**8. Other therapies for HAART-associated dyslipidemia**

The use of hypolipidemic drug therapy becomes necessary when HAART-associated dyslipi‐ demia occurs or persists for a long period and when alterations in diet, exercise and other HAART strategies are ineffective. Difficulties in the treatment of dyslipidemia in HIV-1 patients involve potential interaction between drugs, toxicity, intolerance, and low patient adherence to multiple drug regimens. Several alternatives are available, which, when ade‐ quately monitored, may be beneficial in reducing HAART-associated dyslipidemia.

#### **8.1. Statins**

Statins is the name given to the group of drugs that help lower cholesterol. These will normally be prescribed to people who have harmful cholesterol levels present in their blood, especially if other control methods have failed or if the individual is at risk of developing health com‐ plications. Statins benefit users to prevent and treat atherosclerosis, which is the hardening of the arteries as a result of accumulation of cholesterol (atherosclerotic plaques) [100, 101]. They are drugs that inhibit the enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl coen‐ zyme A reductase) and are considered the primary drugs for the treatment of primary hypercholesterolemia [100]. In clinical practice, the use of statins has achieved excellent results in reducing TC and LDL, leading to a decreased risk of coronary artery events and in the primary and secondary prevention of heart diseases [100-102]. Statins inhibit the key ratecontrolling enzyme in the de novo synthesis of cholesterol, which is responsible for production of >50% of total body cholesterol. Inhibition of HMG-CoA reductase also promotes an increase in the synthesis of hepatic LDL receptors and reduced VLDL production [101-103]. The most important drugs of this class are simvastatin, fluvastatin, atorvastatin, lovastatin, pravastatin and rosuvastatin. All of these drugs reduce LDL concentrations, although the use of simvas‐ tatin and atorvastatin has shown superior effects in HIV-1 seronegative patients [101-103]. In HIV-1 patients affected with dyslipidemia, the use of simvastatin, pravastatin, fluvastatin and rosuvastatin promotes reduction of dyslipidemia, but not in complete remission once other factors and elements are associated with the dyslipidemia in these patients [101-104]. The different drugs that compose HAART have metabolizing effects similar to statin (Table 4). In general, statins are metabolized by CYP3A4, and may cause clinically relevant interactions with other agents that are changed by this enzymatic complex, such as oral anticoagulants, ketoconazole, cyclosporine, erythromycin, itraconazole, PIs and NNRTIs [104-106]. Addition‐ ally, statins serve as substrates for G-glycoprotein, a known carrier of drugs in the small intestine, which may influence their oral bioavailability [105-107]. The presence of elevated statin levels in plasma increases the risk of liver toxicity, promoting elevations of serum transaminases and possible toxic hepatitis as well as skeletal muscle toxicity and myalgia with elevations of serum creatine kinase (CK) levels, especially in the case of simvastatin and atorvastatin [105-109]. Fluvastatin is metabolized by CYP2C9 enzyme; pravastatin and rosuvastatin are not significantly metabolized by the CYP450 system and have a very low risk of drug interactions. Reductions in the levels of TC and TG were observed in patients with dyslipidemia associated HIV-1 infection undergoing treatment with a PI and the use of rosuvastatin therapy. Simvastatin, lovastatin and atorvastatin should be avoided because they present a high risk of pharmacological interactions with PIs. Moreover, in a recent study, pravastatin had the lowest binding to plasma proteins of the statin agents and dietary advice associated with the statin compound significantly reduced TC levels in HIV-1 patients treated with HAART, without significant adverse events [104-108]. It is reasonable to recommend the use of pravastatin and/or rosuvastatin as a first-line treatment for hypercholesterolemia in PItreated patients and the use of fluvastatin, characterized by a slightly lower efficacy, as a second-line regimen. Additional benefits are obtained in patients treated with indinavir or pravastatin and fluvastatin, which significantly reduces the levels of TC and LDL, while maintaining good tolerability. Different associations between statins and antiretrovirals present considerable tolerability but always require monitoring of serum transaminases and CK. Different clinical studies and the routine use of fluvastatin, pravastatin, or rosuvastatin have shown that they are most suitable and safe to reduce LDL levels in HIV-1 patients [104-110].

#### **8.2. Fibrates**

of TC, LDL and TG were kept within the desirable limit in the groups treated with nevirapine and efavirenz, including HDL levels within the reference values [95-98]. Only the HIV-1 patients treated with a PI-based regimen showed lipid abnormalities and increased risks for cardiovascular disease [13, 24, 96]. In addition, possible alterations in lipid metabolism resulting from the use of NNRTI-based therapy are easier and faster to reverse with the use of statins, fibrates, diet and lifestyle. Although the individual effects of NRTIs remain unclear, stavudine was associated with TC and TG elevations greater than zidovudine and tenofovir. The addition of fusion inhibitors to the existing therapies, such as enfuvirtide/T-20, had little effect on plasma lipids. The possibility of different HAART strategies eliminating or reducing the dyslipidemia in HIV-1 patients must be evaluated, and the risk of development of variants of the virus with MDR must be taken into account [99]. In HIV-1 patients with favorable historical responses to HAART and accompanied by a physician experienced in HIV-1 infection, the transition from a PI-based to a therapy with nevirapine, abacavir, or even atazanavir may be preferable to the use of a hypolipidemic agent. In practice, many patients will show pre-existing resistance to the drugs, limiting options for the exchange of the treatment [83, 92-94]. Experts must assess the risks of toxicity of the new treatment and the

possibility of virologic relapse when switching HAART regimens.

140 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

**8. Other therapies for HAART-associated dyslipidemia**

**8.1. Statins**

The use of hypolipidemic drug therapy becomes necessary when HAART-associated dyslipi‐ demia occurs or persists for a long period and when alterations in diet, exercise and other HAART strategies are ineffective. Difficulties in the treatment of dyslipidemia in HIV-1 patients involve potential interaction between drugs, toxicity, intolerance, and low patient adherence to multiple drug regimens. Several alternatives are available, which, when ade‐

Statins is the name given to the group of drugs that help lower cholesterol. These will normally be prescribed to people who have harmful cholesterol levels present in their blood, especially if other control methods have failed or if the individual is at risk of developing health com‐ plications. Statins benefit users to prevent and treat atherosclerosis, which is the hardening of the arteries as a result of accumulation of cholesterol (atherosclerotic plaques) [100, 101]. They are drugs that inhibit the enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl coen‐ zyme A reductase) and are considered the primary drugs for the treatment of primary hypercholesterolemia [100]. In clinical practice, the use of statins has achieved excellent results in reducing TC and LDL, leading to a decreased risk of coronary artery events and in the primary and secondary prevention of heart diseases [100-102]. Statins inhibit the key ratecontrolling enzyme in the de novo synthesis of cholesterol, which is responsible for production of >50% of total body cholesterol. Inhibition of HMG-CoA reductase also promotes an increase in the synthesis of hepatic LDL receptors and reduced VLDL production [101-103]. The most important drugs of this class are simvastatin, fluvastatin, atorvastatin, lovastatin, pravastatin

quately monitored, may be beneficial in reducing HAART-associated dyslipidemia.

Fibrates or fibric acid derivatives are the drugs of choice for the treatment of hypertriglyceri‐ demia and play an important role in the control of mixed dyslipidemia. Clinical studies have shown that fibrates may reduce the risk of coronary atherosclerosis in patients with hyper‐ cholesterolemia and also in individuals in post myocardial infarction with higher LDL, lower HDL, and TG with discrete increases. Fibrates may be used in combination with statins for hyperlipidemia or when HDL levels are decreased, besides acting in the hepatic synthesis of TG, TC, lipoprotein lipase (LPL) and acetyl-CoA carboxylase, it inhibits peripheral lipolysis and controls blood glucose [111-113]. Fibrates are also metabolized by CYP450 system, but they appear to affect only CYP4A enzymes and do not show clinically relevant interactions


**Table 4.** Statins to HAART-associated dyslipidemia.

with PIs. However, concomitant use of both fibrates and statins can increase the risk of skeletal muscle toxicity and should be avoided [112-114]. In HIV-1 seronegative individuals, the use of a fibrate and a statin in a monotherapy regimen exhibits moderate lipid-lowering effects and good tolerability [114-116]. In HIV-1 patients, fibrates do not have the same efficacy of statins in preventing cardiovascular disease. Studies with HIV-1 patients treated with PI-based therapy and fibrates, including gemfibrozil, bezafibrateor fenofibrate, showed a significant reduction in the concentration of TC, TG and hypertriglyceridemia [113, 115, 116]. Fibrates appear as a suitable alternative for the treatment of dyslipidemia associated with HIV-1, especially in the presence of hypertriglyceridemia. Periodic monitoring of serum creatinine, CK, and transaminases should be performed when using fibrates [115-117]. The association between fibrates and statins has been used with relative safety and demonstrated in different studies with large numbers of HIV-1 patients volunteers, except for the use of the combination of statins and gemfibrozil, which is not recommended [116-118]. The use of statins, fibrates, or associated therapeutic agent has shown positive results in HIV-associated dyslipidemia. and the pravastatin/fenofibrate combination has accelerated the an improvement of lipid param‐ eters and is safe and efficacious [119-120].

#### **8.3. Inhibitors of intestinal cholesterol absorption**

Inhibitors of intestinal cholesterol absorption are a class of drugs that prevent the absorption of cholesterol from the small intestine into the circulatory system. Ezetimibe is effective at lowering lipid levels because it has the ability to inhibit the intestinal absorption of cholesterol, and it shows good tolerability because it does not interact with the metabolism of CYPA4 enzymes [121, 122]. In HIV-1 seronegative patients who have dyslipidemia, the monotherapy with ezetimibe or when combined with statins or fenofibrate has shown considerable efficacy and safety [123, 124]. In HIV-1 patients with high serum levels of LDL, the use of ezetimibe has also been considered an effective alternative [122]. Monotherapy using 10 mg/day of ezetimibe has accelerated reductions of more than 20% of serum LDL and, in addition, reduces the concentrations of TC and TG while increasing HDL concentrations [121-124]. Studies have shown that in individuals with HIV-1 that are beyond effective treatments, ezetimibe has no interaction with HAART, and those receiving a PI-based association of fenofibrate/ezetimibe showed greater efficacy compared with pravastatin in monotherapy resolution of dyslipide‐ mia [125-127].
