To the Editor:
Hypercholesterolemia after highly active antiretroviral therapy (HAART)-related toxicity in lipid metabolism1 might require treatment with lipid-lowering drugs, such as statins. The risk of hepatotoxicity of statins and their interaction with the hepatic metabolism of protease inhibitors (PIs) at the level of cytochrome P450 have limited their prescription, however, particularly in HIV/hepatitis C virus (HCV)-coinfected patients. The estimated risk of aminotransferase abnormalities with statins is 0.2% to 2.7%, but a more recent analysis did not confirm the statin-related hepatotoxicity in a low-risk population.2 Few data are available about the hepatotoxicity of statins in chronic liver diseases. Recently, Khorashadi et al3 evaluated the incidence of aminotransferase increase in HCV infection, and neither significant hepatotoxicity nor a significant difference between hepatitis C-positive and hepatitis C-negative treated patients was found. To our knowledge, no data have shown the impact on the liver of statin use in HIV/HCV coinfection. The aim of this study was to assess whether statin therapy increased the risk of hepatotoxicity in an HIV-positive/HCV-positive population compared with an HIV-positive/HCV-negative population.
We retrospectively reviewed all HIV-positive patients, followed as outpatients, who had the use of statins included in their clinical history. Two groups of patients were compared: group A included patients with HIV/HCV coinfection, as defined by HCV RNA positivity, who started statin therapy at least 6 months after diagnosis of hepatitis C, and group B consisted of HIV-positive, HCV/hepatitis B virus (HBV)-negative subjects also starting statin therapy. Patients with alcohol abuse or concomitant hepatotoxic medications other than antiretrovirals and patients on anti-HCV treatment were excluded.
We considered as significant an increase of liver function test (LFT) results ≥1.5 the baseline values (defined as the mean of 3 consecutive controls within 6 months before the introduction of a statin) or if results were above the upper limit of normal for those with normal values at study entry.
Demographic data and laboratory test results were collected at baseline. LFT results obtained 6 months after initiation of statin therapy were considered for the analysis. We registered the type of statin and any other concomitant medication, particularly antiretroviral drugs. Quantitative HCV RNA (branched DNA; Siemens Medical Solutions USA) was collected when available.
Statistical analysis was performed using the χ2 or Fisher exact test, and distributions of continuous variables were compared using the Mann-Whitney test for independent samples. All tests were 2-sided, with 5% type I error (α).
Among the 1421 HIV-1-infected patients currently referred to our clinic, 80 patients who have been treated with statin therapy for hypercholesterolemia were included: 38 patients in group A (HIV positive/HCV positive) and 42 patients in group B (HIV positive/HCV negative). A total of 76.2% of patients were male, and the median (25th to 75th percentiles) age was 45.5 (42 to 54) years, with a significant difference between the 2 groups (P = 0.0006 and P = 0.001, respectively), because a higher percentage of patients in group A were male and younger. Baseline median LFT results were significantly higher in group A (alanine aminotransferase [ALT]: 49.5 vs. 27 IU/L, P = 0.0006; gamma-glutamyl transferase [GGT]: 72 vs. 40 IU/L in groups A and B, respectively, P = 0.006). The overall mean ± SD value of the CD4+ count was 556.4 ± 259.6 cells/μL, and the median HIV level (25th to 75th percentiles) was 50 (50 to 80) copies/mL without significant differences between groups.
The most frequently prescribed statin was atorvastatin (63.7%), followed by pravastatin (28.7%), rosuvastatin (5%) and simvastatin (2.5%), without a significant difference between the 2 groups. The distribution of antiretroviral regimens was also similar, with 36 patients (45%) taking 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus 1 PI, 39 patients (48.7%) taking 2 NRTIs plus 1 non-nucleoside reverse transcriptase inhibitor (NNRTI), and 5 patients (6.2%) taking no antiretroviral drugs. HCV RNA quantification and genotyping were available for 24 patients with HCV RNA median values (25th to 75th percentiles) of 1,702,027 (910,458 to 2,778,835) IU/mL and for 15 patients harboring genotype 1, 8 with genotype 3, and 1 with genotype 2.
As shown in Figure 1A, the fold change of liver enzymes was low in both groups of subjects, with no significant difference. No difference in the percentage of patients developing an increase in aspartate aminotransferase (AST), ALT, or GGT ≥1.5 baseline level emerged between groups A and B (see Fig. 1B): 7.9% versus 4.8% for AST, 7.9% versus 14.3% for ALT, and 15.8% versus 14.3% for GGT in groups A and B, respectively (P = not significant [NS]). The higher increase of GGT (from 50 to 158 IU/L and from 74 to 118 IU/L in groups A and B, respectively) was observed in 2 patients in group A, who were both taking simvastatin. None of the patients discontinued statins because of liver toxicity or modified their antiretroviral regimen because of drug interaction.
Interestingly, overall percentages of 40%, 42.5%, and 37.5% of patients underwent a reduction in LFT values (AST, ALT, and GGT, respectively) after statin introduction. The median percentage (25th to 75th percentiles) reductions in AST, ALT and GGT were −18% (−0.4 to −26), −28% (−0.9 to −47), and −19% (−1.3 to −23), respectively, in group A and −25% (−1 to −33), −20% (−11 to −34), and −18% (−0.9 to −26), respectively, in group B, without a significant difference between the 2 groups and with no correlation with cholesterol reduction. Furthermore, no correlation was found between PI or NNRTI including HAART or between the statin used, with respect to LFT result increase from baseline, although a trend emerged for GGT (P = 0.059), because both patients taking simvastatin had a marked increase in GGT. We found a positive correlation between patients who underwent a reduction in ALT and those with higher baseline values of ALT. In the 18 patients in group A with a reduction of ALT while on statin therapy the a median (25th to 75th percentile) baseline ALT value was 70.5 IU/L (50 to 110) compared with 31 IU/L (22 to 57) of the 20 subjects with ALT increment, (P = 0.0038). Sixteen patients in group B with a reduction in ALT had a baseline median ALT value of 37.5 IU/L (27.5 to 47) versus 21 IU/L (18 to 32) of the 26 who presented ALT increase (P = 0.0007).
Finally, a significant reduction in cholesterol levels was observed (P = 0.01) in both groups.
The Infectious Disease Society of America's guidelines for the management of dyslipidemia in HIV-infected subjects on HAART do not provide any recommendation for the treatment of HCV-coinfected patients,4 who are at a higher risk of hepatotoxicity. Therefore despite the potential usefulness of statins, their use is still debated because of the uncertain risks.
In our experience, statin use in HIV/HCV-coinfected patients showed a low elevation in LFT values. Only 7.9% of coinfected patients on statin therapy experienced an increase in ALT ≥1.5 times the baseline values, which was lower than that observed in the HCV-negative group. Furthermore none of our patients demonstrated an increase in liver enzymes ≥3 times the upper limit of normal, as set by the American Heart Association5 for dose reduction or statin suspension.
The PI inhibition of the cytochrome P450-CYP3A4, resulting in an increase in statin area under the curve (AUC), may account for the major increase of GGT observed in 2 subjects treated with simvastatin.
Recently, Khorashadi et al3 found an association between statin therapy and the reduction of median LFT values in patients with hepatitis C. In a percentage of our HIV-infected patients, we also observed an improvement in the median LFT values but without a difference between HCV-positive and HCV-negative patients. Recent reports showed a promising effect of statins in reducing aminotransferases in nonalcoholic fatty liver disease (NAFLD).6 The hypothesis that treatment of hyperlipidemia may improve LFT abnormalities attributable to NAFLD might partially explain our results, considering that HCV and HIV infections as well as the use of antiretrovirals favor the emergence of nonalcoholic steatohepatitis, although we did not find a correlation between a reduction in LFT results and cholesterol improvement. Another intriguing hypothesis is that statins may modulate immune response by induction of anti-inflammatory activity.7,8 Patients with HIV-1 or HIV/HCV coinfection demonstrate a chronically activated inflammatory response with high levels of circulating inflammatory cytokines; moreover, liver inflammation is enhanced by HAART-related chronic toxicity. The anti-inflammatory activity of statins may account for the amelioration of LFT results in both groups, with the correlation found between patients with a decrease in ALT and higher values of ALT at baseline possibly expressing liver inflammation.
Our results suggest that the use of atorvastatin, pravastatin, and rosuvastatin is safe in HIV and HIV/HCV-coinfected patients with hypercholesterolemia.
Laura Milazzo, MD*
Barbara Menzaghi, MD*
Stefano Corvasce, PhD*
Paolo Bonfanti, MD†
Stefano Rusconi, MD*
Anna Lisa Ridolfo, MD*
Spinello Antinori, MD*
*Department of Clinical Sciences University of Milan L. Sacco Hospital Milan, Italy
†First Division of Infectious Diseases L. Sacco Hospital Milan, Italy
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