End-Stage Liver Disease in HIV+ in France A Leading Cause of Death
"ESLD is currently a leading cause of death in this population, with hepatocellular carcinoma representing a quarter of liver-related deaths. Recommendations for the detection of hepatocellular carcinoma should be strictly applied in these patients.....
.....From 1995 to 2005, the proportion of AIDS-related deaths in HIV-infected adults decreased from 92 to 35% of all causes of death. Over the 10-year period, the proportion of ESLD-related deaths dramatically increased (by 11-fold) in HIV-infected patients, and ESLD now constitutes a leading cause of mortality. In 2005, ESLD-related deaths represented 26% of all non-AIDS-related deaths and ESLD was the most frequent non-AIDS-related cause of death in this population.....HCC has become a major problem in HIV/HCV-coinfected patients . In this study, among 36 patients who died from HCV-related ESLD, seven died from HCC.....In our study, approximately half of the patients who died from ESLD had high alcohol consumption...."
"Among the approximately 24 000 HIV-infected patients followed in these departments in 2005, 313 deaths were reported. Case report forms were completed for 287 cases. AIDS events accounted for 100 cases (34.8%); ESLD for 48 cases (16.7%); non-AIDS and non-viral hepatitis-related cancer for 42 cases (14.6%); cardiovascular diseases for 18 cases (6.3%); and other various causes (including accidents and suicide) for 79 cases (27.5%). Deaths from ESLD represented 25.7% of the non-AIDS-related deaths."
Liver-related deaths in HIV-infected patients between 1995 and 2005 in the French GERMIVIC Joint Study Group Network (Mortavic 2005 Study in collaboration with the Mortalite 2005 survey, ANRS EN19)*
E Rosenthal 1 , D Salmon-Ceron 2 , C Lewden 3 , V Bouteloup 3 , G Pialoux 4 , F Bonnet 3,5,6 , M Karmochkine 7 , T May 8 , M Francois 3 , C Burty 8 , E Jougla 9 , D Costagliola 10,11 , P Morlat 3,5,6 , G Chene 3,5,6 , P Cacoub 12 and the Mortavic/Mortalite 2005 Study Group
1 Department of Internal Medicine, Archet Hospital Centre, University of Nice-Sophia Antipolis, Nice, 2 Department of Internal Medicine, Cochin-Tarnier Hospital Centre, Paris, 3 Institut National de la Sante et de la Recherche Medicale (INSERM) Unit 593, Victor Segalen University, Bordeaux 2, Institut de Sante Publique, d'Epidemiologie et de Developpement (ISPED), Bordeaux, 4 Department of Infectious Diseases, Tenon Hospital, Paris, 5 INSERM, Unit 593, Bordeaux, 6 Department of Internal Medicine, Bordeaux University Hospital, 7 Department of Internal Medicine, Georges Pompidou European Hospital, Paris, 8 Department of Infectious Diseases, Brabois University Hospital, Vandoeuvre-Les-Nancy, 9 INSERM, CepiDc, Le Vesinet, 10 INSERM, Unit 720, Paris, 11 Pierre et Maris Curie University, Paris and 12 Department of Internal Medicine, La Pitie Salptriere Hospital Centre, Assistance Publique des Hpitaux de Paris and Centre National de la Recherche Scientifique, Unit 7087, Pierre et Marie Curie University, Paris, France
Correspondence: Professeur Eric Rosenthal, Service de Medecine Interne-Cancerologie, Hopital Archet 1, 151 Route de Saint-Antoine de Ginestiere, 06202 Nice Cedex 3, France. Tel: +33 492 035 824; fax: +33 492 035 896; e-mail: email@example.com
*GERMIVIC, Joint Study Group on Hepatitis C Virus of the French National Society of Internal Medicine and the French Society of Infectious Diseases (see Appendix A); ANRS, Agence Nationale de Recherche sur le SIDA. Data were presented previously at the 58th Annual Meeting of the American Association for the Study of Liver Diseases, Boston, 2-6 November 2007 and published as an abstract in Hepatology 2007; 46: 296A (Abstract 135).
More than 10 years after the introduction of combination antiretroviral therapy (cART), we examined the trend in the proportion of deaths caused by end-stage liver disease (ESLD) in HIV-infected adults in France between 1995 and 2005.
Design and methods
In 2005, 34 departments prospectively recorded all deaths in HIV-infected patients who were followed in those departments (around 24 000). Results were compared with those of four previous cross-sectional surveys conducted since 1995 using the same methodology.
Among 287 reported deaths in 2005, 100 (35%) were related to AIDS, and 48 (17%) to ESLD. Three out of four patients who died from ESLD-related causes had chronic hepatitis C. Excessive alcohol consumption was reported in approximately half of the patients (48%). At death, 62% of patients had undetectable HIV viral load and the median CD4 count was 237 cells/μL. From 1995 to 2005, the proportion of deaths caused by ESLD increased from 2 to 17% (P<0.001). The proportion of deaths caused by hepatocellular carcinoma increased from 5% in 1995 to 25% in 2005 (P=0.0337)..
Over the 10 years from 1995 to 2005, the proportion of deaths caused by hepatitis C virus-related ESLD has increased in HIV-infected patients. ESLD is currently a leading cause of death in this population, with hepatocellular carcinoma representing a quarter of liver-related deaths. Recommendations for the detection of hepatocellular carcinoma should be strictly applied in these patients.
The widespread use of combination antiretroviral therapy (cART) in northern countries has increased life expectancy among individuals infected with HIV. The primary reason for this increased longevity is the decreasing rate of opportunistic infections which have often been a direct cause of death. Studies from single institutions have shown that liver disease caused by chronic hepatitis C virus (HCV) infection has become a significant cause of mortality among coinfected patients [1-4]. However, few studies have addressed the trends in mortality caused by HCV infection over a long period of time.
In the last several years, the proportion of deaths caused by end-stage liver disease (ESLD) in French HIV-infected patients has progressively increased with time, and ESLD has become a leading cause of mortality [5-7]. This is likely to be related to prolonged longevity as a result of decreasing AIDS-related mortality, prolonged exposure to chronic HCV infection and high alcohol consumption. In parallel, large trials have demonstrated that HIV/HCV-coinfected patients may achieve a sustained virological response on combined treatment with pegylated interferon plus ribavirin, leading to histopathological improvement [8,9]. In daily clinical practice, continuing efforts to educate physicians and patients have increased access of HIV/HCV-coinfected patients to HCV treatment [10,11]..
In light of the critical role of time in the progression of HCV-related liver disease, and with a view to contributing to improved management of HIV/HCV-coinfected patients, we aimed to describe the trend in the proportion of deaths caused by ESLD over a 10-year period (1995-2005) using data from four previous surveys conducted by our study group [5-7]. We also aimed to describe the characteristics of individuals who died from ESLD.
Study population and mortality
Overall, 34 hospital departments participated in the Mortavic surveys between 1995 and 2005. Among the approximately 24 000 HIV-infected patients followed in these departments in 2005, 313 deaths were reported. Case report forms were completed for 287 cases. AIDS events accounted for 100 cases (34.8%); ESLD for 48 cases (16.7%); non-AIDS and non-viral hepatitis-related cancer for 42 cases (14.6%); cardiovascular diseases for 18 cases (6.3%); and other various causes (including accidents and suicide) for 79 cases (27.5%). Deaths from ESLD represented 25.7% of the non-AIDS-related deaths. The causes of death are presented in Table 1 and are compared with those in the 1995, 1997, 2001 and 2003 studies.
Deaths from ESLD
The main characteristics of the 48 cases of ESLD-related deaths are given in Tables 2 and 3. ESLD occurred with hepatitis virus infection in 45 cases (94%). HCV infection was present in 80% of liver-related deaths. Daily alcohol consumption was >30 g in almost half of cases. Among patients with HCV-positive serology, death from ESLD was related to alcohol consumption in four cases according to the patients' physicians. Conversely, alcohol consumption plus HCV infection was reported as the underlying cause of liver-related death in eight cases. Cirrhosis-related death in one case was not attributable to hepatitis virus infection or to alcohol consumption. Thirty-six patients died from cirrhosis (75.0%) and 12 from HCC (25.0%) caused by HCV (seven cases) or HBV (five cases) infection.. Seventeen (37.7%) of the 45 patients whose deaths were ESLD-related had previously received IFN-α-based treatment in combination with ribavirin. When compared with deaths from other causes, patients whose deaths were ESLD-related more often were injecting drug users, had a high alcohol intake, had previously received HCV treatment, and had better control of HIV infection (Table 2).
Comparison with the 1995, 1997, 2001, 2003 and 2005 surveys
Between 1995 and 2005, the proportion of ESLD- and HCC-related deaths increased (Tables 1 and 3). Among cases of ESLD-related death, the percentage of patients who had received HCV treatment significantly increased with time. Of the patients who died from HCV-related ESLD in 2005, 47.2% had received HCV treatment. The prescription of cART at the time of death was more frequent in 2005 and 2003 than in the earlier years. Median CD4 cell counts at death increased from 113 cells/μL in 1995 to 237 cells/μL in 2005 (P=0.3).
Between 1995 and 2005, while mortality in HIV-infected patients decreased, in particular when specific AIDS-related causes of death were considered, mortality caused by ESLD seemed to slowly increase (Table 1).
This study is the largest observational study to date of liver-related causes of death in a nationwide population of HIV-infected patients followed for over a decade. All centres participating in Mortavic 2005 were involved in five consecutive surveys of similar design. From 1995 to 2005, the proportion of AIDS-related deaths in HIV-infected adults decreased from 92 to 35% of all causes of death. Over the 10-year period, the proportion of ESLD-related deaths dramatically increased (by 11-fold) in HIV-infected patients, and ESLD now constitutes a leading cause of mortality. In 2005, ESLD-related deaths represented 26% of all non-AIDS-related deaths and ESLD was the most frequent non-AIDS-related cause of death in this population. These data confirm the results obtained in previous studies carried out by our group [5-7,16] and in other European and US studies which have shown the significance of liver disease as a cause of mortality in the global HIV-infected population [17-19], and its top rank as a cause of mortality in HCV/HIV-infected individuals . As they live longer, HIV-infected individuals treated with highly active antiretroviral therapy (HAART) are exposed to a wider range of complications than in the pre-HAART era. In addition to the impact of chronic viral infections (i.e. HIV and hepatitis viruses), ageing, long-term exposure to treatment and to traditional risk factors such as smoking, alcohol consumption or dyslipidaemia may have contributed to the major causes of death observed in 2005: ESLD (17%), cancers not related to AIDS or hepatitis (15%), and cardiovascular diseases (6%).
As in previous studies carried out by our group, in 2005 mortality caused by ESLD in HIV-infected patients was predominantly related to HCV coinfection (75%). Over the 10 years from 1995 to 2005, considerable progress was achieved in the treatment of HIV/HCV-coinfected patients, with the recent use of pegylated IFN-α and ribavirin [8,9,20]. In large clinical trials, this combination produced a sustained virological response in 27-44% of patients, the majority of whom also demonstrated hepatic histological improvement. The present study did not examine HCV treatment except in patients who died from ESLD. However, 17 out of 36 patients (47%) who died from HCV-related ESLD had previously received pegylated IFN-α and ribavirin. Access to HCV treatment in HIV/HCV-coinfected patients has been limited to a small number of patients [21,22]. In daily clinical practice, more than half of HIV/HCV-coinfected patients had not received any HCV treatment in France in 2004 . The main reported reasons were benefits of treatment deemed to be questionable (because of minimal hepatic lesions, alcohol use or active drug use), a lack of available liver biopsy, a psychiatric contraindication and physician conviction of poor patient compliance. However, the care of HIV/HCV-coinfected patients is changing . In a very recent French survey comparing care in 2004 with that in 2006, more HIV/HCV-coinfected patients were found to have received treatment in 2006 , with treatment being less frequently contraindicated, physicians' conviction of poor patient compliance being less frequent and liver damage being assessed more often. Thus, we may anticipate a positive effect of HCV treatment on both liver-related morbidity and mortality.
HCC has become a major problem in HIV/HCV-coinfected patients . In this study, among 36 patients who died from HCV-related ESLD, seven died from HCC. Overall, 12 patients died from HCC. The role of HIV/HCV coinfection in increasing the rate of progression to cirrhosis  and in the clinical course of HCC  has been well established. A recent study showed that HIV-infected patients with HCC were younger and more frequently symptomatic than HIV-negative controls . However, whether HIV also increases the incidence of HCC remains to be elucidated [26,27]. Although our study was not designed to determine whether HIV increases the likelihood of HCC development in HCV-infected patients, our data suggest that a further increase in the incidence of HCC in the future is very likely in this specific population. Recently, Davis et al.  produced a projection of future complications of chronic hepatitis C in the USA, using a modification of a previously described natural history model for HCV infection. Despite a projected gradual decline in the prevalence of infection as a result of ageing and natural death in the infected pool, and because the duration of infection will increase in the surviving cohort, they showed that cirrhosis and complications of cirrhosis can be expected to increase dramatically over the next 20 years: liver-related death by up to 180%, and HCC by up to 81%. Although treatment regimens eradicate HCV in over 50% of cases in the context of HCV monoinfection, they concluded that current therapy and practice patterns will not be sufficient to control the future complications of HCV infection. No projection model of HCV natural history is available in the context of HIV coinfection, but a comparable or even worse course seems plausible, as HIV infection accelerates HCV-related liver fibrosis progression .
In contrast to the subanalysis of the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) collaborative observational study , daily alcohol consumption was evaluated in the present study. Excessive alcohol consumption is a well-known factor in morbidity and mortality resulting from chronic liver diseases [29,30]. In our study, approximately half of the patients who died from ESLD had high alcohol consumption. Moreover, four deaths from alcohol-related ESLD with no hepatitis virus coinfection were reported in 2005 for the first time in the GERMIVIC surveys. A recent study in HIV-infected patients with current or past alcohol problems showed that individuals who were aware of their HCV diagnosis were more likely to abstain from alcohol or to drink less than patients who were not told about their HCV infection , confirming suggestions made in the context of HCV monoinfection . Education about the importance of alcohol abstinence is certainly crucial, and may have a positive effect on the morbidity and mortality caused by liver disease.
Coinfection with HBV was a factor in the ESLD-related deaths of nine patients. HBsAg was positive in 27% of patients who died from ESLD. Therefore, the role of HBV in liver-related causes of death should not be underestimated, although more than 70% of patients with HBV/HIV coinfection in France receive lamivudine, tenofovir or emtricitabine, antiviral drugs with dual anti-HBV and anti-HIV activity . HCV superinfection is associated with increased morbidity in patients with HBV infection. In this series, there were no deaths reported in patients with HDV superinfection..
There are conflicting data regarding the potential benefit of cART in slowing the progression of fibrosis [33,34]. However, good immunovirological control of HIV infection using cART may slow down the progression of liver fibrosis . In 2005, 94% of patients who died from ESLD-related causes were receiving cART. Most of them had good control of their HIV infection, as shown by a lower HIV viral load and a higher median CD4 cell count (2003-2005), compared with the pre-cART era (1995) and the early years after the widespread introduction of cART regimens (1997-2001).
Some limitations of the present study should be pointed out. HCV infection was defined by the presence of HCV antibodies. As 25% of patients may resolve HCV infection spontaneously, HCV coinfection may be overestimated. Persons included were restricted to patients being treated for HIV infection in the hospital. A substantial proportion of HIV-infected subjects at risk of ESLD might seek treatment elsewhere or seek treatment sporadically (i.e. not regularly enough to be included in the study) or not seek treatment at all. These potential biases were present in the five consecutive studies and should not have had an effect on the comparison of mortality rates in the 10-year period from 1995 to 2005. Despite the fact that the same centres participated in all five studies, some doctors and a proportion of patients may have changed during the study period, thus introducing biases into comparisons of mortality rates in the population under study. For example, the proportion of immigrants from HBV-endemic areas in Africa and Asia may have increased in recent years, potentially driving up deaths from liver cancer. This should be further investigated.
In contrast, the present study has notable strengths, in particular its large size, rigorous review and central coding of causes of death. It also provides a unique nationwide representation of persons followed up in daily clinical practice.
In conclusion, ESLD, predominantly associated with HCV coinfection, is a leading cause of death in the HIV-infected population. Over the 10-year period of 1995-2005, the significance of liver disease as a cause of death slowly increased in HIV-infected patients. The proportion of HCC-related deaths increased over the same period. High alcohol consumption is frequent in these patients and constitutes a major risk factor for liver disease progression. These findings emphasize the importance of developing effective strategies for the prevention and early diagnosis and treatment of chronic HCV infection, routine screening for HCC and reduction of alcohol intake.
Patients and methods
The current study (Mortavic 2005) was a multicentre prospective cross-sectional survey of French hospital departments of internal medicine and infectious diseases participating in the treatment of HIV-infected individuals, performed with the same methodology and in the same centres as in the four previous studies carried out by the group [5-7]. This study was embedded in the Mortalite 2005 survey which aimed to describe the distribution of all causes of death among HIV-infected adults in France in 2005 .
Physicians who agreed to participate were asked to prospectively record all deaths and to describe the precise causes of death using a standardized questionnaire similar to that used in our previous studies [5-7,13]. The questionnaire was prospectively completed on a quarterly basis between January and December 2005. It included information regarding the total number of HIV-infected patients regularly seen (i.e. at least every 3 months), risk factors for HIV transmission, and the number of deaths during the period. The underlying cause of death was defined, using the definition in the International Classification of Diseases (ICD) 10th revision (ICD-10) , as the disease or injury that initiated the train of morbid events leading to death. Information contained in the case report form was used to determine the underlying cause of death for each case according to this ICD-10 definition. The algorithm of determination was adapted to specific concerns in HIV infection . The underlying cause of death was classified as AIDS-related when active disorders at death included one AIDS-defining disease [1993 Centers for Disease Control and Prevention (CDC) clinical classification] . The cause of death was classified as liver disease when death was from cirrhosis (i.e. ascites, variceal bleeding, encephalopathy, spontaneous bacterial peritonitis or hepatocellular deficiency), hepatocellular carcinoma (HCC) or fulminant hepatitis.
A second questionnaire [5-7,13] was completed for each patient who died of ESLD by the physician in charge of the patient's follow-up, who disclosed the primary origin of liver-related cause of death [i.e. HCV-, hepatitis B virus (HBV)- or alcohol-related]. When death occurred in a different institution, the reporting physician used the medical report and information directly obtained from the physician of the ward in which the patient died. The questionnaire covered the patient's demographic data; mode of HIV transmission; criteria for diagnosis of cirrhosis and/or HCC (considered 'definite' if documented histopathologically or 'probable' if documented clinically, based on elevated serum α-fetoprotein levels and/or imaging); positive test results for HCV [anti-HCV antibody revealed by a third-generation enzyme-linked immunosorbent assay (ELISA)], HBV [HBV surface antigen (HBsAg) revealed by ELISA] and hepatitis D virus (HDV; anti-HDV antibody revealed by ELISA); self-reported current daily alcohol consumption; concomitant use of hepatotoxic drugs; previous treatment with interferon (IFN)-α or ribavirin (response to therapy was not recorded); latest CD4 cell count; CDC stage of HIV infection ; and antiretroviral therapy at death.
Assessment of completeness of death ascertainment
In a previous study, the completeness of death ascertainment was assessed by examining the patients lost to follow-up and by reviewing hospital charts in a sample of wards. The coverage was assessed in a capture-recapture study using the national death registry . The capture-recapture exercise showed an estimated national coverage of the survey of 70% [95% confidence interval (CI) 62, 78%], with similar distributions of causes of death for reported and missed data. Our conclusion was that our study sample was representative of the target population. For this reason, we did not perform this analysis in the 2005 study.
We determined the distribution of the three main cause of death categories (ESLD, AIDS and others) and compared trends for these categories between 1995 and 2005 using a χ2 test. We also compared the characteristics of patients who died in 2005 from ESLD with those of patients who died from other causes using χ2 and Kruskal-Wallis tests.
The characteristics of patients who died from ESLD between 1995 and 2005 were compared using the χ2 for linear trend test or linear regression models in order to determine whether there was a trend across years.
For descriptive purposes, 1-year mortality was estimated as the ratio between the number of deaths from each cause and the approximate number of HIV-infected patients followed in the hospital departments in the previous year. Statistical Analysis System (sas) software version 9.1.3 (SAS Institute, Cary, NC) was used for all analyses.