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Now that advances in treatment have transformed HIV into a chronic, manageable disease, patients are facing cardiovascular and metabolic complications you might not have expected 15 years ago. Here's how to help your patient manage them.
INFECTION WITH HIV used to mean an imminent and certain progression to AIDS and death. Since the introduction of antiretroviral therapy (ART), however, survival with AIDS has improved dramatically from an average of 3.1 years to over 13 years.1 (For a review of the disease, see "The Changing Face of AIDS" in the August issue of Nursing2004.)*
Worldwide, over 40 million people are infected with HIV disease. In the United States and other countries where the latest therapies are readily available, many patients have been managing their HIV infection with ART for more than 20 years. In the United States alone, ART has saved an estimated total of at least 3 million years of life.1
Although ART provides an important survival advantage, it's associated with clinically important adverse reactions, such as diabetes and cardiovascular disease. In this article, I'll discuss some significant complications that a patient undergoing long-term treatment for HIV infection may encounter and your role in helping him prevent or manage them. Let's start with a review of current drugs used in ART.
Nucleoside reverse transcriptase inhibitors (NRTIs) block reverse transcriptase, a protein HIV needs in order to replicate. When the first NRTI, zidovudine (Retrovir), was approved, it was administered as monotherapy and slowed viral replication, but it had a minimal impact on survival. With the approval of subsequent NRTIs such as didanosine (Videx) and lamivudine (Epivir), a new treatment strategy emerged: combining these newer drugs with zidovudine. This approach provided some survival benefit but more often led to an increase in drug-related adverse reactions, ranging from nausea to painful peripheral neuropathy to life-threatening pancreatitis. Because many patients had a hard time coping with treatment-related adverse reactions, many opted not to be treated with ART and quickly succumbed to AIDS.
In December 1995, saquinavir (Invirase) became the first protease inhibitor (PI) approved for use in combination with NRTIs. Protease inhibitors block protease, a protein needed for HIV replication. (For a complete list of approved drugs for HIV infection arranged by class, see Drugs to combat HIV infection.)
The PI class ushered in the era of highly active antiretroviral therapy (HAART). This treatment regimen combines three antiretroviral drugs, generally two from the NRTI class and one from the PI class, to suppress viral replication. With the widespread use of PIs in 1996, successful treatment of HIV infection extended lives by decades, not just weeks or months. "Two NRTIs plus one PI" quickly emerged as the preferred strategy for managing HIV infection.
Along with their successes, however, early HAART regimens were plagued with problems, including poor oral bioavailability, high pill burden, intolerable adverse reactions, and long-term toxicities. These factors contributed to poor patient adherence, which, in turn, encouraged HIV resistance to antiretroviral drugs.
Many of these problems have now been minimized. New formulations have improved bioavailability, and several different drugs have been combined, reducing a patient's pill burden.
Today, in addition to the NRTI and PI classes of drugs, these major classes of drugs attack HIV infection: the nonnucleoside reverse transcriptase inhibitors (NNRTIs), fusion inhibitors, CCR5 entry inhibitors, and HIV integrase strand transfer inhibitors. For patients who are new to antiretroviral therapy, the preferred combination is two NRTIs with either a PI or an NNRTI. For experienced patients (patients who have used multiple medications and who may have resistance to some of them), the HIV specialist uses resistance testing to help guide which combination of medications should be used to form an active regimen.
Because HAART has significantly reduced mortality, HIV infection is now considered a chronic, manageable illness. Patients and their families must face the difficulties of any chronic disease as they cope with new adverse reactions, medication toxicities, exacerbation of their mental health issues, complex medication regimens, and lifestyle adjustments.
The very treatments that have saved patients' lives have also been linked to lipid and glucose abnormalities that can increase the risk of cardiovascular disease. Let's look at these risks of cardiovascular events and your role in reducing them.
Patients infected with HIV who aren't on HAART have lipid abnormalities, mostly high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C). Although the reasons for these aren't known, increases in interferon alpha may contribute to increases in plasma TG levels, in part by decreasing the clearance of TG.2
The dyslipidemias associated with HAART and particularly PIs include elevated TG, decreased HDL-C, and increased low-density lipoprotein cholesterol (LDL-C). Of all of the HIV medications, certain PIs are most often associated with dyslipidemias, especially hypertriglyceridemia. Some patients treated with PIs have had severe hypertriglyceridemia (greater than 1,000 mg/dL; normal is less than 150 mg/dL). Lipid abnormalities associated with PI therapy probably have other causes as well, including HIV infection itself, genetic factors, and body fat changes.
Compared with other PIs, ritonavir (Norvir) is associated with a higher rate of hypertriglyceridemia.3 Ritonavir may increase TG levels 200% to 300% and total cholesterol levels 30% to 40% above baseline.
Hyperlipidemia associated with the PI component of HAART can lead to accelerated atherosclerosis; affected patients need to be treated. Patients should be evaluated and treated for dyslipidemia according to the National Cholesterol Education Program/Adult Treatment Panel III guidelines. (See http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.)
Patients with baseline hyperlipidemia or who are otherwise at risk for cardiovascular disease may receive a PI-sparing regimen or a PI that has a beneficial effect on lipids, such as atazanavir (Reyataz). Besides being a potent ART agent with low pill burden, atazanavir can significantly improve hyperlipidemia. Because NNRTIs are also implicated in dyslipidemias, most clinicians use atazanavir; when this isn't feasible, they use other drugs along with lipid-lowering therapy.
In a small study, 33 HIV-infected patients with severe hyperlipidemia were switched to an atazanavir-containing regimen. After switching, patients showed a significant decrease in TG and total cholesterol levels. Most of these changes occurred as soon as 4 weeks after switching the regimen.4 Besides the favorable lipid changes, therapy with atazanavir is safe, effectively reduces viral load, and is generally well tolerated by patients. However, whether the improvements in lipid profile will decrease cardiovascular events isn't yet known.
Using statins to manage dyslipidemia in patients receiving ART is problematic. Statins are metabolized by the cytochrome P450 3A4 isoenzyme pathway. (This is often shortened to CYP 3A4.) Protease inhibitors inhibit this pathway, which increases serum statin levels and raises the patient's risk of muscle toxicity.
A patient taking a PI should avoid simvastatin (Zocor) and lovastatin (Mevacor), which are extensively metabolized by the CYP 3A4 pathway; combining them with a PI may lead to myopathy, including rhabdomyolysis. Pravastatin (Pravachol) is the statin least likely to interact with CYP 3A4 inhibitors. (For more on interactions between PIs and statins, see Should a patient using a PI also take a statin?)
Among patients with HIV/AIDS who receive a regimen that doesn't contain PIs, the prevalence of insulin resistance is about 20%.5 Currently about 25% of the population has insulin resistance. In those receiving a PI-based regimen, rates have been as high as 60% to 85%.6-8 Insulin resistance usually appears some 10 to 20 years before type 2 diabetes, and virtually all patients with type 2 diabetes have insulin resistance. Although insulin resistance can be reduced with lifestyle modifications and treatment, it can't be completely reversed.
Rarely seen alone, insulin resistance is a chronically prothrombotic, proinflammatory state associated with endothelial dysfunction and accelerated atherogenesis. It's often accompanied by elevated diastolic BP, hypertriglyceridemia, low HDL-C levels, and increased LDL-C levels.9,10
How PIs induce insulin resistance may be drug specific and involve various mechanisms. For example, ritonavir, nelfinavir (Viracept), and saquinavir (Invirase) induce peripheral insulin resistance and impair glucose-stimulated insulin secretion from beta cells; indinavir (Crixivan) inhibits glucose transport in skeletal muscle.
Insulin resistance is a component of metabolic syndrome, defined as a combination of abdominal obesity, dyslipidemia, elevated BP, insulin resistance or glucose intolerance, prothrombotic state (such as high levels of fibrinogen or plasminogen activator inhibitor-1 in the blood), and proinflammatory state, such as elevated C-reactive protein in the blood.11 Metabolic syndrome increases a person's risk of cardiovascular disease. The risk of cardiovascular disease and acute coronary syndromes is an increasing concern for patients with HIV infection. Because no specific test can be routinely used to diagnose insulin resistance, you should assess your patient for risk factors traditionally associated with metabolic syndrome. (See Who has metabolic syndrome?)
Encourage your patient to exercise, control his weight, and take other steps to reduce his cardiovascular risk. For instance, when appropriate, he should quit smoking, use low-dose aspirin therapy, manage lipids, and maintain BP at optimal levels.
Recent studies suggest that cardiovascular disease and acute coronary syndromes are more prevalent in HIV-infected patients than in the general population. Perhaps HIV itself may have some role in the development of cardiovascular disease through its proinflammatory and immune activation properties, which are currently thought to cause cardiovascular disease in the general population.
Because of the widespread use of PIs, their tendency to cause abnormal lipid levels, and increased reports of heart disease and stroke in patients taking them, several case reports were published.12,13 For many years, these drugs were blamed for the increased incidence of cardiovascular disorders in patients with HIV.
More recently, the relationship between cardiovascular disease and HIV was described by the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study, an international collaboration of investigators following 23,437 HIV-infected patients at 188 clinics in Europe, the United States, and Australia. This study enrolled a large number of patients to answer the clinically important question about the relationship between antiretroviral drugs and the risk of cardiovascular disease.14
The DAD study demonstrated that in patients infected with HIV, traditional risk factors (especially smoking) play a more significant role in cardiovascular disease than PIs. The DAD study also found a statistically significant increased risk of myocardial infarction (MI) in patients treated for HIV.14 The study investigators concluded that at least for up to 6 years of exposure to combination ART, patients had a relative increase in the incidence of MI of 26% per year. Although it wasn't addressed by this study, the increased rate of MI in drug-exposed patients may be due to the effect of drugs on the development of insulin resistance or dyslipidemia.
However, this study also found that other factors are independently associated with an increased rate of MI: older age, any history of smoking, previous cardiovascular disease, and being male. As a result, the rates of MI observed in the treated and untreated HIV-infected patients recruited to the DAD study are similar to those that might be expected among people not infected with HIV who have similar cardiovascular risk profiles.
Research conducted at Massachusetts General Hospital and Brigham and Women's Hospital, both in Boston, compared information on almost 4,000 HIV-infected patients with data from more than 1 million patients without HIV.15 In this study, the risk of MI was almost double in those with HIV and almost triple among HIV-positive women compared with noninfected patients. The reason for these observations has yet to be fully explained.
The DAD study and the study done by Triant and colleagues provide important messages to nurses about the incidence of cardiovascular disease and MI in patients infected with HIV. Based on these findings, health care providers should carefully assess the risk of cardiovascular disease in their patients receiving ART and intervene appropriately to reduce risks, in much the same way you do for patients without HIV infection. (The study didn't analyze data in HIV-infected patients who weren't on ART.)
Cardiovascular and metabolic complications of HIV infection can be prevented or modified by providing lipid-lowering therapy when indicated, maintaining BP within normal limits, and monitoring for diabetes. These independent nursing interventions can reduce cardiovascular risk the most: teaching patients about smoking cessation and encouraging exercise and optimal weight control.
Smoking and HIV infection. The prevalence of adult smokers in the United States is estimated to be 21%.16 In the overall HIV population, the prevalence of cigarette smoking may be as high as 72%. In HIV-infected I.V. drug users, the prevalence of smoking may be as high as 96%.17,18 Besides contributing to cardiovascular disease, smoking is a major contributor to bacterial pneumonia, abdominal aortic aneurysm, cataracts, periodontal diseases, acute myeloid leukemia, and cancers of the lung, stomach, uterus, cervix, pancreas, and kidney.17,18
Incorporate smoking-cessation interventions into the routine care of all patients but especially those with HIV. When nurses advise and encourage hospital patients who are smokers to quit, 15% to 20% of them quit, compared with 3% who don't receive counseling at all.19
Brief counseling about smoking consists of the four A's: ask, advise, assist, arrange. At discharge or at any nurse/patient encounter, you can simply:
1. ask about his smoking
2. advise him to quit smoking
3. assist him with quitting by providing educational materials, motivational interviewing, or referral for pharmacologic aids
4. arrange follow-up to discuss progress toward smoking cessation.
Obesity and HIV infection. Over 23% of Americans are estimated to be obese (body mass index [BMI] of 30 kg/m2 or more), and about 50% are considered overweight (BMI of 25 to 29.9 kg/m2).20 Being obese also predisposes the patient to diabetes and cardiovascular disease.
Seeking to determine the prevalence of obesity and overweight among clinic patients infected with HIV, investigators from the University of Pennsylvania in Philadelphia reviewed the records of nearly 1,700 patients. Of the patients in the cohort, 78% were men, 60% were African-American, 18% were injection drug users, and all but 9% were treated with ART. The mean BMI among men was 24.9 kg/m2; for women, it was 27.5 kg/m2. In this cohort, overweight, obesity, and HIV wasting had a prevalence of 31%, 14%, and 9%, respectively. Although women and men were equally likely to be overweight, women were significantly more likely than men to be obese. Having a CD4 count of more than 200 was associated with being overweight or obese.
The investigators concluded that although the prevalence of overweight and obesity wasn't more common than in the general population, the prevalence of obesity was increased in HIV-infected women compared with men. The rate of obesity in this population of women was almost three times that of the rate in the overall population of Philadelphia. They found no correlation between obesity and the use of ART. This study was interesting because the authors also concluded that some HIV-infected patients, especially women, may favor elevated weight as a way to protect themselves from future HIV wasting or to mask their disease from their friends and acquaintances.21
Obesity might add to metabolic abnormalities seen in HIV infection and contribute to cardiovascular disease. Encourage a patient who's obese or overweight to make dietary and lifestyle modifications. Your nutrition education and behavioral counseling are effective interventions to help him alter his daily eating patterns and food preparation practices.22
Your patient may be confused and even resist losing weight because in the past, weight loss was associated with advancing HIV infection. Explain to him that the wasted appearance of patients with advanced HIV infection reflects muscle loss and is generally associated with poorly treated or untreated HIV infection. The goal of any weight-loss program is to lose fat, not muscle.
In many HIV centers, nurses can measure the loss of fat with a bioelectrical impedance analysis (BIA) machine. A BIA measurement is considered one of the most exact and accessible methods of screening body fat. In performing a BIA measurement of body composition, an electrode is typically placed on the patient's hand and foot, then a small, painless current of electricity is sent from one to the other.
The BIA machine measures how long it takes for the current to be conducted and uses that, along with some other data points such as age and sex, to estimate body fat percentage. The more muscle a person has, the more water his body can hold. The more fat a person has, the more resistance he'll have to the current.
When a patient is trying to lose weight, monthly or bimonthly BIA measurements are recommended to ensure that he's losing fat, not muscle. This should help alleviate some of his fear about losing weight. Weight loss targets for patients with HIV infection are the same as for the general population.
For a patient infected with HIV, living longer with HIV disease also means having to deal with many problems of chronic illness, including adverse reactions to therapy. Additionally, he may have to deal with common health problems that plague people in the general population, such as metabolic syndrome and cardiovascular disease. By educating him about his risks and teaching him how to modify them, you can help him maintain his health despite chronic HIV infection.
The statins are metabolized by the CYP 3A4 pathway. Protease inhibitors inhibit this pathway, resulting in potentially toxic serum statin levels. Given the potential for drug interactions, a patient taking a PI who needs statin therapy should be started on a low dose of either pravastatin or atorvastatin.
When a patient has three or more of the following risk factors, he has metabolic syndrome.
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