Cardiovascular, renal diseases present complications for clinicians treating HIV

Data from a national Veterans Affairs sample of more than 17,000 people with HIV indicated that glomerular filtration rates and albuminuria levels were strongly associated with increased risk for cardiovascular disease and heart failure.

Andy I. Choi, MD, and colleagues from the San Francisco Veterans Affairs Medical Study said in their conclusions — published in early 2010 — that kidney function and albuminuria provide complementary prognostic information that may assist in predicting cardiovascular disease risk in patients with HIV.

“As in the general population, if you have HIV and have a protein leak or low [glomerular filtration rate], you will have increased cardiovascular event rates,” Mohamed G. Atta, MD, MPH, associate professor of medicine at The Johns Hopkins University School of Medicine, said in an interview.

Atta and many physicians said traditional complications associated with cardiovascular and renal disease such as diabetes, hyperlipidemia and hypertension affect people with HIV more than the general population.

HIV and cardiovascular disease

Steven Grinspoon, MD, of the neuroendocrine unit at Massachusetts General Hospital in Boston, said findings from Triant and colleagues observed a 1.75 (95% CI, 1.51-2.02) greater risk for acute myocardial infarction in a cohort of 3,851 patients with HIV compared with 1,044,589 seronegative individuals after adjusting for age, gender, race, hypertension, diabetes and dyslipidemia.

“A lot of studies come up with a twofold increased risk for cardiovascular events among patients with HIV,” Grinspoon told HemOnc Today. “This is not as dramatic as it could be, but it is still very significant.”

Research from Lichtenstein and colleagues indicated that in a cohort of 2,005 patients, CD4 count of less than 500 cells/mm³ was an independent risk factor for incident cardiovascular disease. Findings such as these raise the question of whether HIV itself is a risk factor for cardiovascular complications, according to Grinspoon.

“Through studies of the etiology of the disease, we are coming to understand that cardiovascular risk in HIV populations is in part due to traditional risk factors and in part due to the virus,” Grinspoon said. “In a broad sense, there is subclinical inflammation and endothelial dysfunction associated with the infection.”

He said atherosclerotic plaques may be associated with age and Framingham risk score, but those plaques are also associated with low CD4 and CD8 cell counts and longer duration of HIV. “Simply the length of time an individual has HIV may be a surrogate for longstanding clinical inflammation.”

ART and cardiovascular disease

Findings from the Strategies for Management of Anti-Retroviral Therapy (SMART) study indicated that interruptions in ART increased risk for cardiovascular disease. SMART results also suggested that abacavir use was associated with a fourfold increase in myocardial infarction incidence.

“It was initially thought that ART was associated with increased cardiovascular risk,” Priscilla Hsue, MD, assistant professor of medicine at the University of California, said in an interview. “There was definitive evidence of [protease inhibitors] associated with increased cardiovascular risk. However, the SMART study showed that in the short term, controlling HIV-related inflammation with ART is good.”

George Behrens, MD, PhD, an assistant professor of T-cell immunology at Hanover Medical School in Germany, said during a presentation at the 2010 International AIDS Conference that most HIV therapies are connected to modest increases in cholesterol, some increases in triglycerides and have a negligible effects on HDL levels.

“Having said that, we all know that this is oversimplified because certain drugs — [non-nucleoside reverse transcriptase inhibitors], for instance — have a more beneficial effect on HDL, whereas protease inhibitors defer their effects on triglycerides, and that more recently developed drugs such as CCR5 inhibitors also have less effect at all,” Behrens said.

Hsue said many of the findings on specific ART regimens and HIV risk are inconclusive. “Each of these studies kind of slices and dices the data differently,” she said. “It is up to clinicians to make their own decisions.”

Carl J. Fichtenbaum, MD, of the division of infectious diseases at the University of Cincinnati College of Medicine, noted the fact that PIs alter lipids significantly. “Lopinavir, ritonavir, other PIs, all of these drugs impact the lipids, which in turn increases cardiovascular risk,” he said. “Ritonavir is of particular concern because most regimens now have a small boost of it. However, it is difficult to determine the impact it is having and to study it because it is used so commonly and in combination with other drugs.”

Fichtenbaum said pharmaceutical companies are not studying the long-term complications of the medications they produce.

“They are focused on finding a vaccine or a cure rather than real treatments,” he said. “There is a limited pot and competing realities.”

A basic problem with ART and the cardiovascular system is simply the pill burden, according to Fichtenbaum. He said the drugs are difficult to process for the kidneys, exacerbating the associations between heart and renal disease.

HIV and renal disease

Recent results published by Laparrra and colleagues indicated that in a cohort of 100 individuals with HIV from the pre-ART and ART eras, renal failure was present in 42% of patients at the time of death. “Renal lesions were frequent in HIV patients independent of the presence or absence of HAART,” they wrote.

Lucas and colleagues studied glomerular filtration rates in a cohort of 1,202 patients with HIV and 664 controls in Rakai, Uganda. They concluded that before the availability of ART, the prevalence of decreased glomerular filtration rate and the incidence of a decline in glomerular filtration rate category during follow-up were both significantly higher in the HIV arm.

Fichtenbaum said that any time there is protein in the kidneys, it is cause for concern. “Certain strains cause more protein in the kidneys than others,” he said. “Certain strains cause more damage by attaching to cells within the kidney and causing pathology.”

ART and renal disease

Atta said there are positives and negatives of early vs. late ART initiation from a renal perspective.

“If you start early, you get toxicity, which is obviously not good for the kidneys,” he said. “But the benefit of ART from the renal perspective is the reduction in HIV-associated nephropathy, which is the most aggressive kidney disease that is related directly to the HIV virus.”

There are three ART medications associated with renal complications, according to Atta. He said that the protease inhibitors indinavir is associated with kidney stones; atazanavir is associated with kidney stones and renal toxicity; and tenofovir is associated with Fanconi syndrome, a proximal tubular dysfunction of the kidney.

Fichtenbaum also said ART places stress on the renal system. He said that the amount of control the kidneys have over the body is not to be underestimated, and that the role that HIV infection and HIV treatment plays with the kidneys will continue to be investigated.

For clinicians

Hsue said that clinicians should be aware that cardiovascular disease risk is increasing in patients with HIV and it is important to assess familial risk factors, adding that the symptoms of cardiovascular disease can be subtle.

“At our HIV and cardiovascular clinic in San Diego, we often get patients referred to us after the cardiac event, but as cardiologists, we want to intervene before the event,” she said.

A key diagnostic issue in recent research surrounds measuring risk for cardiovascular disease in patients with HIV. Grinspoon said that using the Framingham risk score is “good but not perfect” in HIV populations. “The score may underestimate risk, particularly in smokers, which is obviously a concern given the prevalence of smoking among HIV positives.”

Grinspoon said an equation similar to the Framingham score may assist clinicians in assessing cardiovascular risk. “It may be helpful to have an equation where you simply plug in the numbers for basic components and risk factors,” he said.

Screening for C-reactive protein markers — which are higher in HIV populations — may be beneficial for assessing renal risk, according to Fichtenbaum. He also said that using CT scans to find calcium deposits could help clinicians determine cardiovascular risk.

“However, C-reactive proteins may not necessarily be associated with higher cardiac risk,” he said. “And though these strategies have research value, they may not be clinically valuable to the patient.”

Most clinicians said the component parts of cardiovascular and renal disease in HIV patients should be evaluated and treated separately.

Clinicians should be aware of genetic factors such as dyslipidemia, high blood pressure and cholesterol levels in their patients, and they should always encourage patients to stop smoking and control other lifestyle factors that may be causing complications.

“Factors in glucose metabolism and dyslipidemia — and associated factors such as central obesity induced by HIV therapy — contribute to later cardiovascular disease,” Behrens said. “Complications arise because these factors are interrelated. Further complications become evident when age, genetics, diet and other underlying mechanisms are taken into consideration.” — by Rob Volansky

For more information:

• Choi AC. Circulation. 2010;121:651-658.
• El-Sadr WM. N Engl J Med. 2006;355:2283-2296.
• Lichtenstein KA. Clin Infect Dis. 2010;51:435–447.
• Lucas GM. JAIDS. 2010; doi: 10.1097/QAI.0b013e3181e8d5a8.
• Nicolau Laparra MC. Nefrologia. 2010;30:420-426.
• Triant VA. J Clin Endocrinol Metab. 2007;92:2506-2512.