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XVII International AIDS Conference

Mexico City, Mexico / August 3-8, 2008

Suspicion about potential adverse cardiovascular (CV) effects of nucleoside reverse transcriptase inhibitors NRTIs initially centred on those agents that alter patient lipid profiles. However, the focus shifted following an analysis of D:A:D (Data Collection on Adverse Events in Anti-HIV drugs), which counter-intuitively implicated agents that do not affect lipids, such as abacavir (ABC). Specifically, data derived from 33,347 patients and 157,912 person-years of treatment found an association between recent—but not current—use of ABC and didanosine and myocardial infarction (MI) in moderate- and high-risk patients. The analysis showed no such association with other NRTIs (Sabin et al. Lancet 2008; 371:1417-26).

The D:A:D findings spurred re-analysis of data from other clinical trials. Presentations at the 17th Annual Canadian Conference on HIV/AIDS Research in April 2008 failed to uncover any evidence to corroborate D:A:D findings. The re-analysis and discussion continued at this year’s IAC.

Clinical Experience

Since its introduction into clinical use almost a decade ago, ABC (all marketed formulations) has accumulated more than 1 million patient-years of exposure, stated Dr. Jürgen Rockstroh, Department of Medicine, University of Bonn, Germany. This large clinical experience has demonstrated that ABC is generally recognized as having a favourable metabolic impact in comparison to other members of the NRTI class. It improves mitochondrial toxicity following treatment with a thymidine analogue and is associated with reduced hypersensitivity-related morbidity and mortality. In a brief communication that appeared in the same issue of The Lancet as the D:A:D report, a summary of data from the manufacturer’s database showed no difference in the rate of coronary artery disease or MI between clinical-trial patients randomized to ABC-containing therapy or treatment without ABC (Cutrell et al. Lancet 2008; 371:1413).

Dr. Rockstroh explained that D:A:D investigators previously linked an increased risk of MI in HIV/AIDS patients to combination antiretroviral therapy (ART) (Friis-Moller et al. N Engl J Med 2003;349:1993-2003). At that time, the investigators also emphasized statistically significant contributions of multiple CV risk factors, including older age, positive family history, dyslipidemia and diabetes. “A review of preclinical and clinical pharmacology has not indicated a clear contribution of ABC therapy to enhanced risk of MI via plausible biologic mechanisms,” he observed.

Dr. Rockstroh noted that CV disease accounts for more than 20% of mortality in HIV-infected patients (Crum et al. J Acquir Immune Defic Syndr 2006;41:194-200). To some extent, the increased CV burden reflects the advances of modern ART, which have greatly improved long-term survival in HIV/AIDS patients. “Monitoring and management of CV disease are increasingly important to HIV care and call for close collaboration between all care providers,” he remarked. “Clinicians should regularly assess all CV risk factors in patients receiving chronic care.”

An Evolving Analysis

Studies reported here reflected the ongoing efforts to clarify and explain the D:A:D results. Data from 54 clinical trials involving 14,174 adults treated for at least six months showed no difference in the frequency of ischemic coronary events or MI with ABC-containing vs. non-ABC regimens, reported Dr. Jaime Hernandez, Triangle Park, North Carolina. Overall, MI and ischemic events were uncommon. Patients treated with non-ABC regimens had an MI incidence of 0.139%, whereas ABC-containing combination therapy was associated with an incidence of 0.114%. The incidence of ischemic coronary disease or events was 0.416% without ABC and 0.249% among patients whose combination ART included ABC.

Similar results emerged from an analysis limited to 12 randomized trials involving a total of 3200 adult patients. The MI rates were 0.355% in patients who received non-ABC regimens and 0.127% in those exposed to ABC. Ischemic disease and events occurred in 0.768% and 0.318% of patients treated without or with ABC, respectively. “The low event rate limited the statistical power of the analysis,” noted Dr. Hernandez. “However, there was no difference in the incidence of ischemic coronary artery events or MI in subjects who received ABC-containing vs. non-ABC-containing combination ART. Further study is needed to fully evaluate the association of ABC and CV disease.”

Dr. Jens Lundgren, University of Copenhagen, Denmark, echoed the view that the story behind ABC and CV risk continues to evolve. Dr. Lundgren presented data from a subgroup of 2752 patients enrolled in the SMART (Strategies for Management of Antiretroviral Therapy) trial (El-Sadr et al. N Engl J Med 2006;355:2283-96). Like the D:A:D study, the SMART analysis suggested an increased risk of CV events in patients treated long-term with ABC.

However, the NRTI-associated risk was limited to patients who were already at high risk for heart disease, i.e. those with five or more existing CV risk factors when they started ART. “The risk was not significantly increased in patients with fewer than five CV risk factors,” observed Dr. Lundgren.

NRTI Efficacy Data

Controversy also has arisen regarding the efficacy of NRTI-containing combination ART. At the Conference on Retroviruses and Opportunistic Infections earlier this year, investigators from the AIDS Clinical Trials Group (ACTG) 5202 study reported shorter time to virologic failure with ABC/lamivudine (3TC) vs. tenofovir/emtricitabine in ART-naive patients with a baseline viral load exceeding 100,000 copies/mL. The data on patients with lower viral loads remain blinded in that ongoing trial.

In contrast, a re-analysis of six clinical trials, using ACTG 5202 definitions of virologic failure, showed no difference in treatment outcomes with ABC/3TC by baseline viral load. “The ACTG 5202 results were unexpected, not consistent with prior clinical experience, and raise the question of whether the two nucleoside backbones have comparable efficacy and safety,” stated Dr. Keith Pappa, Triangle Park, North Carolina.

The primary end point of ACTG 5202 was virologic failure, defined as a viral load ³1000 copies/mL at 16 to 24 weeks or a viral load ³200 copies/mL at 24 weeks or later. Applying the ACTG 5202 efficacy end point, Dr. Pappa presented data on the probability of protocol-defined virologic survival at week 48 by baseline viral load. His analysis included 2940 ART-naive patients who received ABC/3TC-containing regimens. Rates of virologic survival ranged from 89% to 95% across the six studies and did not differ between patients with baseline viral loads ³100,000 copies/mL and those with lower viral loads at entry.

Further illustrating the variance of the ACTG 5202 results, Dr. Pappa presented data from an analysis of a 96-week outcomes in the HEAT (Head to Head Epzicom and Truvada) trial. Previously, the 48-week results showed no significant difference in outcome by baseline viral load between patients randomized to ABC/3TC or tenofovir/emtricitabine. The trial was powered to demonstrate non-inferiority of the ABC-containing regimen.

The updated HEAT results showed that 60% of ABC/3TC patients and 58% of tenofovir/emtricitabine patients had a viral load £50 copies/mL at 96 weeks. Separate analyses by baseline viral load of <100,000 copies/mL or higher showed viral suppression rates of 63% and 56% for the ABC-containing regimen, respectively, vs. 58% and 58% for the tenofovir/emtricitabine combination.

Summary

More than 20 years after the first NRTI was introduced, new data about the drug class continue to emerge to guide clinical decision-making, commented International AIDS Society President Dr. Pedro Cahn, Chief, Infectious Diseases Unit, Juan Fernandez Hospital, Buenos Aires, Argentina. Clinical guidelines consistently cite NRTIs, including ABC, as preferred or recommended agents for highly active ART (HAART). They have demonstrated safety and efficacy in extensive investigation. The ABC/3TC combination in particular has established efficacy, good short-term tolerability, minimal mitotoxicity, and no contribution to lipoatrophy. “Since their introduction in 1987, NRTIs have been the foundation of ART. HAART remains NRTI-based today,” Dr. Cahn concluded.