Drugs that lower lipids (fats) in the blood may be prescribed for people with HIV who have high lipids and body fat changes known as lipodystrophy. Although the cause of these changes in fat metabolism is uncertain, they are often associated with the use of protease inhibitor therapy.

Lipids include triglycerides and cholesterol. Cholesterol is divided into two main groups: low density lipoprotein (LDL) or 'bad' cholesterol, associated with hardening of the arteries, and high density lipoprotein (HDL) or 'good' cholesterol, which clears cholesterol from the arteries.

There are five groups of anti-lipid drugs: statins, fibrates, anion-exchange resins, nicotinic acids and fish oils. These drugs are used to treat high lipids or coronary heart disease in people who have not responded to dietary changes. If a person has extremely high lipids, or if initial therapy with a single class has been unsuccessful, drugs from more than one class of lipid-lowering drugs can be combined. However, combining statins with either nicotinic acid or a fibrate increases the risk of side-effects, including a potentially life-threatening condition called rhabdomyolysis, where muscle cell products are released into the blood causing severe muscle pain, swelling and possibly damage to the vital organs.

Statins

Statins are a class of drugs used to treat high lipids, especially high LDL cholesterol. They include simvastatin (Zocor), pravastatin (Lipostat), fluvastatin (Lescol / Lescol XL), atorvastatin (Lipitor), cerivastatin and rosuvastatin (Crestor). The statins are more effective than other classes of lipid-lowering drugs at reducing LDL cholesterol, but less effective than the fibrates in reducing triglycerides and increasing HDL cholesterol. In the general population, they reduce the risk of heart disease, stroke, diabetes and death.

Statins are generally regarded as very safe drugs, although their main side-effects are gastrointestinal problems (nausea, vomiting, flatulence and stomach pain) and inflammation of the muscles. A person taking a statin is advised to report muscle weakness, tenderness or pain to their doctor promptly. The risk of muscle pain and weakness is increased if a statin is taken with gemfibrozil (Lopid), ciclosporin (Neoral / Sandimmun) or nicotinic acid. Kidney and liver function should be closely monitored if these drugs are taken with a statin.

Most statins are metabolised in the liver in a similar way to the protease inhibitors, primarily using the P450 CYP3A4 pathway. Some protease inhibitors cause substantial and potentially dangerous increases in blood levels of statins, increasing the risk of muscle damage. Drug interaction studies in HIV-negative subjects found large increases in atorvastatin and simvastatin levels when dosed with saquinavir (Invirase / Fortovase) and ritonavir (Norvir). However, the decline in pravastatin levels was less pronounced, indicating this may be the safest statin for use with protease inhibitors. Another study has recommended that simvastatin not be taken with nelfinavir (Viracept) due to a drug interaction, and that caution should be exercised when nelfinavir and atorvastatin are co-administered. Similarly, efavirenz (Sustiva) can cause reduced exposure to simvastatin, pravastatin and atorvastatin, possibly requiring higher doses to maintin the drugs' lipid-lowering actions (Gerber 2005).

In contrast to other members of the drug class, rosuvastatin is not metabolised by the P450 pathway. A pilot study has shown that it is a safe and effective treatment for increased cholesterol and triglycerides in patients taking protease inhibitors (Calza 2005).

Other drugs can also interact with the statins. For example, when fluvastatin is taken concurrently with fluconazole (Diflucan), levels of fluvastatin are elevated and exposure is prolonged.

A recent study has suggested that statins may also have a direct antiretroviral activity, through their inhibition of the enzyme Rho guanosine triphosphatase. This prevents the formation of the protein Rho, which is necessary for the entry of HIV into T-cells and the release of virus particles from infected cells. In their small proof-of-concept study, the investigators showed that giving lovastatin to antiretroviral-naive patients for one month caused reductions in viral load and increases in CD4 cell counts (del Real 2004). However, this finding requires verification in further clinical studies.

Similarly, some doctors have expressed concern that statins may affect the levels of immune system cells and chemical messengers or 'cytokines', potentially altering the course of HIV disease or therapy. Despite their beneficial effects on lipid levels, they warn that more research is needed to establish whether the drugs have long-term effects on the immune system (Corrales-Medina 2005).

Fibrates

Fibrates are active against elevated triglyerides but they also tend to lower LDL cholesterol and raise HDL cholesterol. Fibrates include clofibrate, bezafibrate (Bezalip / Bezalip Mono), ciprofibrate (Modalim), fenofibrate (Lipantil / Supralip 160), ispaghula and gemfibrozil.

These drugs should not be used in people with kidney, gall stone or liver problems, and should not be taken by pregnant women. Side-effects include nausea, stomach pain, rash, impotence, dizziness, fatigue and muscle pain.

The fibrates are less likely to interact with protease inhibitors than statins because they are not primarily metabolised by the P450 CYP3A4 pathway. The clinical effects of taking fibrates with antiretroviral therapy are not currently known.

Anion-exchange resins

The anion-exchange resins, colestyramine (Questran / Questran Light) and colestipol (Colestid) lower LDL cholesterol but can aggravate high triglycerides and thus should not be used to treat HIV-related high lipids.

Nicotinic acid or niacin

Nicotinic acid is also known as vitamin B₃ or niacin. In the human body niacin plays a role in fat synthesis, protein and carbohydrate breakdown, tissue respiration and digestion.

As a high dose supplement, niacin is effective at lowering both cholesterol and triglycerides in people taking antiretroviral therapy but its use is limited due to side-effects including dilation of the veins, headache, flushing, dizziness, palpitations, nausea, and insulin resistance (Gerber 2003). A second member of this group, acipimox (Olbetam), has fewer side-effects but is less effective at reducing lipids.

Fish oils and other supplements

A fish oil preparation that is rich in omega-3 triglycerides is able to reduce elevated triglycerides but may aggravate cholesterol levels. It is considered a relatively weak treatment and a large dosage would be needed to reduce the very high triglycerides associated with protease inhibitor therapy.

One trial has shown that taking 2g of a fish oil preparation called Maxepa three times daily reduced triglyceride levels in patients taking antiretroviral therapy by an average of 26%, with no significant adverse events. Despite the high pill burden, this treatment may be attractive due to the lack of drug interactions and its efficacy (de Trucis 2005).

Carnitine products and a food supplement made from fungus fermented on red rice may also reduce lipids.

Reducing lipid levels

A number of trials have found that lipid-lowering agents can reduce cholesterol and triglyceride levels among people on protease inhibitors. These are discussed in more detail in Treating body fat and metabolic changes in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment. In many instances, lipid-lowering agents produce only moderate benefit.

To date there is no evidence that taking the statins undermines the anti-HIV effect of protease inhibitors. The Chelsea and Westminster Hospital in London is conducting a study investigating the effect of pravastatin for individuals with protease inhibitor-related high lipids. However, as described above, taking both protease inhibitors and statins may increase the risk of side-effects such as muscle pain and weakness. Atorvastatin or pravastatin, which have less of an efect on the P450 CYP3A4 pathway, or a fibrate such as gemfibrozil may be the best alternatives from this perspective, although recent findings have cast doubt on whether pravastatin is effective at reducing cholesterol levels in patients taking protease inhibitors (Mallon 2005).

American HIV Dyslipidemia Guidelines have been drafted to guide clinicians in the monitoring and treatment of people taking highly active antiretroviral therapy (HAART) with elevated lipids. These guidelines recommend that HIV-positive patients should be treated in line with the National Cholesterol Education Program, although clinicians should select treatments which are least likely to lead to drug interactions (Dubé ²000).

For further information and details of specific studies see Treating body fat and metabolic changes in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment.

References

del Real et al. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med 200: 541-547, 2004.

de Truchis P et al. Treatment of hypertriglyceridemia in HIV-infected patients under HAART, by (n-3)polyunsaturated fatty acids: a double-blind randomized prospective trial in 122 patients. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 39, 2005.

Calza L et al. Rosuvastatin for the treatment of hyperlipidaemia in HIV-infected patients receiving protease inhibitors: a pilot study. AIDS 19: 1103-1105, 2005.

Corrales-Medina VF et al. Statins and HIV: beyond the metabolic and cardiovascular benefit. J Acquir Immune Defic Syndr 39: 503-504, 2005.

Dub頍P et al. Preliminary guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy: Recommendations of the Adult ACTG Cardiovascular Disease Focus Group. Clin Infect Dis 31: 1216-1224, 2000.

Fichtenbaum CJ et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG study A5047. AIDS 16: 569-577, 2002.

Gerber JG et al. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin and pravastatin. Results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr 39: 307-312, 2005.

Gerber M et al. Niacin in HIV-infected individuals with hyperlipidemia receiving potent antiretroviral therapy. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract P726, 2003.

Mallon P et al. A randomised, placebo-controlled trial of pravastatin for the treatment of protease inhibitor-induced hypercholesterolaemia in HIV-infected men. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract TuPe2.4C21, 2005.