Statin Use in HIV-Positive People
At CROI 2013, statins use in HIV management was the focus of a poster discussion and two late breaker oral presentations.
Most usefully, this poster session included an overview by Steven Grinspoon from Massachusetts General Hospital prior to the main discussion and a summary afterwards by Priscilla Hsue from University of California, San Francisco.
The introduction covered both general population and HIV positive issues. Data on statins comes largely from non-HIV populations where they are widely used to reduce cardiovascular risk by inducing plaque regression and reducing LDL cholesterol. However, the Jupiter study looked at primary prevention in the general population (with normal LDL: men were over 50 and women over 60) and reported clinical benefits based on their anti-inflammatory properties, that were independent of the lipid effect.
In a recent meta analysis of 76 studies in the general population, including >170,000 patients with 14,878 deaths, statin use significantly reduced cardiovascular-related mortality by about 20% and all cause mortality by 10%. Side effects included increased liver enzymes and CPK and were generally mild, but 17 randomised clinical trials reported a 9% increased risk of development of incident diabetes (OR 1.09; 95% CI 1.02-1.17, p=0.001).2
In the Jupiter study, patients had no prior cardiovascular disease and normal LDL (<130 mg/dL) but increased CRP (>2 mg/mL). CVD deaths were reduced by 50% using rosasuvastatin, with a slight reduction in deaths from cancer (0.4% vs 0.7%), but statistically significantly higher rates of new diabetes (3% vs 2.4%) were also reported, with the mechanism for this unknown.3
However, how and when HIV may have an impact on statin use and optimal use of statins in HIV positive people is unclear. While statins are widely recommended for lipid-lowering in HIV management, data in HIV positive people, especially long term safety data, is limited.
A review of the efficacy of lowering LDL in HIV positive people reported broadly similar results to HIV negative studies, even though this was slightly lower in some HIV studies (by approximately 2% less, but statistically significant). Also, although tolerability was good, rate ratios for some of the complications were also slightly (and significantly) higher compared to HIV negative studies.4
Some statins are commonly contraindicated (simvastatin and lovastatin) due to drug-drug interactions with some antiretrovirals and dose adjustment is often required with others.5 While rosuvastatin (10 mg) is more effective than pravastatin (40 mg) at lowering LDL and triglyrcerides in patients on protease inhibitors, drug levels were increased in HIV negative studies using atazanavir/ritoanvir.
Similarly, interesting preliminary data from patients on ART reported survival benefits from comorbidities (relative Hazard Ratio 0.33 (0.14, 0.76), p=0.009) in the 15% of patients on statins.6 Statins may have potential antiretroviral activity and may disrupt CCR5 and RANTES and decrease CCR2 expression in monocytes.
Four posters were also selected for discussion but although these are summarised below, all had methodological issues that highlighted the need for further research.
Line Rasmussen from Odense University Hospital presented results from a Danish observational study of HIV positive people starting ART from 1998 with undetectable viral load within 6 months, and statin use before and after a cormorbidity diagnosis (CVD, renal disease or diabetes mellitus), compared to the general population.7 A reduction in all cause mortality was only reported in patients with diagnosed comorbidities, and only in a censored model when VL >400 copies/mL (adj mortality RR 0.32, 95%CI 0.10-0.99; without censoring aMMR was 0.57, 95%CI 0.28-1.15).
No difference was seen without a comorbidity diagnosis. However, this was a retrospective study and statin prescription is likely to have been for a clinical indication (suggesting confounding factors), suggesting that the beneficial impact in this analysis may have been underestimated.
Henning Drechsler from the University of Texas Southwestern Medical Centre reported on the impact of statins on mortality and non-AIDS complications in >25,000 patients on ART in the Veteran's Association (VA) cohort, stratifying by virological suppression and choice of statin.8
Approximately 35% of patients used statins. There were 6435 deaths during a median follow up of 6.3 years (>25,000 PY). There were also 2199 cardiovascular events (acute myocardial infarction and cerebrovascular accident), 5011 malignancies, 3196 cases of chronic kidney disease (CKD), and 610 fragility fractures.
Adjusted multivariate analysis showed significant reductions in deaths with statin use, irrespective of viral suppression but with a greater benefit in patients using atorvastatin or rosuvastatin but no effect was seen on CVD (which was inexplicably increased), malignancy or fracture outcomes. As with the Danish study, confounding by clinical indication was suggested for the lack of effect seen in these results. The lack of mortality data in the VA cohort limited further understanding of the cause of death.
Vincenzo Spagnuolo from the San Raffaele Hospital, Milan, presented a retrospective longitudinal data on the incidence of Type-2 diabetes mellitus (DM) in 5380 HIV positive patients on ART (n=726 using statins) followed for 9.8 (IQR 4.4-14.9) years.9
Significant differences at baseline included median age of the statin users was slightly older (50.7 vs 45.7 years), with longer use of ART (14.1 vs 9.6 years) and significantly worse lipid profiles.
The overall crude incidence rate (IR) for new DM was 2.82 per 1000 PYFU (95%CI 2.74-2.91). Approximately 14% patients used statins (81% rosuvastain, 18% pravastatin) for a median of 24.4 months (IQR 10.2-42.4). However DM occurred significantly less in 12/726 (1.7%) statin users (IR 1.32; 95%CI 0.68-2.18) compared to 150/4654 (3.2%) not statin users (IR 3.40; 95%CI 2.86-3.95); p = 0.020.
In multivariate analysis, older age, higher BMI, basline triglycerides and glucose and prior use of d4T or ddI were all significantly associated with increased risk of DM, with higher CD4 nadir and statin use being protective. Data on choice of statin and dose were not available.
This study reported very low rates of DM, below general population incidence, but only 5% of participants had BMI >30 kg/m2. This was raised in the question session, including how DM was diagnosed.
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