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CROI 2009: Elevated Rate of Heart Attacks and Strokes in HIV Patients on HAART Begins to Decline at California Kaiser Permanente

As HIV positive people began to live longer thanks to the development of effective antiretroviral therapy, cardiovascular disease became a growing concern, especially given evidence that HIV infection itself and the drugs used to treat it can increase cardiovascular risk.

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CROI 2009: Nicotine Replacement Aids Smoking Cessation in Program for HIV Positive Participants

It is well known that tobacco smoking is a risk factor for lung cancer, cardiovascular disease, and other illnesses, and several surveys have indicated that people with HIV are more likely to smoke (50%-70% in some studies) relative to the general population (20%) -- a major concern since HIV positive people taking antiretroviral therapy (ART) are already at increased risk for these conditions.

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Study Shows High Prevalence of Metabolic Syndrome and Associated Cardiovascular Risk in Older HIV Patients

Metabolic abnormalities and cardiovascular disease are a growing concern for HIV positive people, but there is a lack of specific data about patients older than 50 years of age, who now account for some 25% of all HIV cases in the U.S. As described in the December 1, 2008 issue of AIDS Patient Care and STDs, Oluwatoyin Adeyemi and colleagues conducted a cross-sectional study to determine the prevalence and predictors of the metabolic syndrome among a cohort of older HIV-infected patients, as well as their 10-year Framingham cardiac risk scores.

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Atherosclerosis and Endothelial Dysfunction Associated with HIV Infection and Antiretroviral Therapy

As people with HIV live longer thanks to effective antiretroviral therapy (ART), management of cardiovascular disease has become an important aspect of HIV care. Large cohort studies continue to indicate that certain antiretroviral drugs are associated with an elevated risk of myocardial infarction (heart attack), and there is growing evidence that HIV infection itself also plays a role.

Two recent journal articles looked at specific manifestations of cardiovascular damage in people with HIV.

Carotid IMT

In the first study, published in the February 2009 Journal of Acquired Immune Deficiency Syndromes, Marit van Vonderen and colleagues from the Netherlands aimed to identify the effects of HIV infection, ART, and lipodystrophy on carotid artery intima-media thickness (C-IMT) and arterial stiffness in the limbs.

Carotid IMT is a surrogate measure of atherosclerosis ("hardening of the arteries" and build-up of plaque) that gauges thickness of the lining of the arteries in the neck that supply the brain. Arterial stiffness, or loss of elasticity, is another marker of cardiovascular risk.

This case-control study included 77 HIV positive men and 52 HIV negative control subjects. Among the men with HIV, 55 were exposed to ART and 22 were ART-naive; 23 had lipodystrophy.

C-IMT was measured using ultrasound, while arterial stiffness was estimated by distensibility and compliance coefficients of the carotid, femoral (inner thigh), and brachial (inner upper arm) arteries. The investigators also assessed carotid Young elastic modulus and pulse wave velocity.

Results

  • After adjusting for known cardiovascular risk factors such as age, smoking, and obesity, HIV positive patients had a C-IMT 10.8% greater than that of control subjects (0.69 vs 0.62 mm; P = 0.001).
  • HIV positive participants had distensibility coefficients 13.6% lower for the carotid and 29.5% lower for the femoral arteries compared with HIV negative subjects, indicating greater stiffness.
  • The HIV positive group also had compliance coefficients 14.1% lower for the carotid and 31.0% lower for the femoral arteries compared with the HIV negative group.
  • Young elastic modulus and pulse wave velocity were similar in the HIV positive and HIV negative groups.
  • Within the HIV positive group, ART-exposed and ART-naive patients had similar C-IMT measurements.
  • However, the ART-exposed patients had a 25.9% lower distensibility coefficient and a 21.7% lower compliance coefficient of the femoral artery than the unexposed HIV patients.
  • Cumulative exposure to either protease inhibitors or nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) was associated with greater femoral artery stiffness.
  • Arterial properties did not differ between patients with and without lipodystrophy.
  • Arterial indicators also did not vary according to CD4 cell count or HIV viral load.

"HIV infection is independently associated with C-IMT and generally increased arterial stiffness," the study authors concluded. "ART use is associated with increased stiffness of the femoral artery."

In their discussion, the researchers suggested that chronic viral infection leading to ongoing inflammation may lead to damage of the of the blood vessel endothelium (lining) over time.

This lends support to the argument that maximally suppressive antiretroviral therapy, started before significant immune deficiency occurs, may help maintain cardiovascular health -- outweighing the potential negative effects of antiretroviral drugs themselves -- though clinicians increasing recognize the importance of assessing individual cardiovascular risk factors when making treatment decisions.

Department of Internal Medicine and Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, Netherlands; Department of Internal Medicine and cardiovascular research institute, University hospital Maastricht, Maastricht, Netherlands; Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands; Department of Infectious Diseases, Tropical Medicine, and AIDS, Center for Infection and Immunity and Center for Poverty-related Communicable Disorders, Academic Medical Center, Amsterdam, Netherlands.

Endothelial Dysfunction

In the second study, which appeared in the January 27, 2009 advance online edition of AIDS, Daniela Francisci and colleagues from Italy looked at endothelial dysfunction and activation of platelets (cell fragments involved in blood clotting) as markers of atherosclerosis and their association with HIV infection and its treatment.

This retrospective cohort study included 56 HIV positive participants evaluated before and 3, 6, 12, and 24 months after starting HAART, half including a protease inhibitors and half including a non-nucleoside reverse transcriptase inhibitor (NNRTI).

The HIV positive patients were compared against 28 healthy HIV negative control subjects matched for age and sex, and 10 HIV positive ART-naive patients studied at the time of diagnosis and after 12 months of untreated infection. Soluble endothelial and platelet activation markers were measured in plasma by flow cytometry.

Results

  • Levels of soluble P-selectin, soluble vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and von Willebrand factor were all significantly higher in HIV positive patients compared with HIV negative control subjects.
  • Soluble CD40 ligand and tissue type plasminogen activator, in contrast, were within the normal range in the HIV positive group.
  • During follow-up, levels of soluble vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and von Willebrand factor -- but not soluble P-selectin -- decreased progressively in the treated HIV patients.
  • Decreases were similar in patients treated with protease inhibitors and NNRTIs.
  • The untreated ART-naive HIV patients had elevated plasma markers of endothelial dysfunction at diagnosis, but these did not change over the 12 months of follow-up.

Based on these findings, the investigators concluded, "Chronic HIV infection, and not its pharmacological treatment, induces alterations of markers of endothelial function."

"Short-term treatment with HAART reduces some markers of endothelial dysfunction, with no differences between protease inhibitors and non-nucleoside reverse transcriptase inhibitors," they added.

Division of Infectious Diseases, Department of Experimental Medicine and Biochemical Sciences, Italy; Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy.


Monitoring and Risk Reduction

Much remains to be learned about cardiovascular disease in people with HIV. The persisting conflict between studies that find a solid link between heart disease and ART, and others that observe no association, remains unexplained.

Taken together, however, these 2 recent studies underlining the importance of cardiovascular risk assessment and ongoing monitoring of HIV patients on ART, as well as the need for risk-reduction measures such as smoking cessation, healthy diet, adequate exercise, and -- if needed -- lipid-lowering medications.

2/10/09

References

MG Van Vonderen, YM Smulders, CD Stehouwer, and others. Carotid Intima-Media Thickness and Arterial Stiffness in HIV-Infected Patients: The Role of HIV, Antiretroviral Therapy, and Lipodystrophy. Journal of Acquired Immune Deficiency Syndromes 50(2): 153-161. February 2009. (Abstract).

D Francisci, S Giannini , F Baldelli, and others. HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction. AIDS. January 27, 2009 [Epub ahead of print].

Advanced Liver Disease in People with HIV

As HIV positive people live longer due to effective antiretroviral therapy, liver disease has become an increasingly important cause of illness and death in this population.

In some cases, advanced liver disease in people with HIV is related to coinfection with hepatitis B or C virus (HBV or HCV), certain antiretroviral drugs are known to cause liver toxicity, and in other cases the cause of liver disease is unclear. Three presentations at the recent 9th International Congress on Drug Therapy in HIV Infection (HIV9) in Glasgow discussed end-stage liver disease (ESLD), advanced liver fibrosis, and severe portal hypertension in HIV-infected individuals.

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Longer Exposure to NRTIs, especially Stavudine, Increases the Risk of Insulin Resistance in Women with HIV

As people with HIV live longer thanks to effective antiretroviral therapy (ART), cardiovascular disease and long-term metabolic problems are a growing concern, leading researchers to focus on the relationship between these conditions, HIV infection itself, and antiretroviral treatment. As reported in the December 1, 2008 Journal of Acquired Immune Deficiency Syndromes, Phyllis Tien and colleagues looked at factors associated with insulin resistance, which may progress to diabetes and can increase the risk of cardiovascular disease.

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ICAAC 2008: Atherosclerosis, Coronary Plaques, and Heart Rhythm Changes in People with HIV

Cardiovascular disease is a growing concern as people with HIV live longer, but the complex relationship between HIV infection itself, immune activation triggered by the virus, and antiretroviral drugs used to treat it remains poorly understood. Three studies presented at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) in late October shed further light on factors associated with cardiovascular risk in HIV positive patients.

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Zoledronate Improves Bone Loss in People with HIV

Research indicates that people with HIV are more susceptible to bone loss -- osteopenia or the more severe osteoporosis -- compared with HIV negative individuals. Some studies have reported rates as high as 50%-70%, but it is not yet clear whether this is due to HIV infection itself, immune dysfunction, systemic inflammation, antiretroviral therapy, or some combination of factors.

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ICAAC 2008: Continuous HAART Associated with Elevated Risk of Bone Loss in SMART Treatment Interruption Trial

Evidence has accumulated over the past several years showing that antiretroviral treatment interruption guided by CD4 cell count is a risky strategy that can lead to a higher risk of both AIDS-defining opportunistic illnesses and serious conditions such as cardiovascular disease that are not traditionally considered HIV-related, but may be due to inflammation and other abnormalities associated with ongoing viral replication.

Researchers initially explored structured treatment interruption in an effort to spare patients some of the side effects, inconvenience, and costs of life-long therapy. But most studies to date have demonstrated few such benefits, especially given the development of more tolerable and easier to use drugs.

The latest analysis from the large SMART trial, however, indicates that continuous HAART may increase the risk of bone loss (osteopenia, or the more serious osteoporosis). Data were presented this week in a late-breaking poster at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in Washington, DC.

Research looking at bone mineral density (BMD) in people with HIV has produced conflicting results. Several studies have shown that HIV positive people have lower BMD compared with the general population, but it is not clear whether this is related to HIV infection itself, antiretroviral therapy, an accelerated aging process, or other unknown factors.

Briefly, the SMART study included 5472 HIV positive participants with a CD4 cell count above 350 cells/mm3 at baseline who were randomly assigned to either stay on continuous antiretroviral therapy (the "viral suppression" arm), or to interrupt treatment when their CD4 count was above 350 cells/mm3, resuming when it fell below 250 cells/mm3 (the "drug conservation" arm). The study was halted prematurely in January 2006 after interim results showed that people who periodically stopped therapy had both a higher rate of AIDS-related opportunistic infections or death and serious heart, liver, and kidney disease.

The substudy presented at ICAAC included 275 SMART participants, of whom 214 had sufficient available bone data (98 in the continuous therapy arm, 116 in the treatment interruption arm). Most (81%) were men, the median age was 44 years, and about 45% smoked (a known risk factor for bone loss).

Hip and spine BMD were measured annually using dual-energy x-ray absorptiometry (DEXA), and trabecular BMD of the spine was assessed using quantitative computed tomography (CT). The investigators used longitudinal models to compare BMD changes in the 2 arms, and assessed the incidence of reported fractures in the study as a whole. Further, they evaluated associations between BMD decline and cumulative antiretroviral drug use in the continuous therapy arm.

At baseline, 12% of the patients had osteoporosis, median t-scores (a standard measure of bone density) were -0.5 for the femur, -0.9 for the spine by CT, and -0.7 for the spine by DEXA. Participants were followed for a mean of 2.4 years.

Results

• In the continuous therapy group, patients received ART for 93% of total follow-up time, compared with 37% in the treatment interruption group.

• In the continuous therapy group, femur BMD declined by 0.9% per year, spine BMD by CT declined by 2.9% per year, and spine BMD by DEXA decreased by 0.4% annually.

• BMD decreases were significantly smaller in the treatment interruption group, especially during the first year when most were not yet on therapy.

• Over the entire follow-up period, the estimated differences in BMD changes in the treatment interruption group compared with the continuous therapy group were:

• Femur: 1.4% (P = 0.002);

• Spine by CT: 2.9% (P = 0.01);

• Spine by DEXA: 1.2% (P = 0.05).

• No consistent significant associations were observed between BMD decline and use of specific antiretroviral drugs.

• In the study as a whole, during a mean 2.8 years of follow-up, 10 of 2753 patients in the continuous therapy arm and 2 of 2720 in the treatment interruption group reported fractures as grade 4 adverse events.

• The rate of fractures was nearly 5 times higher in the continuous therapy arm compared with the treatment interruption arm (0.13 vs 0.03 per 100 person-years; hazard ratio 4.9; P = 0.04).

Based on the results of this analysis, the researchers concluded that, "Continuous antiretroviral therapy is associated with decline in BMD and possibly more fractures relative to intermittent, CD4-guided antiretroviral therapy."

Given the now-obvious detrimental effects of treatment interruption, however, they emphasized that "Intermittent antiretroviral therapy is not recommended due to increased risk of AIDS and death observed in the SMART study."

Univ. of Minnesota, Minneapolis, MN; St. Vincent's Hosp. and Univ. of NSW, Sydney, Australia.

10/31/08

Reference

B Grund and A Carr (for INSIGHT/SMART Study Group). Continuous Antiretroviral Therapy (ART) Decreases Bone Mineral Density: Results from the SMART Study. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-2312a.