Screening for and management of cardiovascular risk factors in the hiv-infected patient

Introduction

In 2013 more than 2 million people infected with HIV started antiretroviral therapy (ART) and at the start of 2014 12 million HIV-infected patients in low- and middle-income countries (LMIC) were receiving ART(1). This is the largest ever growth in people on ART. As a result the life expectancy of many HIV-infected people is expected to improve considerably.
Because of this improved access to ART availability and good outcome results, there is increasing focus on the long-term effects of suppressed infection and ART. In Western studies it has been shown that HIV-infected patients on ART can now have a near normal life expectancy. However, the incidence of noncommunicable diseases and especially that of atherosclerotic vascular diseases in this population is increasing(2). A recent study found subclinical atherosclerosis in 18% of HIV-infected adults in Uganda(3). They also found an association with traditional cardiovascular disease (CVD) risk factors and subclinical atherosclerosis.

Atherosclerotic vascular disease and hiv

The increase in atherosclerotic vascular diseases in this group of patients is thought to be caused by both the effects of HIV and of ART (4,5). HIV infection results in low-level chronic inflammation that affects endothelial cells and induces a pro-thrombotic state, resulting in a higher incidence of atherosclerosis. ART may have additional effects on the risk CVD as well, though it is unclear to which extent ART independently contributes to CVDR. Lowering HIV viral load with effective ART reduces chronic inflammation, which lowers the cardiovascular risk. However ART also causes metabolic changes like insulin resistance and dyslipidemia that increase the cardiovascular risk. The latter is especially true for ART regimens containing a protease inhibitor (PI).

Therefore it is assumed that low-level chronic inflammation and the metabolic changes caused by ART will contribute to the CVDR in an ageing HIV-infected population on long-term ART. Studies on this subject in non-Western populations are ongoing. It is thought that these effects may be attenuated in LMIC, because ART on average is started later and ART with more side effects is used.

Assessment

It is recommended to screen HIV-infected patients for cardiovascular risk annually, before initiating ART and after initiating or changing ART. Recommendations on the time of screening after initiating or changing ART differ. Most guidelines recommend doing so in three to six months. However, if TG levels are elevated prior to initiation of ART it is recommended to repeat the fasting lipid profile one to two months after starting ART. Obtaining a baseline fasting lipid profile when initiating or changing ART is also recommended.

Screening HIV-infected patients for cardiovascular risk should consist of a fasting lipid profile and assessment of established risk factors(6). The decision whether or not to treat dyslipidemia should take into account other, general cardiovascular risk factors (age>45 for men, age>55 for women, family history of premature CVD, cigarette smoking, hypertension, LDL>40mg/dL) and should not be based solely on plasma lipid levels. If two or more risk factors exist a 10-year risk calculation should also be performed. This 10-year risk calculation is available at http://cvdrisk.nhlbi.nih.gov/calculator.asp.

Art choice and treatment

When starting combination ART in patients with a high risk of CVD preference should be given to drugs with favourable effects on plasma lipid levels (6). Atazanavir or darunavir are preferable to other PIs when initiating therapy in treatment-naïve patients with a high risk of CVD. When no evidence of drug resistance or renal disease exists tenovofir and emtricitabine may be a preferred backbone in the ART regimen for these patients.

Several options for the management of dyslipidemia are available. In mild cases of dyslipidemia therapeutic life style changes are advocated for normalization of plasma lipid levels. In cases of clear ART-related dyslipidemia one could consider changing ART, though this may not be preferable in patients on effective combination ART. Finally one could consider starting lipid-lowering drugs, although in HIV-infected patients the use of these drugs can give significant interactions with ART.

Therapeutic life style changes

The recommendation of life style changes as a therapeutic option for dyslipidemia in HIV-infected patients is based mainly on observations in the HIV-uninfected population. Recommended life style changes include optimal management of hypertension and diabetes mellitus, dietary and exercise interventions, and cessation of cigarette smoking(5).

Switching pi

Studies show that in those who are on a PI it may be beneficial to switch to a non-PI based regimen as HDL plasma levels may improve (5,6). However, with new PIs like atazanavir this may not be necessary anymore. In addition, switching to e.g. efavirenz from a PI-based regimen will not always improve hypercholesterolaemia. Only very few studies have evaluated the effect of switching ART on dyslipidemia. Switching from a lopinavir-containing regimen to an atazanavir-containing regimen in patients with dyslipidemia has a positive effect on lipid levels. Switching from a boosted PI to a raltegravir-based regimen has similar positive effects. It should be noted that some patients who were switched to raltegravir did, however, experience virologic breakthrough, while this was not reported in patients who were switched to another PI.

Statins

Statins are as effective in the HIV-infected population as in the general population. A statin is therefore the first choice therapy when plasma LDL levels are elevated, without severe hypertriglyceridaemia (TG < 5.65 mmol/l). Use of statins in ART-treated patients is, however, complicated by pharmacokinetic interactions.

PIs, by inhibiting CYP3A4, may cause up to a 32-fold increase in simvastatin and lovastatin levels. Therefore these statins should be avoided when PIs are used. Also delavirdine, an NNRTI, inhibits this enzyme. Nevirapine and efavirenz on the other hand induce CYP3A4. Atorvastatin activity is doubled, and pravastatin levels are decreased by co-administration of PIs. Rosuvastatin in combination with boosted lopinavir or boosted atazanavir can increase levels of rosuvastatin via an unknown pathway. As a consequence, in PI-treated patients in which statin-therapy is indicated it is best to prescribe pravastatin, atorvastatin or fluvastatin (6).

Conclusion

The management of cardiovascular risk in an ageing HIV-infected population is a complex problem that is of great importance to the individual patient. It is therefore important to closely monitor lipid profiles and other risk factors in HIV-infected patients, and to treat accordingly. This is especially important in patients who are currently being treated with a PI. However, with the availability of newer and better antiretroviral drugs, this cardiovascular risk may become less important.

Recommendations for the treatment of dyslipidemia in HIV-infected patients are very similar to those for the general population. Smoking cessation and other life style changes are equally important in an HIV-infected patient as in a non-HIV-infected patient. Additionally, pharmacological treatment of dyslipidemia in HIV-infected patients is more complicated than in non-HIV-infected patients because of pharmacokinetic interactions. However, there are lipid-lowering drugs that can safely and effectively be used in the HIV-infected patient. Substitution of antiretroviral drugs to normalize lipid levels should only be considered if indicated treatment with lipid-lowering drugs is unsuccessful.

New guidelines from the WHO on the diagnosis and management of non-communicable diseases in HIV-infected patients are expected this year(2). In the meantime it is good to remind ourselves that the chronic care that comes with HIV treatment provides the clinician working in LMIC with a great opportunity for cardiovascular risk screening. It is an opportunity that we should not miss out on and that we should use to decrease the risk of cardiovascular diseases in the HIV-infected population.

References

1. World Health Organization. Global update on the health sector response to HIV. Geneva, 2014.
2. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. Geneva, 2013.
3. Ssinabulya I, Kayima J, Longenecker C, Luwedde M, Semitala F, Kambugu A, et al. Subclinical atherosclerosis among HIV-infected adults attending HIV/AIDS care at two large ambulatory HIV clinics in Uganda. PloS One 2014;9(2):e89537.
4. Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet 2013;382:1525-33.
5. Thienemann F, Sliwa K, Rockstroh JK. HIV and the heart: The impact of antiretroviral therapy: A global perspective. Eur Heart J 2013;34:3538-46.
6. Dubé MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: Recommendations of the HIV medical association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003;37:613-27.