having a low risk (n = 60 patients, 69%) or a high risk of death (n = 24 patients, 31%). This cut-off was chosen to ensure an equal number of deaths in both subsets. Figure 2(C) shows the Kaplan-Meier survival curves for these groups. Survival (95% CI) rates at 1 and 5 years for recipients with a low or high mortality risk score were 93% (83 to 97) versus 74% (51–87) and 69% (54–80) versus 17% (5–35), respectively (p < 0.001).
This study shows that OLT was an effective short-term (1 year) procedure in HCV/HIV-coinfected liver recipients, with a survival rate similar to that observed in HCV-monoinfected patients (88% vs. 90%). However, post-OLT survival in HCV/HIV-coinfected patients after longer follow-up was lower (at 5 years: 54% vs. 71%, p = 0.008), although acceptable.
The present cohort had three interesting characteristics: (1) It was a nationwide multicenter study with the participation of 17 out of the 23 units performing OLT in Spain; (2) HIV-specific criteria for OLT were previously agreed by all units (17) and, (3) We started the program in the late cART era and managed to collect a relatively large cohort of HCV/HIV-coinfected OLT recipients (N = 84) over a short period of time (2002–2006). In addition, we waited a minimum of 3 years before reporting our results. Consequently, our findings are even more valid, as previously published studies (5,10,11) in HCV/HIV-coinfected liver transplant patients were performed in single institutions with smaller sample sizes collected over longer periods.
We found that HIV-infection was an independent predictor of death in HCV-infected liver transplant recipients. When we compared the cohort of HCV-infected recipients exposed to HIV infection or not, the results of matched variables were obviously similar, but the MELD score before transplantation, which was not a matching criterion and has been reported to have prognostic value in HCV-infected liver transplant recipients (11), was the same in both cohorts. Furthermore, other variables capable of influencing post-OLT outcome were also similar, such as the donor risk index and its individual components. On the other hand, the rate of HCV genotype 1, a poor prognostic factor for HCV-infected transplant recipients (25,26), was higher in our HCV-monoinfected patients, although this group of patients had a better 5-year survival. The most likely explanation for the worse outcome in HCV/HIV-coinfected patients is HCV recurrence after OLT, which has been reported to be more aggressive in this group than in HCV-monoinfected recipients (10,11). Consistent with this possibility, severe graft fibrosis was observed more often and earlier in HCV/HIV-coinfected patients than in HCV-monoinfected patients (Figure 3), and almost twice as many HIV/HCV-infected recipients as HCV-monoinfected recipients died due to HCV recurrence (21% vs. 12%; p = 0.049; Table 2). The similar survival in both cohorts at 1 year and the lower survival in HCV/HIV-coinfected patients beyond this time point also support this hypothesis, because the negative impact of HCV recurrence predictably becomes apparent in the medium or long term after OLT.
A remarkable finding in our study was the higher incidence of biopsy-proven acute rejection in HCV/HIV-coinfected recipients than in HCV-monoinfected patients: 38% vs. 20% (p < 0.001). This high rate of rejection in coinfected patients is consistent with the 30–40% incidence of rejection reported elsewhere (10,11,27). The reasons for this finding are elusive. However, it has been attributed to the immunomodulatory effects of HIV and difficulties in achieving optimal immunosuppression due to strong interactions between some antiretroviral agents and immunosuppressive drugs (10,11). On the other hand, because rejecting patients could have received a more powerful immunosuppression as antirejection therapy, the higher incidence of rejection in coinfected recipients could have indirectly contributed to their worse HCV recurrence (26).
Once we realized that survival in HCV/HIV-coinfected recipients was relatively poor, we tried to identify variables with prognostic significance in this population. A multivariate analysis adjusted for pre-, peri- and postoperative variables, revealed that the donor risk index and HCV genotype 1 were independently associated with an increased risk of death, whereas having a negative HCV RNA before or after OLT was a protective factor. It is well established that donor-related factors such as donor risk index correlate clearly with survival after liver transplantation (13). This association has also been seen in HCV-monoinfected liver transplant recipients (28). HCV genotype 1 has been found to be a predictor of mortality in HCV-monoinfected OLT recipients (25,26). Conversely, clearance of HCV after treatment with pegylated-interferon and ribavirin is a protective factor that confers a favorable long-term outcome (29). However, with current anti-HCV therapy, the rate of sustained virological response is very low in HCV/HIV-coinfected recipients, mainly in patients with HCV genotype 1 (29,30). The development of better drugs to treat HCV will probably improve these results.
An additional analysis including only the three pretransplant variables independently associated with post-OLT death (MELD score, HCV genotype 1 and center activity in OLT in HCV/HIV-coinfected patients) identified a subset of HCV/HIV-coinfected patients, comprising two-thirds of our cohort, with a 5-year life expectancy that was very similar to that of HCV-monoinfected recipients (69% vs. 71%). The importance of HCV genotype 1 and MELD score as poor prognostic factors has already been discussed earlier (11,25,26,29,30). In our series, coinfected patients who underwent transplant in centers with a low activity (<1 OLT/year) had almost three times higher mortality. This finding agrees with previous studies indicating that transplant center volume has an impact on survival (31–33). Although not evaluated in our study, a training effect cannot be excluded. Conversely, we also identified a subset of HCV/HIV-coinfected patients, including the remaining third of the cohort, with poor expected survival after OLT: only 17% at 5 years. Therefore, patients with the characteristics of this subset should theoretically be excluded from OLT. Nevertheless, the low number of patients in this subset (only 24), the lack of studies verifying the reproducibility of our results, and the possible improvement for genotype 1 HCV infection with new anti-HCV drugs preclude robust conclusions on this key issue. Further investigations involving large series of patients from other countries, or even the inclusion of more patients in our own study, are necessary before formal recommendations can be made.
Although 12% of our HCV/HIV-coinfected patients did not fulfill the HIV inclusion criteria for OLT, survival did not significantly differ from that of patients fulfilling these criteria, suggesting that some of our criteria were probably too restrictive. Consistent with the findings of previous studies (11,34), our cohort had very good immunological and virological control on cART, with a low rate of opportunistic infections after OLT.
Our study has three main limitations. First, we could not analyze prognostic factors in patients stratified according to the different HCV genotypes. Nevertheless, the prognosis of patients with non-1 HCV genotypes is clearly better; therefore, this group should not be excluded from OLT. Second, the number of recipients who reached at least 5 years of follow-up is small, and the results might change with a larger sample size. Several prospective cohort studies in Europe and the United States and the present cohort may provide more results on this issue either individually or by merging data. Third, although an intention-to-treat analysis from the time of admission of HIV/HCV-coinfected and HCV-monoinfected patients to the OLT waiting list would have been a very interesting addition to our cohort study, we were unable to perform such an analysis, because we did not collect information on patients on the waiting list who had not received a transplant.
In conclusion, OLT is an effective short-term procedure in HCV/HIV-coinfected recipients. Patient and graft survival in the medium term were lower than that of the matched HCV-monoinfected patients, although it remained acceptable. Our study was able to identify subsets of patients with a more favorable prognosis. Liver transplantation in HCV/HIV-coinfected patients restricted to sites with more experience and better anti-HCV therapies could improve long-term outcome in these patients.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
We are indebted to the study participants and to the staff of the liver transplant units at the centers for retrieving detailed data on donors and transplantation. We dedicate this article to Drs. Gabi Rufi (Barcelona) and Carles Margarit (Barcelona) who played a key role in launching the project and who died. We also acknowledge the following: “Fundación para la Investigación y Prevención del Sida en España (FIPSE)”, Madrid, Spain; the National AIDS Plan Secretariat and the National Transplant Organization (ONT) of the Spanish Ministry of Health, Madrid, Spain; the Spanish Society of Liver Transplantation (SET), Madrid, Spain; and the HIV/AIDS (GESIDA) and Infections in Transplants (GESITRA) Working Groups and the SEIMC/GESIDA Foundation (FSG) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), Madrid, Spain for their constant support from the beginning of the project. CIBEREHD was supported by Instituto de Salud Carlos III, Spain.
Funding Sources: This study was supported by the Spanish Foundation for AIDS Research and Prevention (FIPSE, Madrid, Spain), grants TOH-VIH/05 and TOH-VIH/08. JMM holds an INT10/219 Intensification Research Grant (I3SNS & PRICS programs) from the Instituto de Salud Carlos III, Madrid (Spain) and the Departament de Salut de la Generalitat de Catalunya, Barcelona (Spain).
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List of Investigators of the Spanish OLT in HIV-Infected Patients Working Group: J.D. Pedreira, M.A. Castro, S. López, F. Suárez, P. Vázquez, Hospital Universitario de A Coruña; J.M. Miro, F. Agüero, J. Blanch, M. Brunet, C. Cervera, E. de Lazzari, C. Fondevila, A. Forner, J. Fuster, N. Freixa, J. C. García-Valdecasas A. Gil, J.M. Gatell, M. Laguno, M. Larrousse, J. Mallolas, C. Manzardo, M. Monrás, A. Moreno, J. Murillas, D. Paredes, I. Pérez, F. Torres, C. Tural, M. Tuset, A. Rimola. Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona; A. Antela, E. Losada, E. Molina, E. Otero, E. Varo, Hospital Clínico Universitario, Santiago de Compostela, A Coruña; R. Lozano, J.J. Araiz, E. Barrao, J. Larraga, S. Letona, P. Luque, A. Navarro, I. Sanjoaquín, T. Serrano, E. Tejero, Hospital Clínico Universitario Lozano Blesa, Zaragoza; M. Salcedo, R. Bañares, J. Berenguer, G. Clemente, J. Cosín, J.P. Ferreiroa, J.L. García-Sabrido, I. Gutiérrez, J.C. López, P. Miralles, M. Ramírez, D. Rincón, M. Sánchez, Hospital General Universitario Gregorio Marañón, Madrid; M. Jiménez, J. de la Cruz, J.L. Fernández, J.M. Lozano, J. Santoyo, J.M. Rodrigo, M.A. Suárez, Hospital Regional Universitario Carlos Haya, Málaga; M. Rodríguez, M.P. Alonso, V. Asensi, M.L. González-Diéguez, I. González-Pinto, Hospital Universitario Central de Asturias, Oviedo; A. Rafecas, C. Baliellas, J. Carratalá, J. Fabregat, N. Fernández, R. Jorba, L. Lladó, X. Xiol, Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona; M. Montejo, J. Bustamante, J.R. Fernández, M. Gastaca, J. González, E. Montejo, J. Ortiz de Urbina, P. Ruiz, M.J. Suárez M. Testillano, A. Valdivieso, A. Ventoso, Hospital Universitario de Cruces, Bilbao, Vizcaya; M. Abradelo, J. Calvo, J.R. Costa, A. García-Sesma, C. Jiménez, A. Manrique, J.C. Meneu, E. Moreno, V. Moreno, S.P. Olivares, F. Pulido, R. Rubio, Hospital Universitario Doce de Octubre, Madrid; M. Blanes, V. Aguilera, M. Berenguer, J. López, R. López, M. Prieto, Hospital Universitari La Fe, Valencia; M.C. Fariñas, F. Casafont, S. Echevarria, E. Fábrega, J.D. García-Palomo†, M. Gomez-Fleitas, M. Gutiérrez-Cuadra, G. Saravia, Hospital Universitario Marqués de Valdecilla, Santander; S. Moreno, R. Barcena, S. del Campo, P. Martin-Dávila, J. Fortún, A.M. Moreno, Hospital Universitario Ramón y Cajal, Madrid; J. Torre-Cisneros, P. Barrera, J. Briceño, JJ. Caston, G. Costan, M. de la Mata, R. Lara, P. López-Cillero, JL. Montero, A. Rivero, S. Rufian, Hospital Universitario Reina Sofía-IMIBIC, University of Córdoba; Ll. Castells, I. Bilbao, I. Campos-Varela, R. Charco, J.I. Esteban, J. Gavaldá, O. Len, A. Pahissa, E. Ribera, V. Vargas, Hospital Universitari Vall d’Hebrón, Barcelona; J.A. Pons, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia; E. Cordero, C. Bernal, J.M. Cisneros, M.A. Gómez, J.M. Pascasio, M.J. Rodríguez, M. Sayago, J.M. Sousa, G. Suárez, Hospital Universitario Virgen del Rocío, Sevilla; J. González-García, Hospital Universitario La Paz-IdiPAZ, Madrid, E. Aznar, E. Barquilla, H. Esteban and B. Moyano, SEIMC-GESIDA Foundation, Madrid.
Steering Committee: J.M. Miro (Chair), L. Castells, G. de la Rosa, J. Torre-Cisneros, J. Fortún, J. González-García, L. Guerra (FIPSE), F. Lozano, M. Manzanera (FIPSE), P. Miralles, A. Moreno, A. Rafecas, A. Rimola (Vice-Chair) and A. Valdivieso. P. Stock (University of San Francisco, San Francisco, California, USA), M. Roland (University of San Francisco, San Francisco, California, USA) and D. Samuel (Hôpital Paul Brousse, Paris, France) were the external advisors of the committee.
Follow-up Committee: J.M. Miro (Chair), S. del Campo, H. Esteban, J. González-García, C. Manzardo, E. Montejo, B. Moyano and M. Manzanera (FIPSE).
Coordinating Center Staff: E. Aznar, E. Barquilla, H. Esteban, J. González-García and B. Moyano from the SEIMC-GESIDA Foundation, Madrid.
Methodological Committee: J.M. Miro, I. Perez, C. Mazardo, A. Moreno and A. Rimola from Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona.