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 electrocardiogram (ECG) . 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 . 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 transcriptase 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.
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 ; 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 250 cells 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 .
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).
Data collection and follow-up
Before randomization, an ART and medical history were obtained and CD4+ cell count and HIV-RNA level were measured. Follow-up visits were scheduled monthly for the first 2 months, every 2 months thereafter for the first year, and every 4 months in the second and subsequent years. At each visit, a medical and ART history was taken and CD4+ cell count and HIV-RNA level were measured. At the baseline visit and at each annual visit, a 12-lead ECG was obtained.
Ascertainment of ECG abnormalities
Identical electrocardiographs (GE MAC 1200 models; GE, Milwaukee, Wisconsin, USA) were used in all SMART clinics and standard 12-lead ECGs were recorded in all participants by strictly standardized procedures. The digitally recorded ECGs were transmitted regularly over phone lines to the SMART central ECG Reading Center, EPICARE, located at Wake Forest University, Winston Salem, North Carolina for analysis. ECGs were evaluated blinded to treatment group and ART used. The study ECGs were automatically processed (after being visually checked for quality) using the 2001 version of the GE Marquette 12-SL program (GE). Heart rate corrected QT (QTc) was calculated using Bazett's (QTcB = QT*[heart rate/60]1/2)  and Fredericia's (QTcF = QT*[heart rate/60]1/3)  formulae. Because the PR interval is also heart rate-dependent , we adjusted for baseline heart rate in all of the PR models. In this analysis, ECG data from the baseline, month-12 and month-24 visits were used.
Based on the ART regimen which participants were receiving at the time of randomization, patients were categorized into one of six groups: SQV/r; LPV/r; atazanavir boosted with ritonavir (ATV/r); other ritonavir boosted protease inhibitors (protease inhibitor/ritonavir); any nonboosted protease inhibitor; or an NNRTI without a protease inhibitor.
Linear regression analysis was used to compare baseline values of QTcB, QTcF and PR for SQV/r, LPV/r, ATV/r, other protease inhibitor/ritonavir, and nonboosted protease inhibitor compared to an NNRTI, no protease inhibitor regimen (reference value). Four different models were considered: model 1 [unadjusted], model 2 [adjusted for age, sex, race (black, Asian, white (referent), and others) and NRTI backbone regimen], model 3 [adjusted as in model 2 and smoking status, total/high-density lipoprotein (HDL) cholesterol ratio, body mass index (BMI), prior cardiovascular disease (CVD), diabetes mellitus, use of blood pressure-lowering drugs and use of lipid-lowering drugs], and model 4 (adjusted as in model 3 and duration of HIV infection, baseline CD4 cell count and HIV-RNA levels). All PR models were additionally adjusted for the heart rate. With this same approach, we also assessed whether QTcB, QTcF, and PR varied among the four boosted protease inhibitor groups.
Changes in QTcB, QTcF, and PR after 12 and 24 months were examined separately within each treatment group according to protease inhibitor used at entry. We also compared changes in these ECG measures between the drug conservation (interrupted use) and viral suppression (continuous use) groups. Those taking ATV/r were combined with other protease inhibitor/ritonavir groups in this part of the analysis. Two analyses were carried out: an ‘on-treatment’ analysis, which excluded viral suppression patients who changed their ART regimen following baseline and drug conservation patients who reinitiated ART prior to the 12-month and 24-month follow-up visit; and an ‘intention-to-treat’ analysis, in which all participants meeting the criteria in Figure 1 and with a follow-up ECG at the designated visit (12 or 24 months) were included. The results of ‘intention-to-treat analysis’ are shown in the supplementary materials. Comparisons of changes in QTcB, QTcF, and PR between the drug conservation and viral suppression groups are adjusted for demographic, clinical and HIV characteristics at entry. Two-sided P values and 95% confidence intervals (CIs) are cited. SAS, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA) was used in all analyses.
Role of the funding source
The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. E.Z.S., M.P.R., and J.D.N. had full access to all the data in the study and all authors had final responsibility for the decision to submit for publication.
Characteristics of the study population
The analysis included 3719 participants (Fig. 1), of whom 27% were women, 55% were white, 28% were black, and 5.3% were Asian. Mean age was 44 years. Approximately, 31% of the participants were receiving protease inhibitor/ritonavir regimens. SQV/r, LPV/r, and ATV/r were the most commonly used protease inhibitor/ritonavir regimens. In the ‘other protease inhibitor/ritonavir’ group, indinavir/ritonavir (95 participants) was the most common. Characteristics of the study population at baseline according to HIV treatment regimen are shown in Table 1. A number of factors varied by type of ART regimen used. Notably, the percentage of women (44%) and Asians (60%) prescribed SQV/r were much higher than the other groups. The majority of participants prescribed SQV/r (60%) were enrolled by sites in Thailand.
Associations with QTc interval
QTcB duration was longer than QTcF duration in all subgroups (Table 2). In these univariate analyses, those in the SQV/r subgroup showed greater values of QTcB and QTcF as well as a greater percentage with abnormal QTcB and QTcF (using 440 ms as a cut-point). However, no participants in any of the protease inhibitor/ritonavir subgroups had extreme QTcB or QTcF values (≥500 ms; Table 2).
Table 3 gives the baseline unadjusted and adjusted differences between each of the five protease inhibitor regimens and the NNRTI, no protease inhibitor regimen. Also shown are unadjusted and adjusted differences between all boosted protease inhibitor groups combined and the NNRTI group. Differences between regimens varied by the method of QT heart rate correction, whether QTcB or QTcF. In the unadjusted models and compared to NNRTI-containing regimens (no protease inhibitor), SQV/r use was associated with prolongation of both QTcB and QTcF (P < 0.01), LPV/r was associated with shortening of QTcB (P < 0.01), and nonboosted protease inhibitor use was associated with prolongation of QTcF (P = 0.02). The difference between ATV/r or other protease inhibitor/ritonavir groups and the NNRTI group was not statistically significant for QTcB or QTcF. Except for SQV/r, these associations persisted after multivariable adjustment for demographic and clinical/HIV characteristics (models 2–4, Table 3). The adjustment for race had a large impact on the QTcB and QTcF differences between SQV/r and the NNRTI group. As shown in Supplemental Table 1, http://links.lww.com/QAD/A101 QTcB is higher for Asians than whites by 6.62 ms and, as previously noted, a higher percentage of Asians were prescribed SQV/r (Table 1). To explore this further, we carried out analyses by race. Adjusted differences between the SQV/r group and NNRTI-containing regimen (no protease inhibitor) group were 2.25 ms (95% CI:−7.66–12.16; P = 0.65) for Asians, 0.35 (95% CI: −9.19–9.88; P = 0.94) for blacks, 0.38 (95% CI: −4.24–5.01; P = 0.87) for whites, and −3.65 ms (95% CI: −12.38–5.08; P = 0.41) for participants in other race groups. These differences did not differ by race (P = 0.47).
We also considered whether there was significant variation in QTcB and QTcF among the four boosted protease inhibitor groups. Neither adjusted levels of QTcB nor adjusted levels of QTcF varied significantly (P = 0.26 and P = 0.34 for QTcB and QTcF, respectively). For all boosted protease inhibitors combined versus the NNRTI group, the average difference in QTcB at baseline after adjustment for baseline covariates (model 4) was −1.53 ms (95% CI: −2.95 to −0.10; P = 0.04). For QTcF, this difference was 0.60 ms (95% CI: −0.82 to 2.01; P = 0.41).
In the full model (model 4) for QTcB, older age, female sex, Asian race, BMI, and use of blood pressure-lowering drugs were associated with greater levels; for QTcF, older age, female sex, diabetes, and use of blood pressure-lowering drugs were associated with greater levels. Higher total/HDL cholesterol ratios and prior CVD were associated with lower levels of QTcF. For both QTcB and QTcF, levels varied among NRTIs used (P = 0.004 for QTcB and P = 0.001 for QTcF). Those taking a tenofovir-containing regimen or stavudine and lamivudine (d4T + 3TC) had lower levels of QT than those taking zidovudine and 3TC (ZDV+3TC). (Supplemental Table 1, http://links.lww.com/QAD/A101).
Changes in QTc after 12 and 24 months of interrupted versus continuous antiretroviral therapy use
Table 4 and Table 5 summarize the changes in baseline QTcB and QTcF interval durations after 12 and 24 months of follow-up for participants with both baseline and month-12 or month-24 ECGs. These analyses are not protected by randomization as participants who reinitiated ART in the drug conservation group and those who changed their treatment regimen in the viral suppression group are excluded. In the viral suppression group, for which sample sizes are larger, durations of QTcB and QTcF in all groups did not significantly change after 12 or 24 months of continuous ART use. In the drug conservation group, QTcB levels did not change significantly from baseline; QTcF declined for each boosted protease inhibitor group with greater declines after 24 months. The changes in QTcB among those who discontinued different boosted protease inhibitors did not differ significantly from one another at 12 months (P = 0.89) or 24 months (P = 0.73). Likewise, the changes in QTcF did not differ significantly at 12 months (P = 0.96) or 24 months (P = 0.30). For the combined boosted protease inhibitor groups, QTcF declined significantly at 12 months (−3.27 ms; P = 0.03) and 24 months (−7.79 ms; P = 0.01) among participants in the drug conservation group who discontinued a boosted protease inhibitor. QTcF changes differed between the drug conservation and viral suppression groups for both those taking any protease inhibitor/ritonavir and those in the nonboosted protease inhibitor group after 12 months (P = 0.04 for both) and 24 months (P < 0.01 and 0.03, respectively).
We also carried out an ‘intention-to-treat’ analysis (see Supplemental Tables 2 and 3, http://links.lww.com/QAD/A101). For any protease inhibitor/ritonavir group, changes in QTcF for the drug conservation group and drug conservation-viral suppression differences in QTcF were reduced in these analyses as compared to those in Tables 4 and 5.
Associations with PR duration
The mean PR interval duration in all participants was 158.1 ms (± 23.1). In univariate analyses, among participants in the LPV/r group, a greater percentage had durations greater than or equal 200 ms compared to those in the NNRTI group (6.6 versus 2.8%; P = 0.02). Percents for the other protease inhibitor/ritonavir groups ranged from 3.0 to 6.0%. Extreme values (≥300 ms) were observed in only two participants, both in the other protease inhibitor/ritonavir group (Table 2).
As shown in Table 3, in the unadjusted models, those taking protease inhibitor-containing regimens (boosted and nonboosted) had longer PR duration than those in the NNRTI group. Differences between each protease inhibitor group and the NNRTI group in PR duration were reduced with adjustment. Adjusted levels of PR durations did not vary significantly among the four boosted protease inhibitor groups (P = 0.56). For all boosted protease inhibitors combined versus the NNRTI group, the average difference in PR duration baseline after adjustment (model 4) was 5.11 ms (95% CI: 3.35–6.86; P < 0.01).
In the full model (model 4), lower heart rate, older age, male sex, black and Asian race, higher total/HDL cholesterol ratio, higher BMI, and use of blood pressure-lowering drugs were associated with longer PR intervals. Current and past smokers had lower PR durations than those who never smoked (Supplemental Table 1, http://links.lww.com/QAD/A101).
Change in PR after 12 and 24 months of interrupted versus continuous antiretroviral therapy use
Table 4 and Table 5 summarize the change in baseline PR interval duration after 12 and 24 months of continuous versus interrupted use of ART in participants who had both baseline and month-12 or month-24 ECGs and had not either re-initiated ART (drug conservation group) or changed their treatment regimen (viral suppression group) through the indicated follow-up period (on-treatment analysis). No statistically significant changes were observed in the viral suppression group after 12 or 24 months. However, PR duration significantly shortened at 12 months among drug conservation participants who discontinued taking any boosted protease inhibitor at 12 and 24 months. Significant reductions in PR duration were also observed at 12 months among those who discontinued nonboosted protease inhibitors. The changes in PR duration among those who discontinued different boosted protease inhibitors did not differ significantly from one another at 12 months (P = 0.84) or 24 months (P = 0.36). A significant difference (P < 0.01) in change in PR duration at 24 months between the drug conservation and viral suppression groups was evident for those taking a boosted protease inhibitor. The ‘intention-to-treat’ analyses (Supplemental Tables 2 and 3, http://links.lww.com/QAD/A101) showed that there was no significant change in PR interval after either 12 or 24 months of discontinuation of protease inhibitor-based regimens.
Unwitnessed sudden deaths
Fifteen participants died suddenly without a witness. Out of these, three participants had reported a prior history of CVD at baseline, but none had a CVD event during follow-up. These three participants reported having a myocardial infarction prior to randomization; two of them additionally reported having coronary artery disease requiring surgery prior to randomization.
The average level of QTcB, QTcF, and PR duration for these 15 participants were 423, 408, and 141 ms, respectively. None of these unwitnessed deaths occurred in the SQV/r group. The deaths occurred in the LPV/r group (three deaths, 0.5%), other protease inhibitor/ritonavir group (one death, 0.5%), nonboosted protease inhibitor group (three deaths, 0.4%), and NNRTI-no protease inhibitor group (eight deaths, 0.4%).
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 . Also, in April 2009, the FDA changed the label of LPV/r (Kaletra) to include caution regarding potential prolongation of QTcF and PR in some patients . 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 . 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 . The prevalence of abnormal PR (>200 ms) 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 durations 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 prolongation 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 . At entry, the average difference in PR duration between those taking a boosted protease inhibitor regimen and an NNRTI regimen was only 5 ms. 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., methadone) 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 β-blockers and calcium channel blockers, we have adjusted for class II (β-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.
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 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.
The SMART study was sponsored by the National Institute of Allergy and Infectious Disease, National Institutes of Health (grants U01AI042170, U01AI46362, and U01AI068641).
J.H.S. serves on data and safety monitoring boards for non-HIV-related research studies sponsored by Abbott, Lilly, and Takeda. P.R. reported serving as a scientific advisor to Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Theratechnologies, Tibotec Therapeutics, and Tobira Therapeutics; has served on data and safety monitoring boards and endpoint adjudication committees for Tibotec Therapeutics; has received honoraria for speaking engagements at scientific conferences from Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Theratechnologies; and has received research support from Gilead Sciences, ViiV Healthcare, and Boehringer Ingelheim Pharmaceuticals. B.M. has received travel support, lecture or consultant fees from Abbott, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck Sharp Dome, Roche Diagnostics and Tibotech. Z.T. is on advisory board –of Gilead, Merck, and ViiV and received research and education grants from Pfizer, Gilead and Tibotec.
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