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NEW FRONTIERS - XVIII International AIDS Conference (IAS)

Vienna, Austria / July 18-23, 2010

The most commonly used first-line nucleoside reverse transcriptase inhibitor (NRTI) combinations are abacavir/lamivudine (ABC/3TC) and tenofovir/emcitrabine (TDF/FTC). In most guidelines, both are considered appropriate for what is referred to as the NRTI backbone of a regimen that also includes a non-NRTI (NNRTI) such as efavirenz or a ritonavir-boosted protease inhibitor such as atazanavir. However, NRTIs differ markedly in their influence on long-term function of organ systems that have now emerged as most susceptible to accelerated age-related impairment in HIV patients. These include the cardiovascular (CV) system, the renal system, the skeleton and the brain.

“As the studies in aging HIV patients have emerged, there has been a risk of focusing on the most recent problem getting attention, but what is really needed is to weigh all the risks,” stated Dr. David Hardy, UCLA AIDS Institute, University of California, Los Angeles. As a participant in one of the many symposia at the IAS meeting that addressed this issue, Dr. Hardy submitted that it is now clear that CV disease is accelerated in patients with HIV, but so is renal impairment, bone loss leading to osteoporosis and cognitive decline. These risks are not equally distributed among patients.

The same point was made at a symposium entitled “Double-Edged Sword,” which attempted to capture the fact that HIV regimens save lives but may also carry varying risks for specific organ damage. In that symposium, a series of four experts were assigned to assess the risk of CV disease, osteoporosis, renal impairment and dementia. In each case, the data suggest overwhelmingly that HIV infection is an independent risk factor for progressive dysfunction in these areas but with a varying influence of antiretroviral therapies on risk.

Cardiovascular Disease and Renal Impairment

Of these, CV disease has received the most attention, probably because it is the second most common cause of death in patients with HIV after liver disease. In patients with HIV, like those without HIV, increasing age is a major CV risk factor but the much earlier onset of CV events in HIV patients is likely to be multifactorial, including higher rates of risk factors such as smoking in those with HIV, an inflammatory state induced by HIV, and antiretroviral agents that exacerbate the risk by altering lipid metabolism. The pro-inflammatory state induced by failure to control infection provides an apt illustration of the double-edged-sword concept of antiretroviral therapy.

“With HIV therapy, we decrease the viral load and by doing that we also presumably reduce the inflammation, which would be expected to reduce the CV risk, but we also have some patients who might have adverse effects from therapy, such as elevated lipids or hyperinsulinemia and diabetes mellitus, so the net benefit might be reduced or lost,” explained Dr. Georg M. N. Behrens, Division of Clinical Immunology, Hanover Medical School, Germany. Noting that renal impairment is also a CV risk factor, Dr. Behrens indicated that no relative risk should be considered in isolation.

This is an important reorientation because the potential risks of NRTIs have often been evaluated individually. The controversial decision by the guideline committee of the U.S. Department of Health and Human Services (DHHS) to classify ABC/3TC as an alternative to TDF/FTC—which was not repeated by several other major guidelines, including the European AIDS Clinical Society (EACS)—was based in part on data from the European D:A:D cohort suggesting increased CV risk from ABC. Yet, an increase in CV events on ABC has not been observed consistently across studies, and the change in guidelines overlooks different types of toxicities associated with alternative NRTIs, such as TDF, some of which are also relevant to CV risk. Advancing renal disease, another CV risk factor, in aging patients is an example.

In his analysis of risk of renal impairment in HIV patients, Dr. Mohamed G. Atta, Director, DaVita Health Care Dialysis Center, Johns Hopkins University, Baltimore, Maryland, suggested that baseline risk is a critical factor to consider. Although TDF is implicated as an important source of renal impairment, data from his centre demonstrated “a much worse decline in renal function in patients on TDF after age 45.” He also reported that the risks of renal impairment intensify in patients who already have a low glomerular filtration rate. However, he returned to the double-edged-sword concept in noting that the risk of renal disease from progressive and untreated HIV is probably greater than the risk of treatment.

The same concern is relevant to CV disease. While Dr. Atta characterized TDF as a proximal tubular toxin, there is no clear mechanism of CV risk from ABC. Dr. Behrens reported that there are at least four different studies which were unable to associate this agent with increased inflammation, and ABC does not significantly alter lipid metabolism. If ABC does increase CV risk, baseline risk factors may be very important. In fact, not all studies, including a recently completed meta-analysis of 29 randomized controlled trials with 9611 patients, have shown an association, raising questions about whether such cohort studies as D:A:D were able to control for biases.

“Potential confounding factors not adjusted for in the D:A:D study have been reported, including the fact that ABC has been preferentially prescribed to those with metabolic syndromes, lipoatrophy, dyslipidemia, renal disease and coronary heart disease,” observed Dr. Mario Cruciani, HIV Outpatient Clinic, Verona, Italy. Senior author of the meta-analysis, he reported that the relative risk (RR) of myocardial infarction on ABC was actually non-significantly lower than on an alternative NRTI or placebo in his study (RR 0.74; 95% CI, 0.39-1.42; P=0.36), which would be expected to be more reliable than a cohort analysis because patients were randomly assigned to the comparator arms.

Osteoporosis and Cognitive Loss

However, overall risk for any adverse outcome associated with HIV or its therapies may not be as important as RR. In the analysis of the risk of osteoporosis, Dr. Paddy Mallon, consultant in infectious diseases, Mater Misericordiae University Hospital, Dublin, Ireland, estimated that 50% of patients with HIV have low bone mineral density (BMD) based on published studies, but the increased risk of bone fracture appears to be very age-related. Although this is true in the non-HIV population, the age is younger in patients with HIV.

“In patients without HIV, the prevalence of fractures really kicks off as people get into their 60s and 70s, but in those with HIV, the prevalence starts to take off much earlier,” Dr. Mallon told delegates. Again, HIV alone appears to play a role in BMD loss, making control of HIV a priority, but some therapies may exacerbate the problem, which resurfaces the double-edged sword of therapy.

One issue is that adverse changes in bone remodelling are exacerbated by renal impairment, which is linked to skeletal resistance to the calcemic action of parathyroid hormone, altered vitamin D metabolism and phosphate retention. Again, the risk of clinically significant osteopenia is highly individualized, based on baseline BMD and lifestyle risks such as lack of exercise as well as the presence of renal disease.

In cognitive loss, HIV appears to be a key risk factor, but the ability of current therapies to penetrate the cerebrospinal fluid may play a critical role in the risk of clinical symptoms, according to Dr. Victor Valcour, Department of Neurology, University of California, San Francisco. Although this is not a double-edged-sword dilemma for treatment selection, he characterized HIV cognitive impairment as “a silent epidemic.” Again, individual risk level as well as treatment choice may be important determinants of clinical manifestations.

Summary

For NRTI combinations, the relative risks for organ systems must be individualized. HIV control is paramount for survival so an effective therapy must be the first priority. However, the cumulative long-term risk of adverse events is also critical for selection of specific agents. For NRTIs, the relative role of ABC/3TC and TDF/FTC are dependent on an understanding of baseline function in multiple organ systems. Both combinations are effective and well tolerated, but they are not interchangeable. Although newly presented data from the Canadian Observation Cohort Collaboration (CANOC) reaffirmed ABC/3TC as equally effective as TDF/FTC for first-line therapy in antiretroviral-naive HIV patients, the choice of any NRTI combination should be individualized according to the overall safety across organ systems at risk.