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Select Updates From the 16th CROI: Treatment-Related Cardiovascular Risk, Pharmacokinetic Issues, and Interleukin-2 Use

Select Updates From the 16th CROI: Treatment-Related Cardiovascular Risk, Pharmacokinetic Issues, and Interleukin-2 Use

Key words: HIV/AIDS, Antiretroviral therapy, Conference coverage, Conference on Retroviruses and Opportunistic Infections

The 16th Conference on Retroviruses and Opportunistic Infections (CROI) was held in Montreal from February 8 to 11, 2009. This conference provided significant new insights into HIV therapeutics. Here we summarize new findings presented on the effect of antiretroviral therapy on cardiovascular disease (CVD) risk; new pharmacokinetic data, notably, the progress in developing pharmacokinetic boosters as alternatives to low-dose ritonavir; and the lack of clinical benefit with interleukin (IL)-2.

ANTIRETROVIRAL THERAPIES AND CVD RISK
The D:A:D Study: Abacavir and Certain Protease Inhibitors Increase CVD Risk
The contribution of antiretroviral therapy and specific antiretroviral agents to myocardial infarction (MI) continues to be the subject of intensive investigation. The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has previously described associations with cumulative years of exposure to combination antiretroviral therapy, cumulative exposure to protease inhibitors (PIs), and current or recent exposure to abacavir and didanosine.1 Support for the association of abacavir with MI risk was provided by the analysis of the Strategies for Management of Antiretroviral Therapy (SMART) study, which also suggested that abacavir recipients showed somewhat higher levels of inflammatory markers (high-sensitivity C-reactive protein [hsCRP], IL-6).2

These observations were not supported by GlaxoSmithKline's safety database or the analysis of the prospective HEAT study, which was a head-to-head comparison of the 2 fixed-dose NRTI combinations abacavir/lamivudine and tenofovir/emtricitabine.3

As more events accumulate in the D:A:D cohorts, the ability to assess associations with specific agents increases. The D:A:D study findings were updated for the 16th CROI, and this iteration included 580 MIs evaluated across 178,835 person-years of follow-up.4 Individual agents associated with an increased relative risk of MI by cumulative years of exposure were abacavir (relative risk [RR], 1.07; 95% confidence interval [CI], 1.01 - 1.14), indinavir with or without ritonavir boosting (RR, 1.12; 95% CI, 1.07 - 1.18), and ritonavir-boosted lopinavir (LPV/r) (RR, 1.13; 95% CI, 1.05 - 1.21). The association with these PIs was partially corrected by adjusting for their effect on lipid levels and suggested that PI agents with lesser effects on lipid parameters should be preferred pending more data.

Other antiretroviral agents, such as tenofovir (RR, 1.05; 95% CI, 0.92 - 1.19), nelfinavir, saquinavir, nevirapine, and efavirenz, were not associated with increased risk. Assessment of more recently approved agents, such as atazanavir and darunavir, are not yet available. When current or recent use of NRTIs and MI relative risk were considered, abacavir (RR, 1.68; 95% CI, 1.33 - 2.13) and didanosine (RR, 1.41; 95% CI, 1.09 - 1.82) remained significantly associated with MI, whereas tenofovir (RR, 1.14; 95% CI, 0.85 - 1.52) was not.

ANRS CO4 Study: Increased CVD Risk With Abacavir
CVD risk associated with abacavir was also assessed in a case-control study by the French ANRS group, which included 268 patients with MI within their database matched with 865 MI-free controls for age, sex, and care center.5 The results showed an association of recent (ie, less than 1 year) abacavir use with MI (odds ratio [OR], 2.19; 95% CI, 1.19 - 4.02) but not of other NRTIs. Unlike the D:A:D findings, however, cumulative exposure to abacavir was not associated with MI. Cumulative exposure to LPV/r (OR, 1.38/y; 95% CI, 1.1 - 1.74) and fosamprenavir (OR, 1.55/y; 95% CI, 1.2 - 1.99) was also significantly associated with MI risk.

ACTG A5001 Study: No CVD Risk With Abacavir
In contrast to the D:A:D and French studies, the results of the AIDS Clinical Trials Group (ACTG) A5001 study, which combined 5 prospective ACTG studies with 27 MI events and 63 severe cardiovascular events across 10,187 patient-years of follow-up, did not demonstrate an association between recent abacavir use and either cardiac-related event type.6 The relatively low number of events and relatively smaller number of patient-years of follow-up in this study leave wide confidence intervals around the conclusions and so do not rule out a possible modest drug-related effect.

Potential Mechanisms of CVD Risk
Given the relative reproducibility of the association between recent abacavir use and MI, a mechanism is now being sought. In both the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study, no association between abacavir and elevated levels of the inflammatory markers hsCRP and IL-6 or the clotting factor d-dimer were found.7 These observations were supported by the prospective HEAT study comparing abacavir/lamivudine with tenofovir/emtricitabine, each given with LPV/r, which found no differences in the levels of hsCRP; IL-6; and soluble vascular cell adhesion molecule-1 (sVCAM-1), a marker of endothelial dysfunction.8

However, other groups noted that there was platelet hyperreactivity in abacavir-treated patients but not in matched participants who received alternative NRTIs and that vascular reactivity as measured by brachial artery reactivity was more impaired in patients with viral suppression treated with abacavir than in persons treated with alternative NRTIs.9,10

PHARMACOKINETIC ISSUES
Raltegravir and Atazanavir PK Interactions
The combination of atazanavir and raltegravir has been thought to render beneficial pharmacokinetic properties because of their unique metabolic pathways. Atazanavir is a direct inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1, which is the major mechanism for the clearance of raltegravir.

To demonstrate the pharmacokinetics of these agents when they are concomitantly administered, a 2-way pharmacokinetic study was conducted in healthy volunteers using atazanavir 300 mg and raltegravir 400 mg, with both given twice daily.11 Of the 22 participants enrolled, 19 completed the study. Each participant received raltegravir 400 mg twice daily for the first 5 days, atazanavir 300 mg twice daily from day 6 to 12, and then a combination of both for 2 weeks. Trough concentrations, routine laboratory test results, and serial ECGs were obtained at regular intervals.

The results showed that coadministration of atazanavir and raltegravir decreased the bioavailability (measured as the area under the plasma concentration versus time curve) and minimum plasma concentration of atazanavir compared with the administration of atazanavir alone; however, all of the atazanavir minimum concentrations were greater than 10 times the concentration needed to suppress wild-type virus. Raltegravir concentrations, on the other hand, increased to an extent similar to that seen when it has been coadministered with boosted atazanavir.

No ECG changes were noted with raltegravir when given alone. However, with atazanavir alone, the mean QRS interval increased from baseline mean 88 milliseconds (range, 72 to 101) to day 12 mean 11 milliseconds (range, 2 to 25). No QRS interval was longer than 120 milliseconds during atazanavir administration. There were also mild increases in the PR interval during the same period. The significance of these ECG changes is unclear and warrants further investigation. Hyperbilirubinemia was reported but was comparable with historical data for boosted atazanavir. No other major adverse events were observed.

The clinical data suggest that this combination of atazanavir and raltegravir potentially provides another option for an NRTI- and ritonavir-sparing regimen. Given the known potency and safety profiles of both drugs, the atazanavir plus raltegravir combination is expected to show good clinical efficacy while offering a good safety and tolerability profile, which is needed for long-term treatment of HIV infection. A pilot study looking at this treatment strategy in treatment-naive patients is currently under way.

IL-2 DOES NOT IMPROVE CLINICAL OUTCOMES
The combination of antiretroviral therapy and IL-2 has been demonstrated to result in improved CD4 counts, but no clinical improvement has been shown as measured by a reduction in clinical end points.12,13 In addition, it has been unclear whether the increased levels of CD4+ cells that resulted from IL-2 exposure would, during long-term follow-up, confer greater immunological health and reduce the risk of clinical disease. As it turns out, they do not.

In the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT), more than 4000 patients whose CD4+ cell count was 300/μL or higher were randomized to receive antiretroviral therapy only or antiretroviral therapy plus IL-2.14 The results of the study demonstrated that IL-2 could significantly increase the number of CD4+ cells over time and maintain those increases for a 7-year period; however, the CD4+ cell count increases failed to produce any clinical benefit—that is, there was no difference seen in the primary end points of rates of death or opportunistic disease. Further, IL-2 use was associated with a significant increase in grade 4 clinical events (hazard ratio [HR], 1.23; P = .003), such as local reactions to IL-2 administration (HR, 1.92; P = .01) and vascular reactions, primarily deep venous thrombosis (HR, 2.81; P < .001).

In another IL-2 trial, Study of IL-2 in People with Low CD4+ T Cell Counts on Active Anti-HIV Therapy (SILCAAT), 1695 patients were randomized to receive antiretroviral therapy alone or antiretroviral therapy plus IL-2 if their CD4+ cell counts were between 50/μL and 300/μL.15 Median follow-up was more than 7 years, and during that time the mean CD4+ cell count in IL-2–treated patients was 59/μL higher than in those who received only antiretroviral therapy (P < .001). Unfortunately, just as in ESPRIT, there were no significant differences regarding the occurrence of clinical end points for the duration of the study.

The lack of clinical benefit seen in both ESPRIT and SILCAAT may be due to a variety of factors, including that the expanded CD4+ cell population seen with IL-2 use was qualitatively different and not as effective immunologically as a normal CD4+ population. It was also postulated that there may be harmful effects of IL-2 that are not mediated by CD4+ cells. An additional factor could be that the immunological improvements associated with effective antiretroviral therapy are adequate, without IL-2, to provide adequate functional immunological protection. The more pressing question may be why did these studies continue after their initial results were so disappointing?

Dr Boyle has reported no potential conflict of interest relevant to this article. Dr Cohen reports having received consulting fees and grant or research support from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, and Virco Labs; speaking fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, and Tibotec; and honoraria from all of the above. Dr DeJesus reports having received research support from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman-La Roche Laboratories, Merck, Pfizer, Schering Plough, and Tibotec and having served as a consultant or on an advisory board for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences (regional consultant), GlaxoSmithKline, Merck, Tibotec, and Vertex Pharmaceuticals. Dr Elion reports having received grant or research support from Gilead Sciences, GlaxoSmithKline, Koronis, Panacos, and Tibotec; consulting fees from Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline; speaking fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Tibotec; and honoraria from all of the above. Dr Frank reports having received research grants from Bavarian Nordic, Merck, and Tibotec; having served as an advisor for Abbott, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Tibotec; and having received honoraria from Abbott, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Tibotec. Dr Moyle reports having received grant or research support from Ardea Biosciences, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, NeurogesX, Theratechnologies, and Tibotec; consulting fees from Ardea Biosciences, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Incyte, Merck, Monogram Biosciences, Pfizer, Roche Laboratories, Tobira, and Tibotec; speaking fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, and Tibotec; and honoraria from all of the above. Dr Sax reports having received grant support from GlaxoSmithKline; having served as a consultant for Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, and Tibotec; and having received teaching honoraria from Abbott, Bristol-Myers Squibb, Gilead Sciences, and Merck.

References

References
1. D:A:D Study Group, Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration [published correction appears in Lancet. 2008;372:292]. Lancet. 2008;371:1417-1426.
2. Strategies for Management of Anti-Retroviral Therapy/INSIGHT; DAD Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22:F17-F24.
3. Cutrell A, Hernandez J, Yeo J, et al. Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials. 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract WEAB0106.
4. Lundgren J, Reiss P, Worm S, et al. Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI, and NRTI drug classes: The D:A:D Study. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 44LB.
5. Lang S, Mary-Krause M, Cotte L, et al. Impact of specific NRTI and PI exposure on the risk of myocardial infarction: a case-control study nested within FHDH ANRS CO4. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 43LB.
6. Benson C, Ribaudo H, Zheng H, et al. No association of abacavir use with risk of myocardial infarction or severe cardiovascular disease events: results from ACTG A5001. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 721.
7. Palella F, Gange S, Elion R, et al. Inflammatory markers among abacavir and non-abacavir recipients in the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 150LB.
8. McComsey G, Smith K, Patel P, et al. Similar reductions in markers of inflammation and endothelial activation after initiation of abacavir/lamivudine or tenofovir/emtricitabine: The HEAT Study. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 732.
9. Satchell C, O’Connor E, Peace A, et al. Platelet hyper-reactivity in HIV-1-infected patients on abacavir-containing ART. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 151LB.
10. Hsue P, Wu Y, Schnell A, et al. Association of abacavir and HIV disease factors with endothelial function in patients on long-term suppressive ART. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 723.
11. Zhu L, Mahnke L, Butterton J, et al. Pharmacokinetics and safety of twice-daily atazanavir (300 mg) and raltegravir (400 mg) in healthy subjects. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 696.
12. Emery S, Abrams DI, Cooper DA, et al; ESPRIT Study Goup. The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT. Control Clin Trials. 2002;23:198-220.
13. Levy Y, Mitsuyasu R, Tambusi G, et al. CD4 count increases in patients with CD4 counts of 50-300 treated with intermittent IL-2: immunologic results from the Study of IL-2 in Combination with Active Antiretroviral Therapy (SILCAAT) Trial. 9th European AIDS Conference; October 25-29, 2003; Warsaw. Abstract F 14/3.
14. Losso M, Abrams D, and INSIGHT ESPRIT Study Group. Effect of Interleukin-2 on clinical outcomes in patients with a CD4+ cell count of 300/mm3: primary results of the ESPRIT Study. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 90aLB.
15. Levy Y, SILCAAT Sci Committee. Effect of Interleukin-2 on clinical outcomes in patients with CD4+ cell count 50 to 299/mm3: primary results of the SILCAAT study. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 90bLB.

 
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