We identified a large cohort of persons with exposure to PIs. Just more than 200 of these persons were exposed to combined therapy with PIs and statins. Our data show that rates of combined use of statins with PIs were increased in the TennCare population during 2001 through June 2002 compared with the previous 4 years.
Use of combinations of PIs and statins with the greatest potential for adverse effects decreased significantly in the latter period after preliminary guidelines were published. The relative rate of inappropriate combination therapy remained high, however, with 1 in every 5 persons treated with a PI and statin between January 2001 and June 2002 receiving a contraindicated combination. Potential reasons for continued prescribing of these drug combinations include lack of knowledge of potential drug-drug interactions and/or practice guidelines, the relative rarity of toxicities, the limited in vivo data characterizing these interactions and their effects, and other factors that contribute to guideline nonadherence by health care providers.27,28
A possible confounder of prescribing is the effect of formulary restrictions during the study. During the course of the study, more than 10 managed care organizations (each with its own formulary, which was modified frequently) were part of the TennCare program; thus, the impact of formulary restrictions cannot be quantified. Throughout the study, however, prior authorization for nonformulary drugs was available and could typically be obtained with submission of a 1-page telefaxed request form. This should have kept formulary restrictions from significantly limiting the use of more appropriate drug combinations, especially in the setting of potential drug-drug interactions.
There are several limitations of our study. We used antiretroviral prescriptions as a surrogate for HIV infection. Although it is possible that this resulted in misclassification, we believe this to be unlikely. Combination ART is only indicated for treatment of HIV infection and has no other use except as postexposure prophylaxis (PEP) after possible exposure to HIV. Recommended PEP treatment is generally for 28 days; thus, it is highly unlikely that a patient with a second filled prescription >30 days after the first would be incorrectly identified as having HIV. Furthermore, in the case of a health care-related exposure, PEP is provided by the employer; thus, it would not appear in our pharmacy database. Persons receiving monotherapy with either of the 2 antiretroviral medications used to treat chronic active hepatitis B infection in HIV-negative individuals were also excluded. We therefore believe that the use of multiple antiretroviral prescriptions is a highly sensitive and specific method of identifying HIV-infected persons receiving treatment in the TennCare program. Obviously, this method does not allow for identification of untreated persons with HIV infection, but this population was not necessary to address our question.
As with any study of this type, there are limitations in generalizability. A recent study examined prescribing patterns in the California Medicaid HIV-infected population and found a 6-fold increase in lipid-lowering drug use in PI-treated persons from 1996 to 2000, from 1.7% to 10.6%.29 Although that study did not characterize specific drug combinations, overall rates of PI-statin prescribing in California were comparable with our results, and simvastatin and lovastatin were the third and fourth most frequently prescribed statins in their HIV population. We believe our findings corroborate these data describing PI and statin use in a demographically and geographically distinct patient population.
We acknowledge that the use of guideline publication as the point of transition between study periods is artificial. It is likely that there were changes during the study period that influenced prescribing practice and were unrelated to the guidelines. Nevertheless, the initial guidelines in 2000 were the first time that emerging data and treatment recommendations regarding PI-statin interactions were made widely available within the HIV health care community. From a public health perspective, the most important question is not the magnitude of effect of the guidelines, per se. Rather, it is the extent to which prescribing of a potentially harmful drug combination decreased over time, regardless of what influenced these changes.
Our results are also limited by the fact that TennCare enrollees make up only a proportion, albeit a substantial proportion, of HIV-infected persons in Tennessee. TennCare currently includes 1,400,000 covered lives (26% of state's population). As of 1997, 43% of persons in Tennessee infected with HIV and 54% of those with AIDS had enrollment in TennCare programs for at least 1 day. Thirty-four percent and 44%, respectively, were enrolled for more than 320 days.30
Knowledge about the epidemiology of PI-associated hyperlipidemia and the role of ART and PIs in contributing to cardiovascular disease in HIV-infected persons is evolving. Early studies attempting to find an association between treatment with PIs, lipid abnormalities, and adverse cardiovascular events in patients with HIV reported conflicting results.31-34 More recent data have shown a modest but statistically significant increased risk of myocardial infarction in persons on combination ART35 and in those with ≥18 months of PI exposure36 as well as an increased risk of any first cardiovascular event in patients aged 35 to 65 years with more than 1 year of PI exposure.37 At least some of this excess risk is believed to be a result of PI-associated hyperlipidemia. Additionally, a preliminary report from the first large-scale, randomized, controlled trial of lipid-lowering therapy in HIV-infected subjects, AACTG study 5087, suggested that single-agent therapy was not effective in achieving NCEP guidelines in HIV-infected patients with mixed hyperlipidemia.38 Only patients on dual therapy with pravastatin and fenofibrate were able to meet composite NECP goals. Recently approved39,40 and future PIs may have more favorable effects on lipids, but as the HIV-infected population lives longer and ages along with the general population, use of lipid-lowering drugs in persons receiving PIs is likely to increase.
Current recommendations are that persons on HIV therapy be routinely screened for dyslipidemia and treated according to NCEP guidelines for non-HIV-infected persons.3 Based on estimates of prevalence and incidence of hyperlipidemia caused by PIs, the rates of statin use among PI users in the TennCare population seems to be low. This may be a result of low screening rates and/or low treatment rates. Korthuis et al41 have recently reported lipid screening rates of <60% among HIV infected veterans receiving PIs. Our study was not designed to address questions of provider adherence to screening guidelines and/or appropriate responses to such screening. Future studies should examine these rates in TennCare and other cohorts.
Because we were unable to assess clinical events caused by the use of contraindicated PI-statin combinations, we cannot comment on the clinical implications of such use. Even with limited data on the clinical implications, however, the available evidence provides a rationale for the most appropriate clinical practice. Statins known to have more favorable pharmacokinetics are available and effective. Thus, any use of drugs within the same class having even the theoretic potential for dangerous interactions should be unnecessary, especially when the intervention is for primary prevention. Although prescribing in the TennCare population seems to have improved in response to practice guidelines, continued education of HIV health care providers about the appropriate use of PI-statin combinations is needed.
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