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ECG Abnormalities With PIs Versus NNRTIs in SMART Trial
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50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
People taking a protease inhibitor (PI) with or without ritonavir boosting had an increased electrocardiographic (ECG) PR interval duration compared with people taking a nonnucleoside (NNRTI) in the SMART trial [1]. A PR interval longer than over 0.2 sec may indicate first-degree heart block. Use of boosted PIs was associated with shorter QTc intervals than use of NNRTIs; QTc prolongation has been tied to higher rates of sudden cardiac death in the general population.
SMART randomized HIV-infected people to continuous antiretroviral therapy or to treatment interruptions guided by CD4 counts. Cardiovascular disease incidence proved significantly higher in the treatment interruption group [2], as did the risk of death from cardiovascular disease [3]. Because case series and single-site studies have yielded conflicting results on PI use and QTc and PR prolongation, the SMART team assessed these rhythm abnormalities in people taking a PI versus an NNRTI, and in people who interrupted treatment versus those on continuous therapy. SMART had a standardized ECG collection methodology and centrally automated ECG readings.
The analysis involved 3719 SMART trial participants, 1879 of whom (50.5%) took CD4-guided drug breaks. There were 1821 people taking an NNRTI (with no PIs), 742 taking an unboosted PI, 548 taking lopinavir/ritonavir, 236 taking saquinavir/ritonavir, 188 taking atazanavir/ritonavir, and 184 taking another ritonavir-boosted PI. SMART investigators calculated heart rate-correct QT (QTc) using Bazett's formula (QTcB) and Frederica's formula (QTcF).
When patients entered SMART, average QTcB, QTcF, and PR durations were 415 msec, 406 msec, and 158 msec. After statistical adjustment for baseline risk factors, QTcB and QTcF duration did not differ significantly between any of the boosted PI groups. But for anyone taking a boosted PI, QTcB was an average 1.5 msec lower than people taking an NNRTI (P = 0.04).
Both boosted and unboosted PI regimens were significantly associated with longer PR intervals than were NNRTI regimens (P < 0.01 for each comparison). After statistical adjustment for age, gender, race, nucleoside backbone, and an array of cardiovascular risk factors, the average PR interval was 5.11 msec longer for boosted PIs versus NNRTIs (P < 0.001) and 3.00 msec longer for unboosted PIs versus NNRTIs (P < 0.01).
After treatment interruption in SMART, PR duration dropped significantly in people who had been taking either a boosted or an unboosted PI compared with people who continued taking a boosted or unboosted PI regimen. PR duration declined significantly 24 months after interruption of a boosted PI (P < 0.01).
The SMART investigators concluded that various PI-based regimens have a similar, minimal effect on QTc compared with NNRTI-based combinations. Both boosted and unboosted PIs were associated with PR interval prolongation, and suspending PI treatment reduced the prolonged PR duration. The SMART team cautioned that further study, preferably a randomized trial, is needed to confirm these findings.
References
1. SMART/Insight Study Group, Soliman EZ, Lundgren JD, Duprez DA et al. Associations between protease inhibitors and QTc and PR interval durations in the strategies for management of antiretroviral therapy (SMART) trial. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-218.
2. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.
3. Phillips AN, Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther. 2008;13:177-87.
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