HIV – UNDETECTABLE, NOW WHAT?
CCAS 2014
Helmut Albrecht, MD
Heyward Gibbes Distinguished Professor Internal Medicine
University of South Carolina
Outline
What the HIV medicines have done
Background – Current State of the ART
What the medication do not affect as well
Inflammation
Comorbidities
Frailty/premature aging
How will we address this in the future
HIV infection
Antiretroviral treatment
Restore Immune function
Prevent AIDS Improve quality of life
Prolong life
Most of the research and clinical focus over the past 25 years has been on inhibiting HIV replication
Probability
of survival
no antivirals
nucleosides
HAART
days
100%
80%
60%
40%
20%
100 200 300 400 500
Survival in patients with PML (Albrecht et al, AIDS 1998)
p < 0.0002
With over 20 drugs and several viable regimens, the motivated patient with life-long access to therapy can control HIV indefinitely, eliminating the risk for AIDS
Volberding Lancet 2012
ART scale up and capacity building
• Africa
• Project HEART: 68,000 on ART (5000 children) in 4 countries1
– Mean CD4+ elevation 250–300 cells/mm3; <10% loss to F/U; quality monitoring
1. Marlink R, et al. XVI IAC, Toronto 2006, #THAB0201; 2. Munderi P, et al. ibid,
#THLB0208; 3. Ningsanond P, et al. ibid, #THLB0209; 4. Zhan F, et al. ibid, #WEPE0128
Pro
port
ion a
live
0.00
0.25
0.50
0.75
1.00
0 1 2 3 4 5 Years from entry
Historical cohort
DART
Mortality from study entry2
Asia
• Thailand national scale up: 99,220 on ART, 90% on d4T/3TC/NVP3
– 10% mortality, highest with CD4+ <50 c/mL
– 15% change to 2nd-line in 12 mos: AEs 70%, Rx failure 28%
• China4: 2350 in care, 50% on ART, 88% retention
– Mentoring of Master Trainers, scale up of training of 8759 HCW in 2 yrs
• Uganda: DART (n=1015) mortality (vs historical cohort 1995–2000)2
– 17-fold reduction in mortality with ART; 94% 2-year survival
A whole lot of effective drug regimens
>20 potent regimens Safety
Tolerability
Ease of administration
Acceptance/Adherence
Concurrent conditions
Cost
The major unmet need is getting treatment
to all in need and keeping them there
Piot and Quinn, NEJM 2013 Micek et al., JAIDS 2009 Gardner et al., CID 2011 Hall et al., JAMA IM 2013
The majority of people globally
(> 20 million) are not on therapy
After adjusting for traditional risk factors, inflammatory biomarkers remain elevated during long-term ART, although the increase is moderate
Neuhaus JID 2010
A single measurement of IL-6 or D-dimers predicts morbidity or mortality over several years
Grund et al, CROI 2013
Predictors of Mortality in HIV Infection: The SMART Study
Kuller et al. PLoS Med. 2008 Oct 21;5(10):e203. Sandler et al. J Infect Dis. 2011 Mar 15;203(6):780-90. Hunt, PW. Curr HIV/AIDS Rep. 2012 Jun;9(2):139-47.
Inflammation predicts disease in treated HIV infection, as it does in the general population
Mortality (Kuller, PLoS Med, 2008, Sandler JID 2011, Tien JAIDS 2011)
Cardiovascular Disease (Baker, CROI 2013)
Lymphoma (Breen, Cancer Epi Bio Prev, 2010)
Venous Thromboembolism (Musselwhite, AIDS, 2011)
Type II Diabetes (Brown, Diabetes Care, 2010)
Cognitive Dysfunction (Burdo AIDS 2012)
Frailty (Erlandson, JID 2013)
Incident rate ratio for acute MI by age
30-39 40-49 50-59 60-69 70-79
2.2 1.3 1.8 1.5 1.5
Impact of HIV on risk comparable to traditional risk factors including HTN, DM and hyperlipidemia
Models adjusted for recognized risk factors
Can We Measure Inflammation?
Immune Measures T cell activation
Monocyte activation
Soluble Markers C-reactive protein (CRP)
Interleukin-6 (IL-6)
D dimer
Soluble CD14 (sCD14)
Novel Markers Oxidized lipids
Potential biomarkers to measure inflammation with respective targets
General inflammation: IL-6*, hs-CRP*, amyloid A,
leukotrienes, TGF-beta
Macrophage activation: sCD14*, sCD163*
T-cell activation: CD69, CD40L, H400, CD71, CD95, IL2-R
Microbial translocation: I-FABP
Endothelial activation: sVCAM-1*, sICAM-1, sFasL, sE-selectin, vWF
Angiogenesis: VGEF, PIGF, HGF
Coagulation: d-dimer*
Lipid oxidation: oxidized LDL/HDL redox potential* , PPAR
Glucose homeostasis: insulin, HOMA-IR*, PPAR
Platelet activation: P selectin, sCD40L
* Shown to be associated with mortality, cardiovascular disease or other end-organ disease in persons with HIV/AIDS
1 in 8 HIV-infected in Africa are over age of 50
Rates of co-morbidities higher in Botswana than US
Community-based chronic care delivery models will be needed to address changing needs
More than 50%
of HIV-infected
adults age 55-
60 had two or
more co-
morbidities,
higher than
uninfected
adults more
than a decade
older
Reiss et al
Age
Polypharmacy
Clinical Aging and Geriatric Syndromes
(frailty/sarcopenia, neurocognitive decline)
Social isolation
HIV-infected adults have many traditional risk factors for frailty and other geriatric syndromes, raising concerns that the real burden of disease will only become apparent late in life
Chang et al., Archives of Gerontology and Geriatrics, 2012
Age
Frailty-like syndrome occurs much earlier in HIV disease (predicted by CD4 nadir)
Frail state is associated with elevated levels of immune activation
Inflammation ↑ Monocyte activation
↑ T cell activation Dyslipidemia
Hypercoagulation
Microbial
translocation
HIV-associated
Metabolic syndrome HIV replication
Coexisting
pathogens
Loss of regulatory
cells
Co-morbidities Aging
Therapeutic Options in Development
Chemokine receptor inhibitors: Maraviroc, TB-652
Anti-infective therapy: CMV, EBV, HSV, HCV/HBV
Microbial translocation: sevelamer, colostrum, rifaximin, pre-biotics, probiotics, isotrentinoin
Enhance T cell renewal: growth hormone, IL-7
Anti-fibrotic drugs: perfenidone, ACE inhibitors, ARBs
Anti-aging: caloric restriction, sirtuin activators, vitamin D, omega-3 fatty acids, sirolimus, diet, exercise
• Anti-inflammatory drugs
– Chloroquine,
hydroxychloroquine
– Minocycline
– NSAIDs (COX-2 inhibitors),
aspirin
– Statins
– Methotrexate (low-dose; CIRT)
– Talidomide, lenalidomide,
pentoxyfylin
– Biologics (e.g., TNF inibitors,
IL-6 inhibitors, anti-INF-alpha)
• Anti-coagulants: low dose
warfarin, dabigatran, aspirin,
clopidogrel
Changes in Inflammatory Biomarkers in Subjects Switching to Raltegravir
1Lake et al. CROI 2013. Poster 794. 2Martinez et al. AIDS. 2012 Nov 28;26(18):2315-26.
500
1000
1500
2000
2500
3000
3500
-1 4 9 14 19 24
sC
D14
(n
g/m
L)
Study Week
Immediate (RAL)
Delayed (PI or NNRTI)
WIFAT Study1 SPIRAL Study2
Early ART is associated with less inflammation during ART Will this result in benefit?
START
ART-naïve with CD4+ count > 500 cells/mm3
Early ART Group
Initiate ART immediately
N=2,300
Deferred ART Group
Defer ART until the CD4+ count
declines to < 350 cells/mm3
N=2,300
HIV infection is associated with a state of chronic inflammation and immune activation that does not fully resolve with suppressive ART.1,2
Chronic inflammation and immune activation contribute to mortality and the development of comorbidities in HIV-infected persons, including cardiovascular disease, bone loss and neurocognitive decline.
Blood biomarkers can be used to monitor changes in inflammation and immune activation in patients on ART.
Understanding the effect of antiretroviral medications and other supportive agents to chronic inflammation and immune activation is important for minimizing risk of comorbid disease, premature aging, and frailty.
Chronic Inflammation in Treated HIV Infection
1Neuhaus et al. J Infect Dis. 2010 June 15;201(12):1788-1795. 2French et al. J Infect Dis. 2009 Oct 15;200(8):1212-5.
Other issues
Social and financial issues
Association with poverty
Ethical, philosophical, political, and social implications of HIV pos status
Societal response
Disparities
Lack of understanding/information => stigma
Prevention (PrEP, vaccines, microbicides)
Testing
Is cure the answer?
It would address a lot of issues but
can a cure address all of the many
limitations of ART, including
chronic inflammation, excess co-
morbidities and overwhelmed
health care systems?
Although the barriers are real, there is some hope – and some disappointments
Hematopoietic stem cell transplant from CCR5-delta 32 donor (the “Berlin Patient”) (Huetter, NEJM, 2009)
Early therapy in an infant (Persaud, CROI 2013)
Early and prolonged therapy results in “functional cure” (VISCONTI, PLoS Pathogens 2013)
Allogeneic stem cell transplant under ART may be curative (Henrich, IAS 2013)
Dendritic cell vaccines may be curative (Argos, IAS 2013)
Latency can be reversed therapeutically (Arch Nature 2012; Lewin CROI 2013, Tolstrup IAS 2013)
The
Global Scientific Strategy
“Towards an HIV Cure”
www.iasociety.org
Towards an HIV cure: a global scientific strategy
Nature Rev. Immunol. 18 Jul 2012
HIV Infection
Antiretroviral Treatment
Testing, linkage to care, retention
Immune Dysfunction/Inflammation Treatment Toxicity Anti-inflammatory drugs
Overburdened Health Care Delivery Systems
Non-AIDS Morbidity Aging
Preventative medicine
Healthy aging
Operational research
Research and clinical priorities in the era of “complete “ viral suppression: Test and treat, reduce inflammation, ensure healthy aging, and provide care using chronic disease model approaches until there is a cure
The old model The new model
Specialized HIV Providers (usually ID physicians)
Antiretroviral therapy
Suppression of HIV viral load and increase of CD4 cell count Prevent AIDS Improve quality of life Prolong life
Cooperation between primary care and HIV as well as other specialists
Prevention, testing, linkage to care, ART, retention Anti-inflammatory and/or immune modulating medications? Preventative medicine Innovative research (operational, health care delivery, and cure research)
Suppression of HIV viral load and restoration of immune system, prevent AIDS, improve quality of life, prolong life, decrease transmission (Treatment as prevention) Addressing inflammation, treatment toxicity, frailty, immune senescence Decrease non-HIV morbidity & address healthy aging Addressing overburdened health care delivery systems and cost
Who
What
Why
Why bother?
If we can replace the somewhat passive approach focusing on treating patients after they were found to be infected with a renewed enthusiasm where we will push back and try to end AIDS through a combination of novel preventative modalities, early diagnosis, innovative treatment approaches in comprehensive care settings, as well as cure research If we can muster the political will and make it a financial and societal priority we might be able to leave our children and grandchildren a world without AIDS