HIV lipid guidelines good for your heart

by Enid Vázquez

Gene Coughlin, Positively Aware’s cover boy for July/August 1996, started having difficulty walking two years ago. Or as he puts it with his usual dry wit, “The little old ladies were outpacing me.” Coughlin couldn’t go a block without stopping to breathe. At first he thought he was recovering from pancreatitis, which had laid him up in the hospital for a month.

But after two months of breathing difficulties, he mentioned the problem to his HIV specialist. His doctor, conscious of cardiac problems in people with HIV taking protease inhibitors, had him come in right away for a stress test. Not four minutes passed before the treadmill was stopped and a chair placed on it so that Coughlin could rest. He was admitted to the hospital on the spot. The next morning, a look at the four main arteries leading to his heart found that one was 100% blocked, another was 90% blocked, and the other two were 80% blocked—a heart attack waiting to happen. He underwent quadruple bypass surgery a few days later. He was 46 at the time.

Coughlin was never careless about his diet or about exercising, because he had two major risk factors for heart disease: he always had high cholesterol levels and he had a family history of cardiac woes. Although no one knows for sure what’s causing the high levels of sugar, cholesterol and triglycerides (fat) in the blood seen in many HIV positive people taking antiviral medicines, people with pre-existing risk factors like Coughlin’s are at greater risk for these abnormalities. In HIV negative people, these conditions can cause heart disease. One leading HIV specialist with a special interest in this area says that everyone with HIV who’s on medications should be treated like a 50-year-old heart patient.

Now the Adult AIDS Clinical Trials Group (Adult ACTG) has released guidelines for controlling dyslipidemia, as they’re calling it (“dys” for impaired and “lipid” for fat). Lead author Dr. Michael P. Dubé, of Indiana University, says, “If nothing else, the guidelines would be a success if people begin using the right drugs to control their triglycerides and cholesterol. I see patients on drugs they shouldn’t be on because of interactions with antivirals. Physicians should look at interactions before they ever reach for a prescription pad.”

But just as important—if not more—is to control risk factors by making healthy changes, such as getting regular exercise and watching your intake of saturated fat. “Unfortunately, in a written document you can’t have neon lights and flashing signs saying, ‘Diet and exercise first,’” says Dr. Dubé. “Everyone should be doing the lifestyle changes that are good for longterm health, but at the end of my talks on this subject, 90% of the questions are, ‘OK, what drug do we use?’ That’s very frustrating, because like [HIV specialist] Carl Grunfeld said, if you quit smoking, that cuts your risk more impressively than a 20 or 30-point drop in cholesterol with use of a statin drug.”

Both physicians and people with HIV should be aware that there may be a problem and make sure risk factors are examined and treated, says Dr. Dubé. So far there’s no clear increase being found among people with HIV, but this kind of data takes time to collect, he notes, and besides, “There’s abundant evidence that there are increased risk factors for cardiovascular disease. There’s also reason to believe that high cholesterolemia may affect people with HIV more because of insulin resistance and other problems they’re having. For now, I wouldn’t recommend anything for HIV that wouldn’t be recommended for someone without HIV.” The guidelines were published this summer in the journal Clinical Infectious Diseases.

The following is taken almost word-for-word from the AACTG lipid guidelines.

Effects of switching antiviral therapies

One published study suggests that in people who’ve never taken an NNRTI, substituting Viramune (nevirapine) for PI [protease inhibitor] therapy can improve the lipid profile. The substitution of Sustiva (efavirenz) for a PI has not consistently had a beneficial effect in several studies that have been presented in abstract [summary] form. Trends for improvement in lipid levels have also been reported with the substitution of Ziagen (abacavir) for a PI in several abstracts. High rates of increased viral load with substitution of an NNRTI or Ziagen for PI have not been reported in these small studies. In practice, however, many people will have already received NNRTI therapy or are extensively NRTI-experienced and the long-term viral load benefit of switching is unknown. At the present time, there are no studies that compare the effects of treatment switching to those of adding lipid-lowering agents to ongoing successful therapy. Clinicians will need to weigh the risks of new treatment-related toxicities and the possibility of virologic relapse when switching from a PI-based regimen to an NNRTI-based or Ziagen-based regimen to the risks of potential drug interactions and new treatment-related toxicities from lipid-lowering agents added to PI-based regimens.

Measuring lipids

Evaluation of serum lipids should be performed after fasting for a minimum of eight hours, and preferably 12 hours. While total cholesterol and HDL cholesterol [the “good” cholesterol] are not markedly altered when tested in the non-fasting state, measurement of triglycerides and thus the calculation of LDL cholesterol [the “bad” cholesterol] must be performed while fasting. In general, the standard screening lipid profile should include measurement of total cholesterol, HDL cholesterol, and triglycerides, with calculation of LDL and VLDL cholesterol. It is recommended that a fasting lipid profile be obtained prior to therapy. This should be repeated within 3-6 months following the initiation of HAART. For individuals with elevated triglyceride levels at baseline, it may be preferable to repeat a lipid profile sooner, within 1-2 months of initiating HAART.

Fasting triglyceride levels will exceed 400 mg/dL in a substantial proportion of HIV positive PI-treated individuals and will make calculation of LDL cholesterol unreliable. Direct measurements of LDL cholesterol may not be readily available in some clinical laboratories. In these individuals, initial intervention decisions can be based upon the total cholesterol level, HDL cholesterol level, and triglycerides. The treating clinician must keep in mind that with high triglyceride levels, total cholesterol levels can be misleading, especially if used as a surrogate (substitute) for LDL cholesterol treatment.

Patients should be routinely screened for other cardiovascular risk factors such as family history, smoking, hypertension, menopausal status, physical inactivity, obesity, and diabetes. In addition, those with dyslipidemia should be screened for potential exacerbating factors such as excessive alcohol use, hypothyroidism, renal disease, liver disease and hypogonadism. The clinician should also consider the effects of glucocorticoids, beta-blockers, thiazide diuretics, thyroid preparations, and hormonal agents such as androgens [testosterone, Anadrol and Oxandrin, among others] and estrogens, on both cholesterol and triglyceride values.

Cholesterol treatment

Non-drug therapies should generally be instituted first and given a thorough chance before instituting drug therapies. Dietary needs are frequently competing in the HIV positive population, where the need for lipid lowering and weight gain may co-exist in patients who often experience prominent gastrointestinal problems. In many patients it will be preferable to address their wasting prior to their dyslipidemia. Attention must be given to other correctable risk factors for CHD (coronary heart disease), such as cigarette smoking, obesity, physical inactivity, diabetes, and hypertension.

Drug therapies for hypercholesterolemia in people taking PIs are problematic. The HMG-CoA reductase inhibitors, or statins, have been used extensively for first-line therapy for hypercholesterolemia in other diseases. Considerable evidence demonstrates their beneficial effects in both reducing the risk of CHD in patients without prior CHD (primary prevention) as well as reducing the progression of coronary artery stenoses and risk of recurrent CHD events (secondary prevention).

Most statin agents can provide similar LDL cholesterol lowering, even though to a modest extent Zocor, but particularly Lipitor, can more substantially influence these cholesterol levels. Pravachol may be the statin least susceptible to interaction with CYP3A4 inhibitors. A recent abstract reported that, in HIV negative people, the median 24-hour concentration area-under-the-curve for Pravachol co-administered with Norvir/Fortovase decreased a median of 0.5 fold while there was a 4.5-fold increase for Lipitor and 32-fold increase for Zocor.

Potential problems include significantly increased skeletal muscle toxicity due to increased levels of statins caused by CYP3A4 inhibition by HIV PIs and lower levels of PIs (possibly leading to virologic failure—increased viral load) caused by p450 induction [liver function] by statins. Elevated levels of statins have been associated with the development of rhabdomyolysis [a muscle disorder], such that the FDA has issued warnings about using these medications in patients known to be taking an agent which inhibits their metabolism. Similarly, interactions between statin agents and the CYP3A4 inducers Viramune and Sustiva may occur, possibly resulting in lower serum levels of statins.

None of the statins are known to be strong inhibitors or inducers of CYP3A4, although data are limited in this regard. If this is indeed the case, it is unlikely that the statins would significantly lower or raise levels of PIs. However, there exists a possibility for clinically significant drug interactions resulting in decreased levels of the active metabolite of Viracept. Given the potential interactions, it is reasonable to recommend the use of low initial dosages of either Pravachol (20 mg daily) or Lipitor (10 mg daily) in HIV patients who require drug therapy for hypercholesterolemia and who are taking PIs. Lescol and Baycol are acceptable alternative agents, but no data on interaction with PI’s have been reported. Mevacor and Zocor should be avoided.

Fibrates are alternative agents for hypercholesterolemia when it is accompanied by elevated triglycerides. A 32% reduction in total cholesterol level occurred in 25 HIV positive people treated with Lopid (gemfibrozil) 600 mg twice a day. Clinically significant drug interactions with PIs are unlikely. Although they generally have a greater effect on lowering triglycerides than on LDL cholesterol, many patients will also have hypertriglyceridemia and low HDL cholesterol, which tend to improve with use of fibrates. Concomitant use of fibrates and statin agents may increase the risk of skeletal muscle toxicity, and they should be used together only with caution.

An alternative to Lopid (gemfibrozil), Tricor (fenofibrate), was recently introduced in the US after many years of use in Europe. While Tricor may have potential advantages over Lopid such as more favorable effects on LDL cholesterol and greater ease of administration, at the present time there is no compelling reason to prefer Tricor to Lopid in HIV patients.

Because it causes insulin resistance even in non-diabetic individuals, niacin should be avoided as first-line therapy in patients receiving HIV PIs. Bile sequestering resins (cholestyramine, colestipol) are discouraged because their use can be associated with increased triglyceride levels, and their effects on antiviral drug absorption have not been studied.

Isolated elevation of LDL cholesterol

Based on their efficacy in other groups of patients, statins represent the most reasonable initial choice. Until more detailed pharmacokinetic data is available, either Pravachol (20 mg/d initial dose) or Lipitor (10 mg/d initial dose) is recommended, along with careful monitoring of virologic status [viral load] and creatine kinase values. Baycol and Lescol are reasonable alternative statin agents. A fibrate, either Lopid (600 mg twice a day) or micronized Tricor (200 mg once daily) are reasonable alternative agents when statins are not appropriate, or when patients fail to respond to adequate doses of statins. There exists the possibility of increased risk of myopathy (muscle damage) when a fibrate such as Lopid is combined with a statin.

Hypercholesterolemia with hypertriglyceridemia

Many HIV positive patients will fall under this classification of combined hyperlipidemia. Either Lopid or Tricor or a statin agent (see above) represent reasonable initial choices for management.

Hypertriglyceridemia

Non-drug therapies should be instituted first and given a thorough therapeutic trial. Smoking cessation and regular aerobic exercise are general health measures that will reduce triglycerides and improve the overall cardiovascular risk profile. Weight reduction should be strongly encouraged if obesity is present. Fat intake should be decreased, but a concomitant increase in carbohydrate intake may raise triglyceride and lower HDL levels. If this occurs, replacing some of the saturated fat with monounsaturated fat, which will not raise LDL cholesterol, may be valuable.

Fibrates represent the cornerstone of drug therapy for hypertriglyceridemia (Table 3). Treatment is with Lopid (600 mg twice a day, 30 minutes prior to the morning and evening meals) or micronized Tricor (200 mg once daily). Significant drug interactions with common agents used in HIV treatment are unlikely to occur, but these have not yet been studied.

Because of its propensity to cause insulin resistance, niacin should be avoided as first-line therapy in patients receiving HIV PIs. Preliminary data suggest that Lipitor is safe and effective for lowering triglyceride levels in patients receiving PIs. However, only small numbers of patients were studied, thus further data are needed before the use of this agent can be routinely recommended. As a class, HMG-CoA reductase inhibitors are not generally recommended as first-line therapy for isolated hypertriglyceridemia. If the use of a fibrate results in inadequate triglyceride lowering, or if LDL levels remain elevated, a cautious trial of adding a statin agent should be considered.

The AACTG guidelines are available at http://aactg.s-3.com/pub/docs/lipid_guidelines.htm. For more information, also see the National Cholesterol Education Program guidelines at www.nhlbi.nih.gov/guidelines/cholesterol/atp.txt. A simpler description of NCEP is available at www.americanheart.org/Heart_and_Stroke_A_Z_Guide/ncep.html.

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