The VA is the largest provider of HIV care in the United States. VA patients with HIV are also older and have more comorbidities than do other populations of patients with HIV. Cardiovascular disease and co-infection with hepatitis C virus (HCV) complicate the care for HIV and make management decisions regarding antiretroviral and anti-viral treatments especially complex.
This study evaluated cardiovascular risk from specific Anti-Retroviral Therapy (ART) medications used to treat HIV positive Veterans seeking care in the Veterans Health Administration. Certain antiretroviral medications for HIV have been implicated in increasing risk of cardiovascular disease. However, antiretroviral drugs are typically prescribed in combination.
The study also compared the liver disease and mortality outcomes in Veterans co-infected with both HCV and HIV relative to infection by HCV alone, comparing outcomes between persons who had successful treatment, treatment that was not successful, and in those still waiting for treatment to become available. We considered how poor HIV viral control affects outcomes in those with dual infection.
We determined the cardiovascular risks from ART using data from the VA clinical case registry (CCR). We identified Veterans with HIV infection, the specific antiretroviral regimens that they received, their cardiovascular risk factors, and their cardiovascular events, including heart attacks, strokes, and cardiac interventions: percutaneous coronary intervention and coronary artery bypass surgery. We created a time-varying repeated measures data set included information on ART exposure, cardiovascular risk, and events. Since ART treatments were not randomly assigned estimates of cardiovascular risk could be subjected to confounding by indication. We used a statistical method, the Marginal Structural Model, to control for confounding by indication. This method uses analytic weights simulate a randomized clinical trial. We applied this method to determine if there was an association of current exposure to antiretroviral drug combinations and cardiovascular events.
We determined liver disease and mortality outcomes using data from the VA Corporate Date Warehouse. We identified Veterans with HCV infection who received care from VA during the 5 years ending on 9/30/2014 and extracted results of laboratory tests to determine the FIB4, a non-invasive marker of liver disease. We included veterans who had necessary testing to determine the FIB4 on at least two different dates. We obtained pharmacy data to determine if they received HCV treatment and laboratory data to determine HCV and HIV viral loads.
Cardiovascular risk component. We analyzed data from 24,510 patients infected with HIV from January 1996 through December 2009 and assessed the association of current exposure to 15 antiretroviral drugs and 23 pre-specified combinations of agents on the risk of cardiovascular event by using marginal structural models. Traditional Cox models were also used estimate time-to-event associated with drug exposure. Over 164,059 person-years of follow-up, 934 patients had a cardiovascular event. Current exposure to abacavir, efavirenz, lamivudine, and zidovudine was significantly associated with increased risk of cardiovascular event, with odds ratios ranging from 1.40 to 1.53. Five combinations were significantly associated with increased risk of cardiovascular event, all of which involved lamivudine. One of these - efavirenz, lamivudine and zidovudine -- was the second most commonly used combination and was associated with a risk of cardiovascular event that is 1.60 times that of patients not currently exposed to the combination (OR=1.60, 95% CI: 1.25-2.04).
HCV dual infection component: There were 186,749 persons with chronic HCV infection who had two FIB4 scores in the study time frame. The cohort included 12,002 (6.4%) with who had HIV co-infection. HIV co-infected patients were slightly more like to have received HCV treatment, with treatment rates of 26.3% compared to 24.5% of mono-infected patients who were treated. Sustained viral response rates were somewhat higher in the mono-infected than in the dual-infected. Persons with sustained viral response to HCV treatment had a marked reduction in the risk of FIB4 progression beyond the threshold 3.5, an indicator of the development of cirrhosis. This benefit was nearly equivalent in dual and mono-infected individuals. Among untreated persons, those with dual HIV-HCV infection had significantly higher risk of FIB4 exceeding 3.5 at follow-up, relative to untreated mono-infected individuals. Persons with dual HIV-HCV infection had higher mortality risk than those who were mono-infected with HCV. This risk was especially high among those with HIV virus that was not controlled at either baseline or follow-up.
We determined that HIV positive VA patients exposed to certain anti-retroviral drugs and drug combinations had a modestly increased risk of a cardiovascular event. In situations in which equally effective regimens are available, clinicians may want to consider the potential elevation in risk of cardiovascular events, particularly in patients who are older or who have cardiovascular risk factors.
Patients with HCV who are not yet treated are at greater risk for liver disease and death if they are dual-infected with HIV. Successful HCV treatment reduces the progression of liver disease. This benefit is not reduced by the presence of dual infection.
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