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

Median CD4 cell count at treatment initiation 2004

Median CD4 cell count at treatment initiation 2007

Median CD4 cell count at treatment initiation 2010

Median CD4 cell count at treatment initiation 2013 (some extrapolated)

Deeks 2011

The problem of persistent

inflammation during ART

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

IAS 2014

Can inflammation, multi-

morbidity and “premature”

aging be reversed or

prevented?

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

IAS 2014

IAS 2014

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

1984 2014

Healthy aging requires aggressive

risk factor management,

exercise and diet

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

In Memoriam Joep Lange