Diabetes, high blood pressure and smoking raise risk of death for all people with HIV

A number of modifiable or preventable medical conditions can nearly double the risk of death in people with HIV, a large cohort study has found, and can double the risk of death due to specific causes. Colette Smith of University College Medical School, London, presented the latest analysis of the D:A:D study to the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal on Wednesday.

The D:A:D study (Data collection on Adverse events of anti-HIV Drugs) has collected information on antiretroviral safety and participants’ experiences of illness and death since 1999. This observational study includes eleven prospective cohorts from the US, Australia and Europe. For this analysis, a total of 33,347 participants were followed from the time of enrolment until February 2007, reflecting 158,959 person-years of follow-up.

The average age of D:A:D participants was 39, three-quarters were men, 45% were white and 43% were gay. Three-quarters were on antiretroviral therapy (ART) at the start of the study of which 58% were on a protease inhibitor and about one-third on a non-nucleoside reverse transcriptase inhibitor (NNRTI).

Over this period there were 2192 deaths, a rate of one death in every 72.5 patients a year. The major underlying causes of death were AIDS (32%), liver-related illness (14%), non-AIDS cancers (12%) cardiovascular disease (11%) ‘non-natural’ deaths such as accidents, drug overdose and suicide (9%); and bacterial infections (9%). Thirteen per cent experienced other causes of death. The D:A:D study only started in December 1999, so missed the dramatic falls in death rates after the introduction of ART, but the death rate during the study has fallen from 1.6% to 1.0% per year during that time.

A number of risk factors were analysed to reveal likely associations with the risk of death: firstly, the two non-modifiable ones of age and gender; secondly, modifiable but non-HIV-related risk factors that could have been prevented or cured, such as infection with hepatitis B or C, body mass index (BMI), smoking, high blood pressure (hypertension) and diabetes; and lastly HIV-related modifiable factors including antiretroviral use, CD4 count and viral load. As D:A:D is a large cohort study, only basic data is gathered, so other modifiable risk factors that were not collected (drink and drugs, diet, stress, to name a few) might have had even greater effects on mortality.

There were 22% more deaths for every five years’ increase in age and 20% more deaths in men than in women.

The following non-HIV related modifiable risks factors were found to be associated with the risk of death, in order of the degree to which they raised the risk of death.

• Underweight. Low body mass index (2) was associated with a tripling of the risk of death in general, and four times the risk of AIDS and non-AIDS-related cancer; in this case the illness that caused death was more likely to be the cause of the low weight rather than the other way round, Smith commented.
• Diabetes was associated with all specific causes of death except for non-AIDS cancers. It raised all-cause mortality by over 80%, the risk of AIDS by 50%, and more than doubled the risk of death due to liver or cardiovascular disease.
• High blood pressure was associated with a 50% raised risk of death in general, with 2.2 times the risk of death from cardiovascular disease and three times the risk of death from liver disease.
• Hepatitis C raised the general risk of death by 45%, but was only associated with liver-related deaths, which were four times more common in people with hepatitis C. Hepatitis B raised the general risk of death by 30% and doubled the risk of liver death. This was lower than expected, and Smith commented that this might be evidence for the beneficial effect of HIV therapy on hepatitis B. Eighty-three per cent of deaths from liver disease were in people with hepatitis B or C.
• Smoking. Thirty-four per cent of the cohort were current smokers and another 17% were ex-smokers, so just over half of the cohort had smoked. Current smokers were about 15% more likely to die from any cause and ex-smokers about 30%. Presenter Colette Smith of University College Medical School in London commented that some of the ex-smokers might have given up recently, possibly because of illness. Smoking was associated with a 60% raised risk of death from cardiovascular disease and non-AIDS cancers, and having smoked with a doubling of the risk.

In terms of HIV-specific risk factors, Low current CD4 count raised the risk of death by 19% for every 50 fewer CD4 cells. Detectable viral load raised the risk of death from any cause by 56% and doubled the risk of death due to AIDS. But viral load had no significant relationship with non-AIDS-defining cancer at any level, and only very high viral loads (over 100,000) were related to heart disease deaths. Very high viral loads were also related to liver deaths, and so was being on, but not off, ART with a viral load between 400 and 100,000. This could be a marker for poor adherence.

In response to audience questions, Smith commented that despite its size, D:A:D had only just become large enough to tease out factors associated with the four most common causes of death. Over time, as it accumulated more person-years, Smith commented, it would be possible to make risk analyses for other outcomes such as kidney failure.