All analyses were repeated using only the 13 liver-related deaths as main end point, and the results did not change significantly; however, the limited number of hepatic deaths precluded us from drawing any reasonable conclusion.
The present study examined the rate and predictors of survival in HIV-positive patients with compensated liver cirrhosis. Furthermore, we examined different methods to predict mortality in this population. Overall mortality rates in HIV-infected individuals have declined dramatically in the HAART era, with current estimates ranging from 1.3 to 1.6 deaths per 100 patient-years . In our study, HIV-positive patients with compensated liver cirrhosis had a mortality of 5.8 deaths per 100 patient-years, which is almost four-fold higher than in the general HIV population. The deleterious impact of liver cirrhosis on survival in HIV-infected persons has already been shown by others. In one study  conducted between 1999 and 2004, the mortality rate was 7.1 deaths per 100 patient-years in HIV-positive cirrhotic patients; however, in that study, only 58% of patients were under ART, whereas 93% of our study population was receiving HAART.
A benefit of HAART on liver fibrosis progression and risk of liver-related complications and deaths in HIV-positive patients with chronic viral hepatitis B or C is well proven [35–40]. In this regard, it is reassuring that both low CD4 cell counts and detectable plasma HIV-RNA were independent predictors of mortality in our cirrhotic population, in whom chronic viral hepatitis represented more than 98% of all cases. Overall, 65% of patients had undetectable plasma HIV-RNA and 77% had CD4 cell counts above 200 cells/μl. The proportion of the whole population with both undetectable viremia and high CD4 cell counts was 57%, whereas, conversely, 18% had detectable viremia and low CD4 cell counts. Deaths occurred in seven of 110 (6.4%) patients of the former group and in six of 35 (18%) of the latest group (P = 0.08). Given the limited number of deaths in the study population, this trend towards a higher mortality in cirrhotic individuals with CD4 cell counts below 200 cells/μl and virological failure compared with completely suppressed patients with higher CD4 cell counts may support a role for ART to reduce death rates in this subset of patients. This opportunity, however, has being difficult so far using potentially hepatotoxic drugs but is currently easier using new antiretroviral agents with a safer hepatic profile (e.g., raltegravir, maraviroc, etc.) [41,42]. Overall, our results further reinforce the current recommendation to provide ART as soon as possible in all HIV-infected persons with chronic viral hepatitis [43–45].
The mortality rate we saw in HIV-infected patients with compensated cirrhosis was also higher than that previously reported in HIV-negative cirrhotic individuals, in whom 3–4% annual rates of death have been recorded [46,47]. This occurred despite most HIV-positive cirrhotic patients in our study being treated with ART. Thus, control of HIV replication and CD4 reconstitution with HAART might not completely overcome the deleterious impact of HIV infection on survival in HIV-positive cirrhotic patients. Unfortunately, information on mortality rates in HIV-uninfected cirrhotic individuals or from HIV-positive noncirrhotic individuals at our institution was not available to make our conclusions more robust.
In our study, older age was associated with increased mortality in HIV-positive patients with compensated liver cirrhosis. Other studies [12,39,40,48] have found a similar strong influence of age on liver fibrosis progression and liver-related mortality in coinfected individuals. In contrast with studies conducted in HIV-negative individuals with HCV-related liver cirrhosis, in which male sex was associated with accelerated liver fibrosis progression , in our cohort, women showed nearly twice increased risk of death than men, although the difference did not reach statistical significance.
To our knowledge, our study shows for the first time that hepatic elastometry may predict mortality in patients with compensated liver cirrhosis. This observation is important, as elastometry may allow diagnosis of cirrhosis in a substantial proportion of patients with chronic hepatic disease in whom liver biopsy is not performed. It is noteworthy that the prognostic value of transient elastometry has already been demonstrated for predicting clinical complications of end-stage liver disease, as esophageal varices [17,49]. In our study, liver stiffness values above 28.75 kPa in cirrhotic patients were significantly associated with shorter survival. This information may assist to prioritize persons who may be candidates for liver transplantation.
The MELD score predicts mortality in the short-term in cirrhotic patients without HIV infection , and recent observations have extended this value to cirrhotic HIV-infected patients [51,52]. In our study, the MELD score accurately predicted mortality, and a threshold of 11 predicted mid-term survival in HIV-positive cirrhotic patients. This information reinforces that HIV-positive cirrhotic patients should be considered for liver transplantation at lower MELD scores than HIV-negative individuals with cirrhosis in whom higher MELD scores better predict mortality.
Baseline Child–Pugh scores did not predict mortality in our HIV-positive population with liver cirrhosis. Although short-term survival tended to be shorter in patients with Child–Pugh class B than A, this difference vanished with extended follow-up. As pointed out by others , the heterogeneity of patients classified as Child–Pugh class B may explain this observation. The impact of this heterogeneity might be further pronounced in HIV-infected patients, as progression of liver fibrosis tends to be accelerated in this population. As in our study, in the study referred before by Murillas et al. , the Child–Pugh score did not predict mortality.
Several potential limitations of our study must be mentioned. First, overall mortality rates instead of liver-related deaths were used as major end point. As mentioned in the Results section, we repeated the same analyses performed for the whole 25 deaths only for the 13 patients who died from liver-related complications. Overall, the interpretation of results did not change significantly, largely due to the limited number of hepatic deaths. A second limitation of our study was the use of elastometry instead of liver biopsy to make the diagnosis of cirrhosis. Clearly, liver biopsy cannot be performed in all patients with chronic liver disease, whereas noninvasive tools may permit to obtain histological estimates for most patients, avoiding biases. Moreover, two studies [19,20] have now confirmed the excellent value of elastometry for predicting cirrhosis. Thus, we are confident that the population recruited in our study considered as having compensated cirrhosis was accurate enough in the absence of definitive histological documentation. Finally, a third limitation of our study was the use of historical controls as comparison for the death rate in HIV-infected cirrhotic patients. Unfortunately, we did not have the opportunity to examine mortality rates in similar control groups of either HIV-uninfected cirrhotic individuals or HIV-positive individuals with noncirrhosis followed at our institution.
In summary, in a cohort of 194 cirrhotic HIV-positive patients, 89% of them with chronic hepatitis C, baseline hepatic elastometry values predicted mortality. Further studies are warranted to define what will be the best threshold in elastometric values to discriminate survival. A MELD score of at least 11 was also associated with shorter survival in our series. Older age, low CD4 cell counts and detectable plasma HIV-RNA were predictors of increased mortality in this population.
P.T., J.M. and V.S. designed the study. I.J. and J.dA. did the statistical analyses. E.V., L.M.C., P.L., P.B. and V.S. provided and checked the clinical data for all patients. P.T., J.dA. and V.S. wrote the manuscript. All authors reviewed the draft and approved the final version.
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