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.

NEW FRONTIERS - 10th International Congress on Drug Therapy in HIV Infection

Glasgow, UK / November 7-11, 2010

Morbidity related to accelerated aging in HIV infected individuals, a major focus of recent HIV/AIDS scientific programs, including the congress here in Glasgow, is now the single most important threat to patients with controlled HIV infection. Although essentially all organ systems appear to be affected by a process that has been attributed by some researchers to the ability of HIV to induce mitochondrial senescence, the kidney may be an underdetected source of potentially terminal events.

“What is unclear in HIV patients is how we should be monitoring renal function and whether it is different than what should be done in an uninfected individual,” stated Dr. Ole Kirk, Copenhagen HIV Programme, Copenhagen University, Denmark. Epidemiological studies, including those conducted at Dr. Kirk’s institution, indicate that declining renal function occurs at higher rates and at an earlier age in those with HIV than in those without. However, there is limited consensus on how frequently to evaluate proteinuria and albuminuria or overall renal function with such tools as an estimated glomerular filtration rate (eGFR).

Renal Dysfunction May Be Overlooked

As a single threat, cardiovascular (CV) disease is a far more important source of morbidity and mortality than renal dysfunction in aging patients with HIV just as it is in the general population. Similarly, hepatic complications are likely to pose a greater threat in those HIV patients co-infected with hepatitis. However, both CV and liver diseases are processes that typically declare themselves years, if not decades earlier through risk factors such as hyperlipidemia, hypertension or elevated liver enzymes. Although the presence of chronic kidney disease (CKD) can also be anticipated by routinely evaluated risk factors such as hypertension and diabetes mellitus, rapidly declining renal function can occur in the absence of risk factors, making detection in some patients particularly dependent on screening programs.

In HIV patients, it appears that screening for all age-related diseases, including CKD, should be conducted earlier and perhaps more frequently. In a non-HIV population, diseases of aging typically begin in the sixth decade of life or later, and screening in the absence of early signs of pathology may not begin until at least this time, but age-related diseases are occurring much earlier in those with HIV and traditional guidelines may not be applicable. Several experts here at the International Congress of Drug Therapy in HIV suggested that the strategies for screening should be re-evaluated.

“Management of older persons with HIV should include baseline evaluations of CV risk and regular monitoring of fasting lipid and glucose levels, renal function and markers of bone disease,” suggested Dr. William Powderly, University College Dublin, School of Medicine & Medical Science, Ireland. He indicated that there is a sizeable body of evidence suggesting that both screening and management of age-related problems should be different in patients with HIV relative to those without infection, but conceded that specific recommendations are largely being made on an expert-opinion basis rather than driven by evidence.

“Furthermore, comorbidities have an important influence on antiretroviral selection, as avoidance of metabolic and other toxicities or drug-drug interaction is a key issue,” Dr. Powderly told delegates. He noted that it is clear that some antiretroviral agents appear to accelerate specific types of organ impairment more than others. Consequently, treatment adjustments based on the specific risk profile of the patient are appropriate.

Prevalence of Renal Disease Is Age-Related

For renal function, the most recent evidence of the need for screening comes from an observational study conducted in Antwerp, Belgium, in which the prevalence overall of CKD was 3% but with a clear age-related increase in risk. The senior author of the study, Dr. A.W. Colson, University Hospital Antwerpen, suggested that the findings, which were drawn from a single-centre clinical database, project a growing problem as patients age. He predicted that CKD would become an increasingly important source of related morbidities including CV disease.

“Screening for chronic renal disorders and prevention of evolution toward chronic renal failure is a crucial challenge in the management of people living with HIV/AIDS,” confirmed Dr. Colson, who indicated that these data are consistent with the contention that renal function should be assessed at a baseline examination in patients with HIV and then followed with greater frequency than might be performed in an otherwise healthy population.

Patients who have evidence of renal dysfunction will have to avoid drugs that exacerbate this problem. In new data from EuroSIDA presented by Dr. Lene Ryom, Copenhagen HIV Programme, 4 antiretroviral therapies were found to be associated with a significant increase in the OR of renal dysfunction in univariate analysis. Three of these are protease inhibitors (PIs) and one is a nucleoside reverse transcriptase inhibitor (NRTI). The OR for the PIs was 1.37 for atazanavir (P=0.0032), 1.37 for lopinavir (P<0.0001) and 1.24 for indinavir (P=0.0005). The OR for the lone NRTI, tenofovir, was 1.33 (OR P=0.0011).

PI vs. Efavirenz: Change in Renal Function

The ability to alter CKD risk of through antiretroviral therapy choice was suggested by a separate study presented here. It compared measures of renal function in 91 treatment-naive HIV patients receiving tenofovir (TDF) and emtricitabine (FTC) who were randomized to receive efavirenz (EFV) or ritonavir-boosted atazanavir (ATV/r). Although renal function as measured with eGFR fell from baseline in both groups, those receiving TDF with ATV/r had a greater decline, which is consistent with the data generated by the EuroSIDA study.

While CKD is a well-known risk factor for CV disease, it is also now appears that impaired renal function participates in the pathogenesis of osteoporosis, another age-related complication that appears to begin much earlier in life in the presence of HIV infection. The pathogenic link between renal insufficiency and accelerated bone loss may be linked to the kidneys role in vitamin D metabolism. However, like all other age-related pathologies that appear to be accelerated in patients with HIV, other independent risks, such as genetics, alcohol use and sun exposure, may be major influences on cumulative likelihood of a bone fracture. According to Dr. Christoph Fux, University Clinic for Infectious Diseases, Inselspital Bern, Switzerland, the multifactorial pathophysiology of osteoporosis involves treatment-independent and treatment-dependent risks.

“While viral replication results in cytokine production that directly and indirectly activates the osteoclasts which reduce bone density, several studies suggest that starting antiretroviral therapy accelerates bone loss irrespective of the regimen used,” Dr. Fux told delegates, providing the rationale for a more rigorous screening program in HIV-infected individuals.

Attention to renal impairment in individuals infected with HIV should not take precedence over monitoring and adjusting therapy in response to other age-related processes, particularly CV disease. Rather, renal function is just one of a variety of organ systems threatened by accelerated aging in patients with HIV, as based on discussions here at the Glasgow meeting. However, the problem of renal insufficiency served as an example of a critical change in HIV care. Now that this infection can be controlled indefinitely in most patients, slowing the aging process in patients with long-term HIV infection is emerging as the critical issue in effective management.

Summary

Renal impairment is not the greatest threat to the long-term survival of aging patients with HIV, but it is a particularly insidious process that can be overlooked in patients without clear risk factors who are not routinely screened. The focus on renal impairment in aging patients with HIV is representative of a reorientation in HIV care that places emphasis on recognizing the threat of accelerated senescence in an array of organ systems and the interaction between systems, such as between renal function and bone metabolism, that may have compounding effects.