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Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations - publication pdf attached
 
 
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AIDS:
POST AUTHOR CORRECTIONS, 9 December 2010
 
"Conclusion: Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI- based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with pro- longation of PR, and interruption of protease inhibitor regimens reduced PR duration. These results should not limit the use of protease inhibitor/ritonavir regimens when indicated, as the clinical relevance of these findings requires further research."
 
Abstract

 
Background: There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown.
 
Methods: This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazett's (QTcB) and Fredericia's (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group.
 
Results: Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P < 0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P < 0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P < 0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P < 0.01).
 
Conclusion: Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.
 
Introduction
 
Despite the known benefits of protease inhibitors, there have been concerns about their potential adverse effects on cardiac conductivity manifested as prolongation of QT and PR interval durations in the standard electrocardio- gram (ECG) [1]. A number of case reports and small single center studies have reported prolongation of QTc and PR in patients receiving protease inhibitors [2-5] but others reported the opposite [6,7].
 
In the past 2 years, the Food and Drug Administration (FDA) has issued warnings that ritonavir-boosted lopinavir (LPV/r) and ritonavir-boosted saquinavir (SQV/r) may cause prolongation of QTc and PR [8,9]. Nevertheless, with the current conflicting reports, it is hard to derive a definitive conclusion about the association between protease inhibitors, especially those boosted with ritonavir, which may enhance the bioavailability of the boosted protease inhibitor [10]. Also, it is not clear whether discontinuation of protease inhibitor-based regimens results in normalization of QTc and PR and how long it takes for these ECG markers to return to normal.
 
The purpose of this analysis was to compare QTc and PR durations at study entry in participants using nonboosted and ritonavir-boosted protease inhibitor regimens with those in participants using nonnucleoside reverse tran- scriptase inhibitors (NNRTIs) and to compare the effect of continuous versus interrupted use of ritonavir-boosted protease inhibitor and other antiretroviral therapy (ART) regimens on QTc and PR after 12 and 24 months. The Strategies for Management of Antiretroviral Therapy (SMART) study, a clinical trial that compared continuous versus interrupted use of ART, provides a unique opportunity to address both of these issues.
 
Methods
 
The Strategies for Management of Antiretroviral Therapy (SMART) study The SMART study was an open-label randomized trial comparing two ART strategies [11,12]. The viral suppression strategy (viral suppression group) was designed to be consistent with the guidelines for the use of ART agents in HIV-infected adults and adolescents [13]; that is, all available ART regimens were to be used in an uninterrupted manner with the goal of maximal and continuous suppression of HIV replication. The experimental drug conservation strategy (drug conservation group) entailed the episodic use of ART according to prespecified CD4 cell count thresholds; that is, ART was to be interrupted until the CD4 cell count decreased to less than 250cells per cubic millimeter, at which time ART was to be reinitiated and continued until the CD4 cell count increased to more than 350 cells per cubic millimeter. On 10 January 2006, the data and safety monitoring board recommended stopping enrollment in the SMART study because of a safety risk in the drug conservation group. After a change in protocol, participants who had previously received ART in the drug conservation group were advised to reinitiate ART. All participants were followed for another 1.5 years [12].
 
Study population
 
All SMART participants (N = 5472) were considered eligible for the present analysis, except those who were off ART, on an ART regimen not containing a protease inhibitor and/or an NNRTI at baseline or on an ART regimen not containing a nucleoside reverse transcriptase inhibitor (NRTI), who were missing their baseline ECG or those with ECG conditions that interfere with appropriate measurement of PR and/or QT. After these exclusions, 3719 participants remained and were included in this analysis (Fig. 1).
 
Discussion
 
We examined differences in QTc and PR duration among different protease inhibitor-based regimens and an NNRTI-based regimen, and the impact of ART interruption on these ECG measures. We studied QTc and PR as continuous variables in the multivariable adjusted analysis to increase power and to avoid choosing cut-points that appear to vary in terms of the normal values and prognostic significance between men and women and between race groups [17 - 23].
 
The key findings from comparisons at baseline were as follows: unadjusted levels of QTcB and QTcF were greater for those on SQV/r than those in the NNRTI (no-protease inhibitor) group; however, these differences did not persist after adjustment (primarily for Asian race); in adjusted analyses, average QTcB and QTcF levels did not vary by boosted protease inhibitor group, and average QTcB was significantly lower for any protease inhibitor/ritonavir group compared to the NNRTI group; and protease inhibitor-containing regimens (boosted and nonboosted) were significantly associated with longer PR intervals compared to the NNRTI group. Key findings from the analyses of change after 12 and 24 months were as follows: QTc interval and PR duration did not change significantly for those in the viral suppression group (continuous ART) for any of the ART subgroups; QTcF, but not QTcB, declined following discontinuation of boosted protease inhibitor regimens, and compared to the viral suppression group, the changes at 12 and 24 months were significantly different (relative to the viral suppression group, levels of QTcF also declined for participants in the nonboosted protease inhibitor group); and PR duration declined for both boosted and nonboosted protease inhibitors in the drug conservation group and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors.
 
In February 2010, the FDA announced that there is an ongoing review of clinical trial data to investigate the effects of SQV/r on QTc and PR intervals [9]. Also, in April 2009, the FDA changed the label of LPV/r (Kaletra) to include caution regarding potential pro- longation of QTcF and PR in some patients [8]. In our investigation, after adjustment for baseline covariates, there was no evidence that any of the boosted protease inhibitors prolonged QT. In fact, as a group, average levels of QTcB were lower for those taking boosted protease inhibitors compared to those taking an NNRTI-based regimen. This was most evident for the large group of participants taking LPV/r. In these analyses, we noted a substantial confounding effect of Asian race. This had a greater effect on SQV/r as many more Asian participants were taking that treatment. The higher QT levels for Asians compared to other race groups are consistent with other studies [22,23]. Without the adjustment for Asian race, both QTcB and QTcF were significantly greater for the SQV/r group than the NNRTI group. With respect to PR duration, consistent with the concerns raised by the FDA, we found that for all of the protease inhibitor regimens considered, PR duration was increased compared to those taking an NNRTI.
 
Short QTc has been linked to arrhythmogenesis and sudden death, and both long and short QT share common pathophysiological and molecular basis [24,25]. Therefore, the FDA concerns about the effect of boosted protease inhibitors on the heart may remain valid, but perhaps for a different reason. Alternatively, NNRTI-containing regimens may be associated with greater prolongation of QTc compared to LPV/r. Considering our data on changes in QTcB through 12 and 24 months, it seems likely that the effect of boosted protease inhibitors on QTcB levels is minimal (at baseline, the average difference was -1.53 ms between the all boosted protease inhibitors and the NNRTI group). Some previous reports have shown no prolonging effect of LPV/r [6,7], which accords with the latter explanation.
 
The PR interval is a measure of atrioventricular node function as well as atrial conduction [26]. Prolongation of PR interval could be an early manifestation of an ongoing conduction defect that may lead eventually to complete atrioventricular block. In the general population, prolonged PR has been shown to predict atrial fibrillation [27,28] and mortality [29]. The prevalence of abnormal PR (>200ms) was more in the LPV/r users; however, differences in average levels among the boosted protease inhibitor groups did not vary significantly, and levels were also higher in the nonboosted protease inhibitor group compared to the NNRTI group. With interruption, PR dura- tions declined, suggesting a direct effect of protease inhibitors. For those continuing on their protease inhibitor regimens in the viral suppression group, there was no further increase in PR duration. For HIV participants, prolongation of PR should be interpreted with caution. Studies are needed to examine the molecular and genetic basis of drug-induced pro- longation of PR as well as the prognostic significance and clinical relevance of such prolongation in HIV- infected population. In the general population, a 20 ms higher PR duration was associated with an 8% increase in all-cause mortality [29]. At entry, the average difference in PR duration between those taking a boosted protease inhibitor regimen and an NNRTI regimen was only 5ms. The clinical relevance of this difference is uncertain.
 
Our study has some limitations. Comparisons of QTc and PR intervals among different ART at entry are subject to possible confounding by factors we either did not consider or measure. The potential effect of unmeasured confounders is illustrated with the striking effect of adjustment for Asian race on SQV/r levels. Although we adjusted for many potentially confounding factors, information on QTc-prolonging drugs that are commonly used in HIV/AIDS patients (e.g., metha- done) was not available to us, which is a major limitation. Also information on antiarrhythmic drug use, which may affect QTc and PR was not collected in SMART. Nevertheless, by adjusting for blood pressure- lowering drugs, which include b-blockers and calcium channel blockers, we have adjusted for class II (b- blockers) and class III (calcium channel blockers) antiarrhythmic drugs - unless these agents were used specifically for arrhythmia not for blood pressure. Information on the baseline duration of receiving ART was not collected. However, we adjusted for the baseline duration of HIV infection, which is likely correlated with the duration of taking ART. Another limitation is that ECGs were only recorded annually. By 1 year, many of the participants in the drug conservation group had reinitiated ART. This resulted in small sample sizes for some of the protease inhibitor/ritonavir subgroups. In addition, the 'on-treatment' analyses, though adjusted for several factors, are also subject to unmeasured confounders.
 
Despite the above-mentioned limitations, our study has many strengths that warrant highlighting. This is the first to examine the effects of various protease inhibitor-based regimens on key measures of cardiac conductivity in a large unselected cohort from a well defined diverse population of HIV-infected patients. This contrasts with prior reports, which were based largely on case reports and case series. Detailed medical history, including ART use as well as clinical and laboratory data were available in the majority of our study population. ECGs were conducted in a consistent manner by trained research staff, QT and PR intervals were measured automatically (0% variability) in a central ECG core laboratory and we used two different QT heart rate correction formulae to confirm the results. In addition, this study is the first to evaluate the effect of discontinuation of protease inhibitor-containing regimens on these intervals in a prospective manner from a large cohort.
 
Conclusion
 
Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI- based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with pro- longation of PR, and interruption of protease inhibitor regimens reduced PR duration. These results should not limit the use of protease inhibitor/ritonavir regimens when indicated, as the clinical relevance of these findings requires further research.
 
 
 
 
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