Cardiovascular, renal diseases present complications for clinicians treating patients with HIV

HIV-related morbidity and mortality has substantially decreased since the emergence of new HIV therapies more than a decade ago. However, physicians have long suspected that more potent medications, such as antiretroviral therapy, are associated with adverse effects that are not typically characteristic of HIV, including changes in body fat, elevated cholesterol and triglycerides, and metabolic syndrome.

As HIV medications continue to improve and physicians stay on top of the associated adverse effects — putting HIV-infected patients on cholesterol-lowering drugs along with antiretroviral therapy, for example — HIV has become more of a chronic disease and less of a death sentence in recent years.

“Patients with HIV are taking very effective ART and are living longer. As a result, they are becoming susceptible to all of the typical metabolic and cardiovascular diseases that the aging general population faces,” Kevin Yarasheski, PhD, professor of medicine, cell biology and physiology at Washington University School of Medicine, St. Louis, told Infectious Disease News.

“HIV in and of itself is a risk factor for endocrine, metabolic and cardiovascular disorders,” he said. “In addition, some HIV medications are known endocrine disruptors or have been associated with poor glucose control, dyslipidemia, obesity, bone loss, and so on.”

Still, disagreement exists about when and how to screen for these risk factors in patients with HIV, what the optimal measures are to use for screening, and when and what ART regimens to use. Depending on prior risk factors, therapy can vary from patient to patient.

HIV and cardiovascular disease

Steven Grinspoon, MD, director of the Program in Nutritional Metabolism at Massachusetts General Hospital in Boston and Professor of Medicine at Harvard Medical School, noted findings from Triant and colleagues, who 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 number of studies suggest that cardiovascular events are increased approximately twofold among patients with HIV,” Grinspoon told Infectious Disease News. “The relative increases may be more significant among older HIV patients.”

Research from Lichtenstein and colleagues indicated that in a cohort of 2,005 patients, CD4 count, 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. “Subclinical inflammation and endothelial dysfunction associated with the infection may contribute to the increased risk.”

Grinspoon added that atherosclerotic plaques may be associated with age and Framingham risk score, as well as with the ratio of CD4 and CD8 cell counts and longer duration of HIV. “The length of time an individual has HIV may be a surrogate for longstanding clinical inflammation.”

Ashok Balasubramanyam, MD, estimates that “somewhere between 60% and 90% of all patients with HIV who are taking ART end up with atherosclerotic markers.

“The basis of this atherosclerotic risk appears to be mediated tremendously by insulin resistance,” said Balasubramanyam, professor of medicine in the division of diabetes, endocrinology and metabolism at Baylor College of Medicine. “The onset of these markers is rapid,” he said, noting that studies show the average time from onset of treatment to onset of markers is about 1 year. The onset of disease to actual hard endpoints, such as MI, is typically within a few years.

“It is an accelerated form of atherosclerosis happening in younger people — even people who do not have traditional risk factors.

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 MI 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 (PIs) associated with increased cardiovascular risk. However, the SMART study showed that in 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 effect 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 high-density lipoprotein cholesterol, whereas PIs defer their effects on triglycerides, and that more recently developed drugs such as CCR5 inhibitors also have less effect,” Behrens said.

Hsue agreed that 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 most PIs alter lipids significantly.

“Lopinavir, ritonavir, and other commonly prescribed PIs impact the lipids, which in turn affects cardiovascular risk,” he said. “Ritonavir is of particular concern because most PI 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.”

Switching the cocktail of HIV drugs has been marginally successful, but Balasubramanyam said that drugs are probably not the whole reason. One approach in the treatment armamentarium has been to add antilipid drugs, such as metformin, to ART. The response was “much less satisfying” than in the general non-HIV population, he said. Balasubramanyam cautioned against adding statins to ART, with the exception of pravastatin and low-dose atorvastatin. The bottom line is, “we do not know what the best cocktail of lipid drugs and insulin-lowering drugs is when added to ART,” he said. “We are very intrigued by the possibility that maybe the HIV itself or the immune response to the virus or treatment could be a major trigger in causing the atherosclerosis and diabetes.

“A clever approach in the long run will be a combination of preventive factors, anti-lipid drugs and effective methods to attack chronic immune deficiency,” Balasubramanyam said.

A basic problem with ART and the cardiovascular system is simply the pill burden, according to Fichtenbaum. He noted that 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.

In a different study by Lucas and colleagues, researchers 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 excess protein spilling from the kidneys, it is cause for concern. “Certain strains of HIV may cause more protein spillage from the kidneys than others,” he said. “Certain strains of HIV appear to cause more damage by attaching to cells within the kidney and causing pathology.”

ART and renal disease

Mohamed G. Atta, MD, associate professor of medicine at the Johns Hopkins University School of Medicine, noted the 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 PI 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 said the importance of the kidneys in the healthy functioning of the body should not to be underestimated, and that the role that HIV infection and HIV treatment plays in long-term kidney function 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 stressed the importance of assessing familial risk factors. She added 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 patients with HIV.”

Grinspoon suggested that an equation similar to the Framingham developed specifically to assess risk in the HIV population may assist clinicians in assessing cardiovascular risk.

A more controversial issue is how aggressively to use highly sensitive but expensive and still experimental screening techniques such as coronary angiography, according to Grinspoon. There is no consensus on this approach as of yet, but early studies are showing that these techniques can pick up a high prevalence of soft, noncalcified plaque, which may be more vulnerable to rupture, in the HIV population.

Screening for inflammatory markers — which are generally higher in HIV populations — may be beneficial for assessing both cardiovascular and renal risk, according to Fichtenbaum. He also said that using specialized imaging techniques such as computed tomography scans to find calcium deposits could help clinicians determine cardiovascular risk.

“However, inflammatory markers, like C-reactive proteins, may not necessarily be associated with higher cardiac risk in individuals with HIV,” he said. “These strategies need more research and are not ready to be used every day by patients and clinicians.”

Most clinicians agree that 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.” Fichtenbaum said there is a lot of research being conducted in these fields, but “the complications and risk factors are many.” – by Rob Volansky

How aggressively should we be screening for renal complications in patients with HIV?

Active screening is required

As more and more people with HIV benefit from effective ART, they are living longer but face new challenges, particularly premature aging. Patients are disproportionately affected by atherosclerotic heart disease and its risk factors, diabetes, hypertension and chronic kidney disease (CKD). CKD — either reduced kidney function (estimated glomerular filtration rate less than 60 mL/min/1.73m2) or abnormally elevated urinary protein excretion — is an important predictor of cardiovascular disease and mortality in HIV. It is generally asymptomatic but treatable. It is relatively rare in younger patients but its prevalence increases with aging. In the United States, kidney disease clusters with health care disparities associated with race, injection drug use and socioeconomic status. Active screening is therefore required for early detection and intervention.

Infectious Diseases Society of America guidelines published in 2005 remain relevant. Kidney function should be tested using serum creatinine and a routine urinalysis in all HIV-infected patients. Patients at higher than baseline risk for kidney disease because of race, family history, diabetes, hypertension, co-infection or AIDS-defining illness should be tested annually. A routine urinalysis is insensitive to low but epidemiologically important levels of urinary albumin excretion, termed microalbuminuria. In patients with diabetes, microalbuminuria predicts future clinically significant declines in kidney function, so screening in these patients must include the urinary albumin-creatinine ratio. Cumulative evidence indicates that microalbuminuria in non-diabetics can predict future cardiovascular events. Screening HIV-infected patients already at risk for atherosclerosis, because of hypertension or dyslipidemia, might be worthwhile because its presence could lead to more aggressive cardiovascular risk factor modification and more liberal use of angiotensin inhibitors in hypertensives.

Jonathan A. Winston, MD, is professor of medicine in the department of renal medicine at Mount Sinai School of Medicine.

As aggressively as we do in patients with diabetes

After many years of research, we can definitively point to all of the papers that complete our ability to shift the paradigm that we use in people with diabetes to one for use in people with HIV. It is ingrained in every internist that patients with diabetes should get a urine test twice yearly. The main reason for this is that small amounts of protein predict larger amounts of protein, and both predict CV morbidity and mortality as well as progression to end-stage renal disease. Just like in diabetes, the ability to predict CV morbidity and mortality is even stronger than the ability to predict the progression to dialysis. Because we have all of the links that we had in diabetes that drove us for decades to test urine twice yearly, we now have similar evidence to use that strategy in patients with HIV.

There have been concerns that urine testing is labor intensive, particularly in light of the fact that only a handful of patients will progress to dialysis. The important point here is that people with kidney disease or urinary abnormalities are more likely to die than to progress to dialysis. Of course it would be optimal to prevent progression of kidney disease; however, if we can’t prevent kidney disease, then keeping people alive long enough for their kidney disease to progress could still be considered a “win.”

The whole idea of screening is to treat the disease. That said, protein in the urine can be considered a sign of kidney disease but needs to be recognized that it is an even stronger sign of cardiac disease. Protein in the urine is an even more potent marker than cholesterol. Every patient who has had a cholesterol test should also have their urine protein tested twice as frequently, if not more frequently. It is cheap, easy and the best way to identify a person who is a heart attack waiting to happen.

Lynda Anne Szczech, MD, division of nephrology, Duke University Medical Center.

For more information:

• Choi AC. Circulation. 2010;121:651-658.
• El-Sadr WM. N Engl J Med. 2006;355:2283-2296.
• George. AIDS. 2010 Jan 28;24:387-394.
• 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.