Epidemiology and Social
Survival of HIV-infected patients with compensated liver cirrhosis
Tuma, Paulaa; Jarrin, Inmaculadab; del Amo, Juliab; Vispo, Eugeniaa; Medrano, Josea; Martin-Carbonero, Luza; Labarga, Pabloa; Barreiro, Pabloa; Soriano, Vincenta
aDepartment of Infectious Diseases, Hospital Carlos III, Spain
bEpidemiology National Center, Instituto de Salud Carlos III, Madrid, Spain.
Received 28 October, 2009
Revised 8 December, 2009
Accepted 8 December, 2009
Correspondence to Dr Vincent Soriano, Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain. Tel: +34 91 4532500; fax: +34 91 7336614; e-mail: firstname.lastname@example.org
Introduction: Since the advent of HAART, liver-related mortality has become the leading cause of non-AIDS deaths in HIV-infected patients in western countries, complications of end-stage liver disease due to chronic hepatitis B, chronic hepatitis C or both being mainly responsible.
Methods: The incidence and predictors of mortality were examined in HIV-infected patients with compensated liver cirrhosis. The accuracy of three different methods (elastometry, Child–Pugh and Model for End-Stage Liver Disease scores) to predict mortality was further examined. Cirrhosis was defined for hepatic elastometry values above 14.5 kPa.
Results: A total of 194 (11.4%) out of 1706 HIV-positive individuals were cirrhotic and were prospectively followed since October 2004 until December 2008. Overall, 89% of cirrhotic individuals had chronic hepatitis C, 10.3% chronic hepatitis B, 4.6% hepatitis delta and 4.1% liver disease of other causes or unknown cause. The overall mortality rate was 5.8 deaths per 100 patient-years. Multivariate analyses showed that age of at least 50 years (hazard ratio 4.76, 95% confidence interval 1.66–13.59, P = 0.004), CD4 cell counts below 200 cells/μl (hazard ratio 3.01, 95% confidence interval 1.26–7.23, P = 0.03) and detectable plasma HIV-RNA (hazard ratio 3.97, 95% CI, 1.53–10.27, P = 0.005) were associated with mortality. A baseline Model for End-stage Liver Disease score of at least 11 (P = 0.03) and hepatic elastometry values above 28.75 kPa (P = 0.001) were independent predictors of mortality.
Conclusion: The death rate in HIV-infected patients with compensated liver cirrhosis in the HAART era is 5.8% yearly, higher than mortality previously reported for either HIV-uninfected individuals with cirrhosis or noncirrhotic HIV-positive patients. Factors associated with mortality were older age, low CD4 cell counts and detectable plasma HIV-RNA. Both Model for End-Stage Liver Disease and especially hepatic elastometry accurately predicted mortality in this population.
Liver cirrhosis is the final stage of several conditions, which primarily cause persistent hepatic injury. Chronic infection due to hepatitis C virus (HCV), hepatitis B virus (HBV), hepatitis delta virus or all, and alcohol abuse are the most common causes of liver cirrhosis worldwide . Given that, all these conditions are quite prevalent in HIV-infected individuals, it is not surprising that in recent years liver disease has become one of the leading causes of death in HIV-positive patients [2–4]. This is particularly manifest in developed countries, where the introduction of HAART in 1996 has been followed by a dramatic decline in the incidence of opportunistic infections and deaths associated with advanced immunodeficiency [5,6].
Liver fibrosis progression is accelerated in HIV-infected individuals with chronic viral hepatitis B, hepatitis C or both, especially in patients with low CD4 cell counts [7–11]. In the absence of successful treatment for viral hepatitis, progression to liver cirrhosis may occur in a substantial proportion of these patients [12,13]. Once cirrhosis is established, decompensation events, including ascites, encephalopathy, variceal bleeding, jaundice, hepatorenal syndrome or even liver cancer may steadily develop, shortening survival [14,15]. Liver transplantation is often the only medical intervention, which may protect patients with decompensated cirrhosis from short-term death. However, liver transplants are particularly challenging in HIV-infected persons .
The recognition of early stages of liver cirrhosis may allow set up of preventive measures to reduce decompensation events. As example, the use of beta-blockers or variceal band ligations may reduce the risk of bleeding in patients with esophageal varices . Given that, liver biopsies cannot be made routinely and periodically in all individuals with chronic liver disease, the use of noninvasive tests for estimating liver fibrosis staging has rapidly gained support in clinical practice . These tests are particularly accurate for diagnosing liver cirrhosis [19,20]. Using either serum fibrosis biomarker indexes (e.g., FIB-4, AIDS Project Rhode Island, SHASTA, Fibrotest, etc.), hepatic elastometry or all, the prevalence of liver cirrhosis can be estimated in large populations, avoiding the bias introduced when only patients undergoing a liver biopsy are considered.
The identification of the main predictors of mortality in cirrhotic patients with HIV infection is important, especially considering that the opportunities for liver transplantation are growing in this population . In HIV-negative individuals, both Child–Pugh and Model for End-Stage Liver Disease (MELD) scores have been shown to accurately predict mortality in the short and mid term, allowing prioritization and allocation of organs [21–23]. The value of these tools in HIV-infected patients has mainly been examined in decompensated cirrhosis [14,24–26], and information for compensated cirrhosis is scarce [26,27]. Apart from considerations for liver transplantation, new therapeutic approaches for ameliorating liver fibrosis progression are actively being investigated , and are eagerly awaited for this subset of patients. Herein, we examine the rate and predictors of survival in HIV-positive patients with compensated liver cirrhosis, and assess different methods to predict mortality.
Patients and methods
Since October 2004 to December 2008, a total of 194 HIV-infected individuals had been diagnosed of liver cirrhosis, using hepatic elastometry (stiffness values above 14.5 kPa) at our institution. During this period, 2381 distinct HIV-positive individuals had been attended, of whom 1706 (71.6%) underwent at least one FibroScan (Echosens SA, Paris, France) evaluation. It is routine practice at our institution to perform a yearly FibroScan (Echosens SA) examination in all HIV-infected individuals, regardless of presence of any underlying chronic liver disease. The overall estimated prevalence of compensated liver cirrhosis in this population was 11.4%. The threshold used to define liver cirrhosis using elastometry has already been shown to accurately predict cirrhosis in paired liver biopsies, including studies [18,19,29,30] conducted in HIV populations.
A prospective dynamic cohort with all HIV-infected patients with compensated liver cirrhosis was created in October 2004 and followed until December 2008. Patients with terminal end-stage liver disease, hepatocellular carcinoma or both at first assessment were excluded. Clinical and laboratory data were recorded at the time of inclusion into the dynamic cohort. The entry time was the moment of the first reliable transient elastometry measurement above 14.5 kPa. MELD  and Child–Pugh scores  were calculated for each patient at that time. Deaths were examined in all clinical records and the vital status was cross-checked on 31 January 2009 in the National Death Registry of the Ministry of Health , censoring for 31 December 2008 in order to allow delays in case reporting.
Descriptive analysis of patient's characteristics was carried out using frequency distributions or median and interquartile ranges (IQRs) when appropriate. Person-years of follow-up were calculated from the date of entering the cohort until the date of the last visit or death. Mortality rates were calculated as the number of deaths per 100 person-years.
Kaplan–Meier estimates of the cumulative probability of survival according to baseline hepatic elastometry values, Child–Pugh and MELD scores were built. The severity of baseline liver cirrhosis was categorized for each of these tools, which is as follows: tertiles for hepatic elastometry; A (5–6 points), B (7–9 points) or C (10–15) for the Child–Pugh score; and values below 11 or at least 11 for MELD. The predictive value of mortality was then compared using the log rank test.
Cox proportional hazard models were built to assess the predictive value of hepatic elastometry, Child–Pugh or MELD scores for the risk of death, adjusting for potential confounders and testing for effect modification. Wald tests were used to derive P values. All statistical analyses were performed using Stata 10 (Stata Corp., College Station, Texas, USA).
The 194 HIV-infected patients identified with liver cirrhosis using transient elastometry contributed with 434.69 person-years of follow-up (median 2.35, IQR 1.4–5.5 years). Table 1 displays the main demographic characteristics of these individuals at entry. Mean age was 44.2 years; 79.9% were men, 83.5% had a past history of intravenous drug use. Chronic hepatitis C was the most prevalent viral hepatitis, being found in 89% of the study population. Of note, infection with HCV genotypes 1 or 4 represented 59% of patients. Chronic hepatitis B was present in 10.3% and chronic delta hepatitis in 4.6% of cirrhotic patients. Finally, liver disease of other causes (i.e., alcohol abuse, autoimmune hepatitis, steatohepatitis, etc.) or unknown cause was seen in 4.1% of patients. The median CD4 cell count in the study population was 325 cells/μl at study entry, and the median plasma HIV-RNA was 1.7 log10 copies/ml. Overall, 93% of cirrhotic patients were on antiretroviral therapy (ART), and accordingly, 65% had plasma HIV-RNA less than 50 copies/ml and 77% had CD4 cell counts at least 200 cells/μl. Median aspartate aminotransferase and alanine aminotransferase values were 67 and 59 IU/l, respectively.
The median baseline liver stiffness was 21.2 kPa. Following allocation of patients by tertiles, 34% of patients had values between 14.5 and 17.7, 33% between 17.8 and 28.5 and 33% between 28.6 and 75 kPa. All patients had Child–Pugh scores A or B, in a proportion of 77.3 and 16.6%, respectively. Patients with decompensated liver cirrhosis, Child–Pugh score C or both at recruitment were excluded. The median MELD score was 9.6, with 66% of patients having MELD scores below 11.
Deaths occurred in 25 (12.5%) patients during follow-up, yielding an all-cause mortality rate of 5.8 deaths per 100 patient-years. Deaths were due to liver-related complications in 13 (52%), whereas four were due to cardiovascular events. Other reasons (accidents, cancers, etc.) were recorded in four patients. It was unknown in the remaining four patients. Mortality rates according to baseline characteristics are shown in Table 2. Considering tertiles of baseline liver stiffness values (14.5–17.7, 17.8–28.5 and 28.6–75), the mortality rate was 4.1, 1.9 and 12.7 deaths per 100 patient-years, respectively. Person-time was different when classifying patients based on MELD or Child–Pugh scores. Mortality rate in patients with MELD scores below 11 and at least 11 was 3.9 and 11.7 deaths per 100 patient-years, respectively. Patients classified as Child–Pugh A and B had mortality rates of 5.3 and 10.4 deaths per 100 patient-years, respectively.
Overall, deaths occurred in seven of 110 (6.4%) patients with both undetectable plasma HIV-RNA and CD4 cell counts above 200 cells/μl, whereas there were six of 35 (18%) deaths in patients with lower CD4 cell counts and detectable viremia (P = 0.08).
Hazards of death
Univariate and multivariate Cox regression analyses for risk factors associated with death in the study population are displayed in Table 3. In a nonadjusted analysis, patients with elastometry values of at least 28.75 kPa [hazard ratio 2.99, 95% confidence interval (CI) 1.17–7.65, P = 0.002] had a higher risk of death. When a multivariate analysis corrected for age, sex, CD4 cell count, plasma HIV-RNA, mode of transmission and liver disease cause, a liver stiffness value above 28.75 kPa (hazard ratio 3.46, 95% CI 1.24–9.69, P = 0.02) was predictor of mortality. Figure 1(a) displays the survival by baseline liver stiffness tertiles; again statistical differences in survival only were seen for elastometry values above 28.75 kPa (log-rank test, P = 0.001).
The risk of death stratified by baseline Child–Pugh scores is also displayed in Table 3. In the unadjusted model, the relative risk of death did not differ between patients with Child–Pugh class A or B (hazard ratio 1.85, 95% CI 0.73–4.66, P = 0.20). After adjustments for age, sex, CD4 cell count, plasma HIV-RNA, mode of transmission and liver disease cause, a Child–Pugh score class B tended to be associated with a higher risk of mortality (hazard ratio 2.07, 95% CI 0.75–5.71, P = 0.16) but without statistical significance. In the Kaplan–Meier curve (Fig. 1b), this not significant trend in differences between patients with Child–Pugh classes A and B was reproduced.
Finally, the risk of death stratified by baseline MELD score is displayed in Table 3. In the multivariate analysis adjusted for age, sex, CD4 cell count, plasma HIV-RNA, mode of transmission and liver disease cause, patients with a MELD score of at least 11 had a higher risk of death (hazard ratio 3.85, 95% CI 1.53–9.66, P = 0.004) than those with lower MELD scores. Likewise, survival was significantly lower in patients with MELD score of at least 11 than in those with lower MELD scores (Fig. 1c).
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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