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.

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.

Terms of 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.

Facing chronic challenges

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.

Dyslipidemia dilemma

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.

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.

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?)

Resist insulin resistance

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.

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.

Cardiovascular disease risk rises

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.

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.

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.)

How you can intervene

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.

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.

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.

Living longer and better

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.

Should a patient using a PI also take a statin?

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.

Who has metabolic syndrome?

When a patient has three or more of the following risk factors, he has metabolic syndrome.

REFERENCES