Since receiving regulatory approval in 2007, the integrase strand transfer inhibitor (INSTI) raltegravir has proven to be a valuable addition to the treatment options available for HIV infection. It is noteworthy for the velocity with which it suppresses HIV-1 RNA levels and its durable efficacy in treatment-experienced and treatment-naive adults.1–6
Derived from a beta-diketo acid moiety, the chemistry of raltegravir (and other current INSTIs) is distinct from that of reverse transcriptase and protease inhibitors.7 As such, raltegravir use is less likely to result in the metabolic toxicities typically associated with other combination antiretroviral therapy (cART) drugs, but may give rise to its own unique long-term adverse events (AEs). Thus far, the most common AEs reported with raltegravir are headache and gastrointestinal effects (nausea/vomiting, diarrhea), which are usually self-limiting and of mild severity. Early data suggest nonsignificant effects upon plasma lipids and bone mineral density.8,9
However, raltegravir has been rarely associated with rhabdomyolysis, with 4 cases reported since 2008.10–13 Apart from peak creatine kinase (CK) levels >6000 U/L, the cases varied in length of raltegravir exposure (10 days–23 months), stage of HIV disease, the degrees of motor weakness, and renal impairment, and lacked any clear predisposing factor. In phase 2 and 3 trials of raltegravir, the frequency of Division of AIDS (2009) grade 3–4 CK elevation was greater than in control groups and ranged between 4% and 13%.14–16 Most instances occurred in the first 48 weeks, and of 3178 exposed subjects, there was 1 case of myopathy.5 The disparity in grade 3–4 CK prevalence between raltegravir and control groups persisted when corrected for statin or fibrate use, and the elevations were unrelated to clinical events when assessed retrospectively, with no study participant discontinuing raltegravir solely because of a CK elevation.
Thus, although myopathy seems to be a rare event, it has not yet been assessed for as an outcome prospectively. The consistent data on CK elevation also suggest that raltegravir may be associated with low-grade muscle toxicity with minimal or mild symptoms, the prevalence of which remains unknown. The United States Food and Drug Administration has advised that raltegravir be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as those receiving statins, a recommendation echoed in the most recent Department of Health and Human Services antiretroviral guidelines.17
This study was conducted to compare the prevalence of skeletal muscle toxicity in HIV-infected adults receiving raltegravir with that of a control group and analyze for associated factors—particularly the relationship with length of raltegravir exposure and plasma trough levels. We hypothesized that there would be a higher prevalence of skeletal muscle toxicity in patients receiving raltegravir-based cART.
HIV-infected adults (age ≥18 years) receiving cART were eligible for enrolment. No restrictions were placed on statin use, recent exercise, duration of cART, or a previous diagnosis of AIDS for study entry. Patients were excluded if they had a history of major trauma (<1 month before study entry), intramuscular injections or a generalized tonic–clonic seizure (<1 week before study entry), were receiving zidovudine or another INSTI, or if they were acutely unwell with a systemic infection.
The study was approved by the St. Vincent's Hospital Human Research Ethics Committee, and conducted in accordance with the Helsinki II declaration and the International Committee on Harmonization's Good Clinical Practice Guideline. Each participant provided signed, informed consent before enrolment.
Study Design and Procedures
This was a cross-sectional, 2-arm prevalence study with consecutive recruitment of outpatients at 2 sites in Sydney, Australia, funded by the Clinical Research Program, St. Vincent's Centre for Applied Medical Research. The patients were consecutively approached at their routine clinic visits. Consenting participants were assigned to the raltegravir and control groups based on the presence or absence of raltegravir, respectively, in their cART regimens. Investigators and assessing clinicians were not blinded to the participants' study arms.
Study procedures were conducted at a single visit; history of antiretroviral use was documented, and any strenuous exercise (aerobic or resistance training) in the 7 days before study entry was recorded using a standard questionnaire. The participants underwent a targeted cardiovascular system and neuromuscular examination. For the latter, upper and lower limb muscle strength was assessed proximally, with any weakness considered abnormal. Blood was sampled for CK, cardiac troponin T, and plasma raltegravir trough levels (taken 9–12 hours after the previous dose of raltegravir). All diagnostic pathology was performed at a single laboratory. Troponin T was measured using a high-sensitivity electrochemiluminescence assay (Modular Analytics E170, Roche Diagnostics, Mannheim, Germany) and plasma raltegravir levels measured using a high-performance liquid chromatography assay with tandem mass spectrometry detection (SydPath, Sydney, Australia), following the method described by Merschman et al.18
The primary outcome of interest was the prevalence of skeletal muscle toxicity in each arm. Secondary objectives were frequency of myocardial damage and identifying significant associations between skeletal muscle toxicity and participant/treatment characteristics.
The study definition of muscle toxicity was derived from the 2002 definition of statin myopathy proposed by the American College of Cardiology, American Heart Association, and the National Heart, Lung, and Blood Institute.19,20 We defined skeletal muscle toxicity by the presence of ≥1 of the following components: (1) isolated CK elevation (reference range 0–250 U/L for males <60 years; 0–200 U/L for males >60 years; 0–150 U/L for females) without symptoms/signs; (2) diffuse myalgia without weakness; (3) proximal myopathy (proximal weakness on examination); and (4) rhabdomyolysis (acute syndrome of muscle weakness, myalgia, and CK elevation >10 × upper limit of normal with myoglobinuria or elevated serum creatinine).
To counter any possible contamination of the reporting of myalgia (due to the nonblinded nature of this study), the investigators were instructed to note the presence of myalgia only if it was of a generalized distribution, and/or there was tenderness of multiple muscle groups upon palpation. Muscular pain isolated to a single muscle group or associated with a history of physical injury was excluded from being recorded as myalgia.
Myocardial damage was assessed on the basis of troponin T and physical examination, correlated with any history of cardiac disease. Electrocardiography and echocardiography were not performed routinely for participants with troponin T elevations.
The analysis population consisted of enrolled participants who completed all the study procedures. Although it was not possible to perform a sample size calculation for a hypothesis-generating, hitherto unstudied endpoint, we aimed to recruit ≥100 patients on raltegravir-based cART (with matching numbers of control participants). This represents a majority of the patients receiving raltegravir managed at the 2 study sites. Final data were analyzed using STATA statistical package Release 11 (StataCorp LP, College Station, TX). The primary outcome—prevalence of skeletal muscle toxicity, both overall and by component (isolated CK elevation, myalgia, proximal myopathy, rhabdomyolysis)—was calculated for each arm. Between-group differences were compared using the Fisher exact test.
The relationships between muscle toxicity outcomes and patient/treatment characteristics were tested by univariate and multivariate analyses using logistic regression models. Overall skeletal muscle toxicity, isolated CK elevation, myalgia, and proximal myopathy were analyzed in turn as the dependent variable against a selection of continuous, categorical, and discrete variables (age, gender, race, alcohol intake, recent exercise, prior AIDS, and serious non-AIDS events (SNAEs),21 duration of any cART and raltegravir, and previous zidovudine exposure, current statin and atazanavir therapy, body mass index (BMI), CD4 cell count, HIV viral load, plasma trough raltegravir levels). Any variable having <5 members was excluded. Independent associations with all muscle toxicity outcomes were determined separately by multivariate logistic regression using backward stepwise variable selection. Only those variables with a P value of ≤0.10 in univariate analysis with a given toxicity outcome were assessed in the multivariate model building, with raltegravir kept a priori in the final model.
Patient Disposition and Baseline Characteristics
The study commenced on July 5, 2011, and the final participant was enrolled on April 27, 2012; in total, 323 individuals were consecutively recruited (Fig. 1). Five were excluded from analysis (2 ineligible, 3 failed to complete all the study procedures). The remaining 318 participants were evenly divided between the raltegravir (n = 159) and control groups (n = 159). None of the control group participants had previously undergone treatment with raltegravir.
The study cohort was homogeneous. Overall, 98% of the participants were male, 89% were white, with the median age being 51 years, and strenuous exercise in the week before study entry was reported by 42%. Demographic and anthropometric baseline characteristics were well balanced between the 2 groups (Table 1). The mean duration of raltegravir therapy was 27 months. Disease and treatment characteristics were also similar between the raltegravir and control groups, including the total mean duration of cART (123 vs. 119 months), although the raltegravir group had more individuals with previous zidovudine exposure (50% vs. 41%).
Skeletal Muscle Toxicity
Of the 318 participants, 89 (28%) satisfied the criteria defining skeletal muscle toxicity overall (Fig. 2); 59 (37%) in the raltegravir group and 30 (19%) in the control group (P < 0.001). By component, there were significant between-group differences in the prevalence of myalgia (19% vs. 3%, respectively; P < 0.001) and proximal myopathy (4% vs. 0%, respectively; P = 0.030), but not isolated CK elevation (14% vs. 16%, respectively; P = 0.639). No case of rhabdomyolysis was identified. Prevalence of symptomatic muscle toxicity (myalgia, proximal myopathy) was significantly higher in the raltegravir than in the control group (23% vs. 3%, P < 0.001).
Elevations of CK were mild; stratified by the Division of AIDS grading scale, 54 of 55 (98%) were ≤grade 1. One control group participant recorded a grade 4 elevation. The median CK values in the raltegravir and control groups were similar [138 U/L (range 29–1290 U/L) vs. 121 U/L (range 31–5140 U/L), respectively; P = 0.178].
Six participants, all in the raltegravir group, had symmetrical upper and lower limb proximal weakness on examination; the degree of weakness was mild (Table 2). The median duration of raltegravir exposure in these participants was 37 months (range 8–43 months). Apart from raltegravir, the other antiretroviral drugs varied. One participant was receiving rosuvastatin for cardiovascular disease, and 2 (33%) had an elevated CK—both were ≤grade 1.
Comparing these 6 patients with the other 153 raltegravir arm participants, the median duration of raltegravir exposure was higher [37 months (range 8–43 months) vs. 26 months (range <1–69 months), respectively] and median raltegravir trough levels were lower [67 µg/L (range 19–959 µg/L) vs. 120 µg/L (range 19–5361 µg/L), respectively], whereas the median CK levels [165 U/L (range 83–687 U/L) vs. 134 U/L (range 29–1290 U/L), respectively] and CD4 count [485 cells per microliter (range 200–690 cells per microliter) vs. 552 cells per microliter (range 4–11,450 cells per microliter), respectively] were similar. The frequency of previous exposure to zidovudine (50%) and median HIV viral load (<50 copies per milliliter) were identical.
One participant with proximal myopathy underwent electromyography (EMG) that was reported as normal but declined further investigation. A muscle biopsy taken from the participant receiving rosuvastatin showed variable myofiber size and regeneration, whereas EMG demonstrated small amplitude, long duration polyphasic motor unit potentials with rapid recruitment in multiple proximal muscle groups, all of which was consistent with myopathy. A third myopathic participant underwent muscle biopsy and magnetic resonance imaging, both of which were reported as normal. These last 2 patients had their raltegravir switched to another agent, and follow-up examination 2–3 months later showed a noticeable improvement in proximal strength on physical examination.
Assessment for Myocardial Toxicity
Elevated troponin T levels were detected in 9 participants (3%), 6 in the raltegravir and 3 in the control group (P = 0.502). Of the 6 in the raltegravir group, 5 had a history of congestive cardiac failure and/or coronary artery disease. No elevation was accompanied by symptoms, and no patient had signs of congestive cardiac failure on physical examination.
Assessment for Associated Factors
Using the overall definition of skeletal muscle toxicity as the dependent variable, raltegravir [odds ratio (OR) 2.54; 95% confidence interval (CI): 1.52 to 4.23; P < 0.001] and recent strenuous exercise (OR 2.15; 95% CI: 1.31 to 3.54; P = 0.002) were significantly associated with skeletal muscle toxicity on univariate analysis (Table 3). With the multivariate model, both these variables were independently associated with overall skeletal muscle toxicity—raltegravir (OR 2.64; 95% CI: 1.57 to 4.45; P < 0.001) and recent strenuous exercise (OR 2.25; 95% CI: 1.35 to 3.75; P = 0.002).
Additional multivariate analyses with isolated CK elevation, myalgia, and proximal myopathy as the dependent variables revealed stratification of the above associations. There was significant association between isolated CK elevation and recent strenuous exercise (OR 2.41; 95% CI: 1.28 to 4.54; P = 0.006) but not raltegravir (P = 0.673). Conversely, myalgia was significantly associated with raltegravir (P < 0.001), but not with strenuous exercise (P = 0.209) or statin use (P = 0.144). As there was no case of proximal myopathy in the control group, no variable was associated with proximal myopathy on the univariate analysis except for raltegravir therapy. Duration of cART or raltegravir, raltegravir trough level, and previous zidovudine exposure did not show a significant association with any definition of muscle toxicity.
Other variables included in the multivariate model for ≥1 toxicity outcomes but which proved nonsignificant were gender, higher BMI, statin and atazanavir therapy, and CD4 cell count.
This study identifies a significantly higher prevalence of symptomatic skeletal muscle toxicity (diffuse myalgia, proximal myopathy) in patients treated with raltegravir-based cART. This association is not dependent upon either the duration of raltegravir exposure or raltegravir trough levels.
No relationship was found between raltegravir and isolated CK elevation, as there was a similar proportion of elevated CK in the 2 arms, all but one of which was ≤grade 1. This is at odds with safety data from clinical trials of raltegravir, in which grade 3–4 CK elevation is the most common laboratory AE in the first 96 weeks and significantly higher than in commonly prescribed statins, which all have a grade 3–4 CK prevalence of <0.5%.22 Although CK elevation is consistently more frequent with raltegravir than comparator arms, only the PROGRESS study has shown the difference to be significant, for raltegravir vs. emtricitabine, and tenofovir at 48 weeks (P = 0.02).15 These elevations have usually been attributed retrospectively to exercise. Our results indicate that although recent strenuous physical activity was associated with isolated mild CK elevations, it was not associated with myalgias or proximal myopathy. However, it is worth noting that these prospective trials involved multiple assessments during the first 6–12 months of raltegravir therapy. The participants in our study were already highly raltegravir experienced, with the mean exposure being 27 months. Only 41 (26%) of the raltegravir group were exposed for <12 months. Therefore, even at the point of recruitment, our single-visit study design was inadequately powered to detect the early, transient elevations in CK reported in phase 2 and 3 trials, although it was better suited to detect chronic pathology.
Although CK before commencing raltegravir was not assessed in this study, after a mean of 28 months of raltegravir, the mean CK in both arms was similar. This is in keeping with observations that raltegravir-associated grade 3–4 CK elevations recorded in the first 12 months were brief in duration and self-limiting.23 Drug-induced and metabolic myopathies also frequently have a normal or mildly elevated CK.24,25 A lack of CK elevation therefore does not exclude muscle damage, and it suggests that used alone, CK may not be a sensitive marker of muscle toxicity in the setting of long-standing raltegravir therapy.
Only one other study, a cross-sectional analysis of the Italian SCOLTA cohort, has investigated CK increases with raltegravir-based cART, reporting similar rates of CK elevation in raltegravir- and darunavir-based cART (9% vs. 11%, respectively). Also reported was a higher rate of weakness for raltegravir compared with darunavir (P = 0.04), but not muscle pain (P = 0.20).26 Our study is the first to describe a significantly higher rate of diffuse myalgias with raltegravir, and expands the comparison to cART regimens beyond those based on darunavir, and is the first to look specifically for patient/treatment characteristics independently associated with muscle toxicity and raltegravir therapy.
Although proximal myopathy was uncommon, it was restricted to the raltegravir group. The mechanism of the myopathy is unknown,13 and our study does not shed further light on this, with no clear predisposing factor apart from raltegravir emerging from the analysis. Additional clinical follow-up of these patients was of special interest, as both myopathic patients who switched from raltegravir to another antiretroviral agent had an objective improvement in proximal strength, suggesting a reversible process. A much larger case series will be required to reliably identify risk factors and plot the clinical course, but the results nevertheless indicate that proximal myopathy may be an infrequent, but clinically relevant side effect of raltegravir.
Importantly, no independent association was identified between any component of muscle toxicity and the duration of raltegravir exposure or its trough plasma concentration. Similarly, there was no relationship with duration of cART, nor with concomitant atazanavir therapy; the latter is relevant as atazanavir, with or without ritonavir, modestly increases plasma levels of raltegravir via inhibition of glucuronidation.27
A key obstacle in the study design was the problem posed by defining skeletal muscle toxicity, as a review of the literature confirmed the absence of any consensus definition or grading system.20 This is made difficult by the diverse manifestations of drug-induced muscle toxicity.28 Although the available definitions for statin myopathy also lack consensus, they do attempt to take heterogeneity into account, categorizing the manifestations according to CK measurement and symptoms.
It is worth noting that the component of skeletal muscle toxicity accounting for the majority of the significant between-group difference was myalgia, which is a subjective measure. We were unable to demonstrate that CK would be a useful objective biomarker for skeletal muscle toxicity in this population of patients.
Additional limitations of our study include the cross-sectional design, which makes assigning causality difficult. A prospective design would confer the abilities to detect early transient CK elevations or acute clinical AEs, permitting the natural history of any muscle toxicity to be documented. However, serial assessments of our raltegravir-experienced population are unlikely to refine our findings, considering the lack of an association between any component of muscle toxicity and duration of raltegravir. Further to this, serial assessments would prove optimal if baseline, raltegravir-naive measures of study variables were also available for all the participants. Our results can be used to perform a sample size calculation, providing a useful basis for additional prospective studies of skeletal muscle toxicity, both with raltegravir and with newer INSTIs.
The nonrandomized, nonblinded assignment of participants to arms according to the primary study factor (raltegravir exposure) could have resulted in selection and reporting biases. We limited this by standardizing the methods for examining proximal muscle strength and reporting myalgia. Participant characteristics were also largely similar in both groups. There were a number of factors where the relationship approached statistical significance for at least 1 component of muscle toxicity—higher BMI, statin use, gender, and atazanavir use. Our study may have been inadequately powered to define these apparent associations, and to detect early, transient CK elevations in the raltegravir group. The study population was not diverse, being almost entirely adult, male and of white race. Although this may limit the generalizability of our results to women, children, or other race groups, raltegravir-associated rhabdomyolysis has been reported in males, females, and different ethnicities.13 Polymorphisms of the hepatic isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) that metabolizes raltegravir do vary in frequency with race; the UGT1A1*28 polymorphism results in decreased enzyme activity and higher plasma raltegravir levels.29 However, the elevation in levels is less than that seen with atazanavir–raltegravir interactions,27 which has been demonstrated in the analysis as not being associated with muscle toxicity.
A possible confounding factor in recording clinical events in this study was that the participants were aware of the primary study objective, raising the possibility of subjective overreporting of symptoms. However, the only myopathy found was proximal weakness assessed objectively by an investigator, making this less likely.
The implications for therapy are unclear; although we found proximal myopathy in 4%, raltegravir has proven efficacy. Myalgia, although a common clinical finding (19%), is unlikely to be a sufficient reason alone to switch from raltegravir, but cases should be considered on an individual basis. Additional, prospective studies are necessary to better assess the long-term sequelae of muscle toxicity and uncover associated factors that may predict the likelihood of damage. These studies will need to follow the evolution of myalgia and weakness over time with multiple testing modalities (clinical, radiological, tissue biopsies) because of the protean manifestations of drug-induced myopathy. At this stage, however, refining a clinical case definition before establishing the natural history may be premature. Given that myalgia and myopathy both were seen in patients with normal or only low-level elevations in plasma CK, our findings suggest that all patients receiving raltegravir should be actively monitored for myalgia and myopathy, regardless of whether CK is measured or elevated.
The authors thank the patients who volunteered for this study, and the following individuals for their contributions to this study; St. Vincent's Hospital: Bruce Brew, David Cooper, Tony Kelleher (enrollment), Richard Norris, Robyn Richardson (project management), Fiona Kilkenny, Karen McRae, Kate Sinn (study coordination, pathology collection), Karl Hesse, Linda Kightley, and Sharon Mitchell (administrative assistance); Holdsworth House Medical Practice: Andrew Gowers, David Kingston, Dick Quan (enrollment) and Shikha Agrawal, Trina Vincent (study coordination); SydPath Pathology Service: Graham Jones, John Ray, Rebecca Collins, and Shayla Sharmin.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
HIV infection; raltegravir; integrase inhibitor; drug-induced myopathy; creatine kinase; myalgia