Mortality due to AIDS fell, but mortality due to non-AIDS-related diseases, such as lung cancer, increased.
Lifestyle and social factors need to be addressed if the full potential of HIV treatment to lower mortality is to be realised, according to results from a large cohort study published in the May 15th edition of Clinical Infectious Diseases.
Diseases associated with ageing but nevertheless influenced by HIV infection, and risk behaviours associated with HIV infection, such as cardiovascular disease, non-AIDS-defining cancers, kidney disease and liver disease, are the causes of death in a growing proportion of people with HIV, while deaths from AIDS-defining causes such as opportunistic infections and AIDS-defining cancers have fallen over the past ten years.
Investigators from the international Antiretroviral Therapy Cohort Collaboration examined recorded causes of death amongst patients taking HIV treatment in Europe and North America between 1996 and 2006. Mortality due to AIDS fell, but mortality due to non-AIDS-related diseases, such as lung cancer, increased.
Their retrospective analysis included 13 studies, which included a total of 39,272 patients.
These individuals contributed a total of 154,667 person-years of follow-up, the median duration of follow-up for each patients being a little under four years.
At the time HIV treatment was started, the patients had a median age of 37 years. The median calendar month when antiretroviral therapy was initiated was December 2000. The majority of patients (62%) took a combination that included a protease inhibitor.
There were a total of 1876 deaths (5%). The overall mortality rate was 12 deaths per 1000 person-years. Those who died had a lower median CD4 cell count at baseline (110 cells/mm3) than those who survived (217 cells/mm3).
A cause of death was recorded for 1597 patients. Almost half (49.6%) were due to AIDS. When the investigators looked at the AIDS-related mortality in further detail, they noted that 23% of all deaths were due to AIDS-defining infections and 15% to AIDS-defining cancers.
Non-AIDS-defining cancers were the next most common cause of death (12%). Over a third (37%) of non-AIDS-defining cancer deaths were caused by lung cancer.
Infections not considered AIDS-defining caused 8% of all deaths, and 8% of deaths were also attributed to cardiovascular death. Violence accounted for 8% of deaths, liver disease for 7%, respiratory diseases for 2% and renal failure for 2% of mortality.
The cause of death changed over time. The proportion of AIDS-related deaths fell from 58% in 1996-99 to 44% in the period 2003 to 2006. The percentage of deaths due to AIDS-defining cancers fell from 21% in the earlier period to 13% after 2003.
However, at the same time non-AIDS-defining cancers became an increasingly important cause of death. The proportion of deaths attributed to such malignancies more than doubled from 7% before 1999 to 15% in the period between 2003 and 2006.
A low CD4 cell count was associated with an increased risk of death from non-AIDS-related cancers (HR per 100 cell/mm3 fall = 1.43; 95% CI, 1.34 to 1.53)and renal cancers (HR per 100 cell/mm3 fall = 1.73; 95% CI, 1.18 to 2.55).
“The strong inverse association of rates of death due to AIDS with CD4 cell counts at the time of starting antiretroviral therapy supports arguments for earlier initiation of antiretroviral therapy,” comment the investigators.
A baseline viral load above 5 log10/copies/ml was significantly associated with an increased risk of death due to AIDS (HR = 1.31; 95% CI, 1.12 to 1.53), infections (HR = 1.85; 95% CI, 1.25 to 2.73), cardiovascular disease (HR = 1.54; 95% CI, 1.05 to 2.27), and respiratory disorders (HR = 3.63; 95% CI, 1.30 to 10.09).
“Systematic immune activation secondary to high viral replication, rather than additional or additional to immunodeficiency, may promote death from infections and cardiovascular disease,” write the study’s authors.
Mortality rates for all causes with the exception of renal disease were higher for injecting drug users than other risk groups. Especially strong associations between injecting drug use and death due to liver disease, respiratory illnesses, violence and infections were observed.
Older age was strongly associated with an increased risk of death from non-AIDS-related cancers (HR per 10 years = 2.32; 95% CI, 2.04 to 2.63), and cardiovascular disease (HR per 10 years = 2.05; 95% CI, 1.76 to 2.39). The rate of kidney-related death was especially high amongst patients aged over 60.
The investigators believe that these results “imply that the process of aging will become a dominant factor in HIV mortality in the next decade.”
Overall, mortality rates were 16% were lower in women in men. In addition, women were 50% less likely than men to die of non-AIDS-related cancers.
As the duration of antiretroviral therapy increased, the risk of death from AIDS, non-AIDS-related infections, and kidney disease decreased (p < 0.001).
Starting HIV therapy after 2000 was associated with a significant reduction in the risk of death due to AIDS (p < 0.001).
“Antiretroviral therapy continues to dramatically reduce rates of mortality attributable to HIV infection in high-income countries,” conclude the investigators.
However, they express concern about the high mortality rates due to conditions “associated with social and lifestyle factors…the importance of lifestyle is reinforced by the observation that the most common non-AIDS malignancy was lung cancer, likely caused by smoking.”
The investigators believe that these findings have implications for the care of patients with HIV. They suggest: “interventions to address risk factors for lifestyle-related causes of death, as well as monitoring for and care of diseases associated with old age, will be necessary if the full benefit of antiretroviral therapy in decreasing mortality is to continue n the second decade of antiretroviral treatment.”
The Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis 50: 1387-96, 201