Changes in Causes of Death among HIV Positive Adults between 2000 and 2005

By Ronald Baker, PhD

Because HIV positive individuals are living longer due the success of HAART, they may experience a wider range of non-AIDS-related complications than in the pre-HAART era. The effects of aging and of long-term exposure to antiretroviral therapy, in addition to the effects of chronic HIV infection and risk factors such as smoking, alcohol consumption, or abnormal blood lipid levels (dyslipidemia) are now contributing to various causes of illness and death in this population.

For individuals coinfected with HIV and hepatitis C virus (HCV) or hepatitis B (HBV) virus infection, liver complications may arise during prolonged periods of survival, since fibrosis related to viral hepatitis is a long-term process.

Given these developments, surveillance of causes of death creates the opportunity to assess priorities in prevention, care, and future research.

In 2000, the multicenter French Mortalité 2000 survey showed the persistence of AIDS-related deaths and the emergence of cancers and hepatitis-related deaths in France [1]. These findings have been confirmed by other studies in the U.S., Europe, and Australia.

The follow-up Mortalité 2005 survey sought to describe the distribution of causes of death among HIV-infected adults in France in 2005 and to compare it with the distribution in 2000. Physicians involved in the management of HIV infection reported deaths and documented the causes using a standardized questionnaire similar to that used in the 2000 survey. Results were published in the August 15, 2008 issue of AIDS.

Significant changes in the management of patients with chronic HIV infection occurred between 2000 and 2005, the authors noted as background. Combination antiretroviral therapy has evolved toward simplified and more effective drug regimens, resulting in better tolerance of and adherence to therapy. An exception is that the risk of cardiovascular disease may increase with longer duration of exposure to protease inhibitors [2].

Results

• Overall, 1042 deaths of HIV positive individuals were reported in 2005, compared with 964 in 2000.

• Among the patients who died in 2005, 76% were men, the median age was 46 years (vs 41 years in 2000), and the median last CD4 cell count before death was 161 cells/mm3 (vs 94 cells/mm3 in 2002).

• The proportion of underlying causes of death due to AIDS decreased to 36% in 2005 from 47% in 2000.

• Conversely, the proportion of the following causes of death increased:

• Cancer not related to AIDS or hepatitis (17% vs 11%);
• Liver-related disease (15% vs 13%, including 11% hepatitis C and 2% hepatitis B);
• Cardiovascular disease (8% vs 7%);
• Suicide (5% vs 4%).

• Among the 375 AIDS-related deaths, the most frequent event was non-Hodgkin lymphoma (NHL) (28%).

• Among the 154 liver-related deaths, 24% were due to hepatocellular carcinoma.

• Of the cancers not directly related to AIDS or hepatitis, the most frequent sites were the lung (31%) and the digestive tract (14%).

In conclusion, the study authors wrote, "The heterogeneity of causes of death among HIV-infected adults was confirmed and intensified in 2005, with 3 causes following AIDS: cancers and liver-related and cardiovascular diseases."

Discussion

According to the authors, between 2000 and 2005 the proportion of AIDS-related deaths "continued to decrease among HIV positive adults, but it remained the most frequent underlying cause of death, mainly related to NHL."

"The distribution of other causes of death was heterogeneous," they observed. "whereas 3 causes increased and accounted for 40% of them: non-AIDS-defining cancer, liver-related diseases, and cardiovascular deaths.

The authors noted that their results, "[could be] a consequence of a suboptimal detection or management of both HIV infection and viral hepatitis coinfections, and also aging of HIV-infected individuals and a high prevalence of traditional determinants predisposing to cancers or cardiovascular diseases."

Reviewing studies from elsewhere, the researchers found that the distribution of non-AIDS-defining causes of death varied according to specific characteristics of the population under study. For example:

• Among individuals living in New York City in the pre-HAART era, substance abuse was the most frequent non-HIV-related cause of death between 1999 and 2004.

• Until 2004, cancer was the most frequent non-AIDS-defining cause of death in the Australian HIV Observational Database and in the U.S. HIV Outpatient Study.

• Liver disease was the most frequent non-AIDS-defining cause of death in the HAART era among HIV positive individuals with hemophilia in Canada and in the large international D:A:D cohort (23% and 67%, respectively, coinfected with HCV).

In the current study, about 1 in 3 deaths (n = 344; 33%) was related to an AIDS-defining or non-AIDS-defining cancer. Just over a third (38%) of non-AIDS, non-hepatitis-related cancers occurred in the respiratory tract. Other studies have shown that the risk of cancer is higher in HIV positive adults compared with the general population, and that smoking plays a major role, given that around half of HIV positive adults are current smokers.

HIV-HCV Coinfected Patients

HCV was involved in 78% of liver-related deaths, and the proportion of hepatocellular carcinoma increased over time (from 16% in 2000 to 24% in 2005). Excessive alcohol consumption was reported in half of these cases, and two-thirds were infected with HIV through injection drug use; in France, 90% of HIV-positive adults infected via injection drug use also have HCV.

Despite improvement in the management of HIV-HCV coinfection, not all coinfected patients who would be eligible actually receive treatment for hepatitis C. The study authors recommended, "Anti-HCV treatment should be largely proposed even in patients with cirrhosis, provided that they have no decompensation, because early HCV viral kinetics allows the prediction of sustained virological response (SVR) and the cessation of therapy in case of unfavorable prognosis factors." However, they noted, "most French HIV-infected patients are coinfected by HCV genotype 4, which is associated with poorer outcome" compared with genotypes 2 or 3.

Metabolic-related Diseases

Interestingly, the authors observed that in their study, "The proportion of cardiovascular-related deaths only slightly increased. Improvement of antiretroviral strategies and management of dyslipidemia may have slowed an initially worse trend.

Nevertheless, they concluded, "the relative contribution of HIV infection, antiretrovirals, and traditional risk factors in the occurrence of metabolic-related diseases is still debated[3]."

INSERM, U897, Bordeaux, France; Université Victor Segalen Bordeaux 2, Institut de Santé Publique, d'Epidémiologie et de Développement, Bordeaux, France; Centre Hospitalier Universitaire Brabois, Vandoeuvre-Les-Nancy, France; Centre Hospitalier Universitaire L'Archet, Nice, France; Centre Hospitalier Universitaire, Bordeaux, France; INSERM, U720, Paris, France; UPMC Univ Paris 06, UMR S 720, Paris, France; INSERM, CépiDc, Le Vésinet, France; Institut de Veille Sanitaire, Saint-Maurice, France; Centre Hospitalier Universitaire Cochin-Tarnier, Paris, France; Centre Hospitalier Universitaire La Pitié Salpêtrière, Paris, France; Université Pierre et Marie Curie-Paris 6, CNRS, UMR 7087, Paris, France.

8/26/08

Reference
C Lewden, T May, E Rosenthal (for the ANRS EN19 Mortalité Study Group and Mortavic 1). Changes in causes of death among adults infected by HIV between 2000 and 2005: The "Mortalité 2000 and 2005" Surveys (ANRS EN19 and Mortavic). Journal of Acquired Immune Deficiency Syndromes 48(5): 590-598. August 15, 2008.

Other Citations
1. C Lewden, D Salmon , P Morlat , and others. Causes of death among HIV-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. International Journal of Epidemiology 34: 121-130. 2005.

2. The D:A:D Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine 356: 1723-1735. 2007.

3. D Salmon Ceron, C Lewden, and others. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. Journal of Hepatology 42: 799-805. 2005.