“Are new lipid lowering agents a good option for achieving lipid goals in people living with HIV? A case report”

Combination antiretroviral therapy (cART) has increased the life expectancy of people living with HIV (PLWH), transitioning from a fatal disease to a manageable chronic condition. ¹

Patients receiving long-term cART remain at higher risk for major cardiovascular disease (CVD) than individuals unaffected by HIV. Dyslipidemia is a major risk factor for CVD in PLWH.^2,3 However, cART can interact with lipid-lowering agents.^4,5

LDL-C has been identified as the primary interventional target for protection from CVD. ⁶

If lipid goals are not achieved despite lifestyle modification and cART switching, the use of lipid-lowering medications must be considered. ⁷ Several studies showed that 31%–49% of subjects with hyperlipidemia do not achieve LDL-C goals with current lipid-lowering therapies. ⁸

In the last years many new molecules have received approval. Bempedoic acid inhibits ATP citrate lyase in the cholesterol synthesis. ⁹ CLEAR studies have shown safety and efficacy with long term administration of this drug. It functions in the same biosynthetic pathway as the enzyme HMG-CoA reductase but lies upstream along the path. The inhibition of ACLY decreases cholesterol synthesis, upregulating LDL receptors, which is associated with increased liver LDL uptake and decreased LDL-C levels in serum.^10,11 Pinkosky et al. demonstrated that the drug also activates the hepatic AMP kinase pathway. AMP kinase inhibits the rate limiting enzymes of fatty acid pathway and cholesterol pathway. Bempedoic acid targets more than one pathway in lowering cholesterol levels ¹² and it is associated with significant improvements inflammatory markers.

Another new option is inclisiran, a first-in-class, cholesterol-lowering small interfering RNA (siRNA) targeting PCSK9 mRNA and conjugated to triantennary N-acetylgalactosamine carbohydrates (GalNAc). Specific binding of the GalNAc ligand to asialoglycoprotein receptors (ASGPR) enables targeted uptake of inclisiran into hepatocytes. ¹² Following uptake into hepatocytes, the antisense strand of inclisiran is integrated into the RNA-induced silencing complex, directing the catalytic breakdown of PCSK9 mRNA and preventing PCSK9 translation. In vitro, inclisiran delivered into HeLa and Hep3B cells, inhibits PCSK9 synthesis and increases the recycling and expression of LDL-C receptors on the hepatocyte surface, increasing LDL-C uptake and reducing circulating levels.^1,13 In clinical trials, twice-yearly injections of inclisiran (after initial doses at days 1 and 90) approximately halved LDL-C levels in subjects with, or at high risk of developing, atherosclerotic cardiovascular disease (ASCVD) who had hypercholesterolemia.

The vast majority of subjects at highest risk CVD fail to achieve the recommended LDL concentrations with statin monotherapy and require additional therapies.

We present the clinical case of a 62-year-old man living with HIV and dyslipidemia in whom new hypolipidemic drugs were fundamental in achieving adequate LDL values to prevent cardiovascular events. He has been affected by HIV since 1999 and it was necessary to modify multiple cART lines due to virological failure: AZT + 3 TC + ABC, TDF + FTC + EFV, TDF + FTC + LPV/R and the last with TAF + FTC + DRV/c. He was already on hypolipidemic therapy with pravastatin 20 mg and ezetimibe 10 mg, with 29.4% Framingham Risk Score and 67.6 % D:A:D risk score. Despite failure to reach the target, the patient does not tolerate other statins (muscle pain). An episode of NSTEMI in March 2023 complicated the clinical course. To reduce LDL values, the previous therapy was suspended with the introduction of atorvastatin 80 mg and ezetimibe 10 mg. The onset of severe myalgias in the lower extremities, led to a further therapeutic switch and rosuvastatin 10 mg + ezetimibe 10 mg were introduced. The patient never reached the LDL target goal and did not tolerate statins, so we decided to try bempedoic acid/ezetimibe combination therapy. One month after there was an important change in Framingham and DAD score; however, in order to achieve adequate target values of LDL we decided to add inclisiran. The patient has never developed side effects. After 3 months we recalculate Framingham risk score at 21.6 % and DAD score 40.4%, so we finally achieve target LDL values with contemporary increase in HDL (Table 1). During co-administration the he remained persistently viro-suppressed (Figure 1).

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Table 1.

Framingham risk score and D:A:D score (10 years).

	Feb 2023	Jun 2023	Dec 2023
Age y	62	62	62
Gender	Male	Male	Male
Previous smoker	No	No	No
Smoker	No	No	No
Family CVD history	No	No	No
Diabetes	No	No	No
Abacavir	No
PI exposure y	15	15	15
NRTI exposure y	17	17	17
CD 4+ count cell/mmc	928	1010	1379
Systolic BP mmHg	150	125	125
Total cholesterol mg/dl	162	181	101
HDL cholesterol mg/dl	38	55	37
D:A:D CVD (10 y)	67.6%	54%	40.4%

	Feb 2023	Apr 2023	Jun 2023	Sept 2023	Dec 2023
Gender	M	M	M	M	M
Age y	62	62	62	62	62
HDL cholesterol mg/dl	38	34	55	41	37
Total cholesterol mg/dl	162	164	181	174	101
Smoker	No	No	No	No	No
Systolic BP mmHg	150	130	125	150	125
BP therapy	Yes	Yes	Yes	Yes	Yes
Diabetes	No	No	No	No	No
FRAMINGHAM RISK SCORE (10 y)	29.4%	25.3	21.6	29.4	21.6

These drugs represent new avenues for prevention and treatment of cardiovascular disease. The main limitation of literature’s meta-analysis is related to the relatively small number of patients involved in the studies, which were often short or middle term, as well as their heterogeneity, including different populations that were investigated. Therefore, there are currently no experiences or studies on these new drugs for reducing cholesterol in PLWH.

To this it must be added that antiretroviral therapies often interfere with other drugs and therefore new therapies are only used later in the HIV population.OPEN IN VIEWER

This is the first report on the use of bempedoic acid and inclisiran in a PLWH which shows how the new options are well suited to the population and represent a valid option to reach therapeutic targets.

This report shows how studies in PLWH and bempedoic acid and inclisiran are urgently needed.