Stratification by HCV status within each era demonstrated improved outcomes over time among monoinfected patients, such that in the modern transplant era, there was no longer a difference in risk for death between monoinfected and uninfected recipients (aHR, 1.11; 95% CI, 0.52-2.35; P = 0.79). In contrast, survival did not improve over time among coinfected patients, such that, compared to HCV+ alone recipients, increased risk for death persisted over time (aHR, 2.24; 95% CI, 1.43-3.53; P < 0.001) (Table 4).
Among all HIV+ recipients, 5-year GS was 50.7%, and 10-year GS was 35.4% (Table 2). There was no statistically significant difference in GS among monoinfected (HIV+/HCV−) compared to coinfected (HIV+/HCV+) recipients at 5 years (59.3% [HIV+/HCV−] vs 46.4% [HIV+/HCV+]; P = 0.19) and 10 years (35.1% [HIV+/HCV−] vs 41.1% [HIV+/HCV+]; P = 0.28) after transplantation. Among HIV+ recipients, the risk for graft loss was greater with the use of liver grafts from donors over the age of 50 years (hazard ratios, 1.70; 95% CI, 1.11-2.60; P = 0.01) (Table 3).
GS Compared to HIV− Population
Compared to the general HIV− population, 5- and 10-year survivals were significantly worse among HIV+ recipients (5 years: 50.7% vs 70.1%; P < 0.001; 10 years: 35.4% vs 57.8%; P < 0.001). Moreover, monoinfected recipients had significantly lower GS (5 years, 59.3%; 10 years, 35.1%) compared to the uninfected transplant population (5 years, 73.8%; 10 years, 62.2%; P = 0.05). Further, compared to HCV+ recipients (5 years, 66.0%; 10 years, 53.0%), coinfected patients (HIV+/HCV+) had significantly lower GS (5 years, 46.4%; 10 years, 41.1%; P < 0.001) (Table 2). These differences in GS remained even when comparing HIV+ recipients with appropriately matched HIV− controls (5 years: 51.3% vs 68.4%; P < 0.001; 10 years: 34.2% vs 53.7%; P < 0.001; aHR, 1.70; 95% CI, 1.31-2.20; P < 0.001) (Figure 3), and across transplant era (early era aHR, 1.86; 95% CI, 1.23-2.70; P = 0.001; modern era aHR, 1.58; 95% CI, 1.06-2.34; P = 0.02) (Table 4).
Stratification by HCV status within each era demonstrated improved outcomes over time among monoinfected patients, such that in the modern transplant era, there was no longer a difference in risk for graft loss between monoinfected and uninfected recipients (aHR, 0.89; 95% CI, 0.42-1.88; P = 0.77). Differences in risk for graft loss persisted in the modern era among coinfected patients when compared to recipients with HCV alone (aHR, 2.07; 95% CI, 1.33-3.22; P = 0.001) (Table 4).
In this national study of long-term outcomes among HIV+ liver transplant recipients, we found that, compared to the general HIV− liver recipient population, long-term GS and PS were significantly lower among HIV+ recipients, particularly among those recipients coinfected with HCV. In fact, at 10 years after transplantation, only 35.4% of HIV+ recipients had functioning grafts, and 41.0% were still living compared to 57.8% and 60.9%, respectively, among the general population of HIV− recipients. Significant differences in baseline characteristics of HIV+ recipients compared to the general population of HIV− recipients were identified, including factors known to be associated with increased risk of graft loss and death, such as coinfection with HCV and hepatitis B and African American race. Interestingly, however, even after adjusting for these potential confounders, HIV+ liver recipients continued to have lower GS and PS at 5 and 10 years after transplantation compared to their appropriately matched HIV− counterparts.
Although these findings likely reflect the natural history of HIV, it is also possible that residual confounding exists. In particular, cumulative viremia among HIV+ individuals has been identified as an important predictor of progression to liver fibrosis. A recent cohort study of 288 HIV/HCV coinfected participants demonstrated a 1.2-fold increased risk of fibrosis progression for each additional 1 log10 copies/mL HIV RNA cumulative exposure.10 Although an undetectable plasma HIV viral load is generally required for transplant candidacy, SRTR data lack granularity with regard to viral load at the time of transplant, time of suppressed viral load, and HIV suppression after transplantation. Moreover, similar effects of cumulative viremia have been observed among HCV+ individuals. Although most HCV+ patients are viremic at the time of transplant, SRTR data do not quantify HCV viral load or document changes over time.11 Not surprisingly, multiple studies have demonstrated accelerated fibrosis before and after transplantation in the setting of HIV/HCV coinfection, as the individual viral effects appear to be additive in the setting of coinfection.7,8
Since their introduction in 2008, integrase-strand transfer inhibitors have become the recommended ART regimen in the transplant setting, as they do not interact with standard maintenance immunosuppressants, such as calcineurin inhibitors.12-14 We further explored the matched cohort by transplant era (before and after introduction of integrase-strand transfer inhibitors), and observed that among monoinfected patients, there was no longer a significant difference in GS or PS in the modern era, suggesting that outcomes among monoinfected patients have improved over time. In contrast, independent of transplant era, HIV+ recipients coinfected with HCV continued to have worse outcomes when compared to HIV−/HCV+ recipients, suggesting that HCV coinfection was an effect modifier for outcomes among HIV+ recipients.
Although our findings among coinfected patients are worrisome, data suggest that HIV+ recipients do derive a significant survival benefit from transplant, as accelerated cirrhosis and high mortality rates among HIV+ ESLD patients have been well documented.15-17 A study of HIV+ liver transplant waitlist candidates demonstrated that each unit increase in MELD score was associated with a 20% increase in the risk of pretransplantation death.17 Moreover, the study found that detectable HIV RNA at baseline was associated with a 3.2-fold increased risk for death and a 2.79-fold increased risk for liver disease progression as measured by MELD. It is important to note that in the current ART era, liver disease is now the most frequent cause of death among HIV+ individuals, likely related to complications of HCV coinfection as well as hepatotoxicity secondary to ART. As such, the need for liver transplantation among this unique population is on the rise.18,19 Therefore, the ability to assess the potential survival benefit of liver transplantation among HIV+ ESLD patients is of paramount importance. Given the small number of HIV+ liver transplants performed to date, pooled national data are needed to properly address this concern. Currently, HIV serostatus of waitlist registrants/candidates is not reported to United Network for Organ Sharing. This has hampered efforts to study survival benefit among this unique population on a national scale.
Although our study did not identify potentially modifiable recipient factors, we did find a significant increase in risk for graft loss among HIV+ recipients of liver grafts from older donors (≥50 years). Our findings parallel results from studies within the general HCV+/HIV− transplant population that have demonstrated an association between older donor age and increased risk of graft loss and patient death.20,21 Results from our study and others suggest that the effect of older donor age on outcomes after liver transplantation is more pronounced among HIV+ recipients compared to their HIV− counterparts.6,15 These findings motivate a focus in clinical practice to avoid grafts from donors over the age of 50 years among HIV+ recipients, which may serve to improve outcomes among this vulnerable population.
Inferences based on our findings must take into account a number of important limitations. The SRTR data lack granularity with regard to CD4 count, viral loads, infections, and malignancies—factors that are known to influence long-term outcomes among HIV+ patients. However, the NIH protocol used relatively restricted criteria for HIV+ ESLD patients to be considered candidates for transplantation, requiring CD4 counts greater than 100. It is unlikely that there would be major deviations from this protocol in the national data. Moreover, immunosuppressant levels and antiviral regimen are not captured by SRTR data, and as such, it is impossible to determine whether drug interactions between HAART therapy and immunosuppressants led to subtherapeutic drug levels and higher rates of acute rejection and graft loss. Although understanding these interactions would help inform the mechanism of our long-term findings, the absence of these data does not bias our findings. Finally, the sample size available for our subgroup analyses were relatively small and may impact the accuracy of our estimates. However, these data represent the HIV+ liver transplant population in the United States in its totality, and therefore, contribute new and important information about long-term outcomes after liver transplantation in this unique population.
This is the first national study to examine long-term outcomes among the entire United States cohort of HIV+ liver transplant recipients and to compare these outcomes to appropriately matched HIV− counterfactuals. We found long-term GS and PS to have improved among monoinfected patients in the modern transplant era and were similar to matched HIV−/HCV− controls. In contrast, independent of transplant era, outcomes among HIV+ patients coinfected with HCV continue to be worrisome. These results motivate future studies of survival benefit in this vulnerable population.
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