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NEW FRONTIERS in MEDICINE HIV/AIDS - 18th Annual Canadian Conference on HIV/AIDS Research (CAHR)

Vancouver, British Columbia / April 23-26, 2009

Highly-active antiretroviral therapy (HAART) provides a life expectancy approaching that of the non-HIV-infected population, according to the most recent long-term data. However, this triumph against a previously fatal infection is now being accompanied by contradictory evidence that HIV accelerates the aging process. In many instances, it is not clear whether the earlier onset of diseases of aging in the HIV population is due to the infection or the treatments. Both should be considered in a growing focus on preserving quality of life in older HIV-infected individuals.

“HAART works. It works well. Patients can now have a relatively normal life expectancy, which is something that we could not have said in the past,” stated Dr. Sharon Walmsley, Director of Clinical Research, Immunodeficiency Clinic, UHN-Toronto General Hospital, and Associate Professor of Medicine, University of Toronto, Ontario. However, while patients are no longer dying of immunodeficiency, “we are seeing deaths from a growing list of non-HIV-related problems such as heart disease, liver disease and cancers.” She indicated that in patients with otherwise good control of HIV, this has become an important focus of current disease management.

The challenge is recognizing confounding factors that complicate efforts to understand why specific diseases are accelerated in the HIV patient. The most common of these accelerated conditions, coronary artery disease (CAD), provides one of the best examples. The infection, treatments and lifestyle choices among HIV patients are all implicated. For example, HIV reduces levels of HDL while creating a potentially pro-atherogenic inflammatory state. Many antiretrovirals, such as some protease inhibitors (PIs), also adversely affect lipid metabolism in a way that predicts increased CAD risk. Finally, rates of smoking are higher in HIV than in non-HIV-infected individuals.

Caution Called for Regarding Confounding Risk Factors

However, the risk of confounding from multiple variables that may or may not be contributing to disease risk in any single individual is great. This is a key issue raised by recent data from the D:A:D multicohort study implicating some nucleoside reverse transcriptase inhibitors (NRTIs) in increased risk of CAD. In the D:A:D data, exposure to abacavir (ABC) or didanosine (ddI) was associated with a greater risk of CAD relative to other NRTIs, but two other large studies were unable to reproduce the association with ABC. A third study found an association only in patients taking ABC for less than a year but not longer. One of the problems with these data is the absence of a plausible mechanism by which ABC or ddI could increase CAD. For example, neither has a substantial effect on lipids.

In her assessment, Dr. Walmsley emphasized the difference between association and causation. In the absence of a randomized, controlled trial, causality is difficult to prove, but there are criteria that make a link more or less likely. These criteria include consistency among data from different sources; a large increase in relative risk; increasing risk with greater drug exposure; and the presence of a credible and likely explanation for the pathophysiologic mechanism. None of these criteria are fulfilled when evaluating the plausibility of a causal link between CAD and ABC or ddI. Due to the many confounding issues, including the potential for channeling HIV patients known to have CAD to a relatively well-tolerated and lipid-neutral NRTI like ABC, the inconsistent association of these NRTIs and CAD is impossible to interpret.

This context of risk for the individual patient is also important. When the same exercise in risk management is applied to the growing problem of cognitive dysfunction in aging HIV patients, the list of antiretrovirals to avoid or to prefer is not the same as those for reducing the risk of CAD. Surveys now suggest that about 50% of HIV-infected patients over the age of 50 have measurable cognitive loss. Again, confounding factors, such as high rates of drug and alcohol abuse, make the pathologic role of the disease or its treatments difficult to isolate, but all antiretrovirals do not appear to be equal for reducing risk.

HIV-associated Neurocognitive Disorder

“Since the introduction of HAART, we are all under the impression that things have gotten so much better in regard to cognitive loss, and this may be true because we are not seeing the severe AIDS-related dementia that once was so common, but the proportion of patients who are impaired is still very high,” noted Dr. David B. Clifford, Professor of Neuropharmacology, Washington University School of Medicine, St. Louis, Missouri. “It is not wise to think this is not an important clinical issue.”

The phenomenon known as HIV-associated neurocognitive disorder (HAND) has been stratified into three types: mild HAND is impairment readily detected by objective performance tests but unnoticed by the patient; moderate HAND is a degree of cognitive loss sufficient to generate complaints about functional impairment, such as memory loss or delayed thought processing; severe HAND signals a need for supportive care. While AIDS-related dementia fell into this final category, Dr. Clifford estimated that severe HAND is only observed in about 2% of current HIV patients; 20% have asymptomatic HAND and 30% have sufficient symptoms to produce a negative burden on quality of life.

“When we try to control for confounders, such as drug use, drinking and history of head trauma, these factors do track for an increased risk of HAND, particularly moderate or severe cases, but even in a squeaky-clean population for whom we cannot identify any predisposing risks, the prevalence of impairment is still 40%,” Dr. Clifford told delegates.

The relative risk of HAND, like the relative risk of CAD, does appear to be influenced by antiretroviral therapy even if it is not the sole clinical issue. However, while some antiretroviral agents appear to promote CAD, agents with better penetration of the central nervous system (CNS) appear to offer an opportunity to reduce risk by lowering viral replication and diminishing inflammation, both of which appear to impair neurological function.

When antiretroviral agents are scored for CNS penetration, differences are substantial and allow therapies to be ranked into three stratifications. Of NRTIs, ABC and zidovudine have the greatest penetration, while ddI and tenofovir have the least. Of non-NRTIs (NNRTIs), nevirapine has good penetration but efavirenz’s penetration is modest. Of PIs, ritonavir boosting places amprenavir, indinavir and lopinavir in the top rank, while ritonavir itself, saquinavir and ritonavir-boosted tipranavir are in the bottom rank.

“When we compare regimens for rank of CNS penetration, we have seen an increased suppression of HIV in the CNS for those with the highest rank compared to those with a lower rank even though the odds of suppression of plasma HIV do not differ,” Dr. Clifford indicated. He added that there are also preliminary retrospective data associating higher CNS penetration with a lower risk of cognitive decline. A prospective, randomized trial is now being planned.

“We now have good evidence that HAND continues to cause significant disability in patients who are on a successful HAART regimen. These data suggest that the differences in the ability of HAART to control HIV in the brain compartment may be clinically important and that we will need to consider penetration to reduce this risk,” Dr. Clifford stated. He characterized this as an important issue that will only gain momentum as the median age of the HIV-infected population continues to rise.

Summary

In older individuals with HIV, like younger patients, no clinical issue is more important than sustained HIV control. However, evidence that many aging processes are accelerated in individuals with HIV suggests that a paradigm shift will be needed in the definition of optimal management in an aging HIV population. In addition to viral suppression, it will be increasingly important to consider strategies in the context of individual risks for specific age-related processes, such as CAD, cognitive loss, renal dysfunction and osteoporosis. This suggests that the optimal therapeutic choices in regard to overall risk management will require a new degree of individualization of therapy.