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All-cause and liver-related mortality in HIV-positive subjects compared to the general population: differences by HCV co-infection (in Spain)
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Journal of Hepatology
Article in Press, unedited manuscript that has been accepted for publication
June 2012
V Hernando, Santiago Perez-Cachafeiro, Charlotte Lewden, Juan Gonzalez,
Ferran Segura, Jose Antonio Oteo, Rafael Rubio, David Dalmau, Santiago
Moreno, Julia del AmoCoRIS
1 Red de Investigacion en Sida, Centro Nacional de Epidemiologia, Instituto de Salud Carlos III, Madrid, Spain. 2 CIBER de Epidemiologia y Salud Publica (CIBERESP).3 Fundacion IDI Complexo Hospitalario de Pontevedra, Pontevedra, Spain, 4 INSERM, U897, Bordeaux, France, 5 Hospital Universitario La Paz, Madrid, Spain. 6 Corporacio Sanitaria Parc Tauli, Sabadell, Spain. 7 Hospital San Pedro-CIBIR, Logrono, Spain. 8 Hospital Universitario Doce de Octubre, Madrid, Spain. 9 Hospital Universitari Mutua de Terrassa, Terrassa, Spain. 10 Hospital Universitario Ramon y Cajal, Madrid, Spain. CoRIS members are included in Annex1
"To conclude, we have shown an excess of all-cause and liver-related mortality in HIV-positive people compared to the general population in the last decade, despite improvements in the management of both HIV and HCV infections. Co-infection with HCV seems to play a very important role in all-cause and liver-related excess mortality. Rapid changes in the epidemiology of HCV co-infection and major advances in the treatment of these infections are likely to shape future patterns of excess mortality in the coming years."
"mortality in HCV-negative subjects is two and a half times higher than in the general population while death rates in HCV-positive individuals are eleven times higher. Liver-related mortality in HIV-positive subjects in CoRIS is nearly ten times higher than in the general population of the same age and sex, and again, notable differences by HCV coinfection status are seen. While non-significant increases in liver-related mortality are seen in HCV-negative people, liver-related mortality is twenty-two times higher in HCV-infected subjects compared to the general population of the same age and sex......Our data are consistent with these findings, but they also highlight the remarkable excess mortality seen in subjects with HCV co-infection [3, 17, 26, 27]. We observe that the all-cause mortality in HIV-positive HCV-negative subjects who were AIDS-free was 1.4 times higher than the general population's and increased to 20.8 times higher in HCV-positive subjects who had an AIDS defining condition."
"Despite the sustained reduction of HCV serial prevalence from 1997 onwards in our cohort of HIV-positive subjects, overall HCV prevalence was 37.3%, similar to figures reported by EuroSIDA for Southern European countries [17]. HIV and HCV are well established causes for death from all causes [17, 22, 28, 29]. In addition to this, people infected with HIV and/or with HCV have been reported to have higher rates of drug, alcohol and tobacco use than the general population [26, 30, 31]. Data from a subset of CoRIS members shows that 42% of the men and 54% of the women reported current smoking [32] whereas these proportions were 31% and 21% for the general population between 16 and 64 years old according to the National Health Survey [33]. Therefore, it is likely that higher smoking rates are responsible for part of the excess mortality observed in our population. Regarding alcohol use, preliminary data in our cohort show that 75% of the men and 44% of the women had drunk
alcohol in the preceding 12 months [32]]. This is slightly lower than the figures for the general population, 80% and 57% [33], which may be due to sick people drinking less alcohol than those in the general population. A recently published study on the cardiovascular risk in the patients from our cohort has shown a prevalence of smoking of 47% as well as that of other comorbidities, such as diabetes and hypertension, 3% and 9%, respectively [34]."
"As far as we know, only one previous study has estimated SMRs in HIV-positive populations by HCV infection status [6]. Lewden et al found that all-cause mortality in HIV-positive subjects co-infected with HCV was 14 times higher than in the general population, whereas the SMR for those not co-infected was 4.4. Our results are similar"
Abstract
Background & aims
To compare overall and liver-related mortality rates observed in HIV-positive subjects followed-up in the Cohorts of Spanish Network on HIV/AIDS Research stratified by HCV co-infection status, with the expected mortality of the general population of same age and sex in Spain, 1997, 2008.
Methods
We estimated standardized mortality ratio (SMR) and excess mortality, comparing death rates from our cohort (globally and by HCV co-infection) with death rates from the general population standardized by sex in 5 years-age bands.
Results
Overall, 5,914 HIV-positive subjects were included of which 37.3% were co-infected with HCV; 231 deaths occurred of which 10.4% were liver-related. SMR for all causes mortality for the HIV positive subjects was 5.6 (CI 95% 4.9-6.4), 2.4 (1.9-3.1) for HCV-negative subjects and 11.5 (9.9-13.4) for HCV-positive ones. Having HCV co-infection and AIDS yielded a SMR of 20.8 (16.5-26.1) and having AIDS and being HCV-negative had a SMR of 4.8 (3.5-6.7). SMR for liver-related mortality was 1.8 (0.6-5.7) for HCV-negative subjects versus 22.4 (14.6-34.3) for HCV-positive ones. Overall, both mortality rates as SMR and excess mortality rates were higher for IDUs than MSM and heterosexuals, patients with AIDS, with and without cART and for subjects included between 1997 and 2003.
Conclusion
There is an excess of all-cause and liver-related mortality in our cohorts compared with the general population. Further, HCV co-infection in HIV-positive patients increased the risk of death for both all causes and liver-related causes.
Introduction
Since the introduction of combined antiretroviral treatment (cART), important reductions in all cause-mortality in HIV-positive subjects have been observed [1, 2]. Nevertheless, HIV-positive people still have higher mortality rates than the general population standardized for age and sex [3, 4]. These standardized mortality ratios (SMRs) have been reported to be higher in women, injecting drug users (IDU), people with AIDS and in those with lower CD4 cell counts [5-7]. For HIV-positive subjects within 5 years of seroconversion, no difference in mortality is seen as compared to the general population, and in people on cART with high CD4 counts, excess HIV-related mortality seems to be similar to other chronic conditions [4, 8].
This increase in life expectancy, together with the co-morbidities often associated with HIV infection such as co-infection by hepatitis B and C, alcohol, tobacco and drug use, are responsible for increases in non-AIDS defining causes of death [2, 9, 10]. Liver-related deaths are one of the commonest causes of death in the post cART era [11-13]. HIV and HCV co-infection have detrimental effects on the natural history of each virus: HIV infection has been reported to accelerate HCV progression [14, 15], and higher mortality is described in HIV-positive subjects with HCV co-infection [16, 17]. In Spain, despite the continuous decrease of HCV co-infection due to declines in the proportion of injecting drug users (IDUs), HCV prevalence in HIV-positive subjects remains high, and mortality due to liver diseases in HIV populations partly replaces mortality from AIDS prior to cART [18-21]. Liver-related deaths were the second commonest cause of death in CoRIS, the Cohort of the Spanish Research Network on AIDS, accounting for 10% of all events [22, 23] .
Discussion
The all-cause mortality in HIV-positive subjects in the Cohorts of the Spanish AIDS Research Network of Excellence between 1997 and 2008 is nearly six times higher than that of the general population of the same age and sex. However, remarkable differences are seen according to HCV co-infection status: mortality in HCV-negative subjects is two and a half times higher than in the general population while death rates in HCV-positive individuals are eleven times higher. Liver-related mortality in HIV-positive subjects in CoRIS is nearly ten times higher than in the general population of the same age and sex, and again, notable differences by HCV coinfection status are seen. While non-significant increases in liver-related mortality are seen in HCV-negative people, liver-related mortality is twenty-two times higher in HCV-infected subjects compared to the general population of the same age and sex.
As previously reported, HIV-infected populations have higher mortality rates than the general population of the same age and sex. Our data are consistent with these findings, but they also highlight the remarkable excess mortality seen in subjects with HCV co-infection [3, 17, 26, 27]. We observe that the all-cause mortality in HIV-positive HCV-negative subjects who were AIDS-free was 1.4 times higher than the general population's and increased to 20.8 times higher in HCV-positive subjects who had an AIDS defining condition.
Despite the sustained reduction of HCV serial prevalence from 1997 onwards in our cohort of HIV-positive subjects, overall HCV prevalence was 37.3%, similar to figures reported by EuroSIDA for Southern European countries [17]. HIV and HCV are well established causes for death from all causes [17, 22, 28, 29]. In addition to this, people infected with HIV and/or with HCV have been reported to have higher rates of drug, alcohol and tobacco use than the general population [26, 30, 31]. Data from a subset of CoRIS members shows that 42% of the men and 54% of the women reported current smoking [32] whereas these proportions were 31% and 21% for the general population between 16 and 64 years old according to the National Health Survey [33]. Therefore, it is likely that higher smoking rates are responsible for part of the excess mortality observed in our population. Regarding alcohol use, preliminary data in our cohort show that 75% of the men and 44% of the women had drunk alcohol in the preceding 12 months [32]]. This is slightly lower than the figures for the general population, 80% and 57% [33], which may be due to sick people drinking less alcohol than those in the general population. A recently published study on the cardiovascular risk in the patients from our cohort has shown a prevalence of smoking of 47% as well as that of other comorbidities, such as diabetes and hypertension, 3% and 9%, respectively [34].
The SMR for all-cause mortality were higher for people less than 40 years old, and this was observed in both persons who were co-infected with HCV and those not coinfected. As mortality rates in the general population rise, mortality in our cohort increasingly resembles that of the general population. As expected, excess mortality rates increased with age, highlighting the value of using both relative and absolute measures to estimate excess mortality.
Regarding liver-related mortality, we observed an important difference between men and women. In women, liver-related SMR was 38 times higher than for women of the general population of the same age. These differences may be explained by the relative low liver-related death in women from the general population [35], together with the special characteristics of the HIV-positive women; a higher prevalence of comorbidities (29.5% of women in this study were current or former injecting drug users and 40.2% were coinfected with HCV) and their lower socio-economic level [36].
As far as we know, only one previous study has estimated SMRs in HIV-positive populations by HCV infection status [6]. Lewden et al found that all-cause mortality in HIV-positive subjects co-infected with HCV was 14 times higher than in the general population, whereas the SMR for those not co-infected was 4.4. Our results are similar, although slightly lower for the HCV-negative population. Various studies have estimated the SMR for all-cause mortality in cohorts of HIV-infected subjects and have found that their mortality rates are 3 to 14 times higher than in the general population [3-5, 7]. In interpreting these findings, the composition of the cohort, the background HCV prevalence and the mortality rates of the general population have to be taken into account. Lower SMRs have been reported in large international cohorts made up of heterogeneous populations, whereas higher SMRs are derived from smaller cohorts with larger proportions of injecting drug users [3, 4]. Regarding excess mortality, our rate of 1.0 per 100 p-y, is slightly higher than the 0.6 per 100 py for 2004-2006 reported by the CASCADE Collaboration [8]; overall HCV prevalence in that study was lower than ours, and it was composed exclusively of seroconverters with longer periods of disease-free follow-up. Our data are consistent with previous publications reporting important reductions in mortality in the cART era in settings, such as Spain, where access to cART is universal [6, 37].
Treatment for HCV infection in co-infected individuals has been more recent in our setting [38]. In a short survey of 24 European countries, Salmon et al showed that this treatment has been prescribed to only 10% of the subjects who need it [39]. Nowadays this treatment is widely recommended since successful treatment of chronic hepatitis C, besides preventing the development of end-stage liver disease, may also reduce the risk of subsequent liver toxicity during antiretroviral therapy in HIV/HCV-co-infected patients [40].
There are some study limitations that merit discussion. We are aware that variables other than age and sex may account for the higher mortality rates found in our cohort, such as current use of injecting drugs. Unfortunately, this information was not available, but adjustment for this factor would probably have resulted in lower SMRs. Nevertheless, the SMRs for transmission categories other than IDUs also showed an excess mortality. Similarly, information on socio-economic status and alcohol and tobacco use is missing from both numerators and denominators, which means the SMRs found in this study may be an overestimation. Approximately 15% of subjects with HCV infection will clear the infection spontaneously, but this can only be detected by PCR, which was available for only a minority of our patients [41]. Therefore, the assumption that these HCV antibody-positive but PCR-negative people are HCV-positive underestimates the magnitude of the association. We are aware that additional data on chronic hepatitis C and HCV treatment data would be very important but those data were not uniformly collected during all the study period and only were available for few patients.
Deaths were coded in the same way for both the numerators and denominators, based on information provided by the National Basic Death File using ICD-9 and ICD-10 coding algorithms. This is an important asset of this study as the majority of previous studies have coded deaths in cohort members using algorithms different from those used for the denominators. Concordance between different death coding algorithms has been insufficiently studied [23]. With respect to persons excluded from the analysis, we believe that they do not introduce important biases. In the first place, if we perform a sensitivity analysis considering all unknowns as positive, the SMRs are similar to the results obtained. And second, by eliminating those with less than 6 months of follow-up, we are losing subjects who die shortly after cohort entry. Since persons included in the cohort are new cases in hospitals, these early deaths during follow-up would be persons dying from AIDS who have been diagnosed very late, and these represent only a small percentage of the cohort. Finally, the association between HCV infection and liver-related death could be overestimated if the physician who certified the cause of death knew the HCV status of the subject; those with positive HCV serology would be more likely assigned a liver-related death [42]. While this bias may, indeed, account for some of observed association, it has to be highlighted that we obtained the cause of death for all cohort members from the National Basic Death File and that it is unlikely that all doctors certifying deaths had the information on the HCV status of the subject.
To conclude, we have shown an excess of all-cause and liver-related mortality in HIV-positive people compared to the general population in the last decade, despite improvements in the management of both HIV and HCV infections. Co-infection with HCV seems to play a very important role in all-cause and liver-related excess mortality. Rapid changes in the epidemiology of HCV co-infection and major advances in the treatment of these infections are likely to shape future patterns of excess mortality in the coming years.
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