Baseline characteristics of subjects and controls
Of 196 HIV(+) liver transplant candidates enrolled during the study period, 167 (85.2%) were evaluable and 29 (15%) with hepatocellular cancer (HCC) were excluded from analysis. The 167 subjects were matched with 792 HIV(−) liver transplant candidate controls without HCC from the UNOS database. The median (IQR) follow up time for HIV(+) subjects was similar to that of UNOS controls, 166 days (10–526) vs. 194 days (35–598), p=0.09. An additional 136 HIV(+) subjects with advanced liver disease who were screened did not become transplant candidates in this study, among whom 31 (22.8%) died.
Of the HIV(+) subjects, 24/167 (14.4%) died prior to transplantation, similar to the mortality rate in the HIV(−) UNOS controls, 88/792 (11.1%), p=0.30. Limiting the comparison to HCV(+) subjects only, the mortality rate was similar between the HIV(+) subjects,18/125 (14.4%), and the UNOS controls, 62/592 (10.5%), p=0.28. By contrast, although 75% of both groups were HCV(+), a significantly lower proportion of HIV(+) transplant candidates, 58/167 (34.7%) underwent liver transplantation, as compared with the HIV(−) UNOS controls, 377/792 (47.6%) during the study period, p=0.003.
The HIV(+) HIVTR and HIV(−) control subjects did not differ overall in most of the baseline characteristics (,). The two groups were similar in age, gender, and ethnicity. The proportion with private medical insurance coverage was significantly lower in HIV(+) than in HIV(−) control subjects, p<0.0001. Another difference was the median baseline body-mass-index (BMI), significantly lower in HIV(+) than in HIV(−) control subjects, p<0.0001. The geographic regions of the transplant centers also varied between both groups (p<0.0001), with the majority of HIV(+) cases receiving a transplant in New England, New York, the mid-Atlantic states, and the Southwestern US.
Characteristics of HIV(+) and UNOS HIV(−) Liver Transplant Candidates
Characteristics of Liver Transplant Candidates by Transplant Status
The primary causes of pre-transplant death, sepsis and multiple organ system failure, did not differ between groups (). No patients with HIV infection were reported to have died of opportunistic infections. A total of 34% (29/85) of HIV+ subjects not transplanted were either removed early from the study or temporarily inactive on the liver transplant waiting list due primarily to active illicit drug use or no longer meeting HIV-specific inclusion criteria. On review of the UNOS cohort group, 20% had a status of temporarily inactive on the liver transplant wait list as of the data cutoff date (p=0.01).
Causes of Pre-Transplant Mortality in HIV+ and HIV− Candidates
Time to Elevated MELD Score and Death
Comparing time-to-event curves for death, transplant, and MELD score ≥25 between HIV(+) subjects and HIV(−) UNOS controls revealed no significant differences (), even for the HCV-infected subgroups (data not shown).
Figure 1a. Time to Death in HIV(+) Transplant Candidates. This Kaplan Meier plot shows that time to death is similar in HIV(+) and HIV(−) transplant candidates., p = 0.18.
Within the HIV-infected group, HIV-related variables were analyzed by transplant status, as shown in . HIV(+) subjects who died pre-transplant had a significantly lower median CD4 count at enrollment (237cells/μl) than those who received a transplant (315 cells/μl, p=0.01). No significant differences were observed in nadir CD4 count, proportion with detectable HIV RNA at enrollment, history of AIDS-related opportunistic infections, or use of protease-inhibitor containing initial antiretroviral regimen by transplant status, e.g. expired vs. transplanted. No specific antiretroviral medication or combination of medications was associated with death.
Predictors of Pre-Transplant Mortality for the Overall Cohort
In multivariate PH regression models for the overall cohort and the HCV-infected subgroup, adjusting for the baseline MELD, BMI and region, the hazard of pre-transplant mortality was not significantly higher in HIV(+) subjects HR=1.69 (95% CI: 0.76–3.75, p=0.20) and HR=1.71 (95% CI: 0.67–4.35, p=0.26), respectively, as compared to HIV(−) subjects., An additional interaction term between HIV status and baseline MELD was also non-significant (p=0.33), i.e., HIV status did not have a significant impact on the association between baseline MELD and the hazard of death. In both multivariate models the baseline MELD was the only significant predictor of pre-transplant mortality (HR=1.31(95% CI: 1.21–1.41) and 1.36 (95% CI: 1.22–1.51), respectively; p<0.0001).
Predictors of Pre-Transplant Mortality for HIV-Infected Subjects
In univariate proportional hazards models () HCV infection, CD4 count at enrollment, and protease inhibitor use were not associated with increased risk of death or MELD elevation of ≥25. Detectable HIV RNA at baseline, however, increased the hazard of death (HR=3.2, 95% CI: 1.2–8.6, p=0.02) and rate of progression to MELD≥25 (HR=2.79, 95% CI 1.4–5.7, p=0.005). Not surprisingly, high baseline MELD (≥25) was also associated with greater hazard of death (HR=15.0, 95% CI 5.2–43.3, p<0.0001).
Risk Factors for Pre-Transplant Mortality in HIV+ Transplant Candidates
In multivariate proportional hazards models for death, after controlling for CD4 count and detectable HIV RNA, the only significant predictor of mortality was pre-transplant MELD. This was true for MELD as a dichotomous variable <25 and ≥25 (HR=19.5, 95% CI: 5.8–66.0, p<0.001), and as a four-level categorical variable (). When MELD <15 was used as the reference category, relative hazard increased as MELD score increased. When baseline MELD score was examined as a linear variable, after adjusting for both CD4 count <200/μl and detectable baseline HIV RNA, each unit increase in MELD score was associated with a 20% increase in the risk of pre-transplant death (p<0.0001).