Waters, Laura MRCP; Stebbing, Justin MA, MRCP, PhD; Jones, Rachael MRCP; Mandalia, Sundhiya PhD; Bower, Mark MRCP, PhD; Stefanovic, Milena MRCP; Nelson, Mark MD, MRCP; Gazzard, Brian MD, MRCP
Department of HIV Medicine, The Chelsea and Westminster Hospital, London, England
To the Editor:
Hyperlipidemia is an established risk factor for cardiovascular disease1 and is common in HIV-infected individuals receiving antiretroviral therapy.2,3 Highly active antiretroviral therapy (HAART) has been independently associated with an abnormal lipid profile, particularly when a protease inhibitor (PI) and nucleoside reverse transcriptase inhibitors (NRTIs) are used together, whereas evidence for a related increase in cardiovascular events associated with HAART-related dyslipidemia has been conflicting.4,5
Although effective at lowering lipids in HIV-infected individuals, statins may interact with a number of antiretroviral agents, the PI class in particular.6-8 Other effects of statins reported include an immunomodulatory action via an inhibitory effect of major histocompatibility class II expression, inhibition of monocyte adhesion.9 It has also been suggested that statins may influence HIV entry, with evidence from cell culture studies, animal models, and a small clinical trial.10-12 One recent study revealed a benefit with respect to CD4 cell count and HIV viral load when lovastatin was used in 6 patients not receiving HAART, with a corresponding viral load increase when the statin was stopped.11 The proposed mechanism here suggested that statins, as well as inhibiting hydroxymethylglutaryl (HMG) coenzyme A (CoA) reductase, act on Rho guanosine triphosphatase, blocking the intracellular production of Rho protein, and interfere with virus entry into and exit from host cells.
Because most individuals who receive statin therapy in the HIV setting are receiving HAART, we investigated the effect of statins on HIV viral load suppression in an HIV-positive population receiving HAART.
Using the prospective database from the Chelsea and Westminster Hospital, London, we identified all patients within our cohort who commenced antiretroviral therapy during the HAART era (defined as January 1, 1996 to the time of data extraction on September 18, 2003). HAART was defined as a triple-therapy treatment regimen in accordance with published guidelines.13
We identified all patients who had commenced any statin during first-line HAART. This group was compared with those on first-line HAART who had never received any statin. To assess any virologic impact of statins, we compared the rate of viral load rebound (defined as a viral load >500 copies/mL, having achieved <500 copies/mL before this) and blips (defined as a viral load <500 copies/mL, followed by a viral load of >500 copies/mL and then a viral load of <500 copies/mL). We analyzed patients who were stable on HAART, defined as having been on first-line therapy for 3 or more months. Data are presented as the proportion with 95% confidence intervals.
Of 1521 patients who commenced first-line HAART for at least 3 months since 1996, all had a viral load >500 copies/mL at the start of therapy. Of these, 78 patients had commenced a statin once stable on HAART.
Table 1 illustrates the rate of viral rebound and proportion of patients experiencing viral blips in the statin and nonstatin groups. In this small cohort, we observed no statistically significant difference between viral load rebound and blips in patients on stable first-line HAART who did and did not receive a statin.
We found no difference with respect to suppression of virologic response to HAART between the statin and nonstatin groups (see Table 1). A recently published study demonstrated that lovastatin has a beneficial virologic effect in stable HIV-infected patients not on HAART.11 These effects were small (only 1 patient had a greater than 1 log10 reduction in viral load), and the statistical significance of the changes was not reported. This study also presented evidence that statins can prevent HIV infection in cell cultures and in animal models. The 6 patients in this study were not on HAART and had stable viral loads, ranging from 16,800 to 84,000 copies/mL. Our study examined the impact of statin therapy on response to HAART, and in this era, when most patients achieve full viral suppression with their first-line therapy, any small effect of non-HAART medication would be difficult to detect, thus illustrating the importance of measuring blips.
HAART is associated with long-term toxicities, and an increase in the risk of cardiovascular events has been a major concern. Delaying the initiation of therapy to reduce drug-related adverse events has to be balanced against potential disadvantages such as the increased risk of adverse events when HAART is commenced at lower CD4 cell counts.14,15 For most patients commencing HAART, the goal of therapy is to suppress viral replication fully, and, importantly, we did not demonstrate any reduction in viral rebound or frequency of viral blips when statins were used in combination with HAART.
Overall, in our small cohort of HAART-treated individuals on statin therapy, there seems to be no influence on the rate of viral blips or viral rebound. Larger studies with a longer duration of follow-up and studies in patients with detectable viremia receiving and not receiving HAART are necessary to determine any real viral effect of statins and whether this confers any measurable benefit or harm to patients.
Laura Waters, MRCP
Justin Stebbing, MA, MRCP, PhD
Rachael Jones, MRCP
Sundhiya Mandalia, PhD
Mark Bower, FRCP, PhD
Milena Stefanovic, MRCP
Mark Nelson, MD, MRCP
Brian Gazzard, MD, FRCP
Department of HIV Medicine The Chelsea and Westminster Hospital London, England
1. Stamler J, Daviglus ML, Garside DB, et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA
2. Martinez E, Tuset M, Milinkovic A, et al. Management of dyslipidaemia in HIV-infected patients receiving antiretroviral therapy. Antivir Ther
3. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med
4. Kannel WB, Giordano M. Long-term cardiovascular risk with protease inhibitors and management of the dyslipidemia. Am J Cardiol
5. Carpentier A, Patterson BW, Uffelman KD, et al. Mechanism of highly active anti-retroviral therapy-induced hyperlipidemia in HIV-infected individuals. Atherosclerosis
6. Chuck SK, Penzak SR. Risk-benefit of HMG-CoA reductase inhibitors in the treatment of HIV protease inhibitor-related hyperlipidaemia. Expert Opin Drug Saf
7. Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase inhibitors for treatment of hyperlipidemia in patients with HIV infection. Pharmacotherapy
8. Penzak SR, Chuck SK. Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment. Scand J Infect Dis
9. Fehr T, Kahlert C, Fierz W, et al. Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis
10. Mach F. Toward a role for statins in immunomodulation. Mol Interv
11. del Real G, Jimenez-Baranda S, Mira E, et al. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med
12. Giguere JF, Tremblay MJ. Statin compounds reduce human immunodeficiency virus type 1 replication by preventing the interaction between virion-associated host intercellular adhesion molecule 1 and its natural cell surface ligand LFA-1. J Virol
13. Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA
14. Ho DD. Time to hit HIV, early and hard. N Engl J Med
15. Portsmouth S, Stebbing J, Gazzard B. Current treatment of HIV infection. Curr Top Med Chem
© 2005 Lippincott Williams & Wilkins, Inc.