HIV Positive People Can Modify Several Risk Factors that Increase Mortality

By Liz Highleyman

While effective antiretroviral therapy has dramatically reduced the risk of illness and death for people with HIV, positive individuals still have an elevated mortality rate relative to the HIV negative general population. Furthermore, as HIV positive people live longer, they are at increased risk for progressive conditions such as cardiovascular disease, liver disease, and non-AIDS-defining cancers.

As reported at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last week in Montreal, Colette Smith and colleagues with the D:A:D (Data Collection on Adverse events of Anti-HIV Drugs) study team sought to identify modifiable risk factors associated with specific causes of death.

In this analysis, more than 33,000 HIV positive patients from 11 cohorts in Europe, Australia, and the U.S. were followed from date of entry into the study until death or last follow-up, collectively contributing nearly 159,000 person-years (PY) of follow-up data. About three-quarters were men, 45% were white, 10% were black, the mean age was 39 years, 18% had a history of injection drug use, and about half were current (34%) or former (17%) smokers.

The researchers used Poisson regression to calculate adjusted rate ratios (RR) for the association between potentially modifiable risk factors and death after adjusting for other potential confounding factors.

The factors the investigators considered to be "modifiable" included body mass index (BMI), smoking, hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfection, diabetes, hypertension, use of antiretroviral therapy, current CD4 cell count, and current HIV viral load.

Results

During the follow-up period, there were 2192 total deaths (14 per 1000 PY across the entire period, but falling from 16 to 10 per 1000 PY since 2007).

Underlying causes of death were:

AIDS: 32%;
Liver-related causes: 14%;
Non-AIDS-defining cancers: 12%;
Cardiovascular disease: 11%;
Bacterial infections: 9%;
Non-natural causes (e.g., accidents, drug overdose, violence, suicide): 9%.
Other causes: 13%.

Significant non-modifiable risk factors were:

Male sex: 20% increase in mortality risk;
Older age: 22% increase per 5 years.

HIV/AIDS-related risk factors linked to all-cause death were:

Lower current CD4 count (19% increase per 50 fewer cells/mm3);
Higher HIV viral load (56% increase if > 400 copies/mL);
HIV RNA < 10,000 copies/mL if untreated: 77% increase;
HIV RNA > 10,000 copies/mL if untreated: nearly a 4-fold increase;
Among patients on antiretroviral therapy, those with a detectable viral load still had a higher risk of death than those with fully suppressed HIV.

Modifiable risk factors for all-cause death were:

Smoking: 20% increase in risk (15% for current, 30% for former);
Diabetes: 83% increase;
HCV coinfection: 45% increase;
HBV coinfection: 29% increase;
Hypertension: 53% increase;
Low BMI (< 18 kg/m2): 3-fold increase.

The strength of association of modifiable risk factors with cause-specific death rates varied substantially, for example:

Smoking (current and former) was associated with cardiovascular disease and non-AIDS-defining cancers;
HBV and HCV coinfection were associated with liver-related deaths (about 80% of liver-related deaths were attributable to chronic viral hepatitis);
Hypertension was associated with liver-related and cardiovascular deaths.
Diabetes was a risk factor for all specific causes except non-AIDS-defining cancers.
Higher HIV viral was strongly associated with AIDS-related deaths, weakly linked to liver-related and cardiovascular disease, but not associated with non-AIDS-defining cancers.
Lower CD4 count was associated with a higher risk of death due to all specific causes, but was most pronounced for AIDS-related deaths.

"Multiple potentially modifiable risk factors for deaths in HIV-infected persons were identified," the D:A:D investigators concluded. "These factors must be addressed to further reduce mortality. Maintaining higher CD4 cell counts is likely to have the broadest effect on decrease in deaths."

These findings agree with those from the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) study, also presented at the conference. In this cohort of 992 U.S. HIV patients, significant mortality risk factors were older age (61% increased risk per 10 years), low CD4 count (35% increase per 1 log decrease in CD4 cells), and current smoking (nearly a 3-fold increase).

Noting some of the more counterintuitive findings, she explained that the trend toward increased death associated with lower BMI was likely attributable to people losing weight as they get sicker. She did not have an explanation for the link between high blood pressure and liver-related deaths.

In a discussion after the presentation, some argued that these factors are not all necessarily modifiable in all cases. While hepatitis B can be prevented with a vaccine, for example, once a person is infected the virus may not be eradicated with antiviral treatment. Likewise, even state-of-the-art antiretroviral therapy does not always raise a person's CD4 count to a fully protective level.

In a press conference following the session, Smith noted that even in a population with widely available access to care, the most common cause of death was still AIDS, indicating that many people were not getting tested and treated in a timely manner.

The take-home message of the latest analysis, she said, is the important public health message: "You need to try as hard as you can to modify the modifiable risk factors."

2/20/09

References

C Smith and D:A:D Study Group. Association between Modifiable and Non-modifiable Risk Factors and Specific Causes of Death in the HAART Era: The Data Collection on Adverse Events of Anti-HIV Drugs Study. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 145.

L Modrich, R Scherzer, A Zolopa, and the FRAM Study Group. Factors Associated with Mortality in the Study of Fat Redistribution and Metabolic Change in HIV Infection. CROI 2009. Abstract 706.