Aging, Inflammation, and Organ Damage in HIV+ Patients

Jean-Pierre Routy, MD Graeme Moyle, MDBill Powderly, MD

Philippe Morlat, MD

Metabolism

• Visceral damage– Because patients are living longer– Damage associated with both aging and antiretroviral

therapy (ART) use• HIV related inflammation– Can cause organ damage– May not be the ONLY source of organ damage

• Treatment and aging both affect health

Inflammatory Damage as a Multifactorial Issue

• Patients are not just affected by HIV, they are also– Getting older– Getting lifestyle diseases

• Risk factors, before HIV infection, play a major role in disease formation– Smoking– Heart disease

• Antiretroviral (ARV) therapy may only be a minor risk factor for organ damage in most HIV+ patients

Look at the Whole Patient• Don’t just assess HIV and treatment• Remember the role lifestyle plays and other factors

such as– Smoking– Alcohol use– Heart disease– Diet– Age

A broad, holistic approach is importantfor patient health

Amsterdam Aging Cohort - AGEhIV

• HIV+ population vs. similar HIV - controls– 74.5 % of HIV+ patients and 61.6% of controls reported

≥1 age-associated, non-communicable condition (AANCC)

– HIV+ had significantly more AANCC (1.4 vs. 1) in every age group

– Burden of AANCC in HIV+ patients was similar to that seen in HIV – controls, who were 5 years older

• Traditional risk factors played an important role

Source: Schouten, J. et al. Comorbidity and aging in HIV-1 infection:the AGEhIV Cohort Study. AIDS 2012 Abstract: THAB0205

NEW FROM AIDS 2012

Who is at risk?

• After CD4 count is normalized, mortality and morbidity risk normalizes as well

• There may only be a subset of HIV+ patients at an increased risk for aging diseases– Late diagnoses– Treatment with older Antiretroviral (ART) medication– Those who have not achieved optimal immune

recovery

Patient Factors, Host Factors, and Virus

• Antiretroviral (ART) therapy shouldn’t take all the blame for metabolic and inflammatory effects– Relevant in subset of patients

• Risk factors may be more important

• Avoid drugs that might accentuate any risk associated with patient behaviors, such as smoking

Inflammation, T-Cell Recovery, and CVD• SMART Study– When HIV is uncontrolled• More inflammation• More endothelial damage• Increased cardiovascular disease (CVD) risk

– Treating patients earlier may reduce these types of damages• Might increase drug-associated damage• However, there probably is less negative impact than

what would be caused by waiting to treat the patient

PI & Cardiovascular Risk• Ritonavir– Dose-dependent dyslipidemia

• Not all protease inhibitors (PI) are associated with increased risk of myocardial infarction (MI)– Lopinavir and ritonavir are associated– Indinavir is associated, alone or in combination– Atazanavir is NOT associated, alone or in combination

• Inappropriate to claim a class effect

Mechanisms of PI Effect on CVD

• Biological pathways for cardiovascular effect– Dyslipidemia– Insulin Resistance• Kaletra (lopinavir + ritonavir), Indinavir

• Protease inhibitors (PI) choices vary with– Ease of use– Side effects

Not all choices will be suitable for all patients

Use of Statins in HIV+ Patients

• HIV is considered a risk factor for cardiovascular disease (CVD) in France– Affects guidelines for statin use– Drugs started earlier in HIV+ patients

Obesity, HIV, and CVD

• Diabetes– More related to• Lifestyle• Obesity epidemic

– Treatment may contribute through• Direct biological effects on insulin resistance• Making people feel healthier and therefore eat more

– HIV is a risk factor but it isn’t the dominant issue

However…• Some people do quickly gain weight after starting ART– Tends to be central– Kicks-in metabolic syndrome

• Certain drug choices are associated with insulin resistance– Indinavir– Ritonavir– Lopinavir/ritonavir

• Raltegravir and maraviroc are NOT associated with insulin resistance

• C-reactive protein– Increases in lopinavir/ritonavir (Kaletra) patients– Decreases with raltegravir

Specific Drug Choices Matter

• Drug choices can affect– Insulin resistance– Inflammatory markers– Lipid markers

• Cumulative exposure to thymidine analogues is a risk factor, including from past use

Immunometabolics

• Not a lot of data

• Inflammation is related to atherosclerosis– Unknown whether only specific inflammation is a risk– Research needed to determine affect of generalized

HIV-mediated inflammation• Inflammation caused by HIV-associated infections is

also a potential concern

Don’t Forget the Benefits of Treatment• Treatment is a good thing for patients

• Early treatment may be even better– Reduces systemic inflammation

• Try not to get caught up in potential risk factors of treatments, that are helping patients live longer and healthier lives, than they would otherwise

• HIV treatment may also improve overall health, through increased monitoring, when compared to HIV patients

Patients Age 50

• Start statins

• Bone scan

• Coronary calcium scores

• Full health check

• Aggressive intervention for conditions of aging

Co-infection - Hepatitis C

• Major source of– Cardiovascular risk– Renal risk

• Hepatitis C virus (HCV) viremia– Contributes to significant clinical outcomes

HIV and Kidney Disease

• Some drugs affect renal function– Tenofovir (TDF)• Tubulopathies

– Certain protease inhibitors (PIs)

TDF and PIs may be particularly dangerous in combination

Tools for Monitoring Kidney Disease• Calculated GFR (glomerular filtration rate)– Based on creatinine levels– May not always be an accurate assessment of kidney

function– Certain ART medications elevate creatinine, without

affecting filtration rate• Dolutegravir (investigational integrase inhibitor)• Ritonavir• Cobicistat (investigational enhancer)• Rilpivirine

• Need new ways to assess kidney function

Monitoring Kidney Disease

• Don’t forget non-HIV related factors that can affect kidney function such – Hypertension etc…

• eGFR does not do an effective job of monitoring tubular damage, which is the concern with many HIV medications

Take Home Message• Global improvement in HIV management– Patients are living longer– Relatively minor non-inflammatory events

• Medication is better than HIV– However, new drugs may complicate follow-up, even as they improve outcomes

Good news!Patients aren’t sick because of immunodeficiency

The Difficulty in Treating HIV• Non-communicable diseases and HIV infection must

be closely monitored for clinical care• Must back-off from a sole focus on infectious disease• Integrating systems of whole-health care, can

improve quality of life • Oversight is important

When treating HIV infected patients, you must always remain aware of the importance of drug-drug interactions, and immunological concerns