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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 17th Conference on Retroviruses and Opportunistic Infections (CROI)

San Francisco, California / February 16-19, 2010

The initial evidence that cardiovascular risk in HIV patients is influenced by antiretroviral therapy (ART) has been followed by several important new studies that differentiate drugs for relative risks to several additional organ systems that influence long-term survival independent of HIV control. This information is altering the principles of antiretroviral drug selection, particularly in aging individuals. New data have been made available regarding relative risk to skeletal integrity and risk of chronic kidney disease. HIV suppression remains the single most important goal in HIV management, but relative effects of available agents in age-related diseases of major organs may affect long-term survival.

Attenuating Bone Density Loss

Compelling new information is emerging regarding bone mineral density (BMD). In a prospective substudy of ACTG A5202, called ACTG A5224s, highly statistically significant differences were observed between study arms comparing the nucleoside reverse transcriptase inhibitor (NRTI) combinations abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) as well as between arms comparing the non-NRTI efavirenz (EFV) and the ritonavir-boosted protease inhibitor (PI) atazanavir (ATVr). These data are important because it is now known that HIV infection itself is a source of osteoporosis, making drug selection critical in vulnerable patients.

“Bone density loss is a substantial complication of HIV infection, but antiretroviral therapies differ in the relative bone loss over time, and this is likely to be clinically important in a number of groups at risk, including men with a history of fractures or peri- and post-menopausal women,” reported Dr. Grace McComsey, Case Western Reserve University, Cleveland, Ohio, here at CROI.

She presented the results of the four-arm A5224s substudy, in which 269 participants were randomized to ABC/3TC or TDF/FTC with either EFV or ATVr. Dr. McComsey reported that BMD loss was observed on all regimens, but the decline was largest on the two regimens containing TDF/FTC. Measured at the lumbar spine (-3.0% vs. -1.3%; P=0.04) and at the hip (-3.9% vs. -2.6%; P=0.025), the far greater bone loss on TDF/FTC at 96 weeks relative to ABC/3TC predicts a large cumulatively greater deficit over time.

When EFV and ATVr were compared, there was a significantly greater loss on ATVr at the lumbar spine (-1.7% vs. -3.2%; P=0.035) but was not significant at the hip (-3.1% vs. -3.4%; P=0.59), but the substantial loss with either agents underscores the concern about osteoporosis in aging HIV patients.

This risk is not solely theoretical. In a second presentation on behalf of the Veterans Aging Cohort Project Team by Julie Womack, PhD,Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, fragility fractures were already on the rise among male HIV patients with a mean age of only 47. While fracture of the hip and vertebrae were strongly associated with age in men with or without HIV, HIV infection was associated with about a 50% increase in risk on univariate analysis and a 35% increase in risk on multivariate analysis.

Due to the risk of osteoporosis in individuals with HIV, efforts to avoid further complications in aging HIV-infected individuals will require a variety of prophylactic steps beyond appropriate drug selection, according to both Drs. McComsey and Womack. They each suggested that baseline and serial bone density measurements should be undertaken to document the integrity of the skeletal system in HIV patients. In addition to selecting agents that pose the least risk of exacerbating bone loss in patients with advancing osteopenia, they recommended dietary supplementation known to improve BMD and lifestyle changes that will reduce fracture risk.

ACTG 5202 Findings at 96 Weeks

The data from the substudy, which were presented as a latebreaker, here at CROI, followed those of the final results of the parent ACTG 5202 study, which was also a latebreaker. In this study, which randomized 1857 treatment-naïve HIV patients, the objective was to evaluate the equivalence of the two NRTI combinations, ABC/3TC or TDF/FTC. Each was studied as backbones to either EFV or ATVr, producing four study arms. The randomization was also stratified by viral load at baseline. An interim analysis was presented several months ago for the 797 patient population with a high viral load (Sax et al. N Engl J Med 2009;361:2230-40), but the focus of the new data was on the final 96-week results on the 1060 patients with a baseline viral load <100,000 RNA copies/mL.

"During extended follow-up among those in the low viral load strata, there was no difference in time to viral failure when the NRTIs were compared with either the PI or the NNRTI," reported Dr. Eric Daar, Los Angeles Biomedical Institute, Harbor-UCLA Medical Research Center, Torrance, California. "The difference in the viral failure at 96 weeks was very small, less than 2%, with used to define equivalence."

In fact, the failure rates in all arms of the study at 96 weeks were only about 11% in the ATVr arms with either of the NRTI combinations (11% vs. 10.2% for ABC/3TC vs. TDF/FTC, respectively) and 15% in the EFV arms (16.6% vs. 14.7%), reinforcing the durability of benefit with either ABC/3TC or TDF/FTC in those with a viral load <100,000 RNA copies/mL at baseline. However, Dr. Daar noted that resistance mutations emerged more commonly on EFV than on ATVr over the course of the study, regardless of nucleoside combination. The safety of the combinations were generally equivalent, although there was a greater frequency of dyslipidemias with ABC/3TC and a greater rate of renal dysfunction as identified with impaired creatinine clearance with TDF/FTC.

Renal Function

The evidence of differences in renal function is thematic with other evidence that antiretroviral agents pose unequal risk for chronic kidney disease (CKD) in aging individuals with HIV. Like BMD loss, the likelihood of clinically significant CKD accumulates over time, making it a minor issue in younger HIV patients with otherwise healthy renal function but a significant issue in aging individuals, particularly those who have other risks for compromised renal function.

In latebreaking data from the EuroSIDA study on CKD, four antiretroviral agents were identified as being associated with a highly significant increased risk of CKD on univariate analysis of which three remained highly significant on multivariate analysis.

"The increased risk of CKD was observed for TDF, ATV, indinavir and lopinavir (LPV), although the results on multivariate analysis with LPV were less clear," according to Dr. Ole Kirk, Copenhagen HIV Program, University of Copenhagen, Denmark. Of these agents, the relative risk (RR) on multivariate analysis was greatest on ATV (RR 1.21; P=0.0003) and TDF (RR 1.16; P<0.0001), but Dr. Kirk emphasized that there was a clear correlation between risk of CKD with increased exposure to TDF, a finding consistent with previously published data. Not surprisingly, the greatest risk of CKD from TDF is found among those with a low baseline estimated glomerular filtration rate (eGFR) and risk factors for CKD, underlining the importance of individualized therapy.

Results from studies discussed here at CROI results are consistent with the overall evolution in selecting and modifying ARTs to accommodate the adverse effect of HIV on aging organs. The data suggest that there is no optimal therapy for all individuals but there may be an optimal therapy for any single individual when all the patient characteristics and organ systems are considered in a holistic attempt at long-term care.

Summary

In the constant reassessment of how to optimally control HIV infection over a patient's lifetime, there has been increasing attention directed toward the characteristics of the infection and the treatments in aging individuals. No goal is more important than sustained suppression of HIV, but the expansion of therapeutic options means that effective HIV control can be achieved with agents that offer the least risk to organ systems in which the risk of accelerated aging processes may be exacerbated by one antiretroviral agent relative to another. The science of this selection has been improving incrementally.