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Statin drugs decrease progression to cirrhosis in HIV/HCV co-infected individuals.
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AIDS Aug 2016 Oliver, Nora T.; Hartman, Christine M.; Kramer, Jennifer R.; Chiao, Elizabeth Y.
Published Ahead-of-Print
Introduction: Chronic HIV/HCV co-infection carries increased risk of cirrhosis, hepatocellular carcinoma, and death. Due to anti-inflammatory properties, HMG co-A inhibitors (statins) may be useful adjunctive therapy to reduce liver disease progression. Methods: Clinical information was extracted from the Veterans Affairs HIV and HCV Clinical Case Registries (1999 - 2010). HIV-related variables included combination anti-retroviral therapy (cART) era of diagnosis, CD4 cell count, and percent time with undetectable HIV viral load. Metabolic variables included diabetes, low-HDL, and hypertension. Statin use was measured as percent time with active prescription (time-updated throughout the follow-up period). Cox proportional hazards analysis was used to determine risk factors for cirrhosis (ICD-9 or APRI>2) overall and in groups stratified by alanine aminotransferase (ALT) level above and below 40 IU/L.
Results: The cohort included 5985 HIV/HCV co-infected veterans. The majority was black race, and the mean age at index date was 45 years. Statin use was significantly protective of cirrhosis for patients with ALT <=40 IU/L; for every 30% increase in time on statin, there was a 32% decreased risk of developing cirrhosis (HR 0.68, 95% CI 0.47 -0.98). Diabetes and low-HDL were significantly associated with cirrhosis in patients with ALT > 40 IU/L (HR 1.15, p < 0.04 and HR 1.3, p < 0.0001).
Conclusions: Statin drug use is beneficial in mitigating the risk of liver disease progression for HIV/HCV co-infected patients without advanced liver disease. Low-HDL and diabetes in co-infected patients with abnormal ALT have greater risk of cirrhosis development.
Although successful treatment of HCV with direct acting antivirals (DAAs) plays an important role in reducing the risk of ESLD, HCC and mortality compared to those without, [19] cost and other barriers to therapy limit access to these medications for many patients. In addition, there is a residual risk for development of HCC after sustained viral response from DAAs for HCV in patients with cirrhosis. [20] Thus, utilizing other strategies to decrease the risk of ESLD and cirrhosis, including the use of medications that inhibit HMG-CoA reductase(statins) as adjuncts in care for patients with chronic liver disease and HIV are needed. Statins' pleotropic properties including their immunomodulatory, anti-inflammatory, and antineoplastic traits are thought to be beneficial in chronic disease states beyond their primary cardio-protective utility.[21, 22]
Patients who developed cirrhosis were significantly less likely to receive cART (79.5%) and less likely to have CD4 >350 cells/μL (48.9%) compared to those without cirrhosis (85.7% and 59.2%, respectively). HIV viral load was suppressed in over 80% of the time; this was significantly less in the patients with cirrhosis compared to the patients without cirrhosis (19.8% v 29%, p < .0001)
For the metabolic risk factors, over one-fifth of the total cohort was obese based on body mass index (BMI) greater than 30 kg/m2. Diabetes was present in about 16% of the total group, and was not significantly different between the patients with and without cirrhosis. Over 50% of the cohort had hypertension and low-HDL, and these features were more prevalent in the patients without cirrhosis compared to those with cirrhosis (60% and 64% compared to 45.6% and 55.6%, respectively). Initial LDL in patients with cirrhosis was 91.2 mg/dL, and at last follow-up it was 84.4 mg/dL. In patients without cirrhosis, index LDL and last-follow-up LDL were 94.4 and 89.4 mg/dL, respectively. Few patients had ever been prescribed statin medications, and prescriptions were significantly lower in the cirrhotic group compared to non-cirrhotic (8% and 20.6%, respectively). Among all patients, statins were prescribed in 12.5% and 21.2% of patients with and without cirrhosis, respectively (p = 0.0001).
In preliminary multivariate analyses, an interaction between ALT and statin use was statistically significant (Supplemental table 1, http://links.lww.com/QAD/A965). Thus, further multivariate analyses were stratified by ALT level to minimize the effect of modification bias of ALT on statin use in the multivariate analyses. In the ALT <40 IU/L group, every 1% time on statin was associated with a decreased risk of cirrhosis (aHR 0.98, 95% CI 0.97-0.99). This translates to a 32% (aHR 0.68, 95% CI 0.47-0.98) reduction in progression to cirrhosis for individuals with >30% time on statins. (Table 2) For patients with ALT >40 IU/L levels, each 1% of time on statins was associated with a non-significant decreased risk of cirrhosis (aHR 0.95, 95% CI 0.9-1). In order to adjust for the competing risk of death, we performed a sensitivity analysis using multivariate hazard regression models excluding patients who died before the diagnosis of cirrhosis or censor. After excluding patients who died before cirrhosis or censor date, we found that every 30% of time on statin was still associated with a significant 35% reduction in cirrhosis progression (95% CI: 0.45-0.95).
In the ALT <40 IU/L group, other metabolic risk factors including diabetes, low-HDL, and hypertension were harmful, but did not significantly impact progression to cirrhosis. Within the ALT >40 IU/L group, diabetes and low-HDL were consistently associated with an increased risk of cirrhosis (aHR 1.15, 95% CI 1.01-1.31 and aHR 1.3, 95% CI 1.2-1.44), respectively. Hypertension was associated with a greater risk of cirrhosis in both groups, but it was not significant. Obesity was found to have a protective effect in both groups, but was only significant in those with ALT >40 IU/L (aHR 0.85, 95% CI 0.76-0.95).
Several demographic and HIV-specific co-variates were significantly related to cirrhosis incidence. Patients over 50 years old with ALT <40 IU/L group were at higher risk for cirrhosis (aHR 2.5, 95% CI 1.54-4.18). Patients with Deyo co-morbidity score of greater than 1 in the ALT <40 IU/L group also increased the risk cirrhosis (aHR 3.23, 95% CI 2.3-4.5). Alcohol use was significantly associated with liver disease progression only in patients with ALT >40 IU/L (aHR 1.15, 95% CI 1.04-1.26). Poor immunological control with CD4 count less than 200 cells/μL conferred greatest risk of cirrhosis in both ALT <40 IU/L and >40 IU/L groups (aHR 2.4, 95% CI 1.8-3.2 and aHR 1.9, 95% 1.71-2.12), respectively. Those patients with > 80% time with an undetectable HIV viral load in both ALT <40 IU/L and >40 IU/L had a significantly lower risk of cirrhosis (aHR 0.72, CI 0.5-1.0, aHR 0.72, CI 0.64-0.8), respectively.
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