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PRIORITY PRESS - 12th European AIDS Conference

Cologne, Germany / November 11-14, 2009

The holistic approach to the management of HIV has been gaining momentum over several years as data linking the presence of HIV with accelerated disease processes have accumulated. Although the risk of liver failure from hepatitis B and C co-infection has been recognized from the beginning of the HIV epidemic, increased rates of cardiovascular (CV) disease, particularly in patients exposed to protease inhibitors (PIs), was an early indication that a broad perspective was needed in managing the health risks of HIV patients. According to experts speaking at the EAC, the specific demands of a holistic approach to HIV include baseline and then sequential measures of CV risk factors, cognitive function, renal function and more recently, osteoporosis.

Increased Rate of Osteopenia

In a newly completed study of 892 HIV-infected patients with a mean age of approximately 45 years, the increased rates of osteopenia and osteoporosis were particularly remarkable in men. Based on current criteria, 43.5% demonstrated osteopenia and 7.9% had osteoporosis, according to the senior author, Murielle Mary-Krause, PhD, University of Paris, France. In the non-HIV-infected general population, this osteopenia rate would not be reached until age 70.

Although a low CD4+ cell count was a risk factor for bone mineral density (BMD) loss in this study, 77% of patients had HIV suppressed below the limits of detection. Not surprisingly, advancing age was associated with an increasing risk of BMD loss, but the authors also found an association between osteopenia at the spine and cumulative exposure to PIs. They also noted high rates of exposure to the nucleotide reverse transcriptase inhibitor tenofovir (TDF). “During the first two years of cumulative exposure to TDF, the risk of osteopenia and osteoporosis at the spine and osteoporosis at the hip increased by up to fourfold,” Dr. Mary-Krause told delegates.

The Renal Link

This exposure may be important because TDF has been linked to impaired renal function, which in turn may increase the risk of abnormal bone metabolism through an adverse effect on calcium and phosphate homeostasis. Both kidney disease and TDF have been associated with hypophosphatemia, hypocalcemia and BMD loss in previous studies. However, the clinical significance of these effects in patients without baseline osteoporosis is still being evaluated.

Some of the most recent data to address this question came from an interim analysis of ASSERT (Assessment of Safety and Efficacy of ABC/3TC and TDF/FTC in Treatment-Naive HIV-1 Infected Subjects) comparing TDF/emtricitabine (FTC) to ABC/lamivudine (3TC) when both are combined with efavirenz. In this study, there were differences in renal function even though clinically significant effects have not been demonstrated in follow-up to date.

“With respect to renal biomarkers of tubular dysfunction, profound tubular dysfunction and damage and general kidney damage, there was a 47% reduction in ß2-microglobulin excretion of urine with ABC-based therapy compared to an increase of 24% when treatment was TDF-based therapy, which was significant,” reported Dr. Hans-Jürgen Stellbrink, Infectious Diseases Medical Center, Hamburg, Germany. In addition, there “was a significant difference in terms of the change in retinol binding protein:creatinine ratio between the two arms, with no change in the ABC/3TC arm and an increase in the TDF/FTC arm.”

In ASSERT, 385 HLA-B*5701-negative, antiretroviral-naive HIV-infected patients were randomized. The goal was to compare the treatment strategies for effect on renal function, BMD loss and CV risk biomarkers. Renal function is being assessed with estimated glomerular filtration rate (eGFR).

After 48 weeks, the time to interim analysis, no significant differences have been observed in eGFR from baseline, but an evaluation of proximal tubule (PT) markers indicated a mild deterioration of PT function in the TDF/FTC arm compared to an improvement in the ABC/3TC arm. There were no discontinuations in the study due to renal dysfunction.

However, there has been a significant difference between the treatment arms in BMD change from baseline in both the hip (ABC/3TC, -1.9%; TDF/FTC, -3.6%) and spine (ABC/3TC, -1.6%; TDF/FTC, -2.4%), according to Dr. Stellbrink. Moreover, there was a greater rate of bone turnover with TDF/FTC than with ABC/3TC.

“We put this in a clinical context by grouping the patients according to a reduction of <u>></u>2% from baseline, because this is about the maximum BMD reduction that can be expected in postmenopausal women, and a significantly greater proportion of patients in the TDF/FTC arm fulfilled the criterion of a <u>></u>2% loss of BMD,” he told delegates.

For biomarkers of CV risk, there was no clinically significant difference between the groups for high-sensitivity C-reactive protein, which remained stable in both arms, or IL-6, which improved in both arms. Not unexpectedly in the short period of follow-up, there was no significant difference in CV events.

Longer-term Risk Factors in Context

Several cohort studies have suggested that some antiretroviral agents, particularly those with an adverse effect on lipid metabolism, increase the risk of CV events, but the concept of a holistic approach to management of HIV is to put all risks into context. In general, the risks of adverse effects of the most commonly used antiretroviral agents on various organ systems, including the kidney, the heart and the central nervous system, appear to be modest when measured over short time periods but may become significant over long-term use in those with an elevated baseline risk. It is for this reason that several experts have recommended evaluating CV risk factors, kidney function, BMD and cognitive function even in middle-aged HIV-infected patients. While control of HIV infection is critical in all patients, specific antiretrovirals may be more attractive than others based on abnormalities in these measures.

For example, the risk of CV events in the form of myocardial infarction (MI) in the French Hospital Database of HIV, which has been following 278 mostly male HIV patients and 873 controls, traditional risk factors, particularly smoking, were very strong predictors of a CV event in both HIV-infected patients and controls, according to a lead investigator in this study, Dr. Dominique Costagliola, University of Paris. Importantly, the use of cocaine or recreational intravenous drugs, although risk factors for CV events in both populations, were more commonly found in individuals with HIV. In addition, the risk of MI increased with detectable levels of HIV viremia and when the CD4+ cells:CD8+ cells ratio fell below 1.0.

Based on the potential for greater CV risk in some HIV patients than others, Dr. Costagliola suggested that baseline risk factors, including family history of CV disease, should be evaluated. In those at high risk, selecting antiretroviral agents that are not associated with CV disease may be appropriate (i.e. PIs) but may not be useful in those without significant CV risk factors.

Similar conclusions might be drawn about risks to other organ systems, such as the kidney. While many patients are at low risk for renal impairment and osteoporosis and unlikely to benefit from drug selection based on relative renal effects, others at high baseline risk or who develop renal impairment during the course of therapy may be candidates for a drug switch. A baseline deficit in cognitive function, which also appears to be affected differently by different antiretroviral therapies, may also be a criterion for individualized therapy.

The holistic approach to HIV treatment accepts that no antiretroviral regimen may be optimal in all patients because of baseline differences in organ function or other factors such as the use of cocaine or recreational intravenous drugs. Selecting treatment without considering the relative advantages and disadvantages based on a patient profile overlooks the potential to provide optimal long-term management. For the same reason, selecting an agent based on its influence over a single organ system regardless of the patient’s baseline risk may deny patients the most appropriate therapy when all risks are considered.

Summary

The success in identifying highly effective antiretroviral regimens has directed attention to a holistic strategy for managing the HIV patient. While control of HIV infection is essential, it may be possible to individualize therapy to reduce risks to other organ systems such as the heart, the kidney and the skeleton. Such a strategy is dependent on baseline evaluation and sequential monitoring of a spectrum of organ systems to ensure that treatment is well matched to the individual risk profile.