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
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
Ashok Balasubramanyam, MD, investigates atherosclerotic
markers in HIV-infected patients who take ART.
Photo credit: Agapito Sanchez,
Baylor College of
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
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.
Diabetes continues to be studied as a risk factor in patients with HIV
who are taking ART.
Recent data published in the October issue of Diabetes Care
suggest that systemic inflammation may contribute to diabetes pathogenesis in
people with HIV. Todd T. Brown, MD, and colleagues reviewed the large
ACTG Longitudinal Linked Randomized Trials (ALLRT) database for patients with
HIV taking ART. They selected 55 HIV-infected adults who were ART naïve
before ALLRT enrollment who subsequently developed diabetes; these patients
were compared with 55 HIV-infected adults who did not develop diabetes.
According to the results, inflammatory markers at 48 weeks after ART
initiation were associated with an increased risk for diabetes. Median levels
for all inflammatory biomarkers examined, except for high-sensitivity
C-reactive protein, decreased from baseline to week 48. Patients with higher
levels of high-sensitivity C-reactive protein, soluble tumor necrosis factor
(TNF)-alpha receptor-1 and soluble TNF-alpha receptor-2 at 48 weeks had an
increased odds of subsequent diabetes, after adjustment.
One of the big issues in HIV in the Western world is not so much
the care of the HIV because drugs today are very effective at
controlling the virus but whether the residual inflammation, even with
good ART, is detrimental, Brown said in an interview. We know from
the general population that baseline inflammation is associated with incident
diabetes, independent of body composition.
Brown said there seems to be a possible and plausible
mechanism for inflammation in HIV-infected patients taking ART. Other
research is currently focusing on mouse models to determine the role of
inflammation of TNF-alpha and interleukin-6 in the pathogenesis of diabetes in
this patient population, he noted.
The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study,
which was published in Diabetes Care in 2008, found that
combination ART with stavudine and zidovudine was significantly associated with
diabetes, after adjustment for risks factors for diabetes and lipids.
Adjustment for lipodystrophy did not modify this relationship, which suggests
that the two thymidine analogs probably directly contribute to insulin
resistance, potentially through mitochondrial toxicity, researchers
The prospective, observational study included more than 33,000
HIV-infected patients. During follow-up, diabetes was diagnosed in 744 patients
at an incidence rate of 5.72 per 1,000 person-years. The incidence of diabetes
increased with cumulative exposure to combination ART. The strongest
relationship with diabetes was exposure to stavudine; exposures to zidovudine
and didanosine were also associated with an increased risk for diabetes.
The pathogenesis of diabetes and insulin resistance in HIV is
complicated, Brown said. Some ART causes insulin resistance either
through direct mechanisms or indirectly through effects on body composition.
Then, there are the traditional risk factors for diabetes, which may or may not
be more common in the HIV population.
Recent research has also shown that HIV is associated with severe
metabolic complications, including lipodystrophy, dyslipidemia and insulin
resistance, a clustering of risk factors that is similar to that of metabolic
syndrome. A better understanding of the links between metabolic diseases and
morbidities in patients with HIV who are taking ART may allow more effective
clinical management of this patient population, experts said.
Yarasheski and colleagues at Washington University School of Medicine in
St. Louis found that the occurrence of metabolic syndrome was similar in a
group of HIV-infected patients taking ART compared with the general population:
25.5% vs. 26.5%. The results of their 2007 study comparing 471 patients with
HIV and a matched cohort of the National Health and Nutrition Examination Study
population without HIV were published in Clinical Infectious
Diseases. The researchers also found that patients with HIV were more
likely to have diabetes and a high BMI and to be older and white. Another
important risk factor for metabolic syndrome was a high CD4 cell count.
Overall, the HIV-infected people tended to weigh less and have
lower HDL levels, higher triglycerides and lower glucose levels,
Yarasheski said in a press release. But, it didnt seem that HIV
therapy was influencing their risk for metabolic syndrome as much as the more
traditional risk factors that everyone faces. Type or duration of HIV
therapy was not found to be an independent risk factor for metabolic syndrome.
The researchers said that one strength of the study was that they
examined these findings by race. Among HIV-infected black women, the rate of
obesity was nearly 45%. With a rate that high, they said it is likely time to
start investigating the efficacy of exercise and other weight-loss methods in
patients with HIV.
Ward and collegues published data in 2007 showing that substantial
progression to metabolic syndrome occurs within 3 years after ART initiation in
patients with HIV. Of 881 HIV-infected adults examined, 8.5% had baseline
metabolic syndrome using the Adult Treatment Panel III (ATP-III) criteria and
7.8% had the syndrome using the International Diabetes Federation (IDF)
criteria. More patients (n=234) progressed to metabolic syndrome during
follow-up using the ATP-III definition vs. IDF definition (n=178). Researchers
also found that both metabolic syndrome at baseline and incident metabolic
syndrome were associated with increased risk for CVD and type 2 diabetes.
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
A number of studies suggest that CV events are increased
approximately twofold among patients with HIV, Grinspoon said in an
interview. The relative increases may be more significant among older HIV
Grinspoon 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, sex, race, hypertension, diabetes and dyslipidemia.
According to Grinspoon, subclinical inflammation and endothelial
dysfunction associated with the infection may contribute to the increased
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 at metabolism at Baylor College of Medicine. 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 myocardial infarction,
has been reported within a few years of onset of treatment.
It is an accelerated form of atherosclerosis happening in younger
people even people who do not have traditional risk factors.
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, 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 (PIs) 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 PIs differ in
their effects on triglycerides, and that more recently developed drugs such as
CCR5 inhibitors also have less effect at all, 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
Carl J. Fichtenbaum, MD, of the division of infectious diseases
at the University of Cincinnati College of Medicine, said most PIs alter lipids
Carl J. Fichtenbaum
Lopinavir, ritonavir, and other commonly prescribed PIs, impact
the lipids, which in turn affects CV 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 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 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 suggested that 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. It is generally not in the
strategic interests of pharmaceutical companies to study complications of the
medications they produce. Also, the structure of the NIH into different,
somewhat independent funding agencies makes it challenging to study longer-term
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.
Some of these complications are less frequent in Western countries, as
drug therapy has changed, according to Katherine Samaras, MD, associate
professor and head of the Diabetes and Obesity Clinical Group at Garvan
Institute of Medical Research, Australia.
In countries where there is access to newer agents within the
nucleoside reverse transcriptase inhibitors and NNRTI classes, we see less and
less of the disfiguring lipodystrophy, she told Endocrine
Today. However, these are agents that are being offered first line
in poorer nations, such as Africa and South East Asia. Thus, at a global level,
these adverse effects will still present significant comorbidities.
In addition, Samaras noted that physicians are seeing more osteoporosis
in patients with HIV, which appears to be related to a number of factors,
including duration of ART and specific ART drug classes.
We should also be mindful of other non-endocrine complications
that substantially impact health and well being, including neuropathy;
cognitive decline, which is currently under intense investigation; and
increased risk for malignancies such as non-Hodgkins lymphoma, anal
cancer or premalignant conditions, she said.
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 be useful score 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.
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
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 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.
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.
Fichtenbaum said there is a lot of research being conducted in these
fields, but the complications and risk factors are many.
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, Balasubramanyam said.
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
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
How aggressively should patients with HIV be screened for renal risk?
Active screening should be required for all patients
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, 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 CVD 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.
Jonathan A. Winston
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. 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 CV 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 CV risk
factor modification and more liberal use of angiotensin inhibitors in
Jonathan A. Winston, MD, is professor of medicine in the department
of renal medicine at Mount Sinai School of Medicine.
Screening should be as aggressive as for 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 a year. 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 cant prevent kidney disease, then keeping people alive long enough
for their kidney disease to progress option could still be considered a
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 done 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, is associate professor in the division of
nephrology at Duke University Medical Center.
For more information:
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- El-Sadr WM. N Engl J Med. 2006;355:2283-2296.
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- Nicolau Laparra MC. Nefrologia. 2010;30:420-426.
- Triant VA. J Clin Endocrinol Metab.
- Wand H. Aids. 2007;18:2445-2453.