High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial

Abstract

Background: 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) exhibit antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro and may modulate the immune response to HIV infection. Studies evaluating the antiviral activity of statins have yielded conflicting results.

Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial to investigate the effect of atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4-6 week washout phase, participants switched treatment assignments. The study had 80% power to detect a 0.3 log(10) decrease in HIV-1 RNA level. Expression of CD38 and HLA-DR on CD4(+) and CD8(+) T cells was used to measure immune activation.

Results: Of 24 randomized participants, 22 completed the study. Although HIV-1 RNA level was unaffected by the intervention (-0.13 log(10) copies/mL; P = .85), atorvastatin use resulted in reductions in circulating proportions of CD4(+) HLA-DR(+) (-2.5%; P = .02), CD8(+) HLA-DR(+) (-5%; P = .006), and CD8(+) HLA-DR(+) CD38(+) T cells (-3%; P = .03). Reductions in immune activation did not correlate with declines in serum levels of low-density lipoprotein cholesterol.

Conclusions: Short-term use of atorvastatin was associated with modest but statistically significant reductions in the proportion of activated T lymphocytes.

Figure 1.

Decreases in CD8⁺ HLA-DR⁺ T lymphocytes during atorvastatin therapy. Each square and triangle represents changes in the proportion of circulating CD8⁺ HLA-DR⁺ T cells in an individual patient (week 8 – week 0) during the atorvastatin and placebo phases of the study, respectively, while the line represents the median change for the group. Response to atorvastatin was heterogeneous, with most participants (15 of 22) exhibiting a decline. In comparison, participants receiving placebo demonstrate a clustering around the median.

Figure 2.

Correlation between the changes in plasma human immunodeficiency virus type 1 (HIV-1) RNA levels and change in the proportion of circulating CD8⁺ HLA-DR⁺ cells. Changes in panel A reflect the difference of the changes (week 8 – week 0) during the statin phase and (week 8 – week 0) during the placebo phase. Change was calculated for both HIV-1 RNA and proportion of CD8⁺ HLA-DR⁺ T cells using the formula (XFS – XIS) – (XFP – XIP), where X is the measure of the outcome (ie, percentage of CD8⁺ HLA-DR⁺ T cells or HIV-1 RNA level) at either the initial visit (I) (week 0) or the final visit (F) (week 8), while the participant was receiving either atorvastatin (S) or placebo (P). P values are calculated using the Spearman rank correlation. B, Correlation between the changes in plasma HIV-1 RNA levels and change in the proportion of circulating CD8⁺ HLA-DR⁺ cells (analysis restricted to the statin phase). Changes in Panel B reflect changes restricted to the atorvastatin (week 8 – week 0) phase of the study. P values are calculated using the Spearman rank correlation. C, Correlation between the changes in plasma HIV-1 RNA levels and change in the proportion of circulating CD8⁺ HLA-DR⁺ cells. Changes in Panel C reflect changes restricted to the placebo (week 8 – week 0) phase of the study. P values are calculated using the Spearman rank correlation.

Figure 3.

A, Correlation between change in plasma human immunodeficiency virus type 1 (HIV-1) RNA levels and change in serum low-density liproprotein (LDL) cholesterol levels. Change in Panel A reflects the difference of the changes during the atorvastatin phase and those during the placebo phase. Change was calculated for both HIV-1 RNA and serum LDL cholesterol levels using the formula (XFS – XIS) – (XFP – XIP), where X is the measure of the outcome (ie, LDL cholesterol or HIV-1 RNA level) at either the initial visit (I) (week 0) or the final visit (F) (week 8), while the participant was receiving either atorvastatin (S) or placebo (P). P values are calculated using Spearman rank correlation. B, Correlation between the changes in the proportion of circulating CD8⁺ HLA-DR⁺ cells and change in serum LDL cholesterol level. Change in this panel reflects the difference of the changes during the atorvastatin phase and the placebo phase. Change was calculated for both serum LDL cholesterol and proportion of CD8⁺ HLA-DR⁺ T cells using the formula (XFS – XIS) – (XFP – XIP), where X is the measure of the outcome (ie, CD8⁺ HLA-DR⁺ T cells or serum LDL cholesterol level) at either the initial visit (I) (week 0) or the final visit (F) (week 8), while the participant was receiving either atorvastatin (S) or placebo (P). P values are calculated using the Spearman rank correlation.