HIV today

Professor Margaret Johnson

Consultant Physician

Royal Free London Foundation Trust

When to START ART

Life Expectancy and Mortality

Ageing and co-morbidity

HIV - advances

Monitoring

UK: 94% ‘undetectable’ viral load = suppressed

87%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PLWH Diagnosed On ART Suppressed

Adapted from Kirwan PD . HIV in the UK - 2016 report. December 2017. Public Health England, London.

103,00087% 96 % 94 %

HIV - advances

London

90%

Diagnosed

97%

Undetectable*

97%

On treatment

*VL <200 c/mL.

Public Health England, 2016.

HIV - advances

Treatment as Prevention

•Many studies have shown similar results including:

•The PARTNER study of nearly 900 individuals – 58,000 sex acts with no linked transmissions within primary partnership

•Opposites Attract – 358 couples – no transmissions

•Pregnant women on antiretroviral therapy <0.3% transmission

Rodger et al. JAMA 2016 DOI: 10.1001/jama.2016.5148.; Cambiano et al.. 16th European AIDS Conference, 25-27 October, Milan, abstract PS11/4, 2017; Grulich et al. IAS 2017, Paris. Oral abstract TUAC0506LB.

HIV - advances

U=UHIV - advances

What are the benefits of early ART?

Individual

Life expectancy

Morbidity

Population

Health care costs

Transmission

U=UUndetectable

Equals Untransmittable

HIV - advances

HIV - advances

Pre-exposure Prophylaxis = PrEP

•PrEP works if you take it

•Failures are due to non-adherence

HIV Testing

Combination Prevention

Adapted from Hyman Scott CROI2018 #61

Aware ofPrEP

Linked to PrEP

Prescribed PrEP

Retained onPrEP

On PrEP Bar before the Bars Diagnosed Linked to care

Retained in Care

Prescribed ART

VL <50

PrEP Testing Rapid ART U=U

HIV - advances

Can combination prevention affect the HIV epidemic?

HIV - advances

HIV testing and new diagnosesDean Street 2015-2017

HIV - advances

TestsDiagnoses

New HIV diagnoses among MSM attending sexual health clinics England

Current HIV trends in

England

0

50

100

150

200

250

300

350

400

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3

2013 2014 2015 2016

London steep fall clinics Other London clinics

Clinics outside London

Steep fall definition: Clinics with >20% decrease in HIV diagnoses between Oct 2014-Sep 2015 and Oct 2015-

Sep2016, and over 40 diagnoses during this period.

HIV - advances

When to START ART

Life Expectancy and Mortality

Ageing and co-morbidity

HIV - advances

Monitoring

ART: 1980’s-2018

When to START ART

1. Lundgren D, et al. IAS 2015. Vancouver, CAN. Oral # MOSY03; 2. Lundgren D, et al. NEJM 2015 Published Epub ahead of print July 20, 2015 DOI: 10.1056/NEJMoa1506816

(95% confidence interval[CI], 0.30 to 0.62; P<0.001)

START study : ART is protective at any CD4 count

n=2,326n=2,359

When to START ART

CD4 <500

Any CD4

1. Lundgren D, et al. IAS 2015. Vancouver, CAN. Oral # MOSY03; 2. Lundgren D, et al. NEJM 2015 Published Epub ahead of print July 20, 2015 DOI: 10.1056/NEJMoa1506816

(95% confidence interval[CI], 0.30 to 0.62; P<0.001)

ART is protective even at high a CD4 count

n=2,326n=2,359

Average CD4at ART 408

Average CD4at ART 651

When to START ART

When to start

WHO When to start ART

When to START ART

Life Expectancy and Mortality

Ageing and co-morbidity

HIV - advances

Monitoring

Life Expectancy, UK CHIC Cohort

May M et al. AIDS (2014); 28: 1193-202.

Expected age at death* - men Expected age at death* - women

* Expected age at death for a person aged 35 years with different durations of antiretroviral therapy

according to current CD4 count and viral load suppression

Life Expectancy and Mortality

0%

20%

40%

60%

80%

100%

AIDS Liver CVD Cancer Other

Causes of death- only ~ 20% are AIDS related

Adapted from C Sabin : D:A:D Merger 14 dataset

1999/2000 2001/2002 2003/2004 2005/2006 2007/2008 2009/2011

Pro

po

rtio

n o

f d

eath

s

Life Expectancy and Mortality

0 10 20 30 40

Other cancers

Substance misuse

Suicide

Accident

Liver disease

CVD and stroke

Non-AIDS cancers

Non-AIDS infections

Non-AIDS deaths

All-cause mortality

Standardised mortality ratio (SMR)

In 1st year After 1st year

Mortality high in 1st year after HIV diagnosis

Adapted from C Sabin : Croxford S et al Lancet Pub Health (2017); 2: e35-e46.

SMR=1

Life Expectancy and Mortality

When to START ART

Life Expectancy and Mortality

Ageing and co-morbidity

HIV -advances

Monitoring

Ageing and co-morbidity

Prevalence of co-morbidities

Mean number of comorbidities

HIV-positive: 1.3

HIV-negative: 1.0

Raised rates of:

• Hypertension

• MI

• Peripheral arterial disease

• Impaired renal function

Schouten J et al. Clin Infect Dis 2014;59:1787-97.

Ageing and co-morbidity

START trial findings

Immediate initiation incidence rate

Deferred initiationincidence rate

Hazard ratio (95% CI)

non-AIDS cancer (n=27 events)

0.13 / 100 person years

0.26 / 100 person years

0.50(0.22, 1.11)

cardiovascular disease (n=26 events)

0.17 / 100 person yeas

0.20 / 100 personyears

0.84 (0.39, 1.81)

INSIGHT START Study Group, Lundgren JD, et al. NEJM, 2015.

Borges AH, et al for the INSIGHT START Study Group, Clinical Infectious Diseases, 2016.

ART reduces relative risk of comorbidities

Ageing and co-morbidity

CKD and MI increase with age and with HIV

37

PY, patient-year; CKD, chronic kidney disease; MI, myocardial infarction;

1. Adapted from: Goulet J et al. Clin Infect Dis 2007;45:1593–1601; 2. Adapted from: Triant VA et al. J Clin Endocrinol Metab 2007;92:2506–

12.

Rate of MI (1996–2004) according to HIV status and age group2

18–34 35–44 45–54 55–64 65–74

Age, years

<40 40–49 50–59 ≥60

Age, years

10

8

6

4

2

0

100

80

60

40

20

0

Pat

ien

ts,

%

Acu

te M

I ev

ents

pe

r 1

,00

0 P

Ys

HIV-negativeN = 66,840

HIV-positiveN = 33,420

HIV-negative3,747,329 PY

HIV-positive16,983 PY

Rate of CKD according to HIV status and age group1

Ageing and co-morbidity

‘High risk’ plaques in HIV indicative

Leschka S et al. ECR 2010Post WS et al. Ann Intern Med 2014

• PLwHIV have higher prevalence of non-calcified plaque

• Non-calcified plaque is

• Considered high-risk plaque morphology

• Carries highest risk of mortality

• Lipid-rich, pro-inflammatory, more prone to rupture/thrombosis

Ageing and co-morbidity

HIV+ Patients Have Higher Risk of Comorbidities than HIV-

0

2

4

6

8

10

12

14

16

18

20

<40 41-50 51-60 >60

Co

mo

rbid

ity R

isk

(%

)

Age Group (years)

Bone fractures

HIV- HIV+

Rates of bone fractures, are higher in HIV+ compared to HIV- individuals across age groups1,2

• Bone fracture risk ranged between 12-16X more likely for HIV+ vs uninfected, in the <40-60 year old range1

Rates of Bone Fractures in HIV+ vs HIV- Persons, by Age

Optimizing bone health is an important strategy for reducing morbidity and mortality in HIV+ individuals

1. Guaraldi G, et al. Outcomes Res. 2013 Sep 23;5:481-8 (charts adapted); 2. Guaraldi G, et al. Clin Infect Dis. 2011 Dec;53(11):1120-6.

Liver disease the 2nd commonest non-AIDS related death in HIV

HIV ageing and inflammation

The impact of HIV on the immune system mirrors that of age-related immune changes

HIV markers correlate with several co-morbidities:

Degree and duration of prior immune suppression

Duration of detectable viraemia

Inflammation & immune activation improve but do not normalise on HIV treatment

Ageing and co-morbidity

‘Immune ageing’ markers and HIV?

Outcome measure Age >70 years,

HIV uninfected

Untreated HIV

infection

Long-term (5–10 years) treated

HIV infection*

Expanded CMV-specific CD8 cells Yes Yes Yes

Expanded CD28−CD57+CD8 T-cells Yes Yes Yes

Reduced T-cell repertoire Yes Yes Yes (low CD4 nadir)

Increased T-cell activation Unclear Yes Yes

Low IL-2, high IFN-γ (CD8 T-cells) Yes Yes Unknown

Reduced thymus function Yes Yes No

Low CD4/CD8 ratio Yes Yes Yes

Low naïve/memory ratio Yes Yes Yes (low CD4 nadir)

Increased IL-6 Yes Yes Yes

Reduced response to vaccines Yes Yes Possible (CD4 nadir)

Reduced innate immune function Unknown Yes Yes

CMV = Cytomegalovirus; Table adapted from Deeks SG. Ann Rev Med 2011;62:141–155

Ageing and co-morbidity

Comorbidity and traditional risk factors interact to cause mortality

BP

Obesity

Smoking

DiabetesLipids

Alcohol

Mental

health

HIV

CKD

Inflm

Ageing

CVD

Adapted from O’Halloran J, et al. Fut Virol 2013;8:1021-34

Cancer

Watch CROI 2018 Symposium on life expectancy

Ageing and co-morbidity

• Some things you cannot change:• Age• Ethnicity• Family history

• But many you can….• Smoking• Alcohol• Weight• Exercise• Hypertension• Dyslipidaemia• Substance use• Social isolation

50-70% of people living with HIV in the US smoke

Number of years of life lost associated with smoking exceeds HIV-related factors among HIV-infected men

Slide credit: Althoff KHelleberg M et al, AIDS, 2015.

Ageing and co-morbidity

Smoking cessation improves life expectancy a lot

Life expectancy (age in years) for people entering HIV care, based on smoking status

(simulations assumed former smokers quit upon entering care and remained abstinent)

CEPAC Model

Slide credit K Althoff Ref Reddy KP, et al. Journal of Infectious Diseases, 2016.

Ageing and co-morbidity

Burden of mental comorbidities

*Not an exhaustive review. Bing EG, et al. Arch Gen Psychiatry 2001. O’Cleirigh C, et al, Psuchosomatics, 2015. Brand C et al, Clin Psychol Rev, 2017. Druss BG, et al, Arch Gen Psychiatry, 2007. Robins LN, et al, Arch Gen Psychiatry 1988. Israelski et al, AIDS Care 2007. de Sousa Gurgel, et al, AIDS Care 2013. Moore DJ et al, AIDS Behavior, 2012. Applebaum AJ, J Assoc Nurses AIDS Care, 2015. Blank MB et al, Psychiatric Services, 2002. Pence BW, et al, JAIDS, 2006. Galvan FH, Journal of Studies on Alcohol, 2002. Chander G, et al, HIV Med, 2008. Rabkin JG et al, AIDS 2004.

Adults with HIV* General pop in US

Major depressive disorder 20% – 40% 8% (NIMH)

Generalized anxiety disorder 10% – 25% 3% (NIMH)

Bipolar 3% – 9% 3% (NIMH)

Schizophrenia 4% – 15% 1% (NIMH)

PTSD 10% – 30% 8% (American Psychiatric Assoc.)

Heavy alcohol use 8% – 16% 6% (NIAAA)

Substance use disorders 12% – 40% 8% (SAMHSA)

What are the potential pathways between mental illness and HIV health outcomes?

Potential biological mechanisms

Direct effects of depression immune system Chronic immune activation, HPA dysregulation

HIV crosses the blood brain barrier immune activation in the brain and the CNS Inflammatory proteins oxidative stress and neuronal injury

Chronic inflammatory response to HIV infection Elevation in the level of cytokines e.g. Interleukin(IL)-6 and Tumor

Necrosis Factor(TNF)-Alpha trigger chain reaction involving Tryptophan depletion through the activation of Indoleamine 2,3-dioxygenase (IDO) enzyme

Tryptophan depletion reduces serotonin levels and increases Kynurenine (Kyn) and its metabolites (some are neurotoxic and associated with depression, suicide, and anxiety)

Source: Rhenien R from Fu et al, Journal of Neuroinflammation, 2011; Lawson et al, Brain, Behavior, and Immunity, 2011; Capuron et al, Biological Psychiatry, 2011; Castillo-Mancilla et al, Clinical Infections Diseases, 2016; Hunt, Clinical Infections Diseases, 2017; Wada et al, AIDS, 2015; Dantzer, Current Topics in Behavioral Neurosciences, 2016; Martinez et al, JAIDS, 2014

When to START ART

Life Expectancy and Mortality

Ageing and co-morbidity

HIV -population level

Monitoring

NICE guidance

nice.org.uk/guidance/cg181

Monitoring

BHIVA 2016 monitoring guidelines

Monitoring of patients with, or at high risk of, cardiovascular disease

Recommendations

►Patients with established or increased risk of CVD (10 year CVD risk >10%) should be

screened annually for hypertension, diabetes, dyslipidaemia and chronic kidney disease,

BMI, smoking status and antiretroviral therapy reviewed annually (GPP)

►Evaluation of inflammatory or coagulation biomarkers and imaging studies as part of

routine clinical care are not recommended (GPP)

British HIV Association guideline 5.6. Available at:

http://www.bhiva.org/documents/Guidelines/Monitoring/2016-BHIVA-Monitoring-Guidelines.pdf

Monitoring

FRAXQ RISK 3

All this co-morbidity leads to poly-pharmacy!

Monitoring

When to START ART

- start everyone as soon as possible

Life Expectancy and Mortality

- similar to uninfected population

- mortality high in first year of diagnosis

Ageing and co-morbidity

- manage traditional risk factors

- manage drug interactions

HIV : advances

- - U=U; living well; PrEP works

Monitorin Monitoring

- use risk calculators

- early diagnosis of comorbidities