Reports

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 - 16th Conference on Retroviruses and Opportunistic Infections (CROI)

Montreal, Quebec / February 8-11, 2009

Due to the rapid aging of the HIV/AIDS-infected population in many parts of the world, including Canada, attention has turned to addressing long-term health risks of the disease and its therapies. The increasing number of options for maintaining patients at the goal of undetectable viremia (<50 copies HIV RNA/mL) specifically permits clinicians to consider relative risks of adverse events over periods measured in years or even a lifetime. In the specific area of nucleoside reverse transcriptase inhibitors (NRTIs), the relative risks of abacavir (ABC) and tenofovir (TDF) are among the most intensively studied because of their efficacy and their inclusion within competing first-line regimens.

Findings Confirm Complexity of CV Disease in HIV/AIDS

In a comprehensive summary of the data on cardiovascular (CV) risk of ABC here at CROI 2009, Dr. Peter Reiss, Professor of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands, noted the HIV infection alone appears to increase CV risk by promoting a systemic inflammatory response.

“CV disease [in patients with HIV/AIDS] is complex and multifactorial,” he confirmed. Dr. Reiss suggested that a common-sense approach to the principles of managing CV risk in the aging HIV patient is “to maintain HIV suppression, assess CV risk factors, and modify antiretroviral therapy (ART) only if this can be accomplished without jeopardizing HIV control.” He concluded that in low-risk patients, the relative increase in risk from ABC “is very low” in those studies that have shown an association. Often, any modest risk is unlikely to outweigh other key objectives in providing a well-tolerated, effective and convenient combination ART (CART).

One reason to remain circumspect is that several studies have found no association between ABC and risk of myocardial infarction (MI). Two discordant late-breakers on CV risk were presented at the 2009 CROI meeting. In the D:A:D study, relative risk was evaluated in the NRTI, protease inhibitor and non-NRTI (NNRTI) drug classes in an analysis of 33,308 patients being followed in 11 cohorts. Among NRTIs, a modest and often statistically insignificant increased risk of MI was observed for every NRTI but zidovudine. For TDF, the 95% confidence interval (CI) ranged from 0.92 to 1.19, so significance was not reached, but the relative risk (RR) was 1.05. For ABC, the narrower CI (95% CI, 1.01-1.14) did produce significance, but the RR was only 0.02 higher at 1.07.

In another late-breaker, the risk of MI on cumulative exposure was not increased for any NRTI, including ABC. This study did find that recent exposure (less than one year) of ABC was associated with an increased risk of MI, but the absence of a long-term risk counters assertions that risk might be cumulative over time. Relative to D:A:D, the methodology of the case control evaluation may have specific advantages, according to Prof. Dominique Costagliola, INSERM-Pierre and Marie Curie University, Paris, France.

“In a nested control study, new case controls are entered into the cohorts that were defined prior to the study. This reduces the recall bias that is a weakness of cohort studies that simply compare the ‘cases’ of an event to ‘controls,’ which are those without the event,” Prof. Costagliola reported. Of retrospective analyses, all of which are considered inferior to prospective analyses, nested case-control studies are generally considered to be more reliable.

Another set of data at CROI looked at long-term outcome in 3205 patients randomized to initial ART in five ACTG (AIDS Clinical Trials Group) studies. In this analysis, there were no significant associations between recent ABC use and either MI or severe CV disease, although risk of both outcomes was increased for older age and the presence of hypertension. “In contrast to cohort studies such as D:A:D, we did not find a significant association between recent ABC use and MI or severe CV disease risk for antiretroviral-naïve patients randomized to an initial ABC regimen,” stated Dr. Constance Benson, University of California, San Diego. “Our results suggest the association with recent ABC use in other studies may be a marker for other factors not discerned in their analyses.”

In his summary, Dr. Reiss identified six studies that have evaluated an association with ABC and CV risk. Of these, four associated ABC with a modest increase in risk, primarily with recent use, and two did not. Although Dr. Reiss did recommend alternative NRTIs to ABC in patients with established CV risk, he noted that HIV infection is itself a risk factor for MI, probably as a result of systemic inflammation generated by the presence of HIV. He indicated that suppression of the virus may not only be the most important objective for preventing any complication of HIV, but it may also be the most important factor for preventing CV events in patients with HIV.

Renal Dysfunction

Some parallels could be found in the recommendations regarding the association of TDF with impaired renal function. In new data from the Swiss HIV Cohort Study with 1202 patients, the odds ratio (OR) of proximal renal tubulopathy was increased in patients exposed to TDF by more than threefold (OR 3.3; 95% CI, 1.6-7.0) after multivariable logistic regression. An even greater increase in risk was observed in patients taking TDF with a PI. Of note, the investigators identified a mechanistic link between proximal renal tubulopathy and osteoporosis, which has been linked to TDF previously.

“We found an association between use of TDF and a pathological fractional excretion of phosphate,” reported Dr. Christoph Fux, University Hospital, Berne, Switzerland, who said that this study was partially undertaken to evaluate the relationship of excessive renal phosphate losses and compensatory bone resorption leading to osteoporosis. “This pathophysiologically plausible link between the documented renal dysfunction and osteopenia or osteoporosis should be assessed in further studies.”

The risk of TDF-associated renal dysfunction appears to be relative and increases substantially by underlying renal dysfunction. In her analysis of renal complications in HIV, Dr. Lynda Szczech, Director, Nephrology Research, Duke Clinical Research Institute, Durham, North Carolina, discussed the concept of creatinine creep which describes a slow but steady worsening of renal function in patients with HIV. She recommended referring patients with fully suppressed HIV but persistent evidence of renal impairment to a nephrologist. She also noted that “some antiretrovirals have the potential to cause this, and TDF is at the top of the list,” but she suggested early detection and early intervention is key.

“You never get back to where you start [pre-morbid renal function] in patients who experience renal failure,” Dr. Szcezch cautioned. Noting that the risk of renal dysfunction is affected by specific treatments as well as by age and duration of HIV infection, she indicated that this risk, like other age-related risks, appears to be exacerbated by HIV and will be an increasing challenge in an aging HIV population.

Summary

Concluded Prof. Costagliola, “The overall risk:benefit [ratio] of each ART will need to be assessed, accounting for all risks; not only the risk of CV disease, but also the impact on bone or renal disease, for instance, as well as the impact on viral load in reservoirs in the central nervous system and tissues other than plasma.” The current focus on the interrelationship of HIV infection and the normal aging process suggests that the greatest threat to the heart and the kidney is posed by poorly controlled viremia. There is increasing evidence that otherwise effective and well tolerated ARTs such as ABC and TDF can be differentiated for risks of complications to specific organs; however, these relative risks are small and should not confound the pre-eminent focus on suppression of HIV, which by itself has the potential to impose major complications to target organs independent of therapy. Both ABC and TDF remain important options for the primary goal of HIV control.