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Physicians face increasing metabolic, CV complications in the treatment of HIV patients
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HIV-related morbidity and mortality has substantially decreased since new HIV therapies emerged 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 closely follow the associated adverse effects — putting HIV-infected patients on cholesterol-lowering drugs along with antiretroviral therapy (ART), 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, said in an interview.
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Photo credit: Agapito Sanchez, Baylor College of Medicine |
“HIV infection itself is a risk factor for endocrine, metabolic and CV disorders,” he said. “In addition, some HIV medications are known endocrine disruptors or have been associated with poor glucose control, dyslipidemia, obesity and bone loss.”
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 CVD
Studies of the etiology of HIV are helping physicians understand that CV risk in this patient population is “in part due to traditional risk factors and in part due to the virus,” Steven Grinspoon, MD, director of the program in nutritional metabolism at Massachusetts General Hospital in Boston and professor of medicine at Harvard Medical School, said in an interview.
“A number of studies suggest that CV events are increased approximately twofold among patients with HIV,” Grinspoon said. “The relative increases may be more significant among older HIV patients.”
Grinspoon noted findings from Triant and colleagues, who observed a 1.75 (95% CI, 1.51-2.02) greater risk for acute MI in a cohort of 3,851 patients with HIV compared with 1,044,589 seronegative individuals after adjusting for age, sex, race, hypertension, diabetes and dyslipidemia.
“Subclinical inflammation and endothelial dysfunction associated with the infection may contribute to the increased risk,” he said.
Ashok Balasubramanyam, MD, estimates that “somewhere between 60% and 90% of all patients with HIV who are taking ART end up with dyslipidemia and insulin resistance.
“The basis of this atherosclerotic risk appears to be mediated tremendously by insulin resistance and vascular inflammation,” said Balasubramanyam, professor of medicine in the division of diabetes, endocrinology and metabolism at Baylor College of Medicine in Dallas.
“The onset of metabolic derangement is rapid,” he said, noting that studies show the average time from onset of HIV treatment to increase in atherosclerosis markers is about 1 year. The occurrence of CV events, such as MI, has been reported within a few years of onset of treatment.
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“It is an accelerated form of atherosclerosis happening in younger people — even people who do not have traditional risk factors,” Grinspoon said.
He 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,” he said.
Whether the ART is to blame has been a subject of research.
Findings from the Strategies for Management of Anti-Retroviral Therapy (SMART) study indicated that interruptions in ART increased risk for CVD. 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 CV 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 CV 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 effect on HDL levels.
“Having said that, we all know that this is oversimplified because certain drugs — non-nucleoside reverse transcriptase inhibitors (NNRTIs), for instance — have a more beneficial effect on HDL, whereas protease inhibitors differ in their effects on triglycerides, and that more recently developed drugs such as CCR5 inhibitors also have less effect at all,” Behrens said.
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Carl J. Fichtenbaum, MD, of the division of infectious diseases at the University of Cincinnati College of Medicine, said most protease inhibitors alter lipids significantly.
“Lopinavir, ritonavir and other commonly prescribed protease inhibitors impact the lipids, which in turn affects CV risk,” he said. “Ritonavir is of particular concern because most protease inhibitor 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 for the increase in these complications. One approach in the treatment armamentarium has been to add anti-lipid drugs or insulin-sensitizing drugs such as metformin to ART. The response to some standard lipid-lowering drugs was “less satisfactory” than in the general non-HIV population, he said.
Balasubramanyam cautioned against adding statins to ART, with the exception of pravastatin or low-dose atorvastatin. The bottom line is, “we do not know what the best cocktail of lipid drugs and glucose-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 activation,” Balasubramanyam said.
Fichtenbaum said pharmaceutical companies are not studying the long-term complications of the medications they produce.
“It is challenging to engage pharmaceutical companies and obtain NIH funding to study long-term complications because there is a limited pot of money and competing priorities,” he said. “Also, the structure of the NIH into different, somewhat independent funding agencies makes it challenging to study longer-term complications.”
Fichtenbaum cited the example of how the National Institute of Allergy and Infectious Diseases generally funds projects that are associated with infections and the National Heart, Lung, and Blood Institute deal with those related to CVD. “Collaboration between institutes is needed to solve complex problems with support from the pharmaceutical industry,” he said.
One basic problem with ART and the CV 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 metabolic and CV diseases.
For clinicians
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Hsue said that clinicians should be aware that CVD risk is increasing in patients with HIV, and stressed the importance of assessing familial risk factors. She added that the symptoms of CVD can be subtle.
“At our HIV and CV 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. “We want to diagnose them and treat them before they have their heart attack.”
A key diagnostic issue in recent research surrounds measuring risk for CVD 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 CV risk. “It may be helpful to have an equation in which the traditional and nontraditional inflammatory and immunological risk factors may be included,” he said.
Screening for inflammatory markers, which are generally higher in HIV populations, may be beneficial for assessing both CV and renal risk, according to Fichtenbaum. He also said that using specialized imaging techniques such as CT scans to find calcium deposits could help clinicians determine CV risk.
“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.”
Balasubramanyam added that it is necessary to “go back to the science” to try to determine the mechanisms underlying the many complications in patients with HIV taking ART.
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“The approach for endocrinologists is to think of this as a unique endocrine syndrome — not one thing but a mix of things,” he said. “The truth will finally come out that these HIV-related complications are part of a complex disease that involves the virus, immune response to the virus, immune response to the treatment, and perhaps some direct effects of the drugs.”
All aside, the face of the typical HIV patient is changing.
“We now have HIV-infected people who are well into their 70s, walking into the clinic with typical age-associated frailties,” Yarasheski said. “We need to start talking across disciplines about common mechanisms and common pathogeneses that may help us discover better ways to treat patients with HIV who have these endocrine, metabolic, CV and inflammatory conditions.” – by Katie Kalvaitis and Rob Volansky
For more information:
- Brown T. Diabetes Care. 2010;33:2244-2249.
- De Wit S. Diabetes Care. 2008;31:1224-1229.
- El-Sadr W. N Engl J Med. 2006;355:2283-2296.
- Lucas G. JAIDS. 2010. doi: 10.1097/QAI.0b013e3181e8d5a8.
- Nicolau Laparra M. Nefrologia. 2010;30:420-426.
- Triant V. J Clin Endocrinol Metab. 2007;92:2506-2512.
- Wand H. Aids. 2007;18:2445-2453.
Disclosures: Drs. Balasubramanyam, Behrens, Fichtenbaum, Grinspoon, Hsue, and Yarasheski have no direct financial interest in any of the products mentioned in this article, nor are they paid consultants for any of the companies mentioned.