Although dyslipidaemia in HIV-infected patients is common, not all patients with dyslipidemia require lipid lowering therapy. The goal of therapy, as in the HIV negative population, is to reduce an individual’s cardiovascular risk. Therefore treatment of HIV-associated dyslipidemia should be an integral part of a general attempt to improve cardiovascular health, with advice on diet and exercise, smoking cessation, management of hypertension and diabetes where present, and the use of anti-platelet agents where warranted.
Despite this, in a recent retrospective review, HIV-infected veterans in the USA who met NCEP/ATPIII guidelines for dyslipidemia were half as likely to be receiving lipid lowering therapies as HIV-negative controls [93
]. HIV-infected patients should be screening for dyslipidemia at HIV diagnosis, annually, and upon starting HAART. An individual’s cardiovascular risk should be assessed by standardised scoring systems such as the Framingham or Joint British Societies score, and treatment instituted for those with previous cardiovascular disease or a high (>20% in 10 year) risk of cardiovascular disease (Fig.
Screening and treatment algorithm.
Current European Aids Clinical Society (EACS) guidelines recommend target LDL-C levels dependent on an estimated 10 year cardiovascular risk. The Infectious Diseases Society of America guidelines use a similar estimate of risk. These are summarised in Table .
LDL-C Treatment Goal Recommendations
EACS guidelines recommend only treating severe isolated hypertriglyceridemia (TGs >10mmol/L), or combined hyperlipidemia (LDL-C elevated and TG 2.3-10mmol/L) with lipid lowering therapy, while treating isolated hypertriglyceridemia with TG<10mmol/L with dietary and lifestyle advice. IDSA recommend treatment of isolated TGs>5.6mmol/L (500mg/dL) or elevated LDL-C and TGs of 2.2-5.6mmol/L (200-500mg/dL).
The treatment options available for the management of dyslipidemia in HIV-infection are similar to those in the general population; dietary and lifestyle modification and the use of lipid lowering medications. An additional option in those on HAART is the ability to switch antiretrovirals away from those that may exacerbate the dyslipidemia. Although all these options have been studied in HIV-associated dyslipidemia, many studies are open-label, few are randomised and even fewer placebo-controlled. While many of these studies have shown beneficial effects of switching HAART components or lipid lowering therapy on dyslipidemia, there are no data available on the impact of these effects on cardiovascular disease endpoint and any perceived benefit is derived from corresponding beneficial effects on CVD of lipid lowering in the general population.
As in the management of dyslipidemia in HIV-negative subjects, counselling on ‘therapeutic lifestyle changes’ such as reducing fat and cholesterol intake, increasing physical activity, weight reduction and adjusting diet to reduce LDL-C are also important components of managing HIV-associated dyslipidemia [94
], although the data on a beneficial result are inconsistent. Despite similar caloric intake, HIV-infected individuals have been shown to ingest more saturated fat than HIV-negative matched controls, and dietary saturated fat intake correlates with serum triglyceride concentrations [95
]. In an early study in PI-treated patients with dyslipidemia, a diet and exercise program led to an 11% reduction in total-C, and a 21% reduction in TG [96
]. However, in a study examining the effect of fish oil on serum lipids in HAART treated subjects with hypertriglyceridemia, those randomised to dietary and exercise counselling alone only reduced TG levels by 6%, with no change in LDL cholesterol at 16 weeks despite decreased caloric and total fat intake [97
]. In another study of individuals with hypertriglyceridemia on HAART, only 4 of 49 individuals achieved normal TG levels at any stage within an 18 month period with diet and exercise alone [98
]. It is therefore unlikely that lifestyle modifications alone will suffice in correcting HAART-induced dyslipidemia in the presence of ongoing exposure to the antiretrovirals precipitating the problem.
An approach available to some HAART-treated patients with dyslipidemia is to switch away from the presumed offending agent to another ARV with less propensity to induce dyslipidemia [99
]. Studies examining this strategy are summarised in Table
. These options should only be considered when there is a viable alternate antiretroviral agent or regimen, the new regimen is likely to induce less dyslipidemia than the original and is likely to possess similar or enhanced antiretroviral potency compared to the original regimen. At all times, maintenance of an effective ARV regimen capable of durable viral suppression is of paramount importance. Switching therapy needs careful discussion with patients about potential risks and benefits of changing what may be a virologically successful ARV regimen.
Antiretroviral Switch Studies and Effect on Lipids
PI Switches Within Class Switching
Switching from one PI to another has the advantage of maintaining the same class of drug whilst preserving future treatment options. Atazanavir is a potent PI with once-daily dosing and relatively favourable effects on serum lipids [39
], making it an attractive option to switch to from other PIs. The need to “boost” atazanavir by using boosting doses of ritonavir [100
], may reduce the beneficial effects on lipids. However, even when ritonavir-boosted, atazanavir induces less dyslipidemia than other boosted PIs [101
], with the possible exception of the newer agent darunavir, which appears to have similar effects on lipid parameters to atazanavir in HIV-negative individuals [102
Many studies examining switching to atazanavir did not actively recruit patients with dyslipidemia [103
]. However there appears to be a consistent reduction in triglycerides and cholesterol among those who switched compared to those who remained on other PIs (Table
). This appears to hold true even for those who switch to boosted atazanavir, though the margin of reduction in lipids is smaller [104
]. Atazanavir can also be used ‘un-boosted’. One study that examined the effect of switching to un-boosted atazanavir in patients with hypercholesterolemia demonstrated reductions in triglycerides and total cholesterol without concomitant lipid-lowering therapy [107
]. However only 37% of patients achieved LDL-C ≤130mg/dL.
Switching to a Different ARV Class
Until recently, the options for switching away from protease inhibitors had been confined to NRTI or NNRTI switches. Switching a PI to a NNRTI such as efavirenz or nevirapine makes virological sense, as the combination of 2 NRTIs and one NNRTI is a well studied and effective antiviral combination [99
]. However NNRTI have a low genetic barrier to resistance, with only one mutation required to induce high level resistance, raising concerns regarding the efficacy of this approach, particularly in patients who have been previously exposed to NNRTIs. It appears that switching to nevirapine compared to efavirenz has a better effect on lipids [108
]. Studies have shown that switching a PI to nevirapine has a minor effect on lipids and is virologically safe [109
], though the magnitude of the lipid-lowering effect has been shown to be inferior to lipid lowering therapy alone [109
Switching a PI to a NRTI such as abacavir, leaving patients on a triple combination of NRTIs, while well-tolerated and beneficial from a lipid perspective, has been shown to be virologically inferior to conventional HAART comprising drugs from more than one drug class [112
] and is now not generally recommended.
As previously discussed, thymidine analogue NRTIs (tNRTIs) are associated with subcutaneous fat loss, adipose tissue dysfunction, and increases in cholesterol and triglycerides (HIV-associated lipodystrophy). Switching away from tNRTIs to other NRTIs such as abacavir and tenofovir has been investigated as a therapeutic option for HIVLD and have resulted in both increases in subcutaneous fat [114
] and improvements in dyslipidemia [115
Switching from tNRTI to tenofovir appears to have more favourable effects on lipids than switching from tNRTI to abacavir, though the overall lipid improvements are often slight [115
]. In one comparative randomised trial, switching from stavudine to tenofovir rather than abacavir resulted in significantly greater improvements in total cholesterol (median reduction of 0.45mmol/L) and LDL-C (median reduction of 0.25 mmol/L) [114
]. Similarly in the BI-COMBO study, in which patients were randomised to switch from any NRTI to either tenofovir or abacavir, those switching to tenofovir had lower fasting total cholesterol, LDL-C, HDL-C and triglycerides at week 48 than those switching to abacavir [118
]. However the between group differences were relatively small and there was no difference in the use of lipid lowering agents at the end of the study. One study has examined dose reduction of stavudine compared to switching to tenofovir. Despite most patients having normal lipids at baseline, switching to tenofovir resulted in greater lipid improvements than stavudine dose reduction [119
]. The SWEET study examined the effect of switching from zidovudine to tenofovir. Although those switching to tenofovir had lower total cholesterol and triglycerides at 24 weeks (with the greatest reductions occurring in those with the highest baseline values), there were no statistically significant between group differences at 48 weeks between each arm [120
Cessation of HAART has been proposed as a therapeutic option in dyslipidemia, and does result in improvements in TG, total-C and LDL-C even after a short period of time [121
]. However, clinical studies have shown excess morbidity and mortality, including increased major cardiovascular, renal and hepatic events in those undergoing treatment interruption [122
]. As a result this strategy should not be considered as therapy for dyslipidemia.
Lipid Lowering Therapies
Many lipid lowering therapies have been investigated in HIV infection (summarised in Table
). The treatment of dyslipidemia in HIV infection is often complicated by potential drug interactions between ARV and lipid-lowering medications. In addition, other medications used in the treatment of HIV-infection such as macrolide antibiotics [123
], azole antifungals [124
] or the rifamycin antimycobacterials [125
] may also have significant interactions with lipid-lowering agents.
Trials of Lipid Lowering Agents in HIV Infection
Fish oils, rich in omega-3 fatty acids, can help lower triglycerides and have been studied in HIV-infected patients. They are generally well tolerated and have few side-effects. Although a randomised study of 3g of fish oil daily together with diet and exercise resulted in a 19.5% mean decrease in TGs at 16 weeks (though this was not statistically significant compared to diet and exercise alone), LDL-C concentrations actually increased by 22% [97
]. In a further study (ACTG 5186), comparing 6g of fish oil per day to fenofibrate in HIV–infected patients on HAART with isolated severe hypertriglyceridemia, those on fish oil experienced a 46% reduction in median TG at 8 weeks, but only 8.5% achieved TG levels ≤200mg/dL and LDL-C concentrations increased. Combining fish oil with fenofibrate achieved normal TG levels in 22% of patients [126
]. Treatment of HIV-infected patients with moderate HAART-related hypertriglyceridemia with polyunsaturated ethyl esters of n-3 fatty acids resulted in a 11.6% reduction in TG levels at 18 months, with 25.9% of patients achieving normal TG levels at some stage over the 18 months follow-up [98
]. Given the rises in LDL-C observed in these studies, it is unclear if use of fish oils in this clinical setting will have an overall clinical benefit in terms of cardiovascular risk reduction.
Fibrates are an attractive therapeutic option in HIV-infected patients, as hypertriglyceridemia is common and fibrates lack significant pharmacologic interactions with ARV. Fibrates reduce triglycerides by approximately 40-50% in HIV-infected patients with hypertriglyceridemia [109
], with larger reductions in those with higher baseline TG levels [126
]. These effects appear to be similar to the effect of statins [128
] (see below) and in one study were superior to switching PI to NNRTI [109
]. In studies fibrates appear to be well tolerated, with gastrointestinal upset being the most frequently reported side effect. Proportions of patients achieving target goals vary, with one study reporting 70% achieving a target TG≤200mg/dL, but most others report much lower proportions ranging from 1-40% [98
]. Despite these benefits, it is still unclear if reductions in triglyceride concentrations alone will be sufficient to significantly alter overall cardiovascular risk in HIV-infected patients.
HMG CoA reductase inhibitors, or “statins” have been shown to be an effective method of treating hypercholesterolemia in HIV-negative individuals and are also effective in HIV-infected individuals, reducing total cholesterol by approximately 30% and triglycerides by similar amounts [128
]. As with use of fibrates for hypertriglyceridaemia, the percentage of patients achieving LDL-C targets with statin use vary, with some studies reporting 50-60% patients reaching NCEP targets [128
], while others report far lower percentages [131
]. Interactions between statins and antiretrovirals (ARVs) are very common. PIs inhibit the CYP3A4 metabolism of statins, and increase overall exposure to statins, in the case of simvastatin by over 3000% [135
]. This has led to concerns regarding the potential for statin toxicity with PI use and for this reason simvastatin is contraindicated with concurrent PI use. However atorvastatin (at 10-80mg qd) and pravastatin (at 20-80mg qd) are less affected by this interaction and have been extensively studied with PIs [109
]. Conversely, the NNRTI efavirenz induces hepatic metabolism of statins, leading to a marked reduction in the AUC for simvastatin, pravastatin and atorvastatin [137
]. The newer statin rosuvastatin is only marginally metabolised by the CYP3A4 system, with most of the drug being excreted unchanged, and has been used to treat dyslipidaemia in HIV-infected patients [132
]. Despite this, both lopinavir/ritonavir [138
] and atazanavir/ritonavir [140
] increase both the Cmax
and AUC of rosuvastatin. This may be due to blockage of the OATP-1B1 membrane transporter for rosuvastatin, of which ritonavir is a known inhibitor [138
]. This transporter is involved in the hepatic uptake of rosuvastatin, therefore ritonavir inhibition may reduce the effect of rosuvastatin on lowering cholesterol despite inducing higher circulating concentrations of the drug [124
Ezetimibe, which blocks cholesterol absorption in the intestine and is metabolised independent of the CYP3A4 pathway, appears to have minor effects in HAART-induced dyslipidemia as monotherapy [141
]. However when added to pravastatin it allowed 62% of patients with hyperlipidemia to achieve a target LDL-C concentration of ≤130mg/dl [142
]. Its effects seem confined to LDL-C reduction as effects on triglycerides in HAART-induced dyslipidemia appear minor [141
Niacin has been investigated in two small studies, and appears to be well-tolerated, reducing TG levels by approximately 30% with a smaller effect on total cholesterol [143
]. A concern is the increase in insulin resistance seen in both studies. Given the concern over insulin resistance and diabetes in HIVLD the role for routine use of niacin in this setting is unclear.
There are few data reporting the efficacy or safety of combination therapies in HIV-infected individuals. One open label study allowed the addition of pravastatin or fenofibrate to those who had failed to reach NCEP guidelines on either agent as monotherapy for 12 weeks [131
]. Combination therapy was well tolerated and led to reductions in TG levels particularly, but only allowed 4% of patients to achieve combined NCEP guidelines. The increased risk of rhabdomyolysis in HIV-negative individuals from the combination of statins and fibrates [124
] would advise their concurrent use in HIV positive patients only be undertaken with strict caution.