Currently, individuals infected by the human immunodeficiency virus (HIV) and treated with combination antiretroviral therapy (cART) live longer than ever in high-income countries 1 . The spectrum of the disease has switched in this environment from predominantly AIDS-related mortality and morbidity to non-AIDS-related conditions, especially severe infections, end-stage liver disease, cardiovascular disease, and malignancies 2 3 4 5 . In Brazil, a middle-income country with widely available cART, AIDS-related conditions remain an important cause of mortality and morbidity, while an increased representation of non-AIDS defining conditions has recently been reported 6 7 .

Whereas causes of death are now well described 2 4 , severe morbidity has been more difficult to accurately study and data remain scarce about their distribution and determinants over time. Observational hospital-based cohorts from Europe and North America have reported causes of hospitalization in the cART era as a proxy for severe morbidity, especially in the context of universal access to care. Indeed, updated information on severe disease burden can inform HIV clinicians as to the necessary efforts for screening and prevention and can be used for monitoring patients with organ-specific specialists. Policy-makers can also use such information to project future areas of care needs and associated costs. Observational hospital-based cohort studies have shown that HIV-infected individuals continue to be hospitalized at high rates 3 8 9 , with a shift towards non-AIDS severe morbid events 10 . Despite the fast evolution of cART coverage including in resource-constrained settings, there have been only few reports from these areas over the past ten years. Severe morbidity in resource-limited settings might also be characterized by the same shift towards non-AIDS events, though patients are exposed to specific tropical infectious diseases 11 .

Our aim was to describe and contrast severe morbidity trends and determinants among HIV-infected individuals followed in two geographically contrasting settings (France and Brazil) with universal access to treatment and care. To this end, we studied severe morbidity over a 9-year period in two hospital-based cohorts of HIV-infected individuals: the ANRS C03 Aquitaine (Aquitaine) in South Western France and the Evandro Chagas Research Institute (IPEC) Cohort of the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil.

Between January 2000 and December 2008, 7812 patients were followed for a total of 41,668 person-years (PY) of follow-up, 29,866 PY for Aquitaine and 11,802 PY for IPEC. The mean follow-up time per patient for the two cohorts combined was 5.3 years (median 5.4 years, interquartile range [IQR] 2.3-9.0 years). Approximately two-thirds of the study population was from Aquitaine and its mean follow-up time per patient was 6.0 years (median 6.9 years, IQR 3.2-9.0 years), compared to 4.2 years (median 3.3 years, IQR 1.4-7.4 years) for IPEC.

Demographic and clinical characteristics of the study population varied over time (Table 1). The proportion of patients in the age groups 50–59 and ≥ 60 years of age increased from 9.2% and 4.2% in 2000 to 17.8% and 8.2% in 2008, respectively. The relative frequency of heterosexual contact as the mode of HIV transmission increased while injection drug use decreased over time. Patients’ immunological profile at a given year significantly improved with time and half of the study population reaching a CD4 cell count >500 cells/mm³ in 2008; in addition two-thirds of the population had undetectable plasma HIV RNA in 2008. The prevalence of hepatitis C decreased over time. Ageing, decreased proportion of IDUs, and improved immunological profile were observed in the two cohorts when evaluated separately, though trends were more pronounced in the Aquitaine Cohort (see Additional file 1: Tables S1 and S2). In IPEC, an increased proportion of males was observed over time. Throughout the study period, the proportion of patients diagnosed with HIV infection for less than one year remained stable (10%), as was the use of cART (90%), and the co-infection with hepatitis B virus (6%).

^aAge from birth was updated yearly for each participant.

^bPresumed mode of HIV exposure was classified as men who have sex with men (MSM), injection drug use (IDU), heterosexual transmission, other, and unknown.

^cYearly CD4 cell counts and plasma HIV RNAs were defined as the mean value of all measurements taken in a specific calendar year.

^dTime since first HIV + test was calculated for each calendar year.

^eCombination antiretroviral therapy (cART) was defined as two nucleoside reverse transcriptase inhibitors plus either one non-nucleoside reverse transcriptase inhibitor or one protease-inhibitor (boosted or not).

^fHepatitis B infection was defined by the presence of hepatitis B surface antigen (HBsAg).

^gHepatitis C infection was defined by the presence of hepatitis C antibodies.

During the entire study period, hospitalization for a severe morbid event occurred in a pool of 2238 (28.6%) participants, 1473 (29.5%) from Aquitaine and 765 (27.1%) from IPEC. A total of 4689 hospitalizations were recorded, 3049 (65.0%) in Aquitaine and 1640 (35.0%) in IPEC. One severe morbid event was reported in 2348 hospitalizations (50.1%), two morbid events in 1359 hospitalizations (29.0%), and three in 599 hospitalizations (12.8%). In 383 (8.2%) hospitalizations more than three severe morbid events were reported. Among those who were hospitalized (2238/7812, 28.6%), 8696 severe morbid events were reported, 5963 (68.6%) in Aquitaine and 2733 (31.4%) in IPEC. There were 310 deaths reported, a 6.6% fatality ending hospitalizations.

Over the entire study period, the incidence rate of severe morbid events was 21.5/100 PY (95% confidence interval (95% CI): 20.3 to 22.8/100 PY) overall, 20.5/100 PY (95% CI 19.1 to 22.0/100 PY) in Aquitaine and 24.0/100 PY (95% CI 21.8 to 26.4/100 PY) in IPEC. The annual incidence rate of severe morbid events significantly decreased from 27.3/100 PY in 2000 to 19.2/100 PY in 2008 (p < 0.001, Table 2). This downward trend was observed for both AIDS and non-AIDS events. The annual incidence rate of non-AIDS events surpassed that of AIDS-events during the entire study period. These trends were observed in both cohorts though the ratio of annual incidence rates of non-AIDS to AIDS events was much higher in the Aquitaine Cohort (up to 6:1) than in the IPEC Cohort (always <2:1).

Annual mortality rates also decreased over time. Eight hundred and ninety one patients died during the study period yielding a mortality rate that decreased from 1.9/100 PY in 2000 to 1.5/100 PY in 2008 (p < 0.01). In Aquitaine, 498 patients died during the study period and the mortality rate decreased from 1.6/100 PY in 2000 to 1.1/100PY in 2008 (p < 0.01). In IPEC, 393 deaths occurred yielding a higher mortality rate that also decreased from 3.0/100 PY in 2000 to 2.3/100 PY in 2008 although the difference did not reach statistical significance (p = 0.09).

The annual incidence rates of the 21 non-AIDS disease categories are displayed in Table 3. Bacterial infection was the most frequent cause of non-AIDS events with a total of 1602 events yielding a stable incidence rate over time ranging between 3.5 and 4.5 events per 100 PY (p = 0.12). Although similar for each cohort when evaluated separately (see Additional file 1: Table S3 and Table S4), the incidence was much higher in IPEC with a maximum of 9.0 events per 100 PY in 2001 while in Aquitaine the maximum was 3.9 events per 100 PY in 2000. Following bacterial infection and by decreasing order of importance, the following disease categories were: psychiatric diseases, hepatic diseases, viral, hematological, neurological, digestive, cardiovascular, and parasitic diseases. In Aquitaine, psychiatric diseases held the second position while cardiovascular events were the second most frequent event category in IPEC (see Additional file 1: Tables S3 and S4). Psychiatric, viral, neurological, digestive, parasitic and dermatological diseases showed a statistically significant decreasing trend over the study period in the two cohorts combined (Table 3). The incidence rate of non-AIDS defining malignancies ranged between 0.1 and 0.5 events per 100 PY but did not decrease over time (p = 0.73).

The three most frequent diagnoses within the AIDS category and specific non-AIDS categories are shown in Table 4 for both cohorts combined and in the Additional file 1: Table S5 and Table S6 for Aquitaine and IPEC Cohorts, respectively. Overall and in each cohort, the two most frequent diagnoses within the AIDS category were pneumocystosis and toxoplasmosis, while tuberculosis held the third position overall and in IPEC Cohort but not in Aquitaine Cohort. Bacterial pneumonia and sepsis were the most frequent diagnoses within bacterial infections while among psychiatric diseases the most frequent diagnoses were depression, drug abuse and anorexia. Overall, the top three diagnoses within cardiovascular diseases were hypertension, thrombosis, and cerebral infarction. Lung cancer and Hodgkin lymphoma were among the most frequent diagnoses within the non-AIDS malignancy category.

Adjusted incidence rate ratios quantifying the degree of association of demographic and clinical factors with the incidence rate of AIDS and non-AIDS events are shown in Table 5. Immunodeficiency was found to be associated with the severe morbid events. As expected, the association with low CD4 cell count was strong for AIDS events with a dose–response pattern. Albeit the magnitude of the association was smaller, lower CD4 cell counts were also associated with a higher incidence rate of non-AIDS events, of specific non-AIDS events, and of deaths (Table 5). Higher plasma HIV RNA, less than 1 year since first HIV positive test and use of cART were significantly associated with a higher incidence rate of AIDS events.

Bold indicates statistically significant results.

IDU injection drug use. cART combination antiretroviral therapy.

The incidence of non-AIDS events was increased for those with older age and who reported injection drug use. The incidence of non-AIDS events was also significantly higher for those with less than 1 year since first HIV positive test, those who used cART, and those with hepatitis C co-infection. Of note is the fact that, even after adjusting for confounders, IPEC still showed a lower incidence of non-AIDS events when compared to Aquitaine.

Age ≥ 60 years was associated with a higher incidence rate of several specific non-AIDS events categories, including bacterial, hepatic, neurological, and cardiovascular. Age ≥ 60 years showed a particularly strong association with cardiovascular disease (adjusted incidence rate ratio 5.27 95% CI: 2.14-12.93, Table 5). Injection drug use was associated with a higher incidence of psychiatric and neurological events. One year or less since first HIV positive test was significantly positively associated with the incidence of parasitic diseases. Hepatitis C co-infection was significantly associated with an increased incidence of hepatic diseases (adjusted incidence rate ratio 5.18 95% CI: 3.29-8.14).

Mortality was significantly higher with increasing age, decreasing immunity, increased plasma HIV RNA, and the presence of hepatitis B or C co-infection (Table 5).

We report here a unique analysis of multi-morbidity patterns among HIV-infected individuals followed in two geographically contrasting settings (Europe and South America) with universal access to treatment and care in the cART era. Over a 9-year period (2000–2008), ageing, decreased representation of IDUs, and improved immunological profile were observed in both cohorts largely exposed to cART. The rate of severe morbid events decreased by one-third over the period and, in 2008, only one out of five events was AIDS-related; non-AIDS events were always more frequent than AIDS events. Immunodeficiency was associated with a higher incidence of AIDS-related and all types of non-AIDS-related events. Our observations suggest that long-term restoration and preservation of high CD4 cell counts as a result of cART access is highly and durably effective in preventing AIDS as well as non-AIDS severe morbid events.

In this collaboration, sizeable efforts were allocated for the collection, documentation and uniform classification and coding of morbid events leading to hospitalizations. There is indeed a lack of published studies on the long-term causes of severe morbidity leading to hospitalization in HIV-infected patients, although such information is highly valuable in identifying priorities for case management and improvement of the quality of life of subjects living with a chronic disease requiring life-long treatment. Our study population combined two hospital-based cohorts that mainly differed by environment and only modestly by access to care. In this context, non-AIDS related conditions were the most common cause of hospitalizations throughout the study period.

The decreasing incidence rate of AIDS-related events over time confirms the improvements in HIV care as this finding is accompanied by a higher percentage of individuals with CD4 cell counts >500 cells/mm³ and undetectable plasma HIV RNAs. In fact, even beyond severe immunodeficiency, individuals with CD4 cell counts between 350–500 cells/mm³ were found to have a three times higher incidence rate of AIDS events than those with CD4 cell counts >500 cells/mm³. In addition, although the comparison of the incidence rate of AIDS events in Aquitaine and IPEC initially suggested that AIDS events occurred at much higher frequency in the latter, after adjustments for other characteristics (immunological and virological profile as well as time since first HIV positive test), this finding did not hold, suggesting that environment is not a primary determinant of the occurrence of AIDS severe diseases in a population highly exposed to effective antiretroviral combinations 16 . Universal access to cART in both settings as well as more potent and user-friendly cART regimens readily available along the study period 17 18 19 20 have indeed contributed to these findings.

Concerning mortality, the results paralleled the ones described above for AIDS-related events. Determinants of higher mortality rates were immunodeficiency, high plasma HIV RNA, ageing and co-infection with hepatitis B or C, rather than environment. Indeed, these findings corroborate a previous analysis that showed similar rates of early mortality between developed and resource-limited settings when adjusted for immunological and virological factors 13 .

The relative higher incidence of non-AIDS-related events when compared to AIDS-related events throughout the study period confirms the recent findings of the significant burden of non-AIDS events among those living with HIV with a shift from AIDS to non-AIDS severe morbidity for the period 2000 to 2004 10 . A recent study from the Swiss cohort also showed that non-AIDS-related events outnumbered HIV-related events in that setting in the years 2008 through 2010, and that non-AIDS-related events were associated with older age, similarly to our results 21 . Our adjusted analysis showed a lower incidence of non-AIDS events in the IPEC cohort even after taking into account possible confounding factors. An explanation for this finding might be differences in indication for hospitalization in the two settings. Although the overall rates of non-AIDS-related events have significantly decreased between 2000 and 2008, the incidence of bacterial, cardiovascular, hepatic and hematological events remained stable over time. Prevention programs targeting tobacco use cessation, vaccination against influenza and pneumococcal diseases can greatly impact the most frequent non-AIDS severe morbid event category, i.e. bacterial infections. As for non-AIDS defining malignancies, existing screening policies such as anal cancer screening could be applied and additional screening policies, for example for lung cancer, should be evaluated.

Bacterial events were by far the most frequent category with no decreasing trend over the years. A stabilization was also identified in the most recent analysis of North American cohorts 3 where a classification system similar to the one used in the present study was employed. Differently from HOPS, NHS, or prior HIVRN 8 22 , the study by Berry et al. 3 and the present study classified infections (bacterial, viral or parasitic) as hierarchically higher than end-organ categories because antimicrobials are the primary therapy and many cases require specialized case management. In a combined analysis of two cohorts from Côte d’Ivoire, bacterial events were also among the most frequent events that led to hospitalization (23% of all hospitalizations 11 ). In the latter study, though differently from the present analysis, only a minority of patients were receiving cART 11 . Hence, bacterial events do not seem to be impacted by the increase in cART use and represent an important disease burden especially for septicemia and septic shock with important costs for drugs and intensive care units 23 . The high burden of bacterial infections in our study population indicates an urgent need for additional approaches concerning preventable bacterial infections, such as expansion of vaccination for influenza and pneumococcal disease.

Over the years, our study population aged significantly, more likely as a result of patients living longer with HIV/AIDS than of older patients reaching care. As a result, the incidence rate of severe morbid events associated with increased age, such as non-AIDS-defining malignancies, cardiovascular diseases and other end-organ diseases could be expected to increase with time. Although improved management of traditional cardiovascular risk factors and the use of more lipid friendlier ART regimens may have a favorable impact on the incidence of cardiovascular events, the French hospital database showed that HIV replication and immune status are independent predictors of myocardial infarction in HIV-infected individuals 24 . Further investigations should look for optimal monitoring strategies for non-AIDS co-morbidities in individuals on and off cART both in high- and middle/low-income countries, especially among those aged 50 and above.

Hepatic failure secondary to viral hepatitis was the most frequent hepatic event in our analysis. Other studies have demonstrated the increasing impact of chronic viral hepatitis and liver disease on hospital admission rates 22 25 26 27 . Prevention of hepatitis co-infection, timely treatment of chronic viral hepatitis in HIV co-infected patients, and careful monitoring of treatment related hepatotoxicity are important measures to reduce liver-related complications and subsequent hospitalizations.

In the present analysis severe morbidity requiring hospitalization due to non-AIDS malignancies did not show an increasing trend over time. Berry et al., in a contemporary analysis (2001–2008), were also unable to find an increase in hospitalizations for non-AIDS malignancies 3 . In contrast, it was recently shown that the relative frequency of deaths due to non-AIDS malignancies have increased in France 28 . In addition, large epidemiological studies has shown an increased incidence of non-AIDS malignancies in HIV-infected groups, two-fold higher than that found in the general population 29 30 . However, these latter studies included data up to 2002 and therefore did not take into account the long-term benefit of cART. Other recent studies of cancer incidence have reported increases in specific cancers (such as anal cancer and Hodgkin Disease) but no clear increase in overall non-AIDS malignancies since 2001 31 . In our study, malignant neoplasm of the lung was the most frequent diagnosis among the non-AIDS malignancies category. As shown by several studies, the incidence of this malignancy is increased with HIV infection and even more so among patients with AIDS compared to demographically similar populations 32 33 34 . It has been suggested that immunodeficiency-induced recurrent pneumonia and its associated inflammation may contribute to lung carcinogenesis in HIV infected individuals 35 . Given the lack of effective treatment options and as HIV-infected individuals live longer in the era of cART, it is expected that smoking will increasingly manifest its oncogenic potential and that lung cancer may become an increasingly important cause of death. Tobacco cessation programs already in place for the ANRS CO3 Aquitaine Cohort, as well as in other settings, can help reduce lung cancer incidence in this scenario 36 37 .

Among the specific non-AIDS categories, our study shows that psychiatric and neurologic diseases impose a significant burden. Although the incidence rate of psychiatric disease showed decreasing trends over the study period, it was the second most frequent cause of severe morbidity which shows the need for access to outpatient psychiatric care and coverage of psychotropic medicines, as well as careful monitoring of interactions between cART, in particular of efavirenz 38 and psychiatric medications. In our adjusted analyses we found that IDU was significantly associated with a higher overall rate of non-AIDS events, being most likely driven by psychiatric and neurologic severe morbidity. In addition, ageing was also found to be associated with neurologic diseases. This finding, when coupled with the most frequent diagnoses reported in the neurologic category (headache and dizziness) suggests an increased rate of hospital admissions for investigational purposes but without a concrete discharge diagnosis.

The present study has important strengths and limitations. This is the first study to compare causes of severe morbidity from the Northern and Southern hemispheres. In this study, a severe morbid event was defined as any event associated with a hospitalization for at least 48 hours. Thus, the studied events were on the same level of severity. In addition, both cohorts have reference hospitals to which patients refer to for hospitalizations, thus substantially decreasing the chances of missed hospitalizations. On the other hand, by definition, severe morbid events requiring hospitalization of less than 48 hours were excluded and thus it is possible that a fraction of severe morbid events were not represented in this study. Differently from Crum-Cianflone et al. 22 , where each hospitalization was placed into a single category, we captured all diagnoses associated with a hospitalization thus allowing for a more thorough description of the causes and trends of severe morbid events. The present study did not explore the impact of different cART regimens and further studies are needed to evaluate the impact of different treatments (in particular of efavirenz-based treatments) on the overall and specific non-AIDS severe morbidities 38 . The present study sought to harmonize hospital discharge diagnoses of two distinct hospital-based cohorts into comprehensive categories but decisions to group specific diagnoses in one or another category were made arbitrarily and thus could have influenced the results. As we move forward from evaluating mortality alone to include morbidity, data harmonization will become an increasing challenge. Finally, information on the presence of risk factors of severe morbidity, such as tobacco use and alcohol consumption, on important comorbidities as diabetes and hypertension, on the use of preventive interventions such as vaccinations, and on the use of treatment for other comorbidities such hepatitis B/C infections were not taken into account in this study as data was not systematically available. Efforts should be made in all cohorts of HIV-infected individuals to improve the information collected concerning these determinants.

Overall, our study shows that lower CD4 cell counts led to a higher incidence rate of both AIDS-related and non-AIDS-related events. Indeed, only 15% of the events occurred in the CD4 stratum >500 cells/mm³. Several studies have also noted the relationship between lower CD4 counts and severe morbidity 8 22 26 . Higher plasma HIV RNA and shorter time since first HIV positive test were significantly associated with a higher incidence rate of severe morbidity. Late diagnosis is still a major public health issue both in France and in Brazil 39 40 . Our results emphasize the critical need for earlier HIV diagnosis, linkage to care and prompt cART initiation to maintain robust CD4 counts to further reduce morbidity and mortality. Non-AIDS severe morbidity was associated with older age. Increasing age was also associated with increased hospital admissions, especially for non-AIDS causes in other studies 22 . Ageing of the HIV population may be contributing to the high hospitalization rates, a trend that will likely persist in the upcoming years. Poly-pathology, which increases with ageing, may also play a role 41 42 .

In conclusion, our study shows improvements up until 2008 both in South Western France and the region of Rio de Janeiro and allows the identification of priorities for improving the quality of life of patients, beyond specific HIV treatment. Cohorts should increase efforts to record and analyze non-AIDS severe morbidity both in the North and the South, to better reflect the disease burden of a chronic disease requiring life-long treatment and grasp the future epidemiological trends as equally and accurately as possible.

The ANRS CO3 Aquitaine Cohort study group:

Principal investigator: Pr F. Dabis.

Scientific committee: Prs F. Bonnet, D. Breilh, F. Dabis, M. Dupon, G. Chêne, H. Fleury, D. Malvy, P. Mercié, I. Pellegrin, P. Morlat, D. Neau, JL. Pellegrin, R. Thiébaut, Drs S. Bouchet, V. Gaborieau, D. Lacoste, S. Tchamgoué, L. Wittkop.

Composition of the GECSA: Epidemiology and biostatistics: Prs G. Chêne, F. Dabis, R. Thiébaut, Drs M. Bruyand, S. Lawson-Ayayi, L. Wittkop.

Clinical and biological hospital units: Bordeaux University Hospital: Pr P. Morlat (Pr F. Bonnet, Drs N. Bernard, M. Hessamfar, D. Lacoste, MA. Vandenhende), Pr M. Dupon (Drs FA. Dauchy, H. Dutronc), Pr P. Mercié (Drs P. Duffau, J. Roger Schmeltz), Pr D. Malvy (Drs T. Pistone, MC Receveur), Pr D. Neau (Drs C. Cazanave, A. Ochoa, MO. Vareil), Pr JL. Pellegrin (Pr JF. Viallard, Drs C. Greib, E. Lazaro), Pr H. Fleury (Pr ME. Lafon, Drs S. Reigadas, P. Trimoulet), Pr D. Breilh, Pr M. Molimard (Drs S. Bouchet, K. Titier), Pr JF. Moreau (Dr I. Pellegrin), Drs F. Haramburu, G. Miremont-Salamé. Arcachon Hospital: Dr A. Dupont. Dax Hospital: Dr Y. Gerard (Drs L. Caunègre, K. André). Bayonne Hospital: Dr F. Bonnal (Drs S. Farbos, MC. Gemain). Libourne Hospital: Dr J. Ceccaldi (Drs O. Caubet, S. Tchamgoué). Mont-de-Marsan Hospital: Dr S. De Witte (Dr C. Courtault). Pau Hospital: Drs E. Monlun (Dr V. Gaborieau). Périgueux Hospital: Dr P. Lataste (Dr JP. Meraud). Villeneuve-sur-Lot Hospital: Dr I. Chossat.

Permanent team: MJ. Blaizeau, M. Bruyand, V. Conte, M. Decoin, J. Delaune, S. Delveaux, F. Diarra, C. D’Ivernois, A. Frosch, S. Geffard, C. Hanappier, S. Lawson-Ayayi, E. Lenaud, O. Leleux, F. Le Marec, J. Leray, I. Louis, G. Palmer, A. Pougetoux, X. Sicard, D. Touchard B. Uwamaliya-Nziyumvira.

The authors declare that they have no competing interests.

PML conceived of the study and participated in its design and coordination, performed the statistical analysis and drafted the manuscript. SR, FB, RIM, MH, DPC, CG, CC attended the patients, participated in the data collection and validation and helped to draft the manuscript. MB, VGV, FD, BG, and GC conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors have given final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.