Eliminating risk factors impacting on non-Aids conditions in people with HIV

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Preventing smoking, lowering cholesterol, controlling blood pressure and curing hepatitis C would greatly reduce the burden of heart attacks, non-Aids cancers and end-stage liver disease and kidney disease in people living with HIV, according to an analysis of a large North American cohort.

The study found that eliminating the traditional risk factors for these conditions would have a far greater impact than optimal HIV treatment on the incidence of the conditions, emphasising the importance of screening and management of these conditions in the lifelong care of people living with HIV.

As antiretroviral therapy has prolonged the lives of people with HIV and greatly reduced the number of deaths from Aids-defining illnesses, non-Aids conditions such as cardiovascular disease, end-stage liver disease and cancers have become the most important causes of death in people living with HIV in higher-income countries.

Although HIV is known to increase the risk of cardiovascular disease and some cancers, the relative contributions of HIV-associated risk factors and other risk factors to the development of these conditions in people living with HIV has been unclear. As a consequence, screening for risk factors, and interventions to reduce risk factors for these conditions, have not always been prioritised.

NA-ACCORD brings together clinical cohorts of people living with HIV at more than 200 sites in North America. Together, these cohorts have followed over 180,000 patients who have attended a clinic at least twice.

This analysis of cohort participants looked at people in care, with at least two clinic visits, between January 2000 and December 2014. All cases of heart attack, non-Aids defining cancer, end-stage liver disease and end-stage kidney disease that occurred after the beginning of follow-up were evaluated for HIV- and non-HIV-related risk factors and compared with cohort participants in the same period who did not have a diagnosis of the condition.

The HIV-related risk factors evaluated were low CD4 count, detectable viral load, Aids diagnosis and antiretroviral regimen history. The non-HIV risk factors evaluated were smoking, elevated total cholesterol, hypertension, diabetes, stage 4 chronic kidney disease, statin prescription and hepatitis B or C infection. Age, sex, race and HIV transmission risk category were also considered.

Dr Keri Althoff of Johns Hopkins University calculated the population-attributable fraction, or the proportion of cases that would be avoided in the population if the causal risk factor was removed. This measure captures the impact of risk factors that may have a small individual effect but are widespread in the population, as well as risk factors that have a much greater effect but are less prevalent. It allows epidemiologists to judge which interventions that change risk factors are likely to have the biggest population-level impact.

For cancers, 61,500 participants were eligible for inclusion in the analysis. They were followed for a median of 3.7 years and during this period 1405 non-Aids cancers were diagnosed (16% lung, 16% anal, 12% prostate, 7% non-Hodgkin lymphoma, 6% liver, 6% oral or pharyngeal, 6% breast, 5% melanoma, 5% colon or rectum).

Smokers were 61% more likely to develop a non-Aids cancer (aHR 1.61) and even after excluding lung cancer, 36% more likely to develop any other non-Aids cancer. The researchers calculated that 24% of all cancers would have been prevented by never smoking. In comparison, only 3% of cancers would have been prevented by maintaining a CD4 cell count above 200 cells/mm3.

For heart attack (myocardial infarction), 29,515 participants were eligible for inclusion in the analysis. They were followed for a median of 3.5 years and 347 had a heart attack during this period. Smokers were 82% more likely to suffer a heart attack (aHR 1.82). People with elevated total cholesterol were nearly three times more likely to suffer a heart attack (aHR 2.95) and people with hypertension almost three-and-a-half times more likely to suffer a heart attack (aHR 3.34). A CD4 count below 200 cells/mm3 during follow-up was also associated with an increased risk of a heart attack (aHR 2.02).

The researchers calculated that 37% of all heart attacks would have been prevented by never smoking, 44% prevented by controlling cholesterol and 42% prevented by controlling blood pressure. Only 6% of heart attacks would have been prevented by maintaining a CD4 cell count above 200 cells/mm3.

For end-stage liver disease, 35,044 participants were eligible for inclusion in the analysis. They were followed for a median of 3.1 years and 387 developed end-stage liver disease during this period.

Smoking did not affect the risk of developing end-stage liver disease but a CD4 count below 200 increased the risk almost fourfold (aHR 3.89) and infection with hepatitis B or C increased the risk threefold (aHR 3.11 and 3.13 respectively). Indeed, these factors remained more important risks than risky alcohol use (aHR 1.78) in the subset of 12,158 participants with available data on alcohol use.

Nevertheless, due to the high prevalence of risky alcohol use, the researchers calculated that across the population 35% of cases of end-stage liver disease would have been avoided if guidelines for alcohol consumption had never been exceeded. 30% of cases would have been avoided if people had not been infected with hepatitis C during the follow-up period and 16% if they had not been infected with hepatitis B – 19% of cases would have been avoided if participants had maintained CD4 counts above 200 cells/mm3 during the follow-up period.

For end-stage kidney disease, 35,260 participants were eligible for inclusion in the analysis. They were followed for a median of 3.3 years and 255 developed end-stage kidney disease during this period.

High blood pressure was the most important risk factor, increasing the risk of end-stage kidney disease fivefold (aHR 5.18). Elevated total cholesterol raised the risk two-and-a-half times (aHR 2.54) and a CD4 cell count below 200 cells/mm3 increased the risk threefold (aHR 3.03).

Controlling blood pressure would have prevented 39% of cases of end-stage kidney disease and controlling cholesterol would have prevented 22% of cases. In comparison, maintaining viral load below 400 copies/ml would have prevented 19% of cases. Uncontrolled viral load can lead to HIV-associated kidney damage especially in African Americans. Preventing diabetes – a common cause of kidney disease in the general population – would have avoided 6% of cases.

In every case, addressing HIV-related risk factors would have had less effect than addressing modifiable risk factors well understood by physicians to be associated with the negative health outcomes evaluated in this study.

“The evidence from our study is clear,” the investigators conclude. “To avoid sizeable proportions of non-Aids-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease, the continued focus on maintaining HIV viral load suppression after ART initiation must be balanced with screening for traditional risk factors, effective interventions to reduce the burden of traditional risk factors, and a sustainable model of care with the capacity to provide traditional risk factor interventions over the decades of life with HIV.”

Summary
Background: Adults with HIV have an increased burden of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease. The objective of this study was to estimate the population attributable fractions (PAFs) of preventable or modifiable HIV-related and traditional risk factors for non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes.
Methods: We included participants receiving care in academic and community-based outpatient HIV clinical cohorts in the USA and Canada from Jan 1, 2000, to Dec 31, 2014, who contributed to the North American AIDS Cohort Collaboration on Research and Design and who had validated non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, or end-stage renal disease outcomes. Traditional risk factors were tobacco smoking, hypertension, elevated total cholesterol, type 2 diabetes, renal impairment (stage 4 chronic kidney disease), and hepatitis C virus and hepatitis B virus infections. HIV-related risk factors were low CD4 count (<200 cells per μL), detectable plasma HIV RNA (>400 copies per mL), and history of a clinical AIDS diagnosis. PAFs and 95% CIs were estimated to quantify the proportion of outcomes that could be avoided if the risk factor was prevented.
Findings: In each of the study populations for the four outcomes (1405 of 61 500 had non-AIDS-defining cancer, 347 of 29 515 had myocardial infarctions, 387 of 35 044 had end-stage liver disease events, and 255 of 35 620 had end-stage renal disease events), about 17% were older than 50 years at study entry, about 50% were non-white, and about 80% were men. Preventing smoking would avoid 24% (95% CI 13–35) of these cancers and 37% (7–66) of the myocardial infarctions. Preventing elevated total cholesterol and hypertension would avoid the greatest proportion of myocardial infarctions: 44% (30–58) for cholesterol and 42% (28–56) for hypertension. For liver disease, the PAF was greatest for hepatitis C infection (33%; 95% CI 17–48). For renal disease, the PAF was greatest for hypertension (39%; 26–51) followed by elevated total cholesterol (22%; 13–31), detectable HIV RNA (19; 9–31), and low CD4 cell count (13%; 4–21).
Interpretation: The substantial proportion of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes that could be prevented with interventions on traditional risk factors elevates the importance of screening for these risk factors, improving the effectiveness of prevention (or modification) of these risk factors, and creating sustainable care models to implement such interventions during the decades of life of adults living with HIV who are receiving care.

Authors
Keri N Althoff, Kelly A Gebo, Richard D Moore, Cynthia M Boyd, Amy C Justice, Cherise Wong, Gregory M Lucas, Marina B Klein, Mari M Kitahata, Heidi Crane, Michael J Silverberg, M John Gill, William Christopher Mathews, Robert Dubrow, Michael A Horberg, Charles S Rabkin, Daniel B Klein, Vincent Lo Re, Timothy R Sterling, Fidel A Desir, Kenneth Lichtenstein, James Willig, Anita R Rachlis, Gregory D Kirk, Kathryn Anastos, Frank J Palella Jr, Jennifer E Thorne, Joseph Eron, Lisa P Jacobson, Sonia Napravnik, Chad Achenbach, Angel M Mayor, Pragna Patel, Kate Buchacz, Yuezhou Jing, Stephen J Gange

Aidsmap material
The Lancet HIV article summary


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